FOREWORD BY

CHETAN BHAGAT

DIABETOLOGY
for

MANGO MAN







BY HENRY HARVIN
MEDICAL ACADEMY


A comprehensive guide for anyone pursuing a fellowship in diabetology. This book
provided me with a solid foundation in diabetes management, equipping me with
practical skills and up-to-date knowledge. A must-have for aspiring diabetologists.
The book covers a wide range of topics, including the pathophysiology of diabetes,
diagnostic criteria, and treatment options. It also delves into the latest research and
advancements in the field, ensuring that readers stay informed about the evolving
landscape of diabetology. Whether you are a medical student, resident, or practicing
physician, this guide will undoubtedly enhance your understanding and ability to
provide excellent care for patients with diabetes.
- Dr. M. Khan, Diabetologist, MediVaah

This book is an indispensable companion throughout my fellowship in diabetology.

The content is well-organized, evidence-based, and covers the entire spectrum
of diabetes care. It’s my go-to reference for patient management. The book not
only provides comprehensive information on the latest advancements in diabetes
treatment and management but also offers practical guidance on implementing
these strategies in clinical practice. Its user-friendly format and clear explanations
make it accessible to healthcare professionals at all levels of expertise. Additionally,
the inclusion of case studies and real-life examples further enhances its value as a
reliable resource for effective patient care.
- Amrit Patel, JRF, Jaipur National University

I found this book to be of great value as a fellow in diabetology. It provides a

thorough exploration of the complexity of diabetes treatment, ensuring that I am
well-equipped to give my patients the best care possible. The latest findings on
diabetes drugs and cutting-edge therapeutic strategies are among the many subjects
covered in the book. Additionally, it offers helpful hints and methods for encouraging
patients to alter their lifestyles in order to better manage their conditions. This book
has, all in all, substantially improved my understanding of and proficiency in the
topic of diabetology, making it a vital tool for any healthcare professional working
in this area.
-Nikhat Khan, Student, CMC

This book has been my constant companion during my diabetology fellowship

journey. The detailed explanations and illustrative examples have helped me grasp

1
complex concepts with ease. The author’s expertise in the field shines through
the pages, making it a valuable resource for both beginners and experienced
professionals.
The book’s comprehensive coverage of various topics has allowed me to deepen
my understanding of diabetology and apply it effectively in my clinical practice.
- -Dr. L. Thomas, NIMS University
I highly recommend this book to anyone pursuing a fellowship in diabetology. It
covers not only the medical aspects but also the psychological and social dimensions
of diabetes management. The book provides a comprehensive understanding of the
challenges faced by individuals with diabetes and offers practical strategies for
effective patient care. Additionally, it explores the latest research and advancements
in diabetology, making it an invaluable resource for healthcare professionals
seeking to enhance their knowledge in this field.
- V.G. Reddy, Student, Madras Medical College
This book exceeded my expectations. It’s not just a textbook; it’s a mentor
that guided me through every aspect of diabetology, from diagnosis to patient
education. The author’s expertise and clear explanations make complex topics
easily understandable, and the inclusion of real-life case studies adds a practical
dimension to the book. It has become an invaluable resource for both healthcare
professionals and individuals seeking a comprehensive understanding of diabetes
management.
- Dr. Maryam Ahmed, Diabetologist, Ranka Hospital
I’m grateful for this book during my diabetology fellowship. It provides a holistic
understanding of diabetes and equips me to address the diverse needs of my patients.
The book not only covers the medical aspects of diabetes but also delves into the
psychological and social implications of the disease. This comprehensive approach
has greatly enhanced my ability to provide well-rounded care to individuals living
with diabetes. Additionally, the practical tips and case studies included in the book
have been invaluable in guiding my decision-making process and improving patient
outcomes.
- Dr. Ayesha Malik, Consultant Diabetologist, Doctors Door
2 3
This book is a gem for diabetology fellows seeking in-depth knowledge. The real-
world case studies and evidence-based guidelines enhance my decision-making
abilities. The book not only provides comprehensive information on various aspects
of diabetology but also offers practical insights into managing complex cases. The
inclusion of the latest research findings and advancements in treatment approaches
further enriches my understanding and competence in the field.
- Saurav Pandey, Student, Dayanand Medical College
This book has transformed my approach to diabetes care during my fellowship.
I have gained a whole new perspective on managing diabetes and implementing
effective treatment strategies. The insights and knowledge I have acquired from
this book have greatly improved my ability to provide comprehensive care to my
patients. It not only imparts medical knowledge but also emphasizes the importance
of patient education and empathy. By reading this book, I have gained a deeper
understanding of the impact that diabetes has on patients’ lives beyond just the
medical aspect. It has taught me how crucial it is to communicate effectively with
patients, empowering them to take control of their own health and make informed
decisions.
- Dr. Ahmed, Consultant Diabetologist
An invaluable resource for diabetology fellows seeking excellence. This
comprehensive guide provides diabetology fellows with a wealth of knowledge
and practical skills necessary for achieving excellence in their field. From the
latest advancements in diabetes management to the intricacies of patient care, this
resource covers it all. Additionally, it offers valuable insights from experienced
diabetologists, ensuring fellows have access to real-world expertise and guidance
throughout their training. The integration of clinical expertise and scientific
evidence equips me to navigate the complexities of diabetes management. By
combining the knowledge gained from this resource with hands-on experience, I
am confident in my ability to provide comprehensive and effective care to patients
with diabetes. This integration also allows me to stay up-to-date with the latest
research and advancements in the field, ensuring that I am always providing the
most current and evidence-based treatment options.
- Nina Patel, Student, CMC
A compass that navigates me through the intricacies of diabetes management. This
book empowers me to apply evidence-based strategies in my fellowship training and
future practice. It provides comprehensive knowledge on the latest advancements
in diabetes research and treatment, equipping me with the necessary tools to deliver Diabetology for Mango Man
optimal care to my patients. Additionally, it offers practical tips and real-life case
studies that enhance my understanding of the challenges faced by individuals living
with diabetes.
- Dr. Wahida Khan, AMRI Hospital

A beacon of knowledge for diabetology fellows like me. This book’s in-depth
exploration of diabetes management principles has enabled me to provide evidence-
based care with confidence. The author’s expertise and comprehensive approach
have truly elevated my understanding of the complexities of diabetes. With its
practical guidance and up-to-date research, this book has become an invaluable
resource in my practice, empowering me to make informed decisions for my
patients’ well-being.
- Eva Moore, Student, North Bengal Medical College

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Copyright (c) 2023 by Henry Harvin India Education LLP, Delhi
No part of this book, including interior design, cover design, and icons, may
be reproduced or transmitted in any form except with the permission of Henry
Harvin India Education LLP, 179, Sukhdev Vihar, New Delhi - 110025 (India)
Limitations of Liability/Warranty Disclaimer: The publisher and author
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the time this work was produced and the time it is read, some of the Internet
sites included in it may have changed or vanished.
Moreover, Henry Harvin releases its works in a range of electronic formats.
Electronicbooks might not contain all of the material that is available in print.
6 7
Dear Readers,
I am delighted to present to you the Diabetology Book, a comprehensive guide
meticulously crafted by our dedicated experts at Henry Harvin. In the ever-evolving
landscape of healthcare, understanding and managing diabetes is of paramount
importance. This book stands as a beacon of knowledge, illuminating the intricate
nuances of diabetology.
At Henry Harvin, we are committed to empowering individuals with the latest
insights and expertise in various fields. This book reflects our dedication to fostering
a deep understanding of diabetes, its management, and the impact it has on diverse
populations. Our team has poured their expertise into every page, ensuring that you
have access to the most up-to-date information and strategies.
Whether you are a medical professional, a student, or someone with a personal
interest in diabetology, this book will serve as an invaluable resource. It is our
hope that the knowledge shared within these pages will not only enhance your
understanding of diabetes but also contribute to improved patient care and well-
being.
Thank you for choosing the Diabetology Book from Henry Harvin. We are honored
to be part of your journey towards excellence in healthcare.
Warm regards,
Kounal Gupta
Founder & CEO, Henry Harvin Education
 To the Henry Harvin family, you are the living embodiment of our
inspiration. With each word we pen, we honor the love, strength, and unity
you’ve bestowed upon us.

8 9
 Acknowledgement
Writing a book is a journey that can never be embarked upon alone. It is a culmination
of dedication, collaboration, and support from countless individuals who contribute
their wisdom, insights, and encouragement. We are humbled and deeply grateful
for the myriad of hands that have shaped its creation.

First and foremost, we extend our heartfelt gratitude to the patients and individuals
who have battled with diabetes, a condition that is not just a medical diagnosis,
but a complex journey of resilience and adaptation. Your stories, struggles, and
triumphs have been the driving force behind this book.

To my mentors and colleagues, your guidance has been a beacon of light throughout
this endeavor. Your wisdom, insights, and willingness to share your expertise have
been invaluable. From late-night discussions about treatment protocols to spirited
debates about emerging research, your contributions have elevated this book to
new heights.

We would like to express our gratitude to the researchers and scientists whose
dedication to pushing the boundaries of knowledge has paved the way for innovative
approaches to diabetes management. Your tireless pursuit of understanding the
intricacies of this condition has not only expanded our understanding but has given
hope to countless individuals living with diabetes.

To the medical professionals who work tirelessly on the front lines, treating,
educating, and empowering patients, you are the unsung heroes of this battle. Your
commitment to delivering the best care possible, even in the face of challenges, is
nothing short of commendable. This book stands as a tribute to your unwavering
dedication.

In closing, we would like to quote Helen Keller, who aptly said, “Alone, we can do
so little; together, we can do so much.” The creation of this book is a testament to
the power of collaboration and the strength that comes from a shared commitment
to a cause. To everyone who has played a part in this journey, whether big or small,
we extend my heartfelt appreciation.
With gratitude,
The Henry Harvin Team

10 11
 About the Contributors
Arthur Davis is a former medical practitioner based in Los Angeles, California. He
has contributed to many books and articles in the field of medicine.

Oscar Smith is a freelance writer. He contributes to medical literature and news

articles.

Dr Roy Wilson is a renowned medicine practitioner and is well known for his
books on self-care.

Ramon Cooper is a San Francisco, California-based writer and contributor.

Helena Rich is a doctor based in Rochester and contributes to medical literature.

Lucia Miller is a freelance writer based in Buffalo, NY.

Philip Simmons is a medical writer based in Syracuse, NY.

Kounal Gupta is an entrepreneur. His contribution to education is well known.

Ishu Jain is a researcher, and she contributes to education and literature.

Sakshi Kashyap contributes to the design and editing of books and articles.

Sayantani Sen is a medical writer and contributes through her research in medical
writing.

12 13
 Contents
Foreword

Introduction

UNIT 1: Introduction and interview

1. Objectives
1.1 Introduction
1.2 Physiology of Metabolism and the Role of Endocrinology
1.2.1 The Fundamentals of Metabolism
1.2.2 Hormonal Control of Metabolism
1.2.3 Glucose Metabolism
1.2.3.1 Gene Expression in Glucose Metabolism
1.2.4 Organ Systems Involved
1.2.5 Mechanism and Cellular Level Activities
1.3 Key Landmark/historical perspective of diabetes
1.3.1 The History of Diabetes Mellitus
1.3.2 The Classification and Diagnosis of Diabetes
1.4 Diabetes Pathogenesis
1.4.1 Type 1 Diabetes
1.4.2 Insulin secretion irregularities and β-cell defects in type 2 diabetes
1.4.3 Type 2 Diabetes with Insulin Resistance
1.4.4 Diabetes and Metabolic Disturbances
1.4.5 Obesity and Diabetes
1.5 Epidemiology of major types of diabetes
1.5.1 Epidemiology of Type 1 Diabetes
1.5.2 Epidemiology of Type 2 Diabetes
1.5.3 The Global Burden of Diabetes
1.6 Summary
1.7 Review Questions

14 15
 4.2.2 Glycemic Control Implementation
UNIT 2: Diabetes, Monitoring and Comprehensive Medical Evaluation
4.3 Non-Pharmacological Management
2. Objectives
4.3.1 Dietary Interventions
2.1 Introduction
4.3.2 Diet and Blood Glucose Response
2.2 Diagnostic Test
4.3.3 Medical Nutrition Therapy
2.2.1 Tests for Type 1 Diabetes, Type 2 Diabetes, and Prediabetes
4.3.4 Health Benefits Of A Mediterranean Diet In Diabetes
2.2.2 Tests for Gestational Diabetes
UNIT 5: Management of Comorbidities/Complications/DM in Extremes of Age
2.3 Glucose monitoring- self-monitoring, CGM, long-term glycemic
monitoring 5. Objectives
2.3.1 Continuous Glucose Monitoring 5.1 Introduction
2.3.2 Self-Glucose Monitoring 5.2 Comprehensive Management of Cardiovascular Risk Factors
2.3.3 Long-term Glycemic monitoring 5.3 Antiplatelet Therapy in Diabetes
2.4 Comprehensive medical evaluation 5.4 Diabetes in Special Groups
2.4.1 Patient-Centered Collaborative Care 5.5 Microvascular Complications And Foot Care In Individuals
2.4.2 Immunizations 5.6 Summary
2.4.3 Comorbidity Assessment 5.7 Review Questions
2.5 Summary
2.6 Review Questions
UNIT 3: Complications and Comorbities
3. Objectives
3.1 Introduction
3.2 Acute Complications
3.3 Chronic Complications
3.3.1 Macrovascular Disease
3.3.2 Microvascular Complications
3.4 Summary
3.5 Review Questions
UNIT 4: Management of Diabetes
4. Objectives
4.1 Introduction
4.2 General Principles and Goals of Glycemic Control
4.2.1 Treatment Goals

16 17
Foreword
In the ever-evolving landscape of medicine, the pursuit of specialized knowledge is
paramount to providing the best care for patients. It is with great pleasure and honor
that I introduce this fellowship diabetology book, a comprehensive compendium
that illuminates the intricate world of diabetes care and management. As a seasoned
practitioner and advocate for medical education, I am delighted to see such a
valuable resource come to fruition.
Diabetes, a condition that affects millions across the globe, demands a multifaceted
approach that transcends the conventional boundaries of medical practice. It
requires an understanding of not only the physiological intricacies but also the
psychological, social, and cultural aspects that influence an individual’s journey
with this condition. This book, born from the collective efforts of dedicated experts
in the field, reflects a holistic approach that encompasses all dimensions of diabetes
care.
Fellowship programs play a pivotal role in shaping the future of medical practice.
These specialized training avenues empower physicians with in-depth insights,
advanced skills, and the confidence to navigate the complexities of their chosen
fields. This diabetology fellowship book is a testament to the commitment of those
who have undergone this rigorous training and have emerged as authorities in the
field of diabetes care.
As I peruse the pages of this book, I am struck by its comprehensive scope. It
delves into the fundamental principles of diabetes, covering its epidemiology,
pathophysiology, and classification. From there, it traverses the landscape of clinical
assessment and diagnostic approaches, offering readers a thorough understanding
of the tools at their disposal.
Diabetes management is a constantly evolving field, with new advancements and
guidelines shaping the landscape. This book does not merely provide a snapshot
of the current state of affairs; it equips readers with the tools to adapt to future
changes. From pharmacological interventions to emerging technologies, the content
presented here is forward-looking and designed to foster a mindset of continuous
learning.
18
One of the hallmarks of effective medical education is the ability to bridge theory
with real-world application. This book accomplishes this seamlessly by offering
case studies, practical scenarios, and clinical insights that mirror the challenges
practitioners encounter in their daily practice. It encourages critical thinking,
problem-solving, and the development of a patient-centric approach that lies at the
heart of effective diabetes care.
It is important to acknowledge that diabetes care extends beyond the realm of
medical expertise. A patient’s journey is influenced by their environment, lifestyle,
and support network. The chapters on patient education, lifestyle modification, and
psychosocial aspects of diabetes care underscore the holistic approach that defines
modern medicine. By recognizing the interconnectedness of physical and emotional
well-being, this book sets a high standard for compassionate and effective care.
As a fellow in diabetology, you are embarking on a journey that demands
dedication, curiosity, and an unyielding commitment to your patients. This book
is your steadfast companion, offering guidance, knowledge, and insights that will
empower you to navigate the complexities of diabetes care with confidence. It
invites you to embrace your role not only as a medical practitioner but also as a
mentor, advocate, and beacon of hope for those who rely on your expertise.
In a world where medical information is abundant but curated knowledge is
invaluable, this book stands as a beacon of authoritative guidance. It is a testament
to the dedication of its contributors and editors, who have distilled their years of
experience into these pages. I commend their commitment to advancing medical
education and improving patient outcomes.
As I conclude this foreword, I am reminded of the profound impact that each
healthcare professional can make in the lives of their patients. Your journey as
a fellow in diabetology is a noble one, characterized by continuous growth and
unwavering dedication. May this book serve as a guiding light, illuminating your
path and inspiring you to uphold the highest standards of care as you embark on
this meaningful endeavor.
Chetan Bhagat
Author of Five Point Someone, Half girlfriend, 2 States and many more
marvelous feat
19
 Introduction
Diabetes, a complex and prevalent metabolic disorder, continues to pose significant
challenges to healthcare professionals worldwide. The Fellowship of Diabetology
book emerges as a comprehensive guide tailored to cater to the needs of aspiring
diabetologists, healthcare practitioners, and clinicians seeking to enhance their
proficiency in diabetes management. This book not only provides a thorough
understanding of the pathophysiology and etiology of diabetes but also offers
practical strategies for diagnosis, treatment, and prevention. With its evidence-
based approach and expert insights, the Fellowship of Diabetology book equips
healthcare professionals with the knowledge and skills necessary to effectively
address the growing burden of diabetes in their patients. In this journey towards
advanced diabetes education, this book serves as an indispensable resource, offering
a nuanced understanding of the intricacies involved in the management of diabetes
and its related complications. With contributions from leading experts in the field,
the Fellowship of Diabetology book covers a wide range of topics including the
latest advancements in diabetes research, evidence-based treatment strategies, and
practical tips for patient care. It also delves into the psychological aspects of living
with diabetes and provides insights on how to effectively communicate with patients
to promote self-management and improve outcomes. Whether you are a novice or
an experienced healthcare professional, this book will undoubtedly expand your
knowledge and skills in the field of diabetology.

Who Should Read This Book?

A wide range of readers, including medical professionals at various stages of their

employment, are targeted by the Fellowship of Diabetology book. This book will
provide you a thorough grounding in the discipline of diabetology, whether you are
a future diabetologist, an internal medicine specialist, a family physician, a nurse
practitioner, or a medical student. It provides a forum for education for people
pursuing a formal fellowship in diabetology or for those looking to expand their
knowledge of diabetes treatment. Additionally, this book is appropriate for readers
who are just looking to learn more about diabetes. It covers a wide range of issues,
from the fundamentals of managing diabetes to the most recent developments in
research and available treatments.

20 21

What You Will Learn?
Within the pages of this book, you will embark on a journey that explores the
multifaceted landscape of diabetes management. From understanding the
pathophysiology of diabetes to mastering the art of patient-centered care, the book
takes you through a series of meticulously curated chapters that encompass the
breadth and depth of diabetes management. You will gain insights into evidence-
based practices, the latest therapeutic advancements, and strategies for achieving
optimal glycemic control. Additionally, the book delves into the psychological and
emotional aspects of living with diabetes, providing valuable guidance on how to
support patients in coping with the challenges they may face. Furthermore, it offers
practical tips and tools for healthcare professionals to effectively communicate
with patients and empower them to take control of their own health.
What You Need?
Familiarity with key concepts related to endocrinology, physiology, and internal
medicine will facilitate a deeper understanding of the topics covered. Moreover,
an inquisitive mindset, a commitment to lifelong learning, and a passion for
delivering high-quality patient care will contribute to your success in delving into
the intricacies of diabetology. Additionally, staying updated on the latest research
and advancements in the field of diabetology will enable you to provide evidence-
based treatment plans and stay ahead of emerging trends. Furthermore, effective
communication skills and the ability to collaborate with a multidisciplinary
healthcare team will be essential in providing comprehensive care to patients with
diabetes.
What is Covered in This Book?
The Fellowship of Diabetology book is structured to cover a wide spectrum of
topics that are essential for comprehensive diabetes care. From the basics of
diabetes diagnosis and classification to in-depth discussions on pharmacological
interventions, lifestyle modifications, and the prevention of diabetic complications,
each chapter offers a wealth of knowledge. The book also delves into the
psychological aspects of diabetes, emphasizing the significance of patient education,
behavioral interventions, and effective communication.
22
Unit 1-
In this chapter the intricate detailing of the metabolism mechanism and the changes
with the same have been addressed. The different pathways of metabolism and
hormonal control of metabolism have been considered as well. Furthermore, how
the genetic expressions can affect the metabolism and lead to metabolic disorders
like diabetes have been addressed in this chapter. The history of diabetes along
with epidemiology and the global burden of the disease have been discussed, which
shows us, there is a long way to go considering the measures of the disease.
Unit 2-
In chapter 2 we encounter the monitoring process and diagnostic tests of diabetes.
The managing and monitoring needs diagnosis and appropriate care. In some cases,
prevention is also a matter of concern. Patient-centered care is the foundation of
quality healthcare. The understanding of needs and wants of patients and the family
is one of the most important aspects in diabetes care. The medical evaluation of
the disease along with immunization and comorbidity assessment provide the
carers and the patients with the most effective solution. These aspects have been
elaborated within this chapter in a comprehensive manner.
Unit 3-
Here you will know about the complications and comorbidities that come with the
disease. The macro and microvascular complications and their impact on patient
health. The acute complications that come with diabetes have been explained along
with their pathogenesis and burden on global health as well.
Unit 4-
Managing diabetes through pharmacological and nonpharmacological treatment.
The basis of glycemic control, the monitoring, evaluation and proper care of the
same have been introduced in this chapter. The cardiovascular risks of diabetes
and the other risk factors that can elevate the chances of the disease have been
addressed along with the management of the complications. The surgeries and the
combination therapies to treat and manage diabetes have been discussed thoroughly
in this chapter.
23
Unit 5-

In chapter 5, the complications and the comorbidities in diabetic patients along with
the footcare measures have been discussed. The issues within the special group of
people suffering from the disease like old aged and pregnant people have been
discussed along with the treatment and management of the disease.

Moreover, the book addresses the role of technology in diabetes management,

exploring the utility of continuous glucose monitoring systems, insulin pumps,
and telemedicine. It also provides insights into the evolving landscape of precision
medicine and the potential implications of genetics and personalized therapies in
diabetes care.

How to Contact the Author

As you navigate through the pages of this book, you may encounter questions,
insights, or discussions that spark your curiosity. Feel free to reach out to the author
through the provided contact information to share your thoughts, seek clarification,
or engage in meaningful dialogues about the content. Your feedback and interactions
will contribute to the ongoing evolution of this educational resource and foster a
community of passionate diabetology enthusiasts.

In conclusion, the Fellowship of Diabetology book is your gateway to a

comprehensive understanding of diabetes management. By engaging with its
content, you will gain the knowledge, skills, and confidence needed to excel in
providing patient-centered care and advancing the field of diabetology. Whether
you are on a path towards a formal diabetology fellowship or simply seeking to
enhance your expertise, this book stands ready to be your guiding light in the
dynamic world of diabetes care.

24 25
26
 Introduction And Overview
When your blood glucose, also known as blood sugar,
is too high, you have diabetes. Glucose is your body’s
fundamental wellspring of energy. Your body can make
glucose, however glucose additionally comes from the
food you eat.

Insulin is a chemical made by the pancreas that assists

glucose with getting into your cells to be utilized for
energy. Assuming you have diabetes, your body doesn’t
make enough — or any — insulin, or doesn’t utilize
insulin appropriately. Glucose then, at that point, stays in
1
your blood and doesn’t arrive at your cells.

INTRODUCTION AND OVERVIEW

Diabetes raises the gamble for harm to the eyes, kidneys,
nerves, and heart. Diabetes is likewise connected to certain
sorts of malignant growth. Your risk of developing health
issues related to diabetes may be reduced by taking steps
to prevent or manage the condition.

1
In this chapter, the basics of diabetes have been discussed
along with the physiology of metabolism in diabetes.

Chapter Contents
1.1 Physiology of Metabolism and the Role of Endocrinology
1.2 Key Landmark/Historical Perspective Of Diabetes
1.3 Diabetes Pathogenesis
1.4 Epidemiology Of Major Types Of Diabetes
1.5 Summary
1.6 Review Questions

27

1.1 Physiology of Metabolism and the Role of Endocrinology
When your blood glucose, also known as blood sugar, is too high, you have
diabetes. Glucose is your body’s fundamental wellspring of energy. Your body can
make glucose, however glucose additionally comes from the food you eat.
Insulin is a chemical made by the pancreas that assists glucose with getting into
your cells to be utilized for energy. Assuming you have diabetes, your body doesn’t
make enough — or any — insulin, or doesn’t utilize insulin appropriately. Glucose
then, at that point, stays in your blood and doesn’t arrive at your cells. Diabetes
raises the gamble for harm to the eyes, kidneys, nerves, and heart. Diabetes is
likewise connected to certain sorts of malignant growth. Your risk of developing
health issues related to diabetes may be reduced by taking steps to prevent or
manage the condition.
1 1
1.1.1 The Fundamentals of Metabolism
INTRODUCTION AND OVERVIEW
Many individuals visualize food and beverages or the extensive metabolic circuit
diagram with thousands of connections when they think about metabolism.
However, for more than 150 years, biochemists have been fascinated by the topic
of metabolism because it is essential to comprehending life. Hans Krebs, a famous
scientist who won the Nobel Prize, was encouraged to research metabolism by
Prof. France Knoop, a professor at his university who made the discovery of fatty
acid -oxidation. He dissected and explained the urea cycle and citric acid cycle, two
of the most important metabolic processes. Professor Franz Knoop stated:
“The final goal of physiolohical chemistry/(metabolism)” is to “present a scheme that
puts together an unbroken series of equations of all the reactions from the food stuffs
which continously supply to the organism needs, all the way to the slag that again
leaves the organism energyless final oxidation products.” Prof Franz Knoop 1931-Hans
Krebs: The formation of a scientific life 1900-1933 by FL. Holmes.
While it tends to be overwhelming to ponder each metabolic pathway that is
happening, we can separate it and grasp its more modest angles. Knoop’s words
support the genuine significance of digestion and one of its focal jobs in organic
28
chemistry and physiological science. Digestion is derived from the Greek word,
metabolē signifying ‘to change’ and contains the complete of all substance responses
that happen in the cell that are fundamental forever. These chemical reactions, which
include the synthesis and degradation of complex macromolecules, can be broken
down into catabolism or anabolism (see Figure 1.1, which shows the difference
between the two). Catabolism is the corruption of perplexing macromolecules
into less complex particles like carbon dioxide, water, and alkali. Anabolism is the
biosynthetic pathways that produce complex macromolecules, for example, nucleic
acids, proteins, polysaccharides, and lipids.
INTRODUCTION AND OVERVIEW
Figure 1.1: Coupling of anabolic and catabolic pathways
Living things need energy constantly to maintain cellular and overall body
function. Mechanical effort (contraction and cellular movement), active ion/
substrate transport (K+, Mg2+, and Ca2+, for instance, in cardiac contraction), and
the production of complex macromolecules (such as glycogen) all require energy.
Pathways: Why?
Metabolic pathways are essential in catching valuable energy. This is conversely,
with uncontrolled burning, where energy is quickly delivered into the climate, as
intensity and light, which would be impractical forever. Digestion is coordinated
into particular metabolic pathways to either amplify the catch of energy or limit its
utilization. The metabolic pathways of catabolism are organized in such a way that
energy is released gradually in discrete quantities. This energy is captured by the
synthesis of adenosine triphosphate (ATP), guanosine triphosphate (GTP),
nicotinamide adenine nucleotide (phosphate), or the electron transport chain
29
 (ETC). In anabolism, metabolic pathways utilize these discrete quanta of energy as
ATP and NADPH to perform work, for example, the blend of biomolecules.
Note: Metabolic pathways in diabetes, notably disrupted due to insulin deficiency or
resistance, impact how the body utilizes glucose. Gluconeogenesis, impaired glucose
uptake, and altered lipid metabolism are pivotal components. Understanding these
pathways aids in designing targeted interventions for diabetes management, promoting
better glycemic control and reducing associated complications.
1 1
INTRODUCTION AND OVERVIEW
Figure 1.2: Metabolic pathways
Power Available To The System
The nucleotide ATP is one of the most significant biomolecules in the cell. ATP
is a highly charged molecule because of its linear triphosphate structure, which
produces four negative charges. These bonds can store a lot of energy because of
30
their negative charge, which can be easily released at the worksite. NAD+ and ATP
both serve as energy stores for energy in their reduced forms, NADH H+ and NAD+.
In the cell, NAD+ functions as a universal electron carrier, moving electrons from
the site of catabolism to the ETC.
Energy cannot be generated or destroyed; rather, it can only be changed from one
form into another, according to Emilie du Châtelet’s law of conservation. This
explains how energy moves through biological systems and is related to the first
rule of thermodynamics. The rules of thermodynamics also enable us to foresee
whether a reaction will occur and how much energy will be consumed or released.
This introduces us to a crucial idea: the significance of chemical equilibrium,
where reversibility of a reaction is possible (see Figure 1.3). Since both the forward
and reverse reactions are occurring at the same rate at equilibrium, there is no net
reaction.
INTRODUCTION AND OVERVIEW
Figure 1.3: Reaching Equilibrium
The concentration of the substrate or products, the amount of energy released or
needed for the reaction, and in the case of metabolic pathways, the activity of the
enzyme, can all influence the reaction’s direction. Figure 1.2 demonstrates how
changes in the substrates and products can affect simple equilibria and how the
direction of the reaction is determined by which has a higher concentration. The
equilibrium constant or standard free energy change describes how the fulcrum of
the figurative seesaw is not constantly in the middle.
Metabolic pathways are essential in catching valuable energy. This is conversely,
with uncontrolled burning, where energy is quickly delivered into the climate, as
intensity and light, which would be impractical forever. Digestion is coordinated
into particular metabolic pathways to either amplify the catch of energy or limit
its utilization. The metabolic pathways of catabolism are organized in such a way
that energy is released gradually in discrete quantities. This energy is captured
by the synthesis of adenosine triphosphate (ATP), guanosine triphosphate (GTP),
nicotinamide adenine nucleotide (phosphate), or the electron transport chain (ETC).
In anabolism, metabolic pathways utilize these discrete quanta of energy as ATP
31
 and NADPH to perform work, for example, the blend of biomolecules.
................................................................(1)
Enthalpy (H) = total energy;
Entropy (S) = disorder of the system;
T = temperature (measured in Kelvin)
The second law of thermodynamics expresses that for a cycle (response) to happen,
there should be an expansion in entropy in the universe (or framework). This
intends that for a response to occur precipitously there should be an expansion
in entropy and subsequently a negative change in free energy (ΔG). We can now
consider what this implies as far as response energy and how ΔG can direct the
bearing of the response, utilizing the relationship of bicycling (Figure 1.4). On
1 the off chance that the ΔG is negative, a response continues suddenly and with
a deficiency of free energy. Utilizing our bicycle similarity, this would resemble
INTRODUCTION AND OVERVIEW
the energy delivered as you cycle from the highest point of a slope down to the
base. This sort of response is named EXERGONIC, or on the other hand on the off
chance that it discharges heat, exothermic. Assuming then again, ΔG is positive,
and you are gazing toward the slope, then, at that point, the response is negative or
not unconstrained, for example the response is ENDERGONIC, or on account of
intensity, endothermic. As responses can be reversible, in the event that the forward
response has a positive ΔG, the converse response will be negative, subsequently
the response could happen backward.
Figure 1.4: The effect of changes in ΔG on the reaction A+B and C+D
Consider the second reaction in glycolysis, which is catalyzed by glucose-6-
phosphate isomerase (G6PI) (eqn 2), to put this into practical terms.
32
...................................(2)
This reaction has a close to equilibrium ΔG°’ of +1.7 kJ.mol-1, making it endogenic
and not spontaneous. However, “ΔG°’” refers to the free energy present in the steady
state. When the concentration of G6P rises at 37°C, which is a more physiological
temperature, the ΔG turns negative and the process is pushed ahead. The opposite
is true, thus if fructose-6-phosphate (F6P) builds up, the forward process is blocked
(because ΔG is now positive), and the reverse reaction is then encouraged (since
ΔG is negative for this). One of the freely reversible reactions in glycolysis, for
instance.
Another consideration is that under physiological circumstances, some reactions
won’t be reversible. For instance, if the ΔG is extremely negative, altering the
amount of product or substrate won’t have any noticeable impact, especially
since the temperature can hardly ever be changed to any appreciable extent. One 1
instance of this is in one of the crucial regulatory steps of glycolysis, which is the
INTRODUCTION AND OVERVIEW
reaction catalyzed by phosphofructokinase 1 (PFK1) and depicted in (eqn 3). Due
to the extremely negative ΔG°, which is 14.2 kJ.mol, even a buildup of fructose-
1-phosphate is insufficient to stop the process under physiological circumstances.
Under physiological circumstances, this response is essentially irreversible; we
shall go into more depth on this later.
............(3)
One significant admonition about ΔG and responses is that ΔG doesn’t anticipate
the pace of response. The pace of response is represented by the enactment energy
and is catalyzed by catalysts. On the off chance that ΔG is negative, the response
ought to happen unexpectedly, yet there is as yet a need to beat the underlying
initiation energy. Responses that need catalysis can be constrained by the movement
of the chemical. For instance, while the ΔG for (eqn 3) is exceptionally bad,
PFK1 is managed by input restraint and initiation. Expanding groupings of either
phosphoenolpyruvate (Energy; the penultimate transitional in glycolysis) or ATP
hinder PFK1, as they go about as a sign for adequate energy interest. On the other
hand, an expansion in the grouping of adenosine monophosphate (AMP) flags an
energy shortage in the cell and consequently enacts PFK1.
33

Coupled Processes And Reactions
Inherent value exists in the pairing of processes to create intricate paths. Several
reactions, as shown in Table 1.1, have positive ΔG values, and as a result,
theoretically, they shouldn’t be spontaneous or move backward. The outcome of one
reaction becomes the substrate for the next one when the reactions are connected,
though. As a result, coupling reactions allows for the quick removal of products and
the accumulation of substrates, changing the equilibrium seesaw (Figure 1.3) and
shifting the ΔG (for reversible reactions) to negative. Later on, we’ll go into more
depth on glycolysis and how regulation can affect important processes as well as
G6P’s other potential outcomes.
1 1
INTRODUCTION AND OVERVIEW
Table 1.1: Standard free energy and Gibbs free energy of each step in glycolysis
Finally, by coupling the release of energy from its hydrolysis to overcome a positive
ΔG, ATP can be employed to accelerate processes. As we’ve already shown, ATP
contains a lot of energy stored in its phosphate bonds, and the cleavage of only one
phosphate releases -31 kJ.mol1. This can be utilized to defeat endergonic processes,
including the initial step of glycolysis:
Inorganic phosphate addition is an endergonic native process that takes +14 kJ.mol
34
1. However, because Pi is liberated during ATP hydrolysis and Pi serves as a
substrate for the first reaction, these two reactions can be linked and the energy
released during ATP hydrolysis is used to power the second reaction. Noting that
Pi is a shared intermediate in both reactions, this coupling only functions because
of this.
In conclusion, reactions that have a negative ΔG are preferred. Unfavorable
reactions can happen when responses are combined in pathways. Different metabolic
pathways are set up in the body’s metabolism to maximize energy absorption and
minimize unchecked combustion.
Metabolism From Thin Air
Heterotrophs and autotrophs are two separate categories of organisms. A group
of organisms known as autotrophs—from the Greek words “auto” for “self” and
“trophs” for “food”—are able to use the energy from sunlight and inorganic nutrients
from their surroundings to fix carbon into complex macromolecules. The majority
INTRODUCTION AND OVERVIEW
of bacteria and animal cells are heterotrophs, which make up a far bigger collection
of living things. They cannot fix their own carbon, in contrast to autotrophs, and
must instead rely on the carbon that autotrophs fix in order to grow.
Chemoautotrophs and photoautotrophs are the two categories into which autotrophs
are typically divided. These organisms repair carbon dioxide as a usable energy
source by using the energy from inorganic chemical reactions (chemoautotrophs,
such as Nitrobacter) or light (photoautotrophs, such as plants). The diazotrophs,
a class of important chemoautotrophs that includes nitrogen-fixing bacteria and
archaea, are one illustration. They are in charge of converting atmospheric nitrogen
(N2) into inorganic nitrogen molecules like nitrite (NO2), nitrate (NO3), and
ammonia (NH4+). They have the ability to use these substances to generate energy
for the production of macromolecules. To produce their ATP, ammonia- and nitrite-
oxidizing bacteria (AOB and NOB) use procedures like the eukaryotic ETC (in
mitochondria) (Figure 1.4).
When inorganic nitrogen molecules like NH4+ and NO2 are oxidized, electrons are
released that are then taken up and transported to an electron acceptor by enzymes
that contain copper. The pumping out of protons (H+), commonly referred to as
the proton motive force, is caused by the transfer of these electrons. To produce
ATP, these protons then pass via an ATP synthase as they flow back down their
concentration gradient. The Calvin cycle, which absorbs CO2 and transforms it into
35
 carbs, is one biosynthetic process that can use this ATP.
Figure 1.5: The involvement of nitrogen in the production of the macromolecules
AOB, NOB, NH4+, NO2 and NO3 in chemoautotrophs
The main group of autotrophs are photoautotrophs, which use light as a source of
energy to fix carbon dioxide (Figure 1.6). Perhaps the greatest examples of this
1 1
class are multicellular plants and unicellular organisms (algae and cyanobacteria),
which use the process of photosynthesis to convert sunlight into ATP and NADPH.
INTRODUCTION AND OVERVIEW
In essence, these organisms take electrons from water using photons of light and
make oxygen as a byproduct. Once more, these electrons are employed to drive
the synthesis of ATP, which in turn fuels metabolic processes like the Calvin cycle
that produce carbs. The chloroplast is responsible for carrying out this photon-
capturing mechanism in eukaryotic organisms like green plants and algae. These
organelles are absent in cyanobacteria, which instead uses folded membranes for
photosynthesis. Genome analysis results point to a potential candidate for the origin
of the chloroplast in eukaryotic cells: an ancient cyanobacterium.
Figure 1.6: Basic green plant biosynthesis and photosynthesis pathways
36
Animal Metabolism
Animals are heterotrophs, as we’ve already seen, and they rely on organic chemical
ingredients to create physiologically meaningful energy. Animals therefore require
a diet high in carbohydrates, fats, and proteins as well as vitamins and ions in order
to function. Intake guidelines for people vary by nation, however in the UK, the
NHS suggests a diet high in carbohydrates (68.5%), fat (18.5%), and protein (13%).
These numbers are changing among the general population, though. The diet has
a considerably larger emphasis on sugar and fat. A rise in the overconsumption of
sugar and fats may be contributing to the obesity pandemic, with sugar consumption
acting as the main catalyst. Therefore, a deeper comprehension of metabolic
pathways and the mechanisms regulating weight gain and loss is needed. Animal
tissues primarily utilize glucose, fatty acids, ketones, amino acids, and lactate as
sources of metabolic energy. Although some amino acids, fatty acids, and glucose
can be synthesized by some organs, these substances are mostly obtained through
diet. The body can store fatty acids and glucose in polymers called glycogen and
INTRODUCTION AND OVERVIEW
triglycerides (TAGs), respectively. Amino acids can also be released from proteins
during times of hunger. Lactate and ketones are created briefly in the body but are
not preserved.
Many tissues can generate ATP in a variety of ways. Our body prioritizes the
breakdown of food sources during fasting or starvation (fasting for more than 24
hours), using the fuel sources that are least necessary for tissue survival first. The
body uses liver glycogen reserves to keep blood glucose levels stable for the first
24 hours, although as shown in Table 1.2, the body has few reserves of glucose.
Glycogen levels alone would not be enough to maintain normal function in the
brain, which needs between 100 and 120 g of glucose each day. In order to keep the
normal blood glucose level at or around 5.5 mmol.l-1, glucose production must be
increased.By day 2, gluconeogenesis is the main source of glucose, as the body has
increased the synthesis of “new” glucose from other sources during the course of
the first 24 hours. Some tissues, like the heart and muscle, increase their fatty acid
utilization to minimize their glucose utilization in order to maintain appropriate
blood glucose levels. The body begins to break down “mobilisable” protein
in skeletal muscle (proteolysis) as we enter this lengthier fasting and starving
state in order to produce substrates for gluconeogenesis (in the liver). Initially,
these “mobilisable” proteins are thought to be expendable or to have an energy-
demanding function; but, as famine worsens, the breakdown of these proteins is
37
 followed by the breakdown of less expendable proteins. If this protein breakdown
persists, it may cause muscular loss, impaired physiological function, diaphragm
injury, and even death.
Table 1.2: Mass of fuel reserves in tissue and total in a typical 70-kg man
1 type 1 diabetes, lowers blood pH and may result in coma. Figure 1.7 provides an
Selective metabolization occurs with metabolic fuels
INTRODUCTION AND OVERVIEW
The body’s tissues display varying capacities to use various metabolic fuels, and
the majority exhibit flexibility in fuel choice. While glucose serves as the primary
fuel for some tissues, the heart is one of those tissues that may utilize a variety of
fuels. The enormous energy requirements of the human brain are largely met by
glucose, with a tiny quantity of ketones being utilized during fasting. According to
estimates, the skeletal muscle and erythrocytes (red blood cells) use the majority of
the remaining glucose while the brain uses close to two-thirds of it at rest. Because
erythrocytes cannot perform anaerobic glycolysis because they lack mitochondria,
they are totally dependent on glucose, emphasizing the significance of maintaining
normal blood glucose levels. Skeletal muscle will increase its need for glucose
during exercise, causing it to break down its large glycogen stores (around 300 g)
in order to sustain optimal performance.
Due to their capacity to pack tightly into TAGs, fatty acids constitute a significant
source of energy for humans and the majority of terrestrial animals. Mole for
mole, they produce more ATP than glucose. Because they are hydrophobic, TAGs
effectively store fatty acids in lipid droplets, like those found in adipose tissue. Free
fatty acids are released into the blood during lipolysis (the breakdown of TAGs),
where they might be oxidized by various tissues. Fatty acids account for 60–70% of
the heart’s energy needs while it is at rest, emphasizing the significance of this fuel
source. However, illnesses like type 2 diabetes have been associated with elevated
38
levels of fatty acids. In times of fasting and hunger, the liver uses fatty acids as a
fuel source and to produce ketones (also known as ketone bodies).
Acetyl Coenzyme A (CoA) from -oxidation is used by the liver to produce the
two main ketones, acetoacetate and -hydroxybutyrate, in a process known as
ketogenesis. Since the liver lacks the enzyme succinyl CoA transferase, it must be
released for utilization by other tissues, including the heart, skeletal muscle, and
the brain. Although they cannot completely replace glucose, ketones can provide
the brain with an additional source of energy by crossing the blood-brain barrier. In
these tissues, a mechanism known as ketolysis converts ketones into acetoacetate
and -hydroxybutyrate, which produce 20 and 22.5 ATP, respectively. Ketones occur
in the blood in an acidic form, and at low amounts (typically < 0.6 mmol.l-1), they are
not likely to harm the body. The rapid and uncontrolled overproduction of ketones
(3.1 mmol.l-1) that occurs during diabetic ketoacidosis, a severe consequence of
1
overview of tissue interaction during hunger.
INTRODUCTION AND OVERVIEW
Figure 1.7: A list of the metabolic processes that are engaged during starving
Figure 1.8 demonstrates that cross-talk between tissues is necessary for survival
during a starving situation. The same is true for the fed state, where maintaining
normal function depends on the control and metabolic integration of tissues. Each
organ is in charge of performing a particular spectrum of metabolic transformations
and molecular processing at each stage. This is necessary to lessen the possibility
of inefficient cycles, in which a tissue simultaneously synthesizes and degrades a
39
 metabolite, resulting in a net energy loss.
To either renew glucose or regulate the utilization of glucose in the muscle, there
are three main interorgan routes. The Cori cycle (Figure 1.9) is triggered by
intense exercise when the heart or skeletal muscles are exercising anaerobically,
which causes lactate to build up. The transport of lactate to the liver allows for
the regeneration of glucose (gluconeogenesis), which the working muscle can
subsequently consume once again. As you’ll see later, anaerobic glycolysis does
not require oxygen, which can be scarce during intense exercise, even though it
produces far less ATP than the oxidation of glucose.
1 1
INTRODUCTION AND OVERVIEW
Figure 1.8: The two main mechanisms for regenerating glucose in the liver and
recycling lactate or alanine from muscle
During seasons of starvation, the glucose-alanine cycle can recover glucose and
eliminate the abundance of nitrogen shaped in the breakdown of amino acids
(Figure 1.9). During proteolysis, amino acids that are freed can give carbon
skeletons to top up various pathways, however should discard the amino gathering.
This amino gathering is moved to pyruvate by alanine aminotransferase to frame
alanine. Alanine is the transcendent amino corrosive delivered by the muscle.
In the cycle, glucose taken up by the muscle is utilized to create the pyruvate,
consequently supporting proteolysis, without an overall deficit of glucose. The
alanine is delivered by the muscle and taken up by the liver, where it is changed
40
over into pyruvate, and back into glucose to begin the cycle once more. At long
last, the amino gathering freed by the transformation of alanine back into pyruvate
enters the urea cycle for removal.
1.1.2 Hormonal Control of Metabolism
Insulin and glucagon, two tiny peptide hormones, can interact to regulate
metabolism in animals. Insulin and glucagon are both made by pancreatic β-cells in
the islets of Langerhans, which are located within the pancreas. In their respective
cells, vesicles store both glucagon and insulin until a signal to release them into
the bloodstream is received. After eating, for instance, insulin is released from its
vesicles into the blood when blood glucose levels rise. Insulin’s effects are felt
widely. It is able to greatly boost glucose uptake in peripheral tissue in addition to
controlling metabolic activity in the liver. The insulin receptor, a tyrosine kinase
receptor on the cell surface, binds to insulin, causing the insulin receptor substrate
(IRS) to be attracted and autophosphorylated. AKT (also known as PKB), the
protein that mediates or regulates insulin effects, is phosphorylated as a result of
INTRODUCTION AND OVERVIEW
the signaling transduction pathway that IRS then starts.
In accordance with the organism’s metabolic status, insulin can have both
immediate and long-term impacts. Insulin signaling leads to the translocation of
the glucose transporter (GLUT4) from intracellular vesicle storage to the plasma
membrane in skeletal muscle, the heart, and adipose tissue. This considerably
raises the likelihood that these cells will take in glucose. As will be briefly covered
later, insulin has the ability to control gene expression to improve the utilization of
glucose, storage of glucose as glycogen, uptake of fatty acids, and storage of TAGs.
De novo lipogenesis, or the production of fresh fatty acids from glucose, is a further
effect of insulin in adipose tissue.
Hormones intricately govern metabolic pathways, and their disruption is central in diabetes.
Insulin deficiency in Type 1 and insulin resistance in Type 2 alter glucose regulation, fat
metabolism, and protein synthesis. Understanding these hormonal dynamics is pivotal for
effective diabetes management and maintaining metabolic equilibrium.
The beta-cells release glucagon when blood glucose levels drop. The ratio of
glucagon to insulin, which is in a delicate balance, plays a key role in identifying the
metabolic pathways that are active at particular periods. In contrast to glucagon’s
41
 impact, a shortage of insulin can be a potent warning indication. For instance, insulin
prevents the hormone-sensitive lipase (HSL) in adipose tissue from working. By
hydrolyzing a fatty acid from a TAG, HSL plays the role of stimulating lipolysis
(the breakdown of TAGs), although this is blocked by insulin’s ongoing signaling.
This inhibiting signal is lost as blood glucose levels drop, and HSL permits lipolysis
to take place.
Adenylate cyclase is controlled by the G-protein coupled receptor used by glucagon,
which also results in a rise in cyclic AMP. The hormone glucagon causes the liver
to become a net exporter of glucose by promoting the production of new glucose
during gluconeogenesis and inhibiting the use of glucose during glycolysis and
storage as glycogen.
1 Gluconeogenesis - G6P is changed over by glucose-6-phosphatase during
INTRODUCTION AND OVERVIEW
Figure 1.9: Hormonal Control of Metabolism
1.1.3 Glucose Metabolism
Glucose is shipped into a cell through Excesses and sodium glucose cotransporters
(SGLTs) by means of work with dispersion. These carriers can move glucose
into and out of cells. To guarantee that glucose stays inside the cell, it is rapidly
‘caught’ and phosphorylated to frame G6P. This phosphorylation happens through
a kinase protein called hexokinase or glucokinase, which catalyzes the exchange of
a phosphoryl bunch from an ATP particle to an acceptor particle. For this situation,
42
G6P is an exceptionally bad, polar particle meaning diffusing across the cell
membrane can’t. Moreover, the expansion of the phosphate bunch renders G6P
too enormous to even think about getting away from back out of the cell through
Excess carriers. By catching glucose in cells as G6P, the slope of glucose between
the cytosol and the extracellular space increases, bringing about a net development
of glucose into cells. Glucose holds a high osmotic potential, thus by eliminating
glucose, the development of water out of the cell is diminished. This response,
subsequently, guarantees the destiny of glucose as G6P to work with the inception
of additional metabolic cycles.
The key molecule in metabolism is G6P. It is a “crossroad” marker that can take on
a variety of destinies within a cell, depending on its circumstances and metabolic
requirements (Figure 1.10). The center of four metabolic pathways is G6P:
Glycolysis - The development of pyruvate and lactate.
1
gluconeogenesis to shape glucose. Glucose-6-phosphatase is fundamentally
INTRODUCTION AND OVERVIEW
communicated in the liver yet in addition in the kidney cortex now and again
of starvation. It has additionally been viewed as communicated in the β-cells of
pancreatic islets and human gastrointestinal mucosa in starved and diabetic states.
Glycogenesis - Capacity as glycogen. G6P is changed over by means of glycogen
synthase into glycogen for capacity.
The pentose phosphate pathway (PPP) - The age of NADPH particles permits
unsaturated fat combinations. The development of ribose-5-phosphate to
incorporate nucleotides. The PPP recovers the intermediates of glycolysis like F6P
and glyceraldehyde-3-phosphate (Hole).
Figure 1.10: The metabolic crossroad and fate of G6P
To guarantee that the fate of the cell is established, the first step of these pathways
is strictly regulated and serves as a control point.
43
 How significant is glycolysis?
In species that engage in cellular respiration, the first stage of glucose catabolism is
represented by glycolysis. The glycolytic pathway entails the successive catalysis
of glucose into two pyruvate molecules within the cytosol (Figure 1.11).
1 to frame antecedents for the amalgamation of fats, cholesterol, bile, and plasma
INTRODUCTION AND OVERVIEW
Figure 1.11: The pathway is divided into two phases: an initial “investment”
phase in which ATP is utilized, and a subsequent “payout” phase in which ATP
is created
Glycolysis happens in most living cells and can prevail without oxygen. Nonetheless,
the destiny of its finished result relies upon the anaerobic or oxygen consuming
climate of the cell following glycolysis.
Glycolysis depends on NAD+ to acknowledge electrons from glucose framing
NADH and H+. NAD+ can be re-oxidized from NADH to guarantee a cyclic impact
44
of glycolysis in all cells. This can be achieved under both oxygen consuming and
anaerobic circumstances. Notwithstanding, within the sight of oxygen, NADH
passes its electrons into the And so forth, permitting the total oxidation of glucose.
This yields a net creation of 30-32 ATP particles. Under anaerobic circumstances,
aging happens and NADH gives its electrons to recover NAD+, and no further ATP
is shaped.
Notwithstanding glycolysis just yielding two ATP atoms, the cycle is essential. As
recently referenced, the mammalian erythrocytes depend altogether on the ATP
produced through glycolysis as its energy source since they need mitochondria.
Moreover, inside the liver, glucose guidelines are crucial to guarantee glucose
homoeostasis in the body. Here, glycolysis can be firmly managed. Under conditions
of fasting, hepatic glucose creation can be raised, making the liver the principal
wellspring of glucose creation right now. Here, pyruvate can likewise be utilized
1
proteins. For microorganisms, the glycolytic pathway guarantees a wellspring of
INTRODUCTION AND OVERVIEW
energy for breath and bacterial photosynthesis, alongside fundamental biosynthetic
forerunners.
The glycolytic pathway
Glycolysis is an enzyme-driven process that takes place in the cytosol and has two
distinct phases: energy investment and energy recovery (Figure 1.11).
Energy investment phase in Stage I Hexokinase (or glucokinase in the liver
and pancreas) catalyzes the first step of glycolysis, which involves transferring
a phosphoryl group from ATP to glucose to generate G6P. The fructose-1,6-
bisphosphate (FBP) is created when G6P is isomerized to F6P by G6PI and
subsequently phosphorylated by PFK.
This glycolysis step’s irreversible phosphorylation uses the second ATP molecule.
FBP, a 6-carbon molecule, is split into two 3-carbon molecules, GAP and
dihydroxyacetone phosphate (DHAP), through the action of aldolase. Triose
phosphate isomerase (TIM), another isomerase, catalyzes the interconversion of
DHAP and GAP, enabling DHAP to become GAP and continue along the glycolytic
pathway. As a result, two molecules of GAP are created from each glucose molecule.
As a result, all intermediates and byproducts are produced twice as much from this
point forward.
GAP dehydrogenase (GAPDH) catalyzes the oxidation and phosphorylation of
45
 GAP by NAD+ and Pi to produce 1,3-bisphosphoglycerate (1,3-BPG), which is
the energy payout from Stage II. Along with 1,3-BPG, the intermediates NADH
and H+ are created. The first step of glycolysis, which produces ATP molecules by
phosphorylating adenosine diphosphate (ADP), is the conversion of 1,3-BPG into
3-phosphoglycerate (3PG), which is catalyzed by phosphoglycerate kinase (PGK).
Phosphoglycerate mutase (PGM) can interconvert 3PG to 2-phosphoglycerate
(2PG), which is then dehydrated to PEP by enolase. In the penultimate step of
glycolysis, pyruvate kinase (PK) catalyzes a cleavage process that produces the
final ATP molecule and pyruvate.
Due to the creation of two 3-carbon GAP molecules, which are each converted to
pyruvate and ATP, the initial energy investment in the form of two ATP molecules is
doubly returned in the later stage of glycolysis. Consequently, four ATP molecules
are produced, resulting in a net gain of 2 ATP.
1 The overall negative ΔG value for glycolysis is 310 kJ.mol-1. Following is
the response:
INTRODUCTION AND OVERVIEW
Regulation of glycolysis
There are three rate-limiting processes in glycolysis. These more gradual, tightly
controlled steps establish the pathway’s overall speed. These rate-limiting processes
are combined with the hydrolysis of ATP or the phosphorylation of ADP within
the glycolytic pathway. As a result, these actions are assured to be energetically
advantageous, holding a very negative G value, and being irreversible under
physiological circumstances.
Hexokinase/glucokinase Hexokinase and glucokinase are the primary administrative
proteins inside the glycolytic pathway. Hexokinase exists in overflowing tissues in
our body. It holds a low Km esteem, in this manner, guaranteeing its high proclivity
for glucose. Because of its low Km it implies that hexokinase is more valuable in
a condition of hypoglycaemia, where glucose levels are low. Hexokinase is input
hindered by its own item, meaning a development of G6P can restrain hexokinase
and consequently, the phosphorylation of glucose. Hexokinase guarantees the
irreversible development of G6P. In mammalian skeletal muscle, where the
significant wellspring of energy is glycogen and not glucose, this step is at last
survived. Inside pancreatic islets, hexokinase permits the control of insulin and
glucagon discharge in the β-and α-cells, separately.
46
Glucokinase is an isoenzyme of hexokinase that exists in the liver and pancreatic
β-cells. In spite of hexokinase, glucokinase holds a high Km esteem and hence a
high Vmax. This implies that glucokinase exists with a low fondness for glucose.
Subsequently, glucokinase is used in a condition of hyperglycaemia or a post-
prandial state. Inside pancreatic β-cells, glucokinase goes about as a sensor to control
the pace of passage of glucose into the glycolytic pathway by phosphorylation.
Inside the liver, it guarantees that glucose is blended into glycogen or unsaturated
fats postprandially, when glucose levels are high. Not at all like hexokinase,
glucokinase isn’t repressed by elevated degrees of G6P and can hence stay dynamic
to guarantee glucose is put away as glycogen when glucose levels are high. The low
liking of glucokinase for glucose guarantees that inside a condition of low glucose,
fringe tissue hexokinase can phosphorylate glucose to G6P for glycolysis and the
liver and β-cells stop the take-up of glucose.
Another important regulator of glycolysis is the enzyme PFK. It has a very low 1
G value, which guarantees that the reaction will proceed even if FBP builds up.
INTRODUCTION AND OVERVIEW
PFK has two conformational states that are in balance with one another, and ATP
can activate either state while inhibiting the other. In the presence of high ATP
concentrations, such as those found in the liver, ATP functions as an allosteric
inhibitor of PFK, changing its equilibrium and lowering its affinity for F6P. PFK is
activated when ATP levels are low, which changes its equilibrium and affinity for
F6P to create FBP.
PEP’s conversion to pyruvate in the final phase of glycolysis is guaranteed by PK.
Pyruvate is a crucial intermediate building component for many further metabolic
pathways, including fatty acid synthesis, the tricarboxylic acid (TCA) cycle, and
the conversion of pyruvate into lactic acid or ethanol (in yeast) when it is produced
under anaerobic conditions. As a result, PK is acknowledged as the primary
regulator of glycolysis.
Gluconeogenesis
The significance of glucose metabolism In the anabolic process of “gluconeogenesis,”
sources of carbon besides carbohydrates, such as pyruvate, are converted into
glucose. In the renal cortex during famine, the gluconeogenic pathway mostly
takes place in the kidneys and liver to maintain blood glucose levels after glycogen
depletion. Additionally, it has been discovered that in deprived and diabetic
situations, glucose synthesis takes place within the β-cells of the islets of Langerhans
47
 and the intestinal mucosa.
Although gluconeogenesis seeks to reverse glycolysis, it is not merely a reversal
of glycolysis because the glycolytic process contains irreversible stages. In the
process of gluconeogenesis, additional enzymes in addition to those found in the
glycolytic pathway are used to circumvent these irreversible stages. It is essential
that gluconeogenesis is not just glycolysis in reverse. This is so that pyruvate, which
is irreversible and very advantageous energetically, can be formed during the final
step of glycolysis (Figure 1.11).
Gluconeogenesis is divided into a two-step process with distinct stages taking
place in the mitochondria and cytosol to get around this. Pyruvate is transformed
inside the mitochondria into oxaloacetate, which is then transformed into malate
and transported outside the mitochondria into the cytosol. Once it is here, PEP
carboxykinase (PEPCK) rapidly converts it back into oxaloacetate and then
to PEP. This prevents both the cell going through a pointless cycle in which
1 1
pyruvate is promptly transformed back into PEP and the irreversible step within
via the malate-aspartate shuttle.
Oxaloacetate is decarboxylated and phosphorylated by PEPCK at the cost of one
GTP molecule.
F6P formation Fructose-1,6-bisphosphatase (F16BPase) promotes a hydrolysis
event in a phosphate ester at carbon 1 of fructose-1,6-bisphosphate.
G6P is frequently used to produce glycogen, which stops gluconeogenesis. It can
also be dephosphorylated to create free glucose molecules.
The location where glucose is formed Gluconeogenesis’ last phase is when glucose
is created. This takes place in the endoplasmic reticulum lumen. GLUTs, which are
easily accessible and found in the endoplasmic reticulum, are ultimately responsible

INTRODUCTION AND OVERVIEW

for transporting the glucose produced into the cytoplasm.
INTRODUCTION AND OVERVIEW

glycolysis. Additionally, ATP is used in stages 1 and 3 of glycolysis (Figure 1.11) to

phosphorylate the end product.
As a result, if gluconeogenesis were the opposite of glycolysis, it would effectively
imply that gluconeogenesis relies on the regeneration of ATP, which is not a
feasible process. Instead, because gluconeogenesis depends on ATP, extra enzymes Gene Expression in Glucose Metabolism
are needed to skip steps 1 and 3, where ATP is not renewed. One of the activities of insulin is to increment glycolysis, while stifling
The relevance of gluconeogenesis stems from the fact that the brain and erythrocytes gluconeogenesis (in the liver). Because of expanded insulin and glucose, the
nearly exclusively use glucose as a source of energy. As a result, it is crucial that mammalian liver, muscle, and fringe tissue builds the outflow of GLUT1-
gluconeogenesis periodically replenishes the glucose that glycolysis eventually 4, hexokinase/glucokinase and key glycolytic qualities: Hole dehydrogenase,
depletes. PK and the bifunctional compound (which animates PFK action). To smother
gluconeogenesis in the liver, insulin diminishes the statement of glucose-6-
Gluconeogenic pathway
phosphatase, fructose-1,6-bisphosphatase, and EP carboxylase. This adjustment in
Oxaloacetate is created from pyruvate. Pyruvate carboxylase (PC) converts pyruvate
quality articulation design, increments glucose used in the cells, and keeps up with
to oxaloacetate at the cost of one ATP molecule. The mitochondria are where this
glycolytic movement. In the mammalian liver, glucose can expand the declaration
reaction takes place. Acetyl CoA concentration is increased to activate PC, while
of PK through the record factor known as starch responsive component restricting
the presence of glucose and ADP inhibits it.
protein (ChREBP). Strangely, the activity of glucagon on the liver smothers this
record factor, subsequently lessening the outflow of PK.
In the presence of NADH, oxaloacetate is converted to malate, which is then
transported through the mitochondrial membrane and into the cytosol. Malate is
re-oxidized to oxaloacetate after traveling through the mitochondrial membranes

48 49

Gene expression plays a pivotal role in glucose metabolism and diabetes. Altered gene
activity impacts insulin production, sensitivity, and glucose regulation. Understanding
these molecular mechanisms is crucial for developing personalized interventions to
manage diabetes and its associated metabolic imbalances effectively.
Glycogen
Describe glycogen. A substantial, multi-branched polymer of glucose is called
glycogen. It has 1,6-glycosidic linkages at branching points every tenth residue
and 1,4-glycosidic links between neighboring glucose molecules. It is essentially
the form of glucose that is stored by bacteria, fungi, and mammals. It can be
broken down to produce glucose when the body needs it since it serves as a storage
molecule for glucose. The body stores glycogen in the liver and muscles. Glycogen
1 1
is broken down in the muscle to provide energy, whereas it is broken down in the
liver to keep the body’s blood glucose levels stable.
PPP
The significance of PPPs and their intermediaries Within the cytosol of living
things, the PPP is a crucial metabolic activity (Figure 1.12). This route works in
tandem with glycolysis in the cytosol because it makes use of some of the same
elements. It is known to play a number of significant roles.
The process of producing NADPH (nicotinamide adenine dinucleotide phosphate).
NADPH is a vital reducing agent that is employed in the following processes:
● Biosynthesis of cholesterol
● Synthesis of nucleotides
● Synthesis of neurotransmitters
● Synthesis of fatty acids
Pentose sugars, which are precursors for the synthesis of DNA, RNA, FADH2,
ATP, NADH, and CoA, are produced by this process.
It establishes a method for metabolizing 5-carbon sugars that are eaten as part of a
diet.

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

How important glycogen is The body can break down glycogen to produce energy. Additionally, it offers a means to create and digest less common 4- and 7-carbon
This is crucial since the brain’s cells almost exclusively use glucose for energy, and sugars in the body.
liver cells can help supply this by releasing glucose into the bloodstream. When
there is initially little oxygen available during bursts of abrupt exercise, such as
sprinting, the glucose gained through glycogen degradation can nevertheless create
enough energy.
Additionally, it is frequently questioned why all extra energy produced by the
human body cannot be stored as fatty acids. Glycogen storage is preferable to
fatty acid storage for two key reasons. First off, glycogen is easily converted to
glucose and can be promptly used when glucose is required right away. Second, the
decomposition of glycogen is tightly regulated. In order to boost or maintain blood
glucose levels, the subsequent release of glucose is likewise regulated.
Creation and destruction of Uridine diphosphate glucose (UDP-glucose), an
activated form of glucose, is necessary for the formation of glycogen. UTP is
added to glucose-1-phosphate to create this. The non-reducing end of glycogen is
expanded by the addition of UDP-glucose.
In order to justify further degradation of glycogen, glucose-1-phosphate must be
released from glycogen and the substrates of glycogen must be modified. After Figure 1.12: PPP is split into the oxidative and non-oxidative phases
that, glucose-1-phosphate is transformed into G6P, which has a variety of metabolic A PPP The PPP is divided into two main phases: the oxidative phase, which results
destinations.

50 51
 in the production of NADPH molecules, and the non-oxidative phase, which results
in the production of ribose-5-phosphate molecules for nucleotide synthesis.
The intermediates of glycolysis are available throughout the PPP at various locations.
As a result, it is demonstrated that this pathway works alongside glycolysis.
This makes sure that there are enough pentose sugars and NADPH available for
following processes, like electron transfer within the electron transfer chain.
The fate of pyruvate and acetyl CoA
The byproduct of glycolysis, pyruvate, is a crucial intermediary in several metabolic
pathways. The organism in which it was synthesized and the oxygen levels inside
the cell both play a role in its ultimate fate.
Anaerobic utilization of pyruvate
1 1
Ultimately produced during glycolysis, NADH and H molecules are reoxidized
+
to produce NAD+ molecules. A key mechanism that enables glycolysis to carry on
INTRODUCTION AND OVERVIEW
repeatedly is the recycling of these.
Pyruvate and NADH have different outcomes depending on the circumstances
inside the cell. Pyruvate is totally oxidized in the mitochondria in the presence of
oxygen, resulting in carbon dioxide and water as well as ATP molecules. Anaerobic
respiration, on the other hand, happens in the absence of oxygen. Due to lactate
dehydrogenase (LDH), pyruvate is converted to lactate through homolactic
fermentation in animal tissues like muscle.
In order to continue glycolysis and produce two additional ATP molecules, this
renews NAD+ molecules. Therefore, compared to the 30-32 ATP molecules produced
by aerobic respiration, anaerobic respiration only produces 2 ATP molecules,
making it significantly less effective. Because of this, anaerobic respiration’s energy
cannot be used by mammals as a whole and is instead needed by individual cells
for survival. For instance, erythrocytes cannot produce energy through anaerobic
respiration because they lack mitochondria. This is very favorable for erythrocytes
because it prevents them from using the oxygen they transport. Instead, they move
the oxygen to other cells in the body using the energy produced by anaerobic
respiration.
Alcoholic fermentation in yeast yields ethanol and NAD+. Yeast alcohol
dehydrogenase (YADH) converts pyruvate by decarboxylation to carbon dioxide
52
and acetaldehyde, which is then reduced to NADH to create NAD+.
The pyruvate’s aerobic destiny
Following glycolysis, pyruvate is oxidized in an aerobic environment to produce
acetyl CoA, which enters the TCA cycle to promote cellular respiration in cells.
The TCA cycle, glycolysis, lipid, and amino acid metabolic pathways all converge
during this reaction, which is catalyzed by pyruvate dehydrogenase (PDH). Based
on the cell’s need to utilize carbohydrates as energy, PDH is controlled. When
the body’s reserves of carbohydrates are low, PDH activity is down-regulated to
reduce the amount of glucose that is used by oxidative phosphorylation. As a result,
different tissue types like the heart and muscle can utilize alternative energy sources
including fatty acids and ketone molecules.
PDH is composed structurally of the three subunits E1, E2, and E3. PDH activity is
controlled by reversible phosphorylation at serine residues within subunit E1, which
INTRODUCTION AND OVERVIEW
inhibits this enzyme’s activity. This phosphorylation event is catalyzed by PDH
kinases (PDK 1-4), which decreases PDH activity. The reverse dephosphorylation
reaction, on the other hand, is catalyzed by the PDH phosphatases (PDP1 and
PDP2) to restore PDH activity. various tissues throughout the body have various
levels of expression for the kinases and phosphatases, accordingly.
The concentrations of NADH and acetyl CoA, which are indicators of high energy
production, as well as the transcriptional activity of the peroxisome proliferator-
activated receptor (PPAR), which increases fatty acid uptake, stimulate and inhibit
the activity of these enzymes, respectively. whereas in the heart and muscle,
elevated amounts of insulin, Mg2+, and Ca2+ (depending on the cell type) trigger
phosphatases. Since magnesium ions are found grouped around ATP to lessen its
highly negative charge, it has been observed that higher magnesium levels are
associated with the conversion of ATP to ADP. Contrarily, calcium is produced
by contraction, a highly energy-dependent mechanism that necessitates complete
oxidation of glucose.
CoA and acetyl CoA
All living things have CoA, which is a common and essential cofactor. CoA serves
as a carbonyl-activating group carrier and carries acyl groups, both of which are
necessary for the TCA cycle and many other metabolic activities like fatty acid
53
 oxidation. Pantothenic acid, generally known as vitamin B5, is the natural source
of CoA, which is produced in a sequence of steps requiring ATP. Foods including
grains, pork, and potatoes contain pantothenate, which is produced by bacteria and
plants. Following phosphorylation, the result of pantothenate is consolidated with
a cysteine molecule and then subjected to a decarboxylation process. Dephospho-
CoA is created by adding AMP, and after it has been phosphorylated, CoA is
produced. Because CoA is a competitive inhibitor of pantothenate kinase, the initial
enzyme involved in the phosphorylation of pantothenate, this route is controlled by
end-product inhibition.
Acetyl CoA is a particle that lies at the center of starch and unsaturated fat digestion.
Its principal capability is to convey its acetyl gathering to the TCA cycle for energy
creation. Here, acetyl CoA promptly joins with oxaloacetate to frame citrate and
start the TCA cycle. Likewise, acetyl CoA is shaped by means of unsaturated fat
1 β-oxidation and subsequently goes about as a moderate particle for the TCA cycle,
unsaturated fat digestion, and glycolysis. It is realized that acetyl CoA is integral
INTRODUCTION AND OVERVIEW
to keep up with the harmony among sugar and unsaturated fat digestion for a
wellspring of energy. As acetyl CoA can restrain PDH, an expansion in unsaturated
fat take-up into muscle (and heart) causes a development of β-oxidation-determined
acetyl CoA and hindrance of glucose oxidation. This is important for the glucose-
unsaturated fat cycle, otherwise called the Randle cycle. In the fat tissue, a counter-
response happens, by which a development of glucose (utilized for making new
unsaturated fats) hinders lipolysis and lessens unsaturated fat delivery from this
tissue.
1.1.4 Organ Systems Involved
The main metabolic organ that controls blood sugar levels is the pancreas, which
does so by either releasing large amounts of insulin to lower blood sugar levels
or glucagon to raise blood sugar levels. The Randle cycle, which is controlled by
insulin, is how the body uses fats and carbs.
The liver is the organ in charge of digesting the small intestine’s ingested lipids
and amino acids. Additionally, it controls crucial metabolic processes like
gluconeogenesis and glycogen synthesis as well as the urea cycle.
Carbohydrates have the properties of being soluble, comparatively simple to
transport, and non-toxic molecules that operate as the energy source when oxygen
levels are low.
54
Lipids are the main energy source for animals and tissues and are the most energy-
dense molecules. Since they are not soluble, they cannot be used anaerobically,
cannot be transported easily in the blood, and require more oxygen to be converted
into energy (2.8 ATP/oxygen molecule). They cannot be used by erythrocytes or
renal cells, and they cannot penetrate the blood-brain barrier. Only in conditions
of protracted fasting that show the depletion of glycogen stores do amino acids
function as substrates to generate glucose.
1.1.5 Mechanism and Cellular Level Activities
It centers around one explicit sort of sugar, glucose. After a cell takes-up a particle
of glucose, it gets quickly utilized to glucose-6-phosphate, which can’t leave the
cell. The catalyzing protein in this response is called hexokinase (in the liver and
pancreas) or glucokinase in each and every other tissue. This metabolite is usable
1
by pretty much every metabolic interaction, including glycolysis and glycogenesis.
Carbs are put away as glycogen granules for fast preparation of glucose when
INTRODUCTION AND OVERVIEW
required.
Glycogen is a polymer of glucose, gathered by the glycogen synthase, with branch
focuses each ten glucose particles, which gives the glycogen a tree-like construction,
which is valuable for glucose preparation. A few tissues use glycogen for their own
support, similar to a skeletal muscle; a few different tissues use glycogen to keep
serum glucose levels steady, like the liver. The liver can store very nearly 100 g of
glycogen that provisions glucose for 24 hours; the skeletal muscle stores 350 g that
are adequate for an hour of muscle constriction. Glucose is used by glycolysis in
all cells to frame pyruvate. This interaction doesn’t utilize oxygen, and it produces
two particles of pyruvate, 2 NADH and 2 ATP.
Pyruvate might include three destinies inside the cell: it very well may be shipped
into the mitochondria and create acetyl-CoA, it can stay in the cytosol and produce
lactate, or it tends to be utilized in gluconeogenesis by the compound alanine
aminotransferase (ALT). The destiny of pyruvate in tissues will rely upon hormonal
guidelines, oxygen accessibility, and the specific tissue. For instance, in the liver,
abundance pyruvate is utilized to acetyl-CoA, and afterward this is utilized for lipid
amalgamation, while in muscle, it goes through complete oxidation to CO2.
Glucose-6-phosphate is likewise usable by the pentose phosphate pathway. This
pathway blends nucleotides, amalgamation of explicit lipids, and to keep up with
glutathione in its dynamic structure. This cycle is under the guideline of glucose-6-
55
 phosphate dehydrogenase.
Starch digestion is controlled chiefly by insulin, as it invigorates glycolysis and
glycogenesis. Catecholamines, glucagon, cortisol, and development chemicals,
animate gluconeogenesis and
glycogenolysis.
1.2 Key Landmark/Historical Perspective Of Diabetes
• Polyuric illnesses have been portrayed for more than 3500 years. The name
“diabetes “ comes from the Greek word for a siphon; the sweet taste of diabetic pee
was perceived toward the start of the first thousand years, however the descriptor “
mellitus “ (honeyed) was just added by Rollo in the late eighteenth hundred years.
• The sugar in diabetic pee was identified as glucose by Chevreul in 1815. During
1 the 1840s, Bernard showed that glucose was regularly present in blood, and showed
that it was put away in the liver (as glycogen) for discharge into the circulation
Ancient Times
Diabetes-like illnesses with the defining characteristics were known in ancient
times. Georg Ebers found a description of a polyuric condition in an Egyptian
papyrus from around 1550 BC, and Aretaeus of Cappadocia described what we
would recognize as type 1 diabetes in the second century AD. Since the fluid does
not stay in the body but instead uses the man’s body as a conduit for its exit, Aretaeus
was the first to adopt the name “diabetes,” which comes from the Greek word for a
siphon. His detailed description of the illness emphasized the short survival time,
constant flow of pee, unquenchable thirst, and “melting down of the flesh and limbs
into urine.”
1

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

system during fasting.

• In 1889, Minkowski and von Mering revealed that pancreatectomy caused
extreme diabetes in the canine. In 1893, that’s what Laguesse proposed, the
pancreatic “ islets “ depicted by Langerhans in 1869 delivered an inward emission
that controlled glucose digestion.
• Insulin was found in 1921 by Banting, Best, Macleod and Collip in corrosive -
ethanol concentrates of pancreas. It was first utilized for treatment in January 1922.
• Diabetes was partitioned on clinical grounds into diab è te maigre (lean subjects)
and diab è te gras (large) by Lancereaux in 1880, and during the 1930s by Falta and
Himsworth into insulin - delicate and insulin - obtuse sorts. These classifications
were the trailblazers of the etiological classification into type 1 (insulin - ward) and
Figure 1.13: The Ebers papyrus
type 2 (non - insulin - subordinate) diabetes.
• Insulin opposition and β-cell disappointment, the essential imperfections of Diabetes is a terrible disease that affects fewer men than it should because it
type 2 diabetes, have been explored by numerous scientists. The “ insulin cinch causes the body’s flesh and limbs to dissolve into urine. The patients’ constant
“ technique formulated by Andres and DeFronzo was the first exact method for water production and continuous flow resemble the opening of aqueducts. Life is
estimating insulin activity. Development - beginning diabetes of the youthful was brief, uncomfortable, and painful. Thirst is insatiable, drinking is excessive, and
portrayed as a particular variation of type 2 diabetes by Tattersall in 1974. the amount of urine produced is out of proportion to the amount consumed. They
• Lymphocytic infiltration of the islets (insulitis) was portrayed as soon as 1901 cannot be stopped from creating or drinking water. If they go without drinking for
and featured in 1965 by Gepts who recommended that it may be a marker of a while, their mouths get dry and their bodies dry out; their viscera appear burnt
autoimmunity. Islet cell antibodies were found by Doniach and Bottazzo in 1979. up; they experience nausea, restlessness, and a scorching thirst; eventually, they

56 57
 pass away quickly. The sweetness of diabetic urine was probably first noticed by
Hindu doctors Charak and Sushrut, who wrote between 400 and 500 BC (Figure
1.13). The diagnosis was made, in fact, by tasting the urine or observing that ants
gathered nearby.
The condition, according to Charak and Sushrut, is more common in those who
are sedentary, overweight, gluttons, and who often consume sweet and fatty foods.
In contrast to slim persons, in whom the disease was thought to be more serious,
physical activity and a nourishing diet were the pillars of treatment for the obese.
Arabic medical books from the 9th to the 11th centuries and also underlined the
critical fact that diabetic urine smells sweet.

The 17th and 18th centuries

Prior to Thomas Willis’s (1621–1675) publication of Diabetes, or the Pissing Evil,
1 diabetes was mostly ignored in Europe. In his words, “diabetes was a disease so 1

rare among the ancients that many famous doctors made no mention of it... but

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

in our age, given to good fellowship and downing unalloyed wine, we meet with
examples and instances enough, I may say daily, of this disease.” He said the pee
was “wonderfully sweet like sugar or honey,” but he failed to take into account the
possibility that it might have sugar in it.
Matthew Dobson (1735–1784) of Liverpool wrote the first study to describe
Figure 1.14: Excerpt from John Rollo’s 1797 report of two diabetes cases.
hyperglycemia, which was published in 1776 (Figure 1.14). He discovered that
both Peter Dickonson’s pee and serum, which he discovered to be 28 quarts each Rollo understood the issue with non-compliance. The patient was “strongly
day, tasted sweet. Additionally, he turned the urine into “a white cake [that] smelled remonstrated with and informed of the consequences of repeated deviations,”
sweet like brown sugar and could not be distinguished from sugar by the taste.” as the quote states.
According to Dobson, sugar was expelled by the kidneys and wasn’t “formed in the
The 19th century
secretory organ but previously existed in the serum of the blood.”
In 1815, the French scientific expert Michel Chevreul (1786 - 1889) demonstrated
The adjective “mellitus” (derived from the Latin word meaning “honey”) was first
that the sugar in diabetic pee was glucose. In the 100 years, tasting the pee to make
used by the surgeon John Rollo, who had his medical training in Edinburgh and
the conclusion was supplanted by synthetic tests for diminishing specialists, for
died in 1809. His “animal diet,” which became the norm for the most of the 19th
example, glucose as presented by Trommer in 1841, Moore in 1844 and - the best
century, also brought him recognition. Rollo reasoned that an animal-based diet
known - Fehling in 1848. Estimation of blood glucose could just be finished by
was the obvious cure because sugar was created in the stomach from vegetables.
gifted physicists yet required such an excess of blood that it was seldom utilized
So, according to the treatment plan outlined in his 1797 book, An Account of Two
in either clinical consideration or exploration. It just became practicable with the
Cases of the Diabetes Mellitus, Captain Meredith could eat “Game or old meats
presentation in 1913 of a micromethod by the Norwegian - conceived doctor Ivar
which have been long kept; and as far as the stomach can bear, fat and rancid old
Christian Bang (1869 - 1918) furthermore, it was the capacity to gauge glucose
meats, as pork.”

58 59
 more than once which prompted improvement of the glucose resistance test
somewhere in the range of 1913 and 1915. The work of Claude Bernard (1813–
1878), a Frenchman whose various discoveries have earned him a special position
in the history of physiology (Figure 1.15), clarified glucose metabolism. When
Bernard started his research in 1843, the dominant view was that only plants could
synthesize sugar and that compounds generated by animals were broken down by
animal metabolism. Additionally, it was believed that the blood only carried sugar
following meals or in pathological conditions like diabetes. Bernard stated between
1846 and 1848 that normal animals, including those that were starving, had glucose
in their blood.
1 1
INTRODUCTION AND OVERVIEW
Figure 1.15: Claude Bernard (1813 – 1878)
In addition, he discovered “ enormous quantities “ of a material that resembled
starch and could easily be turned into sugar in the liver, as well as higher glucose
concentrations in the hepatic than in the portal vein. He referred to this as “gly
cogen” (i.e., sugar-forming) and saw it as similar to plant starch. According to his
notion, known as the “glycogenic theory,” the liver turned the sugar taken from
the gut into glycogen, which was then continuously released into the blood when
fasting.
Another discovery made by Bernard at a time when the nervous system’s control
60
over body activities was a popular scientific theory left a lasting impression. He
discovered that a lesion in the fourth ventricle’s floor caused transient hyperglycemia,
or piqûre diabetes. Because of the mental strain associated with engine driving,
diabetes was thought to be more common among engine drivers than other railway
workers for a considerable amount of time following this discovery. In fact, J.J.R.
Macleod cited this “evidence” as late as 1914.
The origin of diabetes was unknown during the first half of the 19th century because
autopsies typically revealed no specific abnormalities. When Oskar Minkowski
(Figure 1.16) and Josef von Mering (1849–1908) revealed that pancreatectomy in
dogs resulted in severe diabetes, it was a watershed moment in medical history. They
were looking into fat metabolism, therefore it was coincidental that the lab worker
informed Minkowski that the previously house-trained dog was now incontinent
of pee. When Minkowski noticed the polyuria, he decided to test the dog’s urine.
INTRODUCTION AND OVERVIEW
Figure 1.16: Oskar Minkowski
The pancreas may function to eliminate a toxin that causes diabetes or to create
an internal secretion that regulates carbohydrate metabolism, according to certain
theories. The well-known scientist Charles - É douard Brown - Sé quard (1817 -
1894), who claimed to have regenerated himself by injections of testicular extract,
first introduced the idea of “internal secretions” in June 1889. It gained more support
61
 in 1891 when Murray reported that sheep thyroid extract administered orally or by
injection helped treat myxoedema.

1 1

Figure 1.18: Pictures from Jaeger ’ s Atlas of the

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

Figure 1.17: Paul Langerhans (1847 – 1888)

Optic Fundus , 1869. Top left: Bright ’ s disease. Top right: Jaeger ’ s retinitis
In 1893, Gustave Laguesse proposed that the “islands” of cells dispersed throughout
the parenchyma of the gland, which had been discovered in 1869 by the 22-year- hemorrhagica is now recognized as central retinal vein occlusion. Bottom left:
old Paul Langerhans (1847–1888) (Figure 1.17), were responsible for the purported A 22 - year - old man with suspected diabetes. Bottom right: Central retinal
internal secretion of the pancreas. These cell clusters were separated from the artery occlusion.
overall pancreatic tissue by Langerhans, who described them but did not speculate
Clinical diabetes in the 19th century
on their potential purpose. Laguesse gave them the term “islets of Langerhans.”
The main function of doctors in the 19th century was that of taxonomists, describing
The internal islet secretion that lowers blood sugar levels was still a theory at this
symptom complexes and the natural history of disease because they lacked
time, but Belgian Jean de Meyer gave it the Latin name insulin (which means
therapeutic ability. Because of this, the majority of the significant consequences of
“island”) in 1909.
diabetes were well understood prior to 1900.
It would be inaccurate to imply that Minkowski’s research conclusively proved
The initial description of diabetic retinopathy is attributed to Eduard von Jaeger
that diabetes has a pancreatic origin. In reality, over the course of the following
(1818–1884), who published it in his exquisite Atlas of Diseases of the Ocular
two decades, it came to be widely accepted that diabetes was a diverse condition
Fundus in 1869. In fact, the characteristics shown in Figure 1.18, from a patient
with a number of subtypes and that at least three organs—the brain, pancreas, and
who is 22 years old, more closely resemble hypertensive retinopathy.
liver—were implicated in its pathophysiology. The “polyglandular theory” of Carl
Microaneurysms were discovered in retinal preparations in 1879 by Stephen
von Noorden (Vienna), who postulated that the thyroid, pancreas, adrenals, and
Mackenzie (1844–1909) and Sir Edward Nettleship (1845–1913), and in 1888,
parathyroids controlled carbohydrate metabolism, was inspired by Blum’s 1901
Nettleship characterized new vessels and the beaded appearance of retinal veins
discovery that injection of an adrenal extract induced glycosuria and implicated
[15]. Julius Hirschberg (1843 - 1925), who was the first to assert that diabetic
additional glands.
retinopathy was unique to diabetes, first detailed the whole picture of the condition

62 63
 in 1890.
Rollo had described neuropathic symptoms in diabetic patients towards the end of
the 18th century, and Charles Marchal de Calvi (1815–1873) came to the conclusion
that nerve damage was a unique complication of diabetes in 1864.
Frederick Pavy (1829– 1911), a doctor at Guy’s Hospital, provided a description
of neuropathic symptoms in 1885 that would be worthy of any modern textbook-
attempts over the following 30 years, even those who believed in the existence of
an internal secretion that prevented diabetes turned their focus to diet instead.
The most well-known regimen was that of Frederick Madison Allen (1876–1964),
which Joslin (Figure 1.19) hailed as the greatest development since Rollo’s period
in 1915.

“ The usual account given by these patients of their condition is that they cannot feel
properly in their legs, that their feet are numb, that their legs seem too heavy – as one
patient expressed it, “ as if he had 20 lb weights on his legs and a feeling as if his boots
were great deal too large for his feet. ” Darting or “ lightning ” pains are often complained
of. Or there may be hyperaesthesia, so that a mere pinching of the skin gives rise to great
1
pain; or it may be the patient is unable to bear the contact of the seam of the dress against 1
the skin on account of the suffering it causes. Not infrequently there is deep - seated pain

INTRODUCTION AND OVERVIEW

located, as the patient describes it, in the marrow of the bones which are tender on being
INTRODUCTION AND OVERVIEW

grasped, and I have noticed that these pains are generally worse at night. ”

Additionally, Pavy noted several uncommon occurrences, such as a 67-year-old

who reported “lightning pains on the right side of the waist” and instances where
the third nerve was impacted with “dropped lid and external squint.”
Diabetes was known to be a rather common cause of kidney disease.
Wilhelm Griesinger (1817–1868) reported 64 adult autopsies in 1859, of which half
had renal changes that he attributed to hypertension and atherosclerosis; however, it
wasn’t until the 1930s that the histologic characteristics of diabetic kidney disease
and the significance of renal complications were reported.
It was starting to become clear that there were at least two clinically distinct types
of diabetes by the end of the 19th century. Etienne Lancereaux (1829–1910), a
French physician, first recognized lean and obese individuals as having diabetes
mellitus maigre and diabetes gras in 1880. This discovery served as the basis for
further etiologic classifications of the illness.
The 20th century
After Murray successfully treated myxoedema in 1891, there was hope that
pancreatic extract would soon be used to treat diabetes. However, after several failed
Figure 1.18: Elliott P. Joslin (1869 – 1962), arguably the most famous diabetes
specialist of the 20th century and the frontispiece to his 1916 textbook
This approach was an outrageous use of one that had been proposed as soon as 1875
by Apollinaire Bouchardat (1806 - 1886), who pushed concentrated practice and “
trough le moins conceivable . “ Starvation treatment took care of business from
a restricted perspective, in that a few patients could make due for a long time or
even years, rather than half a month or months with untreated sort 1 diabetes. The
personal satisfaction, notwithstanding, was exceptionally poor, and a few patients
passed on from hunger as opposed to diabetes. In 1921, Carl von Noorden (1858 -
1944) -advocate of the “ oats fix “ - dismissed in dissatisfaction at the point when
he saw Joslin ‘ s prize patient, 17 - year - old Ruth A, who at simply over 1.52 m in
level weighed just 24.5 kg (a weight file of 10.6 kg/m 2).

64 65
 Discovery of insulin
Between 1889 and 1921, numerous attempts were undertaken to identify the
mysterious pancreatic internal secretion. Some preparations may have had modest
biologic activity, but this was not noticed, either because hypoglycemia was
mistaken for a hazardous reaction or because blood glucose was not assessed. These
mostly failed because the extracts were inert or had unacceptably bad side effects.
The three that were closest were Nicolas Paulesco (1869 - 1931) in Romania in
1920 - 1921, Ernest Scott (1877 -1966) in Chicago in 1911, and Berlin doctor
Georg Zuelzer (1840 - 1949) in 1907 (Figure 1.20).
At least superficially, the tale of how insulin was discovered in Toronto in 1921 is
well known (Figure 1.21). After reading an article by the pathologist Moses Barron
(1884–1975), a young orthopedic surgeon named Frederick Banting was inspired
to investigate whether the antidiabetic pancreatic principle was digested by trypsin
1 during extraction. He decided to prevent this loss by ligating the pancreatic duct,
leading to the degeneration of the exocrine tissue. He went to Toronto’s J.J.R.
INTRODUCTION AND OVERVIEW
Macleod, a professor of physiology and an expert on carbohydrate metabolism,
who mocked the notion and said the only possible outcome would be “a negative
result of great physiological importance.”
Eventually, Macleod gave in and placed Banting in a dilapidated lab before
departing for Scotland and a fishing vacation. Banting was assisted by Charles
Best, a student who was selected after a coin flip. Banting and Best (known as B
2 in Toronto academic circles) found the most significant new treatment since the
antisyphilitic drug Salvarsan within six months of this unimpressive beginning.
The excellent book by Michael Bliss includes a detailed account of these incidents.
They started by injecting dogs with diabetes who had undergone pancreatectomy
with extracts of atrophied pancreas (made in accordance with Macleod’s
recommendations). They later learned that beef pancreas, which Best bought from
the abbatoir, could be used to make active extracts. The extraction process (using
ice, cold acid, and ethanol) was significantly improved by James B. (Bert) Collip,
a biochemist on sabbatical leave in Toronto. On January 11, 1922, 14-year-old
Leonard Thompson, who had been on the Allen starvation regimen since 1919 and
weighed just 30 kg, underwent the first clinical trial of insulin (using a Best extract).
His blood glucose level decreased significantly after the first injection, but his
symptoms remained the same, and he also developed a sterile abscess. His blood
66
sugar was brought back to normal the next morning after receiving another extract
made by Collip on January 23. Subsequent injections over the course of the following
ten days resulted in a noticeable clinical improvement and the total eradication of
glycosuria and ketonuria. The Canadian Medical Association Journal’s March 1922
issue revealed the initial clinical findings in seven patients, drawing the startling
conclusion that:
Blood sugar can be significantly lowered, even to normal levels; Glycosuria can be
eliminated; Acetone bodies can be made to disappear from urine; the respiratory
quotient indicates that more carbohydrates are being used by the body; the general
health of these patients has definitely improved; and the patients themselves report
feeling better and having more energy for a while after the medication has been
administered.
The term “ insulin “ was begun by Macleod, who was ignorant of de Meyer’s prior
idea of insulin. Insight about its inexplicable impacts spread incredibly quickly. In 1
1922, there were just 19 references on the planet writing to “ insulin” or comparable
INTRODUCTION AND OVERVIEW
terms, for example, “pancreatic concentrate”; toward the finish of 1923, there were
320 new reports, and a further 317 were distributed during the first half year of 1924.
By October 1923, insulin was accessible generally all through North America and
Europe. Global acknowledgment followed quickly for its pioneers, and the 1923
Nobel Prize for Physiology or on the other hand Medication was granted mutually
to Banting and Macleod. Banting was irritated by the choice, and reported openly
that he would impart his award to Best, whereupon Macleod chose to do likewise
with Collip.
The Postinsulin Era
Insulin was confidently expected to treat juvenile diabetes the way thyroid extract
had treated myxoedema, but it soon became clear that insulin was a very different
kind of medication. A fixed amount of thyroid was ingested once each day. It was
necessary to inject insulin in precise doses that changed from day to day and came
with the constant risk of hypoglycemia. It is common knowledge that insulin
“revolutionized” the way diabetes was treated. While this is true in the sense that
it saved many lives that would have otherwise been lost, insulin’s unintended
consequence was to turn diabetes from an acute, rapidly fatal illness into a chronic
condition with serious long-term complications.
For instance, just 2% of Joslin’s young diabetic patients died from kidney disease
67
 before 1937, but more than 50% of those who passed away between 1944 and
1950 had extensive renal failure. The development of preventative measures for
diabetes’s chronic consequences is still a top scientific and medical priority.
Causes And Natural History Of Diabetes
Research that has helped to identify the reasons for hyperglycemia was vital
in getting started since it recognized that diabetes was not a single disease.
Lancereaux’s distinction between type 1 and type 2 diabetes and his observations
that some patients did not respond “normally” to insulin led to the broad etiologic
division into type 1 diabetes (juvenile-onset, or insulin-dependent) and type 2
diabetes (maturity-onset,or non-insulin-dependent).Harold Himsworth (1905–
1993) of London and Wilhelm Falta (1875–1950) of Vienna claimed that some
diabetics were more susceptible to the effects of insulin on reducing blood sugar
1 there has always been hope that the issue of islet cell transplantation in humans will
levels, whereas others were insulin-insensitive or insulin-resistant. While the latter
were older, heavier, and resistant to ketosis, the former were often lean and needed
temporary and eliminated within a year of the initiation of diabetes, in contrast to
other autoimmune endocrine illnesses where the autoantibody persists. The Barts-
Windsor prospective study of the epidemiology of juvenile diabetes, which Andrew
Cudworth (1939–1982) initiated, revealed an unexpected finding: ICA may be found
in siblings of young persons with diabetes up to 10 years before they got apparently
acute-onset diabetes. This prolonged lead-in time increased the likelihood that an
intervention would be necessary to stop further cell death. Cyclosporine prolongs
the honeymoon phase in persons with newly diagnosed type 1 diabetes, but after
the medication is withdrawn, there are no long-term benefits. While several other
therapies, like nicotinamide and low doses of insulin, prevent diabetes in the non-
obese diabetic (NOD) mice, they had no effect on the relatives of persons with
type 1 diabetes who had high ICA titers. Since 1967, when Paul Lacy (1924–2005)
demonstrated that islet cell transplantation might “cure” diabetes in inbred rats,
1
soon be resolved. In 2000, a group in Edmonton, Canada, revived hope. Only 10%

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

of their transplanted patients were able to survive without any administered insulin
insulin to prevent ketoacidosis.
after 5 years, even though 80% of them were producing some endogenous insulin.
The “insulin clamp” method, invented by Ralph DeFronzo et al. in the United States
in the 1970s, was the first to accurately assess the hypoglycemic action of insulin.
Chronic diabetic complications
It has since inspired innumerable investigations on insulin resistance and its link
Two publications published in the middle of the 1930s that specifically linked
to type 2 diabetes and vascular disease. DeFronzo’s and other organizations have
diabetes to renal and retinal illness cast doubt on the long-held belief that chronic
aided in elucidating the function of beta-cell failure in type 2 diabetes and how it
diabetic consequences were caused by arteriosclerosis. The Mayo Clinic’s Henry
links to insulin resistance. Robert Tattersall (b. 1943) first identified maturity-onset
Wagener (1890–1961) and Russell Wilder (1885–1959) reported patients with
diabetes of the young (MODY) as a unique, dominantly inherited subset of type
retinal hemorrhages but no other signs of vascular disease in 1934. They came to
2 diabetes in 1974. Since 1993, five specific molecular abnormalities have been
the conclusion that “the very presence of retinitis in cases in which patients have
identified in this syndrome.
no other signs of vascular disease must mean that diabetes alone does something to
For a very long time, it was unknown what caused the extreme loss of beta cells
injure the finer arterioles or venules of the retina, probably the latter.” Large hyaline
that resulted in type 1 diabetes’s severe insulin deficiency. Insulitis, a primarily
nodules in the glomeruli were found in the kidneys of eight people at autopsy, and this
lymphocytic inflammation of the islets, was first identified in 1901 by Eugene L.
histologic finding of “intercapillary glomerulosclerosis” was characterized by Paul
Opie (1873 - 1971) and colleagues. However, because it was thought to be extremely
Kimmelstiel (1900–1970) and Clifford Wilson (1906–1997 in 1936 (Figure 1.23).
rare, appearing in only six out of 189 cases examined by Anton Weichselbaum
Kimmelstiel and Wilson highlighted the similar characteristics of hypertension,
(1845 - 1920) in 1910, its significance was undervalued. It wasn’t until 1965 that
severe albuminuria with “oedema of the nephrotic type,” and renal failure in the
the Belgian Willy Gepts (1922–1991) proposed that insulitis may play a role in
eight patients, seven of whom had a known history of diabetes. According to one
the demise of -cells. Deborah Doniach (1912–2004) and GianFranco Bottazzo
author, the “Kimmelstiel - Wilson syndrome” grew to signify everything to all men
first proposed the hypothesis that type 1 diabetes is caused by an autoimmune
during the course of the following 15 years as a result of this research. But because
attack on beta cells in 1979. Islet cell antibodies (ICA) were discovered to be

68 69
 it brought awareness to a specific diabetic kidney condition, it was significant.
Knud Lundbaek of Aarhus, Denmark, who published his findings in a book from
1953 to 1954 and a paper in the Lancet in 1954, is largely responsible for the idea
that diabetic angiopathy is unique to the condition (Figure 1.24).
His main points were that both sexes were equally afflicted by long-term diabetic
vascular disease, which was essentially different from atherosclerosis, and that
microaneurysms, ocular phlebopathy, and Kimmelstiel-Wilson nodules were
specific to diabetes and frequently occurred together.
1 1
INTRODUCTION AND OVERVIEW
Figure 1.19: Nodular glomerulosclerosis
After decades of rigorous investigation, the molecular and cellular mechanisms
behind diabetic tissue damage are still up for debate. The study of J.H. Kinoshita
(b. 1922) in the early 1970s, which indicated the role of the polyol pathway in the
development of diabetic cataracts, was one of the early landmarks in this field.
Figure 1.20: Knud Lundb æ k (1912 – 1995)
70
Physiology
Using standard histologic methods, M.A. Lane, a student of Robert Bensley
(1867–1956), a professor of anatomy in Chicago, was able to identify two distinct
cell types in the islet of Langerhans that he labeled A and B. It took a long time
to identify the hormones released by each of these cell types (Table 1.2). It was
hypothesized that these cells produced insulin, and this was finally confirmed using
immuno-histochemistry by Paul Lacy in 1959. In 1938, Frank Young (1908–1988)
and colleagues reported that injections of anterior pituitary extract could induce
permanent diabetes in dogs. This was accompanied by selective degranulation and
loss of the – cells. Similar localization of glucagon to -cells was discovered in 1962
by John Baum and others.
INTRODUCTION AND OVERVIEW
Table 1.3: Advances in our understanding of the factors that cause diabetes
Frederick Sanger in Cambridge, UK, revealed insulin’s amino acid composition
in 1955, and Dorothy Hodgkin in Oxford, UK, reported the molecule’s three-
dimensional structure in 1969. Both discoveries were honored with Nobel
Prizes (Figure 1.25). The whole insulin molecule was created from amino acids
in Shanghai in 1965 by Wang Ying-lai (1908-2001) and his colleagues. Donald
Steiner, a Chicago-born scientist born in 1930, first described the insulin precursor,
proinsulin, in 1967. The first bioassay for insulin was published in 1950 by
Australian Joseph Bornstein (1918–1994), who was working in London with Robin
D. Lawrence. It was based on the hormone’s capacity to decrease blood sugar in the
alloxan–diabetic rat.
71
 Natural History of Diabetes
Research that has helped to identify the reasons for hyperglycemia was
vital in getting started since it recognized that diabetes was not a single
disease. Lancereaux’s distinction between type 1 and type 2 diabetes and
his observations that some patients did not respond “normally” to insulin
led to the broad etiologic division of diabetes into type 1 (juvenile-onset, or
insulin-dependent) and type 2 (maturity-onset, or non-insulin-dependent).
Harold Himsworth (1905–1993) of London and Wilhelm Falta (1875–1950)
of Vienna claimed that some diabetics were more susceptible to the effects
of insulin on reducing blood sugar levels, whereas others were insulin-
insensitive or insulin-resistant. While the latter were older, heavier, and
resistant to ketosis, the former were often lean and needed insulin to prevent
ketoacidosis.
1 The “insulin clamp” technique, invented by Ralph DeFronzo et al. in the United
States in the 1970s, was the first to evaluate the hypoglycemic action of insulin with
INTRODUCTION AND OVERVIEW
precision. It has since inspired innumerable investigations on insulin resistance and
its link to type 2 diabetes and vascular disease. DeFronzo’s and other organizations
have aided in elucidating the function of beta-cell failure in type 2 diabetes and how
it links to insulin resistance. Robert Tattersall (b. 1943) first identified maturity-
onset diabetes of the young (MODY) as a unique, dominantly inherited subset of
type 2 diabetes in 1974. Since 1993, five specific molecular abnormalities have
been identified in this syndrome.
For a very long time, it was unknown what caused the extreme loss of beta cells that
resulted in type 1 diabetes’s severe insulin deficiency. Eugene L. Opie (1873–1971)
and colleagues first described “insulitis,” a predominantly lymphocytic infiltrate of
the islets, in 1901. However, because it was thought to be extremely uncommon—
only six out of 189 cases were examined by Anton Weichselbaum (1845–1920) in
1910—its significance was not recognized at the time. It wasn’t until 1965 that the
Belgian Willy Gepts (1922–1991) proposed that insulitis may play a role in the
demise of -cells.
Deborah Doniach (1912–2004) and GianFranco Bottazzo (b. 1946) first proposed
the hypothesis that type 1 diabetes comes from the autoimmune death of beta cells
in 1979. Islet cell antibodies (ICA) were discovered to be temporary and eliminated
within a year of the initiation of diabetes, in contrast to other autoimmune endocrine
illnesses where the autoantibody persists. The Barts- Windsor prospective study
72
of the epidemiology of juvenile diabetes, which Andrew Cudworth (1939–1982)
initiated, revealed an unexpected finding: ICA may be found in siblings of young
persons with diabetes up to 10 years before they got apparently acute-onset diabetes.
This prolonged lead-in time increased the likelihood that an intervention would
be necessary to stop further cell death. Cyclosporine prolongs the honeymoon
phase in persons with newly diagnosed type 1 diabetes, but after the medication
is withdrawn, there are no long-term benefits. While several other therapies, like
nicotinamide and low doses of insulin, prevent diabetes in the non-obese diabetic
(NOD) mice, they had no effect on the relatives of persons with type 1 diabetes who
had high ICA titers. Since 1967, when Paul Lacy (1924–2005) demonstrated that
islet cell transplantation might “cure” diabetes in inbred rats, there has always been
hope that the issue of islet cell transplantation in humans will soon be resolved. In
2000, a group in Edmonton, Canada, revived hope. Only 10% of their transplanted
patients were able to survive without any administered insulin after 5 years, even 1
though 80% of them were producing some endogenous insulin.
INTRODUCTION AND OVERVIEW
1.2.1 The Classification and Diagnosis of Diabetes
In the 17th and 18th centuries, diabetes was better understood, with certain examples
mentioning its connection to fat. The unmistakable discovery of excessive glucose
in the urine and later in the blood occurred in the 17th century.
The 19th century saw the discovery of excess ketones. At the end of the 19th
century, a precise definition of the two primary forms of diabetes first developed,
distinguishing between the type that strikes young people with a short time course
before ketoacidosis takes over and the type that strikes older, fat individuals.
A metabolic condition with numerous etiologies is diabetes mellitus. Chronic
hyperglycemia and abnormalities in protein, lipid, and carbohydrate metabolism
brought on by deficiencies in insulin production or action, or both, characterize
it. varying forms of diabetes have varying ratios of these contributions. These are
linked to the emergence of the unique microvascular consequences of retinopathy,
including neuropathy, nephropathy, and renal failure, which can result in blindness.
The latter entails the danger of autonomic nerve dysfunction, foot ulceration, and
amputation. A higher risk of macrovascular disease is also linked to diabetes. Thirst,
polyuria, blurred eyesight, and weight loss are the typical clinical manifestations.
This may result in hyperosmolar non-ketotic coma or ketoacidosis. Often,
symptoms are minimal or nonexistent, and mild hyperglycemia can last for years
73
 without causing tissue damage—even when a person is completely asymptomatic.
Classification
Separate levels of diabetes severity have been recognized for many years;
nevertheless, the potential that there may be two separate forms of the disease
didn’t become apparent until the first decade of the 20th century.
Even so, no clear indication of unique etiologies could be found. Himsworth
proposed that there were two phenotypes in the 1930s. The first WHO Expert
Committee on Diabetes Mellitus made the first sincere attempt to categorize
diabetes, believing that age of onset was the only valid criterion and dividing the
disease into juvenile-onset and mature-onset disease.
There were numerous additional phenotypes that were popular at the time, such
as brittle, gestational, pancreatic, endocrine, insulin-resistant, and iatrogenic
1 diabetes, although the causes of most instances were not always obvious. With the
identification of islet cell antibodies and the HLA genotypes linked to juvenile-
INTRODUCTION AND OVERVIEW
onset diabetes in the 1970s, the picture started to become clearer. This made it
very evident that the autoimmune illness affecting the younger diabetic patients,
all of whom needed insulin therapy, was present. With the second WHO Expert
Committee’s evaluation and revision of the updated classification released by the
National Diabetes Data Group, the contemporary age officially began.
In addition to “other types” and gestational diabetes, this study identified two basic
groups of diabetes: insulin-dependent diabetes mellitus (IDDM; type 1) and non-
insulin-dependent diabetes (NIDDM; type 2). Additionally, there were two risk
categories: pre-diabetes or probable diabetes, which were replaced by earlier types
known as previous abnormality of glucose intolerance (PrevAGT) and potential
abnormality of glucose tolerance (PotAGT). The 1985 revision to the 1980
classification returned to clinical descriptions and removed types 1 and 2 while
keeping IDDM and NIDDM. In acknowledgment of a distinct phenotype prevalent
primarily in Asia and sub-Saharan Africa, malnutrition-related diabetes mellitus
was also recognized.
IGT, or impaired glucose tolerance, was also added as a high risk category.
Both the American Diabetes Association (ADA) and WHO reviewed the
classification in 1999 in light of new information. It was acknowledged that the
labels IDDM and NIDDM, despite being quite tempting, were frequently unclear
and useless, especially for patients with T2DM who were receiving insulin treatment.
74
In addition to being helpful therapeutically, the new classification tried to include
both the genesis and clinical stages of the disease. This was done in response to
Kuzuya and Matsuda’s recommendation. This recognizes that diabetes can have
a single etiologic process, such as an autoimmune attack on the beta cells, while
progressing through multiple clinical stages (for example, from normoglycemia to
ketoacidosis).
The WHO reviewed the classification again in 2006, but no new modifications were
made. It will be reviewed once more in 2010 when, at most, minor changes will be
made.
IGT was kept as a risk state but was officially removed from the classification
of kinds of diabetes because it is not diabetes. Another risk condition, impaired
fasting glycemia (IFG), was introduced. This was crucial in many nations where
the practice of glucose tolerance testing is uncommon outside of pregnancy. As
a result, IGT was not diagnosed and IFG, albeit not precisely identical, has been 1
utilized as an accessible risk marker.
INTRODUCTION AND OVERVIEW
Type I Diabetes
Although some insulin resistance is also present, the main cause of T1DM is - cell
apoptosis. For survival after the earliest phases, insulin is necessary. More than
90% of Europids have detectable anti-glutamine acid decarboxylase (anti-GAD),
anti-insulin, and/or anti-islet cell antibodies, indicating autoimmunity. It exhibits
a high connection with particular alleles at the HLA complex’s DQ-A and DQ-B
loci. Despite being ketosis-prone, non-obese, and typically younger than 30 years
old, not all people with the clinical features of T1DM exhibit these relationships
with autoimmunity. Up to 80% of non-Europid groups may exhibit no detectable
autoantibodies; these people are known to have idiopathic T1DM. There is an older
cohort with slower onset T1DM in addition to the normally youthful persons with
acute onset. They may first exhibit signs of apparent T2DM in middle life, but
subsequent tests for the GAD antibody show indications of autoimmunity and the
development of insulin dependence. Latent autoimmune diabetes of adults (LADA)
is the medical term for this.
Type II diabetes
T2DM is by far the most common type of diabetes worldwide. Insulin resistance
combined with a relative insulin deficiency (patients secrete some insulin, but not
75
 enough to overcome the insulin resistance) characterizes this condition.
In most cases, individuals do not need insulin to survive, but they frequently do in
the long run to keep appropriate glycemia under control.
It is unknown what specific molecular processes underlie T2DM. There have been
significant efforts to identify underlying genetic disorders, but little progress has
been made.
The most promising to date has been TCF7L2, which may have a role in insulin
production but does not account for the bulk of patients’ predisposition to diabetes.
It is evident that T2DM and obesity, inactivity, and the westernization of lifestyles
are intimately related. Over the past 20 years, the significant growth in T2DM has
closely mirrored the global increase in obesity. Physical inactivity and obesity,
especially visceral adiposity, both contribute to insulin resistance, which leads to
diabetes in people who have a limited ability to enhance insulin secretion.
However, as the incidence rises, T2DM is being detected at younger ages, and it is
1 1
now not uncommon in adolescents in many ethnic groups. The incidence of T2DM
1.3.1 Type 1 Diabetes
Since roughly 50 years ago, it has been able to distinguish between the two main
types of diabetes mellitus, type 1 (formerly known as insulin dependent or juvenile
onset) and type 2 (non-insulin dependent or adult onset). Insulitis was uncovered in
1965, confirming the idea that type 1 diabetes mellitus’s (T1DM’s) etiopathology
was caused by autoimmune islet inflammation, a condition not present in type 2
diabetes mellitus (T2DM). However, it was also found that approximately 10% of
adult patients diagnosed with T2DM tested positive for ICA, a group of patients
now referred to as having latent autoimmune diabetes of adults (LADA). There are
some genetic and immunological parallels between children T1DM and LADA,
but there are also some genetic and autoimmune differences between these two
conditions. T1DM is characterized by a nearly total loss of insulin caused by
the selective autoimmune destruction of pancreatic islet cells, which clinically
manifests as symptoms and signs associated with hyperglycemia. More than

INTRODUCTION AND OVERVIEW

90% of T1DM (also called as T1ADM) in non-Hispanic Caucasian populations
INTRODUCTION AND OVERVIEW

also increases with age, which may be associated with a loss in exercise and muscle
mass. is immune-mediated, with HLA association confirmed and one or more islet cell
T2DM runs in families, thus people who have a first-degree relative with the autoantibodies detected at the time of diagnosis.
disease are roughly 50% more likely to have it themselves. Additionally, there
is a noticeable difference between various ethnic groups. Therefore, people of
Polynesian, Micronesian, South Asian, sub-Saharan African, Arabian, and Native
American ancestry are far more likely than Europids to get diabetes.
T2DM is diagnosed by exclusion, and while the prevalence may decrease when
causes are discovered, this is probably going to take some time.

1.3 Diabetes Pathogenesis

A complicated metabolic ailment called diabetes mellitus (DM), commonly
referred to as diabetes, is defined by hyperglycemia, a physiologically abnormal
state represented by persistently increased blood glucose levels. The persistent
and varied symptoms of hyperglycemia include abnormalities in the metabolism
of carbohydrates, fats, and proteins. Hyperglycemia is caused by abnormalities in
Figure 1.21: The natural history of type 1 diabetes (T1DM) is presented
either insulin secretion or insulin action, or both. Diabetes has a complex etiology
and progresses in a gradual manner. schematically, with potential etiopathogenic variables and disease markers
shown

76 77
 T1DM results from a practically complete loss of insulin brought about by
particular immune system annihilation of the pancreatic islets β - cells, which
shows clinically as hyperglycemia - related side effects and signs. Among non -
Hispanic Caucasian populaces, over 90% of T1DM is safe - interceded (likewise
known as T1ADM), in which HLA affiliation is reported and one or then again more
islet cell autoantibodies are distinguishable at season of determination. The leftover
10%, frequently named “ idiopathic “, is profoundly inheritable yet has neither HLA
affiliations nor discernible islet cell autoantibodies.

Note: The loss of islet β-cell secretory function in type 1 diabetes (T1DM) is caused by
strong autoimmune responses that involve both cellular and humoral immune pathways.
This autoimmune response kills these cells specifically.
1
Pancreatic islets become severely infiltrated with inflammatory cells, resulting in insulitis, 1
where CD8 + T lymphocytes are assumed to be in charge of specifically and selectively
destroying β-cells.

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

Figure 1.22: Diagrammatic illustration illustrating how the Diabetes

The last subgroup is found among non-Caucasian ethnic gatherings like Asians,
African - Americans what’s more, Hispanic - Americans and is believed to be
connected with viral contaminations. Clinically, the two structures have comparative
clinical signs and diabetic ketoacidosis might create in both. The pathophysiologic
mechanisms in T1DM include two distinct stages in those who are genetically
susceptible:
● Triggering of autoimmunity leading to one or multiple islet cell autoantibodies
associated with gradual cell death; and
● Loss of - cell secretory function manifested by the loss of first - phase insulin
release (FPIR), reduced C peptide levels, followed by glucose intolerance and
finally hyperglycemia
The autoimmune process that results in mononuclear infiltrates of immune cells,
including autoreactive CD8+ T lymphocytes, specifically eliminates the β- cells.
Both humoral and cellular immune pathways are implicated in the development of
disease; however, the function of B lymphocytes is not shown in humans but is seen
in laboratory animals like non-obese diabetic (NOD) mice.
Prevention Trial Type 1 (DTP-1)’s various islet autoantibodies affect the
chance of developing type 1 diabetes (T1DM)
Islet autoantibodies, however, could exist prior to insulitis and hence might not be
a direct result of insulitis but rather indicators of subsequent islet autoimmunity.
In genetically sensitive people, the development of islet autoimmunity and the
emergence of autoantibodies against particular islet cell autoantigens may occur
months to years before the onset of the clinical illness (Figure 1.22). The frequency
of islet autoantibodies may have an impact on how gradually - cells are destroyed
during this autoimmune period. Although there may be varying degrees of cellular
regeneration and insulin sensitivity, it is hypothesized that clinical manifestations
become obvious after loss of more than 80% of viable β-cell mass.
Numerous longitudinal studies with the goal of identifying risk factors for the
condition and carrying out both preventative and intervention trials will be necessary
to advance our understanding of the natural history of T1DM.

78 79

Figure 1.23: The relationship between insulin sensitivity and beta-cell secretory
ability
1 1
T1DM has a complex etiology that can be broken down into genetic, environmental,
INTRODUCTION AND OVERVIEW
and potential gene-environment interactions. Genetic predisposition increases the
likelihood of inducing islet autoimmune reactions. The failure of -cell secretion in
response to exogenous environmental conditions like obesity may also be sped up
by genetic factors.
Genetics
According to the length of the follow-up period, the concordance rate of T1DM
in monozygotic twins ranges from 30 to 50% to 70%, while it is only 10 to 19%
in dizygotic twins. The intricacy of the etiologic reasons for T1DM, which entail
the interaction of numerous genetic and environmental variables, is highlighted by
this variability. Although more than 85% of T1DM cases include people who have
no prior first-degree family history, the risk is around 15 times higher among first-
degree relatives than it is in the overall population. In comparison to 2–4% risk if
the mother is affected, and up to 30% risk if both parents are affected, an affected
father transfers a 6–9% risk of T1DM to his offspring.
Despite the fact that the mode of inheritance is still unknown, substantial
research has been done on the genetics of T1DM. The substantial connec-
tions between T1DM and HLA have been confirmed by recent genome-wide
association studies, although it is also believed that at least 47 other genetic
80
variables, besides HLA, are involved. Table 1.5 provides a list of the most
important genetic influences.
INTRODUCTION AND OVERVIEW
Table 1.4: The most significant genetic components linked to type 1 diabetic
mellitus (T1DM) risk
The key loci responsible for the genetic predisposition to T1DM and many other
autoimmune illnesses are located in the major histocompatibility complex (MHC)
of the short arm of chromosome 6. Nearly 50% of the familial risk of T1DM
is attributed to the HLA genes. Linkage disequilibrium is a condition in which
specific alleles of the HLA region, such as the HLA class II DR and DQ alleles, are
mostly present in specific connection with one another. Therefore, the haplotype
or genotype of the individual is frequently used to define the HLA association of
T1DM (Table 1.5).
The heterozygosity of the two high-risk HLA class II haplotypes, DR3 - DQ2
(DRB1 * 03 - DQA1 * 0501 - B1 * 0201) and DR4 - DQ8 (DRB1 * 04 - DQA1
* 0301 - B1 * 0302), is the genotype that confers the highest risk of T1DM
(Table 1.5). More than 95% of T1DM patients under 30 years old who had one
or both of these haplotypes were identified, as well as 40% to 50% of the general
population. The simultaneous inheritance of high-risk genes and haplotypes seems
to significantly raise the risk of T1DM through the synergistic interaction of their
individual risks. For instance, DQ8 (DQA1 * 0301 - B1 * 0302) is usually inherited
with specific DRB1 * 04 variations, specifically DRB1 * 0401, DRB1 * 0404, and
DRB1 * 0402 but not DRB1 * 0403 which has a negative correlation in patients
81
 with T1DM (Table 1.5). However, the majority of DQ2 (DQA1 * 0501 - B1 *
0201) is inherited with DRB1 * 03. While some alleles carry a higher risk—for
example, DQB1 * 0302, DRB1 * 03, and DRB1 * 0401—others carry a protective
effect that may “neutralize” high-risk alleles when they are inherited together. DQ6
(DQA1 * 0102 - B1 * 0602 and DQA1 * 0102 - B1 * 0603), as well as DQA1 *
0101 - B1 * 0503 and DQA1 * 0202 - B1 * 0303 are the most prevalent protective
haplotypes. Additionally, other HLA class II (such DPB1) and class I alleles have
also been linked to a higher risk of developing T1DM, and researchers are still
looking for additional connections. Several other non-HLA genes have been linked
to an elevated risk of T1DM using a candidate gene method, but their impact is
less than that of the relationships with HLA haplotypes. The three most significant
genes are PTPN22 (LYP) on chromosome 1, IL2RA (CD25) on chromosome 10,
and INS-VNTR on chromosome 11 (Table 1.5).
1 they were all HLA-susceptible, showing that the presence of islet autoantibodies
INTRODUCTION AND OVERVIEW
Table 1.5: The primary alleged environmental risk factors for type 1 diabetic
mellitus
82
Pathogenesis
Environmental factors are thought to be implicated in the initiation, promotion, or
both of autoimmunity. Autoimmune T1DM develops from lack of immunologic
tolerance to -cells. The specific targeting of -cells by autoimmune reactions,
which involve infiltrating pancreatic islets by CD4 + and CD8 + T lymphocytes
and macrophages to cause insulitis, implies the selective death of β-cells. Before
hyperglycemia manifests itself clinically, autoantibodies directed against specific
islet autoantigens, including insulin, glutamic acid decarboxylase (GAD65), islet
antigen-2 (IA-2) and zinc transporter (ZnT8), may be seen for months to years.
It has been assumed that insulitis was related to the prevalence and abundance of
islet autoantibodies such GAD65Ab and IA-2Ab. However, a recent study found
that 62 (4%) out of 1507 pancreas donors between the ages of 25 and 60 had
islet autoantibodies. Only two of the 62 people had insulitis, despite the fact that
1
is not always a sign of insulitis. Because of this, it is unclear what exactly these
INTRODUCTION AND OVERVIEW
autoantibodies do, and it must be determined to what extent they serve as indicators
of cellular autoimmunity-induced cell death.
The presence of high-risk HLA haplotypes, particularly DR3-DQ2, DR4-DQ8,
or both, appears to be connected to the intensity and length of -cell destruction,
which varies and may be related to both. Antigen-presenting cells (APC) including
dendritic cells and macrophages, as well as activated B and T lymphocytes and even
active endothelium cells, express molecules from the HLA class II family on their
surface. APC’s high-risk HLA molecules are believed to make it easier for CD4
+ T lymphocytes to activate CD8 + T lymphocytes. This activation is indirectly
demonstrated in T1DM siblings who had the condition by the age of 12 years, as
compared to just 5% of siblings who shared zero or one haplotype. T1DM occurred
in 55% of siblings sharing the high-risk HLA DR3 - DQ2/DR4 - DQ8 genotype.
Based on autopsy investigations, it has been frequently asserted that between
80 and 90% of cells are already destroyed at the outset of a clinical condition.
However, a recent reanalysis of patients who passed away shortly after diagnosis
showed that the amount of beta-cell loss necessary for hyperglycemia varied with
age, being roughly 40% in people as young as 20 years old. Furthermore, there are
theories that the approximately 50% of live - cells found at diagnosis may have
resulted from β-cell regeneration. Depending on the age at diagnosis, the gradual
destruction of β-cells is expected to vary in intensity and duration. However, the
83
 lack of direct and accurate measurements of β-cell loss before and after diagnosis
in humans is a significant limitation. Laboratory animals like NOD mice and bio-
breeding rats have provided the majority of the present knowledge about β-cell
function prior to the clinical start. By monitoring insulin output during intravenous
glucose tolerance tests (IVGTT), it is possible to determine the loss of beta cells in
humans. Particularly, it is believed that FPIR assessed by insulin or C peptide can
reflect loss of beta-cells and predict T1DM. According to data from the Diabetes
Prevention Trial Type 1, post-challenge C peptide levels were noticeably lower six
months prior to the onset of clinical symptoms.
Cellular Autoimmunity
A disrupted antigen presentation system may be the explanation for the genetic
predisposition of T1DM leading to immunologic tolerance loss and ultimately
1 T1DM. These cells play a crucial role in the maturation of peripheral tolerance by
autoimmune destruction of -cells.
The HLA class II molecules, which are heterodimers and expressed on the surface
INTRODUCTION AND OVERVIEW
of APC like macrophages, control the immune response. The heterodimer binds
peptides produced intracellularly from either self- or foreign antigens that have been
phagocytosed. The resulting trimolecular complex serves as the T-cell receptor’s
(TCR) ligand. The T lymphocyte is activated by the trimolecular complex’s
interaction with the TCR. The T lymphocyte is activated by the trimolecular
complex’s interaction with the TCR. T-helper lymphocytes (CD4+) are presented
with antigen by the HLA class II molecules on APC.
Macrophages from T1DM patients with the high-risk HLA DQB1 * 0201/ * 0302
genotype secreted large amounts of proinflammatory cytokines and prostaglandin
E2 in response to non-antigenic stimulation. Cytokines can harm cells directly or
indirectly by stimulating T and B lymphocytes and other cells. As a result, the APC
presenting -cell autoantigens may play a significant role in the anti-self autoimmune
response that may develop as a result of a failure to maintain self-recognition or as
a result of encouraging an anti-self response. In pancreatic autopsies of participants
who passed away soon after onset, APC, CD4 +, and CD8 + T cells were all found,
demonstrating their function in insulitis. The autoimmune destruction of -cells may
be most significantly influenced by autoreactive CD8 + T lymphocytes. The activity
and number of natural killer cells (NK) may also be aberrant. In addition to the idea
that immunosuppressive medications like cyclosporine or anti-CD3 monoclonal
antibodies can temporarily halt disease progression, the detection of autoreactive
84
T lymphocytes in insulitis and in the circulation at the time of diagnosis are all
considered to support the role of cellular immunity in - cell destruction. It is not
yet entirely understood how cells are destroyed. One potential explanation is that
virus or another environmental element first kills the cells. Following phagocytosis
by neighborhood dendritic cells (APC), the dying or dead - cell is subsequently
transported to a pancreatic-draining lymph node by lymphatic migration. In the
lymph node, CD4 + T cells are activated and presented with antigens, including
CD8 + T lymphocytes that are specifically activated for islet autoantigens.
These CD8+ T lymphocytes specific for the islet autoantigen circulate again and
finally land in the islets to kill off cells. A new cycle of islet autoantigen presentation
known as epitope spreading will result from the death of -cells. Since they may block
CD4 + T cells that are specific to the islet autoantigen, CD4 + CD25 + regulatory
T lymphocytes are also believed to play a significant role in the pathogenesis of
1
expressing FOXp3 from the X chromosome.
INTRODUCTION AND OVERVIEW
It has been difficult to identify T lymphocytes that are specific to islet autoantigens
(insulin, GAD65, and IA-2) and it is currently difficult to create standardized tests
for these T cells. It has been difficult to identify T lymphocytes that are specific
to islet autoantigens (insulin, GAD65, and IA-2) and it is currently difficult to
create standardized tests for these T cells. Tests to determine anti-islet autoantigen
T-lymphocyte reactivity include soluble HLA class II tetramer assays to evaluate
autoantigen-specific T lymphocytes and ELISPOT (enzyme-linked immunospot)
assays to detect cytokines of each T lymphocyte. These autoantigen-specific T
cells may amass in islets during islet autoimmunity before the onset of clinical
symptoms, making them difficult to find in peripheral circulation.
Humoral Autoimmunity
Indirect immunofluorescence and frozen pancreatic slices were used to identify
ICA in 1974. Islet surface antibodies (ICSA) were discovered four years after that,
and complement-dependent antibody-mediated islet cell cytotoxicity was first
documented in 1980. Assays specific to individual autoantigens were eventually
designed to identify autoantibodies against GAD65, IA - 2, insulin, and most
recently ZnT8 because ICA assays revealed significant variability among ICA-
positive sera (Table 1.7). It has been found that islet autoimmunity—single or
multiple autoantibodies lasting for 3–6 months—helps distinguish T1DM from
85
 other types of diabetes. Within 6 to 12 months of the first islet autoantibody’s
emergence, several islet autoantibodies (2) typically manifest (Figure 1.25).
Despite this, some people experience temporary islet autoantibodies, which are
typically solitary and linked to a decreased risk, maybe as a result of the existence
of protective genes such HLA DR15-DQ6. In more than 95% of newly diagnosed
patients with T1DM, even as early as in the perinatal period, one or more of these
autoantibodies can be found months to years before clinical manifestation.
1 component of the autoantigen, whereas T1DM’s immunoreactivity is focused on
INTRODUCTION AND OVERVIEW
Table 1.6: Islet autoantigens and autoantibodies’ characteristics
Glutamic Acid Decarboxylase Auto-Antibodies
An important inhibitory neurotransmitter known as GABA is produced by the
enzyme glutamic acid decarboxylase (GAD), which is found in neurons and islet
cells. It was discovered that the 64K protein, which had been identified as GAD
after immunoprecipitation of human islet, actually represented GAD65 and not
the previously recognized GAD67 variant, which shared 65% of the amino acid
sequence with GAD65. GAD65, which is mostly expressed in pancreatic islets
and is encoded by a gene on chromosome 10p11, is expressed differently from
GAD67. The GAD65 isoform (GAD65Ab), which was discovered in 70–80% of
children with new onset T1DM, 8% of T1DM first-degree relatives, as well as in
roughly 1% of the general population, is where autoantibodies against GAD are
most frequently found. In contrast to ICA, GAD65Ab continues to be detectable
even after significant loss of β-cell function for many years. Additionally, in T1DM
with fresh onset, the rate of GAD65Ab detection increases with age. Some gender
differences with a predilection for women are seen if the onset occurred before the
86
age of ten. GAD65Ab levels are currently regarded as effective markers for both
prediction and follow-up of - cell dysfunction among individuals at risk because
they are persistent, more common, and have an excellent correlation with plasma
levels of C peptide.
Islet antigen - 2 auto antibodies IA - 2Ab and IA - 2 βAb
The plasma membrane protein tyrosine phosphatase family includes this
autoantigen. IA-2, formerly known as ICA512, is a 40K protein that is encoded
on chromosome 2, while IA-2, also known as phogrin, is a 37K protein that is
encoded on chromosome 7 (Table 1.7). The two isoforms are present in a variety
of neuroendocrine organs, including pancreatic islets, but their functions are
unclear because they lack enzymatic activity. They also have a great number of
similar epitopes. IA-2Ab’s autoantibody reactivity is focused on the cytoplasmic
1
the IA-2 C-terminal region.
INTRODUCTION AND OVERVIEW
IA-2Ab is found in fewer than 1% of the general population and between 60 and
70 percent of patients with newly diagnosed T1DM. IAA, GAD65Ab, and ICA
are frequently preceded by IA - 2Ab, respectively, and the frequency declines
with increasing age of onset. This suggests that younger children benefit more
from the prediction and screening capabilities of IA-2Ab, especially when paired
with GAD65Ab and other markers. It was discovered that autoantibodies to the
juxtamembrane region of IA - 2 (IA - 2 - JM - Ab) were more frequently associated
with progression to T1DM, whereas IgE - IA - 2Ab provided protection even when
IA - 2 - JM - Ab were positive. This information was obtained using radiobinding
assays among healthy siblings of children with T1DM. In contrast to DQ8, higher
frequencies of IA - 2Ab were discovered in conjunction with DRB1 * 0401.
Additionally, patients with DQ2 showed a lower relationship with IA - 2Ab, pointing
to the possibility of additional processes connected to the genetic component of the
HLA. Radiobinding tests that can precipitate IA - 2Ab, IA - 2 Ab, and GAD65Ab
were used to develop and standardize assays to identify IA - 2Ab. These assays were
enhanced in successive DASP workshops and exhibit high levels of sensitivity and
specificity. Similar to this, biotin-labeled preparations were used in ELISA tests
combining IA-2 Ab and GAD65 Ab, and the most recent review of these assays
revealed improvement in their performance.
87
 Insulin autoantibodies
Because they are only expressed in beta cells, proinsulin and insulin are the most
highly specific autoantigens of beta cells. Before starting treatment with exogenous
insulin in 1983, insulin autoantibodies (IAA) were initially discovered in 50% of
individuals with newly diagnosed diabetes using radioligand-binding assays. The
earliest indicator of islet autoimmunity tends to be IAA, which can react with both
proinsulin and insulin. However, their levels are frequently erratic and present
in low titers. Age appears to be a factor in the predictive value for T1DM with
IAA alone; it is higher in younger children, probably due to a higher rate of -cell
breakdown. Compared to just 40–50% of teenagers older than 15 years, IAA were
found in 90% of children who develop T1DM before the age of 5 years (Table 1.6).
The linkage disequilibrium with the high-risk DQ8 haplotype may be responsible
for DR4’s association with a greater frequency of IAA. IAA were also linked to
1 the insulin gene on chromosome 11p15, where it was discovered that the quantity
of tandem repeats (VNTR) was linked to T1DM whether or not IAA were present.
INTRODUCTION AND OVERVIEW
Exogenous insulin antibodies did not correlate with IAA levels found at clinical
T1DM onset and do not appear to be influenced by autoimmunity, but they do share
some binding characteristics. Antibodies against exogenous insulin, in contrast to
IAA, exhibit higher specificity; as a result, they can be found using the ELISA test,
which does not indicate T1DM. The IAA fluid-phase radioimmunoassay, which has
been modified to use less serum volume (25 L rather than 600 L) in a novel assay
called as “micro-IAA,” exhibits great sensitivity and specificity to detect T1DM
(Table 1.6). But the issue of poor inter-laboratory concordance continues to prevent
IAA from becoming standardized.
ZnT8 Transporter (SLC30A8) Autoantibodies ZnT8Ab
In addition to insulin, the zinc transporter (ZnT8 isoform - 8 transporter) has recently
been identified as a second new cell-specific autoantigen. Additionally connected
to the risk of T2DM is a polymorphism in the SLC30A8 gene, which codes for this
autoantigen. Zinc-insulin crystallization and insulin secretion depend on ZnT8. It
helps cytoplasmic zinc move into and accumulate in secretory vesicles of - cells.
Insulin molecules co-crystallize with two Zn2+ ions inside these vesicles to create
solid hexamers. ZnT8Ab was found in about 26% of individuals with new-onset
T1DM who tested negative for the common islet autoantibodies (GAD65Ab, IA
- 2Ab, and IAA), and almost 60-80% of these patients respond favorably to this
88
antibody. Only 2% of controls and less than 3% of T2DM had ZnT8Ab, in contrast.
In 30% of patients with additional autoimmune illnesses connected to T1DM,
ZnT8Ab were also found. ZnT8’s strong cell specificity is thought to provide it an
edge over other non-specific cell autoantigens like GAD65 and IA-2 as a target of
humoral immunity in T1DM. The ZnT8 is encoded by the polymorphic SLC30A8
gene, which is found on chromosome 8. This locus and other chromosome 8
loci have been linked to the risk of ZnT8Ab but not necessarily T1DM risk. The
C-terminus of the autoantigen was discovered to be the site of ZnT8Ab’s reaction,
and variations at amino acid position 325, which can either be arginine (ZnT8 - R)
or tryptophan (ZnT8 - W), dictate two key susceptibility markers of ZnT8Ab. In the
DASP workshop, immunoprecipitation assays for ZnT8Ab were created, and fluid
phase radioassays for the C-terminus of ZnT8Ab were standardized and validated.
1.3.2 Insulin Secretion Irregularities And -Cell Defects In Type 2 Diabetes 1
Phenotypically, genotypically, and pathogenetically, type 2 diabetes (T2DM) is a
INTRODUCTION AND OVERVIEW
diverse condition. Up to 5% of patients have one of the autosomally dominant
inherited forms of maturity-onset diabetes of youth (MODY); another 1% may
have uncommon genetic mutations affecting insulin receptors and components of
the insulin signaling pathway. About 10% of patients have a late-onset form of
autoimmune diabetes, which may be a hybrid of type 1 and type 2 diabetes.
Insulin Resistance Vs. Impaired β-Cell Function
A combination of inherited and acquired variables that negatively impact cell
activity and tissue insulin sensitivity cause the most frequent kind of T2DM. For
many years, it was debatable whether tissue insulin resistance or decreased beta-
cell function was the pathogenetic factor at play. It was previously believed that
insulin resistance was the key genetic cause causing β-cell dysfunction, and that
β-cell dysfunction was a late event brought on by exhaustion following years
of compensatory hypersecretion. The pendulum has tipped toward the idea that
impaired cell function is the main underlying defect over the course of the past
few years due to the mounting evidence from complex studies examining β-cell
function and tissue insulin sensitivity, both cross-sectionally and longitudinally.
89

Note: Metabolic markers including aberrant insulin release and insulin resistance
may be the greatest indications of T1DM in genetically predisposed patients with islet
autoantibodies, particularly close to clinical start.
Several clinical studies have been started with the goal of blocking autoimmune responses,
delaying the course of the illness, or retaining residual beta-cell function following clinical
onset.
The classic studies of Himsworth & Kerr, conducted more than 60 years ago,
showed that lean patients with early-onset diabetes were sensitive to exogenous
insulin injection, whereas obese patients with late-onset diabetes were resistant.
These studies established that insulin resistance may be the primary defect. Twenty-
one years later, when plasma insulin levels were first measured in T2DM patients
1 in the fasting and postprandial states, it was discovered that they had higher than
normal values, further supporting insulin resistance.
INTRODUCTION AND OVERVIEW
Numerous investigations over the next 40 years found that people with T2DM,
those with poor glucose tolerance, and first-degree relatives of those with T2DM
who later got the condition were hyperinsulinemic and insulin resistant. The issue
with how these studies’ findings were interpreted is that they neglected to take the
following factors into account:
● The significance of insulin secretion dynamics.
● The plasma insulin level’s compatibility with the predominant stimulus for
insulin secretion (i.e., plasma glucose level).
● The connection between insulin resistance and beta-cell activity.
The Significance Of The Dynamics Of Insulin Synthesis
Although Yalow & Berson first reported this finding in 1960, it wasn’t widely
recognized until 1967 that, in T2DM patients undergoing oral glucose tolerance
tests, elevated 2-hour post-challenge plasma insulin levels were accompanied by
diminished early (30 minute) insulin responses. Even in people with mild IGT,
these reductions in early insulin release are visible (Figure 1.24). It has been
demonstrated that this decrease in early insulin response lessens the inhibition
of endogenous glucose synthesis following glucose administration. The resulting
hyperglycemia then stimulates the beta cell more strongly, which accounts for the
90
late (2 hour) hyperinsulinemia.
1
INTRODUCTION AND OVERVIEW
Figure 1.24: Relationship between plasma insulin levels at the beginning (30
minutes) and end (2 hours) of oral glucose tolerance tests (n = 294, mean SEM)
The latter had frequently been wrongly explained as the outcome of insulin
resistance. However, studies in healthy volunteers in which somatostatin infusions
reduced early insulin responses to mimic the scenario in individuals with IGT
and T2DM resulted in late hyperinsulinemia. Furthermore, late hyperinsulinemia
is decreased by restoring early insulin responses with either insulin or an insulin
secretagogue.
Adaptability Of The Plasma Insulin Level To The Current Glucose
Level
Plasma glucose levels play a key role in acutely controlling insulin. Increases in
circulating amino acids, free fatty acids (FFA), and gastrointestinal hormones
(incretins: glucagon-like peptide [GLP-1], glucose-dependent insulinotropic
peptide [GIP]) in addition to glucose increase insulin secretion, whereas increases in
other factors, such as catecholamines, cortisol, growth hormone, leptin, and tumor
necrosis factor (TNF-ɑ), can decrease beta-cell responses. Since glucose serves as
the main trigger for insulin secretion, the level of plasma glucose must be taken into
account when determining whether the level of plasma insulin is appropriate. For
instance, the plasma insulin level in a person with diabetes may be twice as high
91
 as that of a person without diabetes at a plasma glucose concentration of 90 mg/
dL (5 mmol/L), but this is obviously inappropriate since the non-diabetic person
would have a plasma insulin level four times higher at the same hyperglycemia.
With information from oral glucose tolerance tests (OGTT), such evaluation is
challenging.

1 1

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

Figure 1.26: From normal glucose tolerance (NGT) to impaired glucose

Figure 1.25: Relationship between insulin sensitivity (measured by the
rate of glucose infusion required to maintain euglycemia [M] during a
hyperinsulinemic clamp) and beta-cell activity (shown by the acute insulin
response to intravenous arginine). People who kept up their normal glucose
tolerance (NGT) remained on the curve. People who slipped below the line,
exhibiting insufficient beta-cell compensation for insulin resistance, were those
whose glucose tolerance deteriorated to impaired glucose tolerance (IGT) and
type 2 diabetes (DM)
tolerance (IGT), with or without impaired fasting glucose (IFG), and finally
type 2 diabetes mellitus (DM), are the phases of glucose tolerance and
associated cell activity and insulin sensitivity
The β-cell adapts to maintain normal glucose homeostasis as a result of obesity and
other acquired conditions that produce insulin resistance. This adaptation raises
the β-cell sensitivity to glucose, which was first shown in the case of obesity in
1974. Bergman et al. first discovered the hyperbolic relationship between beta-cell
function and tissue insulin sensitivity in 1981, and it has since been confirmed
in a large number of other studies. As tissue insulin sensitivity declines, beta-cell
function rises to maintain normal glucose homeostasis. As a result, to determine
if beta-cell function is appropriate, it is also necessary to examine the individual’s
insulin sensitivity status in addition to the current stimulus for insulin production.

92 93
 Role Of β-Cell Defects In The Natural History Of Type 2 Diabetes
Most people who are predisposed to developing T2DM go through five stages,
according to longitudinal and cross-sectional research (Figure 1.28). The first
stage starts at birth, when glucose homeostasis is normal but people are at risk
for T2DM due to genetic polymorphisms (diabetogenic genes) or an environment
that predisposes them to obesity and limits their pancreatic beta cells’ capacity to
compensate for insulin resistance. Even in the absence of obvious insulin resistance,
decreased beta-cell function can be seen in genetically predisposed individuals with
normal glucose tolerance.
In stage 2, alterations in insulin sensitivity typically come from unhealthy lifestyles
(environmental) and are initially offset by an increase in -cell secretion, maintaining
normal glucose tolerance. Even when an individual’s plasma glucose levels are
within the normal range, a loss in -cell function can be seen despite this rise in
1 insulin secretion. When challenged, such as during a glucose tolerance test or a
standardized meal, postprandial glucose tolerance further deteriorates during stage
INTRODUCTION AND OVERVIEW
3, to the point where it becomes abnormal. Although cell function is obviously
aberrant at this time, it is still enough to keep fasting plasma glucose levels within
the normal range. Stage 4 is marked by further decline in -cell function that is caused,
at least in part, by glucose toxicity brought on by postprandial hyperglycemia.
Additionally, this may lessen insulin sensitivity. This stage is characterized by an
increase in basal endogenous glucose production and an increase in fasting plasma
glucose concentrations. Finally, postprandial and fasting glucose levels approach
levels indicative of diabetes in stage 5, as a result of further decline in β-cell activity.
With age, insulin secretion often declines. For adults with normal glucose tolerance,
the rate of reduction for basal and glucose-stimulated insulin secretion has been
demonstrated to be between 0.7 and 1% year. The rate of decrease is around two
times higher in those with IGT and reaches about 6% annually in those with T2DM.
Insulin sensitivity does not decline naturally with age, and any documented
reductions in insulin sensitivity are almost certainly due to other causes, such as
alterations in body composition and physical fitness.
Type 2 Diabetes, Igt, And Genetically Predisposed People With Normal
Glucose Tolerance: Insulin Secretion
The insulin secretory granule in beta cells converts proinsulin, the insulin
precursor, into insulin and C peptide. Prohormone convertases 2 and 3, as well as
94
carboxypeptidase H, must act in sequence during the conversion process in order to
produce the four proinsulin conversion intermediates (des-31,32-split, des-65,66-
split, and des-64,65-split proinsulins) that lead to insulin and C peptide.
Along with insulin and C peptide, a small amount of intact proinsulin and its
conversion intermediates, primarily the des - 31,32 - split proinsulin, are typically
released into the circulation. They are thought to make up 10 to 20 percent of the
total immunoreactive insulin detected in the blood during the basal state.
Complex processes result in the release of insulin from beta cells. Insulin release
is biphasic in response to an acute square wave of hyperglycemia, such as that
used in human hyperglycemic clamp tests or in studies of perfused rat pancreas
(Figure 1.27). It is characterized by a first phase release of insulin that is acute and
lasts for about 10 minutes, followed by a second phase release of insulin that is
slower to increase but more sustained and usually lasts as long as glucose is raised.
First-phase release has been linked to insulin-secretory granules that are near to the 1
plasma membrane of the cell. It is characterized by a first phase release of insulin
INTRODUCTION AND OVERVIEW
that is acute and lasts for about 10 minutes, followed by a second phase release
of insulin that is slower to increase but more sustained and usually lasts as long
as glucose is raised. The immediate releasable pool of insulin-secretory granules,
which are adjacent to the plasma membrane of the cell, has been linked to the first-
phase release.
In light of an expansion in extracellular glucose, islet ATP and cyclic adenosine
monophosphate (cAMP) levels increment, causing conclusion of ATP - touchy
potassium channels; this causes depolarization of the β-cell film and an influx of
calcium through voltage - delicate calcium channels; the resultant expansion in
intracellular calcium prompts development of insulin - containing granules toward
the β-cell film, where they combine/consolidate/soften into the layer with arrival
of the granules ‘ contents. The second-stage insulin discharge includes union of
new insulin particles along with ATP-subordinate preparation of granules from a
capacity pool into the quickly-releasable. Hence, the ordinary β-cell reaction to
an expansion in glucose focus is reliant upon glucose section in the β-cell and
its digestion, blend of insulin and insulin granules, cytochemical structures
(microfilaments/microtubules) and different proteins important for pushing
granules toward the β-cell layer and working with their dissolving into the film so
their items can be delivered.
95

1 1
INTRODUCTION AND OVERVIEW
Figure 1.27: Biphasic plasma insulin responses in healthy volunteers with
and without a first-degree relative with type 2 diabetes during a square wave
hyperglycemic clamp
The pattern of insulin secretion throughout the day is more complex than that observed
in hyperglycemic clamp trials during the acute square wave of hyperglycemia.
Insulin secretion was discovered to be pulsatile in vivo, oscillating for both
short (rapid) and lengthy (ultradian) periods of time. There is evidence that these
responses’ integrity is required for the maintenance of typical glucose homeostasis,
despite the fact that the basis for these is still poorly understood. Serial secretory
insulin bursts are represented by the quick oscillations in Figure 1.29. The majority
of the insulin secreted by people is produced during these high frequency bursts,
which happen every 5 to 15 minutes. Additionally, an increase in the amplitude of
these secretory pulses can be used to explain why insulin secretion is increased
96
after stimulation with GLP-1, sulfonylureas, or oral glucose. Somatostatin or the
insulin-like growth factor 1 (IGF-1) on the other hand, limit insulin secretion by
reducing the amplitude of these pulses. These quick oscillations are superimposed
on slower and larger ultradian oscillations, which happen every 80 to 150 minutes
(Figure 1.29) and are larger and slower. The ultradian oscillations are noticeable
after meals and are present at baseline settings. They also frequently closely mimic
oscillations in plasma glucose levels.
INTRODUCTION AND OVERVIEW
Figure 1.29: An illustration of the fast secretory oscillations before and after
glucose administration can be seen in the insulin concentration demonstrated
in a canine portal vein. After ingesting glucose, there is a noticeable rise in
pulse amplitude (arrow)
Abnormalities In Type 2 Diabetes
By the time T2DM is identified, defects in -cell function are quite clear. For instance,
analysis of beta-cell function using the homeostasis model assessment (HOMA) in
the UK Prospective Diabetes Study showed that beta-cell function was already 50%
lower upon diagnosis and continued to decline over time, regardless of treatment
97
 (Figure 1.30). In hyperglycemic clamp tests, anomalies are frequently observed,
such as nonexistent first-phase and reduced second-phase release in response to
hyperglycemia. A reduction in maximum secretory capacity causes responses to
mixed meal consumption (Figure 1.31) and to non-glucose stimuli to be delayed
or dulled.
Additionally, an abnormal oscillatory pattern is seen. The ultradian and fast
pulses are smaller and less regular. After meals, the ultradian pulses are less
pronounced and less likely to follow oscillations in plasma glucose levels.
Patients with T2DM have blood levels of proinsulin and its conversion products that
are at least twice as high as those in the general population. The ratio has increased
in both the baseline and stimulated insulin secretion stages, which suggests that
the secretory granules in beta cells are not as successful at converting proinsulin to
insulin.
1 1

INTRODUCTION AND OVERVIEW

Prospective Mechanisms
INTRODUCTION AND OVERVIEW

Genetic Aspects
Cell dysfunction in T2DM is caused by a confluence of inherited and acquired Figure 1.30: A patient with a normal weight has a twenty-four-hour insulin
variables. The “garden variety” T2DM, in contrast to MODY, is a polygenic secretory profile indicating ultradian oscillations. Lunch was had at 0900,
condition, which means that numerous genes (i.e. polymorphisms), each insufficient 1300, and 1800. The arrows indicate pulses of secretion that are statistically
in themselves, must be present with or without acquired defects in order to induce significant
diabetes. Cell apoptosis, regeneration, glucose sensing, glucose metabolism, ion
channels, energy transduction, microtubules/microfilaments, and other islet proteins
required for the synthesis, packaging, transport, and release of secretory granules
are among the functions that these genes may affect. The peroxisome proliferator-
activated receptor (PPAR), which is expressed in insulin target tissues and cells,
has an amino acid polymorphism (Pro12Ala) that may increase sensitivity to the
negative effects of FFA on insulin release. This is one of the few polymorphisms
that have been definitively identified as risk factors to date.
The second concerns the gene for calpain-10, a cysteine protease that controls
insulin release and the effects of insulin on muscle and adipose tissue. The third
is the potassium inwardly rectifying channel J11 gene (KIR6.2) E23K mutation, Figure 1.31: 𝝱- Cell function in type 2 diabetes patients from the UK Prospective
which has been demonstrated in a large association study to raise the risk of T2DM Diabetes Study (UKPDS) as assessed by the homeostasis model assessment
likely by its effect on the potassium channel of cells and, in turn, on insulin secretion. (HOMA) approach. - Despite treatment, cell function has already fallen to
50% at the time of diagnosis and continues to diminish

98 99
 More recently, it was discovered that variations of the transcription factor 7 - like 2
gene (TCF7L2) were linked to an increased risk of T2DM. In people who carry the
at-risk alleles, insulin secretion is reduced. The peptide GLP-1, which is expressed
by the human glucagon gene (GCG) and whose production in gut endocrine cells is
controlled by TCF7L2, is likely to be the cause of this.
Several components of the insulin signaling cascade have been identified
through the use of knockout techniques in mice and may represent possible areas
where genetic polymorphisms may impact -cell function, however none of these
components have yet been discovered in T2DM patients.

Acquired Variables
Figure 1.33: β-Cellular activity in people with normal glucose tolerance and
Numerous acquired and/or environmental factors have been found to lower β-cell
function, which may raise the chance of developing T2DM. impaired glucose tolerance (IGT), with or without a history of diabetes in the
1 family 1

Early Childhood Malnutrition And Fetal Malnutrition

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

Prenatal exposure to hyperglycemia and starvation throughout early childhood are

both linked to an increased chance of developing T2DM later in life, according to
research on animals and retrospective studies on people. According to research by
Hales et al., there is a negative correlation between weight at birth and at one year
with the development of T2DM in adults. It has been suggested that undernutrition
during pregnancy and the first few months of life may harm the development of
the immune system. It is also likely that nutritional deficiency at this time may
program the immune system so that it limits its ability to adjust to overnutrition
in the future. The strongest association was seen between people who were born
skinny and later developed obesity, which lends support to the latter hypothesis.
Remember that failing to properly enhance insulin release to offset acquired insulin
resistance is one of the characteristics of those predisposed to T2DM. However, this
circumstance must be seen as one risk factor among many that affect susceptibility
because not all people with early life malnutrition go on to develop T2DM if they
become obese.

Glucotoxicity
There is much proof that both acute and persistent hyperglycemia can negatively
Figure 1.32: Plasma concentrations of glucose and insulin in response to mixed
impact β-cell function. Furthermore, patients with T2DM will see improved -cell
meals in people with type 2 diabetes and non-diabetic control controls

100 101
 function with the use of secretagogues, insulin sensitizers, and even insulin when
their glycemic control is improved. The detrimental effects of hyperglycemia on
-cells are mediated by multiple, multifactorial pathways. Reactive oxygen species
(ROS) formation inside cells, changes in gene transcription and protein expression
brought on by oxidative stress, and an increase in cell death are all thought to
be involved in these pathways. The so-called glucotoxicity, however, is clearly a
secondary phenomenon but one that could speed up deterioration over time because
impaired β-cell dysfunction is clearly evident in genetically predisposed individuals
with normal glucose tolerance and because optimization of glycemic control does
not completely reverse impaired β-cell function in T2DM.
Lipotoxicity
Individuals with T2DM have higher circulating levels of FFA than do obese people
1 in addition to higher plasma glucose levels. Due to their increased fat mass, obese
people have higher plasma FFA levels. As a result of slower FFA clearance rather
INTRODUCTION AND OVERVIEW
than more FFA release into the circulation, obese patients with T2DM had slightly
higher circulating FFA levels than obese individuals without T2DM.
Numerous in vitro and animal investigations have shown that β-cell activity
is impaired by sustained rise of plasma FFA. Fatty acids are believed to disrupt
insulin gene expression, decrease glucose-stimulated insulin release, and—
most significantly— promote β-cell death. Uncoupling protein 2 (UCP-2) is
a mitochondrial carrier protein that separates ATP generation from substrate
oxidation in one suggested method. In β-cells, FFA elevates UCP-2 activity. As a
result, the amount of insulin secreted in response to glucose stimulation declines
due to impaired ATP production from glucose metabolism. By boosting ceramide
production and decreasing the binding activity of MafA and Pdx-1, two transcription
factors required for the control of numerous islet-associated genes including the
insulin gene, FFA diminish the expression of the insulin gene. However, it has
not been possible to reliably show that an acute rise of plasma FFA has a negative
impact on β-cell function in healthy human volunteers. Furthermore, human
studies on the impact of persistent increase of plasma FFA on β-cell function are
lacking. Some animal and in vitro investigations lead to the conclusion that FFA
has harmful effects on cell function only when hyperglycemia is present. For this
reason, glucolipotoxicity is suggested as an alternative to lipotoxicity. It is obvious
that increased plasma FFA is not the main cause of T2DM, but it is plausible that
102
some people may not be able to respond to the negative effects of FFA on -cell
function due to specific genetic backgrounds, which would raise their chance of
developing T2DM.
Obesity
Obesity is the most significant acquired risk factor for the development of T2DM
and is linked to insulin resistance. A number of substances secreted from adipose
tissue, such as increased levels of FFA, TNF-α, resistin, leptin, adipsin, and amylin
as well as tissue buildup of lipid, may be responsible for mediating this. But the
majority of obese people raise their insulin release appropriately to make up for
their insulin resistance and do not develop diabetes.
Insufficient stimulation caused by incretins
The incretin effect, or higher insulin responses after oral glucose than after 1
intravenous glucose despite similar glycemia, is caused by incretins, hormones
INTRODUCTION AND OVERVIEW
secreted by the gut in response to meal ingestion. The incretins GLP-1 and GIP
are both important. They were reported to increase β-cell mass in a mouse model
and to increase β-cell mass in vitro, in addition to boosting the manufacture and
secretion of insulin. When compared to healthy persons, patients with T2DM have
greater plasma GIP levels after eating a meal. In terms of GLP-1, the findings are
conflicting, but if changes have been detected between healthy participants and
patients with T2DM, they have often been small. Nevertheless, T2DM impairs the
incretin action. Insulin responses to GLP-1 and GIP are both diminished. It is unclear
if the impaired incretin effect, like the impaired insulin response to arginine, is only
a symptom of a broader loss in β-cell activity. However, anti-diabetic medications
that increase incretin activity or level (such as GLP-1 analogues and peptidase-IV
inhibitors) have been shown to be efficient in decreasing blood sugar in T2DM.
Islet Amyloid
Islet amyloid deposition is a distinctive trait seen in more than 90% of T2DM
patients. Amyloid is made up of insoluble fibrils that are produced by the protein
islet amyloid polypeptide (IAPP), also known as amylin. IAPP and insulin are
normally released from cells in a 1: 10 to 50 molar ratio. Although the mature form
of human IAPP has been reported to inhibit insulin release and to be cytotoxic to
β-cells, it is unlikely to play a major role in the pathogenesis of T2DM given that
103
 it is not present in all patients with T2DM and is actually present in up to 20% of
islets in elderly people with normal glucose tolerance. Furthermore, even while
IAPP is co-secreted with insulin in the majority of obese people who hypersecrete
insulin, they do not develop T2DM.
Recent evidence from in vitro and animal research suggests that the cytotoxic form
of IAPP is not the mature IAPP fibrils but rather tiny membrane permeant oligomers.
These oligomers develop and function inside the cell, potentially inducing death
due to endoplasmic reticulum stress. There is still no proof that T2DM patients’
pancreatic islets contain these harmful oligomers in humans. However, a rare
familial form of T2DM has been linked to the S20G mutation of the IAPP gene,
which enhances the tendency of IAPP to form oligomers.
Cytokines
1 Cytokines, particularly the proinfl ammatory cytokine interleukin-1β (IL-1β), are
known to affect cell activity and life cycle. In type 1 diabetes, the cytokine IL-1β
INTRODUCTION AND OVERVIEW
is known to cause cell death, but more recently, its part in the pathophysiology of
T2DM has drawn attention. Studies conducted in vitro have demonstrated that IL-1β
can be produced by cells in response to elevated glucose and leptin levels. Patients
with T2DM had pancreatic sections containing IL-1β-expressing cells, but healthy
individuals did not. When present in low quantities, IL-1β promotes human cell
proliferation while inhibiting apoptosis, but when present in larger concentrations,
it inhibits insulin secretion while increasing apoptosis. Here, apoptosis is assumed
to be mediated by Fas, a tumor necrosis factor receptor family member that initiates
apoptotic cell death without the assistance of TNF. In order to enable Fas-induced
apoptosis, IL-1β increases the expression of Fas in cells. In a pilot investigation, an
IL-1β receptor antagonist (IL-1Ra), which shielded human cells from the negative
effects of IL-1β in vitro, improved glycemic control in individuals with T2DM
through increased cell secretory function.
Alterations To Islet And Islet Cells In Type 2 Diabetes
The normal adult pancreas consists of 3–5% pancreatic islets, and 60–80% of the
islet cell population is made up of β– cells.
Islet Histology In Type 2 Diabetes
Abnormal extracellular islet amyloid deposits are a pathologic characteristic seen
in 90% of T2DM patients (Figures 10.26 and 10.27). These deposits are restricted
104
to the pancreas and are not caused by a condition called systemic amyloidosis. The
37-amino-acid peptide IAPP, also known as amylin, is the precursor to the islet
amyloid.
IAPP is typically synthesized by the beta cell, stored with insulin in its secretory
granules, and then released in conjunction with insulin after stimulation of the beta
cell. There is no known physiological role for IAPP in humans. The soluble IAPP
peptides take on a -sheet structure and oligomerize to create insoluble amyloid
deposits in T2DM patients. It is still unknown what initiates this process and
whether this merely reflects the degeneration and death of islet cells. However, a
small percentage of people without diabetes also have similar deposits, especially
as they age. Recent evidence suggests that the production of intracellular smaller
IAPP oligomers is possibly the cytotoxic form associated with increased apoptosis
in β-cells in animal studies. The IAPP and its amyloid deposits have not been
definitively found to be cytotoxic to β-cells. Reduced islet mass, a shift in the 1
relative proportion of the islet cell population, and varying degrees of islet and
INTRODUCTION AND OVERVIEW
endocrine tissue fibrosis are further histologic alterations.
β- Cell Alterations
It is commonly accepted that compared to persons with weight-matched normal
glucose tolerance, T2DM patients’ cell mass is reduced by approximately 30% to
50%. Additionally, it has been noted that individuals with poor fasting glucose have
lower cell mass. It has also been shown that the quantity of -cell secretory granules
has decreased. Instead of a drop in the volume of individual cells, the decline in
“cell mass” is due to a decrease in the number of cells. The decrease in cell counts is
caused by a several-fold increase in cell death without an appropriate compensatory
increase in replication or neogenesis rate.
105

Figure 1.34: Amyloid buildup in the islets of a type 2 diabetic patient.
More than 50% of the islet mass is taken up by amyloid made from islet amyloid
1
polypeptide (IAPP; stained pink with Congo red), which is mostly located in the
center of the islet. Insulin-producing cells (brown immunoperoxidase-labeled
INTRODUCTION AND OVERVIEW
cells) are very few in number and are grouped toward the islet’s periphery
Figure 1.35: Appearances of islet amyloid plaques on electron microscopy in
type 2 diabetes. In a person with type 2 diabetes, the deformed cell membrane
is extensively invaded by amyloid (Am) fibrils, which tightly surround the
affected cells (B). Scale bar: one meter
106
Changes In ɑ-Cells And Glucagon
Because the mass of ɑ-cells decreases as they age, the ɑ-cell mass is either fixed
or slightly increased, which causes a relative rise in ɑ-cells. People with IGT and
T2DM have abnormal beta-cell function, which includes decreased suppression by
hyperglycemia, increased responses to mixed or amino acid meals, and diminished
responses to hypoglycemia. This has been linked to decreased beta-cell function,
suggesting that it may be a secondary phenomena brought on by insulin resistance,
lipotoxicity, and glucose toxicity. T1DM and T2DM both exhibit absolute or
relative hyperglucagonemia as a defining feature. Despite the fact that this worsens
the effects of decreased insulin release on hepatic glucose production, it is likely to
be a secondary occurrence given how easily physiologic insulin replacement can
resolve it.
1
1.3.3 Type 2 Diabetes with Insulin Resistance
INTRODUCTION AND OVERVIEW
Impaired β- Cell Function Vs Insulin Resistance
A combination of inherited and acquired variables that negatively impact cell
activity and tissue insulin sensitivity cause the most frequent kind of T2DM. For
many years, it was debatable whether tissue insulin resistance or decreased beta-
cell function was the pathogenetic factor at play. It was previously believed that
insulin resistance was the key genetic cause causing β-cell dysfunction, and that
β-cell dysfunction was a late event brought on by exhaustion following years
of compensatory hypersecretion. The pendulum has tipped toward the idea that
impaired cell function is the main underlying defect over the course of the past
few years due to the mounting evidence from complex studies examining β-cell
function and tissue insulin sensitivity, both cross-sectionally and longitudinally. The
classic studies of Himsworth & Kerr, conducted more than 60 years ago, showed
that lean patients with early-onset diabetes were sensitive to exogenous insulin
injection, whereas obese patients with late-onset diabetes were resistant. These
studies established that insulin resistance may be the primary defect. Twenty-one
years later, when plasma insulin levels were first measured in T2DM patients in the
fasting and postprandial states, it was discovered that they had higher than normal
values, further supporting insulin resistance.
Numerous investigations over the course of the next 40 years revealed that those
with T2DM, those with impaired glucose tolerance (IGT), and first-degree relatives
107
 of those with T2DM who later got the condition were all hyperinsulinemia and
insulin resistant. The issue with how these studies’ findings were interpreted is that
they neglected to take the following factors into account:
• The significance of insulin secretion dynamics.
• The plasma insulin level’s compatibility with the predominant stimulus for insulin
secretion (i.e., plasma glucose level).
• The connection between insulin resistance and beta-cell activity.

Hepatic Insulin Resistance

Effect of insulin on glucose metabolism at the beginning state
Insulin limits the generation of endogenous glucose after an overnight fast. In Figure 1.36: Relationship between liver fat and hepatic insulin sensitivity
patients with T2DM, endogenous glucose synthesis and fasting plasma glucose in healthy individuals (open circles) and type 2 diabetics (closed circles), as
concentration are significantly correlated, according to isotopic studies of glucose determined by insulin’s capacity to reduce hepatic glucose production
1 1
production under genuinely steady-state conditions. This association, which is seen
Below, we address the pathophysiology and causes of this hepatic insulin resistance.
even in the presence of hyperglycemia and either normal- or hyperinsulinemia,

INTRODUCTION AND OVERVIEW

The primary cause of continuous maintenance of post-meal hyperglycemia is
INTRODUCTION AND OVERVIEW

shows that insulin resistance is a factor in the rise in basal endogenous glucose
persistent hepatic glucose production after eating. In the hours following a meal, the
production. This hepatic insulin resistance is linked to an overabundance of liver
liver stores the remaining third of the glucose while the skeletal muscle uses one-
fat deposition. The absolute rate of glucose utilization is normal or even increased
third and the brain uses one-third. The liver’s capacity to retain glucose throughout
after an overnight fast, when glucose uptake is primarily insulin-independent and
a meal seems unaltered or is only slightly reduced in T2DM patients.
driven by the mass-action effect of hyperglycemia. The therapeutic ramifications
Because hyperglycemia per se compensates for reduced insulin stimulation of
of these findings suggest that rather than further boosting glucose absorption in
glucose absorption into peripheral tissues, the overall rate of glucose utilization
T2DM, attempts to lower fasting glucose should target limiting the overproduction
is quantitatively normal in absolute terms as well. Finally, both individuals with
of glucose from the liver.
T2DM and normal persons use roughly the same quantities of glucose in their
brains. Post-prandial hyperglycemia must therefore be brought on by an insufficient
The effects of insulin on glucose metabolism in the postprandial state inhibition of endogenous glucose synthesis.
Under normal circumstances, endogenous glucose synthesis is virtually fully
Lipoprotein metabolism
suppressed after a meal by rises in insulin and glucose concentrations and a
Studies conducted both in vitro and in vivo have shown evidence that insulin
concurrent drop in glucagon. This suppression is insufficient in T2DM patients
typically inhibits the liver’s synthesis of VLDL, particularly VLDL1 apoB particles.
due to hepatic insulin resistance, insufficient insulin, and excessive glucagon
This impact is caused by insulin’s direct hepatic effect, which prevents the assembly
production. A diminished ability of insulin to inhibit hepatic glucose synthesis has
and synthesis of VLDL particles, in addition to decreases in NEFA availability as
been directly measured as evidence of hepatic insulin resistance. Figure 1.28 shows
a result of the inhibition of lipolysis in adipose tissue. Contrary to normal persons,
a strong correlation between this abnormality and liver fat level.
T2DM patients’ VLDL apoB synthesis is unaffected by insulin, despite the fact
that NEFA concentrations are markedly reduced. One important contributing factor
causing the rise in blood triglycerides in individuals with insulin-resistant T2DM

108 109
 appears to be the overproduction of VLDL and the failure in insulin suppression of
VLDL production, which correlates with the amount of fat in the liver.
In insulin-resistant patients with high serum triglyceride levels, HDL levels are
decreased. Under hypertriglyceridemic circumstances, cholesterol ester transfer
protein (CETP) mediates an excessive exchange of triglycerides and cholesterol
esters between HDL and the enlarged pool of triglyceride-rich lipoproteins.
When HDL particles are loaded with triglycerides, they are better substrates for
hepatic lipase, which eliminates HDL particles from circulation at a faster rate
(mostly separated in the lighter HDL 3 density range). By reducing the conversion
of HDL 3 to HDL 2 particles, abnormal LPL activity may further reduce HDL
cholesterol levels.
The CETP-mediated exchange of cholesterol ester and triglyceride between
VLDL and low density lipoprotein (LDL) cholesterol particles is also increased
1 by elevated VLDL particle concentrations in the blood of T2DM patients. This 1
raises the triglyceride content of LDL particles and improves their suitability as

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

a substrate for hepatic lipase, which enhances the density of the LDL particles by
hydrolyzing their triglycerides. This series of events at least partially explains why
people with T2DM have LDL particles that are smaller and denser than people
without diabetes. Insulin resistance and cardiovascular disease may be related, as
small dense LDL particles are known to be extremely atherogenic.
Figure 1.37: Fatty liver’s part in the pathophysiology of high blood sugar and
high insulin levels Normal levels of glucose are maintained through insulin’s
inhibition of hepatic glucose synthesis. This action of insulin is hindered
once the liver is fatty and insulin-resistant, resulting in hyperglycemia and
stimulation of insulin secretion. As long as pancreatic insulin production
remains unharmed, this leads to the combination of hyperinsulinemia and
glucose levels that are close to normal. The insert in the graphic shows how
fasting serum insulin and liver fat are related. Female circles are pink; male
circles are blue.

110 111

1 1
INTRODUCTION AND OVERVIEW
Figure 1.38: Normally, insulin prevents the liver from producing very low
density lipoprotein (VLDL) cholesterol. This ability of insulin is compromised
if the liver is obese and insulin resistant. This causes hypertriglyceridemia,
which is the primary factor in the decline of high density lipoprotein (HDL)
cholesterol. The insert in the graphic shows how fasting serum triglycerides
and liver fat interact. Female circles are pink; male circles are blue.
The Fatty Liver And The Pathogenesis Of Hepatic Insulin Resistance
Data on the pathophysiology of hepatic insulin resistance in humans are therefore
primarily reliant on in vivo investigations employing stable isotope and hepatic
venous catheterization techniques since it is not ethically possible to sample human
liver for research purposes. The fatty acids in intrahepatocellular triglycerides
can come from de novo lipogenesis, post-prandial chylomicron lipolysis, NEFAs
released from adipose tissue, or remnants of dietary chylomicrons that are too
large to be absorbed by tissues (spillover). After an overnight fast, stable isotope
in vivo investigations have demonstrated that the bulk of hepatic fatty acids come
from adipose tissue lipolysis. In persons of normal weight, splanchnic lipolysis
contributes 5–10% to the supply of hepatic free fatty acids (FFA), while in men and
women with visceral obesity, this contribution rises to 30%.
112
The majority of hepatic FFA delivery is thus accomplished via subcutaneous adipose
tissue. The spillover route and ingestion of chylomicron remnants contribute more
in the post-prandial state and can account for as much as half of the fatty acids
released as VLDL triglycerides. De novo lipogenesis makes up less than 5% of
postprandial fat in healthy participants, but it appears to be significantly higher
in people with fatty liver. A high consumption of carbohydrates may be the cause
of this. Excessive de novo lipogenesis in the liver may also be caused by insulin-
resistant individuals’ decreased capacity to store carbohydrates as muscle glycogen.
Depending on the amount of liver fat present, the intrahepatocellular triglyceride’s
fatty acid content varies. Increased quantities of saturated fatty acids and lower
amounts of polyunsaturated fatty acids are found in the fatty liver. It is uncertain if
de novo lipogenesis, which generates saturated fatty acids, or other sources are to
blame for the rise in saturated fatty acids.
Mechanism of liver insulin resistance at the cellular level
INTRODUCTION AND OVERVIEW
Triglycerides cannot explain hepatic insulin resistance because they are inert
substances. Ceramides and diacylglycerols are at least two lipid mediators that
animal studies have linked to insulin resistance. Ceramides are sphingolipids that
depend on the presence of saturated fatty acids for their sphingoid backbone. In
rat soleus muscle, saturated fatty acids tend to cause insulin resistance, whereas
unsaturated fatty acids do not. Ceramides appear to be necessary for this process.
When eating a diet rich in triolein (18:1 n-9) or tristearin (18:0), ceramides do not
accumulate in the liver. Ceramide levels in human fatty liver are poorly understood,
despite the fact that they are elevated in skeletal muscle and adipose tissue of
insulin-resistant patients.
Triacylglycerols’ immediate precursors, diacylglycerols, stimulate the liver’s
protein kinase C (PKC), which binds to and inactivates the insulin receptor tyrosine
kinase and reduces the tyrosine phosphorylation of insulin receptor substrate
2 (IRS-2). Reduced insulin activation of PI 3-kinase, AKT2, glygogen synthase
kinase 3 (GSK-3), and FOXO phosphorylation in downstream signaling results in a
decrease in hepatic glycogen production and a reduction in the regulation of hepatic
gluconeogenesis. Diacylglycerol concentrations in the human liver rise in direct
proportion to intrahepatocellular triglyceride levels. It has been demonstrated that
T2DM patients’ livers have elevated PKC activity.
113

1 and gout, gynoid obesity was characterized by lower body deposition of fat (around
INTRODUCTION AND OVERVIEW
Figure 1.39: The connection between body mass index and the euglycemic
clamp technique-measured insulin sensitivity of glucose metabolism in persons
without diabetes
Developed Reasons Of Variation In Hepatic Insulin Sensitivity And
Liver Fat Content
Body weight
Obesity and insulin resistance are related, but at any given body mass index (BMI),
insulin sensitivity—a measure of whole-body insulin resistance that may include
both hepatic and peripheral insulin resistance—varies greatly. Insulin sensitivity
is calculated as the amount of glucose needed to maintain normoglycemia during
hyperinsulinemia. Both insulin’s ability to stimulate glucose absorption and its
ability to suppress endogenous glucose synthesis are impaired by obesity.
Although liver fat content and hepatic insulin resistance are linked to BMI and waist
size, there is a wide range for any given BMI. Hepatic insulin sensitivity and liver
fat content alter quickly and significantly as a result of weight loss. The liver’s fat
content and the total mass of body fat in a study of obese women who dropped 8%
of their body weight over 18 weeks fell by 39% and 14%, respectively. In another
study, a 7% weight loss over 7 weeks reduced the amount of liver fat by almost
114
40%. In this study, a low carbohydrate meal ( 1000 kcal, about 10% carbohydrate)
resulted in a 30% reduction in liver fat as early as after 2 days. Directly assessed
hepatic insulin sensitivity significantly increased in both of these experiments.
Liver fat increases with weight growth. In a study where healthy individuals were
overfed, a 9.5% weight gain over 4 weeks was linked to hyperinsulinemia, a 2.5-
fold rise in liver fat, and a 4.4-fold increase in blood alanine aminotransferase
(ALT) activity.
Distribution of fat
Vague divided obese patients into “gynoid” and “android” categories more than
50 years ago based on the level of “masculine differentiation.” While android
obesity was defined by upper body (truncal) adiposity, greater overall muscular
development, and a propensity to develop hypertension, diabetes, atherosclerosis,
1
the thighs and buttocks) and relative underdevelopment of the musculature.
INTRODUCTION AND OVERVIEW
Prospective research has later confirmed these phenotypic observations. It is
unclear how aspects of insulin resistance and upper body fat are related. It has been
proposed that truncal obesity, which is accompanied by visceral fat accumulation
within the belly, is deleterious in terms of hepatic insulin resistance and liver fat
because this fat depot is more metabolically active than subcutaneous adipose
tissue. Omental and mesenteric adipocytes can release excessive amounts of NEFA
into the portal vein, leading to the development of insulin resistance in the liver,
because they have a faster rate of lipolysis than subcutaneous adipocytes. However,
there isn’t any solid in vivo support for this “portal theory.” Only a small body of
evidence suggests that the concentrations of NEFA and glycerol in the portal vein
are comparable to those in arterial plasma, and tracer experiments have revealed
that only 10% of the NEFA delivered to the liver comes from NEFA produced
inside the splanchnic (visceral) bed.
Additionally, it has been discovered that excess NEFA comes from subcutaneous fat
in the upper body rather than the splanchnic bed, despite the fact that the turnover
rate of NEFA is higher in women with upper body obesity compared to those with
lower body obesity. However, these findings do not establish causation. Visceral fat
has also been shown to release more immune cytokines, such as interleukin 6 (IL
6), than subcutaneous adipose tissue. As a result, visceral fat may both be a victim
and an unwitting party.
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Nutrition composition
Regarding the impact of dietary composition changes on hepatic insulin sensitivity
and liver fat content, there is very little human data available. Cross-sectional data
have revealed that the proportion of dietary saturated fat intake is higher in NAFLD
compared to controls and that the relative amount of fat, particularly saturated fat,
in the diet is directly connected with liver fat. According to a small intervention
trial, liver fat may increase on a high fat diet (56% of calories) compared to a low
fat diet (16% of calories) with a high carbohydrate intake. However, the amount
of carbohydrates in the diet could also be significant. A cross-sectional study
involving 247 healthy individuals revealed that a high glycemic index diet is linked
to increased liver fat regardless of intake of carbohydrates, fiber, protein, or fat.
However, there are no intervention trials to support this conclusion.
1 These three tissues are the only ones that can store glucose, and they are also the
Genetic Factors Controlling Liver Function And Insulin Sensitivity
INTRODUCTION AND OVERVIEW
According to twin studies, 35 to 60% of the variation in the levels of circulating
liver enzymes in persons without established liver disease and who do not drink
excessively is genetically determined. An allele in the PNPLA3 (adiponutrin)
gene has recently been identified as being strongly related with greater liver fat.
This finding comes from a genome-wide association scan of non-synonymous
sequence changes in a group of Hispanic, African-American, and European-
American individuals. Numerous studies have confirmed the finding that hepatic fat
accumulation is more than two times higher in PNPLA3 rs738409[G] homozygotes
than in non-carriers. Triglyceride buildup is facilitated by triglyceride hydrolysis
being inhibited by the missense mutation I148M in adiponectin.
Insulin resistance in adipose tissue
Adipose tissue is an active endocrine organ that distributes hormones like
adiponectin and leptin into the circulation, making it more than just a store for
extra energy. Additionally, it has recently been demonstrated that adipose tissue is
inflamed in obese people as well as in subjects with a fatty liver who are not obese.
Macrophage infiltration and elevated expression of pro-inflammatory molecules
including tumor necrosis factor (TNF) and IL-6, as well as chemokines like MCP-
1, are characteristics of this inflammation. Unknown is what initially caused the
inflammatory alterations. According to Cinti et al., > 90% of the macrophages that
116
surround deceased adipocytes in obese (db/db) mice and humans also correlate
favorably with adipocyte size. People with a fatty liver differed from equally
obese people with normal liver fat content in that they had more macrophages
surrounding dead adipocytes. Insulin resistance may result from the inflammation
of adipose tissue and may affect not just that tissue but also other tissues like the
liver. Although it is typically difficult to demonstrate cause and effect in human
studies, it is likely that increases in NEFA from insulin resistance-induced anti
lipolysis and the decrease in adiponectin concentration are likely mediators of
systemic, primarily hepatic, insulin resistance as a result of changes occurring in
adipose tissue. Weight loss can lower both macrophage infiltration and expression
of genes involved in macrophage recruitment, indicating that the buildup of
macrophages in human adipose tissue is at least partially reversible. Skeletal
muscle, fatty tissue, and the liver are the three main tissues that insulin targets.
1
only ones in which IR is overexpressed in the cells. Skeletal muscle is the main
INTRODUCTION AND OVERVIEW
organ targeted by insulin-dependent postprandial glucose disposal, which occurs
into it in about 75% of cases. Patients with type 2 diabetes and insulin resistance
commonly exhibit symptoms of aberrant lipid metabolism, raised circulatory
concentration, and enhanced lipid deposition in skeletal muscle. A rise in plasma
FFA inhibits the absorption of glucose induced by insulin, whereas a fall in plasma
lipid content enhances the action of insulin in skeletal muscle, adipocytes, and liver
cells. Studies have revealed that insulin activation of IRS-1-associated PI3-kinase
activity in skeletal muscle, where IRS-1 is most abundant, is abolished by elevating
plasma fatty acids in rodents and humans. Defects in GLUT4 translocation have
also been demonstrated to be related to lipid-associated insulin resistance. The
production of adipokines by adipose tissue, an endocrine organ, modulates glucose
homeostasis. The ones that are now being discussed the most include TNF-, leptin,
adiponectin, and resistin. TNF- enhances the serine phosphorylation of IRS-1 and
decreases the expression of GLUT4 at the molecular level, both of which contribute
to insulin resistance. Additionally, animals missing functional TNF- were shielded
from the insulin resistance brought on by fat. Leptin plays a well-known role in
controlling calorie intake and energy usage. People who lack leptin or who have
mutations in their leptin receptors are very fat. Additionally, in animals with
congenital lipodystrophy, it has direct impacts on insulin sensitivity and may even
reverse insulin resistance. As it increases inhibition of hepatic glucose production
117
 as well as glucose uptake and utilization in fat and muscle, adiponectin has insulin-
sensitizing effects. In obese mice and humans, adiponectin expression is reduced.
As a result, adiponectin levels and insulin sensitivity are related in people. The
adipokine resistance has gained a lot of interest in preclinical research because
of its insulin-antagonistic actions. Resistin increases fasting blood glucose levels
and hepatic glucose synthesis in vivo while decreasing insulin-dependent glucose
transport in vitro.
Resistance to Insulin’s antilipolytic effect
Adipose tissue is extraordinarily sensitive to insulin, with rates of glycerol synthesis
in healthy persons being reduced by 50% and maximally repressed at a plasma
insulin concentration of 13 mU/L.
In individuals with T2DM compared to normal participants evaluated at equivalent
1 insulin levels, triglyceride breakdown is enhanced and plasma NEFA concentrations
Insulin Resistance In Skeletal Muscle Pathogenesis
Insulin action is impaired in insulin-target tissues such skeletal muscle, adipocytes,
and liver. This condition is known as insulin resistance. The main function
of insulin in skeletal muscle is to promote glucose absorption and metabolism.
Insulin promotes glucose uptake into skeletal muscle in lean healthy adults in a
dose-dependent manner, with a half-maximal effect (EC50) at a plasma insulin
concentration of less than 60 U/mL. Skeletal muscle insulin-stimulated glucose
absorption is significantly decreased in insulin resistance states (Figure 1.40).
1

are greater, indicating that adipose tissue is also impacted by insulin resistance. But

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

because insulin deficiency is not sufficiently severe in T2DM, uncontrolled lipolysis

that could result in ketoacidosis does not happen on its own. Because NEFA and
glucose metabolism interact in a variety of ways, higher NEFA concentrations
may help hyperglycemia get worse. The insulin-stimulated glucose uptake can
be reduced by a significant rise in plasma NEFA concentrations, and NEFA may
be stored as triglycerides in skeletal muscle. The second effect of higher NEFA Figure 1.40: Dose-response curve in normal and type 2 diabetes people linking
concentration is enhanced NEFA turnover, which boosts NEFA delivery to the liver, plasma insulin concentration to the rate of insulin-mediated whole body
where NEFA can be stored as triglycerides. NEFA also promotes glucose synthesis glucose absorption. *P<.01
in the liver, particularly through gluconeogenesis.
Himsworth and Kerr were the first to show that tissue sensitivity to insulin is
decreased in T2DM patients using a combination oral glucose and intravenous
Deficiency of adiponectin tolerance test. In 1975, Ginsberg et al. used the insulin suppression test to further
A hormone made in adipose tissue is called adiponectin. According to animal
demonstrate that T2DM significantly impaired insulin’s capacity to enhance tissue
studies, the liver is its primary target since it reduces hepatic fat content while also
glucose uptake. DeFronzo and colleagues as well as Butterfield and Whichelow have
having anti-inflammatory and insulin-sensitizing actions. The strong correlation
presented the most convincing evidence of enhanced insulin resistance in skeletal
between changes in liver fat and serum adiponectin concentrations and the marked
muscle in lean as well as obese T2DM participants. They showed that both lean and
rise in serum adiponectin levels seen during treatment with PPAR - agonists support
obese T2DM participants experience a considerable drop (>50%) in whole body
the idea that adiponectin controls the amount of liver fat in humans. In comparison
glucose disposal during the insulin clamp using the industry-standard euglycemic
to non-obese persons, obese patients, and subjects with the metabolic syndrome all
hyperinsulinemic clamp technique to measure insulin-stimulated glucose uptake.
have lower serum adiponectin levels.
Although all peripheral tissues engage in insulin-stimulated glucose uptake during

118 119
 the insulin clamp, the majority of this glucose absorption occurs in skeletal muscle.
Studies using the insulin clamp in conjunction with femoral artery and vein
catheterization have demonstrated that skeletal muscle accounts for about 80% of
total body glucose uptake under euglycemic settings.
Leg muscle glucose absorption gradually rises in healthy persons in response to a
physiological rise in plasma insulin concentration (80–100 U/mL) and reaches a
plateau value of roughly 10 mg/kg leg weight/min. Lean T2DM participants, on
the other hand, experience a 50% reduction in the rate of glucose uptake during the
final hour of the insulin clamp trial (Figure 1.41).
1 1
INTRODUCTION AND OVERVIEW
Figure 1.41: Left: Time course of change in leg glucose uptake in type 2
diabetic and control participants, and right: Insulin-stimulated whole body
glucose uptake measured with the euglycemic clamp in lean healthy and type
2 diabetes patients.
Skeletal muscle exhibits insulin resistance long before hyperglycemia is detectable.
Decreases in insulin-stimulated total body and muscle glucose clearance are thus
seen in slim, healthy children of diabetic parents, and these reductions are of a
similar magnitude to those seen in the diabetic parents. Skeletal muscle insulin
resistance can also develop without a familial history of T2DM. Thus, obese NGT
people without a family history for T2DM and persons with essential hypertension
and ischemic heart disease likewise have a 35-50% drop in whole body insulin
mediated glucose clearance (Figure 1.42).
120
Figure 1.42: Lean drug-naive type 2 diabetic subjects (T2DM), lean
normal-glucose-tolerant (NGT) hypertensive subjects (HTN), NGT
INTRODUCTION AND OVERVIEW
hypertriglyceridemic subjects, and non-diabetic subjects with coronary artery
disease (CAD) all demonstrated insulin-stimulated glucose disposal (40 mU/
m2min euglycemic insulin clamp). The solid portion of the bar reflects glucose
oxidation, whereas the open portion represents non oxidative glucose disposal
(glycogen synthesis).
The normal aging process, dyslipidemia (increased plasma triglyceride/decreased
HDL cholesterol), and a number of disease states, such as polycystic ovary syndrome
(PCOs), chronic kidney failure, heart failure, myotonic dystrophy, and lipodystrophy
have all been linked to insulin resistance in skeletal muscle. Acute severe illnesses
including sepsis and injuries also cause the development of insulin resistance,
possibly as a result of the persistent acute inflammatory state. Pharmacological
medication, such as glucocorticoids, anti-HIV therapy, and beta blockers, can also
cause insulin resistance in skeletal muscle. These studies show that even though
skeletal muscle insulin resistance is a hallmark of T2DM, muscle insulin resistance
and the related insulin resistance syndrome are more common, and non-diabetics
are also affected by the metabolic and clinical effects of insulin resistance (such as
elevated cardiovascular risk). We will concentrate the discussion on the molecular/
biochemical pathways that result in muscle insulin resistance in obese and T2DM
subjects since the molecular mechanisms that cause the development of insulin
resistance in skeletal muscle have been thoroughly studied in these two common
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 metabolic disorders. Similar molecular flaws have, however, been discovered in
more insulin resistance conditions.
The plasma insulin concentration is low (5-10 U/mL) in basal circumstances, such
as the fasting state. As a result, insulin is not required for glucose absorption in
skeletal muscle during the postabsorptive state. Insulin resistant people also have
less non-insulin dependent skeletal muscle glucose absorption. The mechanism(s)
underlying the decline in non-insulin dependent glucose uptake are still unknown.
The Reasons For Muscle Insulin Resistance
Obesity
Independent of changes in physical fitness, obesity reduces the amount of insulin-stimulated
glucose that is absorbed by skeletal muscle. Increased NEFA production by adipose tissue
and fat buildup in myocytes may also contribute to this decline.
1 1
Abdominal obesity
INTRODUCTION AND OVERVIEW
Subjects with android obesity have more severe insulin resistance in their skeletal
muscles than do individuals with gynoid obesity. Histologically, persons who are
abdominally obese have a decreased capillary density and skeletal muscle fibers
that are insulin-resistant.
Physical inactivity
The sedentary lifestyle that distinguishes Westernized countries plays a significant
role in both obesity and type 2 diabetes. An unfavorable relationship between physical
activity and the incidence of T2DM has been found in data from various prospective
epidemiologic studies, including the Nurse’s Health Study. By measuring physical
fitness by maximum oxygen consumption (VO2max), maximal insulin sensitivity of
glucose absorption by skeletal muscle is directly proportional to physical fitness.
Reduced capillary density and reduced mitochondrial oxidative phosphorylation are
indicators of lower physical fitness (maximal aerobic power) in muscle in T2DM
patients. Resistance training, which increases total muscle mass without affecting
glucose uptake per unit muscle mass, also improves glucose tolerance and insulin-
stimulated glucose uptake. Exercise and insulin both increase glucose absorption
through separate processes. Exercise has no impact on the tyrosine phosphorylation
of the insulin receptor or IRS-1, but insulin increases glucose absorption in skeletal
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muscle via the traditional insulin signaling route. Adenosine 5 ′ monophosphate -
activated protein kinase (AMPK) is a component of the mechanism of contraction-
stimulated glucose absorption. Human skeletal muscle contractions activate
AMPK, particularly its isoform 2; this causes the translocation of GLUT-4 to the
cell membrane and an increase in the inward transport of glucose. The ability of
insulin to activate tyrosine phosphorylation of the insulin receptor and of IRS-1,
IRS-1 related PI 3 kinase activity, and translocation of GLUT-4 are all abnormal
in insulin-resistant patients with T2DM. However, it has been demonstrated that
aerobic exercise increases skeletal muscle GLUT-4 content and glycogen synthase
expression and activity to levels comparable to those seen in healthy individuals.
Therefore, in people with T2DM, the signaling pathways that exercise uses to
increase glucose absorption may still be functional. This practically means that
insulin resistance does not dampen the glycemic response to exercise.
Chronic hyperglycemia
INTRODUCTION AND OVERVIEW
Human skeletal muscle can develop insulin resistance due to hyperglycemia alone,
without the help of insulin, NEFA, or counter-regulatory hormones. The lower
rates of insulin-stimulated glucose uptake in patients with T2DM compared to
weight, age, and gender-matched subjects without diabetes and measured during
maintenance of similar levels of glycemia and insulinemia may be caused by this
“glucose toxicity” induced insulin resistance. Even in diabetic patients, acute
glucose utilization is promoted by the mass action effects of glucose, despite the
fact that chronic hyperglycemia causes insulin resistance.
This effect explains why, despite the participants’ higher levels of insulin resistance,
hyperglycemic T2DM patients are nevertheless able to use the same amount of
glucose at normoglycemia as healthy subjects. In those with T2DM, the degree of
hyperglycemia is directly related to the degree of insulin resistance.
Therefore, it is possible to think of the hexosamine pathway-induced insulin
resistance in hyperglycemic T2DM patients as a compensatory mechanism that
guards against an excessive uptake of glucose by the muscles. In line with this,
insulin-stimulated glucose transport in T2DM patients with hyperglycemia in
isolated skeletal muscle was comparable to that in normoglycemic participants,
but hindered when assessed following short-term exposure to normoglycemia.
The impairment in insulin-stimulated glucose transport was totally restored after
prolonged normoglycemia exposure. Clinically, the capacity of hyperglycemia to
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 cause insulin resistance in T2DM patients may help to explain why any medication
that improves glycemic management, such as sulfonylureas, may also increase
insulin sensitivity even if its primary site of action is not in insulin-sensitive tissues.
Marshall et al. discovered the hexosamine route in 1991 and demonstrated that
it mediates glucose-induced insulin resistance in primary cultured rat adipocytes.
Three elements were found to be necessary for downregulation of the insulin-
responsive glucose transport system: glucose, insulin, and glutamine.
By inhibiting glutamine: fructose - 6 - amidotransferase (GFA), the rate-limiting
enzyme of the hexosamine pathway, glutamine analogs were able to counteract the
desensitization of glucose transport caused by glucose. Glucosamine-6-phosphate
(GlcN-6-P) and glutamate are produced as a result of the interconversion of
glutamine and fructose - 6 - phosphate, which is catalyzed by GFA.
Patients with T2DM have higher levels of GFA activity in skeletal muscle and other
1 insulin target tissues. UDP-N-acetyl-glucosamine (UDP-N AcGln), the pathway’s 1
last byproduct, is linked to the OH-group of threonine and serine residues in

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

proteins (these same residues can also be phosphorylated), causing O-glycation of
the proteins. These comprise several proteins implicated in insulin- and glucose-
dependent transcriptional and signaling processes.
Figure 1.43: insulin resistance’s causes and effects, as well as the etiology of
metabolic syndrome. Obesity is frequently brought on by overeating and
inactivity. Fat builds up in the liver in many obese people, but it can also happen
in non-obese people. High intakes of refined carbohydrates and saturated fat
may be especially hazardous. At least when it comes to the buildup of fat in the
liver, genetic predisposition plays a part. Adipose tissue is infused in fatty liver
and obese people. enhanced production of cytokines including tumor necrosis
factor (TNF) and enhanced macrophage infiltration surrounding deceased
adipocytes are two characteristics of this inflammation. Unknown as to why
the inflammation occurred.
Insulin-resistant and overproducing free fatty acids, inflamed adipose tissue is
a major contributor to the excess triglyceride accumulation (TG) in the liver.
Additionally, inflamed adipose tissue exhibits adiponectin deficiency, which
lowers insulin sensitivity. Once fatty, the liver overproduces VLDL, plasminogen
activator 1 (PAI-1), and coagulation factors, as well as glucose. Extra refined
carbohydrates may boost liver de novo lipogenesis (DNL), which would raise
intrahepatocellular triglycerides. Insulin resistance of skeletal muscle glucose
absorption is another characteristic of overeating and inactivity.

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 1.3.4 Diabetes and Metabolic Disturbances
Carbohydrate Metabolism
The rate of endogenous glucose release from the liver and, to a lesser extent, the
kidney in the fasting state controls glucose appearance. The sum of these processes
is known as endogenous glucose production. When glucose arrival outpaces
glucose removal, glucose concentrations rise and keep rising until these rates are
equal. Following a 6–12 hour overnight fast, glucose levels in healthy people range
from 4.5–5.5 mmol/L. After an overnight fast, gluconeogenesis produces between
50 and 60 percent of the body’s endogenous glucose, with the proportion rising
with the lengthening of the fast.
Three-carbon precursors including lactate, alanine, and glycerol are used in the
process of gluconeogenesis to create glucose molecules. After an overnight fast,
1 the brain, splanchnic tissues, and erythrocytes account for about 80% of insulin-
independent glucose elimination. Muscle is where the majority of insulin-mediated
INTRODUCTION AND OVERVIEW
glucose elimination takes place. Muscle mostly burns free fatty acids (FFA) for
fuel in the postabsorptive state because insulin levels are low. Low insulin levels
cause the majority of the glucose absorbed by tissues to be oxidized or proceed
via glycolysis, releasing alanine and lactate that the liver can use again for
gluconeogenesis. Different tissues respond to insulin in different ways. Low insulin
levels restrict lipolysis and prevent the uncontrolled breakdown of fat. Insufficient
insulin concentrations limit lipolysis but do not significantly increase muscle
glucose absorption. At insulin concentrations of about 250 pmol/L, endogenous
glucose synthesis is maximally suppressed, while glucose uptake is only partially
stimulated (Figure 1.46) at these values.
126
1
Figure 1.44: Glucose production and utilization insulin dose-response curves
INTRODUCTION AND OVERVIEW
in non-diabetic people. Inspired by Vella A
Within five to ten minutes following a meal, increases in plasma glucose drive
insulin secretion while glucagon secretion is suppressed. Together with the increased
glucose concentrations, the reciprocal changes in hepatic sinusoidal insulin and
glucagon concentrations promote hepatic glucose absorption and inhibit hepatic
glucose synthesis. The majority of the remaining glucose is metabolized by muscle
after the splanchnic tissues extract 10–25% of the ingested glucose initially and
subsequently eliminate about 40% of it. The postprandial rise in glucose is often
restricted to 7–8 mmol/L thanks to these coordinated alterations in hepatic and
extrahepatic glucose metabolism. A gradual increase in hepatic glucose output to
rates that nearly resemble glucose uptake prevents late postprandial hypoglycemia.
The proportional importance of changes in glucose disappearance or appearance
in the transition from normal glucose metabolism to overt diabetes is unknown.
The majority of epidemiologic research, though not all of them, have found that
impaired fasting glucose (IFG; defined as a fasting glucose of 5.8 to 6.9 mmol/L)
patients have lower insulin action. According to Weyer et al., individuals with
IFG produced more fasting endogenous glucose. Bock et al. went on to prove that
individuals with IFG have poor insulin-induced inhibition of endogenous glucose
synthesis and gluconeogenesis, which indicates hepatic insulin resistance. 20
to 30 percent of those with IFG will develop true diabetes within 5 to 10 years,
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 according to epidemiologic research. It is true that people with fasting blood sugar
levels between 5.3 and 5.7 mmol/L are 8% more likely to acquire diabetes in the
following ten years.
After eating a meal, glucose concentrations are more intricately regulated. The
degree to which glucose entering the systemic circulation (equal to the sum of
endogenous glucose production and the systemic appearance of ingested glucose)
exceeds or is exceeded by the rate at which glucose leaving the systemic circulation
(glucose disappearance) determines the pattern of change of postprandial plasma
glucose concentrations.
As a result, variations in the rates of mealtime glucose appearance, suppression
of endogenous glucose production, or stimulation of glucose uptake might
hypothetically result in variations in post-prandial glucose concentrations. Because
the rate of ingested glucose appearance and the reduction of endogenous glucose
1 production are the same in those with IFG and those with normal fasting glucose, 1
Figure 1.45: Major locations for the metabolism of glucose in the post-
postprandial hyperglycemia is predominantly caused by reduced postprandial
absorption and post-prandial phases. After eating a meal, insulin-dependent

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

glucose disappearance. Subjects with IFG have reduced insulin secretion in

response to greater postprandial glucose concentrations, which is accompanied by
abnormalities in glucose disappearance and results in postprandial hyperglycemia.
Overt T2DM eventually develops as insulin secretion continues to decline. Insulin
controls (inhibits) the endogenous synthesis of glucose, increasing hepatic glucose
uptake by glucokinase activity and reducing hepatic glucose release by slowing
down the conversion of glucose-6-phosphate to glucose.
tissues begin to absorb glucose more often than insulin-independent organs.
The majority of the substrates for glucose synthesis come from tissues in the
periphery.
Direct or indirect (gluconeogenesis) mechanisms can both be used for hepatic
glycogen production.
Glucose-6-phosphatase controls the last stage. Additionally, insulin can decrease
glycogen oxidation, promote glycogen synthesis, and suppress gluconeogenesis.
Hyperinsulinemia and postprandial hyperglycemia promote the production of
hepatic glycogen, replenishing hepatic glycogen reserves. Hepatic glycogen
synthesis can take place through either a direct mechanism (using glucose-6-
phosphate that is directly derived from extracellular glucose) or an indirect pathway
(using glucose-6-phosphate that is acquired from gluconeogenesis). The length of
the fast, the nature of the meal, and the current levels of insulin and glucagon all
appear to play a role in determining the relative contribution of these two routes.
Rising hepatic sinusoidal insulin concentrations in the presence of euglycemia
inhibit endogenous glucose synthesis through reducing glycogenolysis. In
healthy adults, insulin levels within the physiological range do not significantly
inhibit gluconeogenesis and route glucose - 6 - phosphate (produced during

128 129
 gluconeogenesis) into glycogen.
The metabolism of carbohydrates in type 1 diabetes
As a result of the pancreatic beta cells being attacked by the immune system, T1DM
is characterized by insulin deficiency. Before the majority (> 80%) of -cells are
destroyed to the underlying autoimmune disease, fasting hyperglycemia does not
emerge. However, in asymptomatic afflicted individuals, defects in insulin secretion
are visible years before the onset of diabetes. In response to intravenous glucose
injection, for instance, siblings of T1DM patients who are islet antibody positive
(a population at high risk for the development of T1DM) usually show a reduced
first-phase of insulin secretion. This suggests that incretins and other secretagogues
are able to make up for decreased islet cell mass since it typically happens when the
response to other stimuli, like oral glucose administration or mixed meal ingestion,
1 is still intact.
Impairment of insulin action typically goes hand in hand with impairment of insulin
INTRODUCTION AND OVERVIEW
secretion. The level of glycemic control influences how severe insulin resistance
is. The same level of insulin resistance may be present in those with poorly
controlled T1DM as in those with T2DM. The insulin action deficit in persons
with T1DM is tissue-specific; for instance, glucose absorption in cardiac muscle
is normal compared to skeletal muscle. People with T1DM have lower rates of
glucose oxidation and non-oxidative storage in relation to glucose uptake, which
may indicate that glucose transport and/or phosphorylation (after transfer across
the membrane) are the sites of faulty insulin action. In contrast, insulin-induced
inhibition of glucose synthesis is not compromised in persons with T1DM and may
even be increased.
130
Figure 1.46: In the post-absorption and post-prandial stages, major sites of
glucose metabolism are found. After eating, insulin-dependent tissues begin 1
to absorb glucose instead of insulin-independent organs as the main site of
INTRODUCTION AND OVERVIEW
uptake. The majority of the sources of gluconeogenic substrates are tissues in
the periphery.
Both direct and indirect (gluconeogenesis) mechanisms can be used to
synthesize hepatic glycogen
Adipocytes from persons with T1DM have been shown to have impaired insulin
binding and action, compared to fibroblasts, which are normal. This may be
explained by the fact that whereas insulin binding to fibroblasts is evaluated
several days after culture, insulin binding to adipocytes is determined immediately
after biopsy. Reduced insulin binding in the former but not the latter shows that
the aberrant metabolic environment is having an impact rather than that insulin
action is intrinsically flawed. Multiple observations showing better whole-body
insulin activity coupled by better chronic glucose control lend credence to this.
It should be noted that when measuring insulin action with a hyperglycemic
hyperinsulinemic clamp, hyperglycemia may be able to make up for minor flaws
in insulin action by stimulating its own absorption and inhibiting its own release
(glucose efficacy). Since subcutaneous injections of insulin are more common than
intraportal injections, taking insulin results in systemic hyperinsulinemia, which
has been demonstrated to impede insulin action in people who do not have diabetes.
However, the better insulin action seen in T1DM patients after receiving insulin
131
 therapy implies that any adverse effects of systemic hyperinsulinemia on insulin
action are more than balanced by the reduction in glucose levels and reversal of
glucose toxicity. Significant glucose disappearance in insulin-deficient individuals
with T1DM occurs by glucose excretion in the urine and by glucose uptake via non-
insulin-mediated mechanisms in the absence of insulin-stimulated muscle glucose
uptake. Consuming food does not cause an increase in insulin or a corresponding
drop in glucagon levels. The increase in splanchnic glucose uptake and the decrease
in endogenous glucose synthesis are therefore out of proportion to the current
glucose levels. The amount of post-prandial glycogen generated is significantly
reduced, with the majority of it being produced via the indirect gluconeogenic
pathway.
By increasing circulating insulin concentrations and preventing the excessive
rise in counter-regulatory hormones that results from insulin deficiency, insulin
1 administration can almost completely normalize post-prandial glucose metabolism
in splanchnic and extra-splanchnic tissues. The postprandial reduction of glucose
INTRODUCTION AND OVERVIEW
production and stimulation of glucose uptake are also restored after insulin treatment
to levels comparable to those seen in persons without diabetes. Diabetes has been
linked to increased intestinal glucose transport and intestinal mucosal hypertrophy,
according to animal research. Initial splanchnic glucose extraction and uridine
diphosphate (UDP) - glucose flux, a measure of hepatic glycogen production, do
not differ across groups when glucose, insulin, and glucagon concentrations are
matched in people with T1DM and age- and weight-matched controls.
This indicates that relative insulin deficiency, glucagon excess, or both, are the
main causes of postprandial hyperglycemia in individuals with poorly managed
T1DM, rather than an intrinsic abnormality in splanchnic glucose metabolism.
T2DM patients have high fasting glucose levels and frequent glycemic excursions
after consuming carbohydrates.
In those with T2DM, insulin secretion normally declines and is delayed after
eating. Early in the development of T2DM, defects in insulin secretion are seen.
In fact, changes in the timing and volume of insulin secretion before the onset
of hyperglycemia have been observed in relatives of patients with T2DM. Insulin
secretion is impaired by chronic hyperglycemia alone or in conjunction with
increased FFA. Insulin secretion can be affected by issues with glucose sensing,
insulin processing, or intracellular signaling. Additionally, as the duration of
diabetes increases, so does the mass of -cells. Most T2DM patients experience
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changes in -cell morphology, with amylin accumulation inside of the islets being
a typical finding. Following the consumption of a meal high in carbohydrates,
postprandial glucose levels rise for extended periods of time because postprandial
glucose appearance outpaces glucose removal. To balance the appearance and
disappearance of glucose, glucose concentrations must increase the more significant
the abnormalities in insulin secretion and activity.
By the systemic rate of appearance of ingested glucose does not differ from that seen
in those without diabetes, glucose appearance is higher by failure to reduce hepatic
glucose synthesis. Despite the fact that following a meal, glucose disappearance
is frequently higher in people with diabetes than in those without diabetes, this is
mostly explained by elevated rates of urine glucose excretion. Additionally, despite
being elevated, the rates of glucose vanishing are inappropriate for the current
glucose concentrations. Post-prandial hyperglycemia is caused by deficiencies in
insulin secretion and action. An excessive glycemic excursion occurs from a delay 1
in the reduction of glucose synthesis, which is brought on by a delay in the early
INTRODUCTION AND OVERVIEW
rise in insulin concentrations. Contrarily, a reduction in insulin activity causes
chronic hyperglycemia but has no impact on peak glucose levels.
A deficiency in both leads to severe hyperglycemia, whereas a single change in
either extrahepatic or hepatic insulin action reduces glucose tolerance. Post-
prandial hyperglycemia is caused by deficiencies in insulin secretion and action.
An excessive glycemic excursion occurs from a delay in the reduction of glucose
synthesis, which is brought on by a delay in the early rise in insulin concentrations.
Contrarily, a reduction in insulin activity causes chronic hyperglycemia but has no
impact on peak glucose levels.
A deficiency in both leads to severe hyperglycemia, whereas a single change in either
extrahepatic or hepatic insulin action reduces glucose tolerance. Both fasting and
post-meal glucose levels are decreased by glucagon secretion inhibition. However,
when insulin secretion is intact, improper suppression of glucagon secretion has
little impact on glucose synthesis and glucose tolerance. Contrarily, it results in
pronounced hyperglycemia when insulin secretion is slowed down and delayed,
which is a feature of T2DM. When considered as a whole, these data indicate that
drugs that simultaneously increase glucagon, insulin, and glucose effectiveness as
well as secretion are likely to have a significant impact on glucose metabolism in
T2DM patients.
The pancreatic β-cells release amylin, a 37 amino acid polypeptide, along with
133
 insulin in response to secretagogues and nutritional cues. Amylin and insulin
plasma concentrations rise and fall simultaneously in the fasting and fed phases,
according to studies on humans. Amylin may be toxic to beta cells; hence, it has
been hypothesized that increased amylin secretion may be a factor in the death of
beta cells in T2DM.
In T2DM, there is a reduction in the release of incretins, such as glucagon-like
peptide 1 (GLP-1). Both intravenous infusion and subcutaneous injection of GLP-
1 can produce supraphysiologic concentrations, which in T2DM patients lower
fasting and post-meal glucose levels. By boosting insulin production, blocking
glucagon secretion, and delaying stomach emptying, GLP-1 does this.
GLP-1, in contrast, does not seem to affect the effectiveness of insulin or glucose
in T2DM.
1 1
INTRODUCTION AND OVERVIEW
Figure 1.47: A non-diabetic (a) or a diabetic (b) insulin profile was administered
to healthy volunteers twice. In one case, glucagon was administered in a way
that mimicked the drop in glucagon levels that naturally happens after eating.
The lack of glucagon suppression seen in type 2 diabetes in response to meal
134
consumption was replicated on the other occasion by continuously injecting
glucagon. Subjects receiving an insulin profile identical to that seen in type 2
diabetes patients experienced significantly higher glycemic excursion in the
absence of glucagon inhibition.
In T2DM, there is a reduction in the release of incretins, such as glucagon-like
peptide 1 (GLP-1). Both intravenous infusion and subcutaneous injection of GLP-
1 can produce supraphysiologic concentrations, which in T2DM patients lower
fasting and post-meal glucose levels. By boosting insulin production, blocking
glucagon secretion, and delaying stomach emptying, GLP-1 does this.
GLP-1, in contrast, does not seem to affect the effectiveness of insulin or glucose in
T2DM. People with T2DM frequently display problems in insulin action in addition
to impairments in insulin secretion. Numerous investigations have demonstrated
that T2DM impairs insulin-induced restriction of glucose production as well as
insulin-induced stimulation of glucose uptake in muscle and adipose tissues.
Exercise, weight, food, and hereditary factors are just a few of the variables that
INTRODUCTION AND OVERVIEW
have an impact on how severe insulin resistance is.
With rising diabetes severity, insulin resistance rises and is improved but not
normalized by better glycemic control. Normoglycemic relatives of persons with
T2DM have defects in insulin’s capacity to control the metabolism of glucose in
muscle and fat, clearly indicating a hereditary basis for at least some level of insulin
resistance. In patients with “mild” and “severe” T2DM, glucose production as well
as the contribution of gluconeogenesis to glucose production are both enhanced.
The degree of hyperglycemia is connected with the rise in glucose production.
T2DM also affects the ability of insulin to stimulate splanchnic (and presumably
hepatic) glucose absorption. The decreased uptake of extracellular glucose, which
suggests lower glucokinase activity, accounts for nearly all of the lower rates of
hepatic uptake in people with diabetes.
Lipid Metabolism In Type 1 And Type 2 Diabetes
Triglycerides are a significant source of energy (and a kind of energy storage) and
are mobilized as FFA. The balance between release and disposal is represented
by plasma FFA concentrations. FFA are either oxidized in muscle (cardiac and
skeletal) or the liver, or they are absorbed into and re-esterified in adipose and
hepatic tissues. They are released from triglyceride reserves within adipocytes and
135
 intravascular lipolysis of triglyceride-rich lipoproteins. In the postprandial period,
the rate of uptake by adipose and hepatic tissue is also a significant factor in FFA
concentrations. In the fasting state, FFA concentrations are primarily influenced by
the rate of entrance into the circulation.
The primary regulator of FFA release from adipose tissue is hormone-sensitive
lipase, which is incredibly insulin-sensitive. The primary hormonal regulator of
lipolysis is insulin. Increased insulin secretion typically results in increased plasma
glucose concentrations, which inhibits lipolysis (e.g., after a meal). Rising insulin
levels inhibit lipolysis, which causes FFA concentrations to decrease. This insulin-
induced decrease of FFA concentrations improves the efficiency of both endogenous
glucose synthesis and insulin-dependent glucose excretion. In contrast, lowering
blood glucose levels in people without diabetes promote lipolysis because they
reduce insulin output. FFA levels will increase as a result, stabilizing or increasing
1 glucose levels. Exogenous hyperinsulinism-induced hypoglycemia will also
decrease lipolysis and hinder counter-regulation.
INTRODUCTION AND OVERVIEW
Most of the excess FFA that is present and available for oxidation in T1DM is
caused by absolute or relative insulin deficiency. Increased FFA directly reduces
peripheral glucose absorption and, at the very least temporarily, increases
endogenous glucose synthesis. Increased ketogenesis, a precursor to ketoacidosis,
is another effect of enhanced FFA flux. Growth hormone or cortisol have limited
impact on lipolysis since insulin can offset the lipolytic effects of other hormones,
unless insulin availability is decreased. Similar to this, hyperinsulinemia blunts and
hypoinsulinemia amplifies the lipolytic effects of catecholamines.
Although glucagon has no impact on the availability of FFA in the body, higher
quantities, as observed in uncontrolled diabetes, may push the liver’s metabolism
in the direction of ketogenesis. Exercise of moderate intensity often causes insulin
levels to drop and catecholamine levels to rise, increasing the availability of FFA
and fatty acid oxidation. Exercise does not lower plasma insulin concentrations in
T1DM, and depending on when exercise occurs in relation to insulin administration,
it may prevent the typical increase in FFA that follows exercise. In such situations,
patients with T1DM rely on the catecholamine response to exercise to activate FFA,
a response that may be compromised in people with long-term diabetes. Exercise
will raise FFA flux much more in those with fasting hyperglycemia, low insulin
levels, and subsequently elevated resting FFA flux. High rates of ketone body
formation will be produced as a result of this in conjunction with the high glucagon
136
concentrations that are frequently present in these conditions.
In order to transfer FFA to the adipocyte, lipoprotein lipase (LPL) activity is
necessary for circulating plasma triglycerides.
Triglyceride and lipoprotein-derived fatty acids are partitioned away from muscle
and into adipose tissue by insulin and glucose, which preferentially stimulate
adipose LPL and inhibit muscle LPL. In T2DM, however, skeletal muscle LPL is
activated while insulin-induced activation of adipose LPL is delayed. Since high
FFA reduce muscle glucose absorption, this is especially important for patients
whose insulin action is already compromised. By preventing glucose transport,
glucose phosphorylation, and muscle glycogen synthase, FFA reduces muscle
glucose absorption.
Direct measurement of splanchnic insulin clearance suggests that whereas increased
FFA concentrations have been shown to reduce hepatic insulin metabolism in
animals, this may not be the case in humans. Both hepatic gluconeogenesis and 1
triglyceride production are stimulated by increased FFA. While chronic elevations
INTRODUCTION AND OVERVIEW
of FFA restrict insulin secretion, acute increases in FFA boost it. Elevated FFA have
been linked to numerous T2DM-related metabolic problems, although not all of
them.
Metabolism of proteins in type 1 and type 2 diabetes
During insulin deficiency, urinary nitrogen excretion, a sign of protein catabolism,
rises. A decrease of muscular mass and cachexia result if this is sufficiently extended.
Due to an overall increase in protein breakdown and a concurrent decrease in amino
acid disposal (utilization in protein synthesis or amino acid oxidation), insulin
deprivation raises the concentration of circulating amino acids. Consuming protein
promotes the release of more glucagon, which helps the body get rid of glucogenic
amino acids like glutamine and alanine. Despite increased appearance from protein
breakdown from insulin deprivation, the raised glucagon concentrations observed
in poorly controlled T1DM stimulate alanine and glutamine absorption, resulting
in normal or low amounts. Branch chain amino acid concentrations are increased in
these circumstances, but therapy with insulin quickly reduces them to non-diabetic
levels.
While some studies found no indication of an increase in catabolism, others indicated
an increase in protein turnover and/or amino acid catabolism, the impact of T2DM
on protein metabolism is less clear-cut. The difference in protein metabolism
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 between T1DM and T2DM most likely results from the ability of those with
T2DM to restrict protein catabolism and maintain lean body mass. Nevertheless,
individuals with poorly managed diabetes have higher levels of whole-body
nitrogen flux, protein synthesis, and protein breakdown. When glycemic control
is achieved through treatment with either oral medications or insulin, these defects
are returned to normal. It’s interesting to note that while T2DM reduces insulin’s
ability to control glucose and fat metabolism, its impacts on whole-body protein
synthesis and breakdown appear to be preserved.
appear to be preserved.
Regional protein dynamics in T2DM have only been studied in a small number of
studies. When compared to healthy and obese subjects without diabetes, subjects
with poorly managed T2DM showed increased 3 - methylhistidine excretion, a
measure of myofibrillar protein degradation. Reduced excretion of 3 methylhistidine
1 resulted from better glycemic management. It has been observed that individuals
with T2DM and/or insulin resistance have higher levels of specific clotting factors
are higher than usual. The pattern of fat distribution might vary significantly at a
defined BMI. The only imaging modalities that can directly quantify the size of
the intra-abdominal visceral adipose tissue are computed tomography (CT) and
magnetic resonance imaging (MRI) scans, which have been used to demonstrate
this in a very spectacular way.
As a simple anthropometric measure to evaluate the pattern of fat distribution,
the waist circumference, which is measured halfway between the lower rib edge
and the higher iliac crest, is employed for practical purposes. The threshold levels
shown in Table 1.8 are now well based on human data sets concerning associated
health concerns because this variable has been employed in several cross-sectional
and longitudinal investigations. Although the waist circumference and BMI are
strongly associated, the waist circumference is unable to distinguish between
subcutaneous and intra-abdominal fat depots.
1

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

in their blood, such as tissue plasminogen activator and plasminogen activator

inhibitor 1 (PAI - 1). This would imply that the liver and endothelial production of
specific proteins is obviously wrong. According to preliminary research, substances
that enhance insulin’s capacity to control hepatic and muscle glucose metabolism
(such as thiazolidinediones) would also help to normalize the concentrations and
possibly the activity of these proteins.
Table 1.7: Body mass index (BMI) classification (kg/m2) is used to classify
1.3.5 Obesity and Diabetes human obesity
Obesity is typically diagnosed and classified based on BMI. This straightforward
anthropometric indicator, which is independent of body height and can be derived
from body weight and height, correlates reasonably well with body fat mass (r =
0.4 to 0.7). The World Health Organization’s (WHO) most recent classification of
body weight is shown in Table 1.8. The primary formal criteria for the definition
of obesity, which is further divided into three classifications based on the degree of
excess body fat, is a BMI greater than 30 kg/m2. The BMI category of overweight
Table 1.8: Fat distribution patterns are classified, along with the thresholds
or pre-obesity, which requires additional criteria to determine the accompanying
for a somewhat and noticeably raised risk of developing metabolic and
health risks, is within the range of 25 to 29.9 kg/m2.
cardiovascular illnesses
The likelihood of developing metabolic and cardiovascular issues is influenced by
both the size of the excess body fat mass and its anatomical location. This is crucial The most significant risk factor for type 2 diabetes is obesity.
for people in the intermediate overweight category and even those with BMIs that The prevalence of body fat mass and the risk of developing diabetes are closely

138 139
 related, according to a significant body of clinical data. It is interesting that the risk
of diabetes already rises in the higher normal range of BMI, unlike other metabolic
abnormalities linked to fat. Both men and women have had this demonstrated.
Women in the upper normal range with a BMI of 23.0 - 24.9 kg/m 2 had a four-
to five-fold greater risk of developing diabetes throughout a 14-year observation
period in the prospective Nurses’ Health Study compared to women with a BMI of
22 kg/m 2. The risk of diabetes was 27.6 times higher in women with a BMI of 29.0
to 30.9 kg/m2 compared to the lean reference group.
Similar findings regarding men were seen in the Health Professionals’ Study.
Additionally, variations in body weight also indicated a higher risk of diabetes. In
comparison to women who maintain their weight, weight gain in women over the
age of 18 between 11.0 and 19.9 kg, which is the average range of weight change
between adolescence and menopause in industrialized countries, was found to be
1 associated with a 5.5-fold higher risk of diabetes, whereas weight loss to the same
extent resulted in an 80% reduction in risk. For men, very comparable data were
at modest levels of overweight and even in the upper normal range. Therefore, even
in patients who are of normal weight, the waist circumference should be frequently
measured when evaluating the risk of diabetes.
It is startling to notice in a clinical context that the majority of diabetic people,
especially those in their middle years, exhibit an evident preferred truncal buildup
of extra body fat. It’s also noteworthy that comparable findings on the link between
cardiovascular disease and BMI have been reported. According to a new study,
INTERHEART, only overweight and obese patients with an abdominal type of fat
distribution are at an increased risk of coronary heart disease.
1

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

reported.
According to a recent analysis of the EPIC Potsdam cohort, gaining 1 BMI unit of
weight between the ages of 25 and 40 raised the relative risk of T2DM by 25% and
had a higher impact than gaining the same amount between the ages of 40 and 55.
It’s also critical to remember that the length of obesity has a significant impact on
the likelihood of getting T2DM.
In a recent analysis of the relative contributions of various levels of overweight and
obesity to the prevalence of diabetes between 1976–1980 and 2000–2004 in the
USA, it was discovered that the rise in obesity was largely responsible for the rise
in the overall prevalence of diabetes from 5.08% to 8.83%. Figure 1.48 shows that Figure 1.48: the prevalence of diabetes across all five body mass index (BMI)
81% of the higher number was related to various types of obesity. The scientists groups. The samples from the 1976–1980 and 1999–2004 waves of the National
came to the conclusion that those with extremely high levels of obesity have been Health and Nutrition Examination Survey (NHANES) were compared
overrepresented in the recent rise in diabetes prevalence. As a result, obesity seems
to be the primary environmental factor that causes T2DM to emerge.
The pattern of fat distribution has a significant impact on the likelihood of Type 2 Diabetes And Obesity Genetic Predisposition
developing diabetes, in addition to the degree and duration of obesity. An early It is well recognized from studies on families, adoption, and twins that T2DM and
human investigation discovered that the pattern of fat distribution in the abdomen is obesity have deep hereditary roots. There was a significant link between the adult
a separate risk factor for type 2 diabetes. This observation was confirmed in numerous BMI of adopted Danish children and the BMI of the biological parents, particularly
age groups and ethnic groupings by further studies. The pattern of fat distribution is the BMI class of the biological mother, in the classic adoption study by Stunkard
a powerful predictor of the risk for diabetes and the metabolic syndrome, especially et al. The concordance rates for various levels of overweight in a twin study

140 141
 of obesity were twice as high in monozygotic twins as in dizygotic twins. This
strong heritability for BMI was observed at age 20 and to a comparable level at a
follow-up of 25 years, indicating that body fatness is largely under genetic control.
Additionally, there is a strong association between the BMIs of monozygotic twins
who were raised apart, further supporting the high heritability of the BMI trait.
According to a recent study of 5092 twins in the London area, the heritability of
BMI and waist circumference was calculated to be 0.77, further demonstrating the
strong influence of the hereditary components independent of the influence of the
environment’s obesogenic conditions.
Numerous monogenic illnesses that cause human obesity have been discovered
within the past ten years. However, typically children and teenagers with early
beginnings of obesity were the only age groups in which these genetic diseases
were discovered. Several homozygous and compound heterozygous mutations
1 have been identified in the leptin-melanocortin signaling system as of late, some of
which have functional repercussions that lead to human obesity. With a frequency of
INTRODUCTION AND OVERVIEW
2–4% of all cases of obesity, functional mutations in the melanocortin–4–receptor
gene are thought to be the most common cause of monogenic obesity in children. It
is remarkable that these flaws impact genes that play a key role in regulating food
intake.
Numerous chromosomes have revealed frequent genetic variations in recent
genome-wide association (GWA) studies in large populations with BMI as the trait.
These population-level variants that predispose to obesity are mostly connected to
the central pathways of food intake. As a result, human obesity may be a heritable
neurobehavioral illness that is highly sensitive to environmental factors, particularly
the availability of attractive, energy-dense meals in many civilizations.
Despite these tremendous developments in our knowledge of the genetic causes of
obesity, the majority of the novel “obesity genes” have rather little effects. Only
those who are homozygous for the FTO gene’s high-risk allele weigh on average 3
kg heavier than those who have two low-risk alleles.
A 2 oxoglutarate-dependent nucleic acid demethylase that is mostly expressed in
the brain and the arcuate nucleus of the hypothalamus is encoded by the gene. The
FTO and MC4R gene variants appear to have the biggest effects on body weight
out of the nearly 20 gene variants discovered in GWA research thus far. All other
recently found gene polymorphisms have a significantly smaller impact on body
weight than 1 kg.
142
Currently, it is believed that only those obese individuals who show a genetic
inability of the pancreas to counteract the effects of insulin resistance, which is a
common side effect of obesity, will develop T2DM; even among severely obese
individuals (BMI 40 kg/m 2), only 30 to 40% will develop diabetes throughout
their lifetime. Therefore, the existence of “diabetes genes,” which most likely
restrict cell activity, is necessary for the development of T2DM.
Developmental Programming For Diabetes And Obesity
The modification of gene expression by epigenetic mechanisms throughout fetal
life is a novel factor that may play a significant part in the emergence of obesity
and T2DM. There is some indication that epigenetics may also be at play in this
situation, despite the fact that this phenomena is still poorly understood and it is
not quite obvious which mechanisms may explain this link. Observational studies
indicate a higher incidence of childhood obesity in offspring of pregnant women 1
with gestational diabetes. According to a different study, siblings who were exposed
INTRODUCTION AND OVERVIEW
to diabetes in utero—that is, those who were born after the mother had developed
gestational diabetes—had a considerably higher chance of developing type 2
diabetes in their early 20s than siblings who were not (odds ratio: 3.7; P = 0.02).
Another intriguing clinical finding is that, regardless of the mother’s beginning
BMI, significant weight gain during pregnancy may also raise the likelihood
that the unborn child would become obese at a young age. It is thought that fetal
hyperinsulinemia, hypercortisolemia, and hyperleptinemia may be caused by both
hyperglycemia and chronic overnutrition throughout pregnancy. These hormonal
alterations may lead to a persistent malprogramming of the hypothalamic regions
in charge of energy regulation and metabolism, raising the lifelong risk for obesity
and type 2 diabetes as well as other potentially harmful long-term health effects.
However, it is hypothesized that epigenetic processes such DNA methylation,
histone modification, and changes in the microRNA pattern are involved in
mediating these effects. According to animal studies, this imprinting process may
primarily alter central neuroendocrine pathways, which may ultimately change the
way hunger regulation functions.
Pathophysiology of obesity
Despite the strong hereditary influences on body weight, there is no denying that
environmental and lifestyle changes have had a significant impact on the global
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 obesity epidemic. The abundance of food in many nations and the fact that physical
exertion is no longer necessary for survival are relatively recent developments
for mankind. This rapid environmental change and the ensuing shift in lifestyle
have taken place in the last few decades, which is probably too little time for the
genetic make-up and biological systems to adapt in a way that maximizes survival.
The relative contributions of the numerous environmental elements to the obesity
epidemic are difficult to estimate in detail at this time, and there are big variations
amongst communities. Similar to other mammals, humans have strong control over
energy homeostasis, which enables the maintenance of a steady body weight. This
ideal body weight might vary greatly between people and over the course of a
lifetime.
Energy homeostasis is governed by a complicated regulatory system that includes
both central and peripheral elements, such as the size of adipose tissue, which is
1 detected by the brain via leptin production. Additionally, in response to the organism’s
dietary intake and nutrient needs, gut hormones, signals from the gastrointestinal
INTRODUCTION AND OVERVIEW
nerve system, and nutrients signal to the brain and cause a complicated central
integration.
The anorexigenic leptin-melanocortin route and the orexigenic NPY-AgRP
pathway are the main pathways.
Numerous additional elements, such as insulin, alter these signaling procedures,
which impacts energy balance. This intricate and powerful homeostatic system also
protects body weight against both chronic overeating and a vital energy deficiency.
Under such fluctuations in energy intake and expenditure, a number of adaptive
processes are known to restore the initial body weight. This may help to explain
why obese people have a high propensity to put on weight after purposeful dietary
weight loss. After experimental overfeeding, the same propensity to regain original
body weight is shown.
Previous research utilizing indirect calorimetry to examine the relevance of the
resting metabolic rate (RMR) to the risk of obesity have elucidated the involvement
of energy homeostasis in the development of obesity. RMR was discovered to be
a family feature and to vary greatly between families in a study of Pima Indians.
Reduced energy expenditure measured in a respiratory chamber was found to be
a reliable predictor of body weight increase over a two-year follow-up period in
prospective studies of American Indians. This result was confirmed in a different
group over a 4-year follow-up period and was reported in the same study, suggesting
144
that a low rate of energy expenditure may be a factor in the accumulation of obesity
in families.
Environmental Factors Are Promoting Diabetes Type 2 And Obesity
The chance that an individual would become obese is now known to be determined
by a complicated gene-environment interaction (Table 1.9). Even in civilizations
where there is an abundance of readily available, delicious food, there is a wide
range in population body weight, from incredibly slim people to those who are
quite obese. Numerous additional elements, including physical activity, education,
and socioeconomic status, may also significantly alter body weight. According to
current data from the USA and other Western nations, the trend towards obesity
appears to hit a plateau after two to three decades of modern lifestyle. The idea
that genetic and biological variables play a significant role in the susceptibility to
develop obesity is further supported by this observation. 1
Despite the genetic propensity, it is generally acknowledged that the enormous
INTRODUCTION AND OVERVIEW
changes in lifestyle and environment that have occurred over the past 30 to 50 years
are substantially to blame for the current global obesity epidemic. While eating
habits and food preferences drastically changed, physical activity significantly
reduced as a result of technological advancements in transportation and the job.
Though there are several causes of food abundance and sedentary lifestyles, both
may equally contribute to a persistently favorable energy balance, which may lead
to energy storage in adipose tissue. The growth of the fast-food culture, which is
characterized by high-fat, low-starch dishes and a high intake of beverages with
added sugar, is a pretty fresh phenomena. The serving sizes on fast food menus are
substantial in addition to having a high energy density.
Due to these factors, it is believed that consuming fast food frequently contributes
to body weight gain and the persistence of overweight and obesity in the general
population. Despite this widely accepted interpretation, the scientific literature
contains just a scant amount of evidence supporting this link. However, a recent
systematic analysis that included six cross-sectional research and seven prospective
cohort studies came to the conclusion that there is enough evidence, at least for the
adult population.
A significant use of beverages with added sugar is another aspect of the worldwide
fast-food culture. Although there was no evidence to suggest that this association
is mediated by increased energy intake, another systematic review clearly
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 concluded that a high intake of calorically sweetened beverages can be regarded
as a determinant of obesity. This suggests that alternative biological explanations
should also be investigated.
This is a crucial problem that may call for a more intense public discussion on the
health effects of this strategy given the rapid expansion of the fast-food sector in many
nations. Americans consume one-third of their daily caloric intake from restaurant
food, and one-third of chain restaurant patrons in New York ordered meals with
more than 1000 calories, per a recent poll. As a result, there is an increasing need
to create new public health regulations to control the use of fast food and promote
better dietary options. The calorie density of modern foods is another factor in the
setting of excessive fast-food intake that may help to further explain the elevated
risk of obesity. There is strong evidence that the calorie intake is significantly
influenced by the energy density of foods. From an evolutionary perspective, the
1 regulation of energy intake in humans is adapted to starchy foods with low caloric
content that must be consumed in large quantities to provide adequate energy.
INTRODUCTION AND OVERVIEW
The majority of fast foods available today have a high energy density, which may
encourage passive calorie ingestion. According to a recent study, fast food menus
typically include 1100 kJ/100 g of energy, which is 65% more than the average
British diet’s 670 kJ/100 g of energy and more than twice the energy density of
suggested healthy diets’ 525 kJ/100 g of energy. It is around 450 kJ/100 g, which
represents the amounts against which human weight regulating mechanisms have
developed, which is 145% more than traditional African diets. The scientists came
to the conclusion that the high energy density of many fast foods presents problems
for human appetite control mechanisms under circumstances for which they were
not designed. The consistent trend toward larger portion sizes over the past few
decades may be another factor contributing to the obesity epidemic. According to a
US study, between 1977 and 1998, the average portion size for various food items
increased significantly, with fast food outlets and home consumption showing
the biggest increases. Other nations have reported seeing comparable patterns.
Increasing the portion size and energy density of food is linked to an increase in
calorie intake, which over time may encourage weight gain and obesity, according
to experimental human studies. Finally, socioeconomic status plays a significant
role in the development of T2DM and obesity. In the majority of nations, there is a
relationship between household income, education, and obesity rates.
Poor diet, little physical exercise during free time, and a lack of health awareness
146
are all indicators of a low socioeconomic class. Typically, women have a higher
gradient than men. Therefore, the low cost of energy-dense meals may act as a
mediating factor in the relationship between low family income and obesity,
whereas prudent healthy diets focused on lean meats, fish, vegetables, and fruit may
be more prohibitively priced for individuals with lower socioeconomic standing.
1
Table 1.9: Environment-related variables contributing to the rise in obesity
INTRODUCTION AND OVERVIEW
Pathophysiologic Connections Exist Between Type 2 Diabetes And Obesity
T2DM is characterized by a reduced ability of insulin to act, a reduced ability of
insulin to secrete, or both. Both faults are assumed to be necessary for the disease to
appear and both are present for many years prior to the disease’s clinical beginning.
The mechanisms by which obesity raises the likelihood of developing T2DM are
still poorly understood, and the situation is becoming increasingly complicated
as time goes on. Obesity also has a detrimental effect on insulin secretion. The
main negative impact of obesity is on the action of insulin, particularly in the liver,
muscles, and adipose tissue.
Our understanding of how an excessive fat mass, as well as persistent overeating,
may produce metabolic disruptions leading to overt changes has significantly
advanced in recent years.
Pathophysiologic connections exist between type 2 diabetes and obesity
T2DM is characterized by a reduced ability of insulin to act, a reduced ability of
insulin to secrete, or both. Both faults are assumed to be necessary for the disease to
appear and both are present for many years prior to the disease’s clinical beginning.
The mechanisms by which obesity raises the likelihood of developing T2DM are
still poorly understood, and the situation is becoming increasingly complicated
as time goes on. Obesity also has a detrimental effect on insulin secretion. The
147
 main negative impact of obesity is on the action of insulin, particularly in the liver,
muscles, and adipose tissue.
Over the past few years, significant progress has been made in our understanding of
how an excessive fat mass, as well as persistent overeating, may produce metabolic
abnormalities that result in overt T2DM in people with a genetic predisposition for
the disease.
Resistance to insulin and lipids
The “glucose-fatty acid cycle,” first proposed by Randle et al., is the oldest theory
to explain how obesity and type 2 diabetes are related. It is based on the observation
that the oxidation of glucose and fatty acids compete with one another in the heart
muscle. The increasing availability of non-esterified fatty acids from larger adipose
tissue depots competes with the body’s ability to use glucose, especially in the
1 muscle, which is the organ that oxidizes the most of it. The glycolytic enzymes
pyruvate dehydrogenase, phosphofructokinase, and hexokinase are all thought
INTRODUCTION AND OVERVIEW
to be the mechanism of action. As a result, glucose concentrations increase and
glucose oxidation is inhibited. The imbalance in glucose metabolism is further
exacerbated by the concurrent increase in fatty acid turnover and the increased
release of glycerol from adipose tissue, which is then used to produce glucose in
the liver. Another early disorder causing glucose intolerance is increased hepatic
glucose production.
A rise in free fatty acids has also been linked to a direct impairment of insulin
function. Recent research has indicated that a substantial intramyocellular lipid
buildup, a key characteristic of the insulin-resistant state, is seen in obese and
T2DM participants. When skeletal muscle is exposed to an excess lipid supply,
lipid-derived metabolites such ceramide, diacylglycerol, and fatty acyl coenzyme A
(CoA) may also accumulate intramuscularly in addition to neutral fatty acids. This
lipid buildup is linked to concomitant changes in insulin action, which are caused
by the activation of a serine-threonine kinase cascade that results in the serine-
threonine phosphorylation of IRS-1 and IRS-2, which may impair insulin signaling
and impair the activation of phosphoinositide 3-kinase and other downstream
components. Chronic overnutrition with a high dietary fat intake is another factor
contributing to and aggravating this illness. Thus, the most important factor
affecting insulin activity in obesity may be the increased availability of fatty acids.
148
1
Figure 1.49: Hyperbolic relationship between insulin sensitivity and beta-cell
INTRODUCTION AND OVERVIEW
activity. Type 2 diabetes mellitus is also known as impaired glucose tolerance
(IGT), normal glucose tolerance (NGT), and T2DM
Lipids and β- cell function
Increased insulin production and reduced hepatic insulin clearance are two
characteristics of obesity. According to human research, healthy obese persons with
excess body fat have a 50% increase in the volume of their -cells, which is likely
due to the hypertrophy of their existing β-cells.
Insulin release and insulin sensitivity have a close, non-linear relationship to one
another. It is known that disruption of this feedback system contributes to the steady
reduction in beta-cell activity and the onset of type 2 diabetes. Long-chain fatty acids
may, in addition to glucose, stimulate the release of insulin from pancreatic beta
cells by producing fatty acyl CoA and activating protein kinase C. The binding of
fatty acids to the G-protein-coupled receptor GPR 40 on the cell membrane, which
may lead to an increase in intracellular calcium and the exocytosis of secretory
granules, is another way that fatty acids affect insulin secretion. Although fatty acids
are necessary for optimal insulin secretion, continuous exposure of beta cells to too
many fatty acids is linked to a significant decrease in insulin production and severe
impairment of glucose-stimulated insulin secretion. Uncoupling protein 2 (UCP-
2) is expressed more frequently in beta cells, which is another way that high fatty
149
 acids may hinder the release of insulin in response to glucose. Under glucolipotoxic
circumstances, UCP-2 was discovered to be elevated, and mitochondrial superoxide
has been identified as a post-translational negative regulator of UCP-2 activity in
islets.
Pancreatic beta-cell glucose sensing needs a healthy oxidative mitochondrial
metabolism to produce ATP. Normal insulin secretion depends on the consequent
high ATP:ADP ratio. Studies on humans indicate that intracellular fatty acid
metabolites such fatty acid CoA and diacylglycerol may be elevated as a result
of abnormalities in mitochondrial fatty acid oxidation, which may contribute to
insulin resistance. Young children of parents with T2DM who are insulin-resistant
have recently been reported to exhibit symptoms of altered mitochondrial function.
Furthermore, it was discovered that compared to lean controls, obese people have
smaller mitochondria with worse bioenergetic capacity. Despite the paucity of
1 studies on this subject, there is mounting evidence that problems in insulin secretion 1
and action may be significantly characterized by abnormal mitochondrial function.
Figure 1.50: Adipose tissue secretory products and their relevance to function.

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

Adipose tissue as a oozing organ
The discovery that adipose tissue is a secretory organ that produces and releases a
number of substances that may contribute to the development of insulin resistance
and other health problems (Figure 1.50; Table 1.10) provides another theory that
may explain the link between obesity and T2DM. The majority of information
regarding a mediator role for tumor necrosis factor (TNF 𝛂) has been gathered for
this group of variables. The first place that the multifunctional cytokine TNF was
discovered to be expressed was in adipose tissue.
Adapted from Lafontan M. New methods to treat obesity are defined by the
afferent and efferent impulses from fat cells
After then, it was established that TNF-𝛂 exerts a range of catabolic effects on
adipose tissue. It was discovered that TNF-𝛂 and its two receptor subtypes are
overexpressed in the adipose tissue of obese people. At the local organ level, the
upregulated TNF-𝛂 system causes a number of negative effects, including the
inhibition of glucose uptake due to impaired insulin signaling and suppression
of GLUT 4 expression, a decrease in lipoprotein lipase expression and activity,
and an increase in lipolysis. Additionally, TNF- stimulates the NF-B pathway in
adipose tissue, increasing the expression of numerous proinflammatory proteins
including interleukin-6 (IL-6), IL-8, and monocyte chemotactic protein-1 (MCP-
1). The expression of adiponectin, a protein that is highly produced in fat cells
and has direct anti-diabetic and anti-atherosclerotic effects, was also shown to be
decreased by TNF-𝛂. TNF-𝛂 may play a significant role in the development of
insulin resistance by stimulating the phosphorylation of IRS - 1 at serine residue
307, which prevents the insulin signal from reaching downstream components.

150 151
 10. The protein adiponectin, which is the most frequently expressed in adipose
tissue, is by far the most intriguing element. Numerous clinical investigations have
demonstrated the inverse relationship between circulating adiponectin levels and
BMI as well as the ability of low concentrations to foretell the onset of T2DM.
Today, it is understood that adiponectin has a number of anti-diabetic and anti-
atherosclerotic actions, such as stimulating fatty acid oxidation in an AMP-activated
protein kinase-dependent manner.

Adipose Tissue’s Inflammatory Signaling Pathways

Recent studies have indicated that activation of the IKK-NF-B and c-Jun N-terminal
kinase (JNK) pathways mediates the inflammatory response in human obesity. Both
pathways are simultaneously activated by lipids as well as cytokines like TNF-
and IL-6. Experimental investigations have conclusively shown that genetically
1 or chemically inhibiting these pathways can decrease inflammation and enhance 1

insulin resistance (Figure 1.51). JNK activity is increased with obesity not just in

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

adipose tissue but also in muscle, liver, and other tissues.

Table 1.10: Adipose tissue’s secretory role in obesity and potential clinical
Both genetic and nutritional animal models of obesity that lack JNK1 do not
repercussions
develop insulin resistance or diabetes.
In a laboratory model using human adipocytes and muscle cells co-culture, IKK β has the ability to influence insulin signaling through two main pathways.
researchers recently found that factors secreted by fat cells, apart from TNF-α, Firstly, it can directly add phosphate groups to specific serine residues on IRS-1
also play a role in the development of muscle insulin resistance. This suggests (insulin receptor substrate-1). Secondly, it can also phosphorylate IκB (inhibitor
that multiple adipokines together contribute to the negative impact on muscle of NF-κB), leading to the activation of NF-κB, a transcription factor responsible
insulin function. Although we have limited knowledge about the specific nature for stimulating the production of various proinflammatory molecules like TNF-α
and intricate interactions of these proinflammatory and anti-inflammatory factors, and IL-6. Mice that have one copy of the IKK β gene (heterozygous) are partially
some relevant components have been discovered. MCP-1 is one such element that protected against insulin resistance induced by factors like lipid infusion, high-fat
could be involved in this process. Plasminogen activator inhibitor 1 (PAI-1) and diet, or genetic obesity. Both the JNK and IKK β - NF-κB pathways are triggered
lipid metabolites like ceramide are possible additional candidates with a prediabetic by pattern recognition receptors, which serve as membrane receptors for different
effect. It has also been demonstrated that the retinol-binding protein 4 (RBP-4) external signals.
increases hepatic production of the gluconeogenic enzyme phosphoenolpyruvate
carboxykinase and decreases PI 3-kinase signaling, both of which contribute to
insulin resistance. An intriguing finding in this context is that proinflammatory
cytokines generated from adipose tissue may be inhibited by adiponectin in a way
that inhibits their ability to promote insulin resistance.
Additionally, adipocytes are capable of releasing substances that have anti-
inflammatory effects, including adiponectin, IL-1 receptor antagonist, and IL-

152 153

1 that significantly enhance adipocyte inflammation and insulin resistance. Another
INTRODUCTION AND OVERVIEW
Figure 1.51: The potential cellular mechanisms contributing to inflammation
and the development of insulin resistance involve various components,
as follows: AP-1 (activator protein 1), ER (endoplasmic reticulum), IKK
(Iκ kinase), IL (interleukin), IRS (insulin receptor substrate), JNK (c-Jun
N-terminal kinase), NF-κB (nuclear transcription factor κB), PKC (protein
kinase C), ROS (reactive oxygen species), TLR (toll-like receptor), TNFR
(tumor necrosis factor receptor), and TZD (thiazolidinedione)
Fatty acids can bind to and activate TLR-4 on adipocytes, suggesting a direct
connection between certain dietary components abundant in obesity and
inflammation [59]. Mice with a loss-of-function mutation in TLR-4 were found
to be safeguarded against diet-induced obesity and insulin resistance. These mice
also exhibited reduced activity of NF-κB and JNK when fed a high-fat diet, in
comparison to wild-type control mice. In a similar experimental setup, significantly
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lower levels of circulating MCP-1 were observed. However, TLR-4 deficiency did
not diminish the expression of TNF-α and IL-6.
It is important to note that the majority of proteins released from adipose tissue are
not synthesized by fat cells themselves but rather by pre-adipocytes and immune
cells, such as activated macrophages. While leptin and adiponectin are genuine
adipokines primarily produced by adipocytes, TNF-α, IL-6, IL-8, MCP-1, visfatin,
PAI-1, and other molecules are mainly expressed by pre-adipocytes, resident
macrophages within adipose tissue, and possibly other cell types. The exact
contributions of these various cellular components to the secretion of these products
are not fully understood and may differ significantly based on the specific fat depot
and experimental model. Nevertheless, all these locally secreted factors seem to
play a role in initiating and sustaining the subacute inflammatory state associated
with obesity. It is worth mentioning that invading macrophages release factors
1
intriguing observation in this context is that pre-adipocytes and macrophages share
INTRODUCTION AND OVERVIEW
many common characteristics. Different and only imperfectly known biological
processes govern the secretory products. Other elements may potentially play a role
in the chronic inflamatory state of adipose tissue, in addition to the direct effects
of fatty acids and their intracellular metabolites. It has recently been demonstrated
that the production of pro- and anti-inflammatory substances may be significantly
influenced by the size of fat cells. The proinflammatory state is shifted in enlarged
hypertrophic fat cells, which encourages insulin resistance. This is consistent with
clinical research that shows an increased risk of T2DM development is linked to
fat cell hypertrophy.
Endoplasmic Reticulum Stress And Obesity
Recent findings indicate that obesity and chronic overnutrition can overwhelm
the functional capacity of the endoplasmic reticulum (ER), leading to ER stress,
which, in turn, contributes to the activation of inflammatory signaling pathways,
including the JNK pathway. Both high-fat diet-induced and genetically induced
obesity models have demonstrated that obesity induces ER stress, and a critical
player in this process is inositol-requiring kinase-1α (IRE-1α), which acts as a
mediator of JNK activation in insulin receptor signaling. In a mouse model of
type 2 diabetes, increasing the expression of 150-kDa oxygen-regulated protein
(ORP150), a molecular chaperone located in the ER, improved insulin tolerance
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 and enhanced glucose uptake. This suggests that ORP150 plays an essential role
in insulin sensitivity and could be a potential target for treating type 2 diabetes
(T2DM).
Oxidative Stress And Obesity
According to a Japanese study, both in people and animals, systemic oxidative
stress is linked to fat formation.
Obese mice’s adipose tissue showed a selective generation of reactive oxygen
species (ROS), along with enhanced NADPH oxidase expression and decreased
antioxidative enzyme expression. Additionally, the scientists demonstrated that
fatty acids exacerbated oxidative stress in cultured adipocytes by activating
NADPH oxidase, which was followed by dysregulated production of adipokines
like adiponectin, PAI-1, IL-6, and MCP-1. Furthermore, NADPH oxidase inhibitor
1 therapy decreased ROS production, corrected the dysregulation of adipokines
in adipose tissue, and improved diabetes, dyslipidemia, and hepatic steatosis,
INTRODUCTION AND OVERVIEW
demonstrating that the redox status in adipose tissue is a crucial factor in the
development of the metabolic syndrome.
Hypoxia In Adipose Tissues
Fat cell hypertrophy and subsequent tissue hypoxia are brought on by an increase in
the amount of adipose tissue. Recent research has provided strong evidence in favor
of the idea that hypoxia plays a significant, if not essential, role in the emergence of
chronic inflammation, macrophage activation, reduced adipokine production, ER
stress, and mitochondrial dysfunction in white adipose tissue in obesity. Along with
these effects, adipogenesis and triglyceride synthesis are inhibited, and the levels of
free fatty acids in the blood are increased. When compared to lean controls, obese
animals’ interstitial partial oxygen pressure (PO2) in adipose tissue decreased by
up to 70%, resulting in oxygen levels of just approximately 2%. The identification
of hypoxia response genes, including heme oxygenase 1 (HO-1) and others, such as
hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF),
further supported this observation. The low oxygen pressure may potentially be
a factor in the increased generation of lactate due to a decrease in mitochondrial
respiration. In humans, HIF-1 was similarly found to be upregulated in white
adipose tissue of obese patients, and its expression was downregulated following
weight loss caused by surgery. It has also been shown that adipocytes with hypoxia
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express less adiponectin.
The physiologic basis of adipose tissue hypoxia may be connected to a decrease in
capillary density and adipose tissue blood flow, both of which have been observed
in obese people and animals.
Although the hypoxic state causes the production and release of pro-angiogenic
factors from adipose tissue to increase, including VEGF and others, this
compensatory mechanism may not be enough to maintain a normal level of PO 2
because the adipose tissue may have restricted oxygen free diffusion.
Gathering Of Immunological Cells
Leptin, TNF-α, MCP-1, and other chemokines play a crucial role in attracting
macrophages to adipose tissue. Both pre-adipocytes and adipocytes secrete
various chemoattractants that facilitate the recruitment of immune cells. Recent
research indicates that the initial step in this process involves the attraction of 1
T-lymphocytes, possibly mediated by stromal cell-derived factor 1 (SDF-1). This
INTRODUCTION AND OVERVIEW
attraction of T-lymphocytes sets the stage for the subsequent invasion and activation
of circulating monocytes, leading to macrophage accumulation and activation
in a manner resembling the process seen in atherosclerosis. Such immune cell
accumulation and inflammation within adipose tissue have been observed in obese
individuals, and these effects appear to be more pronounced in omental (visceral)
adipose tissue compared to subcutaneous adipose tissue. This observation aligns
with the concept that the amount of visceral fat plays a key role in driving the
metabolic and cardiovascular complications associated with obesity.
Body Fat Distribution Pattern’s Function
The distribution of body fat in this context is a further crucial problem. Although
the higher risk of T2DM and other metabolic and cardiovascular issues in patients
with a more abdominal type of body fat distribution has long been known from
early clinical research, the underlying explanation has only lately become clear.
Compared to subcutaneous adipocytes, intra-abdominal fat cells have a different
expression pattern and are more politically active. Additionally, they exhibit
a larger buildup of lymphocytes and macrophages, which suggests increased
proinflammatory activity.
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1 1
Figure 1.52: Systemic insulin resistance is a result of nutrition and obesity-
INTRODUCTION AND OVERVIEW
induced inflammation
Additionally, they exhibit a larger buildup of lymphocytes and macrophages, which
suggests increased proinflammatory activity. Visceral adipose tissue also contains a
far higher density of blood vessels and nerves, which results in a significantly higher
metabolic activity. Visceral adipose tissue drains into the portal vein, exposing the
liver to fatty acids and proteins produced from this active fat depot and causing the
liver to become insulin resistant. As a result, the immune process is recognized not
just at the level of adipose tissue but also as potentially affecting the liver and other
organs. It was also speculated that secretory components from the visceral adipose
tissue may directly contribute to hepatic insulin resistance because larger visceral
fat depots are frequently linked to fat buildup in the liver.
In conclusion, a variety of evidence points to chronic overnutrition with a high-fat,
high-sugar diet as the main contributor to chronic inflammation in obesity. This
diet may also encourage the development of systemic insulin resistance, which has
an impact on many tissues, including the liver, muscle, and brain (Figure 1.51). It
should not be disregarded that in addition to a poor diet, lifestyle variables such as
inactivity can have a significant impact on these pathologic processes.
1.4 Epidemiology Of Major Types Of Diabetes
The sickness trouble connected with diabetes is high and ascending in each country,
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fuelled by the worldwide ascent in the pervasiveness of weight and undesirable
ways of life. The most recent evaluations show a worldwide pervasiveness of 382
million individuals with diabetes in 2013, expected to ascend to 592 million by
2035. The aetiological grouping of diabetes has now been broadly acknowledged.
The two main types of diabetes are type 1 and type 2, with type 2 diabetes causing
more than 85% of all cases. The two types of diabetes can prompt multisystem
inconveniences of microvascular endpoints, including retinopathy, nephropathy
and neuropathy, and macrovascular endpoints including ischaemic coronary illness,
stroke and fringe vascular sickness. Diabetes is a significant public health condition
due to the high rates of premature morbidity, mortality, decreased life expectancy,
and financial and other costs it causes.
1.4.1 Epidemiology of Type 1 Diabetes
Type 1 diabetes mellitus (T1DM) requires lifelong insulin treatment and is typically
the result of an autoimmune response that destroys the β-cells in susceptible
INTRODUCTION AND OVERVIEW
individuals. This destruction occurs after a variable preclinical period when
islet autoantibodies to insulin, glutamic acid decarboxylase (GAD), insulinoma-
associated antigen 2 (IA-2), and other autoantigens can be detected. Although
autoantibodies are not the cause of the disease, they serve as indicators of ongoing
destruction of β-cells. Distinguishing between autoimmune T1DM (Type 1A, as per
WHO classification) and non-autoimmune T1DM (Type 1B) may not be particularly
useful for clinicians or epidemiologists. Challenges arise from measurement errors
in autoantibody tests, the likelihood of additional undetected autoantibodies, and
the transient nature of autoantibodies, all of which make accurate estimates of the
proportion of autoimmune T1DM problematic.
Note: Type 1 diabetes mellitus (T1DM) needs lifetime insulin therapy and develops
in genetically vulnerable people during a preclinical phase of varied length, often with
immune-mediated death of pancreatic cells.
Although the condition can strike at any age, its prevalence is highest during puberty. Type
1 diabetes (T1DM) and type 2 diabetes (T2DM) classification gets harder as you get older.
Longitudinal studies, such as DAISY, have shown that some individuals with
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 newly diagnosed T1DM test negative for all autoantibodies at diagnosis despite
having previously tested positive for them. Genetic factors play a significant role
in determining the susceptibility to T1DM, especially involving human leukocyte
antigen (HLA) genes. The combination of HLA DR3-DQ2 and DR4-DQ8 represents
a particularly high risk for developing T1DM, while individuals carrying only one
of these risk haplotypes have a moderately increased risk. Diagnosing T1DM in
children is generally straightforward, as they usually exhibit very high glucose
levels and a clear dependence on insulin. However, classifying and detecting T1DM
early becomes more challenging with increasing age.
The rapid presentation of type 1 diabetes mellitus to medical care and its abrupt
onset make accurate case registration possible. These data can be merged with
population denominator data to produce age- and sex-specific occurrences, provided
that ascertainment can be independently validated.
1 Occurrence Of T1DM By Age, Sex, Place And Time 1

Based on notification by the diagnosing physician and the date of diagnosis, which
Figure 1.53: Type 1 diabetes incidence in Sweden among males and females,

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

is defined as the date of the first insulin injection, the World Health Organization
(WHO) DIAMOND Study (Multinational Project for Childhood Diabetes) and the
EURODIAB ACE Study have gathered standardized incidence data for T1DM
among children aged under 15 years. Both projects have used a second source of
data to determine the extent of case undercounting.
Incidence rates are computed as the number of new cases occurring per 100,000
person-years. Person-years are estimated by considering the number of individuals
in the population who contribute as incident patients during the study period (mean
population size in each calendar year, segregated by sex and age group), multiplied
by the number of years covered by the specific age group.
The proportion of the population expected to develop the disease by a certain age
can be approximated by multiplying the average incidence rate within an age group
by the number of years covered by that age group, resulting in the cumulative
incidence rate. For example, if the average incidence rate among individuals aged
0 to 14 years is 20 per 100,000 person-years, then ([20/100,000] × 15 = 0.003 =)
0.3% of children in that population will develop the disease before they reach 15
years of age. Consequently, the prevalence of the disease among individuals aged 0
to 14 years is lower than the cumulative incidence up to 15 years of age.
broken down by age, from 1983 to 1998.
Studies of children conducted in European nations account for the majority of the
incidence data currently accessible. There are currently little incidence statistics
for Africa, but more data on the prevalence of T1DM in South American and Asian
populations has altered our knowledge of the patterns of variance in incidence
around the world.
Occurrence of T1DM By Age
T1DM can potentially occur at any age, but it is uncommon in the first year of life
and becomes increasingly challenging to distinguish from other types of diabetes
after approximately 30 years of age. Incidence rates generally show a consistent rise
with age until around 10 to 15 years old. However, recent data from Finland suggest
that the incidence in 0 to 4-year-olds is nearly as high as that in 10 to 14-year-olds.
The incidence rate increases from birth, reaches its peak around puberty (Figure
1.52), and in most populations, it is lower among 15 to 29-year-olds than among 0
to 14-year-olds. Some populations exhibit a second increase in incidence after the
age of about 25 to 30 years.
In a Swedish nationwide prospective incidence study focused on individuals aged
15 to 34 years, 78% of newly diagnosed patients were categorized as having T1DM,

160 161
 while 15% were classified as having type 2 diabetes mellitus (T2DM) at the time
of diagnosis. Subsequent follow-up revealed that 92% of patients diagnosed before
the age of 30 were treated with insulin at a later stage. These findings align with
recent incidence data from Finland for individuals aged 15 to 39 years, where the
incidence of T2DM surpassed that of T1DM by the age of around 30 years.
In Turin, Italy, which experiences a significantly lower incidence of T1DM, the
incidence of T2DM is about three times higher than that of T1DM at the age of 30
years.
Although outside the purview of this chapter, it is crucial to take into account the
potential for clinical heterogeneity and the escalating difficulty in categorizing
diabetes as people age. It’s possible that some of the apparent heterogeneity
represents extremes along a continuum, but more research is required in this area.
For age groups over 35, there are few population-based incidence data available.
1 Only two population-based incidence studies, one from Rochester, Minnesota,
1945–1969 and the other from Denmark, 1973–1977, have been published and
INTRODUCTION AND OVERVIEW
cover the incidence of T1DM across the entire age range. According to the latter
study, there is a 1- to 1.5% chance that someone will develop T1DM before turning
80.
Frequency By Gender
The peak in T1DM incidence among children occurs slightly earlier in girls compared
to boys (Figure 1.52), suggesting a potential influence of puberty on the disease. In
the 1970s, there was a notable male excess of T1DM in children from populations
of European origin, while populations of African and Asian origin showed a female
excess. However, during the early 1990s, the sex-specific pattern in incidence
among children changed, with more modest differences between genders. Out of
112 centers with data from 1990 to 1999, only six showed a significant excess of
females (e.g., Beijing, Hong Kong, Zunyi in China, New South Wales in Australia,
Puerto Rico, and the Afro-American ethnic group in the USA), and six centers
showed a significant male excess (e.g., West Bulgaria, Finland, Attica in Greece,
Switzerland, Oxford in the UK, and the Dominican Republic). These differences
were generally of modest magnitude.
In general, high-incidence countries tend to exhibit a slight male excess in T1DM,
while low-incidence countries often show the opposite with a slight female excess.
Various studies have demonstrated a male excess in the incidence of T1DM among
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young adults. The male-to-female ratio among children in most populations ranges
from 0.9 to 1.1, whereas among young adults, it ranges from about 1.3 to 2.0 in
many populations.
Prevalence By Nation
Worldwide, there is a significant geographic variance in the incidence rate of
T1DM among children’s populations (Figure 1.53). The age-adjusted incidence
rate of T1DM between 1990 and 1999 ranged from 0.1 in Zunyi, China, and
Caracas, Venezuela, to 37.8 in Sardinia, and 40.9 in Finland. The most current
data from Finland show the highest incidence ever reported in 2006, with a rate of
approximately 60 per 100 000.
European countries have well-established registries for tracking T1DM incidence,
and there is a significant variation in incidence rates across these countries.
The difference between the highest and lowest incidence countries in Europe is 1
approximately 10-fold. For instance, Macedonia reported the lowest rate of 3.6 new
INTRODUCTION AND OVERVIEW
cases per 100,000 people per year during 1989-1994. On the other hand, Sweden
had a high incidence rate of 30 new cases per 100,000 people per year. Countries
like France and mainland Italy reported intermediate incidence rates, around 10 per
100,000 people per year. Some other European countries demonstrated intermediate
to high incidence rates.
Generally, eastern European countries tend to have lower incidence rates. However,
recent data from EURODIAB showed that several countries, where the incidence
rate was previously below 10 per 100,000 people per year, have experienced an
increase in incidence to 10 per 100,000 people per year or more during 1999-
2003. Examples of such countries include Lithuania, Bucharest in Romania, and
Katowice in Poland.
For the age range of 15 to 29 years, standardized data collected between 1996 and
1997 from European centers (in Belgium, Lithuania, Romania, Sardinia, Slovakia,
Spain, Sweden, and the UK) revealed incidence rates between 5 and 12 per 100 000/
year. Although from earlier time periods, incidence rates among 15 to 29-year-olds
in this age group have also been reported in other European cities. For example, 5.5
per 100,000/year in Rzeszow, Poland, 1980–1992, approximately 7 per 100,000/
year in Turin, mainland Italy, 1984–1991 and roughly 13 per 100,000/year in two
regions of Denmark, 1970–1976.
While the incidence rates in Sweden and Sardinia are greater among children than
163
 in the other sites in the multicenter study, they are not significantly higher among
young people. A higher incidence rate of 17 per 100000/year was reported in older
data from Norway (1978–1982), and more recent data from Finland (1992–2001)
reported an incidence rate of 18 per 100000/year among those aged 15–29.
Before further information is gathered using comparable methodologies, it is
prudent to use care when interpreting differences in incidence among young adults
between nations. With incidence rates for children between 11 and 18 per 100,000
per year gathered from Allegheny County in Pennsylvania, Chicago, and Jefferson
County in Alabama during the 1990s, the USA is represented. Figure 1.53 shows
somewhat higher rates for Alberta and Calgary, Canada, whereas data from the
Avalon Peninsula, Newfoundland, showed a higher incidence rate of 35.9 per 100
000/year.
Children in care facilities in Venezuela, Paraguay, and Colombia experienced
1 incidence rates of less than 1 per 100 000 per year, 4 per 100 000 in Chile (Santiago), 1
and 8 per 100 000 on average in Argentina and Brazil. With the exception of Puerto

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

Rico and St. Thomas, many locations in Central America and the West Indies
typically exhibit low to moderate incidence rates with signs of declining time
trends. Children experience moderate to high incidence rates (15 to 25 per 100 000/
year) according to data from New Zealand and some regions of Australia. There
is a shortage of data from other Pacific Island nations, and the limited numbers of
people in most island nations make it difficult to assess what is available. In Asia,
the 23 centers in China’s early 1990s had an average incidence rate of 0.8 per 100
000/years. Kuwait stands out with a high incidence rate of 22 per 100 000/year,
whereas Japan has a slightly higher average incidence rate of 1.7 per 100 000/year
among the three centers.
Information on the prevalence of T1DM in sub-Saharan Africa is scarce. Algeria,
Libya, Sudan, and Tunisia are all in North Africa, as is the island nation of
Mauritius, which is off the coast of Madagascar. Although these locations have
reported incidence rates that range from low to intermediate, these nations cannot
be considered to be typical of Africa.

164 165
 Occurrence Varies Between Nations, Notably By Ethnic Group
Several countries have reported significant within-country variations in the
incidence rate of T1DM. For instance, relatively homogenous populations in
Finland, Sweden, and Norway have demonstrated up to 1.5-fold differences in
the incidence rate. In Italy, the incidence rate among children in Sardinia during
1990-1999 was three to six times higher (38 per 100,000 people per year) than the
average in mainland Italy, where incidence rates varied twofold, ranging from 6.3
in Campania to 12.2 per 100,000 people per year in Pavia during the same period.
In China, there was a substantial 12-fold geographic variation in T1DM incidence
(ranging from 0.13 to 1.61 per 100,000 people per year), with generally higher
incidence rates in the northern and eastern regions. Additionally, there was a sixfold
difference in incidence between the Mongol ethnic group (1.82 per 100,000 people
per year) and the Zhuang ethnic group (0.32 per 100,000 people per year).
1 The variation in T1DM incidence within certain countries can be attributed, in
part, to the ethnic diversity of their populations. For example, the 1.5-fold higher
children) is similar to that among the native Britons, despite the very much lower
incidence recorded in Karachi, Pakistan. This is true even though the incidence of
T1DM among children of immigrants to Germany, Sweden, and mainland Italy has
been shown to correlate with the incidence in the country or region of their parents’
origin, whether the incidence in the country of origin is higher or lower.
In conclusion, several of the research described above also support a role for as-
yet-unidentified environmental factors, despite the fact that there are substantial
ethnic disparities in the incidence rate of T1DM and strong evidence for a role for
hereditary factors.
Seasonal Variations in T1DM Diagnosis
Numerous studies have found that, in both the northern and southern hemispheres,
the number of cases diagnosed peaks in the fall and winter and that the proportion
of cases identified in the spring or summer declines. Although generally consistent, 1
there are some differences in the precise peak and nadir between nations, age

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

incidence among children in the South Island of New Zealand compared to the groups, sexes, and time periods.
North Island was mainly due to the 4.5 times higher incidence among children of In general, those diagnosed between the ages of 10 and 14 experience greater
European origin compared to Maoris. seasonal variance than younger children (Figure 1.53).
However, conducting epidemiologic studies involving different ethnic groups
and immigrants presents several methodological challenges. These challenges
include differences in how ethnic groups are ascertained and defined, potential
underestimation of the base population in certain ethnic groups, genetic admixture
complicating genetic associations, and the possibility of clinical presentation
variations among different ethnic groups. These factors need to be carefully
considered when drawing inferences from such studies. However, it appears that
even in Japan, the vast majority of individuals with juvenile onset have classic
autoimmune T1DM. T1DM has historically been more common in populations
of European origin, especially those who live in Europe, than in groups of non-
European ancestry. Despite earlier reports of reduced prevalence among African
American and Latino populations in the USA, it appears that these communities’
incidence is currently not significantly different from that of children in the country Figure 1.54: Seasonal variation in type 1 diabetes diagnosis among more
who are of European descent. Most South American studies with standardized
than 22 000 children diagnosed between 1989 and 1998 in European centers,
registries appear to have T1DM incidence rates that are significantly lower than
according to age of onset.
those of Latino Americans in the USA and Spaniards living in Spain.
However, the incidence among immigrants from Pakistan to the UK (or their * Age (in years) at the time of the initial insulin injection

166 167
 Different approaches have been used to analyze seasonal fluctuations, frequently
with data covering only a small number of instances and very brief periods of
time; as a result, the outcomes are not always comparable. Given the lengthy and
unpredictable preclinical period associated with T1DM, seasonal variation must
be interpreted carefully. It is hypothesized that viral or other periodic factors
may influence when the disease manifests itself in susceptible people who will
eventually develop it sooner rather than later.
Occurrence Trends With Time
It wasn’t until the late 1980s that the approach for population-based incidence
registries was established, but a number of earlier data sources have been examined
to detect potential temporal trends. Though in Denmark, the prevalence among 0 to
29-year-olds appeared steady from 1924 to the 1970s, there is a prevalent perception
1 that the incidence of T1DM grew significantly after the middle of the 20th century.
A significant increase in incidence rate over time was seen in the majority of
INTRODUCTION AND OVERVIEW
communities, with a sharper relative increase in low-incidence populations than
in high-incidence populations, according to an analysis of incidence trends using
more standardized registry data from 1960 to 1996 in 37 populations worldwide.
From the middle of the 1960s through the middle of the 1990s, the incidence rate
in Finland climbed linearly; however, after that, it increased even more sharply,
reaching approximately 60 per 100,000 per year in 2006 (Figure 1.54).
Figure 1.55: Incidence rate of type 1 diabetes diagnosed in Finland before the
age of 15 with time
168
The total relative rise in incidence rate was 2.8% per year among the 103 sites that
took part in the WHO DIAMOND project for at least three years between 1990
and 1999. According to geography, annual overall growth trends were anticipated
to be 4.0% in Asia, 3.2% in Europe, and 5.3% in North America. The only region
with a general downward tendency was the West Indies and Central America. In
general, the 1990s locations with high and very high incidence rates looked to have
the strongest increasing trend.
There were no appreciable increases in incidence rates over time in the locations
with low and very low incidence rates. However, the 15.2-year (1989-2003) time
trends in Europe reported to EURODIAB showed an overall mean increase in
incidence rate of 3.9% per year, with a tendency towards stronger relative increases
in the countries with lowest average incidence rates during the first 5.2-year (1989-
94) period. In general, the younger age groups experienced the greatest relative
growth over time in the DIAMOND centers throughout the 1990s: 4.0% among 1
0 to 4 year olds, 3.0% in the 5 to 9 year olds, and 2.1% in the 10 to 14 year olds,
INTRODUCTION AND OVERVIEW
with similar rates for boys and girls in most centers. Europe and Oceania showed
the pattern of a larger relative increase among the youngest, whereas Asia and
North America did not. In European studies spanning a wider age range, a relative
decrease in incidence rate over time was observed among older people compared to
younger people. This latter finding is consistent with a scenario in which a subset of
people who are genetically predisposed to the disease get it earlier in life. But the
scant information that is available does not totally support this hypothesis. In some
populations, older age groups have also observed an increased incidence rate, but it
is difficult to draw firm conclusions due to the lack of standardized incidence data
covering the entire age range. Be aware that the highest incidence rate maintained
around puberty despite the historical trends in Sweden that showed a declining
average age of onset.
Studies Using Twins And Familial Clustering
Data on the risk of T1DM among persons with affected relatives may also help the
clinician in counseling family members of newly diagnosed patients. These data
not only offer hints regarding the relative importance of genetic and non-genetic
factors in the etiology of disease, but they may also help people with T1DM. Eighty
to ninety percent of people with T1DM who are newly diagnosed do not have any
affected siblings or parents, although first-degree relatives of someone with T1DM
169
 are at higher risk. By the age of 20, it has been found that 4–6% of siblings of
T1DM probands in groups of European descent develop the disease, compared to
0.2%–1.0% in the similar background populations.
1 1
Figure 1.56: After several years of follow-up, monozygotic twins without
INTRODUCTION AND OVERVIEW
diabetes whose co-twin had type 1 diabetes were still clear of the disease. 95%
confidence intervals are represented by dotted lines.
Compared to children of affected mothers, the children of affected fathers had a
1.5–3 times higher chance of developing T1DM. Only 2 to 5% of the offspring of
women with diabetes have been reported to be impacted by the disease by the age
of 20, compared to 5 to 8% of the offspring of males with the disease. Currently,
no acknowledged theory can explain this phenomenon. Given the well-established
influence of genetic variables, it is not surprising that monozygotic (MZ) twins have
a substantially greater concordance rate for T1DM than do dizygotic (DZ) twins.
In one study from North America, the estimated cumulative risk was calculated
to be about 25% in MZ twins and about 11% in DZ twins 10 years after onset
in the proband (diagnosed before age 40 years). According to data from Finland,
corresponding 10-year cumulative risks were calculated to be 32% for MZ twins
and 3.2% for DZ twins.
Despite the fact that the precise age of onset was unknown in this investigation,
comparable estimations were also discovered in the Danish twin registry. The
earlier the beginning in the proband, the higher the risk for the co-twins and the
shorter the discordance time. More over 50% of MZ pairings remained discordant
for T1DM after a lengthy follow-up of discordant MZ twins from the USA and the
UK (Figure 1.55). MZ twins share 100% of their genomic DNA, which shows that
170
hereditary predisposition is typically not enough to induce disease to emerge. Many
of the non-diabetic co-twins of patients with T1DM acquire islet autoimmunity,
despite the relatively large proportion of MZ twins being discordant for clinical
T1DM.
This supports the notion that environmental factors may play a more significant
role in the progression from islet autoimmunity to overt disease, especially in light
of the limited variation in prevalence of positivity for islet autoantibodies between
nations and animal studies pointing to a two-stage disease process.
Environmental Risk Factors For Type 1 Diabetes: Insights From
Epidemiological Research
Even if the rise is caused by a shift in the age distribution, the time patterns
mentioned above must be attributed to some environmental change. Different
HLA susceptibility genotype frequencies can explain some, although obviously
not all, of the disparity in incidence rates between European nations. Recently,
INTRODUCTION AND OVERVIEW
it has been proposed that the percentage of newly diagnosed T1DM patients who
have the greatest risk genotype (DR3 - DQ2/DR4 - DQ8) has gradually declined.
It is possible to hypothesize that more people with moderate risk genotypes have
developed T1DM recently as a result of increased exposure to some risk factor or
decreased exposure to some protective factor.
The nature of these potential factors is unknown, despite the overwhelming
evidence indicating the crucial role of genetic factors in the genesis of T1DM.
However, the existing information strongly implies that one or more non-genetic
factors are also at play.
Environmental variables are generally thought to play a part in the following:
Beginning the autoimmune disease process, modifying the transition from islet
autoimmunity to clinical T1DM, or “precipitating” disease in those with severe
preclinical disease are all examples of autoimmune diseases.
Although little is known about how autoimmunity begins in people, it is presumably
caused by an immune-mediated mechanism that breaks down self-tolerance.
Although the idea that there are environmental triggers for autoimmunity cannot
be ruled out, the fact that there is little geographic variation in the prevalence of
islet autoimmunity despite the significant regional variations in the incidence of
T1DM suggests a major role for environmental factors in the progression from islet
autoimmunity to T1DM. Responsible elements might work through controlling
171
 metabolism and the immune system. According to in vitro research, actively
secreting insulin-producing cells overexpress islet autoantigens such GAD and are
more vulnerable to the cytokine interleukin 1’s harmful effects. It is possible to
hypothesize that elements that put cells under more strain may indirectly contribute
to the onset of clinical disease. This includes the mechanisms associated with insulin
resistance or other infections, puberty, and growth spurts. Although measuring
insulin resistance in people is challenging, multiple studies have demonstrated that
measures of insulin resistance compared to the first-phase insulin response to an
intravenous glucose tolerance test are predictive of the development of T1DM. The
most popularly researched non-genetic elements that may contribute to the genesis
of human T1DM are discussed here.
Certain Alleged Environmental Variables
1 help to partially explain the rising incidence of T1DM in offspring. There has yet
Viral infections
A substantial amount of research has been done relating infections and T1DM,
INTRODUCTION AND OVERVIEW
including in vitro investigations, trials with different animal models, clinical and
pathologic examinations of diseased people, and epidemiologic case-control and
cohort studies. Congenital rubella syndrome (CRS) has been linked to a multiple-
fold rise in the prevalence of type 1 diabetes. This observation has been used as
a proof of concept that intrauterine factors and viral infections in general can
influence the risk of T1DM in people, even though they do not directly cause the
occurrence of T1DM in the majority of nations today. The consistency of the data
and the absolute risk linked to CRS may have been exaggerated, but it is still the
finest example of a non-genetic factor that increases the risk of T1DM in humans.
A thorough analysis of the data revealed too much variety in methods and findings
for any conclusion to be drawn from a number of early studies based on assays for
antibodies to enteroviruses in people with T1DM and controls. In recent years, the
methodology of these investigations has seen significant improvements because
to the design of prospective studies and the detection of enterovirus RNA. Some
studies, although not all, have linked evidence of maternal enterovirus infections
during pregnancy to an increased risk of T1DM with childhood onset. Independent
prospective studies from Finland have found an association between enterovirus and
an increased risk of islet autoimmunity and T1DM, whereas other similar studies
have not found a significant association, using both serum enterovirus antibodies
and RNA as indicators of postnatal infection. A recent immunohistochemistry
172
analysis of pancreatic biopsies taken postmortem from young people with recently
developed T1DM revealed that 44 of 72 cases exhibited staining for enterovirus
capsid protein VP1 in numerous islet cells. In that investigation, very few of the
controls stained positively. This study confirmed prior findings based on a single or
small number of patients and pointed up issues with the methodologies employed
in a prior investigation of a related subject where no such evidence was discovered.
However, in situ hybridization should be utilized to examine the presence of
enterovirus RNA (rather than protein) in a greater number of islets from persons
with recent onset T1DM and the absence of it in appropriate controls in order to
confirm these findings in the future.
There is evidence that, contrary to the pattern shown for T1DM, the frequency of
enterovirus infections has reduced in recent decades with increased cleanliness. It
has been suggested that the declining level of maternal enterovirus antibodies may
1
to be a direct test of this hypothesis. The so-called “hygiene hypothesis,” which
INTRODUCTION AND OVERVIEW
has been put forth in a variety of ways, basically contends that the rise in immune-
mediated disorders, including T1DM, during the past few decades has been directly
related to the drop in microbial exposure in many cultures. In experimental animals,
a few viruses and microbes lower the prevalence of autoimmune diabetes. Studies
on infectious symptoms and non-specific illnesses conducted by epidemiologists
have shown mixed results. A recent meta-analysis found that there is some evidence
for a lower risk of T1DM among children who attended daycare centers early in
life, but the results were not sufficiently homogeneous to allow a strong conclusion.
Daycare attendance is typically associated with increased exposure to microbial
agents.
Although there are a number of encouraging indications that viral infections may
play a part in the development of T1DM, there is currently insufficient proof to
support this claim. A vaccine against such a strain may be envisioned in the future
as a preventive measure, but it is currently unclear whether or when this could be
feasible. Finding the potential enterovirus strain that might be diabetogenic would
present an additional problem.
Toxins
The poison for mice After ingesting high amounts of vacor, persons have developed
T1DM. Vacor, streptozotocin, and alloxan [88], which are specifically toxic to
-cells and used to produce diabetes in experimental animals, share structural and
173
 mechanistic similarities. However, the majority of investigations utilized ecological
study designs and evaluated levels in community drinking water, which is likely
a poor indicator of overall exposure. Some epidemiologic studies have measured
ingestion of nitrates and nitrites, which may be transformed to related N - nitroso -
compounds. Based on rat trials and in vitro investigations, it has been proposed that
prenatal exposure to the toxin bafilomycin, which is created by bacteria that live on
the skin of root crops like potatoes, may have a diabetogenic effect. The concept
that frequent potato consumption during pregnancy could raise the incidence of
islet autoimmunity in the children was refuted in a prospective research, but it is
unclear whether frequent potato consumption is actually a marker for bafilomycin
exposure. In conclusion, there is little direct evidence that toxins have a significant
role in human T1DM, albeit this may be due to a lack of well-done research.
1 Nutritional factors
Dietary variables and T1DM have been linked through a number of potentially
INTRODUCTION AND OVERVIEW
plausible pathways, including “molecular mimicry” and a negative impact of
bovine insulin in cow’s milk. Numerous case-control studies have demonstrated
a reduced risk given by prolonged breastfeeding and/or delayed introduction of
cow’s milk, however the majority of these studies were vulnerable to recall bias,
and the topic is debatable.
There was no statistically significant correlation between the length of exclusive
or total breastfeeding and numerous islet autoantibodies or T1DM in the largest
prospective trial to date that included these endpoints as its endpoints. In a recent
prospective study with 61 cases, the length of breastfeeding was likewise not
linked to self-reported T1DM up to age 30. The question of whether delaying the
introduction of cow’s milk protein can lower the incidence of islet autoimmunity
and T1DM will hopefully be answered by the ongoing randomized controlled study
(TRIGR). Although the relationship is complex and difficult to understand, two
prospective studies of islet autoimmunity have offered some evidence for a role of
age at introduction of grains or gluten.
Numerous studies have demonstrated the immunomodulatory properties of
vitamin D and the prevention of diabetes development in experimental animals
by pharmacological (hypercalcemic) dosages of 1,25-dihydroxyvitamin D. When
analyzing experimental findings from animal models, it is important to keep in
mind that the hydroxylation of 25-hydroxyvitamin D closely regulates the systemic
174
content of 1,25-dihydroxyvitamin D. A prospective investigation on the relationship
between blood 25-hydroxyvitamin D, an established marker of vitamin D status,
and the risk of T1DM has not yet been reported. Vitamin D is also created in the skin
when exposed to ultraviolet radiation. Although recall and selection bias may have
affected these findings, a multicenter case-control research indicated a significantly
decreased incidence of T1DM related with reported usage of vitamin D supplement
in early life. This was also corroborated by a prospective Finnish investigation.
Prospective research has not established a strong link between maternal vitamin D
intake during pregnancy and the risk of islet autoimmunity in children.
The usage of cod liver oil during the first year of life was linked to a decreased
incidence of T1DM, according to case-control research conducted in Norway. A key
source of vitamin D and the long-chain omega-3 fatty acids docosahexaenoic acid
(DHA) and eicosapentaenoic acid (EPA) in this population is cod liver oil, which is
widely consumed in Norway. It is suggested that n-3 fatty acids, rather than vitamin 1
D, play a role in these investigations because there was no connection with other
INTRODUCTION AND OVERVIEW
vitamin D supplements. Support for the idea that dietary n - 3 fatty acid intake may
prevent islet autoimmunity and/or T1DM recently came from a prospective study
that included dietary assessment and analysis of fatty acid composition of red cell
membranes, which is a biomarker of n - 3 fatty acid status and cannot entirely rule
out recall bias. A randomized intervention trial to use DHA supplementation to
prevent islet autoimmunity and/or T1DM is currently being planned.
The DIPP study found no correlation between serum alpha-tocopherol (vitamin
E) and progressive islet autoimmunity or T1DM in adolescence, despite prior
findings from two prospective trials suggesting such a connection. In conclusion, it
is unclear how nutrition-related factors affect type 1 diabetes.
Postnatal growth and perinatal influences
Children of non-diabetic moms who were 35 years or older when they gave birth
are at an approximately 20–30% higher risk than children of mothers who were
25 years or younger. Results for father age and birth order have been less reliable.
According to a recent meta-analysis of 20 published research, birth by cesarean
section was linked to a 20% higher incidence of T1DM in children.
Although the mechanism is uncertain and there is some possibility of selection bias
in the case-control studies included, it has been suggested that delayed colonization
of the infant’s bowel linked with cesarean section may be at play. In large cohort
175
 studies based on linking population registries, increased birth weight has been
linked to a somewhat weak but significant increase in risk of childhood onset
T1DM, regardless of maternal diabetes and other possible factors. Additionally,
there are studies that find no significant connection, but these were often smaller
case-control studies. Most of the time, it appears that the connection is unrelated to
gestational age. Indirect evidence points to the HLA genes as a potential contributor
to the link with birth weight, however a research that tested this theory directly
found no support for it. Birth weight is undoubtedly just a marker for some other
phenomenon, and the underlying mechanisms are still unknown.
Related elements like postnatal growth or excessive body weight may be significant.
Children with T1DM are taller, heavier, or gain more height or weight before
diagnosis than their counterparts, according to a number of studies. A rigorous
examination of the consistency of these correlations is necessary due to the different
1 size and growth variables considered and the diverse analytical techniques utilized
in these research.
INTRODUCTION AND OVERVIEW
In conclusion, environmental influences may affect people very differently
depending on their genetic history, however there is little direct human evidence
for specific gene-environment interactions. So far, no single identifiable factor has
been found. Given the multifactorial nature of T1DM, specific environmental risk
factors with sufficient clinical relevance and detectability in epidemiologic studies
may not exist. Nevertheless, identifying potential environmental risk factors and
their contribution to the disease process is crucial for the potential prevention of
T1DM in the future, and the lack of consistent results may be due to improperly
conducted prospective studies. Numerous randomized controlled studies using
diverse therapies are currently being conducted with the goal of lowering the risk
of islet autoimmunity or the development from islet autoimmunity to T1DM. Given
the massive amount of resources required for such initiatives and the unsuccessful
outcomes of completed trials, it could be a good idea to start such trials based on
reliable findings from carefully carried out prospective observational studies. This
objective might be attained with the help of the sizable multicenter longitudinal
TEDDY investigation.
Mortality
Prior to the 1922 discovery of insulin, T1DM meant an almost definite early death.
176
An enormous increase in survival happened after the start of insulin replacement
therapy. Diabetes cases diagnosed in the 1950s also saw a significant increase in
survival, but T1DM continues to be linked to a 2- to 10-fold increased risk of
premature death. Relative mortality has been found to vary significantly between
nations. For instance, Finland had a lower standardized mortality ratio (SMR) for
T1DM patients than Lithuania, Estonia, or Japan. It has been found that African-
American individuals with T1DM die more frequently than white patients do, and
this difference appears to be due to acute complications.
Recent data from Europe demonstrated that patients who were followed after
receiving a diagnosis of T1DM as children experienced short-term mortality that
was two times greater than that of the corresponding general populations. The SMR
varied from roughly 1.1 to 4.7 in different nations. The SMR was 4.0 in a national
cohort of T1DM patients in Norway who were monitored from the disease’s
inception before the age of 15 years old and for up to 30 years (mean 24.2 years). 1
The SMR after up to 7 years of follow-up (mean 4.5 years) was 3.7 in a UK cohort
INTRODUCTION AND OVERVIEW
of almost 7000 prevalent cases of T1DM with a mean age of 33 years at baseline.
It can be challenging to determine the cause of death, but in a recent European
multicenter study, about one-third of the early deaths were clearly attributable to
diabetic ketoacidosis (DKA), while about half of the relatively few deaths among
young people with T1DM appear to be unrelated to diabetes. When compared to
DKA, hypoglycemia is now a rare cause of death, but it may become more common
as a result of the stricter glycemic control advised to avoid long-term consequences.
Microvascular and macrovascular chronic diabetes issues begin to have an effect
after about 10 to 15 years of diabetes duration, and after about 30 years of age,
cardiovascular causes start to become more significant. Women experience relative
mortality from cardiovascular causes at least as high as males do. Patients with
T1DM have reported SMRs for cardiovascular causes of mortality ranging from 8
to 40, and this largely depends on nephropathy.
There is mounting proof that enhanced risk factor management, such as decreasing
blood pressure and cholesterol levels, and better glycemic control are linked to a
lower risk of late complications and increased survival. Although there are fewer
large cohorts with long-term follow-up of incident instances of T1DM encompassing
lengthy time periods, the trend in mortality among patients with long-term T1DM
appears to be improving. This makes it difficult to judge overall trends after
the late 1980s. Undiagnosed T1DM instances and patients in impoverished
177
 countries without access to care continue to die, which is a problem. originally thought that a fasting glucose between 6.0 and 7 mmol/L indicated pre-
diabetes, and this condition was referred to as “impaired fasting glucose” (IFG).
1.4.2 Epidemiology of Type 2 Diabetes As the “normal” fasting glucose level is subsequently lowered to 5.6 mmol/L, the
proportion of patients with “pre-diabetes” rises even more. However, oral glucose
One of the most prevalent types of chronic disease worldwide is type 2 diabetes
tolerance testing (OGTT) is the sole way to diagnose IGT, which is an intermediate
mellitus (T2DM), which affects a small percentage of societies and ethnic groups.
hyperglycemia state with a post-load glucose range of 7.8 to 11.1 mmol/L. In 2010,
It is responsible for nearly all instances of diabetes in some non-Caucasians and
it is predicted that 344 million people, or 7.9% of those in the 20 to 79 age range,
about 85% of cases among Caucasians. 285 million people worldwide were
will have IGT. The metabolic syndrome, a group of cardiovascular risk factors
expected to have diabetes in 2010, with 80% of those individuals residing in less
that includes visceral obesity, hypertension, and dyslipidemia, is usually linked to
developed nations and regions. Globally, 6.6% of people between 20 and 79 have
abnormal glucose tolerance. Despite the fact that these individuals have a high risk
diabetes. With 76 million diabetics, the Western Pacific region has the highest
of acquiring diabetes and coronary artery disease, therapies that promote physical
prevalence rate, while North America and the Caribbean has the highest prevalence
activity while lowering fat and caloric intake can significantly lower these risks by
rate at 11.7%. By 2030, there will be 438 million individuals worldwide who have
40% to 60%.
diabetes, a 54% rise over projections for 2010. The economy of nations like China
1 1
and India, which are expanding quickly, will see the biggest rises. More people
are developing T2DM, and the age of diagnosis is getting younger, as a result of Diabetes Type 2 Risk Factors

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

rising sedentary lifestyle adoption, increased consumption of high-energy foods,
and urbanization. Longer periods of hyperglycemia will surely enhance a person’s
chance of acquiring vascular problems in association with diabetes.
Note: Type 2 diabetes is becoming more common everywhere. In 2010, there were
285 million cases of diabetes worldwide, making it one of the most prevalent non-
communicable illnesses. The highest rise is seen in areas that are quickly urbanizing and
growing their economies. This increase in prevalence has been significantly attributed to
the aging population, with an increase in the proportion of persons over 65 years old in the
majority of nations.
T2DM risk is known to be elevated by a number of risk factors. These include getting
older, being overweight (especially central obesity), eating excessively, drinking
carbonated beverages, being sedentary, having a good family history, having
a history of gestational diabetes or polycystic ovary syndrome, having a severe
mental illness, having hypertension or hyperlipidemia, or having cardiometabolic
risk factors (Figure 1.56). The metabolic syndrome is a grouping of some of these
risk factors, including abdominal obesity, high blood pressure, raised blood sugar,
elevated triglycerides, and low HDL cholesterol. Numerous of these risk factors are
related to a westernized lifestyle and become more prevalent as societies become
more urbanized and mechanized. Recommendations for targeted screening for
T2DM in individuals with certain risk factors have resulted from the recognition of
the importance of these factors in the pathogenesis of T2DM.

The diagnostic criteria used to diagnose diabetes, which have been altered numerous times,
play a role in the epidemiology and prevalence of the disease. The fasting glucose cut-off
has been modified when new information becomes available. The diagnostic criteria for
diabetes and impaired glucose tolerance (IGT) are based on epidemiologic research linking
microvascular consequences to specific degrees of hyperglycemia. These modifications have
significant effects on how diabetes epidemiology research is interpreted going forward. The
diagnostic cutoff for fasting glucose was reduced from 7.8 to 7.0 mmol/L in 1999. It was

178 179

Figure 1.57: Factors that increase the risk of developing type 2 diabetes. High
1 density lipoprotein cholesterol, polycystic ovarian syndrome, and triglycerides
are all abbreviations for HDL
INTRODUCTION AND OVERVIEW
Obesity drives the present global spread of T2DM and accounts for 80 to 85% of
the overall risk of getting the condition.
Body mass index (BMI) cut-offs below 24 kg/m2 are associated with an increased
risk of T2DM, while in Asians, the risk may be associated with lower BMI
thresholds. Despite being a particularly potent risk factor, central obesity can
increase risk regardless of the overall level of general fat. This obesity-related risk
is more pronounced in some ethnic groups than others, including Native Americans,
African-Americans, South Asians, Chinese (and other Asian ethnicities), and
Pacific Islanders. It may be linked to higher visceral adiposity.
Newly Discovered Risk Factors
Reduced sleep
Short sleep duration, another aspect of our modern lifestyle, is now acknowledged
as perhaps playing a significant role in the rising prevalence of T2DM, along with
dietary changes and levels of physical activity. The deleterious effects of sleep
loss on insulin sensitivity and glucose tolerance have been recognized in early key
work. Later cross-sectional research has suggested a link between insufficient sleep
and diabetes and obesity. Short sleep duration was linked to a 57% increase in the
chance of diabetes diagnosis throughout a 10-year research period in a prospective
180
analysis of more than 70 000 women in the Nurses Health research.
Similar information was found in the first National Health and Nutrition
Examination Survey (NHANES I), which showed that participants who slept for 5
hours or less each night experienced a 47% rise in the incidence of diabetes over a
10-year period.
The precise mechanism by which sleep deprivation increases the risk of developing
diabetes is unknown, but it may be related to sympathetic nervous system activation,
a reduction in the brain’s ability to use glucose, changes in the hypothalamic-
pituitary-adrenal axis, and other neuroendocrine dysregulation.
Altered Metabolism Brought On By Drugs
More people are becoming aware of the possibility that several widely used drugs
could have negative metabolic effects and raise diabetes risk. Beta-blockers can
affect insulin production, and high dose thiazide diuretics have been shown to 1
worsen insulin resistance. Antipsychotic medication use, particularly second
INTRODUCTION AND OVERVIEW
generation (atypical) antipsychotics, has more recently been associated with
diabetes and hyperglycemia. Highly active antiretroviral therapy (HAART) is
being used more frequently, which has significantly decreased the mortality of HIV-
infected patients. However, protease inhibitors and, to a lesser extent, nucleoside
reverse transcriptase inhibitors have been linked to insulin resistance, abnormal
glucose and lipid metabolism, and a higher risk of T2DM. In regions where HIV/
AIDS is endemic, like Africa, the rising usage of such drugs is anticipated to have
a significant effect on the epidemiology of diabetes.
Environmental pollutants
Although the majority of research on the rising prevalence of diabetes associated
with a westernized lifestyle has been on dietary changes and an increase in sedentary
behavior, new studies have suggested that environmental contaminants may
represent an additional, previously undiscovered relationship between urbanization
and diabetes. For instance, there is a significant cross-sectional correlation between
serum concentrations of chlorinated persistent organic pollutants and components
of metabolic syndrome, as well as diabetes. Another type of organic pollutants
that have lately been linked to diabetes is brominated flame retardants. These
environmental chemicals are thought to build up in adipose tissue and function
as endocrine disruptors, which results in dysregulation of glucose and lipid
181
 metabolism.
Low birth weight and starvation in fetuses
An association between the intrauterine environment, fetal malnutrition, and
the risk of diabetes and cardiovascular disease in later life is now more strongly
supported by the available data.
Rapid postnatal growth, low infant birth weight, and maternal undernutrition have
all been linked to an increased risk of diabetes in the progeny. This “mismatch”
between a metabolic phenotype programmed during intra-uterine development
and the nutrient-rich postnatal environment may be particularly significant in areas
experiencing fast economic expansion. Additionally, children of obese or diabetic
parents are more likely to develop diabetes and cardiometabolic problems. By
creating a vicious cycle of “diabetes be getting diabetes,” the rising number of
1 women with young-onset diabetes is expected to make the diabetes epidemic even
worse.
INTRODUCTION AND OVERVIEW
Increasing age, obesity, physical inactivity, dietary variables, a favorable family
history, and the existence of other cardiometabolic risk factors continue to be the
primary risk factors linked with diabetes, despite the growing knowledge of these
novel risk factors.
Methodological problems in type 2 diabetes epidemiology
One must be cognizant of the significance of the study technique when comparing
epidemiologic data in T2DM. In order to allow for comparison and standardization,
survey methodologies must be reliable. The ideal sample size for a community is a
sizable, genuinely random sample with a high response rate; workplace samples may
show “healthy worker” effects, but selective samples (such as volunteers or people
with another disease) are less informative due to inherent recruiting bias. Study
populations must be age- stratified, and any comparisons must be age-adjusted,
either within the data set or standardized against a reference group, because the
age distribution of sample populations is critical in determining the prevalence of
T2DM, which increases with age. Finally, the procedures used to collect data are
crucial. For instance, it matters whether or not participants have an OGTT after a
preliminary blood glucose test.
There has been an increase in the prevalence of T2DM, according to studies carried
out in various parts of the world. Few would contest that this translates into an
182
increase in the burden of diabetes, but it is crucial to understand the causes of this
rise in prevalence. The prevalence of diabetes is directly impacted by a number of
factors, which may also contribute to the rising prevalence (Figure 1.57):
1 alterations in the ratio of diagnosed to undiagnosed cases of diabetes;
2 population demographic changes with an aging population;
3 An earlier age at diabetes onset;
4 Patients with diabetes are living longer than they did previously;
5 Increasing diabetes incidence
Depending on the population under study, the various elements may each contribute
differently, but most—if not all—of them are significant in most populations.
Diabetes definition modifications and their effects
It has long been known that diabetes is a condition marked by high blood glucose
levels, but until the World Health Organization (WHO) Expert Committee on 1
Diabetes Mellitus defined the syndrome as a state of chronic hyperglycemia that
INTRODUCTION AND OVERVIEW
may be caused by numerous environmental and genetic factors, frequently acting
jointly, there was no widely accepted definition of the syndrome.
The specific threshold of hyperglycemia that defines diabetes has changed
throughout time and is based on epidemiologic research on how glucose levels are
distributed among different populations. The epidemiology of the disease is affected
in a number of ways by the evolution of the definition of diabetes. The threshold
for fasting glucose diagnosis of diabetes was lowered from 7.8 to 7.0 mmol/L
with the American Diabetes Association (ADA) and WHO classification of 1999,
increasing the proportion of people in any given group that satisfies a diagnosis of
diabetes. Furthermore, it’s critical to recognize that in any epidemiologic survey,
the diagnosis might have been made using either post-load readings from an OGTT
or increased fasting glucose. Numerous studies have shown that the fasting glucose
criteria and post-load criteria identify slightly different subjects in most populations,
and the use of fasting glucose alone will reduce the overall prevalence of diabetes
compared to that identified by 2 - hour postload glucose criteria. This is true even
though the lower fasting glucose values were chosen to more closely resemble
the diagnostic significance of the 2 - hour post-load concentration. Furthermore, a
growing number of epidemiologic research uses the HbA1c test as a dysglycemia
indication. Despite the fact that HbA1c is not currently thought to be a reliable
diagnostic tool for diabetes or intermediate hyperglycemia, this is a topic of intense
183
 debate. Table 1.12 provides a summary of the WHO’s recommendations for the
diagnostic standards for diabetes and intermediate hyperglycemia. While the ADA’s
recommendation for diagnosing IFG will identify more subjects with intermediate
hyperglycemia than the WHO does, increased diagnostic activity (such as through
the use of the OGTT) will result in a higher ratio of diagnosed to undiagnosed
diabetes and may have an impact on the prevalence rate reported in epidemiology
studies.
1 lists the countries with the highest prevalence and projected prevalence, while
INTRODUCTION AND OVERVIEW
Table 1.12: Comparison of the 2006 WHO recommendations for the diabetes
and intermediate hyperglycemia diagnostic criteria
According to a thorough research on the prevalence of diabetes worldwide, the
proportion of adults over 65 years old has increased, which is the most significant
demographic change affecting diabetes prevalence globally. The rising age-specific
prevalence of diabetes, particularly in younger age groups, is another significant
factor that has had an impact on its prevalence. This shows that diabetes develops
earlier in life, which may be particularly significant in low- and middle-income
nations. It is also important to take into account the tendency for IGT prevalence
rates to fall as diabetes prevalence rates rise. This may indicate that regions with
184
a high ratio of IGT to diabetes are at an earlier stage of the diabetes epidemic
and should therefore be a particular focus for preventative measures. Changes and
fluctuations in the ratio of IGT to diabetes prevalence, or “epidemicity index,” may
serve as an accurate indicator of the severity of the pandemic in a certain area.
Worldwide type 2 diabetes patterns by region and racial/ethnic group
The International Diabetes Federation’s Diabetes Atlas provides, when possible,
the most complete and current source of information. Furthermore, a study by Wild
et al. used age- and sex-specific estimates of diabetes prevalence from accessible
epidemiologic surveys to extrapolate prevalence in adjacent countries using a
combination of parameters including geographic proximity, ethnic similarity, and
socioeconomic similarity.
Figure 1.58 displays the most recent estimates of the total number of diabetics
worldwide as well as in the nations with the greatest overall numbers. Table 1.13
1
Table 1.14 lists the nations with the greatest number of diabetics.
INTRODUCTION AND OVERVIEW
Africa
T2DM on the African continent paints a picture of the disparity between more rural
and more urbanized places. While diabetes is relatively uncommon in sub-Saharan
Africa, where poverty and malnutrition are still major issues, urbanized regions like
North Africa are reporting rising diabetes prevalence rates. According to estimates,
diabetes presently affects 3.8% of the adult population in the African region, and
that number is expected to rise to 4.7% by 2030. Other significant epidemiological
problems in the area include a low incidence of type 1 diabetes (T1DM), which is
complicated by the occurrence of atypical “ketosis-prone” diabetes, a presentation
of diabetes characterized by an initial clinical presentation that initially appears
to be T1DM with severe hyperglycemia and ketosis and a subsequent long-term
remission with a clinical course more consistent with T2DM. Malnutrition-related
diabetes mellitus (MRDM), a type of early-onset diabetes that is linked to past or
present malnutrition and occasionally includes pancreatic calcification, is another
type of early-onset diabetes.
185

Figure 1.58: Diabetes prevalence estimates (20-79 years) worldwide, 2010
1 Although infectious diseases like HIV infection and tuberculosis are currently
Sub - Saharan Africa
Prevalence data from sub-Saharan Africa are scarce, with the majority coming
from research in Ghana, Cameron, Nigeria, Tanzania, and South Africa. Diabetes
was uncommon, with prevalence rates of 0.2% in urban Ghana in 1963 and 1.65%
in urban Nigeria in 1985, according to a recent systematic analysis of data from
Ghanaians and Nigerians. In Nigeria, the prevalence of diabetes increased to 6.8%
in 2000 (for persons under 40 years old), and in Ghana, it increased to 6.3% in 1998
(for adults under 25 years old). Adults aged 24 to 74 in Cameroon (West Africa)
had an overall diabetes incidence of 1.1% and an IGT rate of 2.7%. These studies
revealed that the majority of cases were undiagnosed, once more reflecting a region
that is already seeing the beginnings of an impending diabetes epidemic.
Diabetes and IGT are increasingly prevalent in both urban and rural areas of South
Africa. Age-adjusted prevalences for diabetes and IGT in Cape Town were 8% and
7%, respectively. Based on a 75-g OGTT using the 1998 WHO criteria, a recent 1

the predominant causes of mortality in sub-Saharan Africa, it is anticipated that study in a rural South African community found that the general age-adjusted

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

non-communicable diseases like diabetes and others may soon replace infectious prevalence of diabetes was 3.9%, IGT was 4.8%, and IFG was 1.5%.
diseases as the leading causes of mortality. Only a small part of the population in
sub-Saharan Africa currently reaches the ages at which T2DM becomes a serious
health issue. Although the mortality rate has been significantly lowered as a result
of increased access to HAART, the increase in life expectancy and the unfavorable
metabolic consequences of HAART are anticipated to substantially raise the
prevalence of T2DM in the area.

North Africa
The prevalence rates are rather high (4.2 - 9.3%) in Egypt, Sudan, and Tunisia. IGT
prevalence was found to be 10% in the research of Egyptian persons over the age
of 20.
Interesting variations between the urban and rural areas were also shown; in Cairo,
diabetes was more prevalent (prevalence: 14–20%, depending on socioeconomic
class), while IGT prevalence was lower (6–9%). In contrast, rural areas had a lower
prevalence of diabetes (5%), but a greater prevalence of IGT (13%). This may Figure 1.59: Relationship between the Epidemicity Index and the prevalence
indicate that the diabetes epidemic is developing more quickly in rural areas (Figure of diabetes and impaired glucose tolerance (IGT).
1.58). Diabetes prevalence was 9.9% in the most recent Tunisian National Nutrition
Survey, with clear urban-rural variations, and an age-adjusted prevalence of 8.5%. r, rural; u, urban; h, high socioeconomic class; l, low socioeconomic status;
Sudan - D, Dangla tribe; OFS, Free State of South Africa.

186 187
 Notably, the survey revealed 85% of the cases of diabetes.
Positive family history, ethnic origin, central adiposity, and physical inactivity are
other factors that influence the risk of T2DM in African populations in addition
to exposure to urban environments. Studies have looked into potential racial
disparities. Migrant Asians had higher incidences of diabetes than native Africans
in Tanzania and South Africa, but this may be due to lifestyle differences. The
disparity was most pronounced in Tanzania (1.1% in Africans vs. 9.1% in Asians),
which highlights the low frequency in urban East Africans once more.
1 1
INTRODUCTION AND OVERVIEW
Table 1.13: Diabetes prevalence in the 20–79 age range in 2010 and 2030.
Americas
North America (USA and Canada)
In North America, diabetes and its consequences are a significant source of morbidity.
According to the NHANES survey, the overall prevalence of diabetes was 9.3%
in 1999–2002, with 6.5% of cases being diagnosed and 2.8% going unreported.
This was much higher than the 5.1% crude prevalence of total diabetes between
1988 and 1994, primarily as a result of an increase in diabetes diagnoses. There
was a noticeable difference in prevalence between the various ethnic groups, with
non-Latino African Americans (11%) and Mexican Americans (10.4%) having a
prevalence of diagnosed diabetes roughly twice as high as White people of Northern
European ancestry (5.2%) in terms of age- and sex-standardized prevalence. These
minority groups’ older members had a very high prevalence of diabetes—more
than 30%. It is commonly known that Latino and African-American Americans in
the US have high incidence rates. Diabetes had an age-adjusted prevalence of 6%
among White persons in 1991, 9% among Cubans, 10% among African Americans,
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13% among Mexican Americans, and 13% among Puerto Ricans. All groups’ rates
have increased, yet these discrepancies seem to still exist. Although the absolute rate
was twice as high in Mexican Americans, both White people of Northern European
ancestry and Mexican Americans experienced a 7 to 8 year incidence of T2DM that
about quadrupled between 1987 and 1996. Additionally, elder Dominicans (35%)
and Puerto Ricans (38%) have significantly higher rates of T2DM than do White
people with Northern European heritage (23%).
Table 1.14: Estimated numbers of diabetics in the 20 to 79 age range in 2010
INTRODUCTION AND OVERVIEW
and 2030.
The Native American Indian communities, particularly the Pima Indians, who have
50% diabetes, are other populations in the USA that are particularly at risk for
T2DM. T2DM is becoming increasingly common among Native American Indian
youth, according to reports. With a sixfold increase in prevalence over the past
20 years, diabetes now affects 5.1% of Pima Indians aged 15 to 19 and 0.2% of
Canadian Cree and Ojibway Indians. The general prevalence for Native Americans
of this age in the US is 0.5%. Secular patterns in the incidence rate of T2DM over
the past 40 years in Pima Indians, which indicated a more than fivefold increase in
incidence rates among Pima Indians aged 5 to 14 years, support this epidemic of
T2DM in young Native American Indians.
Similar circumstances were observed in Canada, where the predominance of
aboriginal peoples was more than two times higher than that of the non-aboriginal
population. Other marginalized groups are not exempt either. In 1998, it was
reported that the crude prevalence rates of T2DM and IGT among native Hawaiians
(Polynesians) were 20% and 16%, respectively. Comparing the study population
to the US NHANES II study population, the age-adjusted risk for T2DM was four
times higher. IGT and diabetes prevalence rates for second-generation Japanese
Americans were 16% and 40%, respectively, in 1991. Incidence rates are still high
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 at 17.2 per 1000 person-years.
The rise in visceral adiposity in a population prone to poor -cell function is thought
to be the cause of this. Chinese Americans are another Asian population in the
US that is particularly susceptible to diabetes, and communication difficulties with
them may make it difficult for them to receive good care and diabetes education.
According to projections, there will be 29 million Americans with diabetes by
2050, up from 11 million in 2000 (an overall prevalence of 4.0%). Among African
Americans, the rise is anticipated to be the fastest. The expected increase of 18
million is due to almost equivalent contributions from population growth, changes
in demographic make-up, and secular increases in prevalence rates. In the USA,
there are thought to be 26.8 million persons with diabetes in 2010, 5.7 million of
whom are undiagnosed. In the USA, diabetes-related medical expenses in 2007
were $174 million in direct and indirect costs. Younger folks will be affected
1 more frequently. The incidence of diabetes was 24.3 per 100 000 person-years in
the multiethnic population-based SEARCH for Diabetes in Youth Study. Native
INTRODUCTION AND OVERVIEW
American Indian and African American teenagers had the greatest incidence rates
of T2DM, at 17 to 49.4 per 100,000 individuals, compared to White people of
Northern European ancestry, at 5.6 per 100,000 people.
Table 1.15: Estimates of diabetes and IGT prevalence at the national level in
Europe in 2010
Central and South America
These regions have limited data available. T2DM prevalence was estimated in the
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Mapuche native population of rural Chile to be 3% in men and 5% in women
in 2001. This is a significant increase from the extremely low prevalence ( 1%)
observed in 1985.
Urban areas definitely have higher rates of diabetes; for instance, in Mexico City in
1994, 14% of the population had diabetes, compared to 5–10% nationwide. Early
1990s surveys in Brazil and Colombia found age-adjusted prevalence rates of
about 7%. In these populations, abdominal obesity was found to be quite prevalent,
affecting more than 80% of women.
Caribbean
Studies from Jamaica provide an example of the West Indies’ secular trend. The
rates were low in the 1960s, but they increased in the 1970s to 4% for those aged
44 and 8–10% for people aged 45–64, reaching an overall rate of 7.4% in 1996.
According to the most recent data, which was published in 1999, prevalence rates 1
were 16% for women and 10% for males overall (or 13% total). Similar to other
INTRODUCTION AND OVERVIEW
places, this increases faster than populations of European ancestry and tracks the
growth in obesity.
Europe
This region is home to some of the most developed nations in the world as well
as a diverse mix of nations with noticeable variances in affluence. However, only
a few of the countries have access to the most recent data from the country-level
surveys. Less than half of the 54 European nations and territories in the European
region were found to have recently released data on national prevalence of diabetes,
which ranged from 2.1% in Iceland to 12% in Germany (Table 1.15) in the most
recent Diabetes Atlas.
UK
Due to the high frequency of T2DM in people from the Indian subcontinent,
inner cities with diverse populations are particularly affected. In typical studies,
Caucasian males and females in the UK had age-adjusted prevalence rates of 3%
and 5%, versus 12% and 11% for their Asian counterparts. Additionally, Asians have
higher rates of IGT, a male preponderance, younger diagnosis ages, and a smaller
percentage of undiagnosed diabetes. It appears that poverty and social hardship
are factors in the rising frequency of T2DM among residents of inner cities. All
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 ethnic groups in inner-city Manchester displayed this, with White people showing
a shockingly high age-standardized prevalence rate of 20%. This phenomena may
be explained by the tendency of social deprivation, obesity, physical inactivity, and
smoking to co-segregate.
Two recent studies that showed a relationship between high dietary energy density
or poor dietary patterns marked by high intake of soft drinks, sugar-sweetened
beverages, burgers, sausages, and snacks and incident T2DM brought attention to
the importance of dietary variables. In the population-based longitudinal Ely study,
the incidence of diabetes over a 10-year period was 7.3 per 1000 person-years.
Scandinavia
The more homogeneous population in Scandinavia may reflect the true prevalence
of T2DM among white Caucasians more precisely. 8.1% of people in Northern
1 Sweden have diabetes, according to a poll. Similar findings came from a recent
study conducted in Finland, where the age-standardized prevalence of diabetes in
INTRODUCTION AND OVERVIEW
those aged 45 to 64 was 10.2% for men and 7.4% for women. Iceland’s prevalence
numbers were found to be lower. T2DM was uncommon in Northern Finland in the
early 1990s, but the prevalence of IGT was there at 29% in men and 27% in women,
which was comparable to the prevalence of 28% in a community of homogeneous
white Caucasian females in Sweden between the ages of 55 and 57. IGT affects
approximately 15% of the population in Denmark. The Finnish Diabetes Prevention
Study, which investigated whether lifestyle modifications could stop the onset of
T2DM, was inspired by the high prevalence of IGT in Finland. Surprisingly, patients
with IGT were revealed to have a 58% lower chance of developing diabetes when
given nutritional guidance and were more active, and the benefit persisted over
additional follow-up. IGT prevalence was found to be 10.5% in males and 9.2% in
women in three regions of Finland, which is significantly lower than the previously
reported figures from Northern Finland. It is unclear whether this variation is due
to regional variations or adjustments in the diabetes:IGT ratio. The incidence rate
of diabetes in Denmark was estimated using a patient registry to be 1.8 per 100 000
at age 40 and 10 per 100 000 at age 70. Before 2004, the incidence rate grew by 5%
a year before stabilizing.
Diabetes has a 30% lifetime risk, according to estimates. A recent study from
Finland found an alarming rise in the prevalence of type 2 diabetes among young
adults, with an age-adjusted incidence of 11.8 per 100 000/year among those aged
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15 to 39. The incidence rate went up 7.9% annually. The incidence of T2DM
among young people in Finland is curiously nearing that of T1DM among the 15-
to 39-year-old age range (age-adjusted incidence of T1DM 15.9 per 100 000/year),
while having the highest incidence of childhood T1DM in the world.
Continental Europe
A population-based survey conducted in Verona, Italy, found that the prevalence
of T2DM was 2.5% overall and significantly higher after the age of 35. Over the
age of 44, the age-adjusted prevalence of T2DM was 8% for women and 9% for
men in northern Italy. In a study comparing the prevalence of diabetes in Casale
Monferrato, northwest Italy, in 1988 and 2000, it was found that the prevalence
had increased from 2.13% in 1988 to 3.1% in 2000, adjusted for age and sex. The
later survey also found higher age-specific prevalence rates of diabetes in every age
group, including a twofold increase in risk for those over 80 years old. According 1
to the MONICA study, men and women aged 35 to 65 in France had an adjusted
INTRODUCTION AND OVERVIEW
prevalence of T2DM of 7% and 5%, respectively, and men and women had an
adjusted prevalence of IFG of 12%. In males and females over 60, the prevalence
of diabetes rises to 19% and 9%, respectively.
8% of senior Caucasians in the Netherlands have T2DM, and 65% of people with
IFG and postload glucose levels went on to develop diabetes within 6 years. Age-
and sex-adjusted prevalence of diagnosed diabetes was 2.2% at baseline and 2.9%
after two years of follow-up in a prospective community-based study conducted
between 1998 and 2000, with senior patients aged 70 or over making up 50% of
the T2DM group. Aging and obesity were linked to both T2DM and IGT, and the
prevalence of diabetes increased from 2.4% in 1974 to 3.1% in 1990 in Greece.
According to a survey done between 2001 and 2002, the prevalence of T2DM was
7.6% in males and 5.9% in women. In a follow-up research, 5.5% of people who
were at baseline free of cardiovascular disease developed diabetes over a 5-year
period. T2DM and IGT prevalence rates in Turkey were 6% and 9%, respectively.
Obesity, family history, and low levels of occupational activity were all linked risk
factors. Following a Mediterranean diet may also help to prevent diabetes. Eastern
European prevalence data are comparatively few.
In Fergana, Uzbekistan, both urban men and women are expected to have an age-
adjusted prevalence of T2DM of 8%, with IGT affecting 5% of men and 6% of
women.
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 Semi-rural residents are said to have lower prevalence rates for both T2DM and
IGT. Similar age-adjusted prevalence rates of diabetes were found in the rural areas
of the Uzbek province of Sirdaria (10% for men and 7.5% for women); however,
prevalence rates of IGT were found to be higher in Sirdaria women (14%) and men
(11%) than in Fergana semi-urban or urban residents. In Russia, it is predicted that
6% of men and 7% of women have diabetes, respectively, and that 6% and 13%
of people with IGT have the disease. Hyperlipidemia, obesity, hypertension, and a
dismal 10-year survival rate were all seen in clusters in subjects with diabetes. A
study based on self-reported medical diagnoses confirmed a survey conducted in
Moscow that found a low rate of reported diabetes diagnoses (2%). Underdiagnosis,
undertreatment, and sparse insulin use are other factors that may increase the burden
of morbidity. Many of the extrapolated estimates of prevalence in other Eastern
European nations come from data from Poland, where the prevalence of T2DM
1 increased from 3.7% to 10.8% between 1986 and 2000, while the prevalence of
IGT increased similarly from 2.9% to 14.5%.
INTRODUCTION AND OVERVIEW
Asia
India
Despite having the second-largest population in the world, India has the greatest
prevalence of diabetes, with an estimated 40.9 million cases in 2007 and a
projected increase to 69.9 million by 2025. Sequential surveys from India show
that the prevalence of diabetes has increased continuously since the 1970s, while
comparisons between these studies are complicated by methodological variances.
The National Urban Diabetes Survey, conducted in six cities in 2001, reported
age-standardized prevalence rates of 14% for IGT and 12% for diabetes (with a
small male preponderance); persons under the age of 40 had a prevalence of 13%
for IGT and 5% for diabetes. Increasing age, BMI, waist-to-hip ratio, a family
history of diabetes, a greater monthly income, and inactivity were all positively and
independently related with diabetes. IGT revealed relationships between age, BMI,
and diabetes in the family history. The incidence rates recorded in later studies
increased, reaching 18.6% in the city of Chennai in the most recent research and
14.3% in the Chennai Urban Rural Epidemiology research (CURES-17).
Along with the rise in diabetes incidence, there also seems to be a decline in IGT
prevalence. Another secular trend is the occurrence of diabetes at younger ages,
particularly in metropolitan settings where up to 36% of diabetics are 44 years of
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age or younger.
The prevalence of diabetes differs between urban and rural areas in India, according
to numerous studies. According to a study from Chennai, the prevalence rate
gradually rose as urbanization increased: from 2.4% in rural regions to 5.9% in
semi urban areas to up to 11.6% in urban areas. The most recent data also showed
an 18.6% prevalence in Chennai city, compared to 16.4% in a town and 9.2% in
peri-urban areas. In a study conducted in 77 sites across India (40 urban and 37
rural), the standardized prevalence rate for diabetes was found to be 4.3, 5.9, and
2.7% in the corresponding urban and rural populations. Although the incidence
rates of diabetes and IGT are significantly greater in urban than in rural areas, it
seems that the gradient between the two is fading with time.
Alarming rates of incident diabetes were recently found by the Chennai Population
Study (CUPS), occurring at a rate of 20.2 cases per 1000 person-years. Identification
of high-risk individuals and raising public awareness are urgently required. A risk 1
score designed specifically for the Indian population is called the Indian Diabetes
INTRODUCTION AND OVERVIEW
Risk Score. Age, family history, frequent activity, and waist circumference are
the four clinical factors used, and a score of > 21 can reliably identify people
with diabetes with a sensitivity and specificity of over 60%. Because lifestyle
modification has been demonstrated to be successful in lowering progression from
IGT to diabetes in the Indian population, this will aid in the identification of high-
risk people for early intervention.
A National Program on Diabetes, Cardiovascular Diseases, and Stroke (NPCDS)
pilot program was recently introduced in seven states in January 2008. This is
intended to assist in coordinating the multisectoral effort that is urgently required to
address the obesity and diabetes epidemic in India.
Pakistan, Bangladesh and Sri Lanka
These nations’ situations are basically similar to India’s.
In Pakistan’s rural Sindh Province, where 16% of men and 12% of women have
diabetes, this condition is particularly prevalent. A more recent study from Pakistan
found that although rural female prevalence rates were lower (5%), the prevalence
rates for IGT were twice as high in females as they were in males (10–11% vs. 5%).
Using data from all four provinces of Pakistan, it was estimated that 22% of urban
residents had some degree of glucose intolerance, with the incidence of diabetes in
urban areas being 6.0% for males and 3.5% for women.
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 The WHO projected a significant rise in T2DM in Pakistan from 4.3 million in 1995
to 14.5 million in 2025 using data from the National Diabetes Survey. Despite the
fact that the average BMI in rural Bangladesh is only 20.4 kg/m2, the prevalence of
diabetes is 2.1%, compared to an IGT prevalence of 13%.
The propensity toward central obesity and insulin resistance, in addition to
urbanization, is the primary cause of the high prevalence of diabetes and metabolic
disorders among Asians. Indian newborns, who are smaller at birth and have lower
birth weights, also have greater body fat as adults, which increases the risk of
cardiometabolic problems. Intriguingly, a recent study found that maternal nutrition,
particularly low maternal vitamin B12 and high folate, may be related to increased
adiposity and risk of T2DM in the offspring, indicating that other dietary factors
may also play a role in addition to increased intake of calorie- and fat-rich foods.
1 Mauritius
In-depth research has been done on the high rates of diabetes and cardiovascular
INTRODUCTION AND OVERVIEW
disease on the island of Mauritius in the Indian Ocean. Diabetes is widespread
among various ethnic groups (Asian Indian, Chinese, and Creole) in this urbanized
area; prevalence rates range from 10 to 13% for each group, and among individuals
between the ages of 45 and 74, they rise to 20 to 30%. A follow-up survey in 1998
found that the prevalence of T2DM had increased to 17.9%. Asian Indians showed
the highest incidence in both surveys.
The Middle East
Numerous countries in the region have experienced significant socioeconomic
upheaval, particularly the affl uent oil-producing nations. As a result, there have
been significant changes in dietary habits, physical activity levels, obesity rates, and
smoking habits. This has caused a noticeable rise in the prevalence of diabetes and
IGT (Table 1.16) along with increased urbanization and increased life expectancy.
individuals from the Middle East were shown to have a stronger family history,
an earlier onset of the disease, and a more rapid reduction in islet cell activity
compared to individuals from Europe. The United Arab Emirates, Saudi Arabia,
Bahrain, Kuwait, Oman, and Egypt all rank among the top 10 nations with diabetes
prevalence rates, highlighting the need for coordinated public health action in this
region to lessen the potential effects of diabetes.
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Western Pacific Region
Australia
The Report of the AusDiab Study, which was released in 2000, offers the most
recWent data on diabetes in a developed nation. The prevalence of diabetes in
Australians under the age of 25 increased from 2.5% in those between the ages
of 25 and 44 to 24% in subjects over the age of 75; the prevalence has more than
doubled since 1981. In this survey, 50% of instances were found that had never
been diagnosed. For Australians aged 25 years or older, the prevalence of IFG
and IGT combined was 16% (males 17%, females 15%). This means that nearly
25% of Australians had impaired glucose metabolism. T2DM accounts for roughly
85% of cases in Australia, and T1DM for 10%. By 2025, it is predicted that the
prevalence of diabetes will have increased from 7.6% in 2000 to 11.4% using data
from the AusDiab research. T2DM affects 16 to 30% of adults in communities of
Torres Strait Islanders and Aboriginal people in Australia. Diabetes was shown to 1
be more common in this community than patients with normal glucose tolerance,
INTRODUCTION AND OVERVIEW
with greater rates of hypertension (69% vs 21%), obesity (44% vs 16%), raised
triglyceride levels, and lower HDL cholesterol concentrations.
New Zealand
T2DM is continuously more prevalent among Polynesians (Maoris and Pacific
Islanders) than Caucasians in New Zealand; it accounts for 95% of diabetes in
Polynesians compared to 89% in Caucasians. Additionally, Polynesians have a
four to eightfold higher frequency of diabetic nephropathy than Caucasians and are
diagnosed on average 5 to 10 years younger than Caucasians. Male unemployment
rates were estimated to be shockingly high (between 37 and 75%), once again
highlighting the importance of socioeconomic position. Prevalence rates for persons
older than 30 years were 4.3% for Europeans, 5.8% for Maoris, 6.5% for Asians,
and 10.0% for Pacific Islanders in the 2006–2007 New Zealand Health Survey.
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1 countries have a diagnosis, compared to 80 to 100% of people with the disease in
INTRODUCTION AND OVERVIEW
Table 1.16: Diabetes prevalence in a few Middle Eastern nations
Pacific Island Countries
The prevalence of diabetes varies greatly across Melanesian, Micronesian, and
Polynesian communities in the Pacific Islands; this is mostly due to disparities in
economic standing and way of life. This region, particularly Nauru and Papua New
Guinea, has some of the highest prevalence rates in the entire globe.
With a longer history of westernization than other Pacific Island nations and a
wealth from bauxite mining, Nauru’s Micronesian population today has an age-
standardized prevalence rate of 40%. Since the late 1970s, Nauru has maintained
high prevalence rates, but they now seem to have stabilized.
The majority of the population of Fiji is bi-ethnic, made up of both immigrants
from India and local Fijians with Melanesian origin.
There are no recent surveys from Fiji, however a survey done 20 years ago revealed
that the prevalence rates of diabetes were already higher among Indian migrants
than among Melanesians. In people over 20 years old, the crude prevalence rates
among Indian migrants were 13% (with no discernible urban-rural gradient),
but among urban and rural Melanesians, they were 7% and 1.7%, respectively.
The discovery of high prevalence rates in urbanized Melanesians in Papua New
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Guinea has since moderated the original conclusion that these results pointed to a
difference in ethnic (genetic) susceptibility. An excellent illustration of the harm
caused by rapid urbanization is the situation in Papua New Guinea, where diabetes
is almost non-existent in highland populations and has an age-standardized
prevalence rate of over 40% among the city-dwelling Koki people (Melanesians) in
Port Moresby. Austronesians with coastal ancestry are known to have intermediate
rates. Additionally, high prevalence rates have been noted in Polynesian groups,
prominently linked to obesity and both of which are more prevalent in Polynesian
women. In 1991, diabetes prevalence in Western Samoa was estimated to be 7–9%
in two rural communities and 16% in Apia; it had increased by 200% since 1978.
The age-standardized diabetes prevalence rate in the Kingdom of Tonga, which is
located south of Samoa, was 15.1%.
According to the evidence, less than 50% of persons with diabetes in affluent
1
some Pacific Island communities. This is probably a factor in the high incidence
INTRODUCTION AND OVERVIEW
of complications and the frequent presentation of diabetes-related issues like foot
infection.
Japan
Data from rural areas of Japan revealed a prevalence of 9.1% for men and 10.8%
for women for T2DM, with matching IGT prevalence of 12% and 16.5% for
Japanese men and women, respectively. T2DM has become more prevalent in Japan
since the 1960s. 9% was the predicted prevalence according to a 2002 National
Diabetes Survey. T2DM, a new issue among Japanese youngsters, is increasingly
acknowledged as a serious issue. In children and adolescents, T2DM outnumbers
T1DM by a ratio of 4:1, and between 1981 and 1990, the incidence rate of T2DM
was 4.1 per 100,000 people, or roughly double that of T1DM. With the prevalence
of diabetes being around twice as high among Japanese-Americans as it is among
Japanese in Japan, nutritional issues are thought to be a significant influence.
The reasons for death in people with T2DM have also changed; higher rates of
renal disease death than in Caucasian populations are now being replaced by rising
rates of coronary artery disease death, probably as a result of westernization of
food and increased fat and total calorie intake. The Japanese government has
started a significant national strategic research effort called J-DOIT to lessen the
burden of diabetes and to increase patient adherence to follow-up care and diabetes
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 complications management.
Korea
Age-adjusted diabetes prevalence was found to be 7.6% in the 2001 Korean National
Health and Nutrition Survey. The frightening 23.9% IFG prevalence predicted a
future diabetes epidemic in the Korean population, similar to that in other Asian
nations.
China and Chinese Populations
One of the most obvious examples of the effect of urbanization on rising diabetes
prevalence is the quick rise in T2DM prevalence in China. With 1.3 billion people,
the People’s Republic of China is the most populous nation on earth. Diabetes was
previously uncommon; between 1980 and 1990, prevalence rates were typically
1 1
1.5% or less, even in cities like Shanghai, and as low as 0.3% in rural Guangdong
Province. However, in recent years, the prevalence has rapidly increased, a tendency
INTRODUCTION AND OVERVIEW
that was first made clear by investigations carried out in the Da Qing region of north-
eastern China. There, the incidence was 1.0% in 1986, but by 1994, it had more
than tripled to 3.5%. Da Qing was one of the 19 provinces included in the 1994
survey of 200 000 individuals aged 25 to 64, which also reported overall prevalence
rates of 2.3% for diabetes and 2.1% for IGT. This rising trend is confirmed by a
community-based study of 40 000 Chinese adults (20–74) conducted between 1995
and 1997, which also shows gradients in prevalence rates between urban and rural
areas. Diabetes and IGT had age-standardized prevalence rates of 3.2% and 4.8%,
respectively, with provincial cities having the highest prevalence and rural areas
having the lowest.
The International Collaborative Study of Cardiovascular Disease in Asia, conducted
in 2000–2001, found that the prevalence of diabetes (both undiagnosed and
diagnosed) had increased further to 5.5%, with IGT affecting an additional 7.3% of
the population (Figure 1.59).
Additionally, only 30% of the 20 million Chinese patients who are considered
to have diabetes based on fasting blood glucose have a prior diagnosis. The high
percentage of patients with IGT is very concerning. In the community-based
Shanghai Diabetes Study, participants with IGT and/or IFG had an 11.7-fold higher
chance of developing diabetes over a three-year follow-up period compared to
participants with normal glucose tolerance.
200
Compared to the People’s Republic of China, Chinese populations in affl uent
societies like Hong Kong, Singapore, Taiwan, and Mauritius all have greater
incidence rates. Between 1990 and 1995, there has been a documented rise in the
prevalence of diabetes in Hong Kong, from 8% to 10%. Recent Taiwanese research
show prevalence rates between 9 and 11%, while methodological differences make
direct comparisons challenging. According to reports, Taiwan’s annual incidence
rate is 1.8%. When compared to mainland Chinese, Chinese in Hong Kong and
Taiwan have a 1.5 to 2.0 fold higher incidence of diabetes, adjusted for age and
diagnostic criteria. This finding was reported in a study synthesizing the findings
from prevalence studies conducted in Chinese communities.
INTRODUCTION AND OVERVIEW
Figure 1.60: Diabetes prevalence among Chinese people 35 to 64 years of age
has changed
The rapid rise in obesity, particularly among children and adolescents, is most likely
to blame for China’s rising diabetes prevalence. In children aged 7 to 12 years, the
prevalence of overweight was 4.1%, and in those aged 12 to 18 years, it was 5.6%,
with obesity prevalence being 2.5% and 1.6%, respectively, for the two age groups,
according to an analysis of data from the 2002 National Nutrition and Health
Survey. Alarming rates of obesity were discovered in Hong Kong in a community-
based study involving more than 2000 teenagers between the ages of 11 and 18; 8 to
10% of those between the ages of 12 and 13 met the criteria for obesity. The rapid
rise in childhood and adolescent obesity is probably to blame for China’s rapidly
rising diabetes prevalence. According to an analysis of data from the 2002 National
Nutrition and Health Survey, obesity prevalence for children aged 7 to 18 years
was 1.6% and 2.5%, respectively, for the two age groups, while the prevalence of
overweight children was 4.1% for those aged 7 to 12 years and 5.6% for those aged
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 12 to 18. A community-based study in Hong Kong that included more than 2000
teenagers between the ages of 11 and 18 found alarming rates of obesity, with 8 to
10% of those between the ages of 12 and 13 meeting the criteria for obesity. These
concerning statistics from the Chinese population show the likelihood of future
increases within China. Given China’s enormous population, if appropriate controls
cannot be put in place, the results could be disastrous. According to the International
Diabetes Federation, 67 million individuals in China will have diabetes by 2030.
South - East Asian Peninsula
Although there is a great deal of economic diversity in this region, current emerging
data from this region revealed that diabetes is becoming more prevalent there
despite many of the countries’ rather conventional lifestyles. A survey conducted in
two villages in Cambodia in 2004 found that the prevalence of diabetes ranged from
1 5% in the rural area around Siemreap to 11% in a semi-urban area. According to a
study done on individuals in Ho Chi Minh City, southern Vietnam, the prevalence
INTRODUCTION AND OVERVIEW
of diabetes has significantly increased from 2.5% in 1993 to 6.9% in 2001. Similar
increases have been noted in the Philippines and Indonesia. With prevalence rates
of diabetes and IGT reported to be 6.7% and 12.5%, respectively, in a recent
national survey, prevalence rates in Thailand appear to be nearing those reported
from Malaysia and Singapore.
Diabetes prevalence has increased in Singapore since serial studies began there
in 1975, going from 2% in 1975 to 4.7% in 1984, 8.6% in 1992, and 9% in 1998.
According to the two most recent studies, the rate of increase might have reached
a plateau. The highest prevalence of obesity and diabetes are found among Indians
and ethnic Malays (14.3–16.7%), particularly among Malay women. IGT affects
an additional 15% of adult population. According to a recent survey carried out in
2004 by the Ministry of Health in Singapore, 8.2% of adults were reported to have
diabetes.
Once more, there is a strong correlation between obesity and adopting a westernized
diet and lifestyle. T2DM in children is also emphasized as a new issue.
Impact Of Diabetes
Both individuals and societies are being significantly impacted by the diabetes
epidemic.
The main burden is the expense of treating its side effects, which include infections,
202
stroke, blindness, coronary artery disease, renal failure, and amputation. About 3.8
million individuals worldwide passed away from diabetes and disorders associated
with it in 2007. Most patients pass away from end-stage renal disease and
cardiovascular disease, especially coronary artery disease and stroke. The scope of
these issues and their respective contributions to overall morbidity and death vary
geographically. Macrovascular problems in Caucasian populations, like coronary
artery disease and amputation, are significant contributors to disability. On the
other hand, stroke and end-stage renal illness are common among Chinese and
Asian ethnic populations. Other challenges include the inhabitants of the Pacific
Islands’ apparent susceptibility to neuropathy and metabolic abnormalities, as well
as South Asia’s apparent susceptibility to coronary artery disease.
Mortality and Morbidity
In most groups, diabetes is linked to a about twofold increase in mortality, with 1
the excess risk lowering with advancing age. Initial data indicate that the excess
INTRODUCTION AND OVERVIEW
mortality from diabetes may be higher among Asian populations, although this is
likely due to variations in how death certificates are coded. According to a recent
estimate, diabetes may have been the cause of nearly 4 million fatalities among
people aged 20 to 79 in 2010, which accounted for 6.8% of all deaths worldwide in
this age range from all causes. More than two thirds of these diabetes-related deaths
are thought to have happened in developing and middle-income nations.
Cardiovascular illness, notably ischemic heart disease and stroke, and end-stage
renal disease are the leading causes of death for T2DM patients. Both the size of
these issues and their proportionate contributions to overall morbidity and death
vary by geographic region.
Since the 1980s, 14 sites in 13 different countries have participated in the WHO
Multinational Study of Vascular Disease in Diabetes, which has produced the
most comprehensive comparison data using uniform methodology. A follow-up
report from 10 of these centers reveals that rates of coronary heart disease and
limb amputation varied between centers by 10 to 20 times, as well as significantly
different rates of clinical proteinuria and renal failure. Retinopathy and severe visual
impairment, however, varied less between centers. The relative rarity of ischemic
heart disease and lower extremity amputation in Hong Kong and Tokyo, in contrast
to a high incidence of stroke, particularly in Hong Kong, are striking aspects.
The two Native American Indian centers, Arizona and Oklahoma, also have high
203
 rates of stroke. The European centers reported the greatest incidence of ischemic
heart disease, particularly among Warsawn women. Renal failure and proteinuria
rates were highest among Native American Indians and in Hong Kong, and
myocardial infarction was also common, particularly among men.
The two Native American Indian centers, Arizona and Oklahoma, also have high rates
of stroke. The European centers reported the greatest incidence of ischemic heart
disease, particularly among Warsawn women. Renal failure and proteinuria rates
were highest among Native American Indians and in Hong Kong, and myocardial
infarction was also common, particularly among men. Other challenges include
the apparent susceptibility of South Asians to coronary heart disease and the people
of Pacific Islands to neuropathy-related diabetic foot disorders. Importantly, in the
IGT stage, the risk of coronary heart disease has already doubled.
The higher incidence of cancer in diabetic people is another factor contributing to
1 morbidity and mortality. Numerous epidemiologic studies from various populations
have revealed a connection between diabetes and an increased risk of colorectal,
ID in Brazil, and 2.5 ID in the United Republic of Tanzania. Between $232.0 and
$421.7 billion will be spent on diabetes-related medical expenses worldwide in
2007, according to estimates. Of that amount, $119.4 billion will be spent in the
USA and $64.0 billion in Europe. The estimated overall expenses of diabetes in the
USA rose from $23 billion in 1969 to $132 billion in 2002 (direct and indirect costs
combined). The American Diabetes Association (ADA) estimates that diabetes
cost the United States $174 billion in 2007 alone, including $116 billion in excess
medical costs and $58 billion in lost productivity (Figure 1.60).
Hospital inpatient care, which accounts for 50% of total costs, and medications
and supplies, which account for 12% of total costs, are the largest components of
medical expenditures attributed to diabetes. However, the actual burden is likely
to be even higher because non-monetary effects like changes in quality of life,
disability, and suffering, as well as care provided by unpaid caregivers, cannot be
taken into account in such analyses. 1

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

breast, endometrial, pancreatic, and hepatocellular cancer. It has been demonstrated

in a sizable prospective study that cancer risk increases with increased fasting
glucose at baseline, even though some of this may be due to the existence of
common risk factors including obesity and dietary variables.
Diabetes-related cardiovascular mortality has been proven to be decreased by
intensive multifactorial interventions to lower cardiovascular risk factors. Recent
long-term follow-up data from the UK Prospective Diabetes Study suggest that
while intensive blood glucose control has not been shown to lower cardiovascular
mortality in the short term, it may have beneficial effects in reducing cardiovascular
and total mortality in the long term. The relative mortality of diabetes appears to be Figure 1.61: According to the cost of care for various complications associated
declining in several nations, which may be due to the increased use of medications with diabetes, there are various economic costs of diabetes in the USA
to treat hyperlipidemia, hyperglycemia, and hypertension.
Type 2 Diabetes Prevention
T2DM is an extremely costly condition. As previously said, treating diabetes and
Health Care Burden And Economic Costs
its consequences accounts for a considerable amount of healthcare spending in
Increased morbidity and mortality linked to microvascular and macrovascular
wealthy nations.
complications, as well as an increase in diabetes prevalence, especially in young
Therefore, it is advantageous to either prevent or postpone the beginning of diabetes,
adults, are projected to result in rising health care expenses and a decline in economic
thereby lowering the complications that are linked to it. Numerous randomized
growth. According to WHO, between 2005 and 2015, diabetes and cardiovascular
clinical studies have been carried out to investigate the impact of lifestyle
disease will cause net national income losses of 557.7 billion international dollars
interventions on the prevention of T2DM as a result of greater understanding of the
(ID) in China, 303.2 billion ID in the Russian Federation, 336.6 ID in India, 49.2
natural history of the development of T2DM and the role of different modifiable risk

204 205
 factors in its pathogenesis. These research have produced a wealth of information
about the usefulness of lifestyle changes in the prevention of diabetes. The majority
of these interventions involve regimented education and exercise plans, lowering
fat intake while increasing fiber intake, moderate exercise for at least 30 minutes
each day, and modest weight loss of at least 5%. Importantly, systematic lifestyle
interventions appear to have a long-lasting impact on reducing the risk of developing
diabetes in addition to being extremely cost-effective.
In a follow-up of the Chinese Da Qing Diabetes Prevention Study, individuals who
received lifestyle counseling saw a 51% reduction in the incidence of diabetes during
the 6 years of the active intervention and a 43% reduction over the subsequent 20
years.
Numerous drugs used to treat T2DM and obesity have been tested in clinical studies
and proved to be beneficial in preventing diabetes in addition to lifestyle changes.
1 Metformin, the thiazolidinedione class of substances, acarbose, and orlistat are
some of these. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin
INTRODUCTION AND OVERVIEW
receptor blockers may also lessen the incidence of diabetes in high-risk patients
with hypertension, according to a number of clinical trials. In patients with IGT
or IFG, a sizable randomized clinical trial compared the ACE inhibitor ramipril
with a placebo. After a median follow-up of three years, it did not demonstrate a
significantly lower incidence of diabetes, despite the fact that ramipril was linked to
a higher rate of reversion to normoglycemia. For the treatment of T2DM or obesity,
numerous pharmacologic treatments are now being developed or put through
clinical studies. As a result, there should always be a supply of promising drugs to
test for T2DM prevention efficacy. However, as a method for diabetes prevention
right now, lifestyle intervention continues to be more cost-effective.
1.4.3 The Global Burden of Diabetes
Epidemiologic evidence quantifies the effects and predictors of disease, identifies
vulnerable populations and their needs, and makes it easier to develop effective
disease prevention and control strategies. Despite this, there are still few
representative epidemiologic data coming from a large number of LMICs.
Additionally, methodological deficiencies (inconsistent diagnostic criteria,
poor method standardization) and limited coverage (regional sampling with a
predominance of urban studies while the vast majority of the populations in question
are rural residents) limit the usefulness of the currently available estimates.
206
The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) produces
estimates of total diabetes deaths, prevalence, years of life lost (YLLs), years
lived with disability (YLDs), and disability-adjusted life-years (DALYs) at the
global, super-regional, regional, and national and territorial levels. These estimates
include type 1 and type 2 diabetes deaths. Type-specific estimations have also been
created since GBD 2017. The most recent estimates were produced in 2021, and
the International Diabetes Federation (IDF) has predicted the prevalence of total
diabetes through 2045. The IDF generates global estimates of diabetes deaths and
prevalence for type 1 diabetes in people aged 19 years or younger and for total
diabetes in people aged 20–79 years.
Major Burdens
Any disease’s burden, including diabetes, can be quantified by the health-related
1
effects it has on people’s lives: the morbidity and death it causes, as well as the
social and economic costs to people’s lives, families, communities, and economies
INTRODUCTION AND OVERVIEW
at large. Evaluation of resources used or lost, whether they be financial, human,
social, or infrastructural, and assigning objective “values” to them may be
intrinsically biased depending on the viewpoint adopted. The term “value” may be
used to refer to the net worth of resources that are used or lost as a result of illness
or infirmity, which is the method utilized in this chapter. This phrase is used by
economists to describe the net benefit obtained from a health care investment in
relation to the quantity of resources spent.
Acute and chronic disease complications
Depending on the type of diabetes, different patterns of significant health-related
burdens exist. 90 to 95 percent of instances of T2DM are found worldwide. The
two most prevalent types of diabetes, T1DM and T2DM, can both lead to acute and
long-term metabolic effects, but the frequency of these events varies depending on
the pathophysiology at play and the degree of glycemic control. If left ignored, acute
fluctuations in serum glucose can quickly develop into emergencies with potentially
fatal consequences. Most frequently, episodes of severe acute hyperglycemia (such
as diabetic ketoacidosis [DKA] and hyperosmolar hyperglycemic syndrome)
or severe acute hypoglycemia necessitate prompt medical attention. The goal
of longer-term monitoring is to encourage improved blood glucose control and
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 prevent the triggers of diabetes emergencies (such as infections, non-compliance
with medicines, skipping meals, and alcohol abuse). The majority of acute
problems affect patients with T1DM, while 10–12% affect those with T2DM, with
the exception of unusual forms such ketosis-prone T2DM in African subjects.
When correctly managed, acute hyperglycemic episodes like DKA have a very low
fatality rate (e.g., DKA mortality in Taiwan, the United States, and Denmark was
estimated to occur in 0.67–4.0% of patients). While the incidence of these problems
in LMIC settings is low, death from DKA can be as high as 25 to 33% in some
African nations.
Individual patient variables, such as age and additional co-morbidities, as well as
resource features, such as hospital resources and staff experience, may potentially
affect the results. Poor accessibility, inadequate therapy tools and medication, and
an inadequate number of qualified professionals, for instance, lead to poor glycemic
1 control and a higher risk of mortality in settings with limited resources. As a result,
people with T1DM in low-resource settings frequently die young. In some parts of
INTRODUCTION AND OVERVIEW
Africa, the life expectancy after diagnosis is only one year.
Table 1.17: Burden evaluation
Both T1DM and T2DM are linked to tissue damage in addition to glucose
dysregulation, which can proceed to life-threatening consequences. Diabetes
208
increases the risk of microvascular diseases (retinopathy and nephropathy),
neuropathies, macrovascular diseases (cardiovascular diseases [CVD], which
include coronary heart disease and cerebrovascular disease or “stroke,” and
peripheral vascular disease [PVD]), and the consequences of these (such as
congestive heart failure and diabetic foot). Significant morbidity, a decline in
quality of life, disability, premature mortality, and large economic consequences
are all linked to these problems. The “metabolic syndrome,” which includes
abdominal obesity, hyperinsulinemia, hypertension, dyslipidemia, proinflammatory
and procoagulant states, is also linked to T2DM. It is thought that these metabolic
and immunological abnormalities are closely related, possibly through a common
mediating mechanism. 53 to 69% of diabetics and 34 to 67% of hypertensives
in Latin America are predicted to have abnormal blood lipid subfractions. As a
result, these risk factors raise the possibility of acquiring new risks, and each new
risk increases the likelihood of atherosclerotic vascular disease-related events and 1
mortality.
INTRODUCTION AND OVERVIEW
T2DM also has a unique relationship with coronary heart disease (CHD). People
with diabetes are two to four times more likely than non-diabetics to develop CHD.
More significantly, however, patients with diabetes have the same age- and sex-
adjusted cardiovascular mortality risk as people without diabetes who have
previously experienced a myocardial infarction (MI). This elevated risk of CHD
is collectively conferred by precursors common to both T2DM and CVD (insulin
resistance, visceral adiposity, and excess inflammation), as well as a complex
mixture of mechanistic processes like oxidative stress, enhanced atherogenicity
of cholesterol particles, abnormal vascular reactivity, augmented hemostatic
activation, and renal dysfunction.
Therefore, it has been determined that, at least in the short term, managing glucose
alone does not reduce CVD events and mortality in large randomized controlled
trials. The implication is that individuals with T2DM have been encouraged to
engage in individualized comprehensive multifactorial risk management, which
includes the treatment of all comorbidities, increasing the load on patients,
healthcare professionals, and healthcare systems. Renal dysfunction risk is also
increased by diabetes. In Africa, it is predicted that 32 to 57% of diabetics will have
developed microalbuminuria within 5 to 10 years of their diagnosis. Additionally,
in the USA, diabetes is the major cause of about 45% of individuals with end-stage
renal disease (ESRD) who need dialysis or a kidney transplant. Meanwhile, 5%
209
 of all incidents of blindness worldwide are related to diabetes, and one in four
people with diabetes have some form of visual impairment. Age, glycemic control,
blood pressure control, and disease duration have all been proven to be significant
moderators of disease initiation, progression, and outcomes, particularly in the case
of retinopathy and nephropathy.
Diabetes frequently results in neuropathies. A similar percentage of diabetics in
African nations were found to have neuropathy or compromised peripheral vascular
circulation, while one-third of Sri Lankans with diabetes who were polled had
lower extremities sensory loss placing them at risk of ulceration. The risk of lower
extremity amputation is raised 15 to 40 times by neuropathy, increased susceptibility
to infection, poor wound healing, and poor distal circulation. The most significant
effect of the early asymptomatic natural history of diabetes and poor community
awareness is the increasing tissue harm caused by subclinical disease.
1 In all parts of the world, microvascular and macrovascular problems in-
crease mortality risk, morbidity, and health-seeking behavior.
INTRODUCTION AND OVERVIEW
Health Utilization Patterns
Numerous individual, provider, and system level factors have an impact on health
seeking and health utilization habits. Diabetes causes an incremental increase in
the use of health services due to morbidity, poor health, and preventative care
goals. For instance, in Costa Rica, people with diabetes visited the doctor 55%
more frequently than people without the disease, and diabetic patients in Germany
saw general practitioners (GPs) and/or specialists an average of 31 times per year.
About half of diabetes-related consultations in Sweden and Italy took place at
hospital outpatient clinics or special diabetes facilities, whilst the other half were
with general practitioners.
Diabetes is thought to be the cause of 35 million medical visits each year in Latin
America.
According to numerous studies, having diabetes doubles a person’s chance of
hospitalization compared to not having it, and this risk is increased by the emergence
of complications associated to diabetes. Hospitalization risk is increased by 70%
when impaired peripheral circulation is present, and by 310% when cardiovascular
disease is present. According to Germany’s Cost of Diabetes Mellitus (CoDiM)
study, 28.8% of people with diabetes had at least one hospital admission in 2001,
210
while the Cost of Diabetes in Europe Type II Study (CODE-2) reported that 13%
of people with T2DM were hospitalized (with an average stay of 23 days) over
the study’s 6-month follow-up. Even though studies from most parts of the world
indicate that late-stage macrovascular or microvascular complications are the main
reason for hospitalizations related to diabetes, lower income countries like Ethiopia
experience a higher percentage (almost two-thirds) of admissions in the form of
acute episodes of dysglycemia.
On health utilization and seeking, health care infrastructure and financing have
a significant impact. According to estimates, households in India pay between
85 and 95 percent of the cost of healthcare for individuals and their families. In
Latin America, 40 to 60 percent of diabetes-related expenses come from personal
funds. A study conducted in Jamaica revealed that 57% of the sample reported
having financial difficulties as a result of their disease, and of those, 50% admitted
to skipping therapy due to financial difficulties. As 19% of older Americans who 1
reported reducing purchases of diabetic drugs due to costs demonstrate, financial
INTRODUCTION AND OVERVIEW
barriers to receiving treatment are not unique to LMICs.
The financial ramifications are significant when you realize that diabetics in India
use 3.5 drugs on average. Along with glucose-lowering pharmaceuticals, these drugs
also include aspirin, lipid-lowering drugs, antidepressants, and antihypertensives.
When compared to the general population, the use of oral hypoglycemics raises
health spending by 40%, and the regular use of insulin adds another 20% to the cost.
This means that using insulin with or without oral medicines raises total expenses
by 3.1 to 3.4 times, according to data from Germany.
Compared to the general non-diabetic population, people with diabetes and its
complications seek out and use healthcare services more frequently, which increases
medical costs.
Disability
In addition to the medical or biologic dysfunction brought on by disease, poor
health has effects on how individuals and groups interact in society. This idea of
“disability” distinguishes it from straightforward biomedical disease models and
indicates that psychosocial illness or physical deviations from normal anatomical
structure or physiologic function may limit one’s capacity for performing daily
tasks and societal roles. As a result, diabetes may limit a person’s overall usefulness
and capacity for full societal integration.
211
 Disability can result from diabetes in a number of different ways.
Diabetes may be seen as a “hidden” impairment if the medical components of its
problems that directly affect physiological function are excluded. In this case, the
person is hindered from performing daily tasks but shows no outward signs of the
condition. Children with diabetes, for instance, might not be able to participate in all
the activities that their peers do and might experience unjustified prejudice. Adults
may perform less well at work due to a variety of symptoms, including diminished
fine motor skills and attention, drowsiness, frequent urination, or even a decline
in cognitive functioning. Additional restrictions for those who need insulin may
include highly structured daily activities (such as the need for meticulous glucose
monitoring, insulin administration, and timed eating), frequent hospitalizations,
episodes of hyper- and hypoglycemia, and regular preventative or therapeutic
doctor visits.
1 In fact, as complications arise, the physical effects of diabetes grow more significant.
Therefore, visual impairment, limited mobility (caused by shortness of breath,
INTRODUCTION AND OVERVIEW
chest pain, or even amputation), and general ill health (ranging from increased
susceptibility to infection to uremia related to irreversible renal dysfunction) are
all significant barriers to productive work and participation in socially beneficial
activity. Cross-sectional research conducted in the USA has shown that elevated
glycated hemoglobin (HbA1c) is linked to increased absence rates, longer absences,
and lower productivity at work.
Disability can be either temporary or permanent, depending on the person’s health
status and the severity of the illness. Although diabetes is the greatest cause of
adult-onset blindness, non-traumatic amputations, and irreversible kidney failure
worldwide, there is a dearth of data on the persistent handicap brought on by the
disease. According to data from Chile, 8% of diabetics were permanently disabled
in some way.
The psychosocial consequences that may accompany diabetes and impair
functioning are less obvious but no less severe. A health maintenance organization
cohort of 1642 adults with diabetes found that 12% were unemployed, 7% had
missed more than 5 days of work in the previous month, and 4% had difficulty
performing duties at work. Over half of those with any type of job disability that
caused absences from work and/or low productivity displayed modest or severe
signs and symptoms of depression.
212
Mortality
It is difficult to estimate the global mortality attributable to diabetes. The majority
of mortality statistics rely on known causes of death and do not take into account the
underlying mortality linked to CVD and renal illnesses and glucose dysregulation.
Danaei et al. have consequently proposed that considering how much diabetes
contributes to 21% of CHD and 13% of stroke mortality globally should be
considered when measuring actual diabetes-related mortality. These opinions were
taken into account by the World Health Organization (WHO) when determining
that diabetes was the fifth largest cause of death globally in 2000.
According to the most recent Diabetes Atlas published by the International
Diabetes Federation, diabetes causes over 6.8% of all deaths worldwide each year
(4 million fatalities). Furthermore, if deaths from IGT were included, the mortality
attributable to diabetes would increase much more. This diabetes precursor, which
affects between 15 and 40 percent of individuals, raises mortality risk on its own. 1
Overall, diabetes reduces life expectancy by 7 to 15 years and is linked to
INTRODUCTION AND OVERVIEW
premature mortality. In wealthy nations, 65 to 75 percent of diabetes-related deaths
are attributable to CVDs. In low-resource environments, diabetes patients still die
most frequently from infections and acute metabolic problems. In most LMICs,
treatment options (dialysis and/or transplantation) are inaccessible (physically
and financially), which contributes to ESRD’s persistently high mortality rate.
Therefore, globally, CVD and nephropathy are the most common fatal outcomes,
and their prevalence is equivalent to their length in that long-standing diabetes
increases susceptibility to developing these diseases.
The global distribution of diabetes-related mortality varies by region. Table 1.18
provides estimates for the percentages of deaths linked to diabetes by geographic
area. Even if the proportion of deaths is lower in LMICs than in more developed
nations, the absolute numbers of deaths are higher due to the bigger populations in
LMICs. The absolute number of diabetes-related deaths recorded annually is now
highest in South Asia. Furthermore, the proportion of deaths in younger age groups
is substantially higher in LMICs, which causes higher loss of life years and affects
the economically active subpopulations in these nations.
213
 Table 1.18: Diabetes-related deaths as a percentage of total mortality, broken
down by age and WHO region. Male/female percentages are used to illustrate
all figures.
It must be noted that the HIV/AIDS epidemic has already changed and is expected
to continue to change patterns of mortality and life expectancy in Africa. Despite
the fact that sub-Saharan Africa is responsible for 72% of all HIV-related fatalities
1 globally, estimates based only on demographic patterns indicate that the prevalence Table 1.19: Examples of various treatment philosophies in high-income nations 1
of diabetes will rise in this area. The prevalence of diabetes will be impacted both

INTRODUCTION AND OVERVIEW

Direct costs
INTRODUCTION AND OVERVIEW

directly (through pancreatic dysfunction brought on by treatment) and indirectly

(by increased life expectancy) by the widespread use of antiretroviral therapy. The
limited amount of data coming from this continent prevents a better understanding
of the relative effects of these dynamics in comparison to current sociodemographic
and epidemiologic shifts.
Economic And Social Implications
For the time between diagnosis and death, diabetes’ characteristic chronic condition
necessitates empowered, self- and clinician-guided control. The main goal of
glycemic control and preventative treatment is to prevent complications and early
mortality. Diabetes has substantial side effects that are both expensive and time-
consuming to treat. For the purpose of guiding effective health care planning,
resource allocation, and response strategies, it is essential to quantify the costs of
diabetes from the perspectives of diabetes patients as well as national resource
consumption and losses.
These expenses cover the full range of outpatient and inpatient care, diagnostic
testing, therapeutic treatments, pharmacology, paramedical care (such as home
nursing and physiotherapy), patient time, transportation, and rehabilitation.
Indirect costs
These costs are typically determined by estimating foregone income by examining
the cumulative effects of absenteeism, employment status, and income, for the
individual and any caregivers. These costs represent the present and future value
of economic productivity lost by society as a result of temporary or permanent
disability, excess morbidity, and premature mortality from disease.
Intangible costs
Costs for the psychosocial effects of an illness, such as stress, depression,
and emotional problems, as well as the altered quality of life they cause, may
include reduced family responsibilities, unpaid caregiving, and lost income for
family members. These costs are typically difficult to estimate due to the lack of
standardized methods.

214 215
 Cost appraisal
Cost - of - illness method
This is the most popular method for describing the direct and indirect costs of
disease to society. It involves examining costs in a group of chosen individuals over
a predetermined, finite period, like a year, or as the disease progresses naturally.
Human capital approach
This approach to estimating disease’s indirect costs places a focus on lost wages
and employment; as a tool, it is criticized for having a propensity to overestimate
future values, accept wage inequality, and ignore socially beneficial pursuits like
housework and volunteer work.
1 The most significant genetic risk factor for T1DM is still HLA-DQ on chromosome
Friction cost approach
This strategy restricts production losses by seeing lost productivity as a finite
INTRODUCTION AND OVERVIEW
resource that can only be restored over a limited period of time (either by replacing
the worker or returning to work); it does, however, call for specific data
. dominant form of diabetes observed in children and young adults. However, with
“Top-down” approach
This calculates costs from national databases and/or estimates, dividing expenses
of various illnesses based on diagnoses; it necessitates proper data entry, especially
when indirect costs are being explored; yet, it reduces the possibility of double
counting.
“Bottom-up” approach
This charts the course of disease-related expenses for a defined subgroup who has
the illness over a set amount of time.
The estimates of the excess expenses produced by resource consumption in studies
that have looked at diabetes costs differ. The main factors that affect direct health
care costs are the following: the use of health services (outpatient or ambulatory
care, which includes both inpatient and outpatient care), medication, diagnostic tests,
self-glucose monitoring, therapeutic medical devices, and therapeutic procedures.
Auxiliary services like paramedical care (dietitians, physiotherapists, occupational
therapists, and home nursing) and preventative checkups (foot care, urine testing,
216
and eye testing) may increase prices in more developed environments. Themes
that emerge from these studies confirm the high costs of complications and related
hospitalization in rich nations, but they also highlight greater relative prices of drug
purchases in LMICs. Drugs for co-morbid CVD risk management do, in fact, come
with additional expenditures.
1.5 Summary
The understanding of T1DM etiology with regard to the emergence of islet
autoimmunity prior to the clinical manifestation of the illness has advanced
significantly. The creation of standardized islet autoantibody tests (GAD65Ab, IA-
2Ab, and ZnT8Ab) has made it possible to start identifying candidates for clinical
trials intended to preserve relic -cell function. For application in clinical trials,
analyses of cell-mediated immunity need to be improved and standardized.
1
6. It is generally known that while these HLA class II heterodimeric proteins are
INTRODUCTION AND OVERVIEW
required for illness, they are insufficient on their own. Several possible factors for
these associations have been revealed by recent genome-wide association studies.
Previously, autoimmune type 1 diabetes mellitus (T1DM) was believed to be the
advancements in our understanding of diabetes pathogenesis, we now acknowledge
that genetic or acquired factors can impact the structure and function of pancreatic
β-cells, leading to a wide range of clinical presentations. There is considerable
overlap between the phenotypes of type 1 and type 2 diabetes, further complicating
the diagnosis.
To accurately diagnose the type of diabetes, healthcare professionals should
conduct a thorough medical history assessment, including family history of
diabetes, the manner of presentation, and any exposure to infections. Additionally,
a comprehensive physical examination is essential, which may include evaluating
body leanness, microvascular complications, metabolic syndrome, and associated
cardiovascular risk factors. To further refine the diagnosis, appropriate laboratory
testing, such as checking for autoantibodies against pancreatic antigens and genetic
markers, should be employed.
Both inherited and acquired defects that negatively impact cell function, mass, and
tissue responses to insulin are present in type 2 diabetes. Current research supports
the idea that while extra acquired features, which are possibly avoidable variables,
217
 may negatively affect cell function and tissue responses to insulin, the primary
genetic impact is on decreased insulin production. The molecular and genetic
causes of the disease have recently received a lot of attention in studies. Since this
condition is polygenic, numerous distinct variants that impair β-cell function are
likely to be found. Future research may lead to the development of new treatments
that maintain -cell functionality and eventually correct the abnormalities. There
is more and more evidence now that obesity raises the chance of acquiring type
2 diabetes. It is clear that carrying around too much body fat encourages insulin
resistance and weakens insulin production. Weight management must be a key part
of any treatment plan because the majority of T2DM patients are overweight or
obese and because weight loss has been conclusively demonstrated to significantly
improve metabolic control. Parallel to this, dietary changes or weight loss benefits
the majority, if not all, underlying problems. However, more effective weight loss
1 strategies should be created and tested because traditional concepts combining an
energy-reduced diet with an increase in physical activity typically have subpar
INTRODUCTION AND OVERVIEW
long-term results.
Although T1DM is one of the most frequently diagnosed chronic conditions in
children, it can strike anyone at any age. The incidence of it varies greatly between
and even within populations. Although there is a significant genetic component
to T1DM and familial clustering, most patients do not have afflicted siblings or
parents.
Few carriers of the susceptibility genes go on to acquire T1DM. In most examined
groups, the prevalence of T1DM is rising at an average rate of about 3 to 4% per
year.
There is no recognized reason for this growth. Although it is thought that some
environmental factors may have played a role, no clear-cut environmental cause
of autoimmune T1DM has yet been found. T1DM was a deadly condition until the
invention of insulin. Despite the fact that diabetes-related mortality has significantly
decreased, T1DM patients still have increased morbidity and early mortality due to
both acute and late consequences. The only way to address these issues would be
to prevent T1DM from occurring in the first place, but sadly, there are presently no
effective preventive measures available.
Globally, the prevalence of impaired glucose tolerance and T2DM has increased
as a result of the combination between genetic predisposition, the rise of fast
food, and sedentary lifestyle. The majority of the cost will fall on Asia-Pacific
218
nations with expanding economies as the number of people with diabetes rises.
The significant rise in diabetes-related macrovascular and microvascular problems
places a significant strain on health care resources. Recent research has confirmed
the benefits of extensive multifactorial risk management in lowering cardiovascular
adverse events and all-cause mortality. Diabetes has a significant negative impact
on health, society, and the economy globally. According to quantitative studies,
the combined direct and indirect expenses of diabetes in the globe in 2010 were
estimated to be US$376 billion. Only 8% of individuals with diabetes live in the
USA, where nearly half of all global spending on the disease took place. More
widespread and trustworthy data are a first step toward greater equity given the
discrepancies in costs, access, and expenditures already described. To improve
estimates of diabetes-related mortality, morbidity, and cost, studies are also
required that take into account both well-known and newly discovered diabetic
consequences, such as cognitive function. 1
It will be easier to understand the complex mix of inherited, predisposing, and
INTRODUCTION AND OVERVIEW
modifiable factors that contribute to diabetes if burdens are assessed using reliable,
consistent methodologies. This will also serve as a platform for developing policies
and advocating for increased global awareness.
Future planning for the rising diabetes burden requires advancement in the broader
collection of trustworthy data (particularly relieving the scarcity from low and
middle income countries regarding diabetes-related mortality, complications,
disability, and costs), as well as a greater emphasis on cost-effective studies that
may inform better resource allocation. Increased funding and political will are
needed in order to overcome low accessibility and awareness and to translate the
evidence into the practical real-world implementation of tried-and-true preventative
techniques.
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 1.6 Review Questions
1. In the context of human metabolism, discuss the regulatory mechanisms and
signaling pathways that govern the switch between glycolysis and gluconeogenesis
in the liver. How does hormonal regulation, particularly involving insulin and
glucagon, influence this metabolic shift, and how do alterations in these regulatory
mechanisms contribute to metabolic disorders such as diabetes mellitus?
2. Explore the intricate interplay between adipose tissue, skeletal muscle, and the
liver in regulating energy homeostasis and metabolic flexibility. How does adipose
tissue contribute to the release of adipokines, such as leptin and adiponectin, and
how do these hormones influence energy expenditure and insulin sensitivity?
Discuss the role of skeletal muscle as a major site for glucose disposal and its
involvement in the development of insulin resistance, highlighting the molecular
1 mechanisms underlying these processes.
3. Examine the historical evolution of our understanding and management of
of diabetes. Discuss the role of insulin resistance, impaired insulin secretion, and
β-cell dysfunction in type 2 diabetes, as well as the contribution of lifestyle and
genetic factors to its development.
7. Explain the concept of latent autoimmune diabetes in adults (LADA) and its
classification within the spectrum of diabetes mellitus. Discuss the clinical and
immunological characteristics that distinguish LADA from type 1 and type 2
diabetes, and explore its potential implications for treatment and management.
8. Discuss the role of epigenetic factors in diabetes pathogenesis and classification.
How do epigenetic modifications influence gene expression and contribute to
the development of various diabetes subtypes? Provide examples of epigenetic
changes associated with specific forms of diabetes and their potential impact on
disease progression.
1

INTRODUCTION AND OVERVIEW

INTRODUCTION AND OVERVIEW

diabetes, tracing its origins from ancient civilizations to modern times. Discuss
how diabetes was perceived and treated in ancient cultures such as Egypt,
Greece, and India, and highlight key milestones in the scientific understanding
of diabetes from the early works of Aretaeus of Cappadocia to the discovery of
insulin by Banting and Best. Analyze the impact of these historical perspective on
shapingthe current approaches to diabetes research and patient care.
4. Investigate the historical socio-cultural, economic, and political factors that
influenced the perception and management of diabetes throughout different
eras. Analyze how changing dietary habits, urbanization, industrialization,
and globalization have affected the prevalenceand management of diabetes in
various regions and populations. Examine the role of public health initiatives,
governmental policies, and the pharmaceutical industry in shaping the trajectory
of diabetes research and treatment paradigms over the centuries.
5. Describe the pathogenesis of type 1 diabetes mellitus, focusing on the
autoimmune mechanisms that lead to the destruction of pancreatic β-cells. Discuss
the role of genetic susceptibility, environmental triggers, and the involvement of
T-cells and autoantibodies in the disease process.
6. Compare and contrast the pathogenesis of type 1 and type 2 diabetes mellitus,
highlighting the underlying mechanisms that differentiate these two distinct forms

220 221
 1
INTRODUCTION AND OVERVIEW

222
Diabetes, Monitoring And Comprehensive
Medical Evaluation

The “Standards of Medical Care in Diabetes” from

the American Diabetes Association (ADA) include
the organization’s most recent clinical practice
recommendations and are meant to give patients
information about the different aspects of diabetes 2
care, basic treatment objectives and standards, and

Diabetes, Monitoring And Comprehensive Medical Evaluation

instruments to assess the quality of care. Each year,
or as frequently as necessary, members of the ADA
Professional Practice Committee, a multidisciplinary
expert committee, are in charge of updating the
Standards of Care. the mechanism for rating the
strength of the evidence supporting the ADA’s clinical
practice guidelines, as well as a full description of its
standards, declarations, and reports.

2 Chapter Contents
2.1 Diagnostic Tests
2.2 Glucose Monitoring- Self-Monitoring, CGM, Long-Term Glycemic
Monitoring
2.3 Comprehensive Medical Evaluation
2.4 Summary
2.5 Review Questions

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 In this chapter, we will delve into the crucial aspects of diabetes management,
focusing on monitoring techniques and comprehensive medical evaluation to
optimize patient outcomes. We will explore the latest advancements in diabetes
monitoring technologies, including continuous glucose monitoring (CGM)
systems and novel point-of-care devices, which have revolutionized our ability
to assess and track glycemic fluctuations with unparalleled precision. Moreover,
we will discuss the importance of self-monitoring of blood glucose (SMBG) and
the integration of technology-driven data into diabetes management algorithms
to achieve optimal glycemic targets. Beyond monitoring, a comprehensive
medical evaluation is essential to identify diabetes type, assess complications, and
2 determine individualized treatment plans. We will elucidate the role of detailed
medical history-taking, physical examination, and the interpretation of pertinent
Diabetes, Monitoring And Comprehensive Medical Evaluation
laboratory and imaging investigations in refining the diagnosis of diabetes subtypes
and guiding therapeutic decisions. Additionally, this chapter will emphasize the
significance of recognizing the interplay between various comorbidities, including
hypertension, dyslipidemia, obesity, and cardiovascular disease, in the context of
diabetes management.
Furthermore, we will explore emerging trends in the application of precision
medicine and personalized approaches to diabetes care, leveraging genomic and
metabolomic profiling to identify unique molecular signatures that influence disease
progression and treatment response. As the understanding of the genetic basis of
diabetes advances, it opens new avenues for targeted therapies and interventions
that hold the potential to revolutionize the landscape of diabetes management.
2.1 Diagnostic Test
Blood tests can be used by your doctor to identify diabetes, prediabetes, and
gestational diabetes. The results of the blood tests indicate whether your blood
sugar, also known as blood glucose, is higher than what is considered to be healthy
for you. Additionally, blood tests can be used to determine the kind of diabetes you
have.
In the event that you suspect you may have diabetes, avoid trying to self-diagnose.
Diabetes cannot be diagnosed with blood testing tools available over the market,
such as blood glucose meters. The effects of a diabetes mellitus diagnosis last a
person their entire life. Therefore, the diagnosis must be fully trusted by both the
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clinician and the person being tested. This is simpler in a symptomatic person,
but in asymptomatic patients, a subsequent test is required to confirm an aberrant
test result. With the expansion of screening programs and the fact that 30 to 50
percent of T2DM patients are asymptomatic and ignorant of their condition, this is
becoming more and more crucial.
2.1.1 Tests for Type 1 Diabetes, Type 2 Diabetes, and Prediabetes
Typical signs of diabetes, such as thirst, polyuria, weight loss, recurring infections,
and, in more severe cases, pre-coma, are frequently what prompt a person to seek
medical attention. A single increased random plasma glucose reading in these
2
people is enough to confirm the diagnosis. If the venous plasma glucose level is
Diabetes, Monitoring And Comprehensive Medical Evaluation
more than 11.1 mmol/L (200 mg/dL) or 12.2 mmol/L (220 mg/dL) in capillary
plasma, a definitive diagnosis can be made. According to WHO, readings between
5.0 and 11.0 mmol/L are unclear.
Diabetes Diagnostic Procedures
For almost a century, diabetes mellitus has been characterized by an elevated blood
glucose level. Although the oral glucose tolerance test (OGTT) was created in
the early 19th century, it wasn’t until easier ways to measure blood glucose that
it became widely used. First and foremost, the first WHO Expert Committee on
Diabetes reviewed diagnostic testing and concluded that neither the presence nor
the lack of glycosuria could confirm or exclude diabetes.
Additionally, they discussed the variety of glucose tolerance tests that were readily
accessible at the time and emphasized the need of using just the 50-g or 100-g
OGTT.
They proposed that the likelihood of diabetes was indicated by a fasting venous
blood glucose level over 130 mg/dL (7.2 mmol/L). In terms of plasma, this would
be equivalent to around 150 mg/dL (8.3 mmol/L) for whole blood; however, at the
time, the majority of blood glucose chemistry tests in use overstated actual glucose
by at least 20 mg/dL (1.1 mmol/L). They heavily relied on the OGTT.
They looked at the readings at 1 and 2 hours after the glucose load, but they
concluded that the 2 hour value alone was sufficient, and this was the primary
diagnostic test recommended. For venous whole blood, a value of 130 mg/dL (7.2
mmol/L) was chosen, and this value was to be used regardless of whether a 50-g
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 or 100-g glucose load was administered. Additionally, they established the crucial
idea of “borderline” diabetes—the precursor to IGT—where readings were to be
higher than average but lower than those that were diagnostic for the disease: 110
mg/dL (6.1 mmol/L) to 129 mg/dL (7.2 mmol/L) for venous whole blood two
hours after the glucose load. Another crucial point is that individuals must ingest
at least 250 g of carbohydrates over the course of three days in order to be ready
for the OGTT. This is still true and is rarely followed, which may account for the
significant proportion of elderly individuals who have increased 2-hour values but
normal fasting glucose levels. Many of these may not actually have diabetes but
rather “starvation” diabetes.
2 With the help of the NDDG and WHO, significant transformation and rationalization
occurred in 1979 and 1980. After reviewing all the information, they came to the
Diabetes, Monitoring And Comprehensive Medical Evaluation
conclusion that a 75-g load would be suitable, and that this should be ingested in
300 mL of water over the course of 5 minutes.
The diagnostic thresholds for fasting and 2-hour values were mostly based on
bimodality data in populations with high prevalence, like the Pima Indians, as well
as some observations of retinopathy risk. The WHO Committee rounded up the
NDDG-recommended fasting and 2-hour venous plasma values of 140 mg/dL (7.8
mmol/L) and 200 mg/dL (11.1 mmol/L) to 8 mmol/L and 11 mmol/L, respectively.
Fasting venous plasma values of less than 8 mmol/L and values between 8 and
11 mmol/L at two hours were used to define IGT. Due to the confusion, a second
review was conducted in 1985 when the WHO group modified their values to
perfectly match the NDDG values.
The release of the ADA and the new WHO report in 1997 and 1999, respectively,
brought about the following significant development. This time, a large amount
of information was available to examine the risk of retinopathy at various
glucose levels. Although the data were cross-sectional, there was a fair amount of
consistency between research on Egyptians, US people from NHANES III, and
Pima Indians. The existing 2 hour cut point of 11.1 mmol/L (200 mg/dL) seemed
fair despite some tolerance on the precise values, but the fasting value was reduced
to 7.0 mmol/L (126 mg/dL; Table 2.4). In addition, the idea of IFG was introduced
at the same time. This test was intended to detect a diabetes risk condition and was
comparable to IGT for the fasting state. The targeted range was 110–125 mg/dL
(6.1–6.9 mmol/L).
The WHO and ADA plans differed significantly in one important way. The
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American Diabetes Association (ADA) advised against using an OGTT for
diagnostic purposes and instead suggested using a fasting glucose alone. Likewise,
it was implied that fasting glucose may be utilized as a screening test to find at-risk
individuals without the need for a glucose tolerance test. The WHO group disagreed
with this and continued to advocate for the use of the OGTT as necessary. The fact
that many individuals with diabetes by the 2-hour measurement have normal or
IFG readings while fasting is one factor. The pivotal shift occurred in 2003 with the
recommendation of a new ADA group to lower the IFG cutoff to 100 mg/dL (5.6
mmol/L), which was examined by WHO in 2006 but rejected.
Who needs to have a diabetes test? 2
Diabetes should be diagnosed in everyone who exhibits symptoms of the condition.
Diabetes, Monitoring And Comprehensive Medical Evaluation
While some people may not exhibit any symptoms, they may nonetheless have
type 2 diabetes risk factors and require testing. Gestational diabetes should also
be screened for in the majority of pregnant women. Doctors can work with their
patients to control the disease and avoid health issues by finding diabetes earlier
thanks to testing.
The abrupt onset of type 1 diabetes symptoms is a common reason to check blood
sugar levels. The American Diabetes Association (ADA) has created screening
recommendations due to the fact that symptoms of other types of diabetes and
prediabetes develop more gradually or may not be obvious.
● Regardless of age, anyone with a body mass index greater than 25 (23
for Asian Americans) and extra risk factors. These include high blood
pressure, abnormal cholesterol levels, a sedentary lifestyle, a family history
of diabetes or polycystic ovarian syndrome, and high blood pressure or
polycystic ovary syndrome.
● A baseline blood sugar test is indicated for everybody over the age of 35.
After that, they should be checked every three years if the results are normal
● It is recommended that women who have experienced gestational diabetes
undergo a diabetes screening every three years
● It is recommended that everyone with prediabetes undergo annual testing
● Testing is recommended for everyone suspected of having HIV
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 Tests for Type 1 and Type 2 Diabetes and Prediabetes
A1C Test: This blood test, which does not call for prolonged fasting, reveals your
average blood sugar level over the previous two to three months. It calculates the
proportion of blood sugar that is bonded to hemoglobin, the protein that carries
oxygen in red blood cells. A test for glycated hemoglobin is another name for it. The
more hemoglobin with sugar linked you have, the higher your blood sugar levels
will be. You have diabetes if your A1C result is 6.5% or above on two different tests.
If your A1C ranges between 5.7% and 6.4%, you have prediabetes. 5.7% or less
is regarded as usual. Hemoglobin variations are certain forms of hemoglobin that
can cause issues when trying to measure A1C levels. The most prevalent variations
2 2
have no impact on the majority of A1C tests used in the United States. Your doctor
Diabetes, Monitoring And Comprehensive Medical Evaluation
should take into account that the A1C test could not be a trustworthy test for you if
the results of your test and your blood glucose levels do not match.
Random blood sugar test: At some random time, a blood sample will be obtained.
If your blood sugar level is 200 mg/dL (11.1 mmol/L) or above, it doesn’t matter
when you last had food. Diabetes is a possibility.
Fasting blood sugar test: You will be asked to fast the previous night before having
a blood sample drawn. It is normal to have a fasting blood sugar level less than 100
mg/dL (5.6 mmol/L). Prediabetes is defined as having a fasting blood sugar level
between 100 and 125 mg/dL (5.6 and 6.9 mmol/L). You have diabetes if it is 126
mg/dL (7 mmol/L) or above on two different tests.
Glucose tolerance test: You must fast the night before this test. The level of fasting
blood sugar is then determined. After consuming a sugary beverage, blood sugar
levels are checked every two hours.
It’s usual to have blood sugar levels under 140 mg/dL (7.8 mmol/L). After two
hours, a result of greater than 200 mg/dL (11.1 mmol/L) indicates diabetes. You
have prediabetes if your blood sugar level is between 140 and 199 mg/dL (7.8
mmol/L and 11.0 mmol/L).
Glucose challenge test: Your doctor may use the glucose challenge test to check for
gestational diabetes if you are pregnant. The glucose screening test is another term
for this examination. A medical practitioner will draw a sample of your blood for
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this test an hour after you’ve consumed a sugary beverage containing glucose. For
this test, you don’t need to speed. You might need to come back for an oral glucose
tolerance test while fasting if your blood sugar is very high—135 mg/dL to 140 mg/
dL or higher.
2.1.2 Tests for Gestational Diabetes
Blood tests are used to determine gestational diabetes. Between 24 and 28 weeks of
pregnancy, you’ll likely undergo a pregnancy test. Your doctor might test you early
if you are at a higher risk of developing gestational diabetes as a result of having
more risk factors. Early in your pregnancy, blood sugar levels that are higher than
normal could be a sign of type 1 or type 2 diabetes rather than gestational diabetes.
Diabetes, Monitoring And Comprehensive Medical Evaluation
Glucose Screening Test: This gauges your blood sugar level at the moment of testing.
One hour after consuming a glucose-containing liquid, blood will be collected to
measure your blood sugar levels. The result should be 140 mg/dL or less. You must
have a glucose tolerance test if your level is greater than 140 mg/dL.
Glucose Tolerance Test: This checks your blood sugar levels before and
after consuming a glucose-containing beverage. Before the test, you will fast
(not eat) and have blood drawn to check your fasting blood sugar level. After
consuming the liquid, your blood sugar level will be monitored an hour, two
hours, and perhaps three hours later. The amount of the glucose drink you
consume and how frequently you test your blood sugar can affect the results.
Issues With Blood Glucose Testing
Since the last century, measuring glucose has been the cornerstone and foundation
of diagnosing diabetes; however, there are certain issues with this method. The
initial assays were non-specific and assessed reducing sugars. This issue has mainly
been eliminated by enzyme tests.
In well-run laboratories with adequate quality assurance measures, accuracy and
precision are not issues, but the introduction of glucose meters has created issues.
The coefficient of variation can frequently be as high as 20% in field use, rendering
them unsuitable for diagnostic purposes even though they are efficient if used
carefully, well controlled, and calibrated. The subject being tested could also have
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 issues. Pathophysiology
Although fasting glucose is relatively repeatable, it can be influenced by
The majority of dietary items contain complex carbs, which are digested to give
medications, concomitant illnesses, or improper fasting on the part of the patient.
our body’s cells energy. Carbohydrate-rich food is converted after ingestion into
The OGTT is notoriously inconsistent from day to day within a single person and
simpler sugars like glucose in the digestive tract. Glucose molecules are taken
is unreliable when they are close to the diagnostic threshold. Although it has long
up by the bloodstream in the small intestine and sent to cells all over the body,
been considered the gold standard, this is primarily due to usage and the lack of
including the liver. Insulin is produced by pancreatic beta cells in response to
an alternative. As more screening programs are implemented and patients with
high blood glucose levels. Insulin helps glucose go from the bloodstream into
asymptomatic diabetes are sought after, this has become more crucial.
cells during the postprandial phase. Additionally, insulin prevents the liver’s
gluconeogenesis and promotes the storage of glucose as glycogen (glycogenesis)
2.2 Glucose Monitoring- Self-Monitoring, CGM, Long-Term Glycemic and fats (de novo lipogenesis, or DNL), which are used as short- and long-term
2 2
Monitoring energy reserves, respectively. The body makes an effort to keep blood glucose

Diabetes, Monitoring And Comprehensive Medical Evaluation

Diabetes, Monitoring And Comprehensive Medical Evaluation

levels (4 to 6 mmol, or around 72 to 108 mg/dL), in a homeostatic range. The

Since the 1980s, the technology used to monitor blood glucose levels has been well-
ability of pancreatic beta-cells to function and the cellular (skeletal muscles,
established. When applied properly, this procedure helps diabetic patients from a
liver, and adipose tissue) sensitivity to insulin affect homeostasis. A shortage of
clinical and financial perspective. Knowing the measured glucose levels can help a
insulin or an improper response to insulin’s effects by the body, known as insulin
patient choose the right insulin dose or make dietary or other lifestyle modifications
resistance, are both factors in diseases like diabetes mellitus. Insulin resistance
to control their glucose levels. The A1C, self-monitored blood glucose (SMBG), and
impairs cellular uptake of glucose or the storage of extra glucose. Deficiencies in
interstitial glucose objectives are suggested by expert groups. Expert groups advise
insulin synthesis or absorption might exacerbate abnormal blood glucose levels.
individualization based on risk of hypoglycemia, polypharmacy, comorbidities,
Diabetes mellitus is more likely to occur in patients with impaired blood glucose
and other factors that may affect the long-term benefit and particular patient
homeostasis and increased fasting blood glucose. If a patient has elevated blood
features, despite the fact that targets differ. The ADA has broadened its guidelines
glucose levels, they may be given a diabetes mellitus diagnosis. Some organs do
for measuring overall glucose levels to include the A1C or CGM measures like the
not have insulin receptors and do not require insulin for glucose uptake, including
Glucose Management Indicator (GMI) or the Time in Range (TIR, the percentage
the brain, kidneys, liver, and erythrocytes. Insulin is used to treat some cases of
of time spent between 70 and 180 mg/dl).
type 2 diabetes mellitus as well as type 1 diabetes. Hypoglycemia is a well-known
Blood glucose monitoring enables the identification of patterns in blood glucose
side effect of insulin therapy that can occur if dosing is not controlled properly.
(sugar) level fluctuations brought on by dietary changes, physical activity,
Monitoring blood glucose levels frequently will be beneficial for patients with
medications, and pathological conditions like diabetes mellitus. Acute and chronic
insulin-dependent diabetes. For people with diabetes mellitus undergoing insulin
illnesses that are potentially life-threatening can result from abnormally high or
therapy, routine daily blood glucose monitoring is advised.
low blood glucose levels. Capillary blood glucose (CBG) tests are frequently
used to refer to blood glucose level (BGL) or blood sugar level (BSL) monitoring
performed outside of clinical settings, such as the home. Contrarily, blood glucose 2.2.1 Continuous Glucose Monitoring
testing carried out in clinical facilities could also include venous blood tests for Blood sugar levels are automatically monitored by continuous glucose monitoring
CBG and plasma glucose. both throughout the day and at night. Your blood sugar level is always visible at
a glance. To spot trends, you can also observe how your glucose levels fluctuate
over a few hours or days. Your ability to balance your diet, physical activity, and

230 231
 medications throughout the day will improve if you can see your glucose levels
in real time. The glucose level display on the CGM is updated every five minutes
and continuously detects glucose levels (usually interstitial glucose). The majority
of CGMs are made up of three components: a monitor to display the data (in
certain situations, the patient’s mobile device serves as the monitor), a sensor
that is typically placed into the subcutaneous tissue, and a transmitter that sends
sensor data to the monitor. Due to accuracy issues, all devices were previously only
approved for adjunctive use; in this scenario, patients must continue to undertake
fingerstick glucose monitoring in order to direct therapy and carry out calibrations.
The Dexcom G5 was the first CGM to be approved by the FDA for standalone
2 usage in 2016, nevertheless. Newer technologies have done away with the need
to calibrate a CGM with a fingerstick glucose reading. In the hypoglycemic range,
Diabetes, Monitoring And Comprehensive Medical Evaluation
where the demand for sensitivity and specificity is greatest in terms of acting as an
alarm for hypoglycemia, all commercially available CGMs continue to have the
lowest accuracy.
To detect: 1) hypoglycemic and hyperglycemic excursions; 2) predict imminent
hypoglycemia; and 3) significant swings in glucose levels, generally known as
glycemic variability, CGM can give both retrospective and real-time information.
For all FDA-approved CGM devices, telephone support is accessible around-the-
clock. The use of CGM can assist the patient and their doctor in fine-tuning their
drug prescription and give the patient advice on behavioral modifications to achieve
glycemic control. A completely working artificial pancreas is also being closer to
reality thanks to current efforts to combine CGM data with automatically controlled
insulin delivery. Systems can be split into professional (which is a device owned
by a clinic and gives either retrospective or real-time glucose data) and personal
(which is owned by the patient and provides real-time glucose data) categories
based on its intended usage.
Professional CGM
Professional CGM refers to CGM data gathered using equipment that belongs to
a healthcare provider. Similar to a 24-hour cardiac Holter monitor, which delivers
information about heart rhythms after they have occurred, it does not always
provide the glucose findings in real time but rather downloads the values after
they have been obtained. This enables the medical professional to collect fairly
unbiased glucose trends throughout normal daily living. According to the Endocrine
232
Society’s recommendations, professional CGM may be helpful for managing
diabetes medicines and detecting nocturnal hypoglycemia, dawn phenomenon,
postprandial hyperglycemia, and other diabetes-related conditions in persons with
diabetes. Personal CGM is more difficult to reimburse than professional CGM,
however competent healthcare practitioners may be paid on a monthly basis to
evaluate both types of CGM reports.
Some personal CGM systems can be used in a blinded mode to provide professional
glucose data. The first continuous blood glucose reading device, the Continuous
Glucose Monitor System (CGMS) by Medtronic MiniMed, was FDA-approved
in June 1999. Since then, newer models have shown improvements in accuracy
and patient acceptance. According to a meta-analysis of 22 articles, professional 2
CGM led to a significant reduction in A1c (-0.28%, 95% CI -0.36% to -0.21%, P <
Diabetes, Monitoring And Comprehensive Medical Evaluation
0.00001) and an increase in Time in Range (TIR) (5.59%, 95% CI 0.12 to 11.06, P
= 0.05) compared to usual practice.
FreeStyle Libre Pro
The Libre personal CGM and FreeStyle Libre Pro both use the same sensor. Since
the Libre is factory calibrated, self-monitored blood glucose calibrations are not
necessary. Since there are a variety of device and user faults that can affect capillary
blood glucose testing, together with the physiological lag time between blood and
interstitial glucose (which is accentuated in the postprandial period), this may be
a possible advantage. Every 15 minutes, glucose measurements are recorded and
stored for up to 14 days. Since the glucose sensor is completely disposable and only
one reader is required to activate and scan several devices, multiple patients can
receive the operation at the same time in the same office. The LibreView website,
which offers a secure cloud-based system, or the FreeStyle Libre desktop reporting
software are the two ways to get reports. A daily glucose report, an evaluation of
glucose variability and hypoglycemia risk, daily patterns, and an overall snapshot
report are all provided in reports.
Overall MARD for the FreeStyle Libre is 11.4%, 86.7% of readings fell into Zone
A of the Consensus Error Grid analysis, and 99.7% of results fell into Zones A and
B (6). MARD is calculated by averaging the absolute values of relative differences
between CGM measurement results and corresponding comparison method
results. It is crucial to remember that sensor accuracy is worse on day 1 and in the
hypoglycemic range (MARD 20.3% for levels 72 mg/dl in one study), according to
233
 a study (7). Over the course of the 14-day wear period, accuracy gets better and stays
consistent. The Libre employs glucose oxidase in a “direct signaling” method that
does not require oxygen and reduces interference from other chemicals, including
acetaminophen, which may cause falsely inflated readings.
2 focused frames, presents a sequential array of frames whose trend predicts the
Diabetes, Monitoring And Comprehensive Medical Evaluation
Figure 2.1: FreeStyle Libre Pro
Dexcom Professional
Depending on whether the objective is to observe glucose patterns without
intervention, to provide immediate feedback to educate and inform patients about
their medications and behaviors, or to facilitate decisions about pursuing personal
CGM, the Dexcom G6 Pro is available in blinded or unblinded mode. It was
approved by the FDA in March 2018. With a quicker starting time and minimal
calibration, the sensor, transmitter, and receiver are nearly identical to those found
in the personal Dexcom G6 system. The device is authorized for usage for 10 days
and detects interstitial glucose levels every 5 minutes. Dexcom CLARITY, a web-
based program used to download and examine personal data, is used to download
the device.
Purposes
The direction, size, duration, frequency, and reasons for changes in blood glucose
levels are all revealed by continuous glucose monitoring. Continuous monitoring
234
offers a lot more information about glucose levels throughout the day than traditional
intensive glucose monitoring, which is defined as three to four blood glucose
readings per day. Continuous glucose monitoring that provides trend information
can be used to spot and avoid unwelcome hypo- and hyperglycemia episodes.
The distinction between a regular camera and a continuous security camera for
monitoring an essential situation is comparable to that between an intermittent and
a continuous monitor for blood glucose monitoring. A typical camera creates a tiny
number of precise photographs that can all be carefully examined, discrete, exact
snapshots that cannot foretell the future, and it requires work to take each picture.
On the other hand, a continuous security camera takes numerous, ineffectively
2
future, generates too much data for each frame to be properly examined, and
Diabetes, Monitoring And Comprehensive Medical Evaluation
starts up automatically once it is turned on. Similar to how the two types of blood
glucose monitors differ, 1) An intermittent blood glucose monitor measures discrete
glucose levels very accurately, whereas a continuous monitor provides multiple
glucose levels with fair accuracy; 2) Current blood glucose levels do not predict
future blood glucose levels with an intermittent monitor, whereas trends in glucose
levels do have this predictive capability with a continuous monitor; and 3) With an
intermittent monitor, it is simple to study every measured blood glucose value over
months.
Using the camera analogy again, the best tool for closely monitoring a situation
when the result is crucial is frequently a continuous security camera rather than a
regular camera, and the same is true for the best way to monitor diabetes, which is
frequently a continuous glucose monitor (CGM) rather than an intermittent monitor.
How exactly does a continuous glucose monitor (CGM) function?
A tiny sensor that is commonly implanted under the skin on the abdomen or arm is
how a CGM functions. Your interstitial glucose level, or the glucose present in the
fluid between your cells, is measured by the sensor. Every few minutes, the sensor
measures the glucose. The data is wirelessly transmitted from a transmitter to a
monitor. You might carry the monitor in your pocket or purse as a separate item
or as a component of an insulin pump. Some CGMs deliver data immediately to a
tablet or smartphone.
235

2 stick glucose test before adjusting your insulin dosage.
Diabetes, Monitoring And Comprehensive Medical Evaluation
Figure 2.2: Under the skin, a small CGM sensor measures glucose. Data is sent
from a transmitter to a receiver. The CGM receiver can be an independent
device or a component of an insulin pump, as it is in this image.
Whether you are taking a shower, working, exercising, or sleeping, CGMs are
always tracking your blood sugar levels. Many CGMs have unique functions that
use data from your glucose readings:
● When your blood glucose levels are too low or too high, an alarm may go
off.
● A CGM gadget also records your meals, exercise, and medications in
addition to your blood glucose readings.
● To more readily see your glucose trends, you can transfer data to a computer
or mobile device.
Benefits and Limits of CGM
Benefits
Using a CGM system instead of a traditional blood glucose meter can help you
better manage your glucose levels on a daily basis, have fewer low blood glucose
emergencies, and require fewer finger sticks.
In order to help you decide the optimal path to achieving your goal blood glucose
level, a visual on the CGM screen displays whether and how quickly your glucose
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is rising or falling. Over time, proper glucose control significantly aids people with
diabetes in maintaining their health and avoiding disease complications. Those that
use a CGM daily or nearly daily are the ones who benefit the most from it.
Limitations
Researchers are working to improve the use and accuracy of CGMs. But to compare
the precision of your CGM to a conventional blood glucose meter, you still need to
perform a finger-stick glucose test twice a day.
You still can’t make treatment decisions solely based on the CGM for the majority
of CGM models. For instance, you need to confirm a CGM reading with a finger-
2
Diabetes, Monitoring And Comprehensive Medical Evaluation
2.2.2 Self-Glucose Monitoring
An essential part of contemporary treatment for diabetes mellitus is self-monitoring
of blood glucose (SMBG). To reach a certain level of glycemic control and avoid
hypoglycemia, SMBG has been suggested for diabetics and their medical experts.
The objective of SMBG is to gather thorough data on blood glucose levels at
numerous time points to enable more precise regimens to maintain a more stable
glucose level. It can be used to help people alter their dietary intake, physical
activity, and insulin doses to enhance glycemic control on a daily basis as well as
to aid in the adjustment of a therapy regimen in response to blood glucose readings.
When a patient uses a blood glucose meter to check their own levels, this is known
as self-monitoring blood glucose (SMBG). The best method for diagnosing and
treating hypoglycemia is SMBG. It can offer feedback on the effects of interventions
promoting healthy behavior and antihyperglycemic drug therapies.
SMBG can help with diabetes control by: facilitating the creation of an individual
blood glucose profile, which can then direct healthcare professionals in the treatment
planning for an individual diabetic regimen; enabling people with diabetes and
their families to make appropriate day-to-day treatment decisions regarding diet,
physical activity, and insulin or other agents; and improving patients’ recognition
of hypoglycemia or severe hyperglycemia.
The genuine effect of SMBG on glycemic control has been the subject of numerous
trials. Various studies, including randomized, controlled trials, have shown how
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 effective SMBG is. SMBG has been linked to better health outcomes in people with
type 1 diabetes.1 Particularly, among type 1 patients in Scotland, SMBG frequency
was directly linked with declines in HbA1c. Among type 2 diabetic patients who
were able to modify their insulin treatment, a higher frequency of SMBG was linked
to better glycemic control.2 However, other studies have indicated that SMBG may
not have had the full impact it may have had on bettering glycemic control.
According to a study that examined data from the third National Health and
Nutrition Examination Survey (NHANES III), there was little connection
between the frequency of SMBGs and glycemic control in people with type 2
2 diabetes. The validity of the NHANES III study design to accurately assess the
association between SMBG and glycemic control has been questioned in reference
Diabetes, Monitoring And Comprehensive Medical Evaluation
to this publication, which has generated a great deal of controversy. It would be
challenging to establish a cause-and-effect link because the NHANES III examined
patient behavior and glucose control in a cross-sectional manner. It is necessary
to use prospective study designs to better comprehend the function of SMBG in
all diabetic patients. However, the majority of diabetologists concur that certain
SMBG data should be included in diabetes self-management and that motivated
patients can profit from the greater empowerment that SMBG produces. Diabetes
specialists now advise both patients and healthcare professionals to use SMBG
data to guide adjustments in medication regimens. Patients should use SMBG data
to make day-to-day regimen changes. In order to develop a patient-centered self-
management program, the American Diabetes Association has approved initiatives
to instruct persons with diabetes how to actively use SMBG data.
2.2.3 Long-term Glycemic monitoring
The development of continuous glucose monitoring (CGM) in recent years has
significantly changed how type 1 diabetes (T1D) is managed. A growing body of
research has shown that using CGM devices can help both adult and pediatric T1D
patients improve their glycemic control and glucose variability (GV) and reduce
their risk of hypoglycemia (1-3). In particular, children and adolescents whose
daily glucose profiles are characterized by wider glycemic excursions and, as a
result, by higher difficulties in obtaining optimal management of T1D, are relevant
to the beneficial role of CGM use in achieving currently recommended glycemic
targets. The expanding usage of CGM devices in clinical settings has demonstrated
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that a crucial component of making efficient use of CGM is for patients and
physicians to comprehend the many metrics of glycemic control and GV produced
from CGM data. A minimum collection period of 2 weeks is recommended by
the International Consensus on Use of Continuous Glucose Monitoring for use of
CGM-derived metrics in clinical practice and research settings in order to perform
optimal analysis and therapeutic decision-making.
Glycemic variability (GV), which refers to oscillations in blood glucose levels,
is often defined by the measurement of fluctuations in glucose or other related
parameters of glucose homoeostasis over a certain time period (e.g., over the course
of a day, between days, or over a longer period of time). Although HbA1c was 2
once thought to be the gold standard for measuring glycemic control, GV is now
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unquestionably acknowledged as being a more useful indicator of glycemic control
than HbA1c in clinical settings. More than 30 million Americans have diabetes
mellitus (DM), which is the main cause of end-stage renal disease and chronic
kidney disease (CKD). Both monitoring and treatment of DM are more difficult in
people with CKD. Monitoring the treatment plan’s impact on long-term glycemic
control is an essential component of care. Glycated hemoglobin (HbA1c) fraction
testing for glycemic control is a common procedure. This test is well recognized
as a trustworthy way to assess chronic glycemia in populations free of kidney
disease. In contrast, there is little information on the usefulness of HbA1c levels in
individuals with CKD.
Without therapy, diabetics are more likely to develop long-term problems such
nephropathy, neuropathy, and retinopathy, which shorten their lifespan. Urine
glucose tests were first developed in the 1800s as a result of early medical practices
that involved doctors tasting their patients’ urine to diagnose diabetes. These urine
glucose assays represented the first techniques for analyzing hyperglycemia, despite
the fact that they used retroactive information.
Clinicians immediately understood the link between insulin and diabetes after the
first clinical use of insulin to treat diabetes in 1922 and created the first insulin-
based therapies intended to reduce hyperglycemia consequences. Insulin over-
administration was however soon shown to cause hypoglycemia, which has
short-term side effects like perspiration, tachycardia, coma, and death. The blood
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 glucose range needed for the best management of diabetes is constrained by the
long-term effects of hyperglycemia and the immediate effects of hypoglycemia.
But more complex alert systems were required to guarantee adherence to the
recommended medication because urine glucose testing is retrospective and can’t
detect hypoglycemia.
In the United States, the Center for Disease Control estimates that 29.1 million
individuals have diabetes (of which 5% have type 1 diabetes), costing $245 billion
in medical expenses per year. The development of warning systems that can identify
and even foretell cases of hypoglycemia and hyperglycemia is driven by the strong
demand for better glycemic management. These alert systems also give patients
2 with diabetes greater mental stability and a higher quality of life.
Diabetes, Monitoring And Comprehensive Medical Evaluation
Temperature and Skin Conductance
The decrease in skin conductance seen during hypoglycemia is depicted in Figure
2.3. Bolinger et al. reported an early study in 1964 that connected a quick decrease
in skin conductance to hypoglycemia episodes. As early as 19578, patents described
hypoglycemia alert systems incorporating electrodes for skin conductance, and
more followed in the 1970s and 1980s.
Figure 2.3: An illustration of the hypoglycemic nadir in skin conductance
The Diabalert from Erpic and the Sleep Sentry from Teledyne were the first
commercially available products to employ skin conductance data as an alarm
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for the night. The Diabalert was made up of a meter that housed the alarm and
was connected to an electrode on the skin’s surface via a lengthy wire. Pickup
evaluated the Diabalert on 7 patients in a clinical setting and discovered that,
despite having blood glucose levels of 12.6 and 37.8 mg/dL, 3 of the patients would
not have been able to respond to an alarm, and 2 of the patients did not exhibit
any indications of perspiration. The original Sleep Sentry was a large wrist watch-
like device that measured both skin conductance and skin temperature. Inducing
hypoglycemia in 17 type 1 diabetics and 10 healthy volunteers, Levandoski et
al. found that the Sleep Sentry alarms were 81% sensitive.For a total of 1444 at-
home nights, Hansen and Duck gathered data on 24 young children with type 1
diabetes. Of these, 42 hypoglycemic incidents were discovered by the Sleep Sentry, 2
4 more were discovered by the patients or their parents without an alarm, and 150
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alarms went off without any hypoglycemia. Furthermore, 6 out of 24 individuals
experienced negative skin reactions in this initial trial because of the high current
density employed.
Hypoglycemic Alarms
“Malaise” is linked to the signs of hypoglycemia. When specific low glucose
thresholds are crossed, these happen. If the capillary or interstitial glucose level
is less than 70 mg/dL (or 3.9 mmol/L), hypoglycemia is considered mild (level 1).
Sweating, anxiety, tremors, palpitations, and occasionally a sense of hunger are the
symptoms. If the blood sugar level is below 54 mg/dL (or 3 mmol/l), hypoglycemia
is deep (level 2), and symptoms include weakness, headache, weariness, dizziness,
blurred vision, slurred speech, weakness, and fatigue. Severe hypoglycemia (level
3): The unconscious individual needs assistance from a third party to provide
glucose or glucagon, for example.
Reactive hyperglycemia is brought on by the unpleasant symptoms of hypoglycemia,
which also cause excessive sugar consumption. As a result, managing hypoglycemia
to prevent and treat it is difficult and necessitates a planned education of diabetes
patients. We won’t go into detail about treating hypoglycemia, but we will discuss
preventing it with CGM warnings. Making wise alarm settings will be the first step
in education. The chosen hypoglycemic warning threshold is often approximately
70 mg/dl and, when taken into account, allows for a > 50% reduction in the amount
of time spent in hypoglycemia.
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 This warning threshold must be customized with the help of the medical staff based
on the patient’s age, medical history, and threshold for hypoglycemia perception.
Additionally, the alarms can be set to only sound during times when hypoglycemia
is more common. Depending on the device, an urgent low blood glucose alarm (less
than 54 mg/dl) will sound if the hypoglycemia alarm is canceled. This alarm cannot
be modified or deactivated.
For whom are the alarms for hypoglycemia set?
People who are at a high risk of hypoglycemia or unaware hypoglycemia have been
the subject of studies made expressly to lower the risk of hypoglycemia. They have
2 shown a decrease in hypoglycemia, indicating that when utilized exclusively for
this indication, real-time continuous glucose monitoring can avoid hypoglycemia.
Diabetes, Monitoring And Comprehensive Medical Evaluation
People with diabetes who are at a greater risk of hypoglycemia should use CGMs
with alarms, such as:
Because of the stricter glucose control desired, type 1 diabetic pregnant women are
more likely to experience hypoglycemia. Less than 4% of time should be spent with
blood glucose levels below 63 mg/dl (3.5 mmol/l), more than 70% of time should
be spent with blood glucose levels between 63 and 140 mg/dl (3.5- 7.7 mmol/l), and
less than 25% of time should be spent with blood glucose levels above 140 mg/dl
(7.5 mmol/l). People with less well-perceived unfeeling hypoglycemia or nocturnal
hypoglycemia. In fact, between 25 and 30 percent of persons with type 1 diabetes
do not experience hypoglycemia’s symptoms. The Clarke or Golden scores might
be used to evaluate this risk in consultation (a score of 4 indicates a significant
chance of unperceived hypoglycemia). These diabetics are typically older, have
had the disease for a longer period of time, and have more glycemic fluctuation.
These people suffer more severe hypoglycemia, according to a retrospective
research, necessitating the administration of glucagon. The systems preventing
hypoglycemia are indeed compromised. Therefore, greater hypoglycemia warning
levels of 75 or even 80 mg/dl are required for those who do not exhibit mild
hypoglycemia symptoms in order to enable prompt intervention. These alarm levels
should provide information to people quickly enough to allow them to correctly
ingest glucose. According to a recent study, 75 mg/dL was the ideal alarm level for
people who spent less than 1% of the time in hypoglycemia.
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How should hypoglycemia alarms be handled?
Three scenarios come up frequently:
Although the person displays hypoglycemic signs, the alert does not
sound.
Before the blood glucose threshold of 70 mg/dl, some individuals experience
symptoms. Not the low blood glucose value per se, but the quick decline in blood
glucose (the glycemic delta) is what causes symptoms. Always remember that the
CGM, which detects interstitial glucose, lags behind capillary glucose fluctuations
2
by a significant amount. Compared to capillary glucose, the CGM really measures
the interstitial glucose level with a slight delay of about 5 minutes. The sensor does
Diabetes, Monitoring And Comprehensive Medical Evaluation
not have enough time to respond if the latter lowers too quickly, more quickly than
the one beneath the skin. When someone has hypoglycemia, it’s not unusual for
them to re-sugarize and then the alarm goes off!
This can be seen when engaging in vigorous physical activity, for instance, where
the blood sugar drop may occur more quickly than indicated by the meter. As a
result, hypoglycemia is present before the sensor notices it in the person. The
hypoglycemia threshold alarm won’t work in this situation. It will be required
to rely on the glucose trend arrows, which, depending on the sensor brand, will
provide information on the rate of glucose decline. Finally, choosing a rtCGM with
hypoglycemia prediction in this situation appears more intriguing.
Despite having blood sugar levels below 70 mg/dl, no symptoms are
present.
These people don’t experience hypoglycemia. According to the recommendation
of the medical staff, a detection alarm at a higher threshold should be set in
this situation. If the person is told beforehand, he or she will be able to take the
appropriate action to prevent hypoglycemia. Finally, using an insulin pump to halt
the supply of insulin when a too rapid drop in blood glucose is noticed may be
advised if the sensor is insufficient.
The sensor glucose measurement and the capillary glucose value differ,
although the patient is exhibiting symptoms.
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 It happens frequently that a person with diabetes is unsure of which sign is
trustworthy—symptoms, the glucose value determined by the sensor, or the
measurement made at the capillary level? If the glucose readings from the sensor
and the capillary sample do not match, the blood glucose may be rapidly rising or
dropping.
It’s critical to understand that CGM results always lag behind blood or capillary
values. Blood glucose levels in capillaries and interstitial tissues will be nearly equal
in a stable environment. However, if there are significant glycemic fluctuations,
such as during a sudden hypoglycemia, there will be a discrepancy between the
2 blood glucose readings obtained with the finger and those obtained with the CGM.
The final analysis will be based on the glucose trend arrows. In other circumstances,
Diabetes, Monitoring And Comprehensive Medical Evaluation
like when the sensor is broken, the CGM will frequently overstate hypoglycemia.
Hyperglycemic Alarms
The bulk of the time, hyperglycemia has subtle symptoms. To notice symptoms like
thirst and the urge to urinate more frequently, especially at night, very high blood
glucose levels (> 250 mg/dl) must be reached. Given that these are signs of ketosis
or possibly ketoacidosis, symptoms including nausea, vomiting, and fruity breath
should receive extra attention.
The Intended Audience For Hyperglycemic Alerts
● Ladies who are expecting need to closely monitor their blood sugar
● Children are more susceptible to ketosis
● Folks who are comorbidly ill and frail.
● Those who use insulin pumps.
● Everyone who wants to lengthen the period between 70 and 180 mg/dL
(TIR)
How should hyperglycemic alarms be handled?
The alarms alert the user in the event of hyperglycemia, beginning at a threshold
decided upon in consultation with the medical staff. An alarm threshold of 170 mg/
dL has been linked in a study to both a shorter duration of hyperglycemia and a
HbA1c close to 7.0%. People who use insulin pumps benefit from hyperglycemia
alerts since they can be informed in case of faulty equipment (warning of an
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excessively high glycemic excursion related to a clogged catheter, bent, etc.). To
prevent a ketosis crisis, a preset alert at 250 mg/dl also enables checking of the
ketone bodies. Setting a low threshold for hyperglycemia detection may result
in more frequent alarms and, consequently, annoyance, similar to the case with
hypoglycemia.
Therefore, in order to optimize glycemic control, it is advised to set a high
threshold (for example, 250 mg/dl) and to progressively lower it after that. When a
hyperglycemic alert is given, the person runs the danger of developing “untimely”
behavior in which they inject extra insulin, raising their risk of hypoglycemic
episodes. It is important to provide appropriate instruction regarding residual insulin
(the length of insulin action) and insulin sensitivity while treating hyperglycemia 2
with insulin supplementation. The majority of CGMs also permit data sharing.
Diabetes, Monitoring And Comprehensive Medical Evaluation
Another crucial aspect is the capability to share info with friends and relatives. It
serves as a security net. Telemedicine is also made possible by this data exchange.
Artificial Pancreas!! What is that?
The most typical contemporary treatment for insulin-dependent diabetes (IDD) is
multiple daily blood glucose checks and insulin injections or pump infusions. Even
the most diligent insulin therapy cannot duplicate the precise metabolic control
found in the disease-free state, despite the fact that this medication helps to regulate
blood sugar levels. Additionally, a sizable portion of patients have challenges with
poor compliance. Numerous consequences result from the insufficient temporal
coordination of glucose load and insulin action, including an elevated risk of heart
disease, kidney failure, blindness, and peripheral vascular and nerve damage.
Several strategies are being studied to enhance glycemic control. These include
the use of minimally invasive or noninvasive glucose sensors that enable blood
glucose measurements and increase patient compliance; an artificial pancreas made
up of a continuous glucose sensor, a controller, and an insulin pump in a closed-
loop configuration; and therapies based on the transplantation of insulin-secreting
cells or of biological substitutes containing such cells, also known as bioartificial
pancreas or pancreatic tissue sutures. In this essay, we examine the state of artificial
pancreas, cell-based therapies, and pancreatic tissue substitute configurations as
well as upcoming obstacles.
A significant contribution to the advancement of artificial pancreas technology has
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 been made by the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK). Insulin injections and manual blood glucose testing are replaced by an
artificial pancreas. A single system continuously checks blood sugar levels and
automatically administers either insulin or insulin and the additional hormone
glucagon. Remote monitoring of the system is also an option, so parents or medical
personnel can do so. A hybrid closed-loop artificial pancreas system was authorized
by the U.S. Food and Drug Administration in 2016 External link. Through a separate
insulin pump, this system uses a CGM to check your blood sugar levels every five
minutes during the day and night. It then automatically administers the appropriate
dose of basal insulin, a long-acting insulin. A closed-loop physicochemical device
2 called an artificial pancreas (Figure 2.4) is made up of a continuous glucose
monitor, an insulin infusion pump, and a controller/control algorithm that controls
Diabetes, Monitoring And Comprehensive Medical Evaluation
the supply of insulin in response to real-time glucose measurements. These devices
have the potential to deliver effective glycemic management with minimal patient
involvement.
All three parts of the artificial pancreas are currently the subject of research and
development; however, the current limiting element is a trustworthy glucose sensor
with enough lifetime.
Figure 2.4: Diagram showing the setup for an artificial pancreas. A wearable
insulin pump’s ability to deliver insulin is controlled by a controller and control
algorithm using data from a continuous glucose sensor.
The more invasive glucose sensors take subcutaneous or intravenous glucose
readings. The short sensor lifetime and low accuracy of subcutaneous readings
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are limitations, with errors contributed to, among other things, the lag in blood
and interstitial fluid glucose concentrations. Intravenous measurements have the
potential to result in blood clots, phlebitis, and catheter-related infections. Less
intrusive sensing modalities are preferred for general use even though invasive
sensors are permitted in hospitals and intensive care units. Microdialysis or
transdermal fluid transport are the foundations of minimally invasive sensors.
Transdermal transport-based sensors detect glucose in a fluid that has been
microporated from the skin using iontophoresis, ultrasound, or a focussed laser
beam. Larger-molecular-weight species are typically filtered out using microdialysis
probes, which aids in maintaining sensor stability. Accuracy, the need for several
minutes to pass between measurements, and the fact that changes in interstitial fluid 2
glucose concentration occur later than changes in blood glucose concentration are
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challenges with minimally invasive sensors.
Evidently, a noninvasive sensor is the best kind to use. Near-, mid-, and far-infrared
spectroscopy, Raman spectroscopy, radio-wave impedance, polarimetry, thermal
emission spectroscopy, optical coherence tomography, and spectroscopic methods
based on the thermal characteristics of tissues are among the technologies being
studied for noninvasive sensors. The most well-liked of these is near-infrared
spectroscopy. The creation of clinically useful noninvasive sensors has been
hampered by issues such as variations in tissue temperature and hydration status,
perspiration, and changes in hematocrit protein. The proportional-integral-derivative
(PID) and model-predictive-control (MPC) techniques are the two primary types
of algorithms being studied for the artificial pancreas’ control algorithm. In PID,
the proportional component administers insulin at a rate inversely correlated with
the difference between the measured and target blood glucose levels, the derivative
component administers insulin in proportion to the rate of change in blood glucose
levels, and the integral component administers basal insulin. In MPC, a mathematical
model that predicts the necessary amount of insulin based on a number of factors
linked to glucose metabolism and, potentially, meal intake determines how much
insulin will be delivered. The Medtronic Minimed external physiologic insulin
delivery (ePID) system is one illustration of an artificial pancreas where the three
components cooperate. This consists of an insulin pump, a PID controller, and a
subcutaneous continuous glucose monitor. According to a recent evaluation of this
configuration by Weinzimer et al. in 17 adolescents with well-controlled type 1
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 diabetes, the system started responding 10-15 min after the subject started eating,
peaked at 120 min, and meal-related insulin infusion lasted for 2-3 h with fully
closed-loop control.
Postprandial glucose control was improved by adding manually initiated, modest
priming bolus doses of insulin 15 minutes before meals. The Advanced Insulin
Infusion Using a management Loop (ADICOL) project, established by the
European Commission for glycemic management in type 1 diabetics, is one more
study utilizing artificial pancreas systems. This system had a portable subcutaneous
insulin infusion pump, a hand-held computer with an MPC algorithm, and a
worn subcutaneous glucose sensor. Additionally, researchers are investigating
2 totally implantable devices like the one Renard created. A Medtronic/MiniMed
intravenous enzymatic oxygen sensor, a PID control algorithm, and an implantable
Diabetes, Monitoring And Comprehensive Medical Evaluation
intraperitoneal insulin infusion pump made up this implantable artificial pancreas.
The creation of artificial pancreas devices might be helpful in hospitals in addition
to the general diabetes population.
Due to glucose intolerance and other metabolic problems, managing blood glucose
in critically ill patients is typically quite difficult. Artificial pancreas technologies
could greatly enhance patient glucose management in intensive care units and on
hospital floors.
Patients with type 1 diabetes are currently the main target of development efforts for an
artificial pancreas. In fact, the creation of a dependable, transportable, or implantable
artificial pancreas system is desirable, and when one is made, it is anticipated to be
widely used. Realistically, it will take some time before a fully closed-loop system
is ready for broad usage. However, the adoption of this technology is likely to be
gradual, and advancements in system elements, particularly glucose sensors, would
greatly enhance open-loop designs for managing the disease. Whether insulin is
administered orally or through a pump, patient compliance would be improved by
the simplicity and convenience of noninvasive glucose testing.
Pancreatic Substitute Cell Types
Islets
The restricted amount of donor tissue available for transplant is a significant concern
with human islets. The in vitro growth of primary human islets has not proven
successful despite numerous attempts. Adult human islets are challenging to grow
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in culture, and as they grow, they dedifferentiate, which typically manifests as losing
their ability to release insulin. The phenotypic stability and in vivo effectiveness of
these cells are yet unknown, despite data on the re-differentiation of enlarged islets
being available. Furthermore, in enlarged and re-differentiated islets, it is unknown
whether the insulin-secreting cells originated from a native stem or progenitor cell
population in the tissue isolate or from the re-differentiation of expanded endocrine
cells. Animal islets, including those from pigs, are widely available, and swine
insulin resembles human insulin only by a single amino acid. The robust xenograft
reaction caused by the implant is a significant challenge when using porcine
tissue. But long-term implant survival might be possible with a combination of
fewer immunogenic islets, islet encapsulation in permselective barriers, and host 2
immunosuppression. One method for lowering the immunogenicity of islets is the
Diabetes, Monitoring And Comprehensive Medical Evaluation
use of transgenic pigs that do not express the [1,3]-galactose (-Gal) epitope. Despite
the fact that the -Gal epitope is also common in neonatal islets, studies show that
neonatal pig islets do not stimulate the same level of T-cell reactivity as adult islets.
Neonatal pig islets may be cultivated in vitro before being implanted as a solution
to this issue. If they are implanted soon after being isolated, it takes a few weeks
before a diabetic animal’s glycemia returns to normal.
Another issue with pig tissue is the unlikely but potential transmission of swine
endogenous retroviruses (PERVs) to human hosts; this issue should be resolved
by using closed, PERV-free herds. Last but not least, the technical challenges
associated with the mass isolation of pig islets under the purity and sterility required
for ultimate regulatory approval have not yet been resolved.
β-Cell lines
Potential applications for cell treatments and tissue substitutes include the use of cell
lines derived from cells that can be multiplied in culture while retaining essential
differentiated features of normal cells. The TC family of insulinomas, which were
produced from transgenic mice bearing a hybrid insulin-promoted SV40 tumor
antigen gene, were some of the first successfully developed cell lines. These cells
proliferated well in vitro and maintained their differentiated characteristics for
about 50 passes. Following TC lines apparently had their hypersensitive glucose
responsiveness reduced by assuring the expression of glucokinase and the high Km
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 glucose transporter Glut2, whereas hexokinase and the low Km transporter Glut1
were either absent or expressed at low levels.
The mouse MIN-6 cell line, which demonstrates glucose-responsive endogenous
insulin production, was created using a similar methodology. Efrat and colleagues
created the TC-tet cell line, in which tetracycline firmly and irreversibly regulates
the production of the SV40 T antigen (Tag) oncoprotein, for the purpose of
controlling growth in vitro and, more crucially, in vivo. As a result, when Tag was
expressed, TC-tet cells multiplied, and growth was halted when Tag expression
was turned off. Through the creation of an inoculum, this reversible transformation
2 can be used to produce a supply of cells, with growth stopping once the desired
population size is attained. The dissolved oxygen concentration in the surrounding
Diabetes, Monitoring And Comprehensive Medical Evaluation
medium can only maintain a specific number of viable, metabolically active cells in
the capsule volume when cells are enclosed in intact capsules. The balance between
cell development and death processes allows for the maintenance of this number
of viable cells. Since the equilibrium cell density in implanted capsules is much
higher than the initial density and could cause hypoglycemia if it is approached
due to cell growth, growth arrest seems to be most helpful in reducing the cellular
turnover in the capsules, preventing the growth of cells that have escaped from
broken capsules in vivo, and in these situations.
A distinct strategy was used by Newgard and colleagues, who introduced genes
involved in -cell performance gradually into a line of weakly secreting rat
insulinoma (RIN) cells. The insulin gene, the glucose transporter Glut2, and
glucokinase, which are required for glucose sensing and responsiveness, were all
iteratively designed into the RIN cells to express multiple copies in a stable manner.
Significant progress was achieved more recently in developing a human pancreatic
β-cell line that appears to operate similarly to normal cells. A difficult approach
involving the retroviral transfection of primary cells with the SV40 big T antigen
and complementary DNAs (cDNAs) of human telomerase reverse transcriptase
was used to achieve this. The long-term phenotypic stability of -cell lines, the
long-term secretory stability of capsules, which may require the implementation of
cell growth control, and their potential tumorigenicity, particularly if cells escape
from capsules and are not immediately rejected by the host’s immune system, are
important issues that need to be addressed with regard to the clinical application of
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encapsulated systems.
Engineered non-β pancreatic cells
Cells from the same patient that have been modified to secrete insulin in response to
physiological stimuli make up a distinct cell source. These cells are obviously not
pancreatic cells, as they have either been eliminated or damaged in insulin-dependent
diabetics. The limits on cell availability and immunological acceptance that are
present with other cell types are relaxed when using non-cells from the same patient.
Such cells might not be detected by autoimmunity as well, according to studies using
a mouse model of diabetes with autoimmune disease. It has been demonstrated
that the ubiquitous endopeptidase furin can convert proinsulin directly into mature 2
insulin by altering the A-chain/C-peptide and B-chain/C-peptide cleavage sites on
Diabetes, Monitoring And Comprehensive Medical Evaluation
the proinsulin gene. In accordance with this theory, hepatocytes, myoblasts, and
fibroblasts have all been genetically modified to produce immunoreactive insulin.
An alternative strategy was used by Lee and colleagues, who expressed a synthetic,
single-chain insulin analog in hepatocytes without the need for post-translational
modification. But whether non-cells release recombinant insulin in response to
metabolic cues, and if so, how, is a crucial concern.
Between cell stimulation and enhanced insulin secretion, as well as between the
removal of secretion agonists and downregulation of the secretory response, there
are noticeable time lags in transcriptional regulation. The latter is more significant
physiologically because it indicates that cells may continue to generate insulin
even after the glucose concentration has dropped, which could result in dangerous
hypoglycemia excursions. Both destabilizing preproinsulin mRNA, as Tang and
Sambanis did, which speeds up the downregulation of secretion after the removal
of the transcriptional activator, and increasing the number of stimulatory glucose
elements in a promoter, which improves the cellular metabolic responsiveness in
vitro, are potential ways to improve secretory kinetics. It should be highlighted,
however, that hepatic insulin gene therapy is sufficient to maintain vascular nitric
oxide production and prevent the acute onset of diabetes-associated endothelial
dysfunction in a rat model, despite the time delays inherent in transcriptional
regulation. As a result, there are still many areas of the therapeutic potential of
hepatic insulin expression that need to be recognized and researched.
More recently, the insulin gene was delivered through a lentiviral vector to the
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 livers of diabetic rats in order to achieve long-term glycemic control, albeit it was
not obvious whether insulin was produced in a controlled manner in this instance.
A pancreatic endocrine phenotype appeared to be transdifferentiation, which was
an interesting finding. The pancreatic and duodenal homeobox gene 1 (PDX-1)
has also been used to transdifferentiate adult human liver cells toward the -cell
phenotype. Hepatocytes that had been exposed to PDX-1 produced insulin, stored it
in granules, and secreted it in a way that was glucose-controlled. In vivo activity of
reprogrammed hepatocytes was also seen in diabetic, immunodeficient mice. Using
adenoviral delivery of the three transcription factors Ngn3, Pdx1, and Mafa, adult
exocrine pancreatic cells in mice were also in vivo reprogrammed into cells that
2 closely mirror the phenotype of -cells. Therefore, it seems that both strategies, i.e.,
expressing the insulin gene and expressing transcription factors unique to β-cells, are
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promising for transforming particular non-β cells into β-like cells. Non-endocrine
cells, which have a controlled secretory pathway and the enzymatic equipment to
convert real proinsulin to insulin, are another alluring target cell type. Recombinant
insulin was first expressed in the mouse anterior pituitary AtT-20 cell line, which
can be repeatedly exposed to bouts of induced insulin secretion utilizing non
metabolic secretagogues. Endocrine cells of the intestinal epithelium, also known
as enteroendocrine cells, are more intriguing cell targets because they emit their
incretin products in a way that closely resembles how insulin is released after an
oral glucose load. Incretin hormones are completely compatible with postprandial
metabolism and glucose control, which is another benefit. Creutzfeldt was the first
to emphasize the significance of enteroendocrine cells (and, in particular, L cells),
with the hope of using glucagon-like peptide-1 (GLP-1) to treat type 2 diabetes as
his main motivation.
Cheung et al.’s groundbreaking research showed that insulin secretion from
genetically altered intestinal K cells in transgenic mice prevented the animals from
developing diabetes after receiving an injection of the drug streptozotocin (STZ),
which particularly kills the cells of the murine pancreas. This significant proof-
of-concept study demonstrated that insulin produced by enteroendocrine cells can
manage blood sugar levels in a small-animal model. A human intestinal L cell line
was used in subsequent research to show that these cells can be made to express
recombinant human insulin, which colocalizes with endogenous GLP-1 in secretory
vesicles and is released with kinetics that are identical to GLP-1 in response to
252
secretion stimuli. Although the largest endocrine organ in the body, the intestinal
tract, may be a desirable target for gene therapy, enteroendocrine cell gene therapy
is challenging because of the enteroendocrine cells’ complex anatomical location
at the base of crypts in the gut mucosa, the harsh environment in the stomach and
intestine, and the quick turnover of the intestinal epithelium.
Ex vivo gene therapy, in contrast to direct in vivo gene delivery, entails surgically
removing the target cells, culturing and potentially expanding them in vitro,
genetically engineering them to express the desired properties, and then reintroducing
them to the host either as they are or in a tissue substitute. Ex vivo testing may
be advantageous because it enables in-depth characterization of engineered cells 2
before implantation, leading to improved quality control; it may also enable the
Diabetes, Monitoring And Comprehensive Medical Evaluation
preservation of some cells for use by the same person in the future; and it enables
the localization and retrieval of the implant. Although the surgical removal, culture,
and in vitro genetic modification of the target cells are considerable hurdles imposed
by the ex vivo technique, such methods are currently under development.
Differentiated stem or progenitor cells
The differentiation of pancreatic progenitor cells or embryonic or adult stem
cells has been used to regenerate cells in vitro or in vivo with varying degrees of
success. Human and animal embryonic stem cells have been used to create insulin-
producing, glucose-responsive cells. Furthermore, when implanted into STZ-
diabetic mice, mouse embryonic stem cells transfected to constitutively express
Pax4, a transcription factor necessary for -cell development, differentiated into
insulin-producing cells and corrected blood glucose levels. However, some research
provides less evidence in favor of the repeatable differentiation of embryonic stem
cells into the phenotype of β-cells. It is unclear whether adult pluripotent stem cells
or specialized endogenous progenitors, such as ductal progenitors, are involved in
the regeneration of adult cells and islets or whether adult cells multiply in vivo by
self-renewal. Overall, the contradictory and erratic results highlight the significant
effort that must be done before stem or progenitor cells can reliably develop into
cells on a scale that is clinically meaningful. A promising strategy might also
involve using the pancreatic endocrine system’s in vivo regeneration capacity.
253
 Engineering cells for improved in vivo survival
Strategies have been attempted to increase the immunological acceptance of islets
and other insulin-secreting cells, including boosting resistance to cytokines and
reducing vulnerability to apoptosis, in order to promote survival and grafting.
A few phenotypic manipulations include islet pretreatment with TGF-1 and
enzymatic treatment of pig islets with -galactosidase to reduce the a-galactosyl
epitope on islets. Extended culturing of pig islets at 37 o C also appears to reduce
their immunogenicity, perhaps by downregulating the expression of the major
histocompatibility class 1 antigens on the islet surface. However, it is unclear whether
these changes will stick around. For instance, 48 hours after receiving therapy with
2 -galactosidase, a-galactosyl epitopes emerge on islets. To lessen procoagulation
and pro-inflammatory responses after implantation, surface engineering of islets
Diabetes, Monitoring And Comprehensive Medical Evaluation
through covalent grafting of certain groups is also being studied. The selection of
clones resistant to cytokines seems achievable when using proliferative cell lines
intended for recombinant insulin production.
In comparison to phenotypic changes, genetic modifications for enhancing survival
in vivo may give sustained expression of the desired qualities, but they also carry
the risk of changing the islets in other, unfavorable ways. The expression of
interleukin-10 (IL-10) and transforming growth factor (TGF)-, which improved
graft survival in mice by preventing immune attack; the overexpression of the anti-
apoptotic bcl-2 gene, which enhanced islet protection when the adaptive immune
response was inhibited by locally produced CTLA4Ig; and the engineering of TC3
mouse insulinomas and of murine islets to express hiv-1; are some of the methods
that have been suggested.
2.3 Comprehensive Medical Evaluation
The “Standards of Medical Care in Diabetes” from the American Diabetes
Association (ADA) include the organization’s most recent clinical practice
recommendations and are meant to give patients information about the different
aspects of diabetes care, basic treatment objectives and standards, and instruments
to assess the quality of care. Each year, or as frequently as necessary, members of
the ADA Professional Practice Committee, a multidisciplinary expert committee,
are in charge of updating the Standards of Care.
254
A comprehensive medical evaluation in diabetes involves a thorough assessment
of various aspects of the patient’s health to effectively manage their condition and
prevent complications. The evaluation may include the following components:
1. Medical History: Detailed information about the patient’s medical history,
including family history of diabetes and other related conditions, past medical
conditions, previous treatments, and medication history.
2. Physical Examination: A comprehensive physical examination to assess overall
health, including blood pressure, weight, height, body mass index (BMI), and
evaluation of any diabetes-related complications. 2
Diabetes, Monitoring And Comprehensive Medical Evaluation
3. Blood Glucose Monitoring: Regular blood glucose testing to assess the patient’s
current glycemic control and identify any fluctuations or patterns in blood sugar
levels.
4. Hemoglobin A1c (HbA1c) Test: This test measures the average blood glucose
levels over the past 2-3 months and provides valuable information about long-term
glycemic control.
5. Lipid Profile: Evaluation of cholesterol levels, triglycerides, and other lipid
parameters to assess cardiovascular risk, as diabetes is associated with an increased
risk of heart disease.
6. Kidney Function Tests: Assessment of kidney function through tests such as
serum creatinine and estimated glomerular filtration rate (eGFR) to detect any signs
of diabetic kidney disease.
7. Comprehensive Foot Examination: Checking for signs of diabetic foot
complications, including neuropathy, vascular issues, and foot ulcers.
8. Eye Examination: Dilated eye exam to screen for diabetic retinopathy, a common
complication affecting the eyes in diabetes.
9. Peripheral Neuropathy Assessment: Evaluation of nerve function in the
255
 extremities to detect any signs of peripheral neuropathy. To support patients in self-managing their diabetes, a range of strategies and
techniques should be employed, including providing education on problem-solving
10. Cardiovascular Evaluation: Assessment of cardiovascular risk factors, such as skills relevant to all aspects of diabetes management.
blood pressure, cholesterol levels, and any pre-existing heart conditions.

11. Lifestyle Assessment: Discussion of the patient’s diet, physical activity, and
other lifestyle habits to identify opportunities for improvement.

12. Education and Self-Management: Providing diabetes education to the patient

on self-monitoring, medication management, meal planning, and lifestyle
2 modifications. 2

Diabetes, Monitoring And Comprehensive Medical Evaluation

Diabetes, Monitoring And Comprehensive Medical Evaluation

13. Psychological Assessment: Addressing the patient’s emotional well-being and

mental health, as diabetes can have a significant psychological impact.

14. Medication Review: Reviewing the effectiveness and safety of current diabetes
medications and making adjustments as needed.

15. Vaccination Status: Ensuring the patient is up-to-date with recommended

vaccinations, including the annual flu vaccine and pneumococcal vaccine.

The comprehensive medical evaluation allows healthcare professionals to create an

individualized diabetes management plan and help patients achieve better glycemic
control while minimizing the risk of complications. Regular follow-up visits are
essential to monitor progress and make necessary adjustments to the treatment
plan. The objectives of diabetes treatment are to prevent or delay complications
and improve the patient’s overall quality of life (as shown in Figure 2.5). Treatment
goals and plans should be customized for each patient, considering their individual
preferences, values, and aspirations. This personalized management plan should
take into account several factors, such as the patient’s age, cognitive abilities,
school or work schedule, health beliefs, support systems, dietary habits, physical
activity level, social circumstances, financial considerations, cultural influences,
literacy, numeracy, diabetes history (including duration, complications, and current
medications), presence of other medical conditions, disabilities, health priorities,
and life expectancy.
Figure 2.5: Decision cycle for patient-centered glycemic management in type
2 diabetes
Supplier correspondence with patients and families ought to recognize that
numerous variables influence glycemic the board yet in addition stress that
cooperatively evolved treatment plans and a solid way of life can essentially
further develop sickness results and prosperity. Therefore, when the outcomes of
self-management are not optimal, the goal of communication between providers
and patients is to establish a collaborative relationship and assess and address
barriers to self-management without blaming patients for “noncompliance” or
“nonadherence.” The natural terms “resistance” and “nonadherence” mean a
latent, respectful job for an individual with diabetes in “following physician’s
instructions” that is in conflict with the dynamic job individuals with diabetes
require in guiding the everyday direction, arranging, checking, assessment, and

256 257
 critical thinking engaged with diabetes self-administration. Patients’ resistance to
reporting self-management issues may be lessened by adopting a non-judgmental
approach that normalizes periodic lapses in self-management. Communication can ≤26 years of age; 27–45
be facilitated by empathizing and employing active listening strategies including Human papilloma years of age may also Three doses over 6
2 for females, 3
open-ended inquiries, reflective statements, and summarizing what the patient virus (HPV) be vaccinated against months
for males
HPV after a discussion
stated. In order to improve diabetes self-management and treatment outcomes,
with health care
patients’ perceptions of their own ability, or self-efficacy, to manage their provider
diabetes are an important psychosocial factor that should be the focus of ongoing
assessment, patient education, and treatment planning. Perceptions and behavior
are significantly influenced by language. In diabetes treatment and education, the All patients; advised
2 use of empowering language can aid in informing and motivating people, but the not to receive live 2
Influenza -
use of language that shames and condemns may work against this goal. “The Use attenuated influenza Annual

Diabetes, Monitoring And Comprehensive Medical Evaluation

Diabetes, Monitoring And Comprehensive Medical Evaluation

of Language in Diabetes Care and Education,” a joint consensus report from the vaccine
American Diabetes Association (ADA) and the Association of Diabetes Care &
Education Specialists (previously known as the American Association of Diabetes
Educators), presents the authors’ professional judgment on how language should
19–64 years of
be used by healthcare providers when communicating about diabetes to individuals age, vaccinate with One dose 2
with diabetes or to professional audiences. Pneumovax

2.3.1 Immunizations
Pneumonia
(PPSV23 One dose; if PCV13
Vaccination Age-group recommen- Diabatology Book GRADE evi- [Pneumovax]) has been given, then
≥65 years of age,
dations dence type* give PPSV23 ≥1
obtain second dose of
year after PCV13 2
Pneumovax, at least
and ≥5 years after
5 years from prior
<60 years of age; ≥60 any PPSV23 at age
Two- or three-dose Pneumovax vaccine
years of age discuss <65 years
Hepatitis B series 2
with health care
provider

258 259
 risk of all-cause mortality, cardiovascular mortality, and cardiovascular events
Adults ≥19 of
age, with an in people with diabetes and cardiovascular disease. Given the advantages of the
immunocompromising annual flu shot, it is advised for everyone under the age of six who does not have
condition (e.g., a contraindication. The severe acute respiratory syndrome coronavirus 2 and
One dose 3
chronic renal failure),
influenza viruses will both be active in the United States during the 2021–2022
cochlear implant, or
cerebrospinal fluid leak season, making influenza vaccination extremely crucial in the coming year. Patients
Pneumonia (PCV13
[Prevnar]) with chronic conditions like diabetes are advised against taking the live attenuated
influenza vaccine and are instead advised to receive the inactive or recombinant
19–64 years of age, influenza vaccination. The live attenuated influenza vaccine, which is administered
None
immunocompetent, no by nasal spray, is an option for patients between the ages of 2 and 49 who are
2 recommendation not pregnant. The high-dose quadrivalent inactivated influenza vaccine may offer 2
significant benefits for people under the age of 65.

Diabetes, Monitoring And Comprehensive Medical Evaluation

Diabetes, Monitoring And Comprehensive Medical Evaluation

≥65 years of age,

One dose
immunocompetent,
have Pneumococcal Pneumonia
Pneumococcal pneumonia is a frequent, avoidable illness similar to influenza.
shared decision-making People with diabetes are more likely to develop pneumococcal infections that are
discussion with health
bacteremic and have a high risk of nosocomial bacteremia, which has been linked
care provider
to mortality rates as high as 50%. The 13-valent pneumococcal conjugate vaccine
(PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) have
All adults; pregnant different vaccination schedules for children and adults. By the age of 15 months, it
Tetanus, diphtheria, 2 for is advised that all children receive a four-dose course of PCV13. The CDC advises
women should have an Booster every 10
pertussis (TDAP) effectiveness, 3
extra dose years a catch-up schedule to make sure that diabetic children who have incomplete series
for safety
by the time they are 2 to 5 years old receive four doses. It is also recommended
that diabetic children aged 6 to 18 receive one dose of PPSV23, ideally following
PCV13. Some senior citizens using assisted living facilities might also think about
Two-dose Shingrix, PCV13. If PCV13 is to be given, it must be given before the subsequent dosage of
≥50 years of age
Zoster even if previously
PPSV23.
vaccinated

Influenza is a frequent, avoidable infectious disease that affects vulnerable
populations, such as children, the elderly, and those with chronic illnesses, and is
linked to high mortality and morbidity rates. It has been discovered that influenza
vaccination dramatically lowers influenza and diabetes-related hospital admissions
in individuals with diabetes. The influenza vaccine has been linked to a reduced
Hepatitis B
People with type 1 or type 2 diabetes have increased hepatitis B infection rates
when compared to the general population. This could be the result of handling
contaminated blood or using equipment (such as infected needles or glucose
monitors) improperly. Adults with diabetes who are younger than 60 years old are
advised to have the hepatitis B vaccine due to the increased risk of transmission.
Depending on the patient’s chance of contracting hepatitis B infection and their

260 261
 age (adults 60 years), the treating clinician may choose to deliver the hepatitis B
vaccine.
COVID-19
The COVID-19 vaccination is advised for all adults and some children, including
those with diabetes, as of August 2021, with full support from the U.S. Food and
Drug Administration. The mRNA vaccines from Pfizer-BioNTech and Moderna, as
well as the recombinant, replication-incompetent adenovirus serotype 26 (Ad26)
vector vaccine from Janssen, are the three choices available in the United States.
With a grade 1 evidence rating for the prevention of symptomatic COVID-19, the
2 Pfizer-BioNTech vaccine is advised for individuals 12 years of age and older. It is
provided as a two-shot sequence spaced out by 21 days. With a grade 1 evidence
Diabetes, Monitoring And Comprehensive Medical Evaluation
rating for preventing symptomatic COVID-19, the moderna vaccine is advised for
anyone 18 years of age and older. The two shots are spaced apart by 28 days.
Grade 2 evidence rates the Janssen vaccine as also being advised for those who
are 18 years of age and older. There is only one injection necessary, unlike the
mRNA vaccines. The evidence for the effectiveness of combining vaccinations is
currently developing. The CDC recently advised the Pfizer-BioNTech booster for
older persons and those with underlying illnesses like diabetes. Booster vaccine
recommendations are also changing. The COVID-19 vaccination is likely to
become a standard component of diabetes patients’ yearly preventative program.
2.3.2 Comorbidity Assessment
Clinicians and their patients should be aware of the typical comorbidities that affect
people with diabetes and that may complicate therapy in addition to assessing issues
connected to diabetes. Diabetes comorbidities are illnesses that diabetes patients
experience more frequently than age-matched individuals without diabetes. While
not necessarily covering all of the reported illnesses, this section highlights several
of the typical comorbidities seen in people with diabetes.
Autoimmune Diseases
Thyroid disease, celiac disease, and pernicious anemia (vitamin B12 deficiency)
are among the autoimmune disorders that are more common in people with type 1
diabetes and put them at higher risk for developing them. Autoimmune hepatitis,
262
primary adrenal insufficiency (Addison disease), collagen vascular disorders,
and myasthenia gravis are additional ailments that are related. In the context of
particular genetic abnormalities or polyglandular autoimmune syndromes, type
1 diabetes may also co-occur with other autoimmune diseases. Routine thyroid
dysfunction screening is advised for all patients with type 1 diabetes due to the high
prevalence, vague symptoms, and sneaky onset of primary hypothyroidism. Adult
patients with suggestive symptoms (such as diarrhea, malabsorption, abdominal
pain) or indicators (such as osteoporosis, vitamin deficits, iron deficiency anemia)
should be screened for celiac disease. For patients with type 1 diabetes, peripheral
neuropathy, or unexplained anemia, vitamin B12 levels should be measured.
2
Cancer
Diabetes, Monitoring And Comprehensive Medical Evaluation
Cancers of the liver, pancreas, endometrial, colon/rectum, breast, and bladder are
more common in people with diabetes. Although there is limited evidence for these
connections, the association may be caused by type 2 diabetes-related factors, such
as underlying disease physiology or diabetic therapies, as well as cancer risk factors
shared by older age, obesity, and physical inactivity. Diabetes patients should be
urged to reduce their modifiable cancer risk factors (smoking, obesity, and physical
inactivity) and go through the recommended age- and sex-appropriate cancer
screenings. The diagnosis of pancreatic adenocarcinoma may be made before the
new start of atypical diabetes (lean body habitus, negative family history) in a
middle-aged or older patient. However, routine screening of all such patients is
not currently advised in the absence of other symptoms (such as weight loss or
abdominal pain).
Cognitive Impairment/Dementia
Diabetes is linked to a notably elevated rate and risk of cognitive deterioration as
well as an elevated chance of dementia. According to a recent meta-analysis of
prospective observational studies, patients with diabetes have a 73% higher risk of
developing dementia overall, a 56% higher risk of developing Alzheimer’s disease,
and a 127% higher risk of developing vascular dementia. The opposite is also true:
those who have Alzheimer’s dementia are more likely to become diabetic than
those who do not. The presence of diabetes at baseline significantly increased the
age- and sex-adjusted incidence of all-cause dementia, Alzheimer dementia, and
vascular dementia compared to rates in those with normal glucose tolerance in a
263
 15-year prospective analysis of community-dwelling people >60 years of age.
Nonalcoholic Fatty Liver Disease
Nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatocellular
cancer are some of the more severe forms of nonalcoholic fatty liver disease
(NAFLD), which is linked to diabetes. Increased hepatic transaminase levels
are linked to reduced HDL cholesterol and greater BMI, waist circumference,
and triglyceride levels. When determining the likelihood of fibrosis, noninvasive
procedures like elastography or fibrosis biomarkers may be employed, but a liver
specialist referral and a liver biopsy may be necessary for a conclusive diagnosis.
2 Fatty liver disease can benefit from the same interventions that help individuals with
diabetes who have metabolic abnormalities (weight loss, glycemic management,
Diabetes, Monitoring And Comprehensive Medical Evaluation
and treatment with particular medications for hyperglycemia or dyslipidemia).
Treatments for biopsy-proven NASH using pioglitazone, vitamin E therapy,
liraglutide, and semaglutide have all been demonstrated to improve liver histology;
however, the implications on longer-term clinical outcomes are unknown. In
preclinical investigations, treatment with sodium-glucose cotransporter 2 inhibitors
and other glucagon-like peptide 1 receptor agonists has showed promise, albeit the
advantages may be at least partially mediated by weight loss.
An international conference was organized by the American Gastroenterological
Association with participation from the ADA to examine and debate published
research on the burden, screening, risk stratification, diagnosis, and treatment of
people with NAFLD, including NASH. For more information, please refer to the
special study “Preparing for the NASH Epidemic: A Call to Action”. Important
knowledge gaps were found, including those about who should be screened and
how to diagnose and treat people who are at high risk for NASH. Diagnoses for
patients with suspected NAFLD involve reviewing medical histories and laboratory
results to look for other or coexisting causes of liver disease.
Hepatitis C Infection
Type 2 diabetes is more common in those who have chronic hepatitis C virus (HCV)
infection and can be found in up to one-third of those people. HCV may affect
glucose metabolism in a number of ways, including directly through viral proteins
and inadvertently by changing levels of pro-inflammatory cytokines. Newer direct-
264
acting antiviral medications have been shown to enhance glucose metabolism in
diabetics and generate a persistent virological response (cure) in virtually all cases.
Following successful eradication of HCV infection, a meta-analysis of mainly
observational studies discovered a mean reduction in A1C levels of 0.45% (95% CI
0.60 to 0.30) and decreased demand for glucose-lowering drug use.
Pancreatitis
Diabetes is associated with exocrine pancreas disorders like pancreatitis, which can
alter the pancreas’ overall physiology or architecture and can cause both exocrine
and endocrine dysfunction. Up to 50% of diabetic people may experience some
exocrine pancreatic dysfunction. Acute pancreatitis is around two times more likely 2
to occur in people with diabetes. However, following an episode of acute pancreatitis,
Diabetes, Monitoring And Comprehensive Medical Evaluation
prediabetes and/or diabetes have been shown to appear in about one-third of patients;
thus, the association is likely to be reciprocal. Post pancreatitis diabetes can be
either newly diagnosed or undiagnosed diabetes in the past. Studies of diabetic
individuals using incretin-based therapy have also suggested that pancreatitis may
be more common when taking these drugs, however the evidence is conflicting and
causality has not yet been proven. To avoid postoperative hyperglycemia in patients
who need a total pancreatectomy due to medically untreatable chronic pancreatitis,
islet autotransplantation should be taken into consideration. One year following
a total pancreatectomy with islet autotransplantation, about one-third of patients
are insulin-free, and observational studies from several locations have shown that
islet graft function can last for up to ten years in certain patients. When choosing
the reasons and timing of this operation, it is important to carefully evaluate both
patient and disease-related aspects. Surgery should be carried out in specialized
settings with a track record of success with islet autotransplantation.
Fractures
Both those with type 1 diabetes and those with type 2 diabetes, regardless of gender,
have considerably higher age-specific hip fracture risk. While type 1 diabetes is
linked to osteoporosis, type 2 diabetes is related with a higher risk of hip fracture
despite having better bone mineral density (BMD). The World Health Organization
Fracture Risk Assessment Tool (FRAX) score and the femoral neck BMD T-score
were linked to hip and non spine fractures in three sizable observational studies of
older persons. For a particular T-score, age, or FRAX score, persons with diabetes
265
 had a higher fracture risk than participants without diabetes. In elderly individuals
with diabetes, healthcare professionals should evaluate the patient’s history of
fractures and risk factors, and if suitable given the patient’s age and sex, consider
measuring BMD. Diabetes patients should use the same fracture prevention
techniques as the general public, which may include vitamin D supplementation.
Thiazolidinediones and sodium-glucose cotransporter 2 inhibitors should only be
used with extreme caution in patients with type 2 diabetes who also have fracture
risk factors.
Sensory Impairment
2 Obstructive Sleep Apnea
People with diabetes are more likely than those without to experience hearing loss
in the high-frequency and low- to mid frequency ranges, and studies of younger
Diabetes, Monitoring And Comprehensive Medical Evaluation
people have shown stronger relationships. Cochlear microangiopathy and auditory
neuropathy are two pathophysiologic mechanisms that have been proposed. They
both include oxidative stress and hyperglycemia. After controlling for age and other
risk factors for hearing impairment, a National Health and Nutrition Examination
Survey (NHANES) analysis found that those with diabetes had a hearing impairment
about twice as frequently as those without. Although it has been suggested that
low HDL cholesterol, coronary heart disease, peripheral neuropathy, and overall
ill health are risk factors for hearing loss in diabetics, a consistent correlation
between hearing loss and blood glucose levels has not been shown. When hearing
impairment was assessed after a lengthy (>20 years) period of follow-up in the
Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions
and Complications (DCCT/EDIC) cohort, time-weighted mean A1C was linked to
an increased risk of hearing impairment. Diabetes patients have also been noted to
have impaired smell but not taste.
Low Testosterone in Men
Although obesity is a significant confounder, men with diabetes had lower
mean testosterone levels than age-matched men without diabetes. In males with
symptomatic hypogonadism, testosterone replacement therapy may enhance
sexual performance, wellbeing, muscular growth and strength, and bone density.
An accurate and trustworthy assay should be used to measure the morning total
testosterone level in diabetic men who have hypogonadism symptoms or indications.
It is reasonable to calculate free testosterone concentrations in males with total
266
testosterone, sex hormone binding globulin, and albumin concentrations when their
total testosterone levels are close to the lower limit or directly from equilibrium
dialysis assays. For comprehensive advice, please refer to the Endocrine Society
clinical practice guideline. To fully assess the patient, additional tests (such
luteinizing hormone and follicle-stimulating hormone levels) may be required.
There is inconclusive evidence that testosterone supplementation increases
cardiovascular risk in hypogonad men, although testosterone replacement in older
men with hypogonadism has been related with increased coronary artery plaque
volume.
2
Obesity, in particular central obesity, is associated with significantly higher age-
Diabetes, Monitoring And Comprehensive Medical Evaluation
adjusted rates of obstructive sleep apnea (4- to 10-fold greater), a risk factor for
cardiovascular disease. In people with type 2 diabetes, the prevalence of obstructive
sleep apnea may be as high as 23% and that of any sleep breathing condition may be
as high as 58%. It topped 80% in those Action for Health in Diabetes (Look AHEAD)
trial participants with obesity. Patients should be evaluated for screening if they
exhibit symptoms of obstructive sleep apnea, such as increased daytime sleepiness,
snoring, or witnessed apnea. Treatment for sleep apnea, including lifestyle changes,
surgery, continuous positive airway pressure, and oral appliances, greatly enhances
quality of life and blood pressure management. There is conflicting information
regarding a treatment’s impact on glycemic control.
Periodontal Disease
Patients with diabetes may experience more severe periodontal disease than those
without the disease, which has been linked to higher A1C levels. According to
longitudinal studies, diabetes occurs more frequently in patients with periodontal
disease. Although there is conflicting information regarding the benefits of
treatment, current research indicates that periodontal disease has a negative impact
on diabetes outcomes. After 12 months of follow-up, a randomized clinical trial
found that extensive periodontal treatment was linked to better glycemic control
(A1C 8.3% vs. 7.8% in control participants and the intensive-treatment group,
respectively) and a decline in inflammatory markers.
267
 2.4 Summary 4. Analyze the impact of continuous glucose monitoring (CGM) versus self-
monitoring of blood glucose (SMBG) on glycemic variability, time in range, and
Diabetes is a chronic condition that requires monitoring and comprehensive quality of life in patients with type 1 diabetes. What are the implications of the
medical evaluation to prevent complications and improve the patient’s quality of study findings for optimizing diabetes management strategies?
life. Collaborative care with patients is essential, tailoring treatment plans based
on individual preferences, values, and goals. This approach considers various
factors such as age, cognitive abilities, lifestyle, cultural background, and medical
history. Patients should be educated in problem-solving skills for effective diabetes
management.
Additionally, immunization is crucial for patients with diabetes to protect against
2 infections, and diagnostic tests play a vital role in assessing overall health and 2
identifying potential complications. Regular glucose monitoring is essential to

Diabetes, Monitoring And Comprehensive Medical Evaluation

Diabetes, Monitoring And Comprehensive Medical Evaluation

achieve optimal glycemic control and adjust treatment as needed. Overall, a patient-
centered approach, continuous monitoring, and proactive preventive measures are
crucial in managing diabetes effectively. These measures can help individuals with
diabetes maintain better overall health and reduce the risk of complications.

2.5 Review Questions

1. How do advanced diagnostic tests for diabetes, such as continuous glucose

monitoring (CGM) and advanced glycation end-products (AGEs) measurements,
contribute to a more comprehensive understanding of the disease pathophysiology
and aid in individualized treatment approaches at the doctorate level?

2. What are the current advancements in diagnostic technologies, such as non-

invasive glucose monitoring methods or point-of-care genetic testing, that have
the potential to revolutionize diabetes diagnosis and management at the doctorate
level? How can these advancements impact patient outcomes and the overall field
of diabetes research and clinical practice?

3. What are the latest advancements in glucose monitoring technologies for

diabetes management at the postgraduate level, and how do they compare in terms
of accuracy, patient adherence, and potential for improving glycemic control and
reducing complications?

268 269
 2
Diabetes, Monitoring And Comprehensive Medical Evaluation

270
Complications And Comorbidities
Diabetes mellitus has become an epidemic in the United
States over the past 20 years. Although type 1 diabetes
may possibly be increasing, the majority of the recent
rise in the incidence of diabetes is due to type 2 disease
and is a result of an alarming rise in the prevalence of
obesity. Treatment innovations have virtually eliminated
ketoacidosis as a cause of death and improved glycemic
control beyond all expectations. As a result, diabetics now
experience longer lifespans, which enables many of them
to experience the chronic problems of the condition. Here,
we examine the data showing that diabetic neuropathy, 3
a serious microvascular consequence, is caused by an

COMPLICATIONS AND COMORBIDITIES

unfavorable reaction to hyperglycemia. With 422 million
individuals globally, type 2 diabetes mellitus is one of the
largest chronic disease burdens. By 2030, type 2 diabetes
is anticipated to rank as the seventh leading cause of death
worldwide, mostly as a result of the disease’s explosive
growth in low- and middle-income nations. In addition,

3
type 2 diabetes is a major contributor to serious morbidities
and impairments, including lower limb amputation, chronic
renal failure, blindness, and cardiovascular disease.

Chapter Contents
3.1 Acute Complications
3.2 Chronic Complications
3.3 Summary
3.4 Review Questions

271

3.1 Acute Complications
Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA), hyperosmolar nonketotic coma (HNC), lactic acidosis
(LA), and hypoglycemia are the four acute metabolic consequences of diabetes.
Hypoinsulinemia is linked to DKA and HNC. Treatment for diabetes, whether
with oral medications or insulin, causes hypoglycemia. Although hypoglycemia
can happen when taking oral hypoglycemic medication, those taking insulin are
more likely to experience it. LA is frequently linked to additional conditions that
may have an impact on diabetes, such as cardiovascular illness (acute myocardial
infarction) linked to hypoxia and excessive lactic acid production.
A dangerous and potentially fatal diabetes consequence is diabetic ketoacidosis
3 (DKA). The majority of persons with type 1 diabetes experience DKA. DKA can
occur in people who have type 2 diabetes as well.
COMPLICATIONS AND COMORBIDITIES
When your body doesn’t produce enough insulin, blood sugar can’t enter your
cells to be used as energy, which leads to DKA. Instead, your liver converts fat
into ketone-producing acids through a process called lipolysis. When ketones are
created excessively quickly, they might accumulate in your body at risky quantities.
DKA Symptoms and Signs
DKA typically develops gradually. Early signs consist of:
● feeling extreme thirst.
● having a lot more urination than usual.
● fast, deep breathing is one of the more serious symptoms that can emerge
fast if left untreated.
● dry mouth and skin.
● face that is flushed.
● breath that smells of fruit.
● Headache.
● muscle pain or stiffness.
● becoming exhausted.
● vomiting and nauseous.
● stomach aches.
DKA may occasionally be the initial indication of diabetes in patients who have not
272
yet received a diagnosis.
Diabetic Ketoacidosis Causes and Risk Factors
Diabetes-related ketoacidosis typically results from a lack of insulin in the body.
Your cells can’t get their energy from the sugar in your blood, so they have to get
it from fat. Ketones are acids produced when fat is burned. They could accumulate
in your blood if the procedure continues for some time. Your blood’s chemical
composition may be altered by that overabundance, which would disrupt your
entire system.
DKA is a rare complication for persons with type 2 diabetes. If you have type 2,
especially as you age, you run a higher risk of developing HHNS (hyperosmolar
hyperglycemic nonketotic syndrome), a disorder having some resemblances to type
2. Severe dehydration may result from it. 3
DKA risk factors include:
COMPLICATIONS AND COMORBIDITIES
● even if undiagnosed, having type 1 diabetes
● frequently missing your insulin dose
● not taking your authorized dose of insulin
● stomach disorder
● Infections
● Heart conditions, including heart attacks
● fresh stroke
● severe disease or stress of any kind
● pregnancy Surgery
● steroids and antipsychotic medications
● using narcotics that are unlawful, like cocaine
Diagnostic and tests for DKA
When your blood sugar is over 250 mg/dL (milligrams per deciliter) or you have
any of the aforementioned high blood sugar symptoms, such as dry mouth, extreme
thirst, or frequent urination, you should test your ketones.
A pee test strip can be used to determine your blood sugar level. Ketones are also
measured by some glucose meters. Lower your blood sugar as much as you can,
then recheck your ketones in 30 minutes.
● Bloodwork, including metabolic panel and electrolytes
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 ● Urinalysis
● Arterial blood gas
● Blood pressure
● Tests for signs of infection
● Chest X-ray
● Electrocardiogram
According to population-based studies, the rate per 1,000 diabetics per year ranges
from 4.6 to 8. It may affect more women than men and is more common in young
diabetics. 20% to 30% of the time, DKA may be the first sign of diabetes. The
prevalence of HNC, LA, and hypoglycemia has not been determined in population-
based investigations. In the Diabetes Control and Complications Trial (DCCT),
there were differences in hypoglycemic episodes between the therapy groups. The
3
level of glycemia normalization was related to these occurrences.
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Definition
DKA is defined by the European Society for Paediatric Endocrinology, the Lawson
Wilkins Pediatric Endocrine Society, and the American Diabetes Association (1),
(2), and the International Society for Pediatric and Adolescent Diabetes (3) as a
triad of:
● hyperglycemia, which is defined as a plasma glucose level of more than
250 mg/dL (or more than 13.88 mmol/L)
● venous pH of less than 7.3
● a bicarbonate level of more than 15 mmol/L
A lower level of hyperglycemia (>200 mg/dL [>11.10 mmol/L]) also fits the criteria
for DKA, according to pediatric specialists. youngsters fasting during an insulin
shortage period, extremely young or partially treated youngsters, and pregnant
teenagers have all been recorded to experience the combination of near-normal
glucose levels and ketoacidosis (also known as “euglycemic ketoacidosis”).
Acute illnesses or comorbidities including cardiovascular disease, injuries or
infections, drugs, and poor compliance or errors in compliance with therapy are
precipitating causes for DKA, HNC, and LA.
The dosage of an oral hypoglycemic agent or insulin, dosing mistakes, when to
take a drug, particularly insulin, when to delay eating, and co-morbid conditions
such renal insufficiency, adrenal insufficiency, and pituitary insufficiency are all
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risk factors for hypoglycemia. The management of these acute consequences still
heavily relies on prevention. These issues will be less common if the causes are
recognized and the proper teaching, awareness, and self-care are provided.
DKA, HNC, and LA all necessitate hospitalization for treatment, utilizing
considerable amounts of medical resources and raising costs. Reducing the expense
of these illnesses’ medical care begins with prevention. Usually, ambulatory care
can cure hypoglycemia without depleting a lot of medical resources. However,
hospitalization may be necessary in cases of severe hypoglycemia accompanied by
loss of consciousness.
DKA, HNC, and LA are each associated with significant morbidity and mortality.
There is improvement when these illnesses and the related morbidity are treated 3
quickly. DKA and HNC have mortality rates of 9%–14% and 10%–50%,
COMPLICATIONS AND COMORBIDITIES
respectively. When accompanied with circulatory collapse or septic shock, serum
lactate concentrations >5 mmol/L have a mortality probability of >50% for LA.
Symptoms of hypoglycemia are typically treatable with timely medical attention.
Long-term neurologic damage may be linked to severe and profound hypoglycemia.
Administrative data sets classify diabetes and diabetic complications using
International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision
(ICD-10), codes. DKA is identified by the ICD-9 code 250.1x (250.10–250.13).
However, coma brought on by extreme hypoglycemia and DKA are also classified
as 250.3 (diabetes with other coma). Subdivision E1x.1 of the ICD-10 categories
for diabetes (E10-E14) designates DKA, while E1x.0 designates hyperosmolar
or hypoglycemic coma with or without ketoacidosis. Absolute insulin deficiency,
increased glycemia (glucose levels typically >200 mg/dl), increased lipolysis,
increased ketone production, hyperketonemia (ketone levels positive at 1:4
dilution of serum or greater or beta hydroxybutyrate >0.5 mmol/L), and acidosis
(pH 7.3 or bicarbonate 15 mEq/L) are the clinical characteristics that define DKA.
Bicarbonate values between 15 and 18 mEq/L have been described for milder forms
of ketoacidosis and normoglycemic ketoacidosis, respectively. For epidemiologic
studies to reliably assess and compare morbidity and mortality, it is crucial to define
DKA precisely.
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 Pathogenesis and Pathophysiology
A frequent and potentially fatal consequence of type 1 diabetes, particularly around
the time of diagnosis, is diabetic ketoacidosis (DKA). When type 2 diabetes is first
diagnosed and as it progresses, DKA is less frequent.
Very low levels of effective circulating insulin and a corresponding rise in the levels
of counterregulatory hormones, including glucagon, catecholamines, cortisol,
and growth hormone, are the two factors that lead to DKA. The metabolism
of carbohydrates, fats, and proteins is altered catabolically as a result of this
interaction. Hyperglycemia is brought on by poor glucose uptake and increased
liver and kidney glucose production.
Continuous fluid and electrolyte loss exacerbates the effects of lipolysis, which
increases the generation of ketones, especially beta-hydroxybutyrate (-OHB),
3
ketonemia, and metabolic acidosis. DKA is initially brought on by underlying
increasing beta cell loss in type 1 diabetic individuals who were undetected. Insulin
COMPLICATIONS AND COMORBIDITIES
omission, insufficient insulin dose during an infection, gastrointestinal disease,
trauma and stress, or pump failure can cause DKA in established individuals. DKA
develops in people with type 2 diabetes when there is an underlying acute illness
present or when they are transitioning to insulin dependence.
Insulin deficiency
Insufficient insulin is the cause of DKA. When normal insulin levels are insufficient
due to a severe infection, for example, insulin deficiency may be relative or
absolute depending on whether insulin therapy is neglected. Lack of insulin causes
unchecked ketogenesis and lipolysis, which raises plasma glucose. It should also be
remembered that insulin deficiency, especially when chronic, leads to accelerated
protein breakdown in the body, as shown by the severe sarcopenia and cachexia
of T1DM patients before the advent of insulin. Ketosis and hyperglycemia may
be caused by excessive protein breakdown and the release of gluconeogenic and
ketogenic amino acids that follows.
Stress hormones and cytokines
At some point, excess “counter-regulatory” or “stress” hormones and cytokines are
paired with insulin deficiency.
Cytokines and general stress factors including dehydration, hypotension, and
hypoperfusion may both contribute to the release of stress hormones. Endotoxin
276
and tumor necrosis factor (TNF) have both been demonstrated to mimic all
metabolic responses to infection, including the release of stress hormones and
hyperthermia. The conventional stress hormones include cortisol, growth hormone
(GH), glucagon, and adrenaline, all of which have well-known metabolic effects.
While GH and cortisol function with a latency of hours, glucagon and epinephrine
act with a quick beginning of action. Even in the absence of infection, DKA
patients have high cytokine levels. It is possible that many of the metabolic effects
of cytokines are mediated by hypothalamo-pituitary activation and the subsequent
release of stress hormones. The metabolic effects of cytokines are generally not
well known. Certain cytokines, like TNF-, can reduce the sensitivity of peripheral
tissues to insulin, which can start a vicious cycle with self-perpetuating increases
in blood glucose and cytokine levels. In critically ill patients, insulin possesses
anti-inflammatory characteristics. Exogenous insulin injection may help raise 3
insulin sensitivity, possibly to some extent by interrupting this vicious cycle but
COMPLICATIONS AND COMORBIDITIES
also because glucotoxicity and lipotoxicity decrease.
Lipid metabolism
Contrary to popular assumption, DKA is mostly brought on by abnormal lipid
metabolism rather than by carbohydrate metabolism. DKA is essentially caused by
unchecked ketogenesis in the liver and unchecked lipolysis in adipose tissue.
Regional depots containing visceral fat, subcutaneous upper and lower body fat,
and adipose tissue are all present. In addition to these traditional depots, fat can be
found in the majority of other tissues, including connective tissue, bone marrow,
liver, and muscle. The fact that fat is spread in compartments within each tissue
further complicates the situation.
Fat can be found intracellularly, intracellularly, and intramuscularly in muscles, for
example. Lipases strictly regulate lipolysis in physiologic circumstances.
Adipose triglyceride lipase and perhaps hormone-sensitive lipase both promote the
release of free fatty acids and glycerol into the bloodstream. Insulin inhibits this
process, while low insulin levels quickly accelerate lipolysis. Lipolysis is induced
by stress hormones such cortisol, growth hormone, and adrenaline. It is conceivable
that lipolysis is stimulated by dehydration in and of itself. The blood concentrations
of free fatty acids may quickly triple or quadruple as a result of these hours-long
occurrences. By oxidizing free fatty acids to ketoacids or ketone bodies in the liver,
ketogenesis takes place (Figure 3.1). Ketone bodies, in particular 3 OH butyrate, are
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 phylogenetically old fuel molecules that are found in abundance in very primitive
organisms, indicating that they have played a significant role in evolution over the
last 2 to 3 billion years. Physically, ketone bodies give the brain and other tissues
vital fuel energy during fasting, protracted activity, and other fuel-scarce situations.
3
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Figure 3.1: Mechanisms of ketogenesis. NEFA, non-esterified fatty acids
In DKA, circulating ketone body levels increase quickly and excessively due
to unregulated ketogenesis. This happens as a result of both an increase in the
availability of fatty acids to the liver and the liver’s promotion of ketogenesis by
low insulin and high glucagon levels. Normal people have compensatory increases
in insulin secretion to stop this uncontrolled process, while T1DM patients do not.
278
Glucose metabolism
Although DKA typically manifests as hyperglycemia, it’s vital to emphasize that
it can sometimes show as normal or very mildly raised glucose levels. This might
be especially true when experiencing calorie restriction due to a condition like
gastrointestinal illness. Insulin resistance is brought on by a lack of insulin combined
with an overproduction of stress hormones, which results in hyperglycemia. This
boosts gluconeogenesis and hepatic glucose synthesis in the liver. It’s doubtful that
the kidney plays a significant part in the early stages of DKA. The resulting high
glucose levels cause an increase in peripheral glucose disposal and a high flux state,
but the higher mass action of glucose is typically insufficient to make up for this.
Because of elevated amounts of stress hormones, elevated levels of free fatty acids,
and varied levels of dehydration, the metabolism of muscle glucose is characterized
by insulin resistance. 3
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Diagnosis And Clinical Presentation
In less than 24 hours, DKA often develops over a short period of time. There may
have been a few days before that were generally depressed and had poor metabolic
regulation. The degree of hyperglycemia will determine whether or not the history
includes symptoms of polydipsia and polyuria. Specific symptoms depend on the
triggering circumstances and any other potential comorbidities. Poor skin turgor,
hyperventilation (Kussmaul respirations), hypotension, tachycardia, and mental
impairment may be discovered during a physical examination. Due to peripheral
vasodilatation brought on by the acidemia, many patients have infections but
normothermia or even hypothermia. Careful clinical examination, determination
of plasma glucose, measurement of ketone levels in blood or urine, measurement
of plasma potassium and other electrolytes, and assessment of acidemia are all
necessary for prompt diagnosis and first treatment.
Unless the patient is severely hypokalemic ( 3.5 mmol/L), fluid and insulin therapy
can typically be started if blood or urine ketones are significantly raised and high
blood glucose is present. DKA is also likely.
Prior to starting insulin therapy, potassium supplementation is required if it is very
low. Rehydration shouldn’t be put off while waiting for a potassium measurement,
though.
Following arterial blood gas analysis, blood electrolytes, including anion gap, serum
lactate, complete blood count, biochemical evaluation of liver and renal function,
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 blood and urine cultures, myocardial biomarkers (if a myocardial infarction is
suspected), electrocardiogram (ECG), and chest X-ray are typically the next
diagnostic steps. It is fortunate in this context that the majority of contemporary
gas analyzers also readily yield potassium concentrations. The recent development
of bedside ketone body monitoring is another benefit. As a result, it is now possible
to measure the levels of 3 hydroxybutyrate in blood quickly and accurately, as
opposed to the unreliable measurements of acetoacetate in urine or the time-
consuming traditional laboratory methods previously utilized.
In spite of potassium depletion, serum potassium is often normal or higher due
to water deficiency, an intracellular to extracellular shift brought on by insulin
deficiency, and acidemia, which causes the extracellular to intracellular shift.
Patients with low potassium levels have a significant total body potassium
3
deficiency and should receive aggressive replacement therapy under the direction
of cardiac monitoring. Due to osmotic changes, sodium concentrations can
COMPLICATIONS AND COMORBIDITIES
fluctuate between normal and low levels. Plasma sodium decreases by 1 mmol/L
for every 3 mmol/L increase in plasma glucose, according to a calculation. As the
hyperglycemia is brought under control, sodium levels typically increase, resulting
in a true hypernatremia. Leukocytosis is a common finding in patients, and it is
more often correlated with ketone body levels than with the presence of infection.
Additionally, there is a hydration deficit of about 10% of body weight. Amylase and
liver enzyme increases without a specific cause are also typical.
All further causes of acidosis are included in differential diagnosis. Be aware that
many severe medical disorders might cause acidosis and stress ketosis. A significant
anion gap and varied levels of respiratory compensation define DKA, a metabolic
acidosis. Therefore, measurements of ketone body concentrations and an arterial
gas analysis are essential.
Lactate measurements are necessary if there is a sizable difference between the
degree of the acidemia and the extent of the ketonemia.
Clinical history is typically able to distinguish between starvation ketosis and
alcoholic ketoacidosis. Lactic acidosis, poisoning with salicylate, methanol,
ethylene glycol (antifreeze), and paraldehyde are additional conditions that can
result in metabolic acidosis. Anytime renal failure or respiratory failure exacerbate
the acidosis, the clinical picture may become hazy. DKA may also resemble other
illnesses. Elevated myocardial enzymes and biomarkers can happen even in the
absence of a clinical myocardial infarction, and high potassium levels can also
280
generate ECG abnormalities that are indicative of myocardial infarction. DKA
might resemble an acute abdomen as well, especially in younger patients.
Prevalence of Diabetic Ketoacidosis
According to the massive, population-based SEARCH for Diabetes in Youth study
conducted in the United States, 29% of type 1 diabetes patients under the age of 20
had DKA when they were diagnosed. While significantly higher rates were reported
by the Pediatric Diabetes Consortium, these results are not based on the general
population. The prevalences reported from hospital series are lower than these
estimates. According to SEARCH data, DKA prevalence is high and steady over
time. Australia, Germany, and Austria have all shown steady, high rates of DKA
upon diagnosis. On the other hand, in Finnish children, the prevalence of DKA at
diagnosis dropped from 30% in 1982–1991 to 19% in 1992–2002. The prevalence 3
of DKA in type 1 diabetes diagnosis has significantly decreased, according to
COMPLICATIONS AND COMORBIDITIES
studies from various emerging nations.
In adults, DKA is a less frequent early manifestation of diabetes. An estimated 20%
to 50% of persons in the United States who are diagnosed with DKA originally
have type 2 diabetes. The later clinical course, however, indicates a 39%–60%
increase in the cumulative incidence of type 2 diabetes among these patients.
African Americans have been found to have a similar percentage (42%–64%)
of type 2 diabetes patients who are at risk for ketosis. The first sign of diabetes
was less frequently observed to be DKA in earlier studies from 1945 to 1980. In
the population-based Rhode Island Hospital Study, 20% of patients had DKA at
the time of diagnosis. DKA was the initial symptom in 23% of diabetic patients,
according to a Rochester, Minnesota, community study. Only 15% of individuals
diagnosed at or after the age of 30 had DKA, compared to 26% of those diagnosed
before the age of 30.
Incidence
The definition, recognition, and ascertainment of DKA from hospital records and
discharge summaries determine its prevalence. Due to the disorder’s severity
and acuteness, it is probably recognizable and simple to ascertain. But different
diagnostic values for pH and bicarbonate could lead to either an overdiagnosis
or an underdiagnosis of the condition. In community-based trials, such as those
conducted in Rochester, Minnesota, and Providence, Rhode Island, the diagnosis of
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 DKA was given with clear-cut criteria1,2. In Rochester, Minnesota, the incidence
rate ranged from 8 per 1,000 person-years for DKA at all ages to 13.4 per 1,000
person-years among diabetics who had their diabetes diagnosed before the age of
30 (Figure 3.2).
3
COMPLICATIONS AND COMORBIDITIES
Figure 3.2: Diabetes Patients’ Risk of Diabetic Ketoacidosis, Rochester,
Minnesota, 1945–1970
In children and teenagers with type 1 diabetes who have it established, the incidence
of DKA varies from 1 to 12 episodes per 100 person-years. For females but not for
males, the prevalence of DKA in children and adolescents rises dramatically with
age.
For adults, there are no comparable population-based data. In Rochester, the
incidence rate for DKA was 8 per 1,000 person-years for all ages and increased to
13.4 per 1,000 person-years among diabetics who had their diagnosis prior to the
age of 30. The incidence of DKA among diabetic patients of all ages was 4.6 per
1,000 person-years in the Rhode Island Hospital Study. Women had a higher rate
of diabetes than males did.
Particularly in the younger age groups, there is a large burden of DKA at diagnosis
with T1D among youth from the United States and India. Although the causes of
this high frequency are not well understood, they must be taken into account when
282
creating strategies to stop DKA before it develops.
One of the biggest global health issues of the current century is diabetes. The
second-highest percentage of diabetics in the world reside in India. By 2045, it
is anticipated that more than 124 million Indians will have been diagnosed with
diabetes, up from an estimated 74 million in 2021.
Over 90% of all instances of diabetes in India are caused by type 2. Diabetes is a
progressive condition that, if undiagnosed and mistreated, may result in crippling
consequences that affect various organs and bodily systems. Nephropathy,
retinopathy, strokes, and coronary heart disease are a few examples. In turn, this
might lead to earlier morbidity and mortality with a shorter life expectancy. Diabetes’
financial toll can be upsetting, especially for those who are socioeconomically
disadvantaged and fall under the country’s lower wealth index. Over 350 thousand
Indian rupees are spent on type 2 diabetes care over the course of a lifetime, or 3
about 14,000 Indian rupees annually. Additionally, the financial strain on the Indian
COMPLICATIONS AND COMORBIDITIES
healthcare system may be significant, affecting households and, in turn, important
macroeconomic indices.
Wealth and diabetes
Studies reveal that random elevated glucose levels were lowest in the poorest 20%
of households, a condition known as a rich man’s sickness. These levels, however,
were highest among individuals who were among the richest 20% of the population.
Higher income earners may afford to purchase manufactured and quick foods, which
are typically more expensive than goods that are purchased locally. One of the main
causes of the diabetes epidemic, along with industrialization and urbanization, is
the quick social shift. A poor diet can cause metabolic dysfunction and the onset of
diabetes, which is exacerbated by a sedentary lifestyle, little exercise, and stress.
Precipitating Factors
DKA in persons with established diabetes is typically brought on by a comorbid
condition or by skipping insulin administration. Infection, which can range from
minor viral infections to full-blown septicemia, is the most frequent contributing
cause. Cardiovascular events (myocardial infarction, stroke), gastrointestinal
illness, immune-mediated disorders, pancreatitis, trauma and major surgery,
alcohol misuse, and pharmaceuticals, particularly glucocorticoids, are additional
triggering variables. Because of the stress hormone reactions, all of these causes
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 produce insulin resistance. Additionally, the patient will frequently take less insulin insulin use. Drug misuse and cigarette smoking may also contribute to DKA.
as a result of their poor appetite and lack of food. In this situation, gastrointestinal Patients with type 2 diabetes who are admitted to the hospital for other medical or
disorders that cause nausea and vomiting present a unique difficulty, necessitating surgical issues run the risk of developing DKA. Patients having a history of prior
the hospitalization of such patients for intravenous glucose and insulin therapy. episodes have an increased risk of developing DKA.
One presenting characteristic of newly diagnosed T1DM may be diabetes
ketoacidosis. A significant role is also played by psychological elements. Younger
patients, those suffering from psychiatric conditions, and members of minority
groups are more likely to exhibit poor compliance because they may not comprehend
the fundamentals of diabetes care due to linguistic or cultural barriers.
Younger age is the main risk factor for DKA at diagnosis, with children under the
age of two having a three times higher risk of developing DKA than older children.
Low parental education, low family income, low socioeconomic status, and
3
absence of private health insurance are additional risk factors for the diagnosis of 3
DKA. DKA occurs more frequently among ethnic minorities as well. Higher risk of

COMPLICATIONS AND COMORBIDITIES

COMPLICATIONS AND COMORBIDITIES

DKA is linked to low social awareness of diabetes symptoms in regions with low
incidence of type 1 diabetes. Diabetes runs in the family, and having a first-degree
relative with type 1 diabetes is highly protective. Children enrolled in long-term
etiological research show a comparable protective effect.
Additionally, drugs (glucocorticoids, atypical antipsychotics, and diazoxide) can
hasten the development of DKA in people who have never been diagnosed with
diabetes.
Figure 3.3: Smoking rates among diabetics in India from 2008 to 2020, broken
Most instances of DKA that go undiagnosed are linked to a lack of insulin, a
malfunctioning pump, or a mistake in the course of treatment. Children’s insulin down by gender
therapy under parental supervision reduces the incidence of DKA. DKA may also A study done in India between 2008 and 2020 found that 2% of female diabetics
develop if insulin medication is not adjusted properly while a patient is unwell or acknowledged smoking. In contrast, during the same time period, nearly 24% of
recovering from surgery. male diabetics smoked.
The key triggering factors for DKA are frequently socioeconomic level and From a low of fewer than 1000 per 100,000 people (USA and Scotland) to a
inadequate access to outpatient diabetes care; however, serious psychological high of 30,000 per 100,000 people (India), the case-fatality rate of DKA varies
problems can play a substantial role. In both adults and adolescents with type 1 by geographic region. DKA is more prevalent in children than in adults, and its
diabetes, continuous subcutaneous insulin infusion (CSII) is efficient and secure; frequency fluctuates with age.
nevertheless, stopping CSII can soon cause DKA. After the introduction of CSII
in children and teens, the incidence of DKA seems to have remained stable over a Cerebral Edema in Childhood Diabetic Ketoacidosis
lengthy period of time (4 years). Similar to children, infections and noncompliance The majority of children experiencing diabetic ketoacidosis (DKA) typically show
with treatment are the main causes of type 1 diabetes in adults. In an adult inner city signs of neurological dysfunction. Consequently, there is a need for evidence-based
population, not having the money to purchase insulin is a major factor in quitting recommendations to identify those patients who are in need of urgent medical

284 285
 intervention to save their lives. While cerebral dysfunction during DKA is often a
result of metabolic imbalances, cerebral edema (swelling of the brain) occurs in less
than 1% of cases. However, this complication is particularly concerning as it can
lead to permanent brain injury and even death. Typical descriptions of neurological
collapse caused by CE include fast start, rapid progression, and recovery reliant on
timely intracranial pressure decrease. Despite the fact that the majority of adults
and children with DKA have asymptomatic CE, CE only rarely develops in persons
older than 20 years.
This age dependence may indicate that alterations in brain metabolism that
occur during development are important players in the pathophysiology of CE.
For instance, compared to adult brains, children’s brains are said to require more
oxygen and fuel.
3
The documented relationship of symptomatic CE with low partial pressures of
carbon dioxide in arterial blood may reflect detrimental cerebral vasoconstriction,
COMPLICATIONS AND COMORBIDITIES
and hypoxia is further implicated since the brains of patients with DKA may extract
blood oxygen less efficiently than healthy persons. Excessive hypotonic fluid
administration and bicarbonate administration may make the CE worse.
Hyperglycemic Hyperosmolar State
Hyperosmolar hyperglycemia is a complication of type 2 diabetes mellitus and
has an estimated mortality rate of up to 20%, which is significantly higher than
the mortality for diabetic ketoacidosis (currently 1%). It was previously known
as hyperglycemic hyperosmolar nonketotic coma (HHNK) and nonketotic
hyperosmolar syndrome (NKHS). It typically appears after a period of symptomatic
hyperglycemia during which there is insufficient fluid intake to prevent severe
dehydration brought on by the osmotic diuresis caused by hyperglycemia. Although
it is challenging to estimate HHS’s prevalence, researchers believe it to be low
compared to other problems associated with diabetes. According to some studies,
HHS is to blame for around 1% of all hospital admissions for diabetes.
Pathogenesis
The fundamental mechanism for both HHS and DKA is a decrease in the effective
action of circulating insulin together with a concurrent rise of counter-regulatory
hormones. These changes result in increased hepatic and renal glucose production,
decreased glucose uptake in peripheral tissues, hyperglycemia, and concomitant
286
changes in extracellular space osmolality. Glycosuria, which causes osmotic
diuresis and the loss of water, sodium, potassium, and other electrolytes, is a
symptom of HHS.
While insulin levels in HHS are insufficient for the use of glucose by insulin-
sensitive tissues, they are adequate (as shown by residual C-peptide) to stop
lipolysis and ketogenesis.
Definition
HHS is characterized as a severe rise of serum osmolality >320 mOsm/kg and
blood glucose >600 mg/dL (>33.30 mmol/L) without substantial acidosis or ketosis.
Ketones may be trace quantities in urine and blood (84).
The HHS code for hyperosmolar (nonketotic) coma or diabetes with hyper-
3
osmolarity is 250.2 in the ICD-9. The code for HHS in the ICD-10 is E1x.0,
which stands for hyperosmolar or hypoglycemic coma with or without keto-
COMPLICATIONS AND COMORBIDITIES
acidosis (the x digit is used to specify the type of diabetes).
Incidence And Prevalence
The absence of population-based studies and the prevalence of numerous
comorbidities in these patients make it impossible to determine the incidence of
HHS. Estimated hospital admission rates for HHS are lower than those for DKA.
HHS affects only 1% of all diabetes-related admissions but up to 4% of newly
diagnosed type 2 diabetics. Between 15% and 45% of adult individuals with acute,
severe hyperglycemia have isolated HHS.
HHS can occur at any age, however it is more common in elderly people with
concomitant conditions. The greater death rate linked with HHS compared to
DKA appears to be caused by the presence of other illnesses, such as infection,
cardiovascular disease, and malignancy. Given that many patients’ clinical
presentations include components of both HHS and DKA, the prevalence of HHS
in children is most likely underreported. More than 50 cases of HHS have been
recorded in several investigations of juvenile and teenage diabetes patients, the
majority of which were case series or single-institution evaluations. The majority
of patients were young people with newly discovered type 2 diabetes, and many of
them were of African American ancestry.
The Kid’s Inpatient Database was used in a study that produced the first nationwide
287
 estimate of pediatric hospitalizations in the United States between 1997 and 2009.
In 1997, there were 2.1 HHS diagnoses for every 1,000,000 children, and by 2009,
that number had increased to 3.2. Children with type 1 diabetes accounted for the
majority (70.5%) of hospitalizations under the HHS.
Risk Factors
The majority of HHS episodes are caused by an infectious process; other causes of
HHS episodes include alcoholism, trauma, medications, pancreatitis, myocardial
infarction, and cerebrovascular accidents. In a case series of 119 HHS patients,
42% experienced a stroke, while approximately 60% of the patients had an
infection. The onset of HHS may also be accelerated by drugs that influence glucose
metabolism, including corticosteroids, thiazides, and sympathomimetic substances
3 like dobutamine and terbutaline. HHS is a risk for older people, especially those
with newly diagnosed diabetes. A comparison between 135 individuals diagnosed
between the ages of 35 and 55, and 15.0% in patients beyond the age of 55.
Similar results were found in a U.S. research involving 613 adult patients hospitalized
for hyperglycemic episodes. Death rates for DKA, mixed DKA-HHS, and isolated
HHS alone were 4%, 9%, and 12%, respectively. The degree of hyperosmolarity
and advanced age were the most effective predictors of death in both investigations.
According to data from the National Vital Statistics System, the number of deaths
attributable to hyperglycemic crises in individuals with diabetes decreased from
2,989 in 1985 to 2,459 in 2002. Age-adjusted death rates for individuals with
diabetes dropped from 42 to 24 per 100,000 throughout that time (Figure 3.5).
This decline was seen in all age categories. In comparison to earlier reported rates
of 33 and 72 per 100 HHS hospitalizations of children dying under HHS, the
mortality rate for children between 1997 and 2009 was recorded at 2.7 per 100
HHS hospitalizations. 3

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COMPLICATIONS AND COMORBIDITIES

with hyperosmolar syndrome and 135 diabetic control subjects, matched for age,
who were hospitalized during the same period, revealed certain significant factors.
These factors include a higher proportion of female participants in the hyperosmolar
syndrome group (71% compared to 53% in the diabetic control group), a greater
occurrence of newly diagnosed diabetes (36 cases per 100 hospitalizations for
hyperosmolar syndrome compared to 7 cases in the diabetic control group), and an
increased presence of acute infections (39 cases per 100 hyperosmolar syndrome
hospitalizations compared to 19 cases in the diabetic control group). These factors
were found to be independently linked to the presence of hyperosmolar syndrome.
In a separate group of 200 hyperosmolar syndrome patients in Rhode Island, it was
noted that 18% of the cases were among residents of nursing homes.

Morbidity And Mortality

HHS is a rare occurrence, according to analysis of hospitalization data from the
National Hospital Discharge Surveys 2001–2010 for Diabetes in America. Ages
18 to 44 had the largest proportion of hospitalizations with HHS listed. When
compared to the average annual number of hospital discharges citing HHS as the
cause (10,800 in 1989–1991 vs. 23,900 in 2001–2010), this number has doubled.
The mortality rates attributable to HHS in adults range from 5% to 25%. Mortality
rises rapidly with age, from zero in patients under the age of 35 to 1.2% in patients
Figure 3.5: Age-Specific Death Rates for Hyperglycemic Crisis Among Persons
With Diabetes Age ≥18 Years, by Age, U.S., 1985–2002
Lactic Acidosis
Non-ketotic acidosis in diabetic people can occasionally be brought on by lactic acid.
Despite the fact that non-ketotic acidosis caused by “unidentified organic acids” had
been documented for many years prior, Daughaday et al. (1962) likely presented
the first examples that could be considered proof. A noteworthy characteristic of

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 the majority of cases is the connection of acute sickness, hypotension, and shock
with the formation of lactic acidosis, and the death rate is very high. While some
of the instances documented by Tranquada et al. (1966) may have manifested as
“idiopathic lactic acidosis,” all of the patients in these cases had severe underlying
illnesses, and the majority of them died.
Although fatal lactic acidosis has also been reported as a side effect of phenformin
medication, recovery was extremely unusual in any of these patients since they
were all quite unwell, with the majority being hypotensive and shocked. Although
it is commonly known that phenformin can induce slight increases in blood lactate,
it is doubtful that this is what is causing the deadly acidosis. However, combining
phenformin with alcohol can create rather severe hyperlactatemia. Nothing in the
literature indicates that lactic acidosis is a particular complication of diabetes.
3 3
Patients who have been shocked frequently but not always develop lactic acidosis.

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COMPLICATIONS AND COMORBIDITIES

Patients in diabetic “comas” are frequently hypotensive and experiencing peripheral

circulatory failure, therefore it’s conceivable for ketoacidosis and lactic acidosis to
develop simultaneously in these patients. The goal of the current experiment was
to determine the contribution of both lactate and the ketone bodies to the acidosis
Table 3.1: Hospitalizations for Diabetes Acute Complications, by Age, United
that occurs in diabetic patients. It does not appear that measurements of both lactic
acid and ketone bodies in “diabetic ketosis” have previously been carried out. This States, 2001–2010
has been done both directly by measuring blood lactate and ketone bodies and
indirectly by looking into the relationship between ketoacidosis and the changes in
acid-base balance.

Incidence
There is a lack of information on LA incidence rates. It is a rare but significant
adverse effect in diabetic people. For Diabetes in America, data from the National
Hospital Discharge Survey on hospitalizations from 2001 to 2010 with a LA code
in patients with and without a concurrent diagnosis of diabetes were evaluated
(Tables 3.1 and 3.2). While patients over the age of 45, women, people of color,
and those whose diabetes was not noted on the hospital discharge summary had the
largest absolute number of LA instances, those under the age of 45 had the highest
percentage of diabetes discharges with LA.
Table 3.2: Annual Lactic Acidosis Hospitalizations, by Diabetes Status, Age,
Sex, and Race, United States, 2001–2010

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 base imbalances may result in cerebral edema. It is unclear how cerebral edema
develops during LA.
High lactic acid levels are correlated with high mortality rates from LA. According
to data from the National Hospital Discharge Surveys conducted between 2001 and
2010, 1.2% of all hospitalizations for diabetic patients occur in LA.

Hypoglycemia
There are many different definitions of hypoglycemia; it is crucial to define criteria
for comparative epidemiologic studies. The Workgroup on Hypoglycemia of the
American Diabetes Association defined hypoglycemia as any episode of unusually
low plasma glucose concentration that puts the person at risk of injury. The
Workgroup defined a hypoglycemic episode as one of the following:
3 ● A situation involving severe hypoglycemia necessitates the active 3
Figure 3.4: By age group and gender, India’s share of people with diabetes
administration of glucose, glucagon, or other resuscitative measures by a

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COMPLICATIONS AND COMORBIDITIES

aged 15 to 49 from 2019 to 2021

Precipitating Factors
Conditions that impede oxygenation, such as hypoxemia, shock, sepsis, carbon
monoxide poisoning, and several drugs, such as phenformin and metformin,
particularly when used in patients with renal failure, are the typical triggering factors
for LA. The biguanide phenformin, which raises the risk of life-threatening LA, is
no longer sold in the United States. Furthermore, metformin is contraindicated in
people over the age of 65 and in people with disorders like cardiovascular, renal,
hepatic, and pulmonary problems that are linked to LA. Metformin is also suspected
to raise the risk of LA in people with diabetes.
The incidence of LA after metformin treatment compared to other antihyperglycemic
medications did not differ, according to a Cochrane Database analysis of prospective
comparative trials and observational cohort studies. In this study, the incidence of
metformin-associated LA was 8.4 instances per 100,000 patient-years, compared to
9 cases per 100,000 patient-years in the non-metformin group.
The reported incidence of metformin-associated LA in people with type 2 diabetes
ranged from 10 to 47 instances per 100,000 patient-years in different investigations.
Morbidity And Mortality
LA causes neurologic dysfunction. Rapid correction of the electrolyte and acid-
second person. The incident could result in a severe neuroglycopenia, a
seizure, or even a coma. Even if there are no measurements of plasma
glucose during an event, neurological recovery is adequate proof that a low
plasma glucose content caused the event.
● Hypoglycemia is characterized as a state where the plasma glucose
concentration is low, putting patients at risk for potential injury. People
with type 1 diabetes frequently experience severe hypoglycemia, with
annual incidence rates ranging from 3.3% to 13.5%. Severe hypoglycemia
is less common in persons with type 2 diabetes, despite the fact that those
taking insulin or insulin secretagogues (sulfonylureas and meglitinides) are
generally at increased risk.
● Symptomatic hypoglycemia that has been documented occurs when there
are the normal symptoms of hypoglycemia and a measured plasma glucose
level of less than 70 mg/dL (or 3.89 mmol/L).
● Asymptomatic hypoglycemia is defined as a situation where the measured
plasma glucose level is below 70 mg/dL but no normal hypoglycemic
symptoms are present.
● Hypoglycemia with probable symptoms is when there is no plasma glucose
reading to go along with the hypoglycemia symptoms.

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 ● Relative hypoglycemia is a situation in which a diabetic reports any usual
hypoglycemic symptoms and interprets them as such, yet the measured
plasma glucose level is greater than 70 mg/dL.
Except when combined with insulin or insulin secretagogues, glucose-lowering
drugs that do not result in uncontrolled insulin secretion include metformin,
dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists,
thiazolidinediones, and sodium-glucose cotransporter-2 inhibitors. A higher risk of
hypoglycemia has historically resulted from reducing the glycemic goals in diabetes
to avoid microvascular and macrovascular problems. The annual incidence rate of
severe hypoglycemia in type 2 diabetes patients getting conventional treatment or
insulin treatment ranged from 0.7% to 1.8% in the United Kingdom Prospective
Diabetes Study (UKPDS), when the HbA1c objective was 7% in the intensive
3 treatment arm. Significantly more hypoglycemia episodes were seen in the
intensive therapy groups in the ACCORD, ADVANCE, and VADT trials compared
COMPLICATIONS AND COMORBIDITIES
to the conventional treatment groups (Figure 3.5). In the Diabetes Control and
Complications Trial (DCCT), 65% of type 1 diabetes patients in the intensive
treatment arm suffered at least one episode of severe hypoglycemia throughout the
follow-up period. Interestingly, observational studies show that the prevalence of
severe hypoglycemia has not significantly decreased over the past 20 years, despite
some recent research reporting decreasing trends, particularly among patients with
type 2 diabetes.
Figure 3.5: ACCORD, ADVANCE, and VADT’s percentage of severe
hypoglycemia incidents
294
The ICD-9 assigns the code 250.3 to hypoglycemia coma brought on by diabetes
therapy; nevertheless, this code is also applied to coma with DKA. The code for
further diabetic hypoglycemia is 250.8. Diabetes-unrelated hypoglycemia is coded
as 251.2. It is advised to include another E code to indicate the medication that
caused the hypoglycemia. The ICD-10 uses the x digit to specify the kind of
diabetes, and E1x.0 signifies coma with or without ketoacidosis, hyperosmolarity,
or hypoglycemia, while E16.0 denotes diabetic drug-induced hypoglycemia
without coma.
Symptoms of hypoglycemia
Autonomic and neuroglycopenic symptoms are hypoglycemic symptoms. These
differ amongst patients based on their age and length of diabetes. For instance, in
addition to the typical autonomic and neuroglycopenic symptoms of hypoglycemia, 3
children may exhibit emotional and behavioral abnormalities.
COMPLICATIONS AND COMORBIDITIES
Anxiety, trembling, palpitations, diaphoresis, paresthesia, and a hungry sensation
are examples of autonomic symptoms. Lack of focus, headaches, blurred vision,
vertigo, confusion, convulsions, speech disturbances, restlessness, and loss of
consciousness are among the neuroglycopenic symptoms.
Brain neuronal glucose deficiency causes neuroglycopenic symptoms.
Neuroglycopenic symptoms often have a glycemic threshold of around 54 mg/
dL. Contrary to autonomic symptoms, counter-regulatory hormonal failure or
prior episodes of hypoglycemia typically have no effect on the emergence of
neuroglycopenic symptoms.
Incidence In Type 1 Diabetes Patients
The prevalence of moderate or mild hypoglycemia is unknown; these conditions are
common in insulin-treated individuals but frequently go unnoticed or unreported.
More people are likely to notice severe hypoglycemia. Incidence rates of severe
hypoglycemia prior to the DCCT ranged from 3 to 86 per 100 patient-years
depending on the criteria, age, length of diabetes, and type of treatment.
Incidences of hypoglycemia among adolescents taking part in the DCCT were 28
per 100 patient years for participants receiving standard treatment and 86 per 100
patient years for those receiving intensive care.
Teenagers experienced coma and seizure incidence rates of 27 and 10, respectively,
per 100 patient-years. The frequency of severe hypoglycemia rose from two to six
295
 times more frequently in all DCCT participants receiving intensive treatment for type
1 diabetes compared to those receiving standard care. Numerous research looked at
the incidence of severe hypoglycemia in young people after the DCCT. Few were
population-based or employed a prospective design. From a sizable cohort of type
1 diabetic children aged 0 to 19 years who were being monitored by the Barbara
Davis Center for Childhood Diabetes, the incidence of severe hypoglycemia was
reported to be 19 per 100 patient-years. In a sample of older kids aged 7 to 16 years,
a Joslin Clinic research using a similar criterion discovered a lower prevalence
of 8 per 100 patient-years. However, children with psychiatric conditions and
those in challenging social situations were not included in this study. Similar rates
were reported from various European, American, and Australian studies, with the
exception of a research from Finland that found a very low incidence (4 per 100
person-years).
3 cells.
eating a very low carbohydrate food portion or fasting for an extended period of
time; absence of endogenous glucose production after drinking alcohol; increase
in glucose consumption during or after physical exercise; and increase in insulin
sensitivity due to a decrease in insulin resistance. Tight glycemic control and severe
hypoglycemia are strongly correlated, particularly in children and elderly adults.
The most often documented predictors of severe hypoglycemia in people
with type 1 diabetes are age (especially childhood and adolescence), male
sex, and longer duration of diabetes.
The risk of hypoglycemia rises with the duration of diabetes, in part because
the alpha cells’ ability to produce glucagon in response to hypoglycemia
gradually diminishes, and it is inversely related to the maintenance of beta
3

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COMPLICATIONS AND COMORBIDITIES

Incidence In Type 2 Diabetes Patients

Impairment in counter-regulatory responses to hypoglycemia
Patients with type 2 diabetes who follow a healthy diet and exercise regimen
Under normal circumstances, a drop in plasma glucose concentration may cause the
do not experience acute hypoglycemia. Rarely does it happen in patients taking
body to react in one of two ways: (1) an increase in endogenous glucose production
oral hypoglycemic medications. The risk of hypoglycemia does, however, rise
through glycogenolysis and gluconeogenesis; or (2) behavioral changes that result
as insulin reliance develops. In the United Kingdom Prospective Diabetes Study
in feelings of hunger and food seeking.
(UKPDS), patients receiving intensive treatment with chlorpropamide had a risk
Reduced insulin production is the initial reaction to a decline in glucose
of severe hypoglycemia of 1 per 100 patient years, glibenclamide had a risk of 1.4
concentration in non-diabetic people. While the glucose level is still in the low
per 100 patient years, and insulin had a risk of 1.8 per 100 patient years. Compared
physiological range, this happens. A further drop in glucose will result in increased
to shorter-acting ones, long-acting sulfonylureas have a higher risk, especially
glucagon and epinephrine secretion (as well as cortisol and growth hormone, whose
for older patients and those with longer histories of diabetes, polypharmacy, and
roles are less significant), so that lower glucose concentrations activate an intense
recent hospitalization. Angiotensin-converting enzyme (ACE) inhibitors and
sympathoadrenal reaction that causes the onset of relevant symptoms. A further
sulfonylurea were prescribed to patients in one investigation, but the conclusion
drop in glucose concentration is likely to result in severe neurological effects and
was not supported by a significant trial. Since 2007, hospital admission rates for
cognitive decline.
hypoglycemia have decreased in the United States, however rates among black
Remaining endogenous insulin secretion in the DCCT indicated a 65% decreased
Medicare users and those over 75 continue to be high.
incidence of severe hypoglycemia. Patients with numerous islet autoantibodies
and the human leukocyte antigen (HLA)-DR3/4 genotype typically experience a
Risk Factors For Hypoglycemia
sudden decrease of endogenous insulin production.
Therapeutic hyperinsulinemia or the lack of “defense mechanisms” in response to a
Aggressive glycemic management in type 2 diabetes patients increases their risk of
decline in plasma glucose content can both be risk factors for hypoglycemia.
hypoglycemia. Patients at risk of hypoglycemia were identified in a sizable cross-
Treatment with insulin, sulfonylureas, or glinides, if administered at high doses
sectional study of older adult patients in the Veterans Health Administration in 2009
or at the wrong time of day for a meal; lack of exogenous glucose, such as when

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 depending on whether they were using sulfonylureas and/or insulin. Utilizing one In Figure 3.6, the alleged processes of hypoglycemic ignorance are enumer-
of these medications in patients with A1c values below predetermined cutoffs, such ated.
as 7.0% (53 mmol/mol), was referred to as overtreating. The rates of overtreatment
were 11.3% for patients with A1c 6.0% (42 mmol/mol), 28.6% for A1c 6.5% (48
mmol/mol), and 50.0% for A1c 7.0% among patients age 75 years with a serum
creatinine >2.0 mg/dL or an ICD-9-CM diagnosis of cognitive impairment or
dementia (31.5% of patients). Patients with diabetes and severe beta-cell loss who
don’t react right away to a reduction in insulin frequently have impaired sensitivity
to the aforementioned defense mechanisms. As a result, the liver takes longer to
secrete glucose during hypoglycemia. The frequency of hypoglycemia episodes
rises with the duration of diabetes, possibly because individuals with type 1 diabetes
lose endogenous insulin more quickly than those with type 2 diabetes, whose loss
3
is more gradual. 3
Additionally, the glucagon response to hypoglycemia in those with type 1 diabetes

COMPLICATIONS AND COMORBIDITIES

COMPLICATIONS AND COMORBIDITIES

deteriorates over time while doing so more slowly in those with type 2 diabetes,
despite being normal in the early stages of the disease. Additionally, there is a
noticeable deterioration of the sympathoadrenal responses to hypoglycemia in the
advanced phases. The decrease in the plasma glucose threshold necessary to activate Figure 3.6: Potential causes of hypoglycemic ignorance. The autonomic
this mechanism is what causes the decline in the adrenal reaction. Hypoglycemia response to hypoglycemia is diminished with repeated hypoglycemia,
risk is increased in people with type 1 diabetes by a reduction in both glucagon and
and the autonomic warning signals are diminished. In an effort to
epinephrine responses to hypoglycemia. Although less frequently as the disease
advances, these mechanisms are present in the early stages of type 2 diabetes. maintain brain function and change glucose sensing in the ventromedial
hypothalamus (VMH), the brain’s maladaptive reaction is characterized
Hypoglycemia unawareness by increased glucose transporter 1 (GLUT1) activity. This is mediated
It is thought that having frequent hypoglycemic episodes reduces the autonomic by higher levels of gamma aminobutyric acid (GABA)
response to subsequent hypoglycemic occurrences, which results in the reduced
Severe hypoglycemia is a modifiable predictor, and extensive insulin therapy is
sympathoadrenal response. This puts patients at risk for a vicious cycle of repeated
indicated by lower A1c readings and higher insulin dose. It has been extensively
hypoglycemia episodes and lowers the glycemic threshold for symptoms to levels
researched how severe hypoglycemia and strict glycemic control are related,
that are nearly enough to impair cognitive function. After 25 years of treatment, type
particularly in youngsters. During the DCCT, more over 60% of the adolescents
1 diabetes patients had a 50% prevalence of this occurrence, compared to a 10%
receiving intensive care experienced a coma or a seizure, compared to 25% of those
prevalence in type 2 diabetics. It is unknown if this occurrence occurs in diabetic
receiving standard care. In pediatric populations, intensive treatment—such as the
people who only take oral medicines. Cryer coined the term “hypoglycemia-
use of insulin pumps—helps lower A1c levels without also increasing the risk of
associated autonomic failure” (HAAF) to describe this illness.
hypoglycemia. The incidence of hypoglycemia have been significantly reduced by
Repeated episodes of hypoglycemia, physical activity, and sleep may compromise
the inclusion of continuous glucose monitoring to insulin pump therapy.
the defense mechanisms, resulting in hypoglycemia.
The failure to recognize hypoglycemia’s symptoms due to hypoglycemia ignorance

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 is another risk factor. It is more prevalent in patients with low average glucose levels
and is present in roughly 10% of patients. Even a single bout of hypoglycemia can
result in a significant reduction in neurohormonal counterregulatory responses and
exacerbate hypoglycemia unawareness.
The primary impact of exercise on glucose metabolism is the reduction of blood
glucose levels by insulin-independent skeletal muscle absorption, which can cause
hypoglycemia without changing insulin dosage or carbohydrate consumption.
Drinking alcohol significantly increases the risk of developing severe hypoglycemia.
Alcohol inhibits the production of gluconeogenesis and glycogen, sharply
increases insulin sensitivity, and may cause hypoglycemia unawareness. Alcohol
consumption can cause severe hypoglycemia when combined with exercise, and
symptoms may not appear for up to 10 to 12 hours after drinking.
3
Particularly in the pediatric population, family dynamics, behavioral variables, and
psychiatric disorders are significant risk factors. According to the DCCT, established
COMPLICATIONS AND COMORBIDITIES
risk variables could only account for 8.5% of the variation in the incidence of severe
hypoglycemia. Glycemic control and the frequency of hypoglycemia have been
shown to be significantly impacted by factors like inadequate diabetes education,
low socioeconomic status, lack of insurance, unstable living conditions, behavioral
factors, and psychiatric disorders affecting patients and their families.
Family dynamics and personality traits have also significantly impacted how
well people with diabetes adjust to their condition and maintain control over
their metabolism. The presence of psychiatric problems has a negative impact on
metabolic regulation and treatment compliance.
In a small longitudinal cohort, the prevalence of psychiatric problems among
people with type 1 diabetes reached 48% by the time they had had the disease for
10 years and were 20 years old. Major depressive disorder was the most common
of these illnesses.
Up to 30% of people with type 1 diabetes have coexisting autoimmune disorders
such as thyroid, celiac, and Addison’s diseases, which raise the risk of hypoglycemia.
Although metabolic control is typically tighter in the final stages of pregnancy,
the incidence of mild and severe hypoglycemia is higher in early pregnancy in
type 1 diabetes. Impaired consciousness and a history of severe hypoglycemia are
predictors of severe hypoglycemia. Up to 23% of diabetic patients have chronic
renal damage. The risk of hypoglycemia is increased in patients with chronic
kidney illness, which increases the risk already existing in diabetics.
300
Implications Of Hypoglycemia In Diabetes
In diabetic patients, hypoglycemia leads to physical and psychological illness.
Hypoglycemia with symptoms is problematic and distracting. It can affect
behavior, judgment, and ability to carry out routine everyday tasks like driving.
Hypoglycemia can cause convulsions and even unconsciousness in more serious
situations. Rarely, there may be permanent brain damage, although occasionally
there may be transitory neurological abnormalities. Patients with type 1 diabetes
did not show a substantial decline in long-term cognitive performance during
systematic follow-up of patients from the DCCT/EDIC over the age of 18 years.
The data did not, however, cover diabetic youngsters or elderly individuals. A
connection between hypoglycemia and cognitive deterioration in people with type
1 or type 2 diabetes has been shown in other investigations. One study discovered 3
a connection between hypoglycemia and a decline in children’s cognitive
COMPLICATIONS AND COMORBIDITIES
performance, including language skills, working memory, and nonverbal processing
speed. According to other studies, older diabetes individuals who had hypoglycemia
had a twofold increased risk of dementia. Patients who have recurrent episodes of
hypoglycemia are also at risk of developing depression and anxiety. Concern about
hypoglycemia is a barrier to diabetes therapy and control.
Hypoglycemia can be fatal in more extreme circumstances, accounting for 4%–
10% of type 1 diabetes patients’ fatalities. The fatality rate from hypoglycemia in
people with type 2 diabetes is unclear.
Even though it is severe, chronic hypoglycemia can result in brain death, with the
majority of cases of sudden death being linked to cardiac arrhythmias brought on
by a heightened sympathoadrenal reflex that prolongs the QT interval. As shown in
Figure 3.6, hypoglycemia may influence cardiovascular events through a number
of different routes.
301
 Morbidity And Mortality
Tables 3.3 and 3.4, which use information from the National Hospital Discharge
Survey, present a new analysis of the incidence of hypoglycemia (ICD-9 codes
250.8 and 251.2) as a discharge diagnosis for hospitalizations in the United States
from 2001 to 2010. About 288,000 hospitalizations, or 5.4% of hospitalizations for
diabetes, had hypoglycemia identified as an underlying cause.
Diabetes patients under the age of 18 had the lowest hospital discharge rates for
hypoglycemia. Females with diabetes experienced more hypoglycemia incidents
overall than males did, whereas males experienced a higher percentage of discharges.
A substantial contributor to excess mortality in diabetic individuals is hypoglycemia.
Between 1968 and 1998, diabetes-related mortality in children did not go down
despite advancements in treatment. The “dead in bed” phenomenon, which has
been described and is known as sudden nocturnal death in young people with type
3 Figure 3.6: cardiovascular events that hypoglycemia may affect and the 3
1 diabetes, is thought to be responsible for roughly 6% of deaths in diabetic patients
underlying mechanisms. By encouraging the release of C-reactive protein

COMPLICATIONS AND COMORBIDITIES

COMPLICATIONS AND COMORBIDITIES

under the age of 40.

(CRP), IL-6, and vascular endothelial growth factor (VEGF), hypoglycemic
Because of the documented weakening of the counterregulatory hormone response
episodes may cause inflammation. Neutrophils and platelets are also more during sleep, the high frequency of nocturnal hypoglycemia reported by the
activated when blood sugar levels are low. Hypoglycemia-induced sympathetic DCCT, and more recent investigations using continuous glucose monitoring,
adrenal response causes an increase in adrenaline release, which can cause nocturnal hypoglycemia is a potential precipitant in these patients. The symptoms
arrhythmias and increase the burden on the heart. The risk of cardiovascular of hypoglycemia can range from minor neurologic signs to coma and convulsions.
disease may also be impacted by endothelial dysfunction. Children with type 1 diabetes who are young patients have a correlation between
hypoglycemia and a decline in cognitive performance.
A 1.5- to 6-fold increase in the risk of cardiovascular events and mortality was
Even after modest hypoglycemia, hypoglycemic seizures cause considerable losses
found in clinical and epidemiological studies based on tens of thousands of type 1
in language abilities, memory capabilities, and the capacity to organize and recall
and type 2 diabetes patients from various health services in various world regions.
information. Children who experience severe hypoglycemia may experience long-
lasting electroencephalographic alterations. On the other hand, while increasing the
Hypoglycemia in pregnancy
incidence of hypoglycemia in the DCCT cohort (aged 13 to 39 at baseline), intensive
To avoid difficulties for the mother and fetus, it is crucial for pregnant women to
insulin treatment did not result in a material worsening of neuropsychological or
manage their diabetes. Because glucose targets are 20% lower during pregnancy
cognitive functioning during the course of the experiment. The risk of hypoglycemia
than they were before, diagnosing and treating hypoglycemia in pregnant women
should be weighed against newly available information about the harmful effects of
might be difficult. Women with type 1 diabetes had a significantly higher rate of
hyperglycemia on the growth of a normal brain.
severe hypoglycemia in the first trimester—up to five times higher.
In general, if the mother is not hurt during the episode, the fetus is not at danger from
maternal hypoglycemia. Breastfeeding significantly raises the risk of hypoglycemia
3.2 Chronic Complications
in diabetic women receiving insulin.
Diabetes is a disease that might have problems with insulin sensitivity, insulin

302 303
 secretion, or both. These include gestational diabetes, Type 1 diabetes (T1D), Type
2 diabetes (T2D), and diabetes that develops as a result of other illnesses. One of
the 21st century’s fastest-growing global emergencies is diabetes. It is projected
that 537 million people worldwide have diabetes; this figure is expected to rise
to 643 million by 2030 and 783 million by 2045, according to the International
Diabetes Federation (IDF) Diabetes Atlas 20211. Additionally, it is projected that
by 2021, 541 million people would have reduced glucose tolerance. Additionally,
it is predicted that by 2021, 6.7 million persons between the ages of 20 and 79 will
have passed away due to diabetes-related causes. For diabetes complications to be
avoided, early diagnosis is crucial. One study indicated that 52%, 10%, and 6%,
respectively, of 200 newly diagnosed individuals had indications of neuropathy,
nephropathy, and retinopathy.2 Another study found that the prevalence of macro-
and microvascular problems was 27.2% and 53.5%, respectively, in individuals
3 3
with insulin-dependent diabetes.
Activation of protein kinase C isoforms, increased expression of the receptor for AGEs
and its activating ligands, increased intracellular formation of advanced glycation end
products (AGEs), increased flux of glucose and other sugars through the polyol pathway,
and excessive activity of the hexosamine pathway are the five main mechanisms by
which intracellular hyperglycemia damages tissues.
A number of research studies that were published over the past 12 months have
just lately comprehensively examined the significance of glycemic management
for macrovascular damage. HbA1c has been proposed as an independent, ongoing
risk factor for macrovascular disease, however this association has not been found
to be as substantial as that for microvascular problems. There is a 10-fold increase
in the risk of microvascular disease endpoints for an increase in HbA 1c from 5.5%
(37 mmol/mol) to 9.5% (80 mmol/mol), but only a 2-fold increase in the risk of

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COMPLICATIONS AND COMORBIDITIES

macrovascular disease endpoints.

3.3.1 Macrovascular Disease
The first step in the development of atherosclerosis is the adherence of monocytes
to the arterial wall, namely to endothelial cells, followed by their transmigration
into the subendothelial region.
Monocytes can differentiate into macrophages, which can then change into foam
cells by absorbing lipids and accumulating in the vascular wall. Fatty streak
lesions are created as a result of the early atherosclerosis process. Over time,
these lesions progress to become more advanced lesions that are characterized by
VSMC infiltration, the development of a necrotic core, and further lipid buildup.
These lesions can show signs of instability and plaque rupture in people, including
intraplaque hemorrhage and increased thrombogenicity.

Function Of Hyperglycemia
In the UK Prospective Diabetes trial (UKPDS) trial, a crucial role for glycemic
control and the length of diabetes exposure has been well established for
microvascular sequelae, however the evidence is less strong for macrovascular Figure 3.7: The development of diabetic vascular problems involves
disease. hemodynamic and metabolic factors. Renin-angiotensin system (RAS) and
other vasoactive factors are examples of hemodynamic factors. Glucose and its
metabolites, such as the creation of advanced glycation end products (AGEs),

304 305
 are examples of metabolic factors. Both mechanisms interact with one another
and result in oxidative stress and inflammation, which support atherosclerosis
and endothelial dysfunction. Nuclear transcription factor (NF ɑ) B and tumor
necrosis factor (TNFɑ) B are two examples.
Clinical Trials And Hyperglycemia
The relationship between tight glycemic control and cardiovascular endpoints has
recently been studied in clinical trials like the Action to Control Cardiovascular
Risk in Diabetes trial (ACCORD), Action in Diabetes and Vascular disease:
PreterAx and DiamicroN - MR Controlled Evaluation (ADVANCE) trial, and the
Veterans Affairs Diabetes Trial (VADT), which investigated tight glycemic control
in patients with T2DM and established CVD. Tight blood glucose control had no
3
impact on macrovascular outcomes, as seen in the initial findings of the Diabetes
Control and Complications Trial (DCCT) in patients with T1DM and the UKPDS
COMPLICATIONS AND COMORBIDITIES
trial in patients with T2DM. Recent research, such as the ACCORD trial and
ADVANCE study, further reinforced this.
Both investigations were unable to show significant cardiovascular benefits, and
the ACCORD study suggested that strict glucose control may have detrimental
cardiovascular effects. The brief duration of these trials (less than 5 years) may
be one reason why rigorous glycemic control has not been shown to improve
cardiovascular outcomes. The benefits of prior intensive cardiovascular risk
management, including aggressive glucose control, may not manifest for up to 10
years after study initiation, as is best demonstrated by the longer follow-up of the
Steno-2 study and a recent long-term follow-up of the UKPDS. Thus, other risk
factor modification strategies need to be stressed in light of the relative absence of
an impact on CVD with strict glucose management.
Direct And Indirect Glycotoxicity
On vascular cells, hyperglycemia is hypothesized to have both a direct and indirect
harmful effect. The production of diacylglycerol may be accelerated by higher
glucose levels entering the polyol pathway at an enhanced flux rate. Additionally,
increased glucose flux into the hexosamine system may be a factor in the
development of glucose-mediated vascular damage in diabetics. Aldose reductase
transgenic mice have been used to specifically examine atherosclerosis mediated
306
by hyperglycemia. These animals displayed early atherosclerosis and enhanced
glucose supply through the polyol route, but they did not produce more severe
vascular lesions.
Clear evidence from studies in cell culture experiments shows that hyperglycemia
causes a variety of pro-atherogenic consequences.
Note: Polymorphisms in the superoxide dismutase 1 gene have been associated
with various individual susceptibilities to microvascular problems. By stifling
hypoxia-inducible factor 1 transactivation, hyperglycemia-induced mitochondrial
reactive oxygen species generation reduces the neovascular response to ischemia.
By raising intracellular hyperglycemia and upregulating the glucose transporter 1,
hypertension hastens microvascular damage. 3
In vitro, glucose directly activates monocytes and macrophages, causing them to
COMPLICATIONS AND COMORBIDITIES
express cytokines like interleukin 1 (IL-1) and IL-6 more often. Additionally, this
results in the activation of nuclear factor B (NF B) and protein kinase C (PKC),
which increases the formation of reactive oxygen species (ROS). Low density
lipoprotein (LDL) oxidation and the production of ROS can both be mediated by
the auto-oxidation of glucose. Modified lipids, such as the pro-atherogenic oxidized
LDL, can be taken up by activated macrophages through scavenger receptors. The
development of modified albumin, which prevents the conversion of cholesterol to
high density lipoprotein (HDL), is caused by the creation of advanced glycation
end products (AGEs) in the hyperglycemic environment. As a result, persistent
hyperglycemia can indirectly cause a number of secondary changes, such as
modifications in lipid profi le, cellular lipid accumulation, the creation of foam
cells, and protein modifications caused by AGE that alter cellular structure and
function.
Animal models
Lack of a suitable animal model has long limited research on atherosclerosis in
diabetes. A murine model of diabetes-related macrovascular disease has been
created by our team andx others using the apoE knockout (KO) mouse, which is
made diabetic through repeated low-dose injections of streptozotocin. This model
is now thought to be a suitable model to research macrovascular disease in diabetes
by the National Institutes of Health/Juvenile Diabetes Research Foundation (NIH/
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 JDRF) co-sponsored Animal Models for Diabetes Complications Consortium
(AMDCC). Mice deficient in the LDL receptor were crossed with transgenic mice
expressing a viral protein under the control of the insulin promoter in order to
explore the distinct roles of hyperglycemia and dyslipidemia in diabetes-associated
atherosclerosis. T cells trigger the killing of pancreatic - cells that express the viral
protein when infected with the virus, closely simulating the autoimmune response
in human T1DM. Even on a normal diet, the development of atherosclerosis was
accelerated in these animals, indicating that hyperglycemia was the cause of
atherosclerosis in these mice. A higher rate of atherosclerosis was observed in mice
fed a high-fat diet, indicating that glucose and lipids may work in concert to speed
up atherosclerosis.
3 Metabolic memory
The concept of “glycemic memory” refers to the delayed consequences of previous
COMPLICATIONS AND COMORBIDITIES
glycemic status on the emergence of diabetic problems in the future. Even when
glycemic control eventually improves, episodes of poor glycemic control during
the initial stages of diabetes might cause or speed up the development of problems
later in the course of diabetes. Such a metabolic imprint has been supported by
two trials, the DCCT/EDIC trial in T1DM and the UKPDS in T2DM. Both trials
demonstrated that having poor glycemic control was linked to a greater burden of
problems down the road. The VADT research, another study in T2DM patients,
compared intensive and routine glucose management (6.9 vs. 8.4%, 52 vs. 68
mmol/mol), but did not show any significant cardiovascular protection after 12 to
15 years of long-term hyperglycemia exposure for the patients. Thus, it would seem
that early glycemic control is essential for a long-term favorable result on diabetic
complications.
The idea of “metabolic memory” brings up two significant concerns. First, years
before T2DM is identified, hyperglycemia may subject patients to its detrimental
effects. In fact, 25% of patients have difficulties at the time of their T2DM diagnosis.
The development of long-term diabetic vascular problems has been linked to the
production of this metabolic memory, therefore it has been hypothesized that early
diagnosis and stringent glycemic control may be crucial to reducing this link.
Second, despite not being reflected in the HbA 1c levels, glycemic oscillations,
including peaks and troughs, may be crucial in regulating the expression of
cytokines and growth factors as well as causing chromatin remodeling.
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Numerous cellular and molecular activities, the majority of which are related to
glycotoxicity, may be involved in the mechanisms driving metabolic memory. These
pathways include the synthesis of PKC, AGE formation, DNA glycation, increased
flux of glucose metabolism, enhanced oxidative damage, and mitochondrial stress.
Recent studies have demonstrated that transitory hyperglycemia causes both in
vitro and in vivo activation of the epigenetic alterations in the promoter region
of the NF-B component p65 in aortic endothelial cells. Reducing mitochondrial
superoxide production or the synthesis of - oxoaldehydes like methylglyoxal, which
superoxide induces, reversed these hyperglycemia-induced epigenetic alterations
and enhanced p65 expression (Figure 3.8).
3
COMPLICATIONS AND COMORBIDITIES
Figure 3.8: Early glucose metabolites like glyoxal and methylglyoxal, highly
reactive dicarbonyls, and important AGE precursors can all play a role in the
production of advanced glycation end products (AGEs).
These investigations demonstrate that transitory hyperglycemia induces long-
lasting chromatin remodeling alterations that result in persistent atherogenic
consequences during subsequent normoglycemia. In particular, hyperglycemia
causes the histone methyltransferase Set7 to be recruited and results in increased
H3K4 mono-methylation of the NF-B subunit p65 gene’s proximal promoter
region, which increases the expression of pro-atherogenic pathways like monocyte
chemotactic protein 1 (MCP-1) and vascular cell adhesion molecule 1 (VCAM-1).
A permanent elevation of pro-inflammatory genes like p65 and MCP-1 as a result
of earlier hyperglycemia has also been shown in later research in mice that were
initially diabetic but spontaneously recovered to normoglycemia. Furthermore,
309
 more in-depth epigenetic studies demonstrated that prior hyperglycemia also
affected various histone methyltransferases and, intriguingly, demethylases like
LSD-1, which resulted in changes in the H3K9 methylation of the p65 promoter.
Insulin Resistance
Insulin resistance, which has been linked to a higher risk of cardiovascular disease,
occurs in people with T2DM and in people who have impaired glucose tolerance.
The evidence that insulin resistance encourages atherogenesis as a separate risk
factor is growing. Additionally, a pro-atherogenic lipid profile with a large very
low-density lipoprotein (VLDL) component, a low HDL, and a small dense
LDL is frequently linked to insulin resistance. Studies conducted in vitro have
demonstrated that insulin has both pro- and anti-atherogenic actions. The theory
3 of pathway-specific insulin resistance has been developed as a result (Figure 3.9).
While the signaling pathways that promote cellular proliferation are unaffected,
COMPLICATIONS AND COMORBIDITIES
it has been hypothesized that insulin resistance to glucose transport also impacts
resistance to insulin’s antiproliferative actions (Figure 3.9). Reduced expression
of adhesion molecules like MCP-1, VCAM-1, and intercellular adhesion molecule
1 (ICAM-1) has been linked to antiproliferative and antithrombogenic effects of
insulin signaling through phosphatidylinositol 3 kinase (PI3K). Nitric oxide (NO)
generation is also compromised in insulin resistance since it is mediated by the
PI3K signal transduction pathway.
Figure 3.9: Pathway-specific insulin resistance causing atherosclerosis
and endothelial dysfunction. Nitric oxide, phosphatidylinositol 3 kinase,
NO, and MAPK stand for mitogen-activated protein kinase
310
It has been demonstrated that NO inhibits VSMC growth and LDL oxidation.
Contrarily, effects on VSMC proliferation and migration are mediated by the Ras/
Raf/MEKK/MAPK signal transduction pathway, which is further stimulated in
the presence of hyperinsulinemia, suggesting that insulin resistance specific to
this pathway plays a role in the pro-atherogenic effects of insulin. More recently,
it has been demonstrated that IL-6 reduces insulin-stimulated endothelial cell
NO generation through decreased insulin signaling activity that is mediated by
increased TNF- production. Contrary to popular belief, neither IL-6 nor insulin
have been associated with increased TNF- expression in skeletal muscle. Instead,
IL-6 and insulin paradoxically boost insulin-stimulated glucose uptake into skeletal
muscle and adipose tissue through enhanced insulin signaling.
Formation of AGE 3
Early glycation products, or Schiff bases, are the source of AGE production. These
COMPLICATIONS AND COMORBIDITIES
Amadori products, including 1 - amino - 1 deoxyfructose derivatives, are more
stable. Additional enzymatic modifications to the Amadori products produce a
variety of reactive intermediates, including 3-deoxyglucosone and methylglyoxal
(Figure 3.10). Methylglyoxal causes browning, denaturation, and redox active
di-amine cross-linking between lysine residues of the target amino acids when
it combines with amino, sulfudryl, and guanidine functional groups in proteins.
Hydroimidazolones, a homolog of carboxymethyl lysine (CML) and methylglyoxal
lysine dimer, are also produced by methylglyoxal, as well as N-E-(carboxyethyl)
lysine.
The AGE-based cross-links are extremely durable because they can withstand
enzymatic deterioration. The ambient amounts of different sugars, including
glucose, the level of oxidative stress, and the length of exposure to these different
stimuli are all factors that affect how quickly AGE forms.
Effects of Direct Vascular AGE Accumulation
Experimental investigations have shown that AGEs directly affect endothelial
function and accelerate the progression of macrovascular disease. Both receptor-
mediated and direct pathways are used by AGEs to exert their effects. Protein
structural integrity alterations, cellular function disruptions, and protein degradation
are all linked to AGE accumulation in the vascular wall. Collagen, albumin,
and apolipoproteins are just a few of the proteins that develop AGEs over time.
311
 Additionally, the interactions between the matrix, the matrix, and the cell can be
hampered by the cross-linking of AGEs with matrix molecules.
It has been demonstrated that AGE cross-linking to collagens affects vascular
compliance and elasticity, increasing vascular stiffness. By promoting the activity
of nicotinic acid adenine dinucleotide phosphate (NADPH) oxidase, AGEs can also
suppress NO and produce ROS.
AGE binding proteins
The binding of proteins like RAGE [57], AGE - R1 (p60), AGE - R2 (p90), and
AGE - R3 (galectin - 3), as well as the ezrin - radixin - moesin (ERM) family
of proteins macrophage scavenger receptor ScR - 11 and CD - 36, results in the
receptor-mediated effects of AGEs. The precise functions of AGE-R1, AGE-R2,
3 and AGE-R3 have not yet been fully clarified. Finally, it has been hypothesized
that interactions between AGEs and certain macrophage scavenger receptors, such
due to AGE buildup in these situations. Upregulation of connective tissue growth
factor (CTGF), which appears to be AGE dependent and may be mediated by
RAGE, has been seen in plaques from diabetic apoE KO mice.
Studies reducing vascular AGE accumulation
The total amount of AGEs present in the body can be decreased, or existing AGEs
can be chemically changed into inactive forms, to reduce the accumulation of
AGEs. Aminoguanidine is a powerful AGE production inhibitor that also reduces
oxidative damage to mitochondrial proteins by scavenging reactive dicarbonyl
AGE precursors. Treatment with aminoguanidine has been demonstrated to lessen
microvascular and, more recently, macrovascular problems in the diabetic apoE
KO mouse, a model of accelerated atherosclerosis. The substance ALT-711, also
known as alagebrium, is another potential inhibitor of AGE accumulation. This 3
thiazolium chemical and its original predecessor, phenylthiazolium bromide, have

COMPLICATIONS AND COMORBIDITIES

COMPLICATIONS AND COMORBIDITIES

CD36, also induce atherosclerosis. Studies employing CD36-knockout mice have been found to cleave pre-formed AGEs based on a variety of in vitro investigations.
supported this hypothesis. As a result, one of the suggested mechanisms of ALT - 711 is as an AGE cross-link
breaker.
Receptor for AGEs, RAGE
RAGE is a cell surface molecule belonging to the immunoglobulin superfamily
that functions as a multiligand pattern recognition receptor. RAGE functions
as an endothelial adhesion receptor for leukocyte integrins and binds ligands
that are actively involved in inflammation and immunological responses. It also
encourages leukocyte recruitment and extravasation of invading cells. RAGE,
which is present on endothelial cells and monocytes/macrophages and has been
linked to inflammatory lesions in various illnesses, is directly relevant to diabetic
macrovascular problems.

Downstream effects of RAGE activation

The pro-inflammatory transcription factor NF-B is activated as a result of RAGE
engagement (Figure 3.11). Extracellular signal-regulated kinases (ERKs), p21 ras,
NADPH oxidase, MAPKs, and PKC are just a few of the signaling pathways that
are activated when AGE binds to RAGE. These pathways also cause the activation
and translocation of NF-B. Furthermore, NF-B has the ability to promote RAGE
expression itself. In response to metabolic abnormalities such diabetes, dyslipidemia,
uremia, and aging, RAGE expression in tissues is noticeably increased, probably

312 313

3 membrane and effector domains. It is still debatable whether sRAGE functions
COMPLICATIONS AND COMORBIDITIES
Figure 3.11: By increasing the production of reactive oxygen species (ROS),
decreasing the availability of nitric oxide (NO), activating the nuclear
transcription factor кB (NFкB), tumor necrosis factor 𝛂 (TNF𝛂), and
profibrotic growth factors like transforming growth factor (TGF𝝱) and
connective tissue growth factor (CTGF) associated with vascular remodel, the
AGE receptor (RAGE) contributes to macrovascular disease associated with
diabetes. Endothelial nitric oxide synthase is referred to as eNOS, extracellular
signal-regulated kinase is referred to as ERK, mitogen-activated protein kinase
is referred to as MAPK, monocyte chemotactic protein is referred to as MCP,
and protein kinase C is referred to as PKC.
It has been demonstrated that the elimination of cross-links that have already
formed in diabetic rats using ALT-711 is linked to reversal of the diabetes-
induced increase in major artery stiffness, enhanced collagen solubility, and
decreased vascular and cardiac AGE buildup. Alagebrium also slows the course
314
of nephropathy, presumably by directly inhibiting PKC-phosphorylation, which
lowers the expression of vascular endothelial growth factor (VEGF) in the kidneys.
Treatment with ALT 711 resulted in a significant decrease in atherosclerosis in
diabetic apoE KO mice. Reduced vascular AGE buildup and RAGE expression
were linked to this anti-atherosclerotic action. Treatment with algebrium was also
linked to decreased expression of pro-fibrotic growth factors, particularly CTGF,
and decreased inflammation.
Soluble RAGE
RAGE has three significant splice variants. The full-length RAGE receptor comes
first, followed by the N-terminal version, which lacks the AGE-binding domain,
and the C-terminal splice variant, soluble RAGE (sRAGE), which lacks the trans-
3
largely as a ligand decoy for AGEs or whether it functions as a competitive
COMPLICATIONS AND COMORBIDITIES
antagonist to the full-length physiologically active RAGE.
Soluble RAGE and diabetes associated atherosclerosis
In the streptozotocin diabetic ApoE KO mouse, a model of diabetes-related
atherosclerosis, soluble RAGE (sRAGE) has been identified as having therapeutic
efficacy. The initial work by Park et al. found that sRAGE treatment of diabetic
apoE KO mice resulted in a dose-dependent inhibition of atherosclerosis and a
reduction in plaque complexity. These positive effects were not affected by changes
in cholesterol or glucose levels. Furthermore, sRAGE decreased AGE levels in these
diabetic mice in a dose-dependent manner to levels comparable to those reported in
non-diabetic animals. Additionally, the impact of sRAGE-based RAGE blockage
in atherosclerosis that has already developed was studied. The administration of
sRAGE decreased RAGE expression, the number of infiltrating immune cells, and
the expression of the genes for type IV collagen, fibronectin, and transforming
growth factor (TGF) in the aorta and kidney, along with the plaque area. These
researchers came to the conclusion that RAGE activation is responsible for both the
development of atherosclerosis and the production of lesions.
Other models of atherosclerosis and diabetes have similarly shown that therapy with
soluble RAGE reduces vascular consequences. The sRAGE therapy significantly
reduced atherosclerosis in the streptozotocin-induced diabetic LDL receptor / /
315
 mice model. An increase in atherosclerosis was observed in ApoE KO mice that
were bred onto a db/db background, a model of T2DM with insufficient leptin
receptor signaling. This atherosclerosis was significantly reduced by daily sRAGE
therapy. Animals that are selectively deficient in RAGE/apoE (RAGE / ) have been
developed to help researchers better understand the unique role that RAGE plays
in the development of vascular lesions. Both soluble and tissue-bound full-length
RAGE are completely absent from these mice. RAGE - knockout mice mated onto
an apoE / background exhibited a substantial reduction in plaque area in the presence
and absence of diabetes, as had been predicted by the pharmacologic intervention
studies focused on the RAGE ligands and AGEs. Recent research on the impact of
RAGE deletion on the onset of atherosclerosis in streptozotocin-diabetic RAGE/
apoE KO mice revealed a significant decrease in the area of atherosclerotic plaques
3
when compared to diabetic apoE KO animals expressing RAGE.
COMPLICATIONS AND COMORBIDITIES
These vascular alterations in streptozotocin diabetic double RAGE/apoE KO mice
were correlated with decreased inflammation, decreased accumulation of RAGE
ligands like S100/CML, decreased infiltrate by macrophages and T lymphocytes,
and decreased expression of pro-fibrotic and pro-infl ammatory growth factors and
cytokines.
The development of RAGE neutralizing substances for clinical usage has been
stimulated by these encouraging results with RAGE antagonism. In phase II clinical
studies, the RAGE modifying drug TTP488 is being examined in individuals with
Alzheimer’s disease and those who have diabetic nephropathy.
However, at this time, the main focus of inhibiting RAGE does not appear to
involve studies addressing CVD in the absence or presence of diabetes. Another
drug, TP4000, will soon begin phase I clinical trials.
The development of RAGE neutralizing substances for clinical usage has been
stimulated by these encouraging results with RAGE antagonism. In phase II clinical
studies, the RAGE modifying drug TTP488 is being examined in individuals with
Alzheimer’s disease and those who have diabetic nephropathy.
However, at this time, the main focus of inhibiting RAGE does not appear to
involve studies addressing CVD in the absence or presence of diabetes. Another
drug, TP4000, will soon begin phase I clinical trials.
316
Interaction With The Renin Angiotensin System
There has been an increase in research into the potential connections between these
various pathways because diabetic complications appear to have a multifactorial
origin and involve interactions between hemodynamic pathways like the RAS and
metabolic pathways like hyperglycemia and the formation of AGEs. Although
these investigations have been conducted mostly in the renal environment, there
is growing evidence that AGE buildup can cause an upregulation of specific RAS
components. Additionally, it has been noted that angiotensin converting enzyme
(ACE) inhibition confers its end-organ protective effect, in part through a decrease
in AGEs and an increase in sRAGE.
As a result, one of the main regulators in diseases brought on by aging could be
the RAS state. More recently, it has been shown that some therapeutic approaches
that have been demonstrated to be anti-atherosclerotic partially exert their 3
vasculoprotective effect by inhibiting the AGE/RAGE pathway. These include
COMPLICATIONS AND COMORBIDITIES
statins, peroxisome proliferator-activated receptor (PPAR) and PPAR agonists, and
angiotensin II receptor blockers (ARBs).
Vasoactive Hormones’ Role In Atherosclerosis Associated With
Diabetes
Classic RAS
Over a century ago, Tigerstedt & Bergman first described renin. However, during
the past ten years, the RAS has become more sophisticated and we still don’t fully
comprehend it. Currently, the traditional approach is extremely well understood
(Figure 3.12). Angiotensin (AT) I and II production is not limited to the systemic
circulation but also occurs in vascular and other tissues (Figure 3.12).
Novel aspects of the RAS : ACE 2
Another enzyme connected to the production of AT peptides, called ACE2, was
discovered in 2000. It is a carboxypeptidase with a similar sequence to ACE [99].
ACE2 enhances the development of AT 1–7 but does not produce AT II (Figure
3.12). This heptapeptide inhibits growth while also causing vasodilatation. To fully
comprehend the numerous roles played by ACE2 both inside and outside of the
RAS, additional research is required, including studies into specific inhibitors.
317
 3 3
COMPLICATIONS AND COMORBIDITIES
Figure 3.12: Overview of the traditional and alternate pathways in the renin-
angiotensin system (RAS) enzymatic cascade. Renin separates the decapeptide
angiotensin I from angiotensinogen in the traditional route. Angiotensin I is
then transformed into angiotensin II, which has a variety of receptor subtypes
but is most important to the vasculature through AT 1 and AT 2 receptors.
tissue plasminogen activator (t-PA), chymostatin-sensitive angiotensin II-
generated enzyme (CAGE).
318
COMPLICATIONS AND COMORBIDITIES
Figure 3.13: new information about the parts of the RAS and their interactions.
Angiotensin II (AT II) is produced from angiotensin I (AT I) by ACE, and its
actions are mediated via the AT 1 receptor, as shown by the classic RAS. The
revised approach highlights the additional RAS components, where ACE2
plays a role in converting AT I to AT 1–9 and AT II to the vasodilator AT 1–7
that works via the Mas receptor.
AT Receptors
All AT peptides exert their actions via distinct cell surface receptors (Figures 3.11
and 3.12). The majority of the effects often linked with AT II are mediated by the
AT 1 receptor. The AT 2 receptor subtype’s function is still debatable, however it
appears to counteract some effects of AT II that are mediated by the AT 1 receptor.
Role of the RAS in Macrovascular Disease
It is now understood that local RAS activation plays a significant part in the
pathogenesis of diabetes-induced atherosclerosis and endothelial dysfunction.
Therefore, there is a compelling case for blocking the RAS in diabetic patients to
prevent cardiovascular events. Additionally, a number of recent clinical trials have
revealed that RAS inhibition may shield at-risk patients from developing T2DM.
319
 endothelial dysfunction in the early stages, in the absence of structural alterations
to the arterial wall. Although studies of RAS components in plasma have generally
suggested that this system is suppressed in diabetes, there is mounting evidence
that the local cardiovascular RAS is activated in this setting. In the aorta wall of
diabetic apoE KO mice, it has been shown that ACE expression and activity, AT II
expression, and AT 1 receptor expression all increase, pointing to a critical role for
RAS activation in the pathophysiology of diabetes-related endothelial dysfunction.

Repair of Regenerating Endothelial Cells and RAS

The RAS has also been shown to have an impact on how many regenerated endothelial
progenitor cells are present in diabetic individuals. A better cardiovascular prognosis
has been linked to a higher concentration of circulating endothelial progenitor
3 cells, which are thought to preserve the integrity of the vascular endothelium in 3
CAD patients. ARB (olmesartan) therapy may enhance the amount of regenerating

COMPLICATIONS AND COMORBIDITIES

COMPLICATIONS AND COMORBIDITIES

endothelial progenitor cells, which may help explain the positive cardiovascular
Figure 3.14: Effects of diabetes-induced renin-angiotensin system (RAS) effects of AT1 receptor blockage, according to research in individuals with T2DM.
activation on endothelial dysfunction and atherosclerosis-related pathways.
Vasoconstriction, inflammation, cellular proliferation, and thrombosis are all ACE 2 and AT1-7’s Involvement in Endothelial Dysfunction
signs of endothelial dysfunction, which is a condition associated with diabetes It has been proposed that an imbalance between ACE and ACE2 may lead to
aberrant blood pressure, with enhanced ACE2 expression serving to defend
brought on by RAS activation. Dysfunctional endothelium is a significant
against hypertension and ACE2 deficiency to fuel it. It has long been known that
contributor to atherogenesis and, consequently, cardiovascular events by losing
AT II causes endothelial dysfunction through a variety of mechanisms, including
its protective characteristics. VSMC, or vascular smooth muscle cells; TPA, or
oxidative stress induction, proliferative, and pro-thrombotic actions. It has recently
tissue plasminogen activator; PAI-1, or plasminogen activator inhibitor-1. been discovered that AT 1–7, which is produced by the enzyme ACE2, encourages
the production of NO and prostaglandins and amplifies the effects of bradykinin in
many experimental paradigms.
RAS Activation And Endothelial Dysfunction
Additionally, AT 1–7 reduces the development of VSMC, platelet aggregation and
Endothelial dysfunction is thought to result from an imbalance between
thrombosis, inflammation, fibrosis, and oxidative stress, all of which may help
vasoconstrictors and vasodilators in the vascular tone, which is accompanied by
endothelial function return. It seems that AT 1 - 7 can counteract AT II effects both
a decline in NO activity and an increase in AT II and endothelin (ET) activity.
by activating other vasodilators and by inhibiting AT 1 receptors. In this regard,
Endothelial dysfunction is characterized by impaired endothelium-dependent
Kostenis et al. reported that the Mas receptor, which is increasingly thought to be
vasorelaxation and increased interactions with blood leukocytes, which depend on
the primary receptor conferring the biologic effects of AT 1–7, appears to act as a
adhesion molecules like VCAM-1 and chemoattractants like MCP-1. Atherosclerosis
physiologic antagonist of AT 1 receptor, thereby counteracting many of the actions
and endothelial dysfunction are closely related (Figure 3.14).
of AT II at the endothelial level.
The activation of the RAS is crucial to the pathophysiology of diabetes-induced

320 321
 Role of RAS in Atherosclerosis
Clinical and experimental data unequivocally show that practically all of these
pro-atherosclerotic pathways depend on RAS activation. According to Diet et al.’s
observations of enhanced ACE protein deposition within atherosclerotic plaque in
human coronary arteries, ACE may help to promote local AT II synthesis, which
may play a role in the pathogenesis of artery disease. Additionally, there is proof
that atherosclerotic plaques overexpress the AT II and AT 1 receptors. Indeed,
pro-inflammatory molecules like VCAM-1 and MCP-1, as well as pro-sclerotic
and pro-proliferative cytokines like CTGF and platelet derived growth factor, are
inhibited by blocking the RAS with an ACE inhibitor or an AT 1 receptor antagonist.
These findings confirm that RAS activation has a significant role in the onset and
development of atherosclerosis.
3
The pathophysiology of atherosclerosis is significantly influenced by the production
of pro-inflammatory cytokines such IL-1𝛂, TNF-β, and IL-6. Both stable and
COMPLICATIONS AND COMORBIDITIES
unstable atherosclerotic plaques have been found to include IL-6, ACE, and AT 1
receptors. ICAM-1 and VCAM-1, E-selectin, MCP-1, and IL-8 expression are all
increased when AT II stimulates the redox sensitive nuclear transcription factor, NF-
B, which may work as a unifying signaling mechanism for inflammatory stimuli
in atherogenesis. The fact that both ACE inhibitors and AT 1 receptor blockers
reduce the expression of several adhesion molecules has been shown in a number
of clinical and experimental studies, confirming that the chronic inflammatory
response linked to atherosclerosis appears to be modulated by AT II at every level
and that RAS inhibition can be used to target it therapeutically.
Additionally, it appears that a continuous pro-inflammatory state is crucial in the
change of a stable atherosclerotic plaque into a weak plaque that is prone to rupture.
There is evidence that AT II is involved in matrix metalloproteinase activation, both
directly and through the induction of pro-inflammatory cytokines like IL-6. Plaque
rupture has been linked to the activation of matrix metalloproteinases in the fibrous
cap of the atherosclerotic lesion.
ACE 2 and Diabetes Accelerated Atherosclerosis
Despite the paucity of studies on ACE2 expression and activity in atherosclerosis,
there is mounting evidence that these more recently discovered RAS components
may contribute to the initiation and development of atherosclerosis. In a recent
study using a rabbit model of atherosclerosis, Zulli et al. found that endothelial
322
cells, macrophages, and smooth muscle cells all exhibit very high levels of ACE2
within atherosclerotic plaques. It’s unclear whether this rise in ACE2 is a result of
an injury or an effort to fortify the vessel by raising AT 1 - 7 levels.
There is evidence that the cardiac RAS is significantly activated in the human
context following coronary artery closure, and it is well known that RAS blocking
lowers remodeling and increases survival in people following a MI. Recent studies
have shown that experimental MI also increases cardiac ACE2 expression and
activity. All of these findings imply that the pathophysiology of atherosclerosis
is largely influenced by an imbalance in the RAS activity. However, it is not yet
known if ACE2 deficiency plays a role in the faster atherosclerotic disease process
found in diabetes.
Oxidative Stress and RAS 3
There is mounting evidence that the local generation of ROS, particularly in the
COMPLICATIONS AND COMORBIDITIES
diabetic environment, plays a critical role in atherosclerosis.
It has been shown that the aortas of diabetic atherosclerotic apoE KO mice produce
more vascular superoxide. These modifications were brought about by an increase
in NAD(P)H oxidase (Nox) activity in the aorta and an uptick in the expression
of several Nox subunits, such as p47phox, gp91phox, and rac-1. The finding of
enhanced nitrotyrosine staining in these diabetic plaques provides additional proof
of increased local vascular ROS generation in diabetes.
Indeed, PPAR-𝛂 and PPAR-𝛄 agonists, which lower the production of vascular
superoxide, have been linked to a reduction in plaque development, further
highlighting the connection between vascular oxidative stress and atherosclerosis.
Additionally, the deletion of antioxidant enzymes like glutathione peroxidase,
specifically the Gpx1 isoform, in the vascular wall causes an increase in plaque
area, especially in the context of diabetes, through increases in inflammatory
mediators like adhesion molecules and chemokines. More recently, it has been
demonstrated that treating diabetic GPx1/apoE KO mice with the Gpx1 analog
ebselen reduced oxidative stress variables and atherosclerosis. Furthermore, there
was a concomitant elevation of RAGE in the Gpx1/apo E double KO animals,
further connecting vascular RAGE expression to increased oxidative stress and
accelerated atherosclerosis in conditions like diabetes.
323
 The Potential For Healing
RAS inhibition and vascular dysfunction
RAS blockage has emerged as an obvious and alluring therapeutic target as a result
of prior observations. The Trial on Reversing Endothelial Dysfunction (TREND),
which demonstrated that ACE inhibition improves endothelial function in people
with coronary artery disease, provided the earliest support for the clinically beneficial
effect of inhibiting this system on compromised endothelial function. Additionally,
O’Driscoll et al. found that ACE inhibition with enalapril enhanced normotensive
patients with T2DM’s baseline and stimulated NO-dependent endothelial function.
Losartan, an AT1 receptor antagonist, is one ARB that has been shown to improve
endothelial function. Additionally, improved endothelial dysfunction in T1DM
patients receiving treatment with the ACE inhibitor ramipril or the ARB losartan
3 for three weeks may have been caused by elevated bradykinin levels with ACE
inhibition or elevated levels of AT 1-7.
COMPLICATIONS AND COMORBIDITIES
Cardiovascular Safety and RAS Inhibition
A growing body of research suggests that RAS-inhibiting medications may
have unique benefits for preventing CVD in diabetics. The Captopril Prevention
Project (CAPP) study found that patients with diabetes who took captopril fared
significantly better than those who received conventional therapy (beta-blockers
and diuretics) in terms of the primary endpoint, MI, all cardiac events, and total
mortality. Particularly among individuals at greatest risk, specifically those with
the highest median fasting glucose or those with higher raised blood pressure,
these relative beneficial effects of ACE inhibitor medication were particularly
obvious. This is in contrast to the UKPDS, where individuals with T2DM who were
randomly assigned to captopril or atenolol experienced equivalent CVD benefits,
possibly reflecting a decreased CVD risk in the newly diagnosed diabetes patients
evaluated in the UKPDS.
There was a risk reduction of 25% for combined CVD events, 37% for CVD mortality,
22% for MI, and 33% for stroke in the 3577 patients who had diabetes and one other
CVD risk factor, according to the MICRO-HOPE sub-study of the Hypertensive
Old People in Edinburgh (HOPE) study. The incidence of CVD events was lower
in the fosinopril-treated group of hypertensive individuals with T2DM than it was
in the amlodipine-treated group in the Fosinopril vs Amlodipine Cardiovascular
Events Trial (FACET) research. In patients with established CAD who did not have
324
left ventricular dysfunction, ACE inhibition decreased cardiovascular mortality
and morbidity, according to the European Trial on Reduction of Cardiac Events
with Perindopril in Stable Coronary Artery Disease (EUROPA). In a meta-analysis
that included 31 555 individuals, the data from these trials were combined with
those from the Quinapril Ischemic Event Trial (QUIET) research. According to
this investigation, ACE inhibitor medication resulted in a significant 14% decrease
in all-cause mortality and MI, a 23% decrease in stroke, and a 7% statistically
significant decrease in revascularization procedures when compared to placebo.
The ACE inhibitor perindopril and the diuretic indapamide, when administered
to high-risk T2DM patients, resulted in a decrease in macrovascular outcome
compared to placebo, according to the recent ADVANCE research.
According to recent data on ARB trials, these drugs offer CVD protective effects in
T2DM patients that are comparable to those seen with ACE inhibitors. Treatment 3
with losartan in patients with T2DM and left ventricular hypertrophy (LVH) led
COMPLICATIONS AND COMORBIDITIES
to a significantly lower rate of death from CVD, particularly all cause mortality,
according to the Losartan Intervention For Endpoint Reduction in Hypertension
(LIFE) research. An analysis of the massive Reduction of Endpoints in NIDDM
with Angiotensin II Antagonist Losartan (RENAAL) trial revealed that losartan
treatment decreased cardiovascular risk to levels comparable to those seen in people
without LVH in patients with T2DM, nephropathy, and LVH. Recent research
from the Ongoing Telmisartan Alone and in Combination with Ramipril Global
Endpoint Trial (ONTARGET) has demonstrated that in high-risk patients with
CVD or subjects with diabetes who have end-organ damage, the ARB telmisartan
offers benefits comparable to those of a known ACE inhibitor like ramipril. This
demographic was previously studied as part of the HOPE research. Furthermore,
the ONTARGET study found that ramipril plus telmisartan did not lower the risk of
cardiovascular events compared to an ACE inhibitor alone, despite further lowering
blood pressure. Instead, it was linked to additional negative effects like hypotension
and renal dysfunction. As a result, an ACE inhibitor or possibly an ARB is the first
antihypertensive medication of choice in diabetic patients because research has
shown that these medications have the ability to stop or delay the onset of diabetic
macrovascular complications, significantly lowering cardiovascular mortality and
morbidity.
The System For Endothelin
One of the most effective known vasoconstrictors is endothelin (ET), which
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 Yanagisawa et al. first identified in 1988.
Three unique ET genes, known as ET-1, ET-2, and ET-3, are responsible for
encoding various mature ET sequences. The ET converting enzyme transforms the
big ET-1 into the mature ET-1, which contains 21 amino acids.
Endothelial cells have the highest concentration of ET-1. ETA and ETB1 receptor
subtypes were cloned in 1990. Vasoconstriction and cell proliferation are mediated
by ETA receptors, which are present in VSMCs (Figure 3.15).
3
COMPLICATIONS AND COMORBIDITIES
Figure 3.15: proposed pathways for how diabetes and the endothelin and
urotensin systems affect atherosclerosis. The formation and progression of
atherosclerosis is facilitated by the activation of the endothelin system in
diabetes, which also causes vasoconstriction, vascular smooth muscle cell
proliferation, wall thickening, inflammation, and tissue remodeling.
Diabetic Macrovascular Problems and The Part of ET
Compared to people without diabetes and atherosclerosis, patients with T2DM
complicated with atherosclerosis have higher plasma concentrations of ET-1 than
do healthy subjects. Kalogeropoulou et al. found that participants with carotid
atherosclerosis and diabetes had elevated ET-1 levels. ET promotes a phenotypic
transition into foam cells by enhancing the absorption of LDL cholesterol by
326
monocytes and stimulating the generation and release of inflammatory cytokines
from these cells.
In turn, ET-1 production is stimulated by cytokines produced by monocytes and
macrophages, creating a positive feedback loop for more cytokine production. Both
selective and non-selective ETA/ETB receptor blockade have been shown to prevent
the growth of atherosclerotic lesions in a number of animal models, suggesting that
elevated vascular ET-1 tissue levels encourage endothelial dysfunction and vascular
structural changes through the activation of ETA receptors. In apoE KO mice,
administration of an ET A receptor antagonist reduced the size of atherosclerotic
lesions in the aorta. In rabbits, a non-selective ET A/ET B receptor blocker produced
outcomes that were comparable. Although it has been demonstrated that the ET B
receptor has anti-atherosclerotic actions via stimulating NO generation, the role of
the ET B receptor in atherosclerosis is still debatable at this time. 3
Finally, ET inhibition may have a role in at least some of the beneficial effects of
COMPLICATIONS AND COMORBIDITIES
ACE-inhibitors on cardiovascular protection. Captopril reduces 24-hour urine ET-1
excretion and prevents the release of ET from
cultivated human endothelial cells. Additionally, it appears to be helpful in the
treatment of diabetic nephropathy, although there is currently no evidence to show
a preventive impact on macrovascular disease in diabetics.
Urotensin II
Urotensin II (UT II) has a substantial vaso contractile effect, which supports its
potential significance in cardiovascular physiology and disorders, according to
a number of recent findings. In 1999, a specific UT II receptor was discovered.
Patients with various CVD conditions, such as heart failure, hypertension, carotid
atherosclerosis, pre-eclampsia and eclampsia, renal dysfunction, and diabetes
mellitus, have been found to have elevated circulating amounts of UT II. In
addition, patients with pulmonary hypertension and congestive heart failure have
been shown to have an upregulated UT receptor system.
Atherosclerosis and the Role Of Urotensin II
In endothelium, myointimal, and medial smooth muscle cells of atherosclerotic
human coronary arteries, UT II expression is elevated. According to research done
by Bousette et al., both atherosclerotic carotid arteries and aortas have elevated UT
II expression. It has been demonstrated that in people with essential hypertension,
327
 the plasma UT II level is strongly linked with carotid atherosclerosis. UT expression
was noticeably increased in apoE KO mice compared to wild-type control mice.
By boosting ROS production and acyl - CoA - cholesterol acyl - transferase 1
expression, chronic infusion of UT II worsens atherosclerotic lesion in the aorta of
apoE KO mice. Following balloon injury in rat carotid arteries, UT II expression is
elevated in endothelial cells and VSMCs. A UT II receptor blocker was also linked
to a 60% decrease in the occurrence of intima lesions during treatment.
The redox-sensitive enzyme NADPH oxidase is activated in the vascular wall
by UT II, and inflammatory cytokines are expressed more often as a result.
Immunostimulatory stimuli, such as IL-1 and TNF, dramatically increase the mRNA
and protein expression of the UT receptor in human peripheral blood mononuclear
3
cells. UT II has been demonstrated, primarily in in vitro investigations, to raise LDL
cholesterol and ROS generation via NADPH oxidase and to promote monocyte
COMPLICATIONS AND COMORBIDITIES
recruitment, all of which have direct relevance to atherosclerosis.
Osteoprotegerin and TNF-Related Apoptosis Inducing Ligand
A member of the TNF ligand family is tumor necrosis factor (TNF) related
apoptosis inducing ligand (TRAIL). Multiple altered cell lines and tumor cells are
rapidly induced to undergo apoptosis by the membrane-bound and soluble forms of
TRAIL, whereas normal cells are not affected.
Osteoprotegerin (OPG), a substance produced by a number of tissues, including
the cardiovascular system, belongs to the TNF- receptor superfamily. The receptor
activator of NF- кB ligand (RANKL) and TRAIL are two TNF family ligands that
are known to bind to OPG. Growing experimental data points to the involvement
of TRAIL and OPG in vascular pathology. In vivo research using streptozotocin-
induced diabetic apoE KO mice has recently examined the potential role of
soluble recombinant (sr) TRAIL in the etiology and/or therapy of diabetes-induced
atherosclerosis. By selectively reducing the number of infiltrating macrophages
and boosting the number of VSMCs within the atherosclerotic plaques, repeated
intraperitoneal injections of srTRAIL significantly slowed plaque formation and
helped stabilize atherosclerotic lesions.
Two investigations in individuals with acute coronary syndrome that found
significantly reduced sTRAIL serum levels in these participants when compared to
patients with stable angina or normal coronary arteries provide additional support
328
for the possible clinical importance of these findings.
The aorta and renal arteries of OPG-deficient mice showed calcifications, indicating
that OPG may play a protective function against vascular calcification. OPG serum
levels were shown to significantly correlate with cardiovascular mortality in a study
of elderly women, which is interesting. The discovery of a single nucleotide variation
in the human OPG gene’s promoter region that affects vascular morphology and
function has provided additional evidence for the relationship between OPG and
vascular disease in humans.
Elevated serum and/or plasma OPG levels have been seen in persons with diabetes,
particularly in those who also have vascular problems from their diabetes, according
to a number of independent investigations. Other findings show an atherosclerotic
role for OPG in the vasculature, despite some authors’ suggestions that the rise
in OPG levels may be a defense mechanism against other variables that induce 3
vascular diseases.
COMPLICATIONS AND COMORBIDITIES
Complement Activation
About 30 proteins make up the complement system, which is a crucial part of the
innate immune system. Three distinct pathways—the traditional, alternative, and
mannose-binding lectin (MBL) complement pathways—are used to activate the
complement system. As these three routes combine, a C3 convertase is prompted
to form (Figure 3.16). Recently, mounting data suggests that complement system
activation, specifically the MBL route, which is the initial pathway of complement
activation in diabetic patients, may have a role in the development of diabetic
macrovascular problems. Compared to patients with normoalbuminuria, people
with T1DM with nephropathy and CVD have significantly higher circulating levels
of MBL. MBL levels may also be relevant for diabetes prognosis, according to
the available data. According to a number of observations, MBL may have a role
in the etiology of both microvascular and macrovascular problems in T1DM, and
determining a patient’s MBL status may help identify those who are more likely to
experience these difficulties.
Early on in the course of T1DM, high levels of MBL are significantly linked to the
development of chronic microalbuminuria and macroalbuminuria. Additionally,
it has been demonstrated that measuring MBL in T2DM patients can predict
mortality and the onset of microalbuminuria. The underlying cause of this putative
complement system activation in diabetic patients is still unknown. Hyperglycemia
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 in diabetics is thought to trigger the complement system through increased RAGE
activation or mitochondrial ROS generation. Pexelizumab, an inhibitor of C5, has
recently been shown in clinical tests to significantly lower mortality after acute MI
as well as the incidence of death or MI in patients following coronary artery bypass
graft surgery. Additional research is required to identify, in particular, whether
manipulating the complement system may represent a promising approach in the
treatment and prevention of macrovascular disease associated with diabetes.
3 3
COMPLICATIONS AND COMORBIDITIES
Figure 3.16: Presentation of the complement system schematically. Any one
of the three pathways—the traditional pathway, the mannose-binding lectin
(MBL) pathway, or the alternative pathway—activates the complement
cascade. The membrane-attack complex, as well as opsonic, chemotactic, and
bactericidal components, are formed as a result of activation.
Both type 1 (T1DM) and type 2 (T2DM) diabetes mellitus are frequently accompanied
by hypertension. It has long been known that the two conditions are related. Eskil
Kylin, a Swedish physician, first reported a syndrome of diabetes, hypertension, and
hyperuricemia in 1923. These three conditions are today recognized as components
of the more comprehensive “metabolic syndrome,” which has been associated with
insulin resistance (IR). Hypertension and diabetes have a complicated interaction.
330
Both are prevalent and may be connected by coincidence, but in some cases,
they may also share a common cause. In addition, diabetes can create diabetic
nephropathy, which can lead to hypertension, and some medications used to treat
hypertension can cause diabetes in people who are susceptible to it.
Because it increases the negative effects of diabetes, hypertension is a significant
cardiovascular risk factor, just like diabetes. Nephropathy and retinopathy, two
microvascular diseases, are also at risk as a result. There is still a need for consensus
on therapeutic goals and tactics for the management of hypertension in diabetes,
despite the fact that the topic has been hotly contested. The evidence base has
grown significantly over the past ten years as a result of multiple well-designed
trials that conclusively show the benefits of decreasing blood pressure (BP) while
also underlining how challenging it may be to do so in everyday life.
Dimensions Of The Issue
COMPLICATIONS AND COMORBIDITIES
The World Health Organization/International Society of Hypertension (WHO/ISH)
criteria (Table 3.5) are frequently used to define hypertension. At blood pressure
levels below these thresholds, diabetics are still at risk for microvascular and
macrovascular problems; as a result, the treatment goal range is lower (130-140/80-
85 mmHg).
Overall, people with diabetes have up to twice as much hypertension as people
without diabetes (based on WHO criteria). Ten to thirty percent of T1DM patients
and sixty to eighty percent of people with newly diagnosed T2DM among white
Europeans have hypertension. There are racial and ethnic disparities in the
prevalence of hypertension, which are likely genetically predisposed at least in
part. For instance, the Pima Indians and Mexican Americans had lower rates of
hypertension (and macrovascular disease). IGT (impaired glucose tolerance) is also
linked to hypertension (20–40% of cases), which may reflect the same antecedents
of these metabolic syndrome components.
There is evidence that, after taking into account the higher number of cases identified
through enhanced screening and the lowering of criteria for treatment of BP, the
true prevalence of hypertension is rising in the diabetic community (particularly
T2DM). The increased prevalence of obesity and the extended longevity of senior
diabetics are likely contributing factors.
331
 a correlation between the mother’s and her offspring’s BP that appears to be non-
hereditary in origin.

3 3

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COMPLICATIONS AND COMORBIDITIES

Figure 3.17: The metabolic syndrome. HDL, high density lipoprotein.

Table 3.5: WHO and the International Society for Hypertension have
defined the criteria for hypertension and the tissue damage it causes

Diabetes-Related Hypertension Causes

Table 3.6 lists the correlations between diabetes and hypertension. Both isolated
systolic hypertension and essential hypertension are prevalent in the non-diabetic
population, particularly in the elderly. About 10% of occurrences of essential
hypertension in diabetics are thought to be caused by this condition.

Metabolic Syndrome And Hypertension

Reaven, DeFronzo, Ferrannini, and others have suggested that IR is a key cause of
T2DM, hypertension, and cardiovascular disease (CVD). In addition to acquired
factors including obesity, physical inactivity, and maybe malnutrition in utero and
during the first few months of life, IR is in part genetically predisposed. Early
growth retardation is thought to program abnormal development of the vasculature
as well as the tissues that control glucose homeostasis. Family studies have shown Table 3.6: Diabetes and hypertension correlations

332 333
 High BP and IR are closely related in both humans and animals. A rise in BP
occurs in conjunction with the experimental induction of IR. More convincingly,
a negative correlation between BP and insulin sensitivity has been found in
humans (Figure 3.18). Numerous theories have been put up to explain how IR
and/or the accompanying hyperinsulinemia could raise blood pressure (Figure
3.19). First, there is some evidence that insulin is an endothelium-dependent
vasodilator that relaxes vascular smooth muscle by releasing nitric oxide (NO)
from the endothelium; blunting of this effect, caused by insensitivity to the action
of insulin on the endothelium as well as on metabolically important tissues, could
contribute to the increased peripheral resistance that is the hallmark of hypertension
in obesity and T2DM. IR states are related with impaired endothelium-mediated
vasodilatation, which may play a significant role in the development and progression
3
of atherosclerosis. 3

COMPLICATIONS AND COMORBIDITIES

COMPLICATIONS AND COMORBIDITIES

Figure 3.19: Possible causes and treatments for hypertension in cases of

Figure 3.18: Insulin resistance and hypertension are related. The metabolic
clearance rate (MCR), which is used to determine insulin sensitivity during an
insulin clamp research, is inversely related to both the mean ambulatory and
24-hour systolic blood pressure.
insulin resistance. Nitric oxide, NO
Contrarily, there are a number of other activities of insulin that can raise blood
pressure, and there is some evidence that these are amplified in IR conditions. This
is likely because sensitivity to the effects of the elevated insulin levels is still there.
Insulin affects the distal renal tubule, where it functions to retain Na+ ions and water.
This action is still present in IR patients, which suggests that it may play a role in
the increase in total body Na+ content seen in obesity and T2DM. Additionally,
insulin stimulates the Na+-K+ ATPase in the cell membrane, boosting intracellular
Na+ concentrations in vascular smooth muscle. By raising systolic Ca2+ levels, this
would improve contractility and elevate peripheral resistance. Insulin may increase
the sympathetic outflow via impacting the CNS. Although there isn’t any concrete
evidence in humans, this might theoretically also raise blood pressure. Last but not
least, insulin might promote the growth of vascular smooth muscle cells, which

334 335
 might result in medial hypertrophy and elevated peripheral resistance.

Hypertension And Diabetic Nephropathy

This connection is more pronounced in young T1DM patients, in whom hypertension
is remarkably associated with renal impairment and even mild levels of proteinuria.
Urinary albumin excretion (UAE) enters the microalbuminuria range (> 30 mg/24
hours), and when UAE reaches the microalbuminuria stage (> 300 mg/24 hours),
BP typically exceeds the WHO criterion. The association may have some genetic
components. People with diabetes and microalbuminuria frequently have parents
who have hypertension, and they may also inherit an overactive cell-membrane
Na+-H+ pump (indicated by increased Na+-Li+ counter-transport in red blood cells),
which tends to raise intracellular Na+ concentrations and subsequently increase
3 vascular smooth muscle tone. 3
Reduced Na+ excretion together with Na+ and water retention are the main causes

COMPLICATIONS AND COMORBIDITIES

COMPLICATIONS AND COMORBIDITIES

of hypertension. The increase in peripheral resistance will be accompanied by

an increase in intracellular Na+. Because both increased and decreased activity
of the renin-angiotensin-aldosterone system (RAS) have been seen, its function
is unknown. Differences in nutrition, therapy, metabolic control, and the type
and duration of diabetes may be to blame for these variances. While it would be
expected that Na+ retention and hypertension would suppress the RAS, additional
consequences of diabetes, such as renal tubular acidosis type 4, may influence renin
levels.
Renin can be elevated in retinopathy and advanced nephropathy, but hyporeninemic
hypoaldosteronism and neuropathy can also lower plasma renin. Insulin-resistant
patients with microalbuminuria seem to be particularly vulnerable to hypertension.
Diabetes and Hypertension: Effects
A significant majority of diabetics with hypertension exhibit cardiovascular aging
and target organ damage.
When combined with the effects of diabetes, hypertension, an independent risk
factor for atherogenesis, significantly speeds up the onset and progression of CHD,
cerebrovascular disease, and peripheral vascular disease. With the biggest increase
happening at the lowest BP levels, the effects of hypertension on mortality from
CHD are often increased by 2 to 5 times in individuals with diabetes (Figure 3.20).
Figure 3.20: Diabetes and hypertension have additive impact on mortality from
coronary heart disease (CHD). data from 35–57 years old, free of myocardial
infarction, 342 815 adults without diabetes and 5163 people with diabetes
Diabetes further intensifies the negative effects of hypertension on left ventricular
function. Impaired left ventricular relaxation and increased left ventricular mass are
two of these, with the latter serving as a standalone predictor of early death from
CHD.
Additionally, hypertension increases the risk of some microvascular consequences,
such as nephropathy and end-stage renal failure (ESRF), by two to three times.
According to the positive effects of better BP control in individuals with T2DM, as
revealed by the UK Prospective Diabetes Study (UKPDS), hypertension is also a
risk factor for retinopathy.
Diabetes Hypertension Screening
People with diabetes and those with hypertension need to be regularly checked
for each other because the two diseases are so frequently linked. Patients with
hypertension should be checked for diabetes at diagnosis and throughout follow-
up, especially if they are obese or using medications that could cause diabetes.
If hyperglycemia is found, potentially diabetogenic antihypertensive medications

336 337
 should be lowered, switched to others, or combined in a way that does not
compromise glucose tolerance; this usually results in normoglycemia, which can
then be often reestablished.
At the time of diagnosis and at least once a year after that, all diabetics should
have their blood pressure monitored. This is particularly crucial for people who
also have other cardiovascular risk factors, like nephropathy (which is linked to
a much higher cardiovascular mortality rate), obesity, dyslipidemia, smoking, or
poor glycemic management.
Blood Pressure Measurement
The patient should be in the supine or sitting position while having their blood
pressure taken using an accurate sphygmomanometer and an appropriate-sized
3 cuff (wider for obese people with an arm circumference greater than 32 cm).
If using a manual sphygmomanometer, systolic and diastolic blood pressure
COMPLICATIONS AND COMORBIDITIES
readings should be taken during phases I and V (the onset and final disappearance
of Korotkoff sounds), to the nearest 2 mmHg. To assure dependability and
prevent “white coat” stress effects, which can significantly raise blood pressure,
usual precautions should be taken. To identify the subject’s usual values and
any tendency toward change, it is best to take at least two readings initially,
then repeat them at regular intervals over the course of many weeks or months.
One minute after the patient stands up, the blood pressure should be tested as
well since patients with diabetic autonomic neuropathy, the elderly, or those using
vasodilators or diuretics may experience a significant postural fall (> 20 mmHg
systolic). A change in antihypertensive medication is sometimes necessary,
especially if symptoms are triggered by substantial postural hypotension, which
can coexist with supine hypertension.
338
Figure 3.21: Diabetes patients may benefit from blood pressure treatment goals
3
that are different from the World Health Organization/International Society
of Hypertension definitions of hypertension and borderline hypertension
COMPLICATIONS AND COMORBIDITIES
In some cases, ambulatory blood pressure monitoring over a 24-hour period may
be helpful to rule out “white coat” effects. It may also be helpful for patients with
early nephropathy who have nearly normal blood pressure during the day but may
be at risk of hypertensive tissue damage because they do not exhibit the physiologic
BP dip during sleep.
Diabetes Hypertension Diagnosis
According to the definitions established in 1999 by WHO and ISH [34], hypertension
is defined as an official blood pressure (BP) reading that is greater than 140/90
mmHg (Korotkoff I-V), and borderline hypertension is defined as a reading that
is lower than these limits but higher than 130 mmHg systolic and/or 85 mmHg
diastolic (Figure 3.21). When blood pressure measurements routinely surpass
140/90 mmHg for several weeks, when the BP is extremely high (diastolic BP >
110 mmHg), or when there are clinical symptoms of tissue or organ damage from
long-term hypertension, established hypertension is diagnosed.
Numerous epidemiologic studies have shown that treating microalbuminuric
subjects whose diastolic blood pressure is less than 90 mmHg has benefits, and
that the WHO/ISH threshold is too high in diabetics due to their increased risk of
both macrovascular and microvascular disease. Alternative, typically lower goal
339
 levels have been proposed by numerous additional expert bodies (Figure 3.21). The
general opinion is to treat any person whose blood pressure is persistently higher
than one or both of these limits, which are generally agreed to be less than 130 to
140 mmHg systolic and 80 to 85 mmHg diastolic.
Examination Of Diabetes And High Blood Pressure
The initial examination of a patient with hypertension and diabetes tries to rule
out uncommon sources of secondary hypertension, determine the degree of tissue
and organ damage brought on by the conditions, and find any additional possible
treatable risk factors for vascular disease.
Cardiac function. Table 3.8 lists the key findings from the medical history and
examination. Standard 12-lead electrocardiograms may clearly exhibit ischemia,
3 arrhythmia, or left ventricular hypertrophy; echocardiography, which will also
show left ventricular dysfunction and a lower ejection fraction, more reliably
COMPLICATIONS AND COMORBIDITIES
demonstrates the latter. A 24-hour Holter monitor and exercise testing (or stress
echo) testing may also be necessary.
Figure 3.22: Right kidney involvement in a patient with diabetes and
hypertension who also has renal artery stenosis. The isotope’s uptake is
significantly slowed down and delayed on this side
340
Renal performance- The presence of microalbuminuria should be checked in
a fresh urine sample, and another should be examined under a microscope for
casts, red and white blood cells, and other indicators of renal illness. Despite the
apparent absence of significant renal dysfunction, patients with T1DM (especially
youngsters) can infrequently have microscopic hematuria, but coexisting renal
disease must always be ruled out. It is important to check the serum urea, creatinine,
and electrolytes. Measurement of the glomerular filtration rate (GFR) should be
taken into consideration if the serum creatinine level is elevated, ideally using a
specific clearance method such chromium ethylenediamine tetra-acetic acid (Cr -
EDTA), iohexol, or cystatin C. An isotope renogram and other tests for renal artery
stenosis may be required as further specialized studies.
Up to 20% of older T2DM patients may develop this consequence of renal arterial 3
atherosclerosis, which, if bilateral, can result in severe and occasionally irreversible
COMPLICATIONS AND COMORBIDITIES
renal impairment if angiotensin-converting enzyme (ACE) medications are
administered.
Lipid professional. Checking the serum lipid concentrations after fasting is
important. It is advised to look into the apo-B: apo - A1 lipoprotein ratio and
the lipoprotein subclasses very low density lipoprotein (VLDL), LDL, and HDL
further if total cholesterol or triglyceride levels are shown to be elevated following
repeated examinations. If the total cholesterol level is greater than 4.5 mmol/L, the
LDL cholesterol level is greater than 2.5 mmol/L, or the LDL:HDL cholesterol
ratio is greater than 4, treatment for hyperlipidemia should be considered.
341
 Peripheral Artery Disease
Peripheral artery disease (PAD) affects more than 3.5 million Americans with
diabetes (African-Americans > White > Hispanics). Peripheral artery disease is
characterized by blockage of the lower-extremity arteries, which can result in
functional impairments101 and disability as well as intermittent claudication and
pain, especially during exercise and activity. Due to these functional limitations as
well as the frequent occurrences of more severe PAD, such as foot ulceration and
lower-extremity amputation, physical therapists regularly encounter patients with
diabetes-related PAD. Physical therapists routinely treat patients with diabetes-
related amputations because people with diabetes are 15 times more likely than
those without diabetes to have lower-extremity amputations. Physical therapists
will see, treat, and recommend exercise to persons with diabetes more frequently
3
as the prevalence of the disease rises. 3
Physical therapists need to be more aware of PAD because CVD is usually blamed

COMPLICATIONS AND COMORBIDITIES

COMPLICATIONS AND COMORBIDITIES

for diabetes and PN patients’ deaths.105 Physical therapists should carefully assess
lower-extremity blood flow (i.e., peripheral pulses) and skin integrity for all diabetic
patients, especially those with known PAD, according to these data because lower-
extremity amputation is more common in people with diabetes and PAD than in
people without diabetes but with PAD.
Similar to the vascular illnesses discussed above, peripheral artery disease is
influenced by the length and severity of diabetes. It has been established that
hyperglycemia, more specifically glycation hemoglobin, is a separate risk factor
for PAD.
Along with diabetes, other risk factors for PAD include high blood pressure,
smoking, obesity (measured by the ratio of the waist to the hips), higher serum
fibrinogen levels, dyslipidemia, a history of cardiovascular disease, and inactivity.

3.3.2 Microvascular Complications

Table 3.11: Examination of the patient with diabetes and high blood pressure
Diabetic Retinopathy
The most common cause of visual impairment and blindness in diabetics is
diabetic retinopathy (DR), a microvascular condition that can affect either the
macula or the peripheral retina. DR can range in intensity from nonproliferative
and preproliferative to more severe proliferative DR, which is characterized by the
unnatural creation of new vessels. A vitreous hemorrhage or retinal detachment can

342 343
 cause whole or partial vision loss, while a retinal vascular leak that leads to macular
edema can cause loss of central vision. As diabetes is present for a longer period
of time, the prevalence of DR rises. After 30 years of diabetes, most patients in
studies involving both type 1 and type 2 diabetics had some form of DR, and more
than half had proliferative DR; those with type 1 diabetes who were taking insulin
had the highest prevalence of DR, and those whose type 2 diabetes was discovered
after age 30 had the lowest prevalence of DR. Recently, it was discovered that 10%
of persons with insulin resistance (prediabetes) had diabetic retinopathy, which
was also linked to hypertension and a higher body mass index. A younger age of
onset, tobacco usage, insulin therapy, abnormal blood lipid levels (defined as total
cholesterol, low-density lipoprotein [LDL], and triglyceride levels), pregnancy,
renal disease, high homocysteine levels, and a family history of DR have all been
linked to the condition.
3 3
COMPLICATIONS AND COMORBIDITIES
Figure 3.23: Transmission electron micrographs of capillary basement
membranes (opposing arrows) from tissues of normal mice (a) and
transgenic diabetic mice (b) of the same age and sex
344
Figure 3.24: Retinopathy due to diabetes and microaneurysms. from
the University of Utah’s Slice of Life collection, which Suzanne Stensaas
is the curator
COMPLICATIONS AND COMORBIDITIES
Poor glycemic (blood sugar) control seems to play the most role in the onset and
progression of DR in patients with diabetes. Hypoxia and retinal injury are possible
under hyperglycemic conditions, which are typically present in diabetics. These
conditions include increased inflammatory cell adherence to retinal blood vessels,
impaired retinal blood flow, and capillary occlusion.
Diabetic Neuropathy
Peripheral neuropathy (PN), either polydiabetic or monodiabetic neuropathy, affects
about 50% of patients with diabetes. Autonomic neuropathy, such as cardiovascular
autonomic dysfunction, which shows up as aberrant heart rate (HR) and vascular
control, is another common complication of diabetes. Because these diseases
usually influence lower-extremity feeling and can induce lower-extremity pain in
patients with diabetes, physical therapists regularly meet diabetes-associated PN
when evaluating and treating balance and mobility disorders. Lower-extremity
(often the foot) ulceration can be caused by loss of lower-extremity feeling in
conjunction with diminished peripheral vascular function. The risk factors for
PN are similar to those for DR and include poor glycemic control (high glycated
hemoglobin and impaired glucose tolerance34), age, duration of diabetes, cigarette
use, dyslipidemia, and hypertension (particularly diastolic). Increased height,
cardiovascular disease (CVD), severe ketoacidosis (i.e., elevated by-products
of fat metabolism in the blood), and microalbuminuria (i.e., albumin in urine,
345
 indicating early renal dysfunction) are additional independent risk factors for PN.
The pathophysiology of PN, in contrast to that of DR, seems to be linked to both
vascular and nonvascular metabolic pathways, albeit this theory is debatable.
Axonal thickening that progresses to axonal loss, thickening of the basement
membrane, pericyte loss, loss of microfilaments (cytoskeletal filaments made
up of actin and myosin), and decreased capillary blood flow to the C fibers are
all characteristics of PN. These features result in decreased nerve perfusion and
endoneurial hypoxia. In the presence of hyperglycemia, neuronal microvasculature
is compromised, and this impairment is mediated by aberrant signaling cascade
start, which may result in the demyelination linked to diabetic PN. The metabolic
(i.e., hyperglycemia) elements of diabetes appear to be predominantly responsible
for both the nonvascular and vascular causes of PN.
3 The hallmarks of PN include axonal thickening that eventually leads to axonal loss,
thickening of the basement membrane, loss of pericytes, loss of microfilaments
COMPLICATIONS AND COMORBIDITIES
(cytoskeletal filaments made up of actin and myosin), and reduced capillary blood
flow to the C fibers. Endoneurial hypoxia and reduced nerve perfusion are caused
by these characteristics. Neuronal microvasculature is impaired in the presence of
hyperglycemia, and this impairment is mediated by abnormal signaling cascade
induction, which may lead to the demyelination associated with diabetic PN. Both
the nonvascular and vascular causes of PN appear to be mostly due to the metabolic
(i.e., hyperglycemia) components of diabetes.
Diabetes-related cardiomyopathy has been linked to cardiac autonomic dysfunction,
a subject outside the purview of this article. In short, diabetic cardiomyopathy
causes anomalies in diastolic filling and relaxation, which are typically followed
by systolic dysfunction and heart failure. Since many of the same risk factors and
mechanisms contribute to the development of both illnesses, it is uncertain whether
cardiac autonomic dysfunction directly promotes diabetic cardiomyopathy.
3.4 Summary
Acute complications in diabetes refer to sudden and potentially life-threatening
events that can arise due to uncontrolled blood sugar levels. These complications
often require prompt medical attention. The main acute complications in diabetes
include:
Diabetic Ketoacidosis (DKA): DKA occurs mainly in type 1 diabetes when the
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body’s insulin levels are insufficient, causing a buildup of ketones (byproducts of
fat breakdown). This leads to a state of acidosis, causing symptoms such as nausea,
vomiting, excessive thirst, dehydration, rapid breathing, and confusion.
Hyperosmolar Hyperglycemic State (HHS): HHS is more common in type 2
diabetes and typically occurs when blood sugar levels become extremely high,
leading to severe dehydration. Symptoms include extreme thirst, dry mouth,
confusion, weakness, and in severe cases, seizures or coma.
Hypoglycemia: Hypoglycemia, or low blood sugar, can result from excessive
insulin or diabetes medication, inadequate food intake, or excessive physical
activity. Symptoms include shakiness, sweating, confusion, dizziness, irritability,
and in severe cases, loss of consciousness or seizures.
Hyperglycemic Hyperosmolar State (HHS): Similar to HHS, hyperglycemic
hyperosmolar state is characterized by very high blood sugar levels, leading to 3
dehydration. However, unlike HHS, there is less of an accumulation of ketones.
COMPLICATIONS AND COMORBIDITIES
This condition is often observed in older adults with type 2 diabetes and can cause
extreme dehydration, confusion, weakness, and even coma.
Lactic Acidosis: Lactic acidosis is a rare but serious complication usually associated
with metformin use. It occurs when there is an accumulation of lactic acid in the
blood, leading to symptoms like weakness, rapid breathing, abdominal pain, and
confusion.
Hypoglycemic Unawareness: Over time, some individuals with diabetes may lose
their ability to sense hypoglycemic symptoms, putting them at risk for severe low
blood sugar events without early warning signs.
Effective management of diabetes, including regular monitoring of blood sugar
levels, proper medication use, balanced nutrition, and lifestyle adjustments, can
help prevent or minimize the occurrence of these acute complications. If any of
these acute complications are suspected, immediate medical attention is crucial to
prevent further complications and ensure the patient’s safety and well-being.
Diabetes is a chronic metabolic disorder that can lead to various complications
affecting blood vessels throughout the body. These complications are broadly
categorized into macrovascular and microvascular diseases.
Macrovascular Diseases: Macrovascular diseases primarily involve large blood
vessels and are more common in individuals with poorly controlled diabetes. The
major macrovascular complications include:
Cardiovascular Disease (CVD): Diabetes significantly increases the risk of
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 coronary artery disease, heart attack (myocardial infarction), and stroke due to the
accumulation of plaque in large arteries.
Peripheral Artery Disease (PAD): Diabetes can cause narrowing and blockage of
arteries in the legs and feet, leading to reduced blood flow, pain, and impaired
wound healing.
Cerebrovascular Disease: Diabetes increases the likelihood of cerebrovascular
events, such as stroke, which can result in damage to brain tissue due to a blocked
or burst blood vessel.
Microvascular Diseases: Microvascular diseases primarily affect small blood
vessels, especially in the eyes, kidneys, and nerves. These complications are more
commonly associated with long-term diabetes and poor blood sugar control. The
major microvascular complications include:
3
Diabetic Retinopathy: High blood sugar levels can damage the tiny blood vessels in
the retina, leading to diabetic retinopathy, which is the leading cause of blindness
COMPLICATIONS AND COMORBIDITIES
in adults.
Diabetic Nephropathy: Persistent high blood sugar levels can damage the small
blood vessels in the kidneys, leading to diabetic nephropathy, a progressive kidney
disease that can ultimately lead to kidney failure.
Diabetic Neuropathy: Prolonged exposure to high blood sugar can damage nerves,
particularly in the legs and feet. This condition, known as diabetic neuropathy, can
cause numbness, tingling, pain, and loss of sensation.
In summary, diabetes can lead to both macrovascular and microvascular
complications, impacting large and small blood vessels, respectively. Proper
management of blood glucose levels, along with other risk factors like hypertension
and cholesterol, is crucial in preventing or delaying the onset of these complications
and improving overall quality of life for individuals with diabetes. Regular medical
check-ups and early intervention can help detect and manage these complications
effectively.
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3.5 Review Questions
1. A 30-year-old patient with type 1 diabetes presents at the emergency
department with nausea, vomiting, deep rapid breathing, and fruity-smelling
breath. Laboratory tests reveal elevated blood glucose and ketone levels. What
acute complication is the patient likely experiencing, and what is the underlying
physiological mechanism involved?
2. An older adult with type 2 diabetes is admitted to the hospital with extreme
dehydration, confusion, and elevated blood sugar levels well above 600 mg/
dL. Despite the high blood glucose, ketone levels are minimal. What acute
complication is suspected, and how does it differ from other hyperglycemic
conditions in terms of ketone production and presentation?
3. A patient with diabetes on metformin therapy presents with weakness, 3
abdominal pain, and labored breathing. Arterial blood gas analysis reveals low pH
COMPLICATIONS AND COMORBIDITIES
and elevated lactate levels. What is the potential acute complication associated
with metformin use, and what are the key pathophysiological factors contributing
to this condition?
4. A 55-year-old patient with type 2 diabetes and a history of poor blood sugar
control presents with chest pain, shortness of breath, and elevated cardiac
biomarkers. Coronary angiography reveals significant narrowing of multiple
coronary arteries. Explain the underlying pathophysiological mechanisms linking
diabetes to accelerated atherosclerosis and increased risk of coronary artery
disease.
5. In a research study involving individuals with diabetes, investigators observe a
higher prevalence of peripheral artery disease (PAD) in those with longer diabetes
duration and poor glycemic control. Discuss the potential interplay between
hyperglycemia, inflammation, oxidative stress, and endothelial dysfunction in the
development and progression of PAD in diabetes patients.
6. A 60-year-old patient with long-standing type 2 diabetes is diagnosed with
diabetic nephropathy based on persistent proteinuria and declining glomerular
filtration rate. Describe the pathophysiological mechanisms that contribute to
the development of diabetic nephropathy, focusing on the role of hyperglycemia,
advanced glycation end products (AGEs), and the renin-angiotensin-aldosterone
system (RAAS).
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 3
COMPLICATIONS AND COMORBIDITIES

350
Management Of Diabetes

Syphilis has long since been replaced as the greatest

imitator by diabetes, and nowhere is this more
clear than in the huge range of potential initial
presentation patterns. Only a small number of new
diabetes diagnoses are caused by the typical triad
of thirst, polydipsia, and polyuria. Type 1 diabetes
mellitus (T1DM) is characterized by the relatively
abrupt onset of such symptoms along with weight
loss. A dramatic presentation to emergency services
may be triggered by ketoacidosis and hyperosmolar
hyperglycemic syndrome. A biochemical diagnosis of
4
diabetes may result from non-specific symptoms such
fatigue, general malaise, and recurrent or chronic skin

MANAGEMENT OF DIABETES
infections. Early diagnosis is made possible through
screening of at-risk individuals or groups.

4 Chapter Contents
4.1 General Principles
4.2 Non-Pharmacological Management
4.3 Pharmacological Approaches
4.4 Combination Therapies for the Treatment of Type 2 Diabetes in Clinical
Practice
4.5 Diabetes Patients’ Hospital Treatment and Surgery
4.6 Summary
4.7 Review Questions

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 Unfortunately, the nature of the disorder makes it possible for it to go years without
causing any symptoms, making the clinical presentation a long-term complication
of diabetes. This may manifest as either macrovascular disease (myocardial
infarction, stroke, black toe), microvascular disease (loss of vision, neuropathy), or
both. Gestational diabetes (GDM), which can develop during pregnancy and may
go away after delivery, does raise the possibility of developing type 2 diabetes.
It is linked to an increased risk of cardiovascular disease and microvascular
problems that impact the kidney, nerve, and eye, as well as early mortality and
morbidity. Improved glycemic control has been linked to a decrease in microvascular
complications, according to high-quality randomized trials, whereas a multimodal
strategy for addressing cardiovascular risk factors will result in a decrease in
cardiovascular morbidity and mortality.
4 4
A person with diabetes will spend the majority of their time managing their condition,
and just 1% of that time will likely be spent interacting with medical personnel. As
MANAGEMENT OF DIABETES
a result, it’s important to help the person with diabetes so they can shoulder a lot of
the burden of managing their condition. The patient should benefit the most from
their time spent with their diabetes health care team, whether this is in a hospital or
primary care setting, so it is crucial that the purposes of the consultation or other
contacts with the diabetes health care team are well defined and their aims are made
clear. This is because the person with diabetes plays a central role and has relatively
little contact with medical professionals. Diabetes care can also be provided over
the phone, via email, or during educational courses held outside of a typical clinic
environment, in addition to the clinic visit.
Diabetes care can also be provided over the phone, via email, or during educational
courses held outside of a typical clinic environment, in addition to the clinic visit.
The objectives and guiding principles of diabetes care are summarized in this
chapter. Diabetes treatment and care have four main goals. Diabetes emergencies that
pose a life-threatening risk, such as diabetic ketoacidosis or severe hypoglycemia,
should be effectively handled using preventative measures. It’s important to deal
with the hyperglycemia’s acute symptoms, like polyuria and polydipsia. In reality,
these make up a relatively small portion of the labor done by diabetes health care
specialists.
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Therefore, a large portion of care is focused on reducing long-term consequences
through screening and collaborating with the diabetic to support better glucose
control and cardiovascular risk factor management. This presents a difficulty for
the diabetes team because individuals are frequently requested to adopt lifestyle
changes and take medications that may put a significant load on them even though
they may not be experiencing any symptoms at the time of care. Additionally, it
is crucial for doctors to keep in mind the fourth goal of care, which is to prevent
iatrogenic side effects like hypoglycemia. The success of comprehensive care
planning depends critically on the diabetic patient’s participation.
Diabetes education is still acknowledged as a key component of efficient diabetes
management, and it supports the outlook of chronic care approaches. It is well
known that engaging with a diabetes educator results in measurable behavior
change and that the practice of diabetes self-management education (DSME) is
essential to the care and management of people with diabetes.
Diabetes educators are being held more responsible than ever for their part in
MANAGEMENT OF DIABETES
diabetes management.
Over time, it has become clear that education standards and a framework or system
describing self-care behavior may play a significant role in encouraging people
with diabetes to think about making behavioral changes that may improve their
quality of life and aid in better diabetes management. The American Association
of Diabetes Educators (AADE) Standards Development for Outcome Measure
and the outcomes model, the AADE7 Self-Care Behaviors framework, recently
updated the 2000 Standards for Diabetes Self-Management Education and serve
as a common reference for setting behavior change objectives and establishing
measurable outcomes. The seven self-care practices are: healthy diet, physical
activity, medication use, monitoring, problem-solving, risk reduction, and healthy
coping.
4.1 General Principles
Considerations From The Perspective Of Medicine
Any consultation concerning the presentation of diabetes has a patient at its core.
Depending on existing information, the term “diabetes” may conjure up images in
people’s minds of blindness, amputation, incapacity, and early death. Alternatively,
353
 it might be connected to hazy notions of malaise, lumbago, or fibrositis. If the
diagnostic consultation is to serve as a therapeutic consultation, it is necessary
to ascertain the patient’s attitudes and beliefs regarding diabetes. In a time when
“evidence-based medicine” is commonly used to justify medicine by numbers, it is
simple to forget the effect that the consultation itself will have on the person who
will have diabetes. The question, “Where were you when JFK was shot?” How did
you feel when you learned you had diabetes? The event is probably going to be
significant and unforgettable.
Note: Diabetes management revolves around maintaining stable blood sugar levels,
adopting a balanced diet, regular physical activity, and tailored medications to prevent
complications and promote overall well-being.
4 4
Listening will be required during the therapeutic consultation, but this process
need not take a lot of time. Do you have any acquaintances who have diabetes?
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What is your current knowledge of diabetes? The knowledge gained will help put
the patient’s probable diabetes type and short-term prognosis into context. It will
alter that person’s perception of the consultation together with other components
of competent clinical history-taking. The quality of a doctor that patients value the
most is “listening.” Although others could listen as well, the medical staff cannot
handle this. Listening will be required during the therapeutic consultation, but this
process need not take a lot of time. Do you have any acquaintances who have
diabetes? What is your current knowledge of diabetes? The knowledge gained
will help put the patient’s probable diabetes type and short-term prognosis into
context. It will alter that person’s perception of the consultation together with other
components of competent clinical history-taking.
The quality of a doctor that patients value the most is “listening.”
Although others could listen as well, the medical staff cannot handle this. How far
along is the diabetic in front of you? The consequences for the person who was
identified during routine screening differ greatly from those for the person who
presents with a black toe. The former is probably at an early stage of a lengthy
procedure with a good probability of slowing disease progression, whereas the
latter is probably already experiencing additional tissue issues. Clearly, both the
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natural history timeline and genetic predisposition to problems play a role.
The former patient may never experience diabetic nephropathy and may only ever
experience microaneurysms in the eyes. Even if they are prone to issues, these can
be treated over a long period of time with intervention. But for the latter patient,
it must be made plain what can be done and how future problems can be avoided.
Hippocrates succinctly put it this way: “Cure sometimes, relieve often, comfort
always.”
It’s important to consider the potential of recovery. For a long time, diabetes was
thought to be incurable. This isn’t always the case, though. It’s important to consider
the potential of recovery. For a long time, diabetes was thought to be incurable.
This isn’t always the case, though.
With the dawn of the twenty-first century and further developments in our
understanding, there will be more situations in which diabetes can be healed. A
slate-gray person with a large liver and a hemoglobin level of 19 gm/dL should be
avoided.
MANAGEMENT OF DIABETES
Although hemochromatosis is a very uncommon cause of diabetes, it is essential
since it can be treated. The person utilizing a beta-blocker and thiazide diuretic
combo will be happy to learn that using alternative medications has at least
partially reduced their hyperglycemia. The person utilizing a beta-blocker and
thiazide diuretic combo will be happy to learn that using alternative medications
has at least partially reduced their hyperglycemia. Diabetes may be treatable if
you have Cushing syndrome. Few patients receiving systemic steroid therapy are
able to discontinue their medication just because they develop diabetes, but it is
encouraging to know that when the steroid cycle is through, the diabetes will either
disappear or become much easier to control. Those with the perseverance and
willpower to alter ingrained behavior patterns may be able to successfully treat
their type 2 diabetes by losing a significant amount of weight over the long term
while also increasing their regular physical activity. Early-stage T2DM can be
dramatically and permanently cured with bariatric surgery.
Thirst, Polydipsia And Polyuria
These signs and symptoms are the outcome of an osmotic diuresis brought on by
hyperglycemia. All forms of diabetes have the same symptoms, albeit T1DM’s
355
 time course is probably shorter and its symptoms are more severe. Carbonated
drinks with added sugar are usually chosen to quench thirst, which worsens the
symptoms. A thorough history that details the onset of symptoms throughout time
and any changes in the consumption of particular drinks is crucial. It can be
difficult to recall how frequently one passes pee throughout the day, but nocturia
is easier to count, thus the frequency of nighttime passing should be recorded.
Plasma glucose concentration must be higher than the renal threshold for tubular
reabsorption of glucose and the absolute amount of glucose supplied to the
renal tubules must be more than the maximum absorptive capacity for glucose
to pass into the urine. The renal threshold ranges from about 6 to 14 mmol/L,
with an average value of 11 mmol/L. Additionally, as people age, their maximal
absorption capacity changes, causing them to experience glycosuria at greater
plasma glucose levels.
Age-related increases in maximal renal tubular absorption are therapeutically
4 4
significant since older patients only experience osmotic symptoms at higher
plasma glucose levels.
MANAGEMENT OF DIABETES
In contrast, a negative pee test is much less likely to rule out a diabetes diagnosis
than it is in younger individuals. In addition to older individuals requiring greater
plasma glucose levels to produce osmotic symptoms, the threshold for inducing
the sense of thirst also increases with age. This is crucial because dehydration
will progress significantly before thirst is felt once the maximum renal absorptive
capacity has been reached. These aging-related alterations are very important
for the emergence of severe hyperosmolar conditions. Chronic hyperglycemia
alters the renal sensitivity to vasopressin, making thirst less noticeable despite
increasing plasma osmolarity. Therefore, untreated diabetes and advanced age
are particularly effective in delaying taking the necessary steps to boost oral fluid
intake as dehydration worsens. In connection to the aforementioned circumstances,
the clinical characteristics identified from the history at presentation will change.
In older persons, polydipsia won’t exist, and thirst may still be felt despite
osmotic diuresis. Therefore, the frequency of nocturia—more specifically, a rise
from usual levels—is the osmotic presentation aspect that can be quantitated with
the greatest degree of accuracy.
Enuresis in children may be the first sign of polyuria. Urine glucose testing should
356
always be done as soon as enuresis suddenly starts. The absence of glucose in the
urine completely rules out hyperglycemia as a potential cause of polyuria, hence it
must be underlined that a urine test is totally suitable as an initial screen in this case.
Weight Loss
The most crucial part of the history is determining whether significant weight
loss has happened, including individuals with recently diagnosed diabetes. The
symptom clearly reflects insulin deficiency and, hence, freshly manifesting T1DM,
barring subsequent disease. Its absence does not rule out T1DM because the rapid
onset of insulin deficiency and the existence of other illnesses, which may have
aggravated osmotic symptoms, may indicate that weight loss has not yet started.
When T2DM first manifests, weight loss may happen as a result of dietary
restrictions, which are frequently implemented out of concern for potential health
issues. It is simple to establish such intentional adjustments in eating habits from
history. The majority of the time, weight remains constant or even increases before
T2DM symptoms appear.
MANAGEMENT OF DIABETES
Note: Weight loss is a cornerstone of diabetes management. Shedding excess
weight improves insulin sensitivity, glucose control, and reduces cardiovascular risk.
It’s a powerful tool for better health.
The proportionate reduction of insulin’s anabolic effects is what the weight loss
primarily reflects. Particularly in young males, muscle loss may be noticeable.
Muscle strength reduction that is related may be seen.
Insulin functions primarily as an anabolic hormone to prevent protein breakdown.
Its relative absence makes it possible to upset the equilibrium between ongoing
protein production and degradation.
The lack of normal lipogenesis promotion and lipolysis inhibition is another result
of insulin deficiency.
Extra non-esterified fatty acids build up in the plasma and serve as a substrate for
ketogenesis. A portion of the weight loss will reflect the loss of both intracellular
and extracellular water if the clinical manifestation of diabetes is acute.
Blurred Vision
Vision blurring will be followed over a few days or weeks by significant changes
357
 in plasma glucose. The symptom usually appears following a very abrupt change,
frequently in the setting of T1DM presentation or in the unique situation of a
hyperosmolar presentation of T2DM. It is crucial to let the patient know that after
the relatively quick cure of excessive hyperglycemia, the visual fuzziness will get
worse. This justification is essential to prevent the worry-inducing assumption that
diabetic blindness is already advancing. Additionally, it’s crucial to avoid making
excessive purchases of eyewear that will be pointless once the hyperglycemia has
been cured.
Blurred vision in diabetes arises from fluctuating blood sugar levels affecting the eyes’
lens. Timely diabetes management and regular eye checkups are crucial for preserving
clear vision.
4 4
It is reasonable to believe that the visual change is caused by changes in the osmotic
pressure between plasma and inside the eyeball. Undoubtedly, this is a useful and
MANAGEMENT OF DIABETES
straightforward explanation. However, thorough examinations haven’t been able to
pinpoint any discernible refractive shift as of yet.
Infections
Leukocytes that are exposed to glucose at levels higher than 11 mmol/L experience
paralysis in their phagocytic and other functions. This effect, along with additional
immune system effects that may be present, accounts for the weakened resistance
to bacterial and fungal diseases. Although there aren’t any conclusive data, viral
infection susceptibility seems to have remained quite stable.
Diabetes may become apparent if a yeast infection is persistent or resistant. Most
typically, this involves male or female vaginal candidiasis or balanitis. Initial
blood glucose regulation will enable infection clearance with ongoing antifungal
treatment. Especially in T1DM, staphylococcal pustules, boils, and carbuncles
may be present when diabetes is diagnosed. A prospective study of 482 patients
who presented to an emergency room with skin or mucous membrane sepsis and
were found to have over a threefold increased incidence of capillary blood glucose
> 7.8 mmol/L compared with a background population supported this clinical
observation.
Consideration must be given to extremely uncommon but serious infectious diabetes
358
presentations. Diabetes, both diagnosed and undiagnosed, is significantly more
likely in individuals with necrotizing fasciitis. Nearly 50% of instances of Fournier
gangrene (gangrene of the perineum and genitalia) involve diabetes. Diabetes is
frequently linked to the uncommon and frequently fatal fungus infection of the
maxillary and/or face sinuses known as mucormycosis.
Macrovascular Presentations
Acute myocardial infarction
IgG and diabetes are over-represented in groups who present with acute myocardial
infarction (AMI), which is not surprising given that the risk of ischemic heart disease
is linearly proportional to fasting and post-prandial blood glucose concentrations.
As a result, T2DM typically makes its first appearance during hospitalization for
AMI.
Stress hyperglycemia brought on by the catecholamine and cortisol increases
MANAGEMENT OF DIABETES
complicates this presentation. Exact definitions of diabetes are irrelevant from the
perspective of the patient with a condition that is life-threatening and made worse by
dysglycemia, despite the difficulties this may present for the purist trying to assess a
diabetic effect in isolation. Both chronic diabetes and stress hyperglycemia enhance
the risk of AMI death. Patients with stress hyperglycemia (defined as entrance
blood glucose > 7.0 mmol/L) had a 3 year mortality rate of 52% in a cohort of AMI
patients from a New York municipal hospital, compared to 42% for patients with
diabetes. In the same study, the 3-year mortality rate for people with normal blood
glucose levels was 24%. This effect has been confirmed by a meta-analysis, which
found that the risk of death related with stress hyperglycemia was 3.9 times higher
than the risk of death associated with established diabetes, which was just 1.7 times
higher. One of the most significant findings of the DIGAMI study is frequently
disregarded in this context. For people without a history of insulin therapy who
were stratified as having minimal coronary risk factors, the effect of acceptable
glycemic control (blood glucose 10 mmol/L) resulted in a 52% improvement in
mortality. There would have been people with stress hyperglycemia in this group.
The DIGAMI research, in contrast, found no significant benefits of acute blood
glucose management for people who had previously had insulin treatment.
The prevalence of stress hyperglycemia at the time of AMI manifestation is estimated
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 to be between 10 and 16%. This contrasts with estimates of 25 to 32% diabetes
prevalence at AMI presentation. The population’s background prevalence of IGT
and T2DM, as well as increasing knowledge and efficient screening procedures to
detect previously undiagnosed T2DM, are likely to be reflected in variation in these
figures.
Measurement of plasma glucose is required as part of good clinical practice after
an acute coronary syndrome diagnosis. Both fasting plasma glucose and HbA1c
should be assessed if the plasma glucose level is elevated (7 mmol/L may be given,
although in each case interpretation relies on when the previous meal was). Raised
plasma glucose should be taken as a sign that adequate glucose control is needed
during the acute event. Since it is unlikely that the HbA1c value will be available
right away, hyperglycemia signals the need for quick treatment in an emergency
situation where the first few hours are crucial. For the acute admission, a fasting
plasma glucose of greater than 5.6 mmol/L and/or an admission plasma glucose
4 4
of greater than 7.8 mmol/L resulted in a sensitivity of approximately 90% and a
positive predictive value of 44% for the diagnosis of diabetes.
MANAGEMENT OF DIABETES
Targeted screening in the post-acute context using a typical 75 g oral glucose
tolerance test (OGTT) is acceptable when there is diagnostic doubt. But when is
the best moment to carry out this test? Both pre-discharge and six weeks after
discharge OGTTs were conducted in a group of AMI patients without a history of
diabetes, and there was good connection with pre-discharge OGTT. Each patient’s
classification in each of the two OGTTs had a concordance rate of 49%.
The 60-minute blood glucose level during the pre-discharge OGTT was found to
be the strongest indicator of abnormal glucose handling (IGT or diabetes) being
detected at 3 months.
Acute Stroke
8–28% of patients with acute stroke have previously been diagnosed diabetes, but
an additional 6–42% have undetected pre-existing dysglycemia. One important
indicator of prognosis is plasma glucose upon presentation. One study of 86 acute
stroke patients showed that only those with presenting blood glucose levels below
8 mmol/L recovered fully functionally at 4 weeks. By 4 weeks, none of the patients
with elevated presenting plasma glucose had fully recovered. These observational
data cannot be used to determine the extent to which this reflects the metabolic stress
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response in relation to the seriousness of the cerebrovascular insult as opposed to
hyperglycemia itself hindering later recovery from ischemic damage.
In regards to acute stroke disease, the findings about a worse outcome in individuals
who experienced stress hyperglycemia after an AMI have been replicated.
According to a systematic review of observational studies looking at the prognostic
significance of hyperglycemia in acute stroke, non-diabetic patients with admission
plasma glucose levels > 6 - 8 mmol/L had an unadjusted relative risk of in-hospital
or 30-day mortality of 3.07 (95% CI 2.50 - 3.79) and those with known diabetes
had an unadjusted relative risk of 1.30 (95% CI 0.49 - 3.43). In individuals with
hyperglycemia who were not diabetic, the relative risk of poor functional outcome
was 1.41 (95% CI 1.16 - 1.73). It seems that people who have not been accustomed
to hyperglycemia are more affected by a rapid spike in plasma glucose levels when
it comes to tissue function.
A larger infarct size, as determined by magnetic resonance imaging, and a worse
stroke prognosis were observed to be associated with persistent hyperglycemia
(defined as blood glucose > 7.0 mmol/L) in the 72 hours following acute stroke.
MANAGEMENT OF DIABETES
However, there are currently no conclusive studies on the impact of controlling
plasma glucose on the course of stroke.
Even after 24 hours, the largest research to date, which involved 993 individuals,
was unable to regulate plasma glucose. Importantly, no examination of plasma
glucose control during the initial hours following presentation with acute stroke has
yet been done, and it is likely that it is during this window of time that this specific
presentation of hyperglycemia may be controlled most advantageously.
Microvascular Presentations
Eye presentations
When hyperglycemia has been present for an unknown number of years, silently
developing tissue damage and retinopathy, symptomatic loss of vision may
occasionally be the first sign of T2DM. The most common cause of vision loss
as a diagnostic event is macula edema, while vitreous hemorrhage can also be a
contributing factor. Diabetes is more likely to have central or branch retinal vein
blockage, which can also lead to symptoms of the illness.
In the UK Prospective Diabetes Study (UKPDS), it was discovered that 8% of
men and 4% of women had significant retinopathy with cotton wool patches or
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 intraretinal microvascular abnormalities (IRMA) at the time of T2DM diagnosis.
Figure 4.1 provides an illustration of the vital significance of scheduling a thorough
retinal examination, preferably using digital retinal imaging.
About 1% of people who have symptomatic T2DM at that point have retinopathy
that threatens their vision. Since the initial therapy for diabetes will lower blood
glucose levels, allow retinal blood flow to abruptly return to normal levels, and
may cause noticeably worsening of the retinopathy, it is crucial to identify diabetes
very early.
4 4
MANAGEMENT OF DIABETES
Figure 4.1: Upper panel: The significant exudative maculopathy evident
at the time of diagnosis necessitated rapid laser therapy for the macular
edema. Lower panel: Both new vessels coming from the optic disk and
the periphery of the retina are visible. Preretinal hemorrhages, which
obscure the fovea and in this case, led to presentation due to loss of
visual acuity, were prominently produced by bleeding from the latter
In the UKPDS, it was discovered that greater fasting plasma glucose levels were
associated with more severe retinopathy. Leaner women had more serious eye
362
lesions, but increasing alcohol use in men was linked to increased retinopathy
severity. The majority of patients had normal visual acuity, although there was a
tendency in men with more serious retinal lesions to have lower visual acuity.
The fact that 15% of those with moderate baseline retinopathy proceed to need
photocoagulation therapy within three years is indicative of the probable severity
of diabetic retinopathy at the time of diagnosis of T2DM. In this group of T2DM
patients, maculopathy alone accounted for 72% of the photocoagulation treatment
indications and proliferative retinopathy for 11%.
Neuropathic Syndromes
Although any of the neuropathic syndromes associated with diabetes may cause
the initial manifestation, the most likely options are symmetrical distal sensory
neuropathy, mononeuropathies, and amyotrophy. It is important to take diabetes
into account while examining the majority of neurologic symptom presentations.
MANAGEMENT OF DIABETES
The most typical type of neuropathy is diffuse symmetrical sensory neuropathy.
It has been challenging to determine the exact prevalence of this neuropathy in
patients with diabetes, and reports range from 7 to 60%, depending on the criteria
and techniques employed to define the neuropathy.
With age and diabetes duration, the prevalence rises. In the UKPDS, during the 12-
year follow-up, 64% of men and 44% of women who had no neuropathy at baseline
had at least one neuropathic abnormality.
Acute diabetic mononeuropathy can affect any nerve, but the most common
symptoms are palsy of cranial nerves III, IV, VI, and VII. T1DM is not affected by
this uncommon style of T2DM presentation.
Weight loss may be a symptom of diabetic amyotrophy, and unless thigh pain is
severe, the clinical picture may mirror that of a cancerous condition. Quadriceps
weakness that is accompanied by apparent wasting and the lack of the knee
tendon reflex should make it possible to diagnose the condition and prompt the
measurement of plasma glucose. Although unusual, such a manifestation is likely
linked to T2DM.
Diabetes may manifest as a foot lesion, and individuals with diabetes are thought to
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 have a 25% lifetime risk of getting a foot ulcer.
Particularly T2DM is linked to presentation with a black toe. In addition to
sensory motor and autonomic dysfunction, callus formation, dry skin, and loss of
the protecting pain sense are also effects of peripheral neuropathy. Loss of pain
perception in the feet is typically undetected, and subsequent trauma is not observed
until a clear injury is visible. Peripheral vascular disease (PAD) coexists with these
foot ulcer patients in about 50% of cases. According to the EURODIALE study,
foot ulcers with PAD had far worse healing rates, greater rates of major amputation,
and higher mortality rates.
Pregnancy
Knowing the pathophysiology of GDM can help anticipate when symptoms
will manifest. Insulin resistance that develops physiologically during pregnancy
4
is the main factor. Although this has been quantified in a number of very small
investigations, the observation of the shift in exogenous insulin needs during
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pregnancy in T1DM provides the best examples. The need for insulin does not alter
while glycemic control is maintained and food intake is maintained until around 18
weeks into pregnancy, after which there is a linear increase until about 28 weeks
into pregnancy. Individual pregnancies see changes ranging from none to more
than a threefold increase, with an average daily insulin dose increase of 40%.
Given the wide variety shown between the same woman’s subsequent pregnancies,
the placenta (fetal-derived tissue) is thought to be responsible for the range.
Given this information, it is clear why the high blood glucose levels associated with
GDM are not present throughout the first half of pregnancy. Later in pregnancy is
when GDM screening will be most accurate, although this accuracy must be weighed
against the chances for intervention. Therefore, current recommendations suggest
testing between 24 and 28 weeks of pregnancy. If the level of insulin resistance
rises too high, predisposed women cannot mount a sufficient β-cell response.
Although raised, the chance of a second pregnancy becoming complicated by GDM
after the first is far from guaranteed due to the fluctuation in insulin resistance
between pregnancies. As would be predicted given the greater background
incidence of T2DM (52-69%) among South Asian and Hispanic populations,
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higher rates have been recorded in these groups. As in T1DM and T2DM, the pace
of intrauterine growth is equally rapid in GDM. For both mother and child, a GDM
diagnosis at an early stage has significant benefits. In people with GDM, the chance
of subsequently getting diabetes ranges from 2.6 to 70% during a period of 6 weeks
to 28 years.
For patients with GDM, it is now advised by NICE guidelines for “Diabetes in
Pregnancy” (March 2008) that fasting plasma glucose tests be done every six
weeks and once a year. This will leave out some women who have normal fasting
plasma glucose and IGT, however it should be underlined that the development of
GDM should be the catalyst for advice about drastic lifestyle changes, including
weight loss.
Mild plasma glucose elevations may be sufficient to harm the fetus, however they
are much less severe than those that could cause osmotic symptoms. Therefore,
4
GDM screening is crucial. In the setting of a healthcare system that offers universal
screening for GDM, symptomatic GDM presentation is infrequent. However, it’s
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crucial to determine if this is new-onset T1DM or T2DM when osmotic symptoms
and severe fungal infections are a component of the clinical presentation.
The former is frequently accompanied by ketonuria and increased plasma glucose
levels. Due to the fact that the hyperglycemia has been present for several weeks
or months, both are associated with obviously high HbA 1c readings. It is likely
that the presentation, if it occurs during the first part of pregnancy, will not go away
after delivery.
The elderly population is more susceptible to the health ailment diabetes. The
percentage of older adults with diabetes and prediabetes is over one-quarter and
fifty percent, respectively, and these numbers are projected to rise sharply in the
future decades. The care of diabetes in older persons necessitates routine evaluations
in the medical, psychological, functional, and social realms. In comparison to
older persons without diabetes, those with diabetes have increased rates of early
death, functional disability, rapid muscle atrophy, and concomitant diseases such
hypertension, coronary heart disease, and stroke. As the findings of screening tests
may have an impact on targets and therapeutic methods, screening for diabetic
complications in older individuals should be tailored to each individual and repeated
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 on a regular basis. In addition, older people with diabetes are more likely than
other older people to experience a number of typical geriatric syndromes, including
polypharmacy, cognitive decline, depression, urine incontinence, dangerous falls,
and chronic pain. If not treated, these problems may affect the quality of life and
ability of older persons to manage their diabetes. When complicating factors or
care transitions occur, the thorough assessment described above may serve as a
framework to determine targets and therapeutic approaches, including whether
referral for diabetes self-management education is appropriate or whether the
current regimen is too complex for the patient’s capacity for self-management or
the caregivers providing care. Complications including those affecting the lower
extremities and vision, which can arise quickly and/or severely impair functional
status, should receive special attention.
Diabetes increases the likelihood of cognitive deterioration and institutionalization
4 4
in older persons. Cognitive impairment can manifest as anything from mild
executive dysfunction to obvious dementia and memory loss. Alzheimer’s disease,
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vascular dementia, and all-cause dementia are more common in adults with diabetes
than in people with normal glucose tolerance. Research is heavily focused on how
hyperglycemia and hyperinsulinemia affect the brain. Cognitive function declines
are linked to poor glycemic control, and cognitive function declines are linked to
diabetes duration. Studies are still being conducted to determine if preventing or
postponing the onset of diabetes can assist older persons preserve their cognitive
function. Clinical trials of particular therapies, such as glutamatergic antagonists
and cholinesterase inhibitors, have not demonstrated positive therapeutic value in
preserving or noticeably enhancing cognitive function or in preventing cognitive
decline. Future clinical trials and mechanistic research will benefit from the
knowledge gained from pilot studies in patients with moderate cognitive impairment
investigating the potential advantages of intranasal insulin therapy and metformin
therapy. Despite the dearth of treatments for cognitive decline prevention or
treatment, diabetes management can benefit significantly from early detection of
cognitive impairment. It may be difficult for clinicians to support their patients in
achieving their unique glycemic, blood pressure, and lipid targets when cognitive
impairment is present.
Patients with cognitive dysfunction find it challenging to complete sophisticated
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self-care tasks, like monitoring glucose and modifying insulin doses. Additionally,
it makes it difficult for them to maintain proper meal timing and diet composition.
Drug regimes must be kept simple for patients with cognitive dysfunction, and
the right support system must be facilitated and enlisted to help the patient in all
aspects of care.
Because of the clinical, cognitive, and functional diversity of older persons with
diabetes, caregiving is made more challenging. Others may have recently been
diagnosed with diabetes after years of undiagnosed diabetes and consequent
problems, while yet other older persons may have the disease that is truly recent
in onset with little or no difficulties. Some older people may have developed
diabetes years earlier and have major consequences. Some elderly persons with
diabetes have additional underlying chronic diseases, significant comorbidities
with diabetes, poor cognitive or physical functioning, or are frail. Other elderly
people with diabetes are active and have few comorbid conditions. Although highly
variable, life expectancies are frequently longer than doctors are aware of. There
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are numerous prognostic techniques for estimating life expectancy in older persons,
including ones created especially for those with diabetes.
No matter how sensible the medical plan, it can only be effective if the family and/
or the affected people can follow it. For children and adolescents with diabetes
to receive the best care, family involvement is essential. In order to successfully
implement a treatment plan, the pediatric diabetes care team must be able to
assess the educational, behavioral, emotional, and psychosocial elements that are
involved. They must also be able to engage with the patient and their family to
remove obstacles or, as necessary, reevaluate their goals. Periodic evaluation is
necessary for diabetes self-management instruction and assistance, particularly as
young people grow, develop, and demand more independent self-care abilities.
4.1.1 Treatment Goals
Due to changes in biology, illness onset, patient characteristics, and environmental
effects, treatment objectives for T1DM and T2DM are different. Glucose
homeostasis for type 1 diabetic adults should return to a nearly normal pattern.
The significance of strict glycaemic control in type 1 diabetes is supported by 20
years of prospectively collected data from the Diabetes Control and Complications
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 Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications
(EDIC) follow-up trial. In a cohort study of 879 people with type 1 diabetes, those
with glycated hemoglobin A1c levels above the median (HbA1c 12%) had higher
rates of all-cause and cardiovascular mortality than those in the lowest quartile
(relative risk [RR] 2.4, 95% confidence interval [CI] 1.5-3.8 and RR 3.3, 95%
confidence interval [CI] 1.8-6.1, respectively). The mean 8-year risk of mortality
was proportionally higher in patients with the highest HbA1c values in another
study from the Swedish Diabetes Register, which compared 33,915 type 1 diabetic
patients with non-diabetics (hazard ratio (HR) for all-cause and cardiovascular
mortality 8.51 and 10.46, respectively). The target HbA1c for adults with type 1
diabetes is typically less than 7%. However, the risk of hypoglycemia must be
evaluated against the advantages of maintaining this goal level for life expectancy
and pre-existing problems. In patients who experience frequent hypoglycemic
episodes or hypoglycemia unawareness, as well as older patients, children, and
4 4
adolescents, the target HbA1c values may be raised. Since lowering HbA1c in
pregnant non-diabetic women has positive effects on the fetus, more strict HbA1c
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values ( 6%) may be suggested in specific people or situations.
With every 1% decrease in HbA1c, glycemic management in T2DM is recognized
to gradually reduce the risk of microvascular and macrovascular disease. However,
there is little proof that strict glycemic management prevents macrovascular disease.
Only one randomized controlled trial found that glycaemic management reduced
the risk of macrovascular disease; numerous other trials failed to find a link; and
one trial even found that glycaemic control had negative effects on macrovascular
health. For the majority of patients, a HbA1c score of 7.0% or below may be
considered appropriate. Therefore, postprandial plasma glucose concentrations
after 90–120 minutes should be 180 mg/dl (10 mmol/l) or less, and fasting plasma
glucose concentrations should be between 70 and 130 mg/dl (between 3.9 and 7.2
mmol/l). HbA1c objectives must be reevaluated in light of each patient’s unique
demands, capabilities, and requirements, particularly in those with T2DM. Patients
who are elderly or have a short life expectancy should have HbA1c levels of around
8%.
Intensive insulin therapy, which is essential in the management of type 1 diabetes,
is effective only when it is administered under the close supervision of a physician.
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These variables include the quantity of carbohydrates consumed per meal, the
circadian levels of hormones that regulate metabolism, disease, and stress.
Hypoglycemia, hyperglycemia, and glucose fluctuation are the acute consequences
brought on by insufficient insulin replacement. Avoiding excessive blood glucose
swings and aiming for a mean HbA1c number that satisfies both evidence-based
recommendations and individual needs based on benefits and hazards are of the
utmost importance.
Two episodes of symptomatic hypoglycemia per week and one potentially
incapacitating episode of severe hypoglycemia per year are typical for type 1
diabetes patients. In T1DM, hypoglycemia is a significant issue that raises the risk
of injury, emotional distress, death, and glucose fluctuation.
The percentage of type 1 diabetic patients who die from hypoglycemia is estimated
to be 4 to 10%. In T1DM, nocturnal hypoglycemia is a significant problem. The
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longest interval between self-checking blood sugar levels and eating occurs at
night, which is also when insulin sensitivity is highest.
Another continuous glucose monitoring (CGM) study in type 1 diabetic patients
showed that hypoglycemia occurred on more than half of the nights examined,
lasting an average of 2.5 hours.
Absolute beta-cell insufficiency along with external insulin replacement prevents
the suppression of the insulin concentration, whereas hypoglycemia inhibits
hepatic glucose synthesis. Increased release of glucagon and epinephrine,
which raise plasma glucose concentrations by promoting glucose synthesis and
counteracting the insulin-induced increase in glucose use, is the last remaining
defense against hypoglycemia. It is important to highlight that in T1DM and
T2DM, the counterregulatory glucagon release is lost. Due to recent antecedent
hypoglycaemic occurrences, it was shown that the release of epinephrine, which is
essential for diabetic patients, attenuates.
Patient-Centered Education
In accordance with public health and chronic disease models of illness management,
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 educators are now promoting “patient-centered” education, also known as “learner-
centered” education, which shifts from provider-directed to “patient-centered”
care and education. Early advocates of this paradigm were diabetes educators who
immediately adapted methods to accommodate each patient’s agenda.
By enabling lessons to be learnt and then applied to patients’ own lives, this more
patient-centered approach frees the educator to deliver tailored (less didactic)
knowledge, providing reinforcement and follow-up.
According to Funnell’s summary, patients have a better chance of success if all
caregivers, educators, and team members communicate the same clear message to
them.
The first step in preparing patients to make the essential lifestyle changes is
diabetes education. Educators and clinicians must understand the importance of
involving patients in determining what they feel they need and addressing this first
as a strategy to engage patients and enhance their retention of information because
4 4
many patients forget most of what is stated in the clinic.
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The sharing of knowledge among medical professionals and the knowledge retention
of diabetes patients are insufficient to assist them in changing their behavior. The
most important determinant of a successful DSME is the number and quality of
good communication between health care professionals and persons with diabetes.
Better regimen adherence and glucose reduction have been linked to increased time
spent interacting with patients by medical personnel.
So how may diabetics be taught in the most effective way? How can we tell if they
are picking things up? What proof do we have that the teaching strategies we pick
are effective?
The learner-centered strategy that is appropriate for adults with diabetes seems to
be best described by a straightforward primary school strategy from Anna Devere
Smith, which “thinks of education as a garden where questions grow.” People with
diabetes require a supportive environment where they may discuss their difficulties
managing their condition, seek advice from medical professionals on solutions, and
afterwards adhere to the recommended regimen.
It has been established that the facilitation and patient-centered intervention tenets
are preferable to a didactic and more passive teaching strategy. There is no one
optimum education program or strategy, however programs embracing behavioral
and psychosocial strategies show enhanced results, according to one of the DSME
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standards. To maintain the gains made by participants during the DSME program,
ongoing support is essential. There is compelling evidence that patient-generated
goals lead to better results than those created by healthcare providers. Diabetes
educators use a variety of teaching strategies to assist patients in acquiring the
knowledge, skills, and commitment to self-care behaviors necessary for successful
diabetes management. Individual adult T2DM education interventions typically
enable the educator to customize the strategy to the patient’s unique needs and, as
a result, deliver effective therapy.
Evidence suggests that group diabetes therapies, however, can be more patient-
centered, cost-effective, and interactive learning opportunities with high levels
of patient satisfaction comparable to individual interventions. Different diabetic
educators use different teaching strategies and methodologies for group education.
Therefore, more study is required to ascertain whether diabetes educators’
instructional strategies and techniques contribute to the efficient instruction that
results in the greatest clinical outcomes for people with T2DM. The best outcomes
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are created with an empowerment strategy, which focuses on when and what patients
desire to learn, according to the current best practices in group education. Results
have improved when using problem-based, culturally appropriate techniques that
take into account psychosocial, behavioral, and clinical issues pertinent to the needs
and receptivity of the patients.
DSME is in line with the chronic disease model, which states that educational
strategies should be simple, tailored to each patient’s needs and lifestyle, reinforced
over time, considerate of each person’s habits, and include social support. As
they concentrate on collaborative issue definition, goal-setting, a continuum of
self-management training, and support services, chronic disease care approaches
apply comparable strategies to DSME. According to research on chronic disease
therapies, individualization, relevance, feedback, reinforcement, and facilitation
are the aspects of education that are most beneficial.
How can we deliver learner-centered instruction in a classroom setting? How do
we assess the various learning requirements of each person and give them the
specialized care they require? Effective self-management education is hampered
by the intricacy of individual needs assessments and group instruction. In a group
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 setting, it can be difficult to individualize the techniques in the same way as a regular
one-on-one session. The patients are able to learn, retain their knowledge, and be
committed to the follow-up action plan when the group session is successfully
customized. It has been demonstrated that traditional didactic education, which
focuses on imparting knowledge through lectures without involving patients, is
inefficient at encouraging patients to alter their lifestyle habits in a way that would
improve clinical outcomes.
Understanding diabetes does not ensure behavioral adjustments that finally result
in improved results. To encourage active participation in the learning process, the
learner-centered approach uses non-didactic and less passive tactics. A patient-
centered approach to education reflects the ideas and best practices that have been
proven to improve patient outcomes in terms of knowledge retention, commitment,
and self-care. These include support that is continual, facilitation, empowerment,
4 4
behavioral goal-setting, behavioral and psychological methods, and motivational
interviewing. Patients are able to communicate their understanding of diabetes,
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internalize their commitment, and establish their priorities through this approach.
Additionally, this procedure enables the continuous implementation of short- and
long-term objectives, allowing for progress monitoring. Instead of receiving advice
from the educator about how to handle their own diabetes difficulties, patients
come up with their own solutions. It is hoped that by determining what is realistic
and doable, patients would ultimately own their commitments and be more likely
to make the necessary lifestyle changes.
The principles of adult learning are aligned with effective diabetes education
because adults learn best when the information is straightforward, applicable, and
relevant (i.e., driven by their interests), when the learning builds on the experiences
of the participants, and when there is a focus on application (i.e., when learning is
put into practice). Learning is a cognitive, emotional, and environmental process
that affects one’s knowledge level, skill development, and worldview.
4.1.2 Glycemic Control Implementation
In the past, hyperglycemia in critically ill patients was thought to be an adaptive
reaction to stress and an unintentional indicator of the severity of the illness. This
idea has been refuted by recent research, which has also raised awareness of the
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harmful effects of hyperglycemia in critically sick patients, both with and without
a history of diabetes. As a result of the stress of an acute illness, the hormones
adrenaline, glucagon, cortisol, and growth hormone are produced in excess, which
increases insulin resistance and reduces peripheral glucose uptake.
Immune system dysfunction, increased coagulopathy and inflammation, oxidative
stress, and endothelial dysfunction are some of the processes through which
hyperglycemia causes injury. Among the observed negative clinical outcomes
include an increase in nosocomial and surgical infections, sepsis, arrhythmias,
congestive heart failure, reinfarction, and a slower rate of functional recovery in
stroke survivors.
The ideal serum glucose level in diabetic patients is glycemic control. In order to
maintain control and avoid complications, it is essential to determine the factors
affecting patients’ glycemic control. To evaluate the variables influencing glycemic
control in people with type 2 diabetes mellitus, we conducted this systematic study.
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In order to avoid macro and microvascular problems, maintaining adequate
glycemic control (GC) is the fundamental therapy objective for all diabetes patients.
The ideal blood sugar level for DM patients is GC. Three measurements—fasting
blood glucose (FBG), postprandial glucose (P PG), and glycosylated hemoglobin
(HbA1c)—can be used to assess the glycemic management of T2DM patients. The
best indicator of glycemic management among these is glycosylated hemoglobin.
Glycemic management is still a fine line to walk. Maintaining euglycemic blood
glucose levels is the responsibility of the diabetic patient. To achieve this goal,
the patient needs knowledge, decision-making techniques, volitional control, and
the wisdom to avoid hyper- and hypoglycemia, with the latter being defined as
plasma glucose less than 60 mg/dl. Continuous glucose control is required, with
no breaks. The inability to keep euglycemia occurs from both biological and
psychosocial variables, such as overmedication and/or incorrect diet, drink, and, in
some circumstances, exercise choices.
The brain lacks the steady supply of glucose it needs for energy when it has
hypoglycemia. The ventromedial hypothalamus detects such low blood glucose
levels. Then, a hormonal counterregulatory cascade that starts with the suppression
of insulin secretion is triggered to quickly restore euglycemia. A subsequent rise in
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 hepatic glycogenolysis, gluconeogenesis, and renal gluconeogenesis is caused by
the release of glucagon and adrenaline, which also increases endogenous glucose
synthesis. Cortisol and growth hormone are slow-acting responses to persistent
hypoglycemia. Because extracellular zinc is released upon glucose reperfusion
and neuronal NADPH oxidase is activated, hypoglycemia may encourage
oxidative stress and neuronal cell death. Therefore, increased glucose levels during
reperfusion may result in cell death. The sympathetic autonomic nervous system
is also stimulated by counterregulatory responses, which can cause symptoms
including sweating, shaking, anxiety, hunger, and agitation. Confusion and anger
are two neuroglycopenic symptoms that are brought on by glucose deprivation.
Recent animal experiments have demonstrated the possibility of treating brain
damage brought on by severe hypoglycemia episodes. Hypoglycemia is considered
to cause the same excitotoxic process that kills neurons after a stroke. The
4 4
effectiveness of two drugs now used to treat stroke patients, NMDA- and -amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor antagonists, in treating
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severe hypoglycemia is being studied. These investigations have demonstrated
that these medications lessened the harm caused by hypoglycemia to the striatum,
neocortex, and hippocampal seizures.
4.2 Non-Pharmacological Management
According to estimates from the International Diabetes Federation (IDF), there are
425 million adults worldwide who have diabetes, or one in every eleven adults.1
The prevalence of diabetes is anticipated to rise exponentially over time due to
the global obesity epidemic caused by inactivity and poor eating habits. In order
to manage the many diabetes patients they see on a daily basis in clinical practice,
doctors and other healthcare professionals must possess the necessary knowledge
and expertise.
In clinical practice, type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus
(T2DM), together with a tiny proportion of other forms of the disease, are frequently
encountered. The main goal of optimal diabetes treatment is to maintain plasma
glucose levels within the healthy, non-diabetic subject’s normal physiological
reference range without increasing the risk of hypoglycemia. Healthy dietary intake
of nutrients, physical exercise, and hormones that regulate glucose homeostasis,
particularly insulin, all contribute to normal plasma glucose levels in an individual.
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Therefore, nutritional therapies, lifestyle changes that include increased physical
activity, and hormonal manipulation (primarily insulin and/or its effects) should be
the focus of diabetes care.
With rising body weight, the risk of T2DM climbs continuously, and those who are
morbidly obese are most at risk.2 Overeating and physical inactivity contribute to
excess body weight, which causes fat to accumulate primarily in the abdomen and
visceral regions. The word “diabesity,” which was created to connect diabetes with
obesity, refers to the modulation of many hormonal and chemical mediators in the
body as a result of this visceral and abdominal adiposity. Another underappreciated
risk factor for the onset of T2DM is the metabolically obese’ phenotype, which is
characterized by normal body weight, normal or low body mass index (BMI), but
increased abdominal fat.
The development of T2DM is brought on by free fatty acids generated from
visceral adipose tissues that decrease insulin sensitivity and harm beta-cell function
(lipotoxicity).
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Since diabetes is a disease that is strongly tied to unhealthy lifestyles, changing
one’s way of life should be the first step in managing the condition effectively.
The stability and sustainability of these effects are frequently low, despite the
possibility that numerous pharmacological interventions may be linked to changes
in obesity and diabetes. Non-pharmacological treatments, such as bariatric surgery,
are therefore crucial for these patients. For the management of this worrying global
epidemic, various novel therapeutic options have been developed in recent years as
a result of a better understanding of the biology of diabetes.
Absolute insulin insufficiency causes T1DM, thus insulin control is the mainstay of
treatment. To achieve the best results, T1DM treatment should also take into account
dietary changes and physical activity. A fraction of T1DM patients are obese, which
raises their insulin needs and negatively impacts metabolic regulation.5 Therefore,
even in cases of T1DM, lifestyle changes are crucial. Obese patients with T1DM
have also demonstrated some positive results with a large reduction in insulin needs
and a slight improvement in diabetes control, despite the fact that bariatric surgeries
are typically performed on patients with T2DM.
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4.2.1 Dietary Interventions
The goal of nutritional treatment in diabetes is to help improve metabolic control
and lower risk factors for long-term problems. This involves achieving blood
pressure values that may be predicted to lower the risk for macrovascular disease as
well as blood glucose and glycosylated hemoglobin (HbA1c) levels that are as close
to normal as is safely practicable. When dietary goals are set, they must take into
account a person’s quality of life and specific therapeutic needs. When providing
dietary guidance to a specific diabetic patient, diabetes health care providers
should employ the greatest available scientific data. The examination of the data
supporting the formulation of evidence-based guidelines for the management of
type 1 (T1DM) and type 2 diabetes (T2DM) has taken on a more professional tone
in recent years.
The current evidence-based nutritional guidelines for diabetics involved a rigorous
4 search of the literature using predetermined sets of descriptors and pertinent
and improved activity levels are accomplished and maintained, they constitute a
tried-and-true therapeutic approach for maintaining goal glycemic control.
There is agreement that such lifestyle changes should start as part of the management
of T2DM with new onset. Even a small amount of weight loss, especially in the
area of belly fat, can enhance glucose tolerance and insulin sensitivity while
lowering blood pressure and serum cholesterol levels. For those with a high waist
circumference, losing weight may have a bigger positive impact on cardiac risk
factors. Waist circumference and body mass index (BMI) are used in conjunction
with visceral body fat to determine the risk of diabetes and cardiovascular disease
(CVD). Patients with T1DM who are overweight may develop insulin resistance,
and weight loss in these individuals may result in a reduction in insulin dosage and
an improvement in glycemic control.
When someone has lost some excess weight, preventing weight gain is a key goal.
To maintain the metabolic advantages that can be attained by weight loss, long-
term reduced calorie consumption is required. 4

databases. According to the type and caliber of published studies, expert committee

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declarations, and clinical experiences of acknowledged professionals, the level of

the evidence supporting various nutritional recommendations is rated. In the ideal
scenario, trials with fatal or non-fatal clinical endpoints would be used to develop
evidence-based guidelines. However, since this data is frequently unavailable,
surrogate endpoints, such as glycemia, body composition, lipoprotein proficiency,
blood pressure, insulin sensitivity, and renal function, are frequently used to assess
the potential impact of dietary changes on glycemic control and the risk of acute
and chronic complications of diabetes. Important dietary recommendations for
individuals with T1DM and T2DM are provided in Tables 4.1–4.3, along with the
level of evidence that the American Diabetes Association (ADA) and the Diabetes
and Nutrition Study Group of the European Association for the Study of Diabetes
(DNSG EASD) have assigned to each recommendation.

Balance Of Energy And Body Weight

It’s crucial to keep your weight under control to lower your risk of developing
diabetes. In T2DM in particular, when weight loss and improved activity levels are
Table 4.1: Nutritional advice for people with type 1 and type 2 diabetes with
accomplished and maintained, they constitute a tried-and-true therapeutic approach
for maintaining goal glycemic control. It’s crucial to keep your weight under control grade A proof. data from at least one randomized controlled trial or meta-
to lower your risk of developing diabetes. In T2DM in particular, when weight loss analyses of randomized controlled trials

376 377
 For those who are genetically prone to fat, losing weight might be very difficult. To
obtain the potential beneficial effects, however, systematic weight loss programs
should be utilized in overweight patients. Typical weight reduction plans recommend
500–1000 fewer calories per day than are recommended for weight maintenance.
Initial body weight reduction of between 0.5 and 1.0 kg per week may come from
this; however, many people gain back the weight they have lost, thus ongoing
support from the medical staff is required to achieve long-term improvements
in body weight and waist measurement. In addition to diet and exercise, regular
physical activity should be a key element of lifestyle therapies for treating obesity.
The use of very low energy diets as a strategy to induce initial weight loss, according
to experts’ current consensus, should be limited to individuals with a BMI > 35
kg/m 2.
4 4
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Table 4.2: For those with type 1 and type 2 diabetes, nutritional advice with a
B grade on the evidence
Distribution Of Macronutrients In Diets For Weight Loss
It has not yet been determined how to distribute macronutrients in weight loss diets
in the ideal way. Low carbohydrate, higher fat diets have lately been shown to
cause even greater weight loss over short periods of time, up to 6 months. Low
fat diets have traditionally and successfully been pushed for weight loss. Low
density lipoprotein (LDL) cholesterol was significantly higher in patients on high
fat, low carbohydrate diets, despite changes in serum triglycerides and high density
lipoprotein (HDL) cholesterol being more favorable with low carbohydrate, higher
378
fat diets than with high carbohydrate, lower fat diets in these trials.
Balancing macronutrients is vital in diabetes weight management. Prioritize complex
carbs, lean proteins, and healthy fats. This synergy supports stable blood sugar, curbs
cravings, and aids weight loss for improved diabetes contrºl.
Low carbohydrate, high fat diets have unknown long-term metabolic effects, and
there are no controlled long-term studies to support their safety with regard to CVD.
These diets cut out a number of items that are vital sources of fiber, vitamins, and
minerals. Additionally, it has been demonstrated that substituting monounsaturated
fatty acids (MUFA) for carbohydrates was challenging because there are few foods
that contain appreciable amounts of MUFA, and even in Mediterranean regions,
people today tend to consume unhealthily high levels of saturated fat in high-fat
diets.
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Weight Loss In The Prevention Of Diabetes
When it comes to the prevention of diabetes in people who are at high risk for
developing T2DM, lifestyle modifications like lowering energy and dietary fat
intake, increasing fiber intake, and engaging in consistent physical activity (such
as 150 minutes per week) have shown improvements in a number of vascular risk
factors like dyslipidemia, hypertension, and markers of inflammation in addition to
the significantly lower risk of developing T2DM. There are currently no scientific
trials on the effectiveness of low carbohydrate diets for the primary prevention of
T2DM.
Carbohydrate And Diabetes
When it comes to the prevention of diabetes in people who are at high risk for
developing T2DM, lifestyle modifications like lowering energy and dietary fat
intake, increasing fiber intake, and engaging in consistent physical activity (such
as 150 minutes per week) have shown improvements in a number of vascular risk
factors like dyslipidemia, hypertension, and markers of inflammation in addition to
the significantly lower risk of developing T2DM. There are currently no scientific
trials on the effectiveness of low carbohydrate diets for the primary prevention of
T2DM. The mean carbohydrate consumption in the EURODIAB Complications
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 Study, which comprised 3250 persons with T1DM from 31 different European
sites, did not significantly differ from baseline intakes at the 7-year follow-up
investigation. People with T2DM from the Mediterranean region have also been
shown to consume high levels of total and saturated fatty acids and relatively
modest amounts of carbohydrates. Generally speaking, patients with diabetes
consume fewer carbohydrates than is advised by nutrition associations for the
general population, who are advised to get about 50% of their total energy from
carbohydrates. Because they worry that eating foods high in carbohydrates will
cause blood glucose levels to rise, many diabetics seek to limit their consumption
of carbohydrates. Low-carb diets in developing nations are typically accompanied
by high fat intake, particularly unfavorable amounts of saturated fat. It is difficult
to acquire sufficient fiber consumption to meet requirements with such a diet.
With this in mind, emphasizing the current resurgence of low carbohydrate
techniques in diabetes does not seem to be beneficial. Furthermore, it is not quite
4 4
apparent from multiple recent papers on this subject what is meant by “low” or
“high” carbohydrate, or whether the 40% of total energy that many patients with
MANAGEMENT OF DIABETES
diabetes consume in carbohydrates already qualifies as a low-carbohydrate diet.
Glycemic Effects Of Different Carbohydrate
For those with diabetes, it’s critical to consider both the quantity and kind of
carbohydrates. A healthy diet should include whole grain meals, fresh fruit,
legumes, vegetables, and low-fat dairy products. Additionally, these meals include
a variety of vitamins and fiber.
Table 4.3: Nutritional intake and further life - style factors in persons with
type 1 diabetes
380
For those with T1DM and T2DM, the amount of carbohydrates is a crucial variable
in postprandial glucose levels. Many people with diabetes utilize carbohydrate
counting, carbohydrate swaps, or experience-based estimation of carbohydrate
intake as a helpful tool to manage their consumption of carbs during meals or
snacks in the process of achieving desired glycemic control. The impact of various
carbohydrates on blood sugar levels vary. The glycemic reaction to foods containing
carbohydrates is influenced by factors besides the amount of carbohydrates, such as
the type of sugar, the type of starch, and the amount of dietary fiber.
The post-prandial blood glucose response of a food containing carbohydrates over
a period of two hours is described by its glycemic index (GI) in comparison to a
reference food containing the same quantity of carbohydrates, typically 50g glucose
(or white bread in certain studies). Foods can be categorized as having a high
glycemic index (GI: 70–100), a medium GI (55–70), or a low GI (GI: 55). However,
measured GIs are only available for a small number of foods, with the data primarily
coming from studies in Canada and Australia. The glycemic load is defined as one
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gram of carbohydrate within the food multiplied by the food’s GI, divided by 100,
taking into account both the quantity and quality of the carbohydrate. It has been
demonstrated that using a food’s GI or glycemic load may offer modest additional
benefits over those seen when only total carbohydrates are taken into account, both
for post-prandial glycemia and the lipid profile. Consequently, if possible, foods
with a known low GI (such as legumes, pasta, parboiled rice, whole grain breads,
oats, and some raw fruits) should be substituted with items with a known high GI
(such as mashed potatoes, white rice, white bread, cookies, and sugary drinks).
For instance, fresh fruit is preferable to fruit juice when both contain the same
quantity of carbohydrates. However, low GI foods are only advantageous if their
other characteristics are also consistent with a balanced diet. Some meals with low
GI are also high in calories and fat. One such example is chocolate, which has a
low GI yet a high concentration of saturated fat. The GI of common foods has been
decreased in some goods specifically marketed for diabetics by substituting sugar
alcohols or fructose for sucrose. These pricey so-called “diabetic” preparations
have not been shown to have a significant benefit. Therefore, it is not advised to
consume particular foods for diabetics.
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 Potential Of Dietary Fiber
Diabetes patients in many nations consume only a small number of foods high in
dietary fiber, resulting in a significantly lower total fiber consumption than is advised
(Figure 4.2). It might be challenging to consume the appropriate amounts of fiber
given that persons with diabetes generally consume relatively few carbohydrates.
In the EURODIAB Complications Study, the average daily consumption of dietary
fiber was 19.5 g, or 8.0 g/1000 kcal. To benefit from the fiber’s well-documented
benefits for glycemic management, insulinemia, and serum lipid concentrations,
people with diabetes should be encouraged to eat a variety of fiber-containing
diets (vegetables, fruits, wholegrain products). Despite the low total fiber intake,
epidemiologic data from the EURODIAB Complications Study showed an inverse
relationship between dietary fiber intake and HbA1c, an inverse relationship between
dietary fiber intake and LDL cholesterol, and a positive relationship between dietary
fiber intake and HDL cholesterol. Additionally, there was a significant and inverse
4 4
relationship between dietary fiber and cardiovascular disease. Dietary fiber was
also linked to lower BMI levels.
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Figure 4.2: Fiber intake (g/day) in persons with
type 1 diabetes (total n = 1102) from 21 centers in Europe
Sucrose And Other Sugars
People with diabetes can consume moderate amounts of sucrose (10% of total
calories) or other added sugars without having their glycemic control deteriorate.
Although replacing sucrose with fructose results in a decrease in postprandial
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glycemia, this potential benefit is mitigated by the possibility that fructose may
negatively impact blood triglycerides and uric acid levels. Although there is no
justification for advising diabetics to stay away from naturally occurring fructose
(found, for example, in fruits, vegetables, and other foods), added fructose,
added sugar alcohols, or other nutritive sweeteners are energy sources that do not
significantly outperform sucrose and should not be encouraged. Increased use of
sugar alternatives may encourage harmful gastrointestinal side effects.
Additionally, even though sugar alcohols are only partially absorbed from the small
intestine, it is doubtful that the amounts anticipated to be consumed of energy-
containing sugar alternatives like these will significantly reduce total calorie intake.
People with diabetes may also use approved non-nutritive sweeteners, albeit a
unique long-term benefit in metabolic control has not been established. However, if
appropriate daily intakes (ADI values) are adhered to, they are secure.
The Modification Of Insulin Or Insulin Secretagogues In Response To
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Carbohydrate Ingestion
It is crucial for patients taking insulin or other hypoglycemic medications to match
their carbohydrate intake in terms of type, amount, and timing in order to prevent
hypoglycemia and severe postprandial hyperglycemia. Individuals receiving
intensive insulin therapy should modify their premeal insulin dose based on the
carbohydrate content of meals or snacks while also taking the GI of these items
into account.
Today, many nutrition education programs for diabetics with intensified insulin
regimens include this guidance. Self-monitoring of blood glucose is a useful tool
for figuring out when to eat and how to choose foods that are best for you. The
most crucial factors in determining the right meal frequency, portion sizes, and
carbohydrate intake continue to be personal preferences and the requirements
of various treatment modalities. Prior to exercise, more carbohydrates may be
required, while adjusting insulin dosage in people receiving intensified insulin
treatment is frequently an alternative and preferable option. To enable people with
diabetes to modify the insulin dosage while taking into account all three factors—
blood glucose results, amount and quality of carbohydrate consumption, and level
of physical activity—structured training and ongoing assistance from the diabetes
team is required.
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 Dietary Fat
Reduced consumption of saturated fatty acids, trans fats, and dietary cholesterol is
the main objective of dietary fat intake in order to lower the risk of vascular disease.
persons with diabetes are more likely to develop vascular disease than persons
without the condition. A well-established strategy for helping diabetics achieve
optimal serum lipid concentrations and prevent arterial lesions in high-risk
populations is fat modification. Despite the fact that the majority of this information
comes from studies of individuals without diabetes, it appears that the guidelines
also apply to diabetics because their risk for vascular disease is higher than that of
the general population.
Even though statins are frequently required to accomplish treatment objectives
for serum cholesterol concentrations, potential lifestyle changes should always be
taken advantage of and remain the primary therapeutic strategy to attain an ideal
lipid profile. The strength of the supporting data for the suggested levels of fat
4 4
consumption or fat modification, respectively.
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Reduction Of Saturated Fatty Acids
For persons on a diet intended to maintain their weight, it is advised that saturated
fatty acids could be substituted with either carbohydrate items high in fiber or
unsaturated fatty acids, particularly cis - monounsaturated fatty acids. In comparison
to diets high in saturated fat, these diets have been proven to improve glycemia,
insulin sensitivity, and serum lipid levels.
Omega-3-Fatty Acids
The use of n-3 polyunsaturated (omega - 3) fatty acids is recommended because they
may lower serum triglycerides and have positive effects on platelet aggregation and
thrombogenicity, providing cardioprotective effects. To get an appropriate intake
of omega-3 fatty acids, consume two to three portions of oily food each day from
sources including nuts, soy, and rapeseed.
Trans-Fats And Dietary Cholesterol
Unfortunately, the amount of trans-unsaturated fatty acids in many dietary products
is not adequately reported in the majority of countries.
When it comes to boosting LDL cholesterol, trans fats have effects that are just as
harmful as those of saturated fatty acids. Therefore, it is advisable to limit your
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intake. Numerous produced goods, including biscuits, cakes, candies, soups, and
even hard margarine, contain trans fats. The ranking of ingredients on the food
label provides at least some insight into whether high amounts of trans-fats may
play a role. Food labeling provides information on whether hydrogenated fats and
oils were added to a food product.
The advice to limit dietary cholesterol is supported by research on both healthy and
T1DM patients. Serum cholesterol levels may rise with increased ingestion and aid
in the emergence of CVD.
Current Fat Consumption Among Diabetics
The EURODIAB Complications Study’s data on the fat consumption of Europeans
with T1DM showed that, on average, the current objective to restrict the intake of
saturated fatty acids below 7% of total energy was not met. In the entire cohort
of this study, the mean intake of saturated fatty acids was 14% of total energy,
which is twice the amount advised by the ADA (Figure 4.3). Even patients from the
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Mediterranean region, who have historically consumed a healthy amount of fat, no
longer meet the target to keep their saturated fat intake below 7%.
Figure 4.3: Saturated fatty acid consumption (% of calories) in people with
type 1 diabetes (total n = 1102) from 21 European locations. The ADA’s
current upper limit of consumption for saturated fatty acids is indicated by
the solid vertical line (7% total energy). The Diabetes and Nutrition Study
Group of the European Association for the Study of Diabetes (DNSG EASD)
suggested a 10% total energy limit for saturated fatty acids in 2004. This limit
is represented by the dashed vertical line
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 In conclusion, fat modification continues to be a key nutritional education issue to
help people with both T1DM and T2DM lower their risk for vascular disease.
Dietary Protein
There isn’t enough proof to suggest that people with diabetes and normal renal
function should modify their usual protein intake. There appears to be little worry
that persons with diabetes may develop protein deficiency, according to nutrition
consumption statistics from various nations and patient groups (Table 4.4). It is
unknown, though, whether a long-term high protein intake that exceeds 20% of
total calories would be harmful to renal function. Although these diets might lead
to temporary weight loss and better glycemia, it is unknown whether these benefits
are sustained over the long run.
Therefore, at this moment, it is not advised to lose weight using a high-protein diet.
4 4
Protein Restriction
MANAGEMENT OF DIABETES
Protein restriction has been the subject of several research looking at how to stop
or slow the progression of proteinuria in diabetics. By enhancing glycemic control,
reducing blood pressure, and maybe reducing protein intake, diabetes problems
may be prevented from progressing. The risk of developing diabetic nephropathy
does not seem to be enhanced with normal protein intake (15–20% of calories). A
reduction in protein intake to about 0.8 g/kg body weight/day was found to favorably
influence urinary albumin excretion rates and declines in glomerular filtration in
some studies of subjects, particularly those with T1DM and macroalbuminuria;
however, there is insufficient evidence to make recommendations about the ideal
type of dietary protein.
Micronutrients
To ensure that recommended vitamin and mineral requirements are met, regular
consumption of a range of vegetables, fresh fruit, legumes, low-fat dairy products,
vegetable oils, nuts, whole grain breads, and oily fish should be promoted.
Consumption of salt or sodium should be kept to a minimum, especially if high
blood pressure is a concern. In hypertensive persons with T2DM, replacing
additional salt with salt replacements made of potassium and magnesium has been
demonstrated to significantly lower systolic blood pressure but not diastolic blood
386
pressure. Such alternatives may be attempted on a small number of patients, but
they cannot generally be advised to control high blood pressure in diabetics.
Numerous research have looked into the possible benefits of advising the intake
of antioxidant vitamins for people with diabetes because they may experience
increased oxidative stress. These studies fell short of demonstrating a definite
benefit from supplementation.
Therefore, due to concerns about long-term safety, routine supplementation is not
recommended (e.g., of vitamins E, C, and carotene). Additionally, the impact of
supplemental folate in lowering cardiovascular events is unclear and is actively
being researched. Diabetes groups do not advocate using functional foods or
supplements in light of the most recent research.
The majority of the fiber-enhanced products being advertised, as well as margarines
with plant sterols or stanols, supplements with various n-3 fatty acids, minerals,
trace elements, and herbs, some of which have been shown to have potentially
MANAGEMENT OF DIABETES
useful functional effects, have not undergone formal long-term clinical trials.
They cannot be advised as long as there is insufficient proof from randomized
studies to show a significant benefit without creating unfavorable side effects.
Supplementing with vitamins or minerals at pharmacologic doses should be seen
as a therapeutic intervention and is only advised in situations where a deficiency
has been established.
It would seem that dietary vitamin D consumption, sun exposure, and vitamin D
levels should be examined given the significance of vitamin D in bone metabolism
and the skeletal effects associated with diabetes. For those with T1DM and T2DM,
nutrition education is crucial to promoting good eating and ensuring that necessary
intakes are met.
Alcohol
Alcohol may have both negative and positive effects that have a U-shaped
connection. A moderate intake (5 to 15 g/day) is linked to a lower risk of coronary
heart disease, but excessive regular alcohol use (> 30 to 60 g/day) is strongly linked
to unfavorable elevated blood pressure in both men and women. While the type of
alcohol-containing beverages drunk does not seem to be particularly significant, the
387
 amount of alcohol ingested appears to be predictive. If people with diabetes decide
to drink, they should limit their consumption to no more than 10 g for females
and 20 g for males each day. Nutrition associations also advise healthy people to
adhere to these limitations. Alcohol consumption by diabetics with food containing
carbohydrates did not have any immediate effects on blood glucose levels. The
potential danger of alcohol-induced hypoglycemia prompts the recommendation
to ingest carbohydrates when alcohol is consumed, especially for patients who are
treated with insulin or insulin secretagogues.
The risk rises as more alcohol is drunk and may persist well into the next day.
Pregnant women, persons with a history of pancreatitis or alcohol misuse, people
with hypertriglyceridemia, and people with severe neuropathy are all recommended
to abstain from alcohol.
Alcohol may also be a significant energy source that overweight people should take
4 4
into account. Independent of BMI, heavy alcohol use is linked to a higher waist-
to-hip ratio.
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Diet In Unique Situations
Diet in pregnancy
It is crucial to achieve blood glucose concentrations as close to normal as possible
without causing hypoglycemia in order to prevent fetal and maternal problems. In
order to achieve the desired fasting blood glucose range of 60 to 90 mg/dL (3.3 to
5.0 mmol/L) and postprandial readings below 120 mg/dL (6.7 mmol/L), nutritional
therapy should be used. Women with known T1DM as well as women who develop
gestational diabetes during pregnancy require thorough dietary counseling as a
crucial component of therapy to achieve this goal. Energy consumption must be
sufficient to promote healthy weight gain, and nutritional intakes must take into
account unique requirements during pregnancy. Pregnant women with normal
weight may need to consume an additional 70–240 kcal per day in the first and
second trimesters and 300 kcal in the third. Obese pregnant women should consume
less extra calories, but their daily energy needs should not fall below 1600 kcal.
Hyperglycemia, ketonemia, and starving ketosis should all be avoided while
pregnant. Folic acid supplementation is advised for all expectant mothers in
order to avoid neural tube abnormalities. Due to their increased risk of neural
tube abnormalities, women with diabetes should take greater dosages of folate
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supplements (5.0 mg vs. 400 g), according to some organizations (such as the
National Institute for Health and Clinical Excellence). To prevent deficiencies,
additional dietary supplements of calcium, iron, and iodine may be taken on an
individual basis (Table 4.4).
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Table 4.4: Pregnancy diet
Diet in diabetic children
Dietary advice should emphasize achieving desired blood glucose levels without
experiencing severe hypoglycemia. Energy and nutrient intakes should be sufficient
to ensure normal growth and development, as they should be for all healthy
youngsters. Maintaining normal serum cholesterol readings and blood pressure
targets may be aided by a healthy diet. To promote appropriate food intake decisions
and flexible insulin dosages based on blood glucose self-monitoring, individualized
counseling is required.
To account for the family’s eating habits and food preferences, meal plans must be
customized.
The two main areas of instruction for children with T1DM and their parents are
meal planning and premeal insulin administration. Growth rates must be monitored,
and the evaluation of a meal plan must be updated at least once a year because
energy requirements fluctuate as people age. Calorie intake needs to be limited in
cases where the youngster gets overweight. The child with diabetes must also learn
that early indications of hypoglycemia require immediate intake of a carbohydrate
389
 (glucose), and that unusual exercise necessitates blood glucose monitoring before
and after exercise, which should be used to guide any potential additions of extra
carbohydrates or adjustments to insulin dosage. Diabetes already affects 382 million
adults worldwide (8.3%), and by 2035, it’s expected to affect more than 592 million
people. Healthcare for people with diabetes cost at least 147 billion USD in Europe,
whereas 263 billion USD were spent in North America and the Caribbean in 2013.
For those under the age of 60, diabetes has grown to be a leading cause of death.1
To combat this global epidemic, investment in efficient diabetes prevention and
control is now required. Numerous nations have seen dietary shifts that encourage
higher calorie intake along with urbanization and economic expansion.

Transition In Nutrition And Dietary Patterns Worldwide Figure 4.5: Global dietary trend changes over time
Urbanization and environmental changes, such as shifts in work patterns from
Quantity And Quality Of Dietary Fat
physically demanding to sedentary employment, increasing computerization and
4 Results from metabolic investigations in humans do not support the hypothesis 4
mechanization, and improved transportation, have all been linked to the type 2
that high-fat diets per se have a negative impact on insulin sensitivity. It has been

MANAGEMENT OF DIABETES
diabetes epidemic on a large scale. Food production, processing, and distribution
MANAGEMENT OF DIABETES

postulated that increased total fat intake contributes to diabetes directly by causing
systems have undergone significant changes as a result of economic development
insulin resistance and indirectly by increasing weight gain. Total fat consumption
and environmental changes, which have also expanded the accessibility of unhealthy
was not linked to an increased risk of diabetes in various observational studies.
foods. In recent decades, the number of fast food restaurants has exponentially
In the Women’s Health Initiative, women who followed a low-fat diet did not
increased on a global scale. Due to the growing accessibility of fast food, many
experience a decrease in the prevalence of diabetes when compared to the control
people now consume unhealthily high-calorie meals that are also heavy in processed
group. The type of fat consumed matters more than the amount, and diets that
meat, highly refined carbs, sugary beverages, and bad fats. Large chain supermarket
prioritize plant-based lipids over animal fats are healthier overall. In the Nurses’
saturation, which displaces fresh local food and farm stores and serves as a source
Health Study, increased consumption of omega-6 polyunsaturated fatty acids
of highly processed meals, high-energy snacks, and sugary beverages, has been
(PUFA) was specifically linked to a decreased risk of diabetes.
another important factor in the change of the food system.

Quantity And Quality Of Carbohydrates

A livestock revolution has occurred in areas of the world experiencing
Prospective observational data suggests that the relative carbohydrate content of a
epidemiological change, increasing production of beef, pork, dairy goods, eggs,
diet has no effect on the likelihood of developing diabetes. However, a diet high
and poultry. According to data from the UN Food and Agriculture Organization,
in fiber, particularly cereal fiber, may lessen the chance of developing diabetes.
this trend has been particularly pronounced in Asian nations (Figure 4.5). The
A meta-analysis of prospective cohort studies revealed an inverse relationship
increased refining of grain products is another aspect of the dietary revolution. The
between the risk of type 2 diabetes and fiber from grain products. Fruit fiber had a
fiber, minerals, and phytochemicals in whole grains are lost during milling and
smaller inverse link with diabetes risk compared to fiber from cereal. By assessing
processing to create refined grains like polished white rice and refined wheat flour.
the glycemic reaction to foods high in carbohydrates, such as the glycemic load
(GL) and glycemic index (GI), one can identify the quality of the carbohydrate.

390 391
 Independent of the amount of cereal fiber consumed, low GI and GL diets were
linked to a lower risk for diabetes compared to diets with higher GI and GL in meta-
analyses of prospective studies.
Vitamins and Minerals
Using analyses of dietary consumption and/or biomarkers, emerging data has
substantiated the connections of certain minerals with type 2 diabetes. Magnesium
consumption and risk of diabetes were found to be adversely correlated in a
meta-analysis of prospective studies. Overweight participants showed a stronger
correlation with this than those who were of normal weight. On the other hand,
a larger heme-iron intake was linked to a higher risk of diabetes. Similar to this,
higher ferritin concentrations, which imply higher iron reserves, were linked to a
higher risk of diabetes.
4 in the diet that affect digestion and absorption, all affect how high or low a food’s GI
In a meta-analysis of prospective studies from various populations, an inverse
relationship between circulating 25-hydroxyvitamin D concentrations and diabetes
MANAGEMENT OF DIABETES
risk was discovered. Plasma vitamin D, however, may be a sign of a healthy
lifestyle in general, including regular outdoor exercise and exposure to sunlight.
Additionally, in tiny RCTs, vitamin D supplements had no effect on hemoglobin
A1C (HbA1C), fasting plasma glucose, or insulin sensitivity. More concrete proof
about the contribution of vitamin D to the prevention of type 2 diabetes will come
from ongoing big RCTs.
Beverages
In a meta-analysis and a more recent pooled analysis of European cohorts, higher
consumption of sugar-sweetened drinks (SSBs) has been linked to a higher risk of
type 2 diabetes. This connection holds true even after correcting for BMI, indicating
that body weight is not the only factor in determining how harmful SSBs are for
diabetes. The risk of developing diabetes was reduced when SSBs were substituted
with ordinary water, coffee, or tea.
Alcohol use and diabetes are linked in a U-shaped pattern. According to a meta-
analysis, the daily alcohol consumption levels that were most protective against
diabetes were 24 g for women and 22 g for men. However, alcohol started to be
harmful at consumption levels above 50 g for women and 60 g for men. Moderate
392
alcohol consumption increased insulin sensitivity in a randomized trial. Drinking
coffee has consistently been linked to lower risk. Coffee drinking was found to
be dose-dependently inversely linked with diabetes risk in a meta-analysis of 28
prospective cohort studies. Additionally, consumption of both caffeinated and
decaffeinated coffee was linked to a lower risk of developing diabetes, indicating
that bioactive substances other than caffeine may be to blame for the advantages.
4.2.2 Diet and Blood Glucose Response
The glycaemic index (GI) and glycaemic load (GL) of the diet influence how blood
glucose reacts to specific dietary items. GI is determined by comparing the blood
glucose reaction two hours after consuming 100g of a certain food item to the
blood glucose response two hours after consuming 100g of glucose. Food ripeness,
processing, and cooking techniques, as well as the availability of other substances
4
rating is. GL is computed by measuring the food’s carbohydrate content, multiplying
MANAGEMENT OF DIABETES
by its GI, and dividing by 100. GL depends on the amount of carbohydrate present
in a specific food item for digestion and absorption. A solution to some of GI’s
shortcomings is the concept of GL. It takes into account the glycaemic effects of
food in a typical serving size, which is a more practical measurement. A GI of 55
is thought to be low, >70 to be high, and in the middle to be medium. A GL of 10 is
regarded as low, 20 as high, and somewhere in between as medium.
Numerous studies have demonstrated the positive impact of a low-GI diet on the
treatment of T2DM and its consequences.In numerous studies, low-GL diets have
also demonstrated advantages for controlling T2DM and lowering complications.
4.2.3 Medical Nutrition Therapy
Medical nutrition therapy (MNT), according to the American Diabetes Association
(ADA), is the best coordination of dietary intake with diabetic medication (both
pharmacological and non-pharmacological) to produce a favorable result. MNT
can be utilized to prevent T2DM on a primary, secondary, or tertiary level. In
order to postpone or prevent the emergence of T2DM, high-risk individuals (such
as those with pre-diabetes, obesity, etc.) should adjust their diets. Secondary
preventive strategies are intended to achieve strict glycaemic control through
393
 food modification and, as a result, lower the risk of diabetes complications in
T2DM patients. Those with T2DM should take tertiary preventive measures to
treat diabetes-related consequences including cardiovascular or renal disease.
MNT seeks to improve co-morbid conditions like obesity, dyslipidemia, and
hypertension in addition to blood glucose control. Low GI diets lessen postprandial
blood sugar fluctuations, which enhance glycemic management. A low-calorie diet
and non-nutritive sweeteners may also aid in managing diabetes. Increasing dietary
fiber consumption also enhances glycemic control. Except in cases of deficiency,
routine supplementation with vitamins, antioxidants, and trace minerals is not
advised. Diets that are hypocaloric and low in carbohydrates aid in T2DM weight
management and metabolic control. A trained dietitian with experience in diabetic
MNT should provide individualized MNT to people with pre-diabetes and diabetes.
4 sources of fat are nuts and seeds and cold-pressed extra-virgin olive oil (EVOO);
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Figure 4.6: Steps involved in planning and implementation of medical nutrition
therapy
394
4.2.4 Health Benefits Of A Mediterranean Diet In Diabetes
The MD is essentially a plant-based diet, which is well known for its many health
advantages, particularly in the treatment of cancer and cardiovascular illnesses.
People who have diabetes benefit from the MD as well.
This eating style, collectively referred to as MD, was adopted in the Mediterranean
region’s olive-growing areas in the late 1950s and early 1960s (particularly in
Greece and Italy). It is used to define the traditional eating style of people who
live in nations surrounding the Mediterranean. Cooking with seasonal and local
ingredients and interacting with others over meals are characteristics of the
traditional Mediterranean diet. It includes a daily abundance of vegetables, a variety
of minimally processed whole grain bread and other cereals and legumes as the
staple food, nuts and seeds, and fresh fruit as the typical daily dessert; sweets made
of nuts, olive oil, and honey are only consumed on special occasions; the main
4
and the amount of dairy products consumed is low to moderate (mostly local cheese
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and yogurt).
Effects of the Mediterranean Diet on the Incidence and Control of Type 2
Diabetes
Insulin resistance, which occurs when you have diabetes, is the inability of your
body to produce or use insulin as it should and maintain normal blood sugar levels.
Your blood sugar levels will surge as a result, which over time may create major
problems. The Mediterranean diet can help lower insulin resistance because it is
high in plant-based foods and low in processed ones. Better blood sugar control
and reduced A1C readings are the results of this. Eating in a Mediterranean fashion
can also benefit:
● Boost cardiovascular health. Both sodium and saturated fats are detrimental
to your heart. They can raise blood pressure and cholesterol levels. You
should restrict the number of these foods in your diet because heart disease
is one of the most prevalent complications of diabetes. You can lower your
risk of heart disease and stroke by eating in a Mediterranean-style.
● Fiber-rich foods are emphasized in Mediterranean cuisine. Fiber aids
in controlling blood sugar and weight. Being physically active is also
395
 encouraged by the Mediterranean way of life. Being active reduces your
chances of heart disease and nerve damage and helps to regulate blood
sugar levels.
● Cut the inflammation. Diabetes-related high blood sugar can lead to
inflammation. Olive oil, fruit, fatty salmon, and leafy green vegetables can
all assist to reduce inflammation and boost your immune system.
4.2.5 Dietary Interventions of Type 1 Diabetes Patients
basal insulin and rapid-acting insulin as bolus doses. Contrarily, utilizing fixed
dosages of short- and intermediate-acting insulin necessitates higher consistency in
time and amount of carbohydrate intake.
Patients who use insulin pumps or short-acting insulin analogs may need to
administer additional bolus injections of insulin with snacks that include more than
10-15 g of carbohydrate.
There are a number of meal planning strategies, such as carbohydrate counting, the
exchange system, and sample meal plans, that can be used to attain carbohydrate
consistency.

MNT is a crucial element of diabetes self-management training and management.

Based on their age, medical history, lifestyle, and personal characteristics, nutrition Carbohydrate counting
recommendations should be customized for persons with T1DM, taking into The following are the techniques for counting carbohydrates:
account any comorbid diseases they may have in addition to their diabetes. An When reading food labels, pay attention to the grams of carbs listed.
individual’s culture, beliefs, eating habits, and access to food should all be taken The estimation of carbohydrate content can be divided into three dietary groups—
4 4
into account. carbohydrate, meat and meat substitutes, and fat—whose carbohydrate contents

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are standardized according to certain quantities. The calories and macronutrient
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The ideas underlying the current dietary guidelines for kids and teens with diabetes
mellitus are the same ones established for all healthy kids and teens without the content of exchange lists are displayed in Table 4.5. The exchange lists also note
disease. In order to satisfy the necessary nutrient intakes for calories, fiber, and key foods that are high in salt and those that are good sources of fiber.
vitamins and minerals, customized meal plans should place an emphasis on a wide
range of healthy food options.
The following information should be given to the patient:
● observing the agreed-upon meal schedule
● insulin and/or dietary changes in response to hyperglycemia
● modifying insulin dosage to account for meal size and composition, and
properly treating hypoglycemia
Following are the glycemic objectives for diabetics:
● BG during a fast: 90–130 mg%
● two hours after eating; blood glucose level of less than 180 mg%
● Glucose excursion: BG was 30–50 mg% higher two hours prior to the meal.
● HBA1c: under 7 mg%
To prevent changes in blood glucose, variations in meal consumption, particularly
carbohydrate, should be reduced. When carbohydrate intake is decreased, medication
or insulin dosages must be decreased as well. The flexibility of adjusting the insulin
dose in response to carbohydrate intake is made possible by utilizing long-acting Table 4.5: Exchange lists’ calorie and macronutrient content

396 397
 Use illustrative menus: These are predetermined meal menus that outline the
timing and serving sizes for each meal and snack. Medical nutrition therapy
(MNT) objectives and food preferences are frequently incorporated into the menus
by dietitians. After reviewing a person’s regular food intake, sample menus are
developed; these are most suited for individuals who have fairly consistent eating
patterns and who don’t consume a broad variety of foods. They are also suitable for
those who require organized advice on what to eat.
Insulin adjustments with food intake
The focus of carbohydrate counting at a more advanced level is on adjusting food,
insulin, and activity based on patterns from meticulous logs. The time of meals
and snacks, the quantity and kind of food ingested, the amount of carbohydrates
consumed, the dose of insulin, physical activity, and blood glucose results must all
be noted by the patient. In order to match baseline insulin requirements to typical
4 4
carbohydrate consumption using pre- and postprandial blood glucose testing
findings, patients should first practice consuming regular amounts of carbohydrate
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during meals and snacks. Following are the insulin-to-carbohydrate ratios that
can be calculated when pre- and postprandial blood glucose levels are within the
desired range.
Another method for calculating insulin-to-carbohydrate ratios is the 450-500 rule:
Calculate the insulin-to-carbohydrate ratio using the 450-500 rule as follows:
450 divided by the total daily dose (TDD) of insulin is the normal insulin-to-
carbohydrate ratio.
500 divided by the insulin TDD is the rapid acting insulin to carbohydrate ratio.
Treatment for hypoglycemia: 10–30 g of fast-acting carbohydrates should be
consumed if the patient has hypoglycemia (blood glucose 70 mg/dL). Retesting and
retreating are necessary until blood glucose levels increase to >70 mg/dL, without
overtreating; at that point, the patient continues taking the prescribed amounts of
insulin and eating the recommended amounts of carbohydrates.
Weight management in T1DM
For a certain patient, the relative significance of calorie intake depends on a number
of variables, including the following:
● Relationship between current weight and ideal and healthy body weight
(BW)
398
● The distribution of fat and waist size
● A1C, or glycated hemoglobin
For overweight (body mass index [BMI] 25-29.9 kg/m2 and obese (BMI 30 kg/m2)
people with diabetes, reducing calorie consumption and causing weight loss are
crucial since these patients are at a higher risk of developing comorbidities linked
to excess adipose tissue.
The Centers for Disease Control and Prevention (CDC) offers pediatric growth
charts and national growth curves that can be used to measure weight gain, BMI,
and growth patterns in children and adolescents.
Gaining weight while receiving high doses of insulin
Weight gain is a potential side effect of intensive insulin therapy and happens when
the amount of insulin given is equal to the amount of food consumed and glycosuria
is stopped.
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In order to prevent weight gain with the intensification of diabetes therapy, calorie
intake must be reduced by an additional 250–300 calories per day if A1C is high
enough to produce glycosuria. Instead of increasing meal sizes or including
unwanted snacks, another way to limit weight gain with intensive therapy is to cut
insulin doses particularly for hypoglycemic patterns. Reduced fat consumption and
steady carbohydrate intake can help reduce calories even more while lowering the
risk of hypoglycemia.
Calculating calorie requirements to encourage weight loss
A daily deficit of 500–1000 calories from weight maintenance calories would result
in weekly weight reduction of 1-2 pounds. To ensure that nutritional demands are
met, low-calorie diets (less than 1200 kcal/day) should be avoided.
There is debate over the ideal macronutrient makeup of the diet for diabetic patients.
However, in general, daily energy intake should be aimed to include 50-55%
carbohydrate, 10-15% protein, and 30-35% fat. This mixture of dietary car-
bohydrate, protein, and fat may be changed to fit the metabolic objectives
and individual preferences of the person with T1DM.
399
 All appropriate diets include low-fat, low-carb, Mediterranean, and vegetarian
options.
Planning meals specifically for each person should optimize food selections to
fulfill the RDA/dietary reference intake (DRI) for all micronutrients.
For infants aged 0 to 6 months, 95 g for those aged 7 to 12 months, and 130 g for
kids and teenagers, the RDA/DRI is 60 g. For children older than 1 year, diets with
less than 130 g of CHO may not supply enough glucose to the central nervous
system without relying on gluconeogenesis from ingested protein and fat. The
vital minerals, energy, and fiber that are contained in carbohydrates found in whole
grains, fruits, vegetables, dried peas and beans, legumes, nuts, seeds, low-fat milk,
and yogurt are also restricted by low-carbohydrate diets.
A crucial tactic for attaining glycemic control continues to be monitoring
4 4
carbohydrates, whether through carbohydrate counting, a choice, or experience-
based estimation. Monitoring carbohydrate consumption is crucial because it
MANAGEMENT OF DIABETES
directly affects postprandial blood sugar levels. Insulin titration as a result can
enhance glycemic control.
For diabetics, using the glycemic index and glycemic load may offer a slight
improvement in glycemic control over what is seen when total carbohydrate is
taken into account alone. Better glycemic management is achieved with meals that
have a low glycemic index and load.
The best sources of carbohydrates are those found in fruits, vegetables, whole
grains, legumes, and low-fat milk.
When ingested within the daily limits set by the US Food and Drug Administration
(FDA), nonnutritive sweeteners are safe. Although there are no comparable studies
done on children, consumption of nonnutritive sweeteners did not result in higher
blood glucose levels or a different insulin response in adults. One-half of the
sugar alcohol content should be taken into account when estimating the overall
carbohydrate content of a product. Foods containing artificial sweeteners should
always be carefully inspected as they still contain carbs.
Sucrose can be exchanged for other carbohydrate sources in the meal plan or, if
400
added, covered with insulin; nevertheless, care should be given to avoid excessive
calorie intake. Foods that contain sucrose frequently lack necessary nutrients and
typically offer extra calories from fat. Consuming these foods in moderation within
the framework of a healthy, well-balanced diet should be the main focus of nutrition
therapy efforts. There is no need to avoid the naturally occurring fructose found in
fruits and vegetables, however it is not advised to use added fructose as a sweetener
because it may negatively alter lipids.
Sucrose can be substituted for other forms of carbohydrates in the meal plan or,
if added, covered with insulin; nevertheless, care should be made to avoid excess
calories. Sucrose intake does not need to be restricted. Foods high in sucrose
frequently lack vital nutrients while also offering extra calories from fat. In the
framework of a healthy, well-balanced diet, nutrition therapy programs should
emphasize consuming these foods in moderation. Although the use of added
fructose as a sweetener is not advised because it may negatively impact lipids, there
is no reason to avoid the naturally occurring fructose found in fruits and vegetables.
MANAGEMENT OF DIABETES
The National Cholesterol Education Program and the American Heart Association
recommend a diet low in saturated fat for all children and adolescents since it lowers
the risk of cardiovascular disease in those with T1DM. Less than 7% of total calorie
consumption should be from saturated fat. Due to their relatively cardioprotective
profile, monounsaturated (about 20%) and polyunsaturated fatty acids (about 10%),
such as those found in fish, olive oil, and nuts, can replace saturated fats (such as
those found in fatty and processed meats, butter, lard, hydrogenated fats, coconut
and palm oils, cheese, ice cream, and other high-fat dairy products). Olive, canola,
and peanut oils, as well as nuts, seeds, avocados, and olives, are some sources.
Trans-fatty acid intake should be reduced since it causes a decrease in low-density
lipoprotein and an increase in high-density lipoprotein. Margarine and processed
and professionally cooked meals have added trans-fatty acids. 200 mg or less of
total cholesterol per day is recommended. Meat-based meals are the only sources
of dietary cholesterol.
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in particular, have
emerged as crucial dietary adjuncts for those at risk of cardiovascular disease as
401
 well as for adults who have previously had a cardiovascular event. Omega-3 fatty
acids from marine sources are currently recommended by the American Heart
Association as a dietary supplement to help lower serum triglycerides, which can
be used safely in kids with diabetes and hypertriglyceridemia. An great source
of omega-3 fatty acids is eating two or more servings of fish per week. Salmon,
tuna, herring, sardines, mackerel, flax seeds, flax oil, different nuts, and canola and
soybean oil are additional powerful sources.
The RDA for all children and adolescents serves as the basis for protein intake
in those with normal renal function. A typical daily intake of protein should be
between 10 and 25 percent of total calories consumed (1.1 g/kg/d).
Lean meat, fish, eggs, legumes, nuts, seeds, low-fat dairy products, beans, peas, and
other legumes should all be advocated as red meat alternatives for patients.
Protein consumption should not be utilized to treat or prevent nocturnal
4 4
hypoglycemia.
Protein intake should be decreased in patients with microalbuminuria to 0.8–1 g/
MANAGEMENT OF DIABETES
kg/d of body weight in order to halt the development of nephropathy. Protein intake
must be decreased to 0.8 g/kg/d due to overt nephropathy.
The recommended daily fiber consumption is at least 14 grams per 1000 calories, or
19 to 38 grams. Diets high in fiber have been shown to lower postprandial glucose
levels in young people with T1DM. Whole grains, fruits, vegetables, dried peas,
beans, legumes, nuts, and seeds all include dietary fiber. Studies in persons without
diabetes reveal that meals high in total and soluble fiber (7-13 g) can reduce total
cholesterol by 2-3% and LDL cholesterol by up to 7%. Therefore, soluble fiber
sources should be prioritized. Oatmeal, oat cereal, lentils, apples, oranges, pears, oat
bran, strawberries, almonds, flaxseeds, beans, dried peas, blueberries, cucumbers,
celery, and carrots are all excellent sources of soluble fiber.
Because there isn’t enough proof of their effectiveness and there are questions about
their long-term safety, it’s not advisable to regularly supplement with antioxidants
like beta-carotene, vitamins E, and C.
Children and adolescents with T1DM are generally associated with low
serum 25-hydroxyvitamin D concentrations. Therefore, vitamin D testing and
supplementation should be explored, and the RDA of 600 IU of vitamin D daily
402
should be met. If a person consumes a well-balanced, healthy diet, supplementing
with vitamins and micronutrients generally is not necessary unless there are
underlying deficits.
Glycemic index and glycemic load
The glycemic index (GI) of a food is a numerical measurement that compares the
item’s glycemic response to that of a reference food, such as pure glucose. The
reference food has a GI of 100. Foods with GI > 70 are regarded as high glycemic
index foods, whereas those with GI 55 are regarded as low glycemic index foods
when glucose is used as the reference food. Non Starchy vegetables, nuts, legumes,
and some grains, such barley and converted rice, are a few examples of foods with
a low glycemic index. Potatoes, sweets, white bread, and other refined grain goods
have a high glycemic index.
The glycemic load of a food is calculated by multiplying its total carbohydrate
MANAGEMENT OF DIABETES
content by the food’s glycemic index rating. The glycemic load idea was created
because both the quantity and quality of the carbohydrates consumed have an
impact on how the body reacts to them in terms of blood glucose levels.
Greater health effects than just glycemic control may result from the glycemic
index and glycemic load. Diets high in glycemic index and glycemic load have
been linked in a number of prospective studies to an increased risk of type 2
diabetes, coronary heart disease, and certain malignancies. Furthermore, evidence
points to the fact that low-glycemic load diets are particularly effective for the most
vulnerable people—those who are already obese and insulin resistant.
Eating disorders
Diabetes patients often struggle with eating issues, particularly female teens and
young adults with the disease. The most typical methods for losing weight are
dieting, skipping insulin, and binge eating. Eating disorders negatively affect these
patients’ long-term outcomes and glycemic control. It’s critical to assess diabetic
patients—especially young women—for eating disorders or inaccurate reporting
of insulin delivery, and when necessary, to set up the proper nutritional and
psychological assistance and counseling.
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 4.2.6 Physical Activity For Patients With Type 1 & 2 Diabetes Mellitus
Exercise on a regular basis improves insulin sensitivity in people with and without
diabetes.
During low to moderate intensity exercise, plasma insulin levels fall in people
without diabetes to make up for gains in insulin sensitivity. In order to maintain
blood glucose homeostasis, both glucose synthesis and disposal rise concurrently.

Exercise Regimen Types And Their Effects On Healthy Individuals

Aerobic Exercise
Regular aerobic exercise typically improves cardiac output and lung function,
which makes it possible to give working muscles more oxygen. Increased muscle
blood flow during peak exertion is made possible by the muscles’ higher plasma
volume and higher capillary density. Eventually, as the oxidative metabolic system
4 4
becomes more efficient, a change in the fuels used to meet the energy requirements Figure 4.7: The relative contributions of blood-borne glucose, non-esterified
of activity can be observed. Changes are typically more obvious with increasing

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MANAGEMENT OF DIABETES

volume and intensity training.
Muscle glycogen serves as the body’s primary energy source during the first five
to ten minutes of activity. The bloodborne substrates, glucose and non-esterified
fatty acids, become more significant as exercise continues. If moderate-intensity
exercise is performed for several hours, non-esterified fatty acids replace glucose
as the main fuel source (Figure 4.7).
Blood glucose levels basically remain steady after moderate-intensity aerobic
exercise. In order to fulfill the demands of the working muscle, insulin secretion is
decreased while glucagon release is encouraged. This results in a two- to fourfold
increase in hepatic glucose synthesis, which is regulated by the glucagon:insulin
molar ratio at the portal vein.
During the “recovery” phase following exercise, glucose synthesis and utilization
drop quickly and parallel to baseline as insulin levels rise and glucagon secretion
falls. A prolonged period of moderately intense aerobic activity without calorie
intake causes the blood glucose level to drop and finally cause hypoglycemia
because hepatic glucose synthesis is unable to keep up with the increased use.
fatty acids (NEFA), and muscle glycogen breakdown and uptake to fuel
utilization at different phases of continuous low-intensity exercise in a healthy
person. The level of workout intensity is 30% of the maximum
In the presence of normal glucose tolerance, aerobically trained athletes without
diabetes exhibit low fasting plasma insulin levels, lower insulin responses to a
glucose challenge, and enhanced insulin-mediated glucose uptake during glucose
clamp conditions. In previously untrained people, physical training has also been
shown to boost muscle and hepatic insulin sensitivity. With consistent exercise,
lipid and lipoprotein levels become less atherogenic: serum levels of high density
lipoprotein (HDL) cholesterol may rise while total and low density lipoprotein
(LDL) cholesterol levels may stabilize or even decrease. According to certain
research, exercising lowers blood triglyceride levels.
Anaerobic Exercise
Regular anaerobic exercise enhances the body’s capacity to supply the fuels required
for anaerobic power production. The levels of phosphocreatine and adenosine
triphosphate (ATP), the two main fuels for brief, intense bursts, rise in muscle
tissue, enabling the person to maintain higher absolute exercise intensities for
longer periods of time. Hepatic glucose synthesis may outpace the rate of glucose

404 405
 consumption during highly strenuous exercise (more than 80% of V-O2max, a level
most people can only sustain for 15 minutes), resulting in a 5 to 10 times increase
in blood glucose. Hyperglycemia frequently develops during recovery from really
strenuous exercise in fit people without diabetes because glucose use declines
more quickly than glucose synthesis. Plasma insulin levels rise in response to the
hyperglycemia, and glycemia returns to normal within 45 minutes.

Exercise’s Effects On Metabolism And Hormones In People With

Diabetes
T1DM
In people with type 1 diabetes mellitus (T1DM), higher levels of habitual physical
exercise are linked to a lower incidence of diabetes-related complications and a
lower mortality rate. To determine the prevalence of complications and mortality,
4 548 patients with T1DM were followed for 7 years in a prospective research. 4
Inverse correlation existed between baseline self-reported exercise levels and the

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MANAGEMENT OF DIABETES

risk of microvascular problems.
After controlling for age, body mass index, smoking, and diabetes comorbidities,
sedentary male patients had a threefold higher mortality rate than those who were
active (Figure 4.8). Females showed a similar association that was statistically non-
significant.
Studies have also revealed a negative correlation between physical activity and
the severity of a number of T1DM problems. A longitudinal research of 1680
people with T1DM found an unfavorable relationship between self-reported levels
of physical activity during free time and tests of insulin sensitivity and glycemic
management. When compared to research participants with higher levels of
activity, women with diabetes who engaged in less physical activity during their
free time tended to have worse glycemic control. Estimates of insulin sensitivity
were likewise greater among men and women who were more physically active.
Figure 4.8: Men’s mortality rates throughout a 7-year follow-up period among
548 type 1 diabetic patients, stratified by quintiles of physical activity. The cut-
offs for the Quintile were as follows: 398, 398 - 1000, 1000 - 2230, 2230 - 4228,
and > 4228 kcal/week. The differences between the groups are very important.
When compared to their more frequently and vigorously active counterparts, those
who engaged in either little or low-intensity physical activity during their free time
were more likely to have impaired renal function, a higher degree of proteinuria,
as well as higher rates of retinopathy and cardiovascular disease. More recently, a
randomized research demonstrated that regular exercise can slow the evolution of
diabetic peripheral neuropathy over a 4-year period and prevent its beginning.
An individual with diabetes may react differently to physical activity depending
on a number of factors, including the type, dose, and site of pre-exercise insulin
injections, the type and timing of the previous insulin injection, as well as the
timing of the meal and exercise (Figure 4.9).

As a result, blood glucose levels may decrease (the most typical response during
moderate aerobic exercise), rise (especially during very intensive exercise), or stay
the same (Table 4.6).

406 407
 4 4
MANAGEMENT OF DIABETES
Figure 4.9: While healthy individuals (as well as patients with type 2 diabetes)
demonstrate a consistent fall during moderate intensity aerobic activity,
patients with insulin-treated diabetes may have broad variations in plasma
insulin levels after exercise.
When the peak activity of a short-acting insulin analog (1), traditional
soluble (regular) insulin (2), or intermediate-acting insulin (3) occurs during
exercise, or if exercise itself accelerates the absorption from the injection
site (4), hyperinsulinemia and hypoglycemia may result. If intermediate or
long-acting insulin has been delivered a few hours before to exercise, or if
the patient is using an insulin pump, steady-state yet increased plasma insulin
concentrations may happen (5). When the previous injection depots are used
up, declining levels (6) or hypoinsulinemia (7) take place.
408
MANAGEMENT OF DIABETES
Table 4.6: The variables affecting a type 1 diabetic’s glucose reaction to
acute exercise
As a result of the enhanced muscle insulin sensitivity brought on by exercise, insulin
production decreases during moderate-intensity aerobic activity in people without
diabetes, but this physiologic fall in insulinemia is not possible in T1DM because
all of the insulin is exogenous. Insulin speeds up the exercise-induced stimulation
of glucose uptake into the contracting muscle while attenuating the appropriate rise
in hepatic glucose production.
There are numerous causes of hyperinsulinemia (Figure 4.10). The maximal activity
of regular insulin administered a few hours earlier may occur during exercise.
Exercise increases insulin absorption, therefore if the previously injected leg is
exercised, the impact is amplified. Furthermore, when intermediate or long-acting
insulin is used, peripheral insulin levels are often greater than they would be in a
person without diabetes with a comparable body composition. Unless the insulin
dose before exercise is reduced or more carbohydrate is ingested, the outcome is
frequently hypoglycemia. The typical increase in lipid mobilization that occurs
during exercise can also be prevented by hyperinsulinemia, which reduces the
409
 availability of non-esterified fatty acids as a fuel. glucose. People with T1DM may use less hepatic glycogen during low-intensity
Conversely, if insulin levels are too low, both insulin’s stimulating action on glucose aerobic activity compared to people without diabetes.
uptake and its inhibitory influence on hepatic glucose synthesis are diminished. Blood glucose levels will drop and the risk of hypoglycemia will increase if
Additionally, when there is an insulin deficiency, the counter-regulatory response
the pace at which glucose enters the system is not high enough to meet the
(catecholamines, glucagon, growth hormone, and cortisol) to exercise is higher
demand.
than usual. Hyperglycemia is the end outcome, which is a considerable increase in
hepatic glucose synthesis and a decrease in glucose uptake by the working muscle.

Regular aerobic exercise’s effects on type 1 diabetes

Patients with long-term T1DM experience variable degrees of impaired insulin
sensitivity. Regular exercise training increases whole-body insulin sensitivity in
these patients, just as it does in those without diabetes, which may assist to induce
and extend remission in T1DM that has just started to manifest. Given that the results
of exercise intervention have been uneven, it has been challenging to determine
4 4
whether or not regular aerobic exercise improves glycemic control in T1DM.

MANAGEMENT OF DIABETES
While some trials have shown benefits in blood glucose management as measured
MANAGEMENT OF DIABETES

by drops in HbA1c, even though these gains were not statistically significant, the
majority of studies have either shown no changes at all or have increased HbA1c.

The main cause of this is either excessive insulin dosage decreases or excessive
carbohydrate eating before exercise in an effort to prevent hypoglycemia. It is
crucial to note that participants in numerous studies continued to benefit from
many exercise-related effects, such as reduced body fat percentage, increased
muscle mass, increased aerobic capacity, improved lipid profiles, and improved
insulin sensitivity (leading to a reduced need for exogenous insulin). When low
insulin and euglycemia are present, people with T1DM can choose their fuels for
mild to moderate exercise in a manner that is quite comparable to that of people Figure 4.10: The type of insulin used and the amount of time between the
without diabetes, with an eventual shift towards lipid oxidation as exercise duration injection and the exercise affect insulin concentrations during exercise. During
increases.
early activity, serum insulin concentrations are higher after lispro (Humalog)
In contrast, muscle, adipose, and liver cells will continue to absorb glucose for
insulin analog injection (A) than after standard soluble insulin (S), whereas
storage if the amount of circulating insulin is too high, rather than making it
the opposite is true during delayed exercise. 30 minutes after breakfast,
available for working muscles.
soluble insulin was administered, followed by lispro insulin 5 minutes later,
Despite the fact that T1DM patients can still create glucagon, the ratio of glucagon and exercise was begun either 40 minutes (early) or 180 minutes (late) after
to insulin in the portal vein may not be high enough for the liver to produce enough breakfast. * P < 0.05.

410 411
 The fuels consumed during aerobic exercise will also depend on the insulinemia also lower. In one trial, people with T1DM were given either 12 weeks of weight
and glycemia levels. Without protecting glycogen reserves, hyperinsulinemia can training or an equivalent amount of time of aerobic exercise. Although the waist
make it more difficult to use exogenous glucose during moderate aerobic exercise. circumference, insulin dosage, and self-monitored blood glucose levels decreased
The contribution of carbohydrates to overall energy metabolism during exercise in both groups following the training session, these variables only attained statistical
was higher in hyperglycemia than in euglycemia in a research where insulinemia significance in the aerobically trained group.
was maintained constant. A diminished cortisol and growth hormone response
went hand in hand with the shift in hyperglycemia towards a higher glucose However, the HbA 1c levels in the aerobic training group increased statistically
metabolism during exercise. The levels of insulin, glucagon, and catecholamine significantly (from 8.7 1.6 to 9.8 1.8%; 72 - 84 mmol/mol), whereas the HbA 1c
were comparable across circumstances. levels in the resistance training group decreased non-significantly (from 8.2 2.9 to
7.6 1.6%; 60 - 66 mmol/mol).
Overall, T1DM sufferers appear to rely more on muscle glycogenolysis and
gluconeogenesis than non-diabetics do to provide energy during physical activity.
Despite the challenges of glucoregulation, committed individuals with T1DM can
successfully complete many hours of strenuous aerobic exercise with the right
4 4
insulin and dietary changes. Patients may be at risk for hypoglycemia for several
hours following intense activity, possibly lasting through the night and into the next

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MANAGEMENT OF DIABETES

day. This can be explained by the exercised muscles’ chronically increased glucose
uptake to restore their depleted glycogen stores, although following some types of
prolonged activity, like a marathon run, increased lipid oxidation can remain, as it
does in healthy people.
In this instance, using glucose as a fuel and insulin sensitivity are decreased after
exercise, lowering the risk of hypoglycemia following exercise. Additionally, it
should be emphasized that those who frequently encounter episodes of hypoglycemia
(whether or not due to exercise) may further dull their counter-regulatory reactions
to exercise, potentially starting a chain reaction of hypoglycemic occurrences.

Figure 4.11: Effect of 30 minutes of moderate continuous exercise

Effects of consistent resistance training during rain in type 1 diabetes
Information on the results of training regimens that simply involve resistance
exercise in people with T1DM is scarce. The only study that has been finished so
far used a cross-over design, which entailed 10 weeks of intense resistance training
three times per week followed by six weeks of no resistance training, or vice versa.
At the end of the no-resistance exercise period, the mean HbA 1c was 6.9 1.4% (52
15 mmol/mol), and at the end of the ten-week resistance exercise training period, it
was 5.8 0.9% (40 10 mmol/mol). At the conclusion of the resistance training phase,
serum cholesterol and glucose levels that were tracked by the individual were
(MOD) or intermittent high intensity exercise (IHE) on normalized
blood glucose levels
A few pre-post studies have also looked at the results of mixed resistance and
aerobic training programs in T1DM patients. These studies had generally excellent
results, with advantages including lower HbA1c, lower blood pressure, enhanced
nerve conduction, higher cardiorespiratory fitness, greater muscular strength,
higher lean body mass, and improvements in lipid profiles. However, it should be
highlighted that the absence of concurrent diabetes control groups in these trials

412 413
 limits the interpretation of the results.
T2DM
Higher levels of physical activity and/or cardiorespiratory fitness have consistently
been linked to a lower risk of acquiring T2DM in large prospective cohort studies.
After controlling for confounding factors, people who exercised the most had a
25–60% lower chance of developing diabetes later in life than those who were
the least active. This held true regardless of the presence or absence of additional
diabetes risk factors, such as obesity, hypertension, and a family history of the
disease. When total energy expenditures are comparable, walking reduces risk in
comparable amounts to more strenuous activity.
Numerous clinical studies have shown that structured physical exercise programs
under supervision, with or without concurrent nutritional changes, lower the risk
4 4
of developing type 2 diabetes (T2DM) in people with impaired glucose tolerance
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(IGT). In the non-randomized Malmgren study, 260 men with IGT between the
ages of 47 and 49 were identified by population screening, and a 6 to 12 month
intervention that included supervised exercise programs and dietary counseling
was made available to them. A 5-year follow-up exam revealed that only 11% of
individuals who had received the intervention had developed diabetes, compared
to 21% of the control participants (those who had denied the intervention). Over
a 12-year period, mortality in the control group was 14.0 per 1000 person-years,
whereas it was only 6.5 in the intervention group.
In the Da Qing IGT and Diabetes Study, 577 IGT patients from 33 clinics were
cluster-randomized to receive either a control, a diet-only regimen, a diet-and-
exercise regimen, or a diet-and-exercise regimen. In the diet, exercise, and diet plus
exercise groups, respectively, the cumulative incidence of T2DM was 44%, 41%,
and 46% lower than it was in the control group, which was 68%. A follow-up paper
to the Da Qing Study, written by Li et al., recently evaluated the long-term impact
of the 6-year intervention on the risk of diabetes. They discovered that, compared
to controls, people who had originally been randomized to one of the intervention
groups had a significantly decreased incidence of diabetes 14 years after the trial’s
conclusion.
523 Finnish people with IGT were randomly assigned to an activity and nutrition
414
intervention or a control group in the Finnish Diabetes Prevention Study. Patients in
the control group met with a doctor and dietitian once a year to obtain conventional
dietary and activity recommendations. Individualized exercise programs,
supervised facility-based aerobic and resistance training three times per week, and
seven 1-hour sessions with a dietician with an emphasis on weight loss, reduced fat
intake, and decreased total calorie intake were provided to the intervention group.
At 4 years, only 10% of the intervention group and 22% of the control group,
respectively, had diabetes, a 58% risk reduction. Participants who were initially
randomized to the intervention group maintained significantly greater levels of
physical activity than those who were initially in the control group three years after
the study’s conclusion. People who had previously been in the intervention group
continued to have a 43% lower incidence of diabetes than people in the control
group.
3234 American men and women with IGT were randomly randomized to receive
a placebo, metformin, or a lifestyle modification program as part of the US-based
MANAGEMENT OF DIABETES
Diabetes Prevention Program. The lifestyle modification program’s objectives
included a 7% weight loss and 150 minutes or more of activity each week. In the
first 24 weeks of the lifestyle intervention, there were 16 classes covering diet,
exercise, and behavior modification (given one-on-one by a case manager). After
then, participants continued to have at least two supervised exercise sessions per
week and at least monthly interaction with the study staff.
Due to the lifestyle arm’s unquestionable superiority, the trial was terminated 1
year sooner than expected, with a mean follow-up of 2.8 years. T2DM incidences
cumulatively ranged from 11.0 per 100 person-years in the placebo group to 7.8
per 100 person-years in the metformin group to just 4.8 per 100 person-years in
the rigorous lifestyle group. In the lifestyle group, T2DM risk was 39% lower than
in the metformin group and 58% lower than in the placebo group. According to
Hamman et al.’s epidemiologic analysis of the data, there was a 16% decrease in
diabetes risk for every kilogram of weight loss among the participants of the lifestyle
intervention, after correcting for changes in self-reported diet and physical activity.
Increased physical activity played a significant influence in weight maintenance
and was a significant predictor of weight loss. Additionally, participants’ risk of
developing diabetes was decreased by 46% when they reached the weekly objective
415
 of more than 150 minutes of moderate exercise.

In T2DM, regular exercise is linked to lower morbidity and death. A 10-year

follow-up of a sizable prospective cohort study (which included 347 people with
diabetes and 1317 people without diabetes) revealed that those with diabetes who
walked a mile or more every day had the lowest aged-adjusted all-cause death rate.
In a similar vein, a prospective study of 1263 diabetic males over a 12-year period
indicated that those with intermediate cardiorespiratory fitness had a 60% lower
risk of cardiovascular and total mortality than those with the least fitness (defined
as the lowest 20% by maximum treadmill testing). According to a review by Ivy et
al., a variety of mechanisms may be involved in the stimulation of glucose uptake
caused by exercise (Figure 4.12). They include changes in adipose tissue mass and
distribution, increased glucose transporter protein and mRNA, decreased release
and increased clearance of free fatty acids, increased muscle glucose delivery due
4 4
to increased muscle capillary density, changes in muscle composition favoring
increased glucose disposal, and increased post-receptor insulin signaling. Figure 4.12: Mechanisms by which physical activity training may enhance

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MANAGEMENT OF DIABETES

Reducing visceral fat also reduces levels of free fatty acids and tumor necrosis factor,
which in turn reduces insulin resistance. Bloodstream immune indicators foretell
the start of cardiovascular disease and its associated consequences. Regular aerobic
exercise training often improves metabolic function and has anti-inflammatory
effects in people with type 2 diabetes. In some but not all trials, exercise training in
people with T2DM has been shown to promote anti-atherogenic blood lipid changes
and to lower other risk factors for coronary heart disease (hypertension, obesity, and
coagulation abnormalities). For instance, exercise training may be less beneficial in
delaying atherogenesis in elderly patients with relatively advanced atherosclerosis.
Exercise may be more effective as a preventative measure against atherosclerosis in
younger, healthier people who have not yet developed the condition.
insulin action and blood glucose regulation in type 2 diabetes. Free fatty acids
(FFA), glucose transporter (GLUT), and Rd, or glucose uptake; HGO, or
hepatic glucose output; Tumor necrosis factor is abbreviated as TNFɑ.
Hepatic and peripheral insulin resistance, as well as hyperinsulinemia in the fasting
state, are characteristics of people with T2DM. The blood glucose concentration
typically decreases during moderate intensity exercise because peripheral glucose
absorption typically increases more than hepatic glucose synthesis.
The risk of exercise-induced hypoglycemia in people with T2DM who are not
receiving exogenous insulin decreases concurrently, and this is true even for
prolonged exercise.
It has been demonstrated that moderate intensity exercise reduces glycogen content
similarly in those with and without diabetes; however, in obese people with diabetes
compared to those without diabetes, whether obese or lean, glycogen and plasma
glucose lowers more.

Regardless of whether the activity is carried out in a single session or over the
course of several sessions of the same total length, moderate exercise has identical
effects on insulin sensitivity and glucose tolerance. It has also been demonstrated

416 417
 that moderate aerobic activity can reduce the rise in blood triglyceride levels that upper gastrointestinal tract bypass. The following four methods have received the
occurs after consuming a high-fat meal. Exercise that depletes glycogen quickly greatest research in terms of their effectiveness and safety in promoting weight loss,
increases peripheral and hepatic insulin sensitivity in people with T2DM, and these improving metabolic state, and enhancing general health (Figure 4.13).
effects last for 12 to 16 hours.
Sedentary persons with T2DM exhibit higher blood glucose levels than both
active adults with diabetes and sedentary individuals without diabetes following
maximum aerobic exercise (> 85% V O 2max). Reduced insulin sensitivity could
result from the age-related loss in muscle mass. Resistance training merits careful
study as an effective intervention in the management of type 2 diabetes because it
may be able to reverse the age-related loss of muscle mass. Resistance training has
been linked to modest improvements in lipid profiles as well as increases in insulin
sensitivity and glucose metabolism in both men and women. Insulin responses to
an oral glucose challenge are lower in both healthy younger and older people after
resistance training, according to longitudinal studies involving healthy untrained
4 4
adults.

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In addition to increasing lean body mass, resistance training has been linked to
higher resting energy expenditure in older persons. Whether this happens in T2DM
is still unknown. High-intensity resistance training, as reported in studies by Dunstan
et al. and Castaneda et al., led to reductions in HbA1c of 1.2% (13 mmol/mol) with
a 26-week program combined with a moderate caloric restriction diet and 1.0%
(11 mmol/mol) with a 16-week program, respectively. Resistance training exercise
successfully lowers HbA1c in those with T2DM, according to meta-analyses. Boulé
et al. observed no difference in HbA1c between aerobic and resistance exercise in
a meta-analysis of clinical trials looking at the impact of aerobic and resistance
exercise interventions on glycemic control and body mass in T2DM. Overall, post-
intervention HbA1c values were 0.66% (7 mmol/mol) lower in exercise intervention
group individuals than in control group participants. Exercise participants’ post-
intervention body weight did not differ from control participants’, indicating that
exercise may have benefits independent of body weight reduction.
4.2.7 Bariatric Surgery
Purely restrictive, malabsorptive, or combinations of these approaches are the three
main differences amongst bariatric operations. Notably, the extent of weight loss
and metabolic results are believed to be significantly influenced by the length of the
Figure 4.13: Graphical presentation of the four best established and
standardized types of bariatric surgery. a) Laparoscopic adjustable gastric
banding, b) Roux-en-y gastric bypass, c) Vertical sleeve gastrectomy and d)
Biliopancreatic diversion
The procedure known as laparoscopic adjustable gastric banding (LAGB)
entails enclosing the upper part of the stomach with a silicone adjustable band
that is connected to a port under the skin so that pressure on the vagal afferent
intraganglionic laminar endings (IGLEs) can be changed by adding or removing
fluid (Figure 4.13 a). The Roux-en-Y gastric bypass (RYGB) procedure combines
the functions of the small bowel and the stomach. An alimentary or Roux limb of
typically 100–150 cm is left after creating a tiny gastric pouch (15–30 mL) on the
lesser gastric curvature,

418 419
 which is isolated from the gastric remnant and anastomosed to the jejunum.
An entero-enteric anastomosis between the excluded biliopancreatic limb and
the alimentary limb restores bowel continuity (Figure 4.13 b). Although it
has occasionally been done up to 250 cm distally in an effort to induce caloric
malabsorption, this anastomosis is typically performed 100 to 150 cm distal to the
gastro-jejunostomy. Caloric malabsorption does not appear to be a factor, either, as
the majority of patients have constipation after RYGB. Although it has occasionally
been done up to 250 cm distally in an effort to induce caloric malabsorption, this
anastomosis is typically performed 100 to 150 cm distal to the gastro-jejunostomy.
Caloric malabsorption does not appear to be a factor, either, as the majority of
patients have constipation after RYGB.
Note: Bariatric surgery offers a transformative approach in diabetes management.
4 Beyond weight loss, it positively impacts blood sugar control, often leading to remission
of Type 2 diabetes. This surgical intervention’s potential to improve metabolic health
MANAGEMENT OF DIABETES
underscores its role in comprehensive treatment strategies for those struggling with
diabetes and obesity.
Finally, caloric malabsorption is a result of biliopancreatic diversion (BPD),
whether it occurs with or without a duodenal switch. The procedure entails a
horizontal gastrectomy and an anastomosis between the stomach that is still
present and the small intestine’s distal 250 cm. Bile and pancreatic secretions are
carried through the bypassed duodenum, jejunum, and portion of the proximal
ileum, which are attached to the alimentary limb 50 cm away from the ileocecal
valve (Figure 4.13 d). With short operating durations and minimal complication
rates, laparoscopic surgery is virtually always used to execute all procedures. The
main drawback of LAGB is that about 20% of patients do not feel any changes
in appetite and, as a result, do not lose weight. They frequently put on weight
again and require numerous revisional surgeries. The most common side effects of
the remaining surgical procedures are physiological (dumping syndrome, chronic
nutritional deficits, loss of bone density, kidney/gallbladder stone development,
and anastomotic stenosis) and mechanical (abdominal pain).
420
After bariatric surgery, the pathophysiology of weight loss and T2DM
remission
Through a number of mechanisms, including caloric restriction brought on by
the anatomical remodeling of the gastrointestinal tract, increased meal-induced
thermogenesis, modulation of hypothalamic neuronal circuits involved in energy
balance and appetite regulation, altered taste, food preferences, and eating behavior
patterns, as well as altered gut-brain signaling pathways, metabolic surgery is able
to induce and maintain significant weight loss.
The favorable benefits of metabolic surgery are significantly mediated by two
essential aspects, the hypocaloric state caused by profound caloric restriction and
the large weight reduction accomplished, with reference to the improvement of
the metabolic environment leading to T2DM remission. Caloric restriction to the
extent seen in the first 10 to 20 days following RYGB had the same rapid impact
4
on insulin sensitivity and blood glucose levels as surgery, according to studies
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including individuals with T2DM. However, there is no improved incretin impact
with caloric restriction alone, and it is very hard for patients with diabetes and
obesity to sustain this severe restriction for an extended period of time.
There are additional well-known therapeutic effects (unique to bariatric surgery)
that are unrelated to weight reduction and cannot be obtained by equivalent
dietary-induced weight loss. These effects can be seen in the early postoperative
period prior to considerable weight loss. In particular, the upper gastrointestinal
tract bypass surgery’s major pathophysiological mechanisms for these favorable
metabolic effects include the following: effects on multiple organ insulin sensitivity
(hepatic and skeletal muscle), -cell function, changes in bile acid (BA) composition
and flow, changes in gut microbiota, intestinal glucose metabolism, and increased
metabolic activity of brown adipose tissue.
Given that non-surgically treated patients who lost the same amount of weight under
a similar dietary caloric restriction also showed a similar improvement in insulin
action, it is debatable whether the effects of surgery, and in particular RYGB and
LAGB, on insulin sensitivity are completely independent of weight loss. Contrarily,
BPD appears to have particular effects on insulin sensitivity, as evidenced by
studies that indicate quick improvement in insulin sensitivity as measured by a
421
 clamp following a 10% reduction in weight. A very exciting area of research right
now is the short- and long-term impact of metabolic surgery on tissue-specific
insulin sensitivity. The abrupt and severe caloric restriction may cause a rapid
improvement in hepatic insulin sensitivity in the short term, whereas the positive
effects on skeletal muscle insulin action are seen later (mid- and long-term effects)
and are therefore primarily influenced by weight loss. After metabolic surgery,
particularly RYGB, the incretin effect and the early phase of insulin secretion, both
substantially compromised in patients with T2DM, are quickly returned to normal.
Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide
(GIP) levels rise quickly as a result of the anatomical bypass of the proximal
intestine and the quick passage of undigested food from the stomach to small
intestine. This may encourage pancreatic insulin release and gradually enhance
beta-cell function (hindgut hypothesis). In addition to incretins, peptide YY (PYY)
and other gastrointestinal postprandial satiety hormones are markedly increased.
4 4
Severe caloric restriction, significant weight loss, and a significant rise in postprandial
MANAGEMENT OF DIABETES
incretin secretion may all play a role in the mechanism underlying the restoration of
first-phase insulin secretion. A study in 11 T2DM patients who underwent calorie
restriction similar to that right after bariatric surgery demonstrated normalization
of beta cell function, increased insulin sensitivity, restoration of first-phase insulin
secretion, and ultimately, diabetes reversal, supporting the first hypothesis.
Studies utilizing intravenous glucose tolerance tests (IGTTs), in which insulin
secretion is by definition incretin-independent, have also demonstrated significant
improvements in early insulin secretion in both diabetic and non-diabetic bariatric
patients, lending support to the effect of weight loss.
The benefits of the increased incretin response, however, cannot be ignored; in a
beautifully designed study of five patients who had undergone RYGB and had a
gastrostomy tube inserted for medical reasons, the administration of a glucose load
through the gastrostomy (thus negating the effect of proximal gut bypass) resulted
in a significantly lower incretin and insulin response than when the same load
was given orally. Therefore, it is extremely likely that all of the aforementioned
hypothesized mechanisms—along with potential additional ones—work together
to restore early postprandial insulin secretion in patients with obesity.
422
Although the hindgut theory seems to be a very good explanation for the increased
incretin response, research have also concentrated on the foregut’s function (foregut
hypothesis). According to a theory, diabetogenic “anti-incretin” hormones are
typically secreted as food passes through the proximal small intestine, and bypass
surgery reroutes food to the stomach, reducing their secretion and encouraging
antidiabetic benefits. Although studies suggest that the foregut plays a part in
T2DM remission following RYGB, no such hormones have yet been discovered.
With a growing body of evidence demonstrating changes in BA composition
and flow following metabolic surgery, bile acid (BA) metabolism has lately
come to light as an additional significant driver of surgically-induced metabolic
improvement. It has been shown that elevated fasting and postprandial serum BA
levels may be related to weight loss following RYGB. There isn’t any concrete proof,
nevertheless, that higher circulating BA concentrations in postoperative patients
result in a better metabolic environment. The data in this area are contradictory.
Contrary to RYGB, LAGB has been linked to lower baseline and postprandial
MANAGEMENT OF DIABETES
serum BA concentrations. However, in comparison to RYGB, this association
has also been linked to an improvement in β-cell function and insulin sensitivity.
Additionally, RYGB-induced weight reduction has been linked to alterations in the
gut microbiota, namely an increase in intestinal microbial diversity and alterations
in the relative abundances of different bacterial phyla and species. Changes in
body weight, nutritional intake, nutrient flow through the intestine, gut motility,
intraluminal pH, and bile flow are the main causes of these alterations. Uncertainty
exists over whether the positive benefits of modified gut microbiota on glucose
homeostasis are unrelated to weight loss.
According to animal studies, RYGB causes villous hyperplasia and raises villus
height in the Roux limb, increasing intestinal glucose intake. An enhanced insulin-
stimulated jejunal glucose uptake 6 months after RYGB has been observed in
patients with and without T2DM in human investigations using positron emission
tomography images and clamps. However, it is believed that the amount of intestinal
glucose retention following the consumption of a mixed meal in people is too low
to result in a clinically significant improvement in postprandial glycemic control.
Last but not least, it has been suggested that the higher BA and incretin levels
423
 attained after RYGB may increase the metabolic activity of residual brown adipose
tissue, which is found in small amounts in the adults’ supraclavicular fat depots,
and even induce browning of white adipose tissue, resulting in a better metabolic
state and facilitating weight loss.
Clinical and biological determinants of weight loss and T2DM remission
after surgery
The preoperative postprandial gut hormone responses (incretin effect) in relation
to weight loss do not predict surgically induced weight reduction. It’s interesting
to note that faster weight loss following bariatric surgery has been linked to higher
baseline levels of the soluble receptor for advanced glycation endproducts (sRAGE)
(RYGB, SG, LAGB).
4
The strongest biological and clinical predictors of T2DM remission following
bariatric surgery have been the subject of numerous studies. The contrast between
MANAGEMENT OF DIABETES
remitters, never remitters, and relapsers after first remission is significant in this
setting. To make it easier to compare the findings of various investigations, T2DM
remission should be precisely and consistently defined. Complete T2DM remission
is defined by HbA1c 6% and/or fasting plasma glucose 100 mg/dl for at least one
year following surgery in the absence of pharmacological treatment to decrease
blood sugar. Fasting plasma glucose 126 mg/dl and/or HbA1c 6.5% without anti-
diabetic treatment for at least a year are considered signs of partial T2DM remission.
A complete T2DM remission that lasts for more than five years may be regarded
as operationally similar to cure. However, using these terminology with caution is
advised, especially when suggesting T2DM monitoring and treatment regimens.
The beneficial impact of medically induced weight loss on T2DM remission seems
unrelated to baseline BMI. Preoperative BMI in the obese range may not accurately
predict cardiometabolic advantages in terms of T2DM prevention and remission,
incidence, and mortality from cardiovascular disease, according to a growing
body of research. Regardless of initial BMI, T2DM remission rates were equal in
both groups, according to a recently published meta-analysis of RCTs, controlled
clinical trials, and cohort studies conducted in two distinct BMI groups (35 and
>35 kg/m2). Preoperative BMI appears to be ineffective in predicting metabolic
improvement, but body weight change trajectories, specifically the amount of
424
weight loss, are crucial in distinguishing between responders and non-responders.
Regardless of initial BMI classification, T2DM remission rates are noticeably
higher in individuals who have substantial weight reduction following surgery than
in subjects who experience less profound weight loss, indicating that weight loss by
se appears to have a predominant influence.
As the emphasis switches from remission to long-term control of all metabolic
parameters, the International Diabetes Federation’s concept of optimal metabolic
control may be more useful. As a result, the advantages of metabolic surgery in
terms of hypertension, dyslipidemia, and glycemia are equally regarded. To extend
and preserve the metabolic advantages of surgery, supplementary drug use is also
promoted.
Beyond weight loss, factors that have consistently been linked to lower rates of
T2DM remission and a higher risk of relapse include baseline T2DM duration,
4
preoperative usage of intensive insulin regimens, and poorer glycemic control.
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4.3 Pharmacological Approaches
A certain balanced diet, regular exercise, and the right administration of drugs
(oral and/or insulin agents) are the main components of the fundamental strategies
for the treatment and control of diabetes. The prevention of acute problems and
the decrease of long-term difficulties require patient education, self-care, and
support from family and medical professionals. Additional key acts related to
disease prevention include regular exams (such as blood pressure and lipid profile
measurements), foot care (to prevent lesions from appearing), stress management,
and a decrease in alcohol and tobacco use.
The majority of people with type 2 diabetes normally do not need daily insulin
dosages, in contrast to people with type 1 diabetes mellitus. Until resistance
becomes difficult to control, the condition can be treated with oral drugs and
lifestyle modifications; at that point, an insulin regimen is typically required.
The severity of the hyperglycemia, the availability of therapeutic choices, and
awareness of patient characteristics all play a role in T2DM medication treatment.
Several oral medications, including biguanide metformin, sulfonylureas, and
425
 thiazolidinediones, have been successfully used for decades to treat diabetes. These
anti-diabetic medications play a significant role in glycemic control and make
up the oral pharmacological class that has been the subject of the most research
worldwide. The American Diabetes Association and the European Association for
the Study of Diabetes frequently suggest using these medications as the first line
of treatment for diabetes. About 180 novel medications are being developed for
the treatment of T2DM as a result of technological advancements and new drug
research pathways. Approximately 180 new drugs are currently under study.

Before insulin, life and death

A lack of insulin causes a severe catabolic state that impacts protein, glucose, and
fat reserves. Insulin is a powerful anabolic hormone. If untreated, absolute insulin
deficiency, such as that caused by type 1 diabetes (T1DM), will cause death (Figure
4.14). The study of diabetic patients in the pre-insulin era informs us that diabetes Figure 4.14: A diabetic patient before and after receiving insulin
4 4
can be managed without insulin for a remarkably long time. The first person to First insulins

MANAGEMENT OF DIABETES
receive an efficient insulin treatment was Leonard Thompson. When he received
MANAGEMENT OF DIABETES

his first injection of insulin at 11 a.m. on January 22, 1922, he had already been
living with diabetes for more than 2 years and was 12 years old when he obtained
his diabetes diagnosis in 1919.
Having said that, life without insulin was dreadful. Aside from the weight loss,
ongoing fatigue, thirst, frequent urination, and infections, there was also the
assurance that one had been sentenced to death and that it would be a painful and
drawn-out procedure. Severe nutritional restriction, possibly best popularized by
Allen from the Rockefeller Institute in New York, looked to be the most successful
treatment at the time. However, this was a difficult regimen that did not appear to
significantly increase life expectancy, and when death did occur, it was unclear if it
was due to malnutrition or diabetes.
Insulin that is used in commerce was initially derived from swine and bovine
pancreas. In order to stop the enzymatic breakdown of the insulin protein, the
organs would be newly removed from the slaughterhouses and instantly frozen.
To solubilize the insulin, the tissue would be treated with acid and ethanol. The
insulin would then be salted out with sodium chloride, precipitated, and finally
crystallized. The process produced insulin with approximately 80–90% purity; the
main impurities were pancreatic polypeptides and glucagon. Despite the fact that
this insulin was efficacious, immune-mediated side effects, particularly lipoatrophy
and antibody-mediated insulin resistance, which can both significantly affect the
kinetics of insulin action, frequently made it less efficient. These contaminants also
played a role in an allergic reaction, which occasionally caused discomfort and
swelling at the injection site.
Long-lasting and soluble insulin patch repairs
Since soluble insulin’s biologic effect doesn’t last more than 5 to 6 hours, the early
preparations were frequently accompanied with discomfort and swelling at the
injection site. Therefore, efforts to meet the patient’s daily insulin needs with a single
injection were made in the 1920s and 1930s. Lecithin, oil, and cholesterol were used
as modifying agents to do this, but their duration of action varied significantly from
injection to injection, making their clinical application challenging. A technique for

426 427
 including insulin into a poorly soluble compound and delaying its absorption was
described in 1936. Protamine, a highly basic protein produced from salmon or trout
sperm, was used in this method.

Protamine-zinc insulin was created by further stabilizing the complex with a modest
amount of zinc so that it lasted for around 24 hours. Making consistent batches was
challenging, and absorption was once more inconsistent. Protamine and zinc were
added in stoichiometric quantities in 1946 (such that there was no free protamine or
zinc), further refining the procedure and producing a preparation that was absorbed
more steadily and lasted for 12 to 24 hours. In 1940, this insulin, also known as
isophane or neutral protamine Hagedorn (NPH), was made therapeutically available.
It was discovered in 1951 that zinc, when added in excess and in an acetate buffer,
may prolong the action of insulin without the requirement for protamine. These
crystals of relatively insoluble zinc-insulin complexes, known as lente insulins, Figure 4.15: The various insulin formulations’ time-action profiles
4 4
were produced as a result. By altering the pH, it was possible to make both smaller
Because it requires forethought, a sizable majority of patients find it challenging
(semilente) and larger (ultralente) crystals, depending on how quickly the crystals

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MANAGEMENT OF DIABETES

to heed this counsel. Even then, the calculated doses could be off, especially if the
were absorbed. The most widely used version of the zinc insulins was lente insulin,
patient has no influence over how the food is prepared.
which was utilized extensively in clinical practice. Lente insulin was a formulation
that had a 70:30 ratio of ultralente and semilente insulins.
Specific modifications to the amino acid sequence of insulin can lessen the
interaction between insulin molecules. These modifications cause the insulin to
Rapid and prolonged insulin analogs
enter the bloodstream more quickly, enabling it to be administered soon before or
In the blood, insulin is present in single molecules at quantities of around 10–9
even right after eating. These three rapid-acting analogs (RAIs)—insulin lispro,
mol/L. Higher doses of insulin, as those seen in commercial solutions, tend to
insulin aspart, and insulin glulisine—are the only ones that have been made
cause the molecules to non-covalently group together to form dimers, tetramers,
available thus far. Compared to soluble insulin, which takes 30–60 minutes and
and hexamers. The hexamer interaction is further stabilized by the zinc presence.
6–8 hours to take effect, these analogs work faster (within 10–20 minutes) and for
a shorter amount of time (3–5 hours). RAIs have now been shown to be safe in a
After injection, fluid is drawn through osmosis into the insulin depot. Before insulin
number of studies in both type 1 and type 2 diabetes (T1DM and T2DM), when used
can pass through capillary walls as monomers into the blood circulation, this causes
in continuous subcutaneous insulin infusion (CSII) and as part of a “basal bolus”
dilution of the insulin and dissociation of the insulin molecules, a spontaneous but
insulin injection regimen in conjunction with intermediate-acting insulins. RAIs
progressive process. In order to ensure that circulating insulin levels are optimal
likely manage post-prandial hyperglycemia better than soluble insulin because of
at the time the patient’s meal is being absorbed, patients are advised to inject their
their time-action profi le, which is ideally adapted to imitating the demand during
soluble insulin 15 to 20 minutes prior to a meal (Figure 4.15).
mealtimes. Patients can therefore obtain better glycemic control with RAIs than
with soluble insulin while experiencing fewer hypoglycemic episodes.

Despite the fact that delayed-action insulins like isophane and insulin lente can

428 429
 last for 12 to 24 hours, their absorption from subcutaneous tissue might vary
significantly. As a result, efforts to maintain strict glucose control may lead to a
higher risk of hypoglycemia. The isoelectric point, which is the point at which the
molecule is least soluble, can shift toward neutrality as a result of changes to the
primary amino acid sequence of the insulin molecule. As a result, after injecting
insulin into subcutaneous tissue (which has a neutral pH), the isoelectric point
shift causes insulin to precipitate, which causes absorption to be slower and, more
significantly, less variable. Early research on long-acting analog insulins, which was
intended to prove equivalence rather than superiority over isophane NPH insulins,
has not been able to clearly establish a benefit in glycemic control. The results
do, however, seem to support the notion that using long-acting insulin analogs
to achieve glycemic control is related with reduced symptomatic and nocturnal
hypoglycemia.

4 4
Size of the issue with reproducing physiologic insulin delivery

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In good health, there are significant postprandial spikes together with a low and
MANAGEMENT OF DIABETES

consistent background insulin secretion between meals (Figure 4.16). To summarize,

the background and postprandial insulin secretion can differ significantly within a
single individual depending on the level of counter-regulatory hormones like growth
hormone and catecholamines, and the postprandial insulin secretion depends on the
carbohydrate and protein content of the meal. The stimulus and pattern of insulin
secretion have already been discussed.
Additionally, the insulin is secreted into the portal circulation, with the liver
removing around 50% of the insulin during the initial passage.
Figure 4.16: a healthy, non-obese person’s pancreatic insulin secretion.
Lunch was had at 0900, 1300, and 1800. The arrows indicate pulses of secretion
that are statistically significant
Administration Of Insulin Subcutaneously
The most common method of administering insulin is subcutaneously, and the
belly, thigh, and deltoid are recommended injection locations. Although there are
few clinical trials on this topic, the current advice is to pinch the skin to lower the
chance of injecting into muscle and to inject at right angles to the skin. The fold
should then be kept for 5–10 seconds before the needle is removed (Figure 4.16).

There has been a shift to using insulin pens instead of the conventional needle and
syringe since they are more widely available and simpler to use. Figure 4.17 depicts
a number of the many pen designs made by the major insulin producers. The needle
lengths that are currently available are 12.7, 8, 6, and 5 mm. The 12.7 mm needle
has few, if any, indications for use, and shorter needles are linked to a lower risk of
intramuscular injection and might even be thought of as less traumatic.

430 431

Figure 4.16: The method advised for administering insulin subcutaneously
4 4
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Figure 4.17: An assortment of the many insulin injection tools. Although there
are additional options, these are the injection tools that are utilized the most
frequently. Most are offered with a prescription
However, there is some data to suggest that the shorter needles are linked to a higher
risk of insulin back-leakage unless the injection technique is good. The 6 to 8 mm
needle is typically best for non-obese patients who use the pinch technique on the
abdomen, arm, or legs. When kept below 25 °C, standard insulin formulations have
a shelf life of 4 to 6 weeks. They must be kept in a refrigerator (4 ° C) for longer
lengths of time in order to be kept until their expiration date. Patients who want
to secretly alter their therapy may use the method of rendering insulin inactive by
432
exposing it to high temperatures or microwaves.
Some delayed-action insulin formulations come in a two-phase solution that
requires thorough mixing to achieve total suspension. To ensure that consistent
doses of insulin are drawn up each time, it is crucial that patients are educated on
the significance of this. The long-acting insulin analogs do not require mixing.
Insulin at or above 40 U/mL, primarily in the form of monomers, dimers, or
hexamers, makes up insulin preparations. Following injection, fluid is pulled into
the injection depot by osmosis, which causes the oligomers to split into single
molecules that can pass through the capillary membrane and enter the bloodstream.
Circulating insulin attaches to the target cell’s insulin receptor, internalizes the cell,
and starts a number of intracellular pathways. Less than 1% of insulin is excreted
by the kidney; the majority of insulin disposal occurs through internalization and
breakdown. Overall, between 60 and 80 percent of insulin is broken down in the
liver, 10 to 20 percent in the kidney, and 10 to 20 percent in skeletal muscle and fat.
Therefore, persistent insulin in the bloodstream can and does increase the risk of
MANAGEMENT OF DIABETES
hypoglycemia when liver or renal function is impaired.
Numerous methods, including utilizing a gamma counter to measure the rate
of loss of labeled insulin from the injection site, have been utilized in stud-
ies evaluating the absorption of subcutaneously injected insulin. According
to studies, the rate might differ significantly not only between persons but
even from one injection to another within the same person. While there do
not seem to be any obvious changes in the rate of absorption between the
various injection sites, absorption rates in obese patients are slower than in
non-obese patients. In the non-obese patient, the upper abdomen appears to
absorb soluble insulin more quickly than the lower abdomen and faster than
the arm or leg. Compared to soluble insulin, these discrepancies across in-
jection locations seem to be less noticeable with the insulin analogs.
Repeated insulin injections at the same place cause local adipose tissue hypertrophy,
which causes insulin absorption to become slower and more irregular. The non-
obese patient must also be informed that the rates may change when they travel
433
 from one section of the body to another. Patients should constantly be encouraged
to rotate their insulin injection sites to avoid this issue. Rates of absorption may be
influenced by other local variables including edema or local inflammation. Exercise
increases blood flow to the skin, which can speed up the absorption of insulin—
especially when it’s administered close to the muscle groups being worked—so
patients planning to run should be informed that injecting into the leg may not be
as advantageous as injecting into the arm or abdomen. Similar to how it affects
cutaneous blood flow, temperature also affects how quickly insulin is absorbed; in
hot climates or while in a sauna, levels of insulin may rise quickly, but in cooler
climates, uptake may be slower. Smoking and hypoglycemia have also been
reported to slow down the rate of insulin absorption.
Subcutaneous Insulin Treatment Complications
For most people, hypoglycemia is the most severe side effect of receiving insulin
4 4
injections. The fear of hypoglycemia may be a significant obstacle to starting an
insulin regimen and achieving tight glycemic control.
MANAGEMENT OF DIABETES
Insulin can cause individuals who need it to gain an excessive amount of weight in
addition to restoring fat and muscle mass in newly or inadequately treated patients.
Many patients continue to have serious concerns about this, especially the already
overweight T2DM patient who is no longer able to regulate their blood sugar with
oral hypoglycemic medications. Combining the dietitian’s recommendations with
an insulin regimen designed to meet each patient’s unique needs and delivering the
majority of the insulin when necessary can help patients avoid gaining weight.
Overaggressive insulin titration regimens leading to low blood glucose and
stimulation in appetite can lead to excessive weight gain. Some patients,
particularly but not exclusively young females, can pose a management challenge
when they reduce their insulin dose to suboptimal levels to manipulate body weight
(see Chapter 55 ). Immune responses to the older animal insulins have been well
reported but such responses to current human and analog insulins are extremely
uncommon. Allergies may very rarely develop in response to both insulin and
agents added to the insulin preparation. Most commonly, but again rarely, local
acute urticarial reactions develop and are best treated by switching to an alternative
insulin. The urticarial reaction might occasionally turn into a subcutaneous nodule.
434
Antihistamines and, in rare cases, the use of high dose steroids, may both be
beneficial for these people.
Antibodies to exogenous insulin are uncommon, but when they are found, they
are typically induced by animal insulin products, polyclonal in character, and
directed against diverse components of the insulin molecule. This is due to the
introduction of increasingly purified animal insulins, human insulin, and analog
insulin. Clinically, they may cause the above-described local allergic reactions
and may impede the action of short-acting insulins by lowering peak and rising
trough levels. These outcomes are probably unpredictable. Lipoatrophy is a rare
allergic reaction that occurs when subcutaneous tissue at the injection site vanishes
or atrophies. It is most commonly associated with older animal insulins. In contrast,
lipohypertrophy, which is a frequent response to insulin and not at all an allergic
reaction, manifests as an expansion of adipose tissue. It typically occurs in people
who do not rotate their insulin injection sites and who have poor injection technique.
Further injections into regions of hypertrophy can result in poor and delayed insulin
absorption with subsequent implications on blood glucose levels. The patient
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typically finds the appearance unpleasant. If injections are not administered in that
location, lipohypertrophy usually resolves.
At the sites of injections, minor ulceration, pitting, and bruising can occasionally
take place. Moving to a different region for the injection is advised, and a shorter
needle may be desirable, especially if bruising develops.
Insulin Dosage Plans
The development of more flexible and adaptable treatment regimens has
accompanied the evolution of insulin preparations from the early animal insulins
to both human and analog insulins, allowing the doctor and nurse to offer the
patient needing insulin a customized treatment that better fits their unique needs
and lifestyle.
It is well known that in people without diabetes, the -cells of the pancreas have
the capacity to release insulin both before and after meals in order to keep blood
glucose levels within a specific physiological range. Exogenous insulin must
be administered to T1DM patients who are no longer producing endogenous
insulin in an effort to mimic physiological insulin release as closely as possible.
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 This requires a combination of fast or rapid-acting insulin to handle the glucose
challenge presented at mealtimes and more longer acting or basal insulin to provide
a background control of glucose between meals.
Basal only regimen
More than 50% of T2DM patients will eventually need to administer insulin
intravenously. As T2DM worsens, many people may experience significant worry
and anxiety as they go from oral hypoglycemic medications to insulin injections
for a variety of connected reasons. While medical practitioners use a range of
abilities and strategies to lessen what some patients perceive to be a life-changing
experience, we are very aware of the numerous worries that insulin injections can
cause. These can include feelings of failure at not being able to control blood
sugar levels through lifestyle, diet, and oral therapy; the belief that the diabetes is
now much more serious than it was because it now requires injections rather than
4 effects. It is primarily used as a medication to reduce insulin resistance in clinical
tablets; trepidations, fears, and, very rarely, actual phobias associated with the need
insulin with the main meal, followed, as necessary, by a prandial insulin before
each subsequent meal. An alternative is to transfer patients from basal insulin to
premixed insulin, which is typically administered twice daily at breakfast and
dinner but is increasingly provided once daily with the main meal and up to three
times daily.
It is obvious that for individuals with T1DM, basal insulin alone is insufficient and
that either a full basal bolus regimen, including prandial insulin before each meal,
is necessary, or that a twice- or three-times-daily insulin premix can be utilized.
4.3.1 Drug Treatment of Type 1 Diabetes
Biguanides
One of the first medications to be shown to be effective in supplementary therapy
is metformin, a derivative that is currently in use. It is thought to have pleiotropic
4
settings. However, there are an increasing number of reports of its other functions,

MANAGEMENT OF DIABETES
to self-inject a treatment; worries that hypoglycemia will result in coma and death;
MANAGEMENT OF DIABETES

such as its defense against cells.

worries about weight gain; and also the idea that using insulin may have unintended
The medication metformin is well-known. There has been a long history of
side effects.
attempts to treat type 1 diabetes using its specimens. It is believed that including
the metformin formulation may be advantageous when insulin resistance in type
One strategy to introduce insulin injections to persons who are no longer able to
1 diabetic patients manifests as a high endogenous insulin need and challenges
control their blood glucose with diet, lifestyle changes, and oral medication alone is
achieving metabolic control.
to begin with just one injection per day. Instead of replacing oral medicines already
It was confirmed that the addition of metformin to intensive insulin therapy had a
in place, this is typically added on. A growing body of research has shown that a
good effect on reducing the need for insulin and lowering body mass. Additionally,
once-daily basal insulin can be used in combination with metformin, a sulfonylurea,
it was discovered that metformin enhances lipid metabolism.
the thiazolidinedione pioglitazone, and other oral medications as a dual or triple
oral therapy.
The effect of metformin in enhancing diabetes control in young patients with type
1 diabetes is the subject of research. In a group of 76 type 1 diabetic adolescent
In order to start patients with T2DM on insulin, national and international
patients, Australian researchers conducted a randomized study to determine the
guidelines in the UK, Europe, and the USA also suggest using a basal insulin with
effects of metformin added to insulin therapy on the function of the cardiovascular
oral medication.
system. According to the scientists, type 1 diabetes in adolescents may benefit from
the supplementary therapy of metformin and insulin in preventing cardiovascular
Combinations of prandial and basal insulins problems.
An increasing HbA1c in T2DM patients shows significant postprandial glucose
Sodium-Glucose Co-Transporter 2 Inhibitors (SGLT-2 Inhibitors)
excursions and the requirement for mealtime insulin in the face of normal or
In the regulation of glycaemia, kidney function is critical. The sodium-glucose co-
almost normal fasting glucose levels. This can be done by consuming a prandial

436 437
 transporters system is crucial for the excretion of glucose in the urine and, as a
result, for preserving glucose homeostasis. There are many new formulations on
the pharmaceutical market right now, most of which are intended to treat type 2
diabetes, however there have also been attempts to use them as adjuvant therapies
for autoimmune diabetes (including type 1 and LADA).
A significant amount of study has been done on the usage of sodium-glucose co-
transporter 2 (SGLT-2) inhibitors among these medications. One of the suggested
treatment options is to modify the sodium-glucose co-transporter’s function. The
goal of SGLT-2 inhibitor therapeutic trials for the management of diabetes mellitus
is to prevent the reabsorption of glucose in the renal tubules. The formulations in
this group promote urine excretion, which lowers blood glucose levels. The lipid
profile is improved by SGLT-2 inhibitors in addition to the enhancement of glucose
metabolism.
4 4
Experimental investigations have supported these medicines’ positive effects in
type 1 diabetes.
MANAGEMENT OF DIABETES
This class of medications has other effects in addition to lowering blood glucose
levels. The usage of preparations from this group may have a positive effect on
the protection and regeneration of cells in type 1 diabetes, according to intriguing
findings of experimental investigations conducted on laboratory animals. According
to some studies, SGLT-2 inhibitors may help diabetic individuals maintain healthy
kidney function. These findings are supported by experimental studies.
Weight loss is another benefit of SGLT-2 inhibitors, which is particularly useful for
the growing number of obese patients with type 1 diabetes. The positive impact on
decreasing high blood pressure was also found.
It is mentioned that there may be an increased risk of ketoacidosis. However, the
general consensus is that SGLT-2 inhibitor medication has more advantages than
disadvantages. There have recently been attempts to use new medications from this
group, but more research is required.
33 individuals with type 1 diabetes were treated with sotagliflozin, a medication
with a dual composition that contains SGLT-1 and SGLT-2 inhibitors, in a trial that
was presented by American authors.
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Amylin
The cells of the Langerhans islets create the peptide hormone amylin. The risk
of severe post-insuline hypoglycemia may rise as a result of its deficit. Amylin is
a hormone that regulates the release of glucagon and insulin and is known as an
anorectic hormone. Type 1 diabetes is characterized by an amylin and insulin deficit.
This fact served as justification for the amylin analogue studies for the treatment of
type 1 diabetes. The analogue of amylin known as pramlindite is mixed with insulin
as a therapy to improve various physiological problems.
Huffman et al. reported a significant improvement in diabetes control in persons with
long-term type 1 diabetes. With the aid of insulin pumps, the scientists conducted a
pilot research on 11 type 1 diabetic patients. Infusion of pramlintide subcutaneously
(CSPI) was well-tolerated and safe. Following a 16-week monitoring period, the
group’s HbA1c levels, body mass, and insulin needs decreased. Other authors
have shown that this therapy has a positive impact on people with type 1 diabetes,
including children.
Herrmann et al.’s multicenter randomized study of patients with type 1 diabetes
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receiving continuous subcutaneous insulin infusion (CSII) therapy along with
pramlintide highlighted the therapeutic usefulness of pramlintide use.
Incretin-Based Agents
Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4
(DPP-4) inhibitors are two medications that belong to this class.
The incretin hormone glucagon-like polypeptide-1 (GLP-1) is one of the most
active ones. It has the capacity to increase insulin secretion while suppressing
glucagon synthesis. In addition to having a protective impact on pancreatic cells,
GLP-1 also prevents their apoptosis. GLP-1R antagonists alter the differentiation
of young pancreatic cells, encourage the growth and differentiation of beta cells,
and may contribute to the reactivation of beta cells. GLP-1 may be used in gene
therapy for diabetes and cell culture for transplants, according to experimental
investigations. It is being attempted to treat some types of monogenic diabetes in
adolescents as well as type 2 DM patients with the incretin-like activity of this class
of medications.
Patients with type 1 diabetes also reported positive outcomes from the use of GLP-
1RA as an adjuvant therapy to insulin.
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 Intensive insulin therapy for type 1 diabetes enables maintenance of nearly
normalized glycaemic control, but it also carries risks for hypoglycemia and
weight gain. The authors added glucagon-like peptide-1 receptor agonists to
insulin treatment. Insufficient metabolic control (HbA1c > 8% [64 mmol/mol]) and
overweight (BMI > 25 kg/m(2)) people with type 1 diabetes were the subjects of
randomized research, the findings of which were presented by Dejgaard et al. The
authors come to the conclusion that adding the supportive therapy of liraglutide
(GLP-1RA) to insulin results in a decrease in hypoglycaemic episodes, bolus and
total insulin doses, as well as body weight.
Recent efforts have also been made to assess how these medications affect type 1
diabetic individuals’ cardiovascular health.
Inhibitors of Dipeptidyl Peptidase-4 (DPP-4) are frequently used in the treatment
of type 2 diabetes. However, there are more and more attempts to use them to treat
4 4
type 1 diabetes.
MANAGEMENT OF DIABETES
The use of these medications in type 1 diabetes in laboratory animals has recently
been the subject of several investigations. In mice with type 1 diabetes, DPP-4
inhibitors have been shown to be helpful in preventing diabetic kidney damage
(DKD).
4.3.2 Drug Treatment of Type 2 Diabetes
If altering your lifestyle is not sufficient to lower your blood sugar, you can take
anti-diabetic medications. It is possible to mix one type of medication with others
that lower blood sugar if one kind is insufficient.
Low blood sugar levels lower the risk of tiny blood vessel damage, particularly
in the eye, according to research. The effectiveness of anti-diabetics in preventing
complications like heart attacks and strokes, however, is unclear. Few long-term
studies have been conducted in this field. Additionally, not enough study has been
done to compare the various drugs.
Blood sugar levels might occasionally dip too low when taking any anti-diabetics.
Hypoglycemia is the medical term for too-low blood sugar.
440
Metformin: This long-used medication decreases the amount of glucose the body
produces. It is among the best tolerated and most thoroughly researched diabetes
medications. Doctors typically advise taking metformin first for this reason.
Diarrhea and feeling sick are potential adverse effects, particularly if metformin
isn’t taken with a meal. People with type 2 diabetes who take metformin may very
rarely (approximately 1 out of 10,000 per year) develop acidosis. This is the medical
word for having too much acid in the blood, which can cause nausea, circulatory
shock, difficulty breathing, and other symptoms. Because of this, metformin is
typically not prescribed to individuals who have impaired heart function, impaired
renal function, or an alcohol habit.
Sulfonylureas: These medications promote the body’s production of insulin. They
have also been in use for a time, much like metformin. Sulfonylureas are somewhat
more likely to cause hypoglycemic episodes than metformin. When the treatment
first begins, some patients also put on weight. Sulfonylureas may cause allergic
responses in certain people.
MANAGEMENT OF DIABETES
Glitazones: The only glitazone still available is pioglitazone. Pioglitazone is less
likely to result in hypoglycemia than sulfonylureas. Weight gain, bone fractures,
water retention, and heart failure are examples of potential side effects. The risk of
bladder cancer may modestly increase as a result of pioglitazone, according to the
European Medicines Agency (EMA). Pioglitazone is not the first choice medication
because of its possible negative effects.
Nateglinide and repaglinide are examples of glinides. They boost the body’s
capacity to produce insulin. Glinides are more likely than metformin to cause mild
to moderate hypoglycemia. Glinides may make you gain weight.
Insulin production is also stimulated by gliptins (dipeptidyl peptidase-4 inhibitors).
They consist of the medications vildagliptin, sitagliptin, saxagliptin, and linagliptin.
Headaches and gastrointestinal (stomach and bowel) issues are two potential side
effects.
Dapagliflozin, empagliflozin, and canagliflozin are examples of gliflozins (SGLT2
inhibitors). They reduce blood sugar levels by increasing the amount of sugar
441
 expelled in urine. Gliflozins may raise the risk of acidosis (excessive blood acidity)
and vaginal thrush.
4.4 Combination Therapies for the Treatment of Type 2 Diabetes in
Clinical Practice
The prevalence of type 2 diabetes mellitus (T2DM) poses complicated problems
for both society and clinicians when developing T2DM prevention and treatment
techniques. T2DM is an epidemic that affects people all over the world, with a
prevalence of 285 million in 2009 and a predicted rise to 435 million by 2030.
According to the Centers for Disease Control and Prevention (CDC), T2DM affected
almost 24 million Americans in 2007. Pre-diabetes, also known as impaired fasting
glucose or impaired glucose tolerance, affects at least 57 million people worldwide,
4 4
increasing the number of T2DM patients. Over the past ten years, the prevalence
of diabetes has increased by 90%, and in many regions of the world, the rate of
MANAGEMENT OF DIABETES
increase has been even faster.
Note: The complexity of treating type 2 diabetes has increased as medication has
advanced. Clinicians now have more pharmacological treatments for obesity and
hyperglycemia than ever before, yet they still have to deal with an illness that is
continuously progressing.
Glycemic management is essential to reducing microvascular problems and, in the
long run, cardiovascular events, according to ongoing clinical research. However, poor
glycemic control, hypoglycemia, and obesity continue to be difficult challenges for
doctors.
Both environmental and genetic factors, such as those that can affect insulin
sensitivity (such as insulin resistance) and insulin secretion capability, are related
to the rising prevalence of diabetes. Obesity and a sedentary lifestyle, which cause
changes in glucose homeostasis and aberrant lipid and protein metabolism, fuel
insulin resistance, which manifests in infancy.
The primary metabolic difference between obesity and the onset of hyperglycemia
442
and the development of T2DM is relative insulin deficiency. Diabetes seems to
advance inexorably due to an increasing insulin deficit. Therefore, the majority of
people increasingly require more therapy. To keep the glycemia under control, a
combination of therapies is needed, such as adopting a therapeutic lifestyle change
in addition to oral and injectable medications. The lack of optimal control for many
diabetic patients is a result of a failure to advance medication at the first indication
of therapeutic failure, particularly a reluctance to advance to insulin.
Targets For Treatment
Over the past two decades, treatment objectives for diabetes patients have
undergone significant modification. The idea of the connection between glycemic
control and microvascular problems in type 1 diabetes was supported by the
Diabetes Control and Problems Trial (DCCT). In the influential UK Prospective
Diabetes Study (UKPDS), similar findings for T2DM were made. The long-term
analysis of participants in these studies revealed a mortality benefit for T2DM and
MANAGEMENT OF DIABETES
a reduction in cardiovascular risk with insulin, metformin, and sulfonylureas at
10 years after a time of improved glycemic control. Treatment objectives must
be taken into account when allocating patients to a treatment program. The ADA
still recommends individualization and a HbA 1c target of 7% (53 mmol/mol) for
overall glycemic control. If the latter can be accomplished without experiencing
hypoglycemia issues, either less stringent control or alternatively more rigorous
normalization of glycemia down to 6% (42 mmol/mol) HbA 1c can be advised
for correctly selected patients. The International Diabetes Federation (IDF) and
American Association of Clinical Endocrinologists (AACE) recommend 6.5%
(48 mmol/mol) as a general target based on comparable data sources. All sources
advise that goals should be tailored to the individual depending on co-morbidities
and susceptibility to hypoglycemia, among other factors.
The ACCORD trial postulated that cardiovascular outcomes would be improved by
close to normal glucose control (HbA 1c 6% or below [ 42 mmol/mol]).
In light of the intensively treated group’s 22% increase in mortality, primarily from
fatal cardiovascular events, and very possibly, though it has not been proven, as a
result of hypoglycemia, a recent analysis of the ACCORD trial warns the provider
against trying to normalize glycemia in those with characteristics similar to this
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 patient cohort (e.g., older and those with existing cardiovascular disease). The
practitioner is faced with the conundrum of how to normalize glycemia while
avoiding hypoglycemia. For some patient groups, this pragmatic factor suggests
that newer medicines with a relatively low risk of hypoglycemia should be taken
into account. Additionally, routinely implementing techniques to identify and
reduce the risk of hypoglycemia in patients who are at high risk. Self-monitored
blood glucose (SMBG) testing, clear communication, and instruction about how
to handle hypoglycemia should it manifest itself frequently or severely are among
these. This is particularly true if hypoglycemia unawareness develops. Patients with
T2DM ultimately need to advance their treatment from combination oral therapy
to combination injectable therapy (basal bolus insulin regimens, incretin insulin
combos).
Early implementation of combination therapy reduces negative effects while
4 4
increasing clinical efficacy, lowering cost and tablet usage while improving
adherence. The latest ACCE recommendations use all medications and adjust the
MANAGEMENT OF DIABETES
dosage and timing of insulin based on the baseline HbA1c.
Diabetes and prediabetes lifestyle recommendations
One of the most difficult obstacles to good diabetes control is lifestyle management.
Finding advice on what to eat, how to exercise, and how to reduce psychological
pressures is usually hard for both the practitioner and the patient. Although fl
awed, it is regrettably a reality for many physicians that complicated patterns of
living behavior can be changed by giving general counsel during a hectic medical
appointment. The agreement that the patient is responsible for aiding in the
treatment of their sickness and is the only source of essential information needed to
manage their illness should take its place. Making patients more conscious of their
own dietary habits is one method.
In order to create a treatment plan for individuals with T2DM that takes into
account both the patient’s physiology and psychology, establishing a baseline for
eating and exercise (type, frequency, duration, and barriers) is just as crucial as
getting the results of first laboratory tests. Gaining a tight focus on a small number
of behavioral goals can boost achievement. We frequently employ the following
strategies for our patients: • Keep a food journal for the upcoming week; and • Wear
444
a pedometer and monitor your daily walks for the following seven days. Patients
are almost always surprised by the facts, but it also enables them to recognize their
own behaviors and to focus and motivate them to take the initiative in creating
important goals.
Initiating the process of working on a lifestyle change, emphasizing its relevance
to the patient, and reinforcing and refining the education to accomplish gradual,
attainable goals are all important parts of the physician’s involvement. The use of
motivational interviewing and determining the patient’s readiness to change are
crucial components of the medical professional and diabetes educator’s evaluation
of the patient.
Our standard approach is to strongly advise diabetes education for any patient who
is willing to do so, and to reiterate the necessity for lifestyle modification whenever
the need for additional medicine arises. We have found that the acronym FIRM
is helpful in helping trainees recall how to support patients in achieving lifestyle
changes. This stands for negotiating Few changes, usually one to three at each
MANAGEMENT OF DIABETES
clinical visit; those changes should be Individualized by the patient’s choice of the
aspects of behavior change to begin; the changes should be Realistic and therefore
likely to succeed by setting moderate, achievable goals within a specific timeframe;
and the changes should be Measurable and monitored through patient record-
keeping to be shared with the provider or diabetes educator at the next clinical visit.
Therapy for obesity as a treatment for T2DM
The utilization of weight loss and increasing physical activity measures as a
helpful treatment to achieve control of glycemia and favorably influence numerous
cardiovascular risk variables is a serious consideration because the great majority
of persons with T2DM are overweight or obese. Plans for T2DM prevention and/
or treatment may legally take into account the use of medication for obesity.
It has been frequently demonstrated that successful weight loss of 10% or less
improves glycemic control (HbA 1c reductions of 0.3–0.5% [3–6 mmol/mol] and
occasionally much more]), as well as favorably impacts lipids, hypertension, and
other cardiac risk factors. In the USA, three medications—phentermine, orlistat,
and sibutramine—have received approval for the treatment of obesity. A recent
loss of support by the European Medicines Agency has put an end to the potential
of broader usage of rimonabant, which was previously permitted in a number of
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 nations outside of the USA. The clinical development of additional endocannabinoid
receptor blocker medicines has also been stopped. The least researched drug, one
that is also the least used and not often advised, phentermine is only approved for
short-term use.
Currently, the use of orlistat in the treatment of obesity has been approved. As
a pancreatic and gastric lipase inhibitor, orlistat works. A dose of 120 mg taken
with meals three times a day results in about 20 to 30 percent of ingested fat
being excreted in the feces. The hardest side effect to control when there is a lot
of fat in the digestive system is anal leaking of oil to postprandial diarrhea, which
may come on suddenly. By paying attention to this anticipated impact and using
daily or twice-day doses, you can reduce gastrointestinal mishaps in patients and
possibly increase their adherence to low-fat diets. Although there hasn’t been any
evidence of long-term malabsorption of fat-soluble vitamins, supplementation with
a multivitamin that contains vitamin D is advised during treatment. There is now an
4 4
over-the-counter variant with a lower dosage (60 mg).
MANAGEMENT OF DIABETES
In patients using metformin or insulin, orlistat has undergone extensive study in
both the prevention and treatment of T2DM. In the XENDOS experiment, 3305
obese participants at risk for T2DM were randomized to receive orlistat 120 mg
three times per day or orlistat with therapeutic lifestyle change. The study lasted
four years. At the end of the study, the subset of participants who had impaired
glucose tolerance at baseline who were given orlistat experienced a 37% relative
risk decrease in developing T2DM. Positive effects on lipids were also seen.
When orlistat was added to the treatment regimen for obese T2DM patients who
were not responding to metformin alone, HbA1c decreased by 0.35% (4 mmol/mol)
and cholesterol and blood pressure management were improved. Similar benefits,
including improved glycemia (HbA1c 0.62 0.08 for orlistat-treated patients vs
0.27 0.08% for placebo; P 0.002, 7 vs 3 mmol/mol) and improved lipids despite
lower dosages of diabetic medication, were also observed in insulin-treated patients
who took orlistat for a year. Sibutramine predominantly affects central pathways,
inhibiting synaptic absorption of norepinephrine, serotonin, and to a lesser amount
dopamine. This promotes satiety and reduces hunger. The dosage ranges from 5 to
15 mg, with the 15 mg dosage having the best efficacy at the expense of the highest
frequency of side effects. Clinical trial settings have employed doses as high as 20
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mg with a comparable finding. A recent meta-analysis looked at eight of 30 clinical
trials that used sibutramine to treat diabetes. Studies combining sibutramine with
sulfonylureas, metformin, or a low-calorie diet were included by the authors.
In general, treatment effects were linked to a decrease of 5.5 kg of body weight,
compared to a rise of about 1 kg in comparison groups.
HbA1c improved on average by 0.28% (3 mmol/mol), while there was variation
amongst the included studies. Without having any negative impact on blood
pressure, triglycerides were reduced and high density lipoprotein (HDL) was
increased. There were slight increases in heart rate. Given how vulnerable patients
with diabetes are to the negative effects of even small changes in blood pressure
and how blood pressure affects complications from diabetes, the presence of
hypertension, especially if it is not optimally controlled, should be regarded as
a contraindication to using sibutramine. Endocannabinoid CB1 receptor blocker
rimonabant was recently taken off the market in Europe due to worries that it could
exacerbate mood disorders (depression).
MANAGEMENT OF DIABETES
Rimonabant clinical trials that were still in progress have also been stopped, raising
concerns about the usefulness and accessibility of medications that operate on the
endocannabinoid system. Despite its exclusion from research and lack of continued
widespread marketing, investigations have discovered a sizable antihyperglycemic
impact comparable to that of other medications for people with diabetes that have
received FDA approval. Such research supports the idea that some pharmacological
options for diabetes have glycemic effects that are comparable to those of treatments
for obesity. It doesn’t seem likely that future marketing of this kind of medication
will be prohibited by safety concerns involving depression. An increasingly popular
alternative is bariatric surgery for suitable individuals (usually BMI > 40 kg/m 2
or > 35 kg/m 2 with co-morbidities) who have failed effective lifestyle therapies
and/or medication for obesity. This method is being used more frequently because
of increased safety and uniformity, as well as growing evidence for its beneficial
outcomes, which include long-lasting remissions of T2DM in the majority of
patients. Such benefits’ physiology is yet not fully understood. The best candidates
to select for surgical treatment of cardiometabolic risk are being determined by
new paradigms. Most patients who are eligible for bariatric surgery are already
receiving a variety of treatments. Most people who were taking insulin will be able
447
 to quit after surgery, unless they have had diabetes for a very long time.
The need for insulin and occasionally other diabetic drugs significantly diminishes
during the hypocaloric diet used to prepare for such surgery. It is typical for patients
who have Roux-en-Y procedures to have a rapid reduction in their need for insulin
within a few days to a few weeks. To prevent hypoglycemia, it is frequently
necessary to cut the insulin dosage in half or more.
Combination medication for T2DM
Secretagogues and incretins are examples of treatments for T2DM, while
biguanides, thiazolidinediones, incretins, -glucosidase inhibitors, amylin analogs,
and colesevelam are examples of medications that enhance the activities of insulin.
Successful T2DM management typically combines pharmacological therapy with
lifestyle modification strategies.
4 4
Based on data from the UKPDS, we draw the conclusion that insulin secretory loss
begins approximately 10 years before a formal diagnosis of T2DM and progresses
MANAGEMENT OF DIABETES
to insulin deficiency approximately 10 to 12 years later. The two facets of T2DM—
insulin resistance and deficiency—are crucial in determining the type of medication
to use and how well it works. This chapter summarizes recent developments in
the treatment of diabetes and obesity, includes evidence and opinions on drug
sequences, and briefly describes several novel drugs being developed for the
treatment of T2DM.
4.5 Diabetes Patients’ Hospital Treatment and Surgery
Diabetes diagnosis is causing an epidemic-level burden worldwide. According to
the International Diabetes Federation, by 2030, type 2 diabetes prevalence rates
will have risen by about 20% in Europe and by 65 to 98% in less developed nations.
Diabetes affects disproportionately many hospital patients. Because diabetes is
poorly coded as a comorbidity, the prevalence of diabetes in the inpatient population
is very certainly underestimated.
This holds true for both planned and unexpected medical care. In the USA, between
12% and 24% of all inpatients have been diagnosed with diabetes, according to
conservative estimates. About 1.34 million days are spent in hospitals each year
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by patients with diabetes, and it is estimated that there are 80 000 unused bed days
per year in the UK. Providing care for diabetic inpatients costs about £ 485 million
a year. Diabetes-related hospital admissions have gone up and will continue to do
so. But because it ignores patients with elevated plasma glucose levels who do not
have a diabetes diagnosis, this simply reflects the tip of the iceberg. Two additional
patient categories with hyperglycemia are hospitalized alongside individuals with
documented diabetes.
First, there are those whose undiagnosed diabetes develops while they are
hospitalized and is subsequently confirmed after they are released. Secondly, there
are those whose so-called “hospital-related” hyperglycemia—also known as “stress
hyperglycemia”—occurs while they are hospitalized but returns to normal after
they are released.
According to recent studies, the combined number of people with elevated plasma
glucose levels may increase by an additional 30% in these two groups.Therefore,
if all three groups are included in the burden of “in-hospital hyperglycemia,” the
prevalence is almost 40% of all hospital inpatients.
MANAGEMENT OF DIABETES
Standards Of Treatment For Diabetic Hospital Patients As Of Right Now
Suggestions for standards of care for hospital inpatients have been presented by
a number of professional organizations from various nations. The International
Diabetes Federation (IDF), an umbrella group for more than 200 national diabetes
associations in more than 160 nations, has also released a standards paper for type
2 diabetes inpatient care. Below is a review of the key periodicals’ content. There
are several themes that keep coming up, including equal access to specialized
treatments, patient empowerment, following predetermined rules for care delivery,
defining glycemic objectives, and incorporating efficient, audited hyperglycemic
management procedures.
International Diabetes Federation 2005
Several guidelines for inpatient care were included in the IDF’s guideline on the
treatment of type 2 diabetic patients. The IDF group’s standard recommendations
might be generally divided into four groups:
1 Hospital inpatient care provider. With a focus on individual plans, including
discharge and follow-up, access to the multidisciplinary team, appropriate laboratory
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 and investigative procedures, raising staff awareness of the needs of people with
diabetes, and implementing strategies to prevent patient disempowerment by
promoting self-management of diabetes, this should be carried out by a trained
diabetes care health care professional.
2. Ward care in general. When it is appropriate, patients should be given the freedom
to self-manage their dietary choices, insulin delivery, and glucose monitoring.
3 Treatment of people having hospital operations. For those undergoing planned
procedures, there should be a provision for the assessment of glycemic control as
well as of metabolic and vascular risk, and established protocols should be in place.
The unique dangers of diabetes, such as the occurrence of new ulcerations, heart
risk, and renal failure, should be made clear to the staff.
4 4
4 taking care of the seriously ill. Patients should be treated in accordance with a
stringent glycemic protocol, with glucose levels maintained at or below 110 mg/dL
MANAGEMENT OF DIABETES
(6.1 mmol/L) and hypoglycemia actively avoided.
American Diabetes Association and American Association of Clinical
Endocrinologists 2006
An extensive evaluation of the relevant literature and recommendations for effective
management strategies were provided in the American Diabetes Association
(ADA) Technical evaluation on the Management of Diabetes and Hyperglycemia in
Hospital. The application of these guidelines and rules had remained a challenging
objective in routine clinical practice. A further consensus statement titled Inpatient
Diabetes and Glycemic Control: A call to action was therefore created in 2006
by the American Diabetes Association (ADA) and the American Association of
Clinical Endocrinologists (AACE) in an effort to identify and remove practice-
related obstacles that stand in the way of better inpatient diabetes care. Based on
recent papers that have shown concern about the detrimental effect of in-hospital
hypoglycemia in various clinical settings, this was modified in 2009 with new
glycemic targets.
450
Canadian Diabetes Association
The Canadian recommendations have distinct sections on post-operative and post-
acute coronary syndrome glycemic control, and they recommend glucose levels of
6.1 mmol/L in post-surgical ITU patients and 128 - 180 mg/dL (7.1 - 10 mmol/L)
in post-myocardial infarction patients.
UK Diabetes Services
The first set of national standards for treating diabetes were outlined in the
Diabetes National Service Framework. For hospital treatment, two standards were
established.
standard seven. The NHS will create, put into practice, and track agreed-upon
guidelines for prompt and efficient treatment of diabetic emergencies by adequately
qualified medical personnel.
The care of acute problems and steps to reduce the likelihood of recurrence will
both be covered by protocols.
MANAGEMENT OF DIABETES
2 Standard 8. Effective diabetes treatment will be provided to all children,
adolescents, and adults with diabetes who are admitted to the hospital for whatever
reason. They will continue to participate in choices pertaining to the treatment of
their diabetes whenever possible.
NHS Diabetes, a national diabetes support organization 2008
The National Diabetes Support Group published a report in 2008 with a specific focus
on commissioning and improving diabetes inpatient services. The commissioning
toolkit for NHS Diabetes has now been updated to incorporate the commissioning
of emergency and inpatient treatment.
A patient guide titled “What care to expect in hospital” has been created by Diabetes
UK and is accessible through Diabetes UK. It is thought that increasing patient
empowerment will raise hospital care standards. Through the “Putting Feet First”
campaign, Diabetes UK, NHS Diabetes, and a number of other professional groups
have encouraged the dissemination of a national guideline for the management of
patients with acute diabetic foot problems in hospitals.
A set of suggestions to raise hospital inpatient care standards was recently released
451
 by the National Health Institute of Innovation and Implementation. The “Think
Glucose” program was named for it and spread to all UK hospitals. A toolbox and
a list of recommendations have been given to each acute hospital in the UK in an
effort to raise standards.
Surgery For Diabetic Patients
Diabetes patients are less healthy than people without diabetes, which increases
their likelihood of needing surgery. According to estimates, 50% of people with
diabetes will need surgery at some point in their lives. Diabetes is linked to an
increased risk of postoperative cardiovascular morbidity and mortality as well
as perioperative infection. Labile glycemic control in the perioperative phase is
caused by the intricate interplay of the surgical technique, anesthesia, fasting, and
extra postoperative factors such artificial feeding and emesis.
it is crucial that all diabetic patients undergoing surgery have a thorough risk
assessment that has a special emphasis on cardiac risk. One must take into account
both the specific patient risk associated with pre-existing co-morbidities and the risk
connected with the surgery itself when assessing risk for elective procedures. Those
with significant cardiorespiratory pathology are at the greatest risk. The literature
has a number of cardiac risk stratification indexes, but they all fundamentally rely
on clinical factors to categorize patients as having a low, intermediate, or high risk
of suffering a significant cardiac event during or after surgery.
In clinical practice, the Goldmann cardiac risk index is frequently employed (Table
4.20).

4 4
Metabolic Response To Surgery

MANAGEMENT OF DIABETES
MANAGEMENT OF DIABETES

Insulin resistance and relative insulin hyposecretion are conditions brought on

by surgery and anesthesia. A complicated set of hormonal and metabolic changes
are brought on by it. The release of the counter-regulatory or “stress” hormones
is considerably enhanced, especially cortisol and catecholamines, and this can
cause an abrupt decline in insulin sensitivity. Increased sympathetic activity and
higher levels of catecholamines in the bloodstream tend to limit insulin secretion.
Overall, these modifications drive metabolism toward catabolism, resulting in
elevated hepatic glucose generation, hyperglycemia, and accelerated protein and
fat breakdown. Each person’s counter-regulatory response has a different intensity,
which increases with extended surgery and other conditions such postoperative
Table 4.20: Goldmann risk index
sepsis.
The guidelines from the American College of Cardiology and American Heart
Preoperative Assessment Association introduce the idea of “surgery-specific risk.” Based on the level of
The majority of patients today are admitted on the day of the planned procedure. hemodynamic stress connected to particular operations, risk stratification is used.
Pre-assessment planning in patients with diabetes can avoid needless cancellation The risk involved with various forms of surgery is summarized in Table 4.21.
of surgery, provide opportunities for joint care planning with the patient, and enable
optimization of glycemic control prior to surgery, which can shorten hospital stays, A thorough medical history and examination are necessary for every patient.
reduce medication errors, and enhance patient experiences. The assessment of glycemic control, long-term consequences, the occurrence of
Diabetes patients must be carefully evaluated due to their complexity and high hypoglycemia and its frequency, and the patient’s awareness and understanding of
risk of coronary heart disease, which can occasionally be asymptomatic. Therefore, all pharmacological therapy should be key components of this. In the days before

452 453
 surgery, patients should receive written information on changes in their medications,
particularly their diabetic medications.
Table 4.22: Surgery - specific risk
HbA1c should be a part of routine tests since research suggests that values over 7%
(> 53 mmol/mol) may be linked to an increased risk of postoperative infections.
4 4
There is strong evidence that a thorough pre-assessment of diabetic patients will
MANAGEMENT OF DIABETES
facilitate a safe and efficient hospital discharge. A DSN has established a patient
pathway from pre-assessment to discharge in Bolton, UK. This pathway involves
assessment, glycemic control optimization, preoperative insulin infusion scale
drafting, implementation of planning for routine diabetes treatment postoperatively,
and assessment. This study has significantly improved patient satisfaction, decreased
medication mistakes, and length of stay.
Each patient should receive an explanation of the procedure and the intended
anesthetic during the pre-assessment appointment. To help the patient make
an informed choice about the diabetes treatment to be provided, the diabetes
management plan should be addressed. If further appointments are necessary for
glycemic control optimization, schedule them now. All material should be backed
up by relevant academic research. All therapy suggestions should be recorded in
the patient’s notes and in a portable record that the patient keeps.
4.6 Summary
Managing diabetes involves a comprehensive approach that combines both
pharmacological and nonpharmacological interventions. Diabetes is classified
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into two main types: type 1 and type 2. Type 1 diabetes is an autoimmune
condition where the body’s immune system attacks the insulin-producing
beta cells in the pancreas, leading to little to no insulin production. Type 2
diabetes is characterized by insulin resistance and impaired insulin secretion.
Type 1 diabetes requires lifelong insulin therapy since the body cannot produce
insulin. Insulin can be administered through injections or insulin pumps. Monitoring
blood glucose levels is crucial for adjusting insulin doses. Carbohydrate counting
helps match insulin doses with food intake. Regular physical activity helps improve
insulin sensitivity and overall health. Continuous glucose monitoring (CGM)
systems offer real-time glucose readings and trend data, aiding better control.
Type 2 diabetes management involves lifestyle modifications and, in some cases,
medication. Lifestyle changes include maintaining a balanced diet with controlled
carbohydrate intake, emphasizing fiber-rich foods, lean proteins, and healthy fats.
Regular exercise enhances insulin sensitivity and weight management. Weight loss,
if necessary, significantly improves glycemic control.
MANAGEMENT OF DIABETES
Oral medications and injectable non-insulin therapies may be prescribed. Metformin
is a commonly prescribed oral medication that improves insulin sensitivity and
reduces glucose production in the liver. Other classes of drugs include sulfonylureas,
meglitinides, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, and
SGLT2 inhibitors. Medications are tailored based on individual patient characteristics.
Type 2 diabetes often requires a combination of medications to achieve target
glucose levels. Healthcare providers determine the most effective combination,
considering factors like the patient’s age, comorbidities, and potential side effects.
If oral medications are insufficient, insulin therapy might be initiated. This can
involve long-acting basal insulin or a mix of basal and prandial (mealtime) insulin.
Insulin regimens are personalized to maintain glucose within the target range
In select cases of obesity-related type 2 diabetes, bariatric surgery may be considered.
Procedures like gastric bypass and sleeve gastrectomy can lead to significant
weight loss, often resulting in diabetes remission. Surgery enhances insulin
sensitivity and modifies gut hormones, positively affecting glucose regulation.
For both type 1 and type 2 diabetes patients undergoing surgery, careful planning is
essential. Blood glucose levels should be well-managed before and after surgery to
prevent complications. Intravenous insulin might be used during surgery, and patients
may resume their usual diabetes medications once they can tolerate oral intake.
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 Both types of diabetes carry the risk of complications. Long-term high blood
glucose levels can damage blood vessels, nerves, and organs. Regular medical
check-ups, eye exams, and foot care are vital to detect and manage potential issues
promptly. Preventing diabetes complications involves maintaining blood pressure
and cholesterol levels within target ranges. Smoking cessation, a heart-healthy
diet, weight management, and regular exercise all contribute to better outcomes.
Effective diabetes management revolves around a holistic approach. Type 1 diabetes
necessitates insulin therapy, while type 2 diabetes management centers on lifestyle
changes, oral medications, and, if needed, insulin. Individualized treatment plans
consider patient characteristics and preferences. Bariatric surgery might be an
option for select type 2 diabetes patients with obesity. Surgical and non-surgical
procedures require vigilant glucose control. Preventing complications involves
continuous monitoring and adherence to a comprehensive care regimen. Regular
communication with healthcare providers ensures optimal diabetes management
4 4
and a higher quality of life.
the role of preoperative assessment, intraoperative glucose management, and
postoperative monitoring in preventing hyperglycemia-related complications.
5. Emerging technologies, such as continuous glucose monitoring (CGM) systems
and closed-loop insulin delivery systems (artificial pancreas), have revolutionized
diabetes management. Describe the benefits and limitations of these technologies,
and evaluate their potential impact on improving glycemic control and patient
quality of life.
6. Diabetic complications significantly contribute to morbidity and mortality.
Discuss the pathophysiological mechanisms underlying microvascular
(retinopathy, nephropathy, neuropathy) and macrovascular (cardiovascular
disease) complications in diabetes. How can intensive glucose control and
management of associated risk factors mitigate the development of these
complications?

MANAGEMENT OF DIABETES
MANAGEMENT OF DIABETES

4.7 Review Questions 7. Personalized medicine has gained traction in diabetes management. Explain
how genetic factors, including HLA alleles in type 1 diabetes and genetic
1. What are the key differences in the pharmacological management of type 1 and
predisposition in type 2 diabetes, can influence disease susceptibility, treatment
type 2 diabetes? Discuss the rationale behind insulin therapy for type 1 diabetes
response, and the development of complications. How might genotyping guide
and the various classes of medications used for type 2 diabetes, including their
treatment decisions in the future?
mechanisms of action and clinical indications.

2. In the context of type 2 diabetes, explore the potential benefits and drawbacks
of different oral anti-diabetic agents, such as sulfonylureas, DPP-4 inhibitors, and
SGLT2 inhibitors. How would you approach selecting an appropriate medication
regimen for a patient with multiple comorbidities?

3. Bariatric surgery has shown promise in achieving diabetes remission in some

patients with obesity-related type 2 diabetes. What are the underlying mechanisms
by which bariatric surgery influences glucose homeostasis? Discuss the selection
criteria for candidates eligible for such surgical interventions.

4. When managing diabetes in surgical patients, what strategies would you

implement to achieve optimal glycemic control perioperatively? Elaborate on

456 457
 4
MANAGEMENT OF DIABETES

458
 Management Of Comorbidities/
Complications/ Dm In Extremes Of Age
Uncontrolled diabetes can have a variety of short- and
long-term pathophysiological repercussions, such as
cardiovascular damage, gastrointestinal problems, an
increased risk of infection, depression, and microvascular
complications (such as neuropathy, retinopathy, and 5

diabetic kidney disease). Considering how negatively

Management Of Comorbidities/Complications/ Dm In Extremes Of Age

diabetic complications can affect a patient’s quality of life,
pharmacists should be on the lookout for the signs and
offer guidance on the appropriate management options.
An estimated 34.2 million Americans, or 10.5% of the
population, have diabetes.

5 Chapter Contents
5.1 Comprehensive Management of Cardiovascular Risk Factors
5.2 Antiplatelet Therapy in Diabetes
5.3 Diabetes in Special Groups
5.4 Microvascular Complications And Foot Care In Individuals
5.5 Summary
5.6 Review Questions

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 In the United States, the anticipated total direct and indirect expenses of diabetes
diagnosis grew from $188 billion in 2012 to $327 billion in 2017. Diabetes now
affects around 20% of people with diabetes, making it the main cause of end-stage
renal disease in that year. Nearly 50% of diabetic individuals experience diabetic
retinopathy, which is currently the main cause of new instances of blindness in
adults between the ages of 18 and 64. Overall, improved glucose control and
lifestyle changes help to lessen all problems associated with diabetes. Numerous
investigations have shown that better glycemic control can prevent and manage
the consequences of diabetes. These include the Actions to Control Cardiovascular
5 Risk in Diabetes Study, the Kumamoto Study, the Epidemiology of Diabetes
Interventions and Complications study, the Diabetes Control and Complications
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Trial, and the Fenofibrate Intervention and Event Lowering in Diabetes study.
Overview of diabetes problems
Hyperglycemia, a partial or complete lack of insulin action, and the emergence
of diabetes-specific pathology in the retina, renal glomerulus, and peripheral
nerve are all characteristics of diabetes. Additionally, accelerated atherosclerosis
disease affecting the arteries supplying the heart, brain, and lower limbs is linked
to diabetes. Diabetes mellitus is now the primary cause of new blindness in adults
20 to 74 years old as well as the major cause of end-stage renal disease (ESRD) in
the developed world as a result of its disease-specific pathology. Dialysis patients
with diabetic ESRD had a 50% worse survival rate than individuals without
diabetes. Neuropathy, which comprises distal symmetrical polyneuropathy,
mononeuropathies, and a number of autonomic neuropathies including erectile
dysfunction, urine incontinence, gastroparesis, and nocturnal diarrhoea, affects
more than 60% of diabetic patients. 50% of all non-traumatic amputations in
the USA are caused by diabetic accelerated lower extremity vascular disease in
association with neuropathy.
Note: Diabetes, a chronic metabolic disorder, disrupts how the body processes
glucose. Classified as Type 1 or Type 2, it necessitates vigilant management to prevent
complications. Lifestyle modifications, medications, and personalized care play pivotal
roles in achieving optimal health for individuals with diabetes.
460
Diabetes and decreased glucose tolerance more than triple or even eight-fold the
risk of cardiovascular disease (CVD). As a result, 35% of patients with acute
myocardial infarction (MI) hospitalized had decreased glucose tolerance and over
40% developed diabetes. Last but not least, diabetes impairs the development of new
blood vessels in response to ischemia, which reduces the production of collateral
vessels in ischemic hearts and causes foot ulcers that do not heal. The microvascular
consequences, which include retinopathy, nephropathy, and peripheral neuropathy,
are the main topic of this chapter.
5
5.1 Comprehensive Management of Cardiovascular Risk Factors
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Heart and blood vessel conditions collectively referred to as CVD include
peripheral artery disease (PAD), congenital heart disease, coronary heart disease,
cerebrovascular illness, heart failure, etc. This scientific statement primarily focuses
on the heart failure, cerebrovascular illness, and coronary artery disease (CAD)
parts of major adverse cardiovascular events (MACE). The buildup of lipoproteins
in the artery wall is the first stage of atherosclerosis. Foam cells build up and low-
density lipoprotein (LDL) particles are oxidized in the subendothelial region,
which ultimately results in vascular changes. When arterial plaque deposits become
unstable and burst, acute coronary and cerebrovascular syndromes develop.
In people with T2D, a number of risk factors for atherosclerosis and CVD, including
hypertension, insulin resistance, hyperglycemia, obesity, and dyslipidemia, are
frequently coexisting. By encouraging the development of atheroma plaques,
diastolic dysfunction, and ventricular hypertrophy, insulin resistance encourages
macrovascular disorders. Among other things, advanced glycosylated end products
and oxidative stress are two ways that hyperglycemia encourages the onset of
CVD. Heart failure, CAD, and cerebrovascular illness are all facilitated by both
insulin resistance and hyperglycemia. Tools for both primary and secondary CVD
prevention are lifestyle modifications, weight loss, and cardioprotective therapies.
Several significant clinical trials have advanced our knowledge of lifestyle, blood
pressure (BP), blood glucose, antithrombotic, and cholesterol management in
primary and secondary prevention of CVD since the “Update on Prevention of CVD
in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific
Statement From the American Heart Association and the American Diabetes
Association” in 2015. This logical assertion (1) combines the ongoing science and
461
 best practices for the extensive administration of cardiovascular gamble factors in
grown-ups with T2D and (2) gives extra setting on the significance of the social
determinants of wellbeing (SDoH) and wellbeing value in cardiovascular gamble
factor the board from the person to the populace level (Figure 5.1).
5 5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.1: Adults with type 2 diabetes who have lower cardiovascular risk:
key illustration. SGLT-2 stands for sodium-glucose cotransporter-2; GLP-1
stands for glucagon-like peptide 1; PCSK-9 stands for proprotein convertase
subtilisin/kexin type 9 serine protease.
The metabolic syndrome and prediabetes, which are caused by insulin resistance
in the liver, skeletal muscles, and adipocytes as well as proinflammatory cytokines,
are steps in the pathophysiological development to type 2 diabetes (T2D). These
mechanisms result in adipocytes that lead to hyperglycemia and lipolysis, as well
as decreased glucose absorption in skeletal muscle and hepatic glucose generation.
Diabetes And Cardiovascular Disease Risk Factors
Glucose
The risk of CVD is lowest when the fasting blood glucose is between 4 and 4.9
mmol/L, although it exists across a wide glucose concentration range that includes
those without diabetes. Despite the well-known link between blood sugar and
atherosclerosis, surprisingly few studies have been able to demonstrate how lowering
blood sugar can improve cardiovascular outcomes. In T1DM, the Epidemiology of
Diabetes Interventions and Complications (EDIC) study found that glucose lowering
462
was associated with a long-term benefit with regard to cardiovascular complications
that became apparent only years after recruitment. The UKPDS intensive glucose
therapy had long-lasting positive effects on macrovascular outcomes in T2DM,
but unlike the microvascular benefits, risk reductions for MI and death from any
cause were only seen with prolonged post-trial follow-up (Figure 5.2). According
to these findings, individuals with T1DM may experience a greater reduction in
cardiovascular risk than those with T2DM due to improved glucose management,
which is consistent with the findings of one meta-analysis.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.2: Results of the UK Prospective Diabetes Study (UKPDS) at 10
years follow - up
Additionally, neither of the recent Action in Diabetes and Vascular Disease:
Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE)
trials nor the Action to Control Cardiovascular Risk in Diabetes (ACCORD)
trials, each involving more than 10,000 participants, were able to demonstrate a
significant beneficial effect on CVD outcome when targeting near-normal glucose
levels in T2DM as determined by a HbA1c 6.5% (48 mmol/mol) (Figure 5.3). The
ACCORD study’s discovery that near-normal glucose management was actually
associated with a significantly higher risk of death from any cause and death from
cardiovascular causes—the very outcomes the trial was intended to prevent—
was more concerning. Our knowledge of the issue of glycemic control and CVD
should be improved by a number of different outcome trials that are currently being
463
 conducted.
5 subjects without diabetes. It was determined that because individuals with diabetes
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.3: Effects of better diabetes management to a HbA1c of less than 6.5%
(48 mmol/mol) in the ACCORD and ADVANCE investigations. cardiovascular
disease (CVD); Hi is traditional glycemic management; Lo is intensive glycemic
control
Dyslipidemia
Targeting dyslipidemia has been shown to be far more effective than addressing
hyperglycemia in preventing the macrovascular consequences of diabetes, but for a
long time, the benefits of intervention on lipoproteins as cardiovascular risk factors
in diabetes remained unclear. The main cause was the exclusion of diabetics from
trials of lipid-lowering treatments. As a result, there is hardly any data from early
research using bile acid sequestrants, fatty acids, or nicotinic acid. Small dense LDL
particles, low HDL cholesterol levels, and high triglyceride-rich residual lipoproteins
(often assessed as hypertriglyceridemia) are its defining characteristics. Diabetes-
related dyslipidemia is likely caused by a number of factors, including peripheral
insulin actions on adipose and muscle tissue, downregulation of lipoprotein lipase
(LPL) as opposed to hepatic lipase, increased cholesteryl ester transfer protein
(CETP) activity, and insulin effects on liver apolipoprotein production.
Low density lipoprotein cholesterol
The main goal of lipid-lowering medication is identified as reducing LDL
464
cholesterol. LDL cholesterol and HDL cholesterol were the two main risk factors
for CHD in this cohort, according to an analysis of the UKPDS. Even relatively
recent studies, like the Scandinavian Simvastatin Survival Study (4S), discouraged
patient recruitment or limited enrollment to those with hypercholesterolemia
and acceptable glycemic control (HbA 1c 8% [64 mmol/mol]). Studies have just
lately been conducted, enrolling sizable T2DM patient populations. Out of 4444
individuals, only 202 had diabetes in the 4S experiment. Simvastatin medication was
related with a 55% reduction in major CHD (fatal and non-fatal CHD) in this small
group of participants (P = 0.002) as opposed to a 32% reduction in major CHD in
5
have a higher absolute risk of atherosclerotic events and CHD, the absolute benefit
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
of decreasing cholesterol in these patients may be greater than in those without
diabetes. This hypothesis was later supported by a number of further studies that
included diabetic patients as a subset. Numerous research using statins specifically
for diabetes have been carried out. The two studies with the most distinction were
the Collaborative Atorvastatin Diabetes Study (CARDS) and the Heart Protection
Study (HPS), in which participants were randomized in a double-blind, placebo-
controlled method to receive either 10 mg/day of atorvastatin in CARDS or 40
mg/day of simvastatin in HPS. As a result, LDL cholesterol was reduced by 40%
and 33%, respectively, along with cardiovascular endpoints by 37% and 31%. The
HPS, the largest statin study to date, comprised 5963 individuals with diabetes as
a subset (29% of the total research population). Only individuals with diabetes
and more than one additional risk factor (such as uncontrolled hypertension and/
or microalbuminuria) but no history of overt cardiovascular disease (CVD) were
included in the CARDS experiment. Due to unexpected early benefits, the trial
was stopped two years early. In contrast, a trial that used atorvastatin and had a
similar design to CARDS, Atorvastatin trial for Prevention of Coronary Heart
Disease Endpoints in Non- Insulin Dependent Diabetes Mellitus (ASPEN), found
a non-significant 15% reduction in occurrences. Despite a 41% decrease in LDL
cholesterol, intensive LDL cholesterol lowering in end-stage diabetes with renal
failure reduced incidents by a non-significant 8%. Therefore, statin medication
seems to have advantages early in the course of diabetic illness. Overall, the data
suggests that statin medication is effective in lowering cardiovascular risk in
patients with diabetes. According to a meta-analysis that assessed the effectiveness
of cholesterol-lowering therapy in 18686 diabetic patients participating in 14
465
 randomized trials of statins, there was a 21% relative decrease in major vascular
events and a 9% relative decrease in all-cause mortality for every 1 mmol/L decrease
in LDL cholesterol (Figure 5.4). Since diabetics were not allowed to participate in
bile acid sequestrant trials, there are minimal data on diabetes and other medications
that lower LDL cholesterol. In contrast to bile acid sequestrants, the cholesterol
absorption inhibitor ezetimibe has very little impact on other lipid fractions. It
reduces upper intestine cholesterol absorption to result in a 20–25% drop in LDL
cholesterol when used alone. The Simvastatin Ezetimibe Aortic Stenosis trial did
not include diabetics. More recently, it has received many warnings about potential
5 problems with surrogate marker assessments as well as hints about possible negative
outcomes. These questions will hopefully be addressed by two ongoing trials: the
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Study of Heart and Renal Protection (SHARP) trial, in which simvastatin plus
ezetimibe is compared with placebo, and the Improved Reduction of Outcomes:
Vytorian Efficacy International Trial (IMPROVE-IT), in which simvastatin plus
ezetimibe is compared with simvastatin plus placebo.
Figure 5.4: Low density lipoprotein (LDL) cholesterol reduction on
cardiovascular events in persons with and without diabetes is compared
Low density lipoprotein subfractions
A variety of particles make up the population of the LDL class. Regarding lipid
composition, charge, density, and particle size and shape, LDL is diverse. The
diameters of LDL particles fall between the dense and small protein-rich HDL
and the big triglyceride-enriched very low density lipoprotein (VLDL) particles.
The in vitro and cell culture investigations imply that these small dense LDL
particles may be more easily oxidized and glycated, which may make them more
466
atherogenic than would be inferred from their concentration alone. Through the
macrophage’s uncontrolled absorption of oxidized LDL, cholesterol is delivered to
the atherosclerotic plaque in atherosclerosis and is elevated in diabetes.
Note: At the time of diagnosis and at least once a year after that, all diabetics
should undergo rigorous screenings for hypertension and signs of hypertensive
tissue damage. Values persistently over the World Health Organization/
International Society of Hypertension limits defined for hypertension in
the general population—130–140/80–85 mmHg—require treatment. 5
Additionally, the blood lipid profile ought to be examined.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
The LDL particle’s fatty acid makeup is another factor. The primary polyunsaturated
fatty acid in the LDL particle is linoleic acid, which is elevated in diabetes. The
insulin-sensitive enzyme 5 - desaturase’s diminished activity may be the cause
of this. The amount of linoleic acid in LDL particles and their susceptibility to
oxidize are strongly correlated. Increased free radical production from uncontrolled
diabetes causes more oxidation. LDL particles carry substantially less cholesterol
per particle because they are smaller and denser. Because there will be more LDL
particles at any cholesterol concentration, estimation of the LDL cholesterol may
consequently be inaccurate. Numerous studies, such as the Quebec Cardiovascular
study, have confirmed the link between small dense LDL and cardiovascular
disease (CVD), finding that men with small dense LDL particles had an increased
risk of coronary artery disease (CAD) compared to men with normal-sized LDL
particles, independent of LDL cholesterol, triglyceride, and the total cholesterol:
HDL cholesterol ratio. However, no prospective studies have specifically examined
whether changing particle size parameters will have an impact on the development
of CVD. The risk of additional cardiovascular events remains high even with
effective LDL cholesterol treatment, highlighting the significance of reducing other
abnormalities and other CVD risk factors frequently seen in these patients.
Triglycerides
Although the origin of the high triglycerides in diabetes is complicated, it has
been suggested that diabetes should actually be called lipidus rather than mellitus
467
 because of this abnormality.
Diabetes patients may experience changes in plasma lipoproteins as a result of
insulin action defects and hyperglycemia. As an alternative, particularly in the
case of T2DM, the metabolic disorder caused by obesity and insulin resistance
that underlies this type of diabetes may also result in lipid abnormalities unrelated
to hyperglycemia. It might be said that this molecular interaction between lipid
and carbohydrate metabolism has produced a “lipocentric” understanding of
the pathophysiology of insulin resistance and T2DM. The largest disruption in
lipoprotein metabolism in diabetes is seen in the triglyceride-rich lipoproteins,
5 resulting from anomalies in chylomicron synthesis and clearance, given that
fatty acids play such a significant role in insulin sensitivity, obesity, and T2DM.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Triglycerides, also known as triacylglycerol, are a heterogeneous set of molecules
that are most usually tested collectively, as a “family” of analytes. They are created
when one molecule of glycerol joins with three fatty acids.
Increased risk for atherosclerosis events is linked to elevated blood triglyceride
levels. It is more challenging to establish hypertriglyceridemia as an independent
cardiovascular risk factor because high serum triglyceride levels are linked
to abnormal lipoprotein metabolism, obesity, insulin resistance, diabetes, and
low levels of HDL cholesterol, among other cardiovascular risk factors. It can
be challenging to demonstrate that increased triglycerides are a risk factor for
atherosclerotic vascular disease since some causes of hypertriglyceridemia have no
discernible impact on the condition. In spite of this, numerous meta-analyses have
established that triglycerides constitute a separate risk factor for CHD.
Plasma triglycerides come from two main sources: endogenous (from the liver)
and exogenous (from dietary fat), which are both carried by VLDL particles. These
lipoproteins and chylomicrons are hydrolyzed by LPL into free fatty acids in
capillaries within adipose and muscle tissue. Apolipoprotein C - II activates LPL by
cleaving the triglyceride core and releasing free fatty acids, which can then be used
by muscle for energy or stored in adipose tissue for later use. Apolipoprotein C - III
inhibits LPL. Hypertriglyceridemia is the most frequent lipoprotein abnormality
discovered in uncontrolled diabetes in ordinary clinical practice. Reduced
catabolism (mostly as a result of LPL’s lower activity) or enhanced synthesis
or absorption are some of the causes for these. T2DM causes an increase in the
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production of liver apolipoprotein B, which is a key protein in LDL and VLDL.
Increased lipolysis in adipose tissue as a result of insulin resistance and/or insulin
deficiency is indirectly responsible for this. Increased lipolysis causes fat cells to
release more fatty acids, which is followed by an increase in fatty acid transport to
the liver. The chylomicron is put together in the intestine, and the VLDL particle
is put together in the liver, by the microsomal triglyceride transfer protein (MTP).
It has been demonstrated that diabetic persons’ intestines have higher MTP levels.
Diabetes patients appear to have a negative impact on cholesterol absorption.
Diabetes patients have higher levels of the Niemann-Pick C1-like 1 protein, which
is essential for the absorption of cholesterol. A functional complex made up of the 5
ATP-binding cassette transporters ABC-G5 and ABC-G8 dimers is required for
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
the removal of dietary cholesterol and non-cholesterol sterols from the liver and
gut. Both the liver and the gut of diabetic patients have demonstrated decreased
levels of these proteins. An enzyme called LPL, which is insulin-dependent, is in
charge of changing lipoprotein triglycerides into free fatty acids. It also performs
a number of additional lipid and carbohydrate metabolism-related tasks. Both
T1DM and T2DM patients have decreased LPL activity, which is further repressed
by cytokines produced from adipose tissue including tumor necrosis factor-alpha
(TNF-alpha) and interleukin-6 (IL-6). Based on their effectiveness in lowering LDL
cholesterol, statins are the mainstay of lipid management. However, they have only
modest effects on the components of the atherogenic dyslipidemia linked to T2DM,
with a maximum reduction in triglycerides of 15–30% and an average increase
in HDL cholesterol of less than 10%. Regarding the advantages of immediately
treating hypertriglyceridemia, there is no universal agreement. It also gets harder to
discriminate between the various advantages because the therapies typically have
an impact on both triglycerides and HDL cholesterol.
Fibrates
The “ fibrate “ class of lipid-lowering medications is helpful for lowering elevated
triglyceride or non-HDL cholesterol levels because these drugs increase lipoprotein
lipase activity, reduce apolipoprotein C-III, and may increase HDL cholesterol or
decrease fibrinogen. They do this by acting on peroxisomal proliferator-activated
receptors (PPAR) (a protein). Despite this, clinical trials of these medications have
often had inconsistent results, and the majority of early trials enrolled only a small
number of diabetic patients. In 2531 males with an acute MI, the VA-HIT study
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 assessed the potential benefits of gemfibrozil. We sought for patients who had
low HDL cholesterol ( 1.0 mmol/L) and low LDL cholesterol ( 3.6 mmol/L). The
primary outcome (fatal and non-fatal MI) was significantly reduced by 22%. T2DM
affected one-third of the subjects. Even though HDL cholesterol only changed by
8% and LDL cholesterol did not alter at all (0%), these results were nevertheless
attained. An analysis of the effects of gemfibrozil revealed that a 31% reduction
in triglycerides—which reflects changes in particle sizes but is unrelated to event
reduction—was the main benefit of the fibrate therapy. However, the Fenofibrate
Intervention and Event Lowering in Diabetes (FIELD) study’s findings have
5 significantly tempered the enthusiasm for fibrate use. A subgroup analysis of the
subjects with diabetes showed a relative risk reduction of 32% compared to 18%
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
in the non-diabetic group. In this investigation, 9795 T2DM patients who were
not receiving statin therapy at the start of the study were randomly assigned to
receive either fenofibrate (200 mg/day) or a placebo. Participants in the experiment
received medication for 5 years.
Figure 5.5: Fenofibrate medication in the FIELD trial reduced mortality,
coronary heart disease (CHD), and cardiovascular events. LDL stands for low
density lipoprotein, TC for total cholesterol, and TG for triglycerides
Niacin
Another possible medication to treat the concomitant conditions of
hypertriglyceridemia and low HDL cholesterol is nicotinic acid (niacin).
It has been referred to as the “broad-spectrum” lipid medication due to its beneficial
effects on LDL cholesterol. The first lipid-lowering drug to significantly cut
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cardiovascular events but not mortality was nicotinic acid. In the Coronary Drug
Project, 3908 men with a history of MI were randomly assigned to receive nicotinic
acid or a placebo. Although there was a reduction in major CHD events, nonfatal
MI, and cerebrovascular events, there was no difference in mortality; nevertheless,
in the 15-year post-trial follow-up, which began approximately 9 years after the
trial’s conclusion, mortality from all causes was 11% lower in the nicotinic acid
group.
Since then, niacin has been used in a number of long-term clinical studies that
have shown it can lower CHD events and death when combined with other lipid- 5
modifying medications including colestipol (a bile acid sequestrant), fibrate, and
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
statins. Niacin has unfortunately been hindered by adverse effects, mainly flushing,
although there are ways to lessen this, as well as by hyperglycemia. There have
been no long-term outcome studies with niacin in diabetic patients. Niacin also has
a negative impact on glycemic control. The amount of nicotinic acid taken has an
impact on this outcome. In clinical practice, there are more extensive variations.
Niacin appeared to be equally helpful in lowering cardiovascular outcomes in
patients with hyperglycemia as it did in those with normoglycemia, according to an
analysis of data from the Coronary Drug Project (Figure 5.6).
Figure 5.6: A post hoc analysis of the Coronary Drug Project found a decrease
in coronary heart disease in participants with a fasting plasma glucose level of
greater than 7 mmol/L
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 On the use of niacin in diabetes, recommendations are conflicting. The American
Diabetes Association’s (ADA) current policy statement recommends using nicotinic
acid as a treatment option for lipoprotein fractions other than LDL cholesterol.
It states that glucose levels only slightly fluctuate and that diabetes treatment can
usually be adjusted to account for these variations.
The most recent National Institute for Health and Clinical Excellence (NICE)
guidelines for management of diabetes in England and Wales also oppose its habitual
usage. Large-scale outcome studies are in progress right now. 2011 is the target
5 reporting year for the Atherothrombosis Intervention in Metabolic Syndrome with
Low HDL Cholesterol/High Triglyceride and Impact on Global Health outcomes
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
(AIM- HIGH) study. The Heart Protection Study 2-Treatment of HDL to Reduce
the Incidence of Vascular Events (HPS2 - THRIVE), a large Oxford-based outcome
trial with extended release niacin/laropiprant (an inhibitor of prostaglandin receptor
D1 which reduces flushing), includes 28000 patients with cardiovascular disease
or at high risk of developing it, including a pre-specified subgroup of 6000 with
diabetes, and is scheduled to report in 2013.
Other triglyceride-reducing agents
Due to insulin’s peripheral effects on adipose and muscle tissue, as well as
their impact on LPL, hypoglycemic drugs may also affect triglyceride levels.
Hypertriglyceridemia and decreased HDL cholesterol are present in poorly
controlled T1DM, even ketoacidosis, and are most frequently treated with insulin
treatment. In T2DM, triglyceride levels are modestly reduced by metformin,
sulfonylureas, and acarbose, and these reductions are correlated with glycemic
control. Compared to sulfonylureas or insulin, thiazolidinediones generally have
superior effects on lipids, however pioglitazone and rosiglitazone have quite varied
impacts on the lipid profile. Rosiglitazone is linked to higher concentrations of
triglycerides while pioglitazone is linked to lower levels. Both drugs increased
LDL cholesterol, although rosiglitazone significantly increased it more than
pioglitazone. Pioglitazone decreased LDL particle concentration but did not
significantly alter apolipoprotein B levels. Rosiglitazone, on the other hand, raised
the levels of both apolipoprotein B and LDL particles. Pioglitazone had no impact
on serum apolipoprotein AI levels, whereas rosiglitazone was linked to a decline
in apolipoprotein AI levels, and both drugs boosted HDL cholesterol. Recent meta-
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analyses have revealed differences in effects on CVD outcomes. Rosiglitazone
outcome data are awaited. There was no proof of a higher rate of cardiovascular
events in the prospective Rosiglitazone Evaluated for Cardiac Outcomes and
Regulation of Glycaemia in Diabetes (RECORD) trial. The prospective pioglitAzone
Clinical Trial In macrovascular Events (PROACTIVE) study, an outcome trial for
pioglitazone that added pioglitazone to the standard of care for T2DM patients,
demonstrated that pioglitazone therapy was associated with decreases in major
atherosclerotic events as defined in the main secondary endpoint. The disparities
between these two medications’ effects on CVD outcomes, as revealed by recent
meta-analyses (Figure 5.6), may be partially explained by their differing effects 5
on lipid profiles. Numerous additional current therapies lower triglycerides as
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
a byproduct of their ability to make people lose weight. In the XENical in the
prevention of diabetes in obese subjects (XENDOS) trial, orlistat was found to
stop the progression of diabetes, and sibutramine and rimonabant (before to their
suspension) both had positive effects on lipid levels in patients with the metabolic
syndrome and diabetes.
High density lipoprotein cholesterol
Similar to LDL, the HDL class consists of a diverse population of particles. The
generally established theory that HDL is atheroprotective has epidemiologic support
in the inverse connection between HDL cholesterol levels and atherosclerotic CVD.
HDL has been demonstrated to have a number of unique but possibly overlapping
atheroprotective activities in experimental investigations, including some limited
human research.
Reverse cholesterol transfer is one of them, and oxidative stress and innate
immunological inflammation are also decreased. The essential involvement of HDL
in innate immunity is suggested by the fact that more HDL-associated proteins are
involved in immune/inflammatory processes than in lipid transport and metabolism.
The drop in HDL cholesterol in diabetes may be caused by a number of factors.
In the condition of hypertriglyceridemia, the exchange of VLDL triglyceride for
HDL cholesteryl esters is expedited by CETP. The clinical laboratory evaluates
the cholesterol component of HDL; as a result, the amount of HDL cholesterol is
reduced when cholesteryl ester is substituted for triglyceride in the core of the HDL
particle. Plasma lipases, particularly hepatic lipase, use the triglyceride in HDL as a
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 substrate instead of the cholesteryl ester to break it down into a smaller particle that
can be removed from the plasma more quickly. Advanced glycation end products
(AGE) precursors can also hinder HDL’s ability to carry reverse cholesterol.
Therapies to intervene in order to boost HDL cholesterol have shown to be “not that
simple,” in contrast to lowering LDL cholesterol. Certain HDL therapy may lower
CVD without actually affecting HDL cholesterol levels. After 3 months, there was
a significant regression of coronary atherosclerosis according to the Intravascular
Ultrasound Study (IVUS) of the effects of 5 weekly infusions of a hyperfunctional
apolipoprotein A - 1 (apoA - 1) Milano. In contrast, HDL cholesterol increased by
5 72% and LDL cholesterol decreased by 25% in the Investigation of Lipid Level
Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE)
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
trial, which examined the CETP inhibitor torcetrapib in 15 000 patients. However,
the trial was prematurely stopped because the treatment arm experienced an increase
in major cardiovascular events of 25% and a 40% increase in cardiovascular death
that may have been related to hypertension. Treatment goals for HDL cholesterol
vary according to guidelines, mainly because there is currently no supporting
scientific data for intervention. There is no treatment target for HDL cholesterol,
according to the Joint British Societies Guidelines and NICE, as it is only mildly
altered and not independently of changes in other lipid variables in clinical trials.
Additionally, no medications are currently on the market that can change
HDL cholesterol on its own. According to the American Heart Association
and the ADA, triglycerides should be kept under 1.7 mmol/L (150 mg/dL)
and HDL levels should be over 1.15 mmol/L (40 mg/dL). Women should
aim for an HDL cholesterol level that is 0.3 mmol/L (10 mg/dL) higher than
this.
Congestive Heart Failure
Congestive heart failure (CHF) and diabetes have long been thought to be closely
related. In a 1954 publication on clinically significant problems in diabetic patients,
Lundbaek emphasized that cardiac disease was prevalent in diabetic patients; in
fact, it was present in two-thirds of aged participants. He was the first to raise
the possibility of a cardiomyopathy specific to diabetes. Rubler et al. released
supporting information 20 years later, coming to the conclusion that myocardial
illness appeared to be a consequence of the diabetic state rather than just being
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brought on by coronary artery disease (CAD). Shortly after, epidemiologic proof of
a significant link between CHF and diabetes was given by the Framingham research.
Because of aging populations and improved outcomes from ischemic heart disease
(IHD), particularly myocardial infarction (MI), CHF is becoming more common
in Western societies. Hypertension, CAD, valve malfunction, arrhythmias, anemia,
renal failure, and thyroid dysfunction are only a few of the many known causes of
CHF. Aging, valvular heart disease, IHD, especially prior MI, electrocardiographic
signs of left ventricular hypertrophy, cardiomegaly detected by chest X-ray,
increased heart rate, hypertension, and decreased pulmonary vital capacity are
risk factors for the development of CHF. Diabetes should be added to this list as 5
a significant risk factor. The Framingham study built a multivariate risk formula
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
using a number of these risk factors to pinpoint CHF candidates at high risk.
In industrialized nations, IHD currently accounts for the majority of CHF cases,
with diabetes emerging as a major risk factor for both CHF and IHD. This indicates
that the coexistence of diabetes and CHF will rise in frequency over time given the
fast rising prevalence of diabetes. The link between a rise in glycated hemoglobin
(HbA1c) and the likelihood of developing CHF indicates that poor glucose control
contributes to CHF development. 9.5% of participants in an epidemiologic study of
an elderly Italian cohort had CHF, and 14.7% had diabetes.
Note: Due to common risk factors like obesity, hypertension, and inflammation,
diabetes and congestive heart failure (CHF) frequently coexist. Elevated blood sugar
levels increase the risk of CHF by causing arterial damage.
It’s interesting to note that about 30% of the people with CHF had diabetes.
Following up confirmed the link, which showed that CHF foresaw the development
of diabetes.
In conclusion, there is a substantial correlation between diabetes and CHF, and both
diseases are becoming more widespread. These illnesses’ complicated relationships
with one another have not yet been thoroughly analyzed.
Symptoms and diagnosis
Modern diagnostic techniques for CHF rely on a combination of clinical symptoms
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 and telltale markers of cardiac failure. In clinical practice, CHF is typically divided
into systolic and diastolic myocardial dysfunction, with the latter also known as
heart failure with preserved left ventricular function. Systolic dysfunction denotes a
reduced ability to expel blood from the left ventricle, whereas diastolic dysfunction
denotes a reduced ability to fill the ventricles due to relaxation abnormalities.
The most prevalent expression for poor systolic dysfunction is left ventricular
ejection fraction, and echocardiography is the technique of choice for documenting
this dysfunction. The echocardiographic indicators of diastolic dysfunction are
evidence of aberrant left ventricular relaxation, decreased diastolic distensibility,
5 or diastolic stiffness. Both persons with diabetes and people without the disease can
benefit from echocardiography, which includes tissue Doppler imaging (TDI), for
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
the detection of myocardial diastolic dysfunction.
Natriuretic peptides or their precursor concentrations in plasma can also be used to
diagnose CHF in individuals, including those with diabetes. The New York Heart
Association’s classification of CHF severity is the primary clinical classification
(Table 5.1). This classification is used for all CHF patients, regardless of whether
they are treated in an inpatient or outpatient setting and regardless of the cause. A
collection of metabolic illnesses known as diabetes and other glucose abnormalities
are defined by hyperglycemia brought on by deficiencies in insulin secretion,
action, or both. Numerous organs might become damaged, dysfunctional, or fail
as a result of diabetes. There are many methods to define metabolic syndrome,
which combines several cardiovascular risk factors, including problems in glucose
homeostasis.
Epidemiology
Risk factors for CHF and diabetes
Family history, smoking, abnormal blood lipids, hypertension, diabetes, obesity,
and socioeconomic variables are the most significant risk factors for cardiovascular
disease (CVD) and MI.
Due to necessity, many of the risk factors for CHF are similar to those for CVD,
with IHD and hypertension as the main contributors. Other prevalent risk factors for
CHF include being a man, smoking, being overweight, being physically inactive,
and having valvular heart disease. Significant significance is also given to type 2
diabetes mellitus (T2DM), poor glucose management, as evidenced by high fasting
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plasma glucose and increased HbA1c. Family history, age, being overweight or
having a higher waist to hip ratio, as well as a sedentary lifestyle, are risk factors for
T2DM. The morbidity is known to rise gradually when more risk factors are present.
Lipid abnormalities, such as low high density lipoprotein (HDL) cholesterol, low
tiny, dense, readily oxidized low density lipoprotein (LDL) particles, and elevated
triglycerides, are specific risk factors for CAD in T2DM. Additionally, low HbA1c
and high fasting plasma glucose are indicators of poor glucometabolic regulation.
Note: The chance of cardiovascular issues rises as a result of arterial damage and 5
inflammation brought on by elevated blood sugar levels. Obesity and hypertension, two
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
coexisting diseases, increase CHF vulnerability. To attenuate these interlaced risk fac-
tors and lessen the onset and severity of CHF, diabetic patients should be cautious
about maintaining their blood sugar, weight, and blood pressure.
Hypertension is yet another crucial element. In comparison to patients without
diabetes, those with diabetes with CHF have greater HbA1c, lower diastolic BP,
higher systolic BP, and more IHD. As a result, there are numerous shared risk
factors for both CHF and high glucose levels.
Table 5.1: Congestive heart failure (CHF) is classified by the New York Heart
Association (NYHA)
Prevalence of CHF and glucose abnormalities
Due in part to variations in how this condition is defined, the prevalence of CHF
varies slightly across research.
In epidemiologic research, it may be challenging to satisfy the requirement that
a heart failure diagnosis be supported by evidence of systolic dysfunction on
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 echocardiography. Many of the investigations, which are still significant sources of
knowledge, were undertaken before the development of modern echocardiographic
techniques. According to estimates, the prevalence of CHF in Swedish men ranges
from 0.6% to 6.2% and rises with age. The Reykjavk Study and the Rotterdam
population’s total prevalence of CHF among both sexes both show similar results.
One to ten percent of the population of British outpatients had CHF. Age has a
significant impact on it when considering older populations, as demonstrated by the
Italian Campania study, where the prevalence was 9.5%. At least 30% of diabetic
individuals are believed to go undiagnosed. A Belgian outpatient population was
5 screened for diabetes and impaired glucose tolerance (IGT) in 11% of those with
one known cardiovascular risk factor. Diabetes was prevalent in men and women
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
in Sweden between the ages of 35 and 79, with a frequency of 7.8% for men and
5.1% for women. Diabetes prevalence may be much greater in a few high risk
populations, including individuals with CAD. Only 29% of the 4961 individuals
had normal glucose metabolism, whereas 31% had diabetes that was known to
them and 12% had never been diagnosed. IGT was present in the final 28% of
individuals. In patient populations with cerebral and peripheral vascular disease,
comparable rates were found. Due to a lack of diagnostic accuracy and a thorough
examination of the glucometabolic state, the association between CVD and glucose
disturbances is therefore relatively common but has been underappreciated in many
prior investigations.
There is a dearth of information regarding the prevalence of diabetes and CHF
together. The most current and comprehensive study on the prevalence of diabetes
and CHF was conducted on the Reykjavik population, and it found that the
combined prevalence of the two conditions was 0.5% in males and 0.4% in women,
with prevalence rates rising with age. Only 3% of the controls without CHF had
diabetes, compared to 12% of those with CHF.
There was a significant correlation between diabetes and CHF as a result.
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5
Figure 5.7: Relationship between the prevalence of congestive heart failure
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
(CHF) and glucometabolic status. Males are shown by yellow bars, females by
red bars, and diabetes is indicated by the letters DM
Incidence
Recent findings from the Framingham research suggest that the prevalence of CHF
has decreased over the past five decades, however other investigations have not
confirmed these findings. Instead, it appears that more people with CHF are being
admitted to hospitals, which is leading to higher healthcare costs for those who
have this diagnosis. The incidence of CHF has been found to be 4.4/1000 person-
years in men and 3.9/1000 in women among British outpatients, rising with age
in both genders. In Finland, the incidence is 4.0/1000 person-years for men and
1.0/1000 person-years for women.
In numerous European nations, the age-standardized yearly incidence of diabetes
is reported to be 2.2 and 2.3/1000 person-years for Dutch men and women,
respectively.
However, when looking at an aged population, like in the Italian study from
Campania, the incidence was much greater at 6.1% annually. The observation in the
Netherlands, where the incidence fell in the oldest age group, is somewhat different
from this. There is a dearth of information regarding the prevalence of diabetes and
CHF together. Once more, it appears that the population of Reykjavik is the source
of the most recent and comprehensive study. The incidence of impaired glucose
regulation was 12.6/1000/year in this study, diabetes was 4.6/1000/year, and CHF
was 5.3/1000/year (Figure 5.8). Additionally, there was a significant correlation
479
 between CHF and the frequency of glucose abnormalities.
In the Framingham research, during the 18 years of follow-up, people with diabetes
had a five times greater incidence of CHF than those without diabetes. Even after
patients with preexisting CAD were excluded, the increased risk of CHF persisted.
Pathophysiology
It is possible to identify structural and biochemical changes in the myocardium in
failing hearts, and many of these changes appear to be unrelated to the cause of
myocardial failure. Myocyte depletion, changed expression of contractile proteins,
5 5
desynchronized excitation-contraction coupling, activation of the beta-adrenergic
receptor, alterations in myocardial energy generation, and enhanced activity of
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
many cytokines are among them. A lot of these anomalies are seen in diabetic
hearts. Here, a discussion of further diabetes-specific components is followed by a
discussion of certain general aspects of the pathophysiology.
Figure 5.8: Amount of incident cases/1000 person years for men and women,
respectively, by age, for aberrant glucose regulation, diabetes, congestive heart
failure (CHF), inappropriate glucose regulation and CHF, and diabetes and
CHF
CHF is a clinical illness that was first brought on by cardiac injury and later
made worse by the activation of an unfavorable neurohormonal response. As
a result, norepinephrine, angiotensin II, endothelin, and aldosterone are all
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connected to the destructive cycle of myocardial remodeling (Figure 5.9),
which if left unchecked will lead to a steady decline in myocardial function.
The remodeling and adaptability of the heart are significantly influenced by
metabolic circumstances. As a result, there is an increase in myosin heavy chain
beta, a change in troponin T (TnT) molecules, a reduction in the storage of creatinine
phosphatases, and a decrease in the activity of the sarcoplasmatic ATPase. This
may cause myocyte hypertrophy, which is linked to impaired contractile function
and a less efficient energy source.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Table 5.2: Diabetes and heart failure prevalence, incidence, and prediction in
general populations and among patients
With ATP serving as a significant energy source, the myocardium has a high
energy turnover rate. Free fatty acid (FFA) and carbohydrate breakdown are the
two mechanisms for energy delivery (Figure 5.8). The Krebs cycle or citric acid
is entered by acetyl coenzyme A (ACA), which receives FFA from the lipolytic
route via -oxidation. Pyruvate is created by the carbohydrate route through lactate
oxidation, glycolysis, and glycogenolysis. Pyruvate is decarboxylated to ACA,
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 which enters the Krebs cycle, by pyruvate dehydrogenase. Although FFA oxidation
is the predominant pathway for cardiac energy production, the heart also depends
on glucose oxidation. The heart tends to shift toward a more dominant glucose
oxidation when it is under ischemic stress or exposed to a sustained increase in
intraventricular pressure. Glucose transport over the cell membrane is hampered in
CHF, which may be countered by a decrease of the glucose transporter 4 (GLUT-4).
The heart is also susceptible to higher FFA concentrations, which are released as a
result of stress and are influenced by an elevated sympathetic tone. The prolonged
intracellular buildup of FFA and its metabolites is thought to be a potential cause of
5 myocardial dysfunction. 5

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

Diuretics, such as low dose bendroflumethiazide (bendrofluuazide), or cardioselective
beta-blockers, calcium channel antagonists (CCAs), angiotensin converting enzyme
(ACE) inhibitors, and angiotensin II type 1 (AT1) receptor blockers (ARBs) are first-line
antihypertensive medications that are appropriate for use in patients with diabetes. The
renin-hypertension in subjects of African descent is often low, and they may not react
to beta-blockers or ACE inhibitors. Angina or arrhythmia (beta-blockers, CCAs), heart
failure (ACE inhibitors, certain beta-blockers), prior myocardial infarction (ACE inhibitors,
beta-blockers), or nephropathy (ACE inhibitors, ARBs) are a few examples of coexisting
conditions for which particular drugs may be chosen for their beneficial effects.
In addition to these processes, changes in gene expression and immune system
activity have also been linked to CHF’s mechanical and metabolic abnormalities.
All nucleated cells, including cardiomyocytes, have the ability to release pro-
inflammatory cytokines in response to harm brought on by conditions including
MI, myocarditis, or failing hearts. Interleukin 6 (IL - 6) and tumor necrosis factor
ɑ (TNF-ɑ) levels rise in direct relation to the intensity and duration of CHF. This
cytokine release could set off a chain of events that results in structural changes to
the myocardium, worsening the clinical presentation of CHF.
Figure 5.9: Depressed cardiac function causes neurohormonal activation,
which creates a vicious cycle that worsens the already damaged myocardial
function
CHF and diabetes
FFA oxidation typically accounts for 70% of the myocardial energy production,
with glucose oxidation (30%) and lactate making up the remaining 30%. FFA are
created through the lipolysis of triglyceride reserves found in the heart or other
external sources.
If there is an adequate supply of oxygen, the oxidation of FFA provides a reliable
source of ATP, which is a form of energy. When oxygen is scarce, glucose oxidation
will produce more energy per mole of oxygen and be able to support more effort than
FFA. Diabetes significantly reduces glucose consumption for energy production,
by roughly 10% (Figure 5.9). A higher oxygen utilization than usual results from
the change to an even more pronounced - oxidation of FFA.

482 483
 5 5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.10: Regarding people with and without diabetes who have congestive
heart failure (CHF), a schematic illustration of myocardial energy generation
is relevant.
Metabolic modulators’ sites of action are identified
A slower rate of glucose phosphorylation, which consequently restricts the amount
of glucose that can enter cells, may also contribute to the reduced glucose oxidation
in the diabetic heart. The increased metabolism of FFA is what causes the decreased
phosphorylation. A lack of insulin makes lipolysis more effective, which raises the
level of FFA in the blood. It is also known that people with diabetes are more
likely to experience additional problems, such as decreased myocardial blood flow
and attenuated hyperkinetic response to myocardial ischemia, which both lead to
decreased myocardial function. In fact, CHF is an insulin-resistant condition that
causes an increase in the release of non-esterified fatty acids, which are absorbed
by muscle tissue and suppress glucose uptake and utilization. As shown in Figure
5.11, oxidative stress and the activation of processes brought on by elevated levels
of diacylglycerol and protein kinase C are additional effects of hyperglycemia.
Additionally, numerous other detrimental effects of the elevated amounts of
immune cytokines in individuals with heart failure may worsen insulin resistance.
484
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.11: The metabolic effects of hyperglycemia resulted in the activation
of diacylglycerol (DAG) and protein kinase C (PKC).
Prognosis
CHF in general
The mortality rate from CHD has significantly decreased among people without
diabetes over the past 30 years. Men with diabetes have shown a significantly lower
rate of decrease than women, though. The prognosis gets bad when CHF is present.
After an episode of CHF, an English population’s 1-month survival rate was 81%,
falling to 57% after 18 months. In a study of CHF patients who were hospitalized,
the yearly mortality was 10–20% with mild–moderate symptoms and 40–60% with
severe symptoms. During a 6-year follow-up period, the mortality rate for an aged
group with CHF recruited in Rotterdam was 47%. This is twice what those without
CHF experience. A similar Italian study found that after three years, the mortality
rate was 21.3%. Therefore, regardless of the underlying cause of cardiac failure,
CHF is a malignant illness. There have been some more positive recent reports.
According to a 50-year follow-up of the Framingham data, there has been some
improvement in CHF survival. An investigation based on the Swedish hospital
discharge registry lends credence to this observation.
Diabetes and CHF
The most common and significant complication of diabetes is cardiovascular disease
485
 (CVD). Between men with angina and MI in terms of cardiovascular mortality are
men with diabetes.
According to estimates, CVD is to blame for 77% of all hospitalizations in the
USA for chronic complications of diabetes. T2DM reduces life expectancy by
approximately 5 years and increases the risk of dying from CHD by twofold. As
a result, the mortality from CVD in persons with diabetes who have never had
a MI is comparable to the mortality in people who have had a MI but never had
diabetes. When CHF is present, the prognosis for diabetes patients gets considerably
worse. CHF was the most frequent cause of morbidity and mortality in the first
5 DIGAMI investigation, which was conducted in patients with diabetes and acute
MI, accounting for 66% of all deaths in the first year of follow-up. In individuals
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
with IHD-related left ventricular failure, diabetes is a significant predictive risk for
cardiovascular mortality. Even after accounting for cardiovascular risk factors and
IHD, the survival rate in a general population in Reykjavik decreased significantly
when both CHF and glucose abnormality were present at the same time. This finding
may be a sign of the serious implications of having diabetes in addition to CHF.
Hyperglycemia and prognosis
Several investigations have clarified the link between plasma glucose and mortality.
According to the UK Prospective Diabetes Study (UKPDS), MI and CHF are reduced
by 14% and 16%, respectively, for every 1% (11 mmol/mol) decrease in HbA1c. In
this study, a decline in HbA 1c was associated with an improved prognosis without
any threshold or observed upper limit. A 2-hour postload of glucose was a stronger
predictor of mortality in the DECODE research than was fasting blood glucose.
The significance of postprandial hyperglycemia and the potentially significant
implications of IGT for cardiac function may be indicated by this.
Treatment
General aspects
Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor
blockers (ARBs), beta-blockers, diuretics, and aldosterone antagonists are the
mainstays of evidence-based CHF treatment. In moderate to severe CHF with or
without diabetes, ACE inhibitors, ARBs, and beta-blockers lower mortality and
ameliorate symptoms. Diuretics are essential for the symptomatic management of
fluid overload, however they should not be taken excessively as they can activate
486
neurohormones. Aldosterone antagonists should be used in cases of severe CHF as
they may increase lifespan. Despite receiving the greatest pharmacological care,
many patients still have poor vital prognoses despite symptomatic improvement.
Therefore, research into new therapeutic approaches is still ongoing. One of these is
metabolic regulation using substances that affect the messed-up metabolic pathways
in CHF and are thought to be especially significant in diabetic people. In situations
like myocardial ischemia and CHF, chemicals that switch energy generation from
FFA oxidation to the energetically more efficient glucose oxidation have received
attention.
Trimetazidine, ranolazine, etomoxir, and dichloroacetate are a few examples of 5
such medications. The effectiveness of pharmacologic therapy in CHF has been
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
investigated using a variety of methods. Among these are an evaluation of physical
capacity determined by exercise tolerance on a bicycle ergometer or treadmill,
as well as the general sense of well-being as measured by various surveys. The
most widely used method for examining myocardial function is two-dimensional
echocardiography. TDI, a relatively new technology, evaluates the function of
several cardiac segments. This method can be used to identify left ventricular
dysfunction in diabetic people even before any symptoms or indicators of CHF
manifest.
Note: Glycemic management and heart health must be carefully balanced. Drugs
including ACE inhibitors, ARBs, and beta-blockers treat both illnesses by improving
heart function and reducing the cardiovascular risks associated with diabetes. It is
essential to choose medications carefully to prevent raising blood sugar levels. By
carefully addressing both CHF and diabetes, lifestyle changes such as a heart-healthy
diet and frequent exercise help to improve results. For best results, collaborative care
is essential.
There haven’t been any guidelines that specifically address diabetes with CVD,
including CHF, until recently. Guidelines for the management of diabetes, pre-
diabetes, and CVD were released in 2007 as a result of a joint initiative by the
European Society of Cardiology (ESC) and the European Association of the
Study of Diabetes (EASD). According to this paper, there aren’t many trials that
specifically address the care of individuals who have both glucose problems and
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 CHF. This results in a lack of specific evidence. The majority of the current findings
come from analysis of diabetic patient subgroups in significant CHF trials.
5 5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Table 5.3: The impact of renin-angiotensin system inhibition in trials for
congestive heart failure (CHF) in a diabetic state
Figure 5.12: Metoprolol, a beta-blocker, and the composite endpoint mortality
or hospitalization in MERIT HF study participants with and without diabetes
who have congestive heart failure (CHF)
Due to an overrepresentation of less severe cases of diabetes, there is a danger for
selection biases, a faulty definition of diabetes, hidden diabetes, and true glucose
lowering medication. The results that are now available support a proportionately
equal efficacy in patients with and without diabetes in light of these constraints.
488
The impact of therapy measured by the number of patients that must be
treated to prevent an event (such as hospitalization for CHF or death) is sig-
nificantly lower in patients with diabetes than in patients without diabetes
since their absolute prognosis is significantly worse.
Pharmacologic Therapy of CHF
ACE inhibition
Both overt CHF and asymptomatic myocardial dysfunction call for the use of ACE
inhibitors. They reduce mortality and ameliorate symptoms in moderate to severe
CHF with and without diabetes, as indicated in Table 5.3. In several trials, diabetic
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
patients make up a sizable subgroup. Enalapril’s impact on impaired left ventricular
function in SOLVD patients with and without diabetes was comparable. Mortality
reduction was at least as effective in patients with diabetes as it was in patients
without diabetes in ATLAS, which compared a high and a low dose lisinopril
treatment regimen. In post-MI patients with diabetes, the GISSI 3 and SAVE
trials demonstrated beneficial effects of ACE inhibitor treatment on morbidity and
mortality. It is advised that plasma glucose be monitored in the initial stages of
the administration of an ACE inhibitor in patients on glucose lowering medication
because hypoglycemia episodes may be triggered by ACE inhibitor therapy in
patients on glucose lowering therapy.
Blockers of the angiotensin receptor
ARBs can be used as an alternative to ACE inhibition or even in conjunction
with it in cases of severe CHF. ARBs reduce morbidity and mortality in both
diabetic and non-diabetic CHF patients.
Beta-blockers
In patients with T2DM and CHF, beta-blockade therapy has the potential to
favorably influence the metabolic pathway since it reduces myocardial FFA
exposure. Beta-blockers lower mortality and improve symptoms in patients with
diabetes and moderate to severe CHF who are enrolled in big studies, according to
subgroup analysis. Therefore, beta-blockers are recommended as the primary line
of treatment for individuals who both have diabetes and CHF. It is important to
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 highlight that both groups experienced a similar relative risk reduction after taking
metoprolol. The diabetic cohort’s remaining incident rate is still significantly higher
than that of the non-diabetic group.
Diuretics and aldosterone antagonists
For the treatment of fluid overload symptoms, diuretics are essential. They should
not be used excessively because, as was already said, they promote neurohormonal
activity. It is advised to use loop diuretics rather than diuretics that can worsen
impaired glucose metabolism. However, there is no evidence on the administration
5 produce fluid retention, which can cause or exacerbate CHF. Patients in New
of aldosterone antagonists in patients with diabetes and CHF. Aldosterone
antagonists are suggested in severe types of CHF and may increase longevity.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Statins
The potential effects of statin therapy on morbidity and longevity in CHF patients
have been a topic of discussion for some time. The Controlled Rosuvastatin
Multinational Study in Heart Failure (CORONA) and GISSI Heart Failure (GISSI
- HF), two recent clinical trials, were both unfavorable in this regard. Therefore, if
statin therapy is not necessary for other reasons, it is not recommended to include
it in the management of CHF.
Treatment To Reduce Blood Sugar
General aspects
According to the pathophysiologic characteristics of CHF in diabetic patients, it
has been hypothesized that careful metabolic control may benefit progression and
prognosis. According to the European guidelines for the management of diabetes,
HbA1c should be less than 6.5% (48 mmol/mol), plasma glucose should be less
than 6 mmol/L (108 mg/dL) during fasting and less than 7.5 mmol/L (135 mg/dL)
after meals. Even if these suggestions are slightly more reliable for type 1 diabetes
(T1DM) than T2DM, the scientific evidence supporting them, as generated from
well planned clinical trials, is scant. Uncertainty in this regard has been highlighted
by the disappointing results of some recent trials on intensive glucose lowering;
however, the patients with CHF were not particularly examined in these trials.
Before forceful glucose normalization can be suggested as a potential remedy for
this group of patients, further research must be done on them.
490
It appears that these presumptions currently reflect data from epidemiolog-
ic studies that demonstrate increased risk with rising plasma glucose and
HbA1c levels, starting much below what is now considered to be normal.
Glucose lowering agents
There is some evidence available regarding specific glucose lowering medications
that is significant for patients with or at risk for heart failure when making treatment
decisions. Thiazolidinediones, which are insulin sensitizers, have a tendency to
5
York Heart Association classes I–II should use these medications very cautiously,
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
and those in classes III–IV should not be prescribed them. Metformin should not
be used in patients with CHF due to the possibility of lactic acidosis. There is
controversy about the use of insulin in people with diabetes and CHF. In addition
to increasing myocardial blood flow, lowering heart rate, and somewhat increasing
cardiac output, insulin’s principal effect is a fall in blood glucose levels.
Although it has been noted that insulin has beneficial effects on cardiac func-
tion, insulin may also be linked to higher rates of morbidity and mortality.
Additional research is required to define the precise function of insulin out-
side of its use as a glucose-lowering medication in people with diabetes
and heart failure (CHF). In general, it may be said that there isn’t much
information available that’s relevant to choosing an agent to manage blood
sugar levels in people with diabetes and CHF. Therefore, broadly known
management principles ought to be used.
Diastolic congestive heart failure
Early signs of diabetes-related cardiovascular involvement include impaired
cardiac diastolic function and endothelial dysfunction, which result in a reduced
myocardial blood flow reserve.
It has been proposed that the early cardiac and microcirculatory abnormalities caused
by hyperglycemia are dynamic and may be corrected by better metabolic control.
491
 An observational study by von Bibra et al. on patients who underwent intensified
glucose control in clinical practice supported the idea that insulin-based glycemic
control, in particular, may be beneficial. Unfortunately, a recent prospective study
called the Diabetes mellitus And Diastolic Dysfunction (DADD) experiment, which
randomly assigned patients with type 2 diabetes and early evidence of diastolic
dysfunction to insulin or oral-based glucose normalization, failed to corroborate
these data. The patients were chosen because they had no history of cardiovascular
problems or symptoms of CAD or CHF. It should be stressed that it is still too early
to rule out the idea that glycemic management and cardiac diastolic dysfunction
5 have a positive relationship. It’s possible that the DADD individuals were in too
good of health to respond when glucose management was normalized. Therefore,
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
it might be beneficial to investigate novel medicines in further studies, such as
incretins, and to include patients with more advanced illness stages than those
chosen for the DADD research.
The evident danger for biases brought on by CAD, hypertension, and other diabetes
problems becomes the issue.
In light of this, such protocols must entail thorough exams of the patients.
Modulators of Metabolism
Patients with myocardial dysfunction and diabetes have been studied on medications
including trimetazidine, etomoxir, and dichloroacetate, whose method of action is
to shift myocardial metabolism away from FFA oxidation and toward glycolysis.
As shown in Figure 5.9, they affect several metabolic pathways in different ways.
Despite some recent encouraging results, their utility has to be further investigated
in clinical studies with the proper design before their therapeutic role can be
regarded as proven.
Cerebrovascular Disease
Epidemiology
One of the primary causes of morbidity and mortality is cerebral vascular disease.
In the USA, there are about 700,000 strokes yearly, making it a very common
condition. Of these, 500 000 occur for the first time, while 200 000 occur repeatedly.
After heart disease and all types of cancer, stroke is the third most common
cause of death in the United States. Thus, a woman’s risk of dying from a
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stroke is 1.5 times higher than her risk of dying from lung cancer and more
than twice as high as her risk of dying from breast cancer.
Additionally, it is the primary diagnosis stated as the cause for release for patients
transferred from hospitals to chronic care facilities. The entire cost of stroke to the
American healthcare system in 2007 was $62.7 billion.
The statistics in other nations are comparable to those in the USA. A total incidence
of 1.62 strokes per 1000 patients per year was found by the Oxford Vascular Study, 5
which collected stroke statistics on every resident of Oxfordshire. The WHO
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
MONICA study examined 21 populations in 11 countries, including 10 European
nations and China, and discovered an incidence of 125–361 patients per 100,000
men and 61–194 patients per 100,000 women.
Diabetes As A Stroke Risk Factor
There is compelling evidence that either type 1 (T1DM) or type 2 (T2DM) diabetes
mellitus increases the risk of developing ischemic cerebrovascular disease (Table
5.3). Observational research has shown links between the two illnesses. According
to a model built using Framingham Heart Study data, diabetes increases relative
risk by 1.4 in men and 1.72 in women. The Honolulu Heart Study found that
among Japanese men residing in Hawaii, diabetes doubles to triple the risk of
thromboembolic stroke compared to those without the condition.
Diabetes has a greater impact on racial and ethnic minorities in the USA. According
to the Greater Cincinnati and Northern Kentucky Stroke Study, diabetes alone
raised the odds of suffering an ischemic stroke in Caucasians by 2.1; whereas, in
African Americans, the odds increased by 2.7. All age cohorts showed the same
results. In a similar vein, the Northern Manhattan Study discovered that Caribbean
Latinos and African-Americans had higher rates of diabetes than Caucasians did of
ischemic stroke. Diabetes raised stroke risk in these ethnic groups by 1.8 and 2.1,
respectively, in part because the condition was more common.
Among African Americans, 14% of strokes may be directly attributed to diabetes as
a risk factor, and 10% among Caribbean Latinos.
According to the Copenhagen City Heart Study, diabetes has different effects on
493
 men and women. In other words, although diabetes increased the relative odds of
first stroke, incident stroke, and hospital admission for stroke by 1.5 to 2 in males,
they increased by 2 to 6.5 in women.
Diabetes not only has consequences as a standalone risk factor, but it also
exacerbates the consequences of other risk factors. Therefore, diabetes confers an
increased risk of an ischemic stroke or transient ischemic attack in patients with
isolated systolic hypertension.
5 5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.13: Infarction in the lacuna of the left posterior thalamus. Diffusion-
weighted imaging (a), demonstrating hyperintensity in the region of constrained
diffusion, signifying acute ischemia. (b) Apparent diffusion coefficient picture
showing hypointensity in the same distribution as the slice shown in (a),
confirming the presence of acute ischemia.
Table 5.4: Risk factors for stroke
494
According to the Copenhagen City Heart Study, diabetes has different effects on
men and women. In other words, although diabetes increased the relative odds of
first stroke, incident stroke, and hospital admission for stroke by 1.5 to 2 in males,
they increased by 2 to 6.5 in women.
Diabetes not only has consequences as a standalone risk factor, but it also
exacerbates the consequences of other risk factors. Therefore, diabetes confers an
increased risk of ischemic stroke or transient ischemic attack (TIA) in patients with
isolated systolic hypertension.
Stroke In Diabetic Patients
According to epidemiological research, persons with diabetes experience ischemic
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
stroke at a younger age. Additionally, they are more likely to be African Americans.
Those with diabetes who have ischemic stroke are more likely to have hypertension,
hyperlipidemia, and a history of myocardial infarction (MI), among other risk
factors.
Diabetes also raises the chance of dying from a stroke. Men had a higher relative
risk of 6 for dying from an ischemic stroke in a prospective analysis of a Finnish
population, compared to women’s relative risk of 8.2. These relative risks were
greater than those for total serum cholesterol, smoking, or systolic blood pressure
(BP). The percentage of stroke deaths in this group that may be directly linked to
diabetes was 33.3% for women and 16% for men.
When it comes to stroke subtypes, lacunar infarcts are most frequently linked to
diabetes. These are a few localized, profound infarcts that only affect one penetrating
artery branch. Contrarily, those with evident microvascular illness have the highest
rate of diabetes. Similar to hemorrhages in the same area, lacunar illness is more
likely to be linked to diabetes (Figure 5.13). Both extracranial and intracranial
stenosis are linked to diabetes. Only 200 of 510 patients in one research who were
referred for asymptomatic carotid bruits developed extracranial stenosis, according
to a Doppler scan. Asymptomatic intracranial stenosis affected sixty-six people,
37 of whom also had extracranial stenosis. 19 patients with intracranial stenosis
(Figure 5.14) had diabetes.
495
 the risk of cardioembolic stroke in patients with atrial fibrillation is the CHADS2
score. Congestive heart failure (CHF), hypertension, being older than 75, diabetes,
and having any of these conditions are given one point each, whereas a past stroke
or transient ischemic attack (TIA) is given two points. A 1.5-fold greater risk of
stroke was linked to each point increment. In a patient with atrial fibrillation,
diabetes alone would thereby double the risk of stroke from 1.9 to 2.8.
The CHADS2 score has the advantage of being fairly simple to use, leading the
non-stroke practitioner towards utilizing anticoagulation in the appropriate segment
of the population, despite the fact that efforts have been made to make it more
5 accurate. 5

There has not been a correlation between diabetes and hemorrhagic strokes

Management Of Comorbidities/Complications/ Dm In Extremes Of Age

Management Of Comorbidities/Complications/ Dm In Extremes Of Age

in large observational studies. Contrarily, diabetes was associated with an

Figure 5.14: Transcranial Doppler imaging of intracranial vertebral artery adjusted odds ratio of 2.4 in the Hemorrhagic Stroke Project, a case-control
stenosis. The first image depicts pre-stenosis normal flow, while the second study of young patients with intracerebral hemorrhage. Hypertension, as ex-
image depicts post-stenosis higher flow velocity pected, had the greatest influence on risk factors and contributed more than
TIA is less frequent in people with diabetes than it is in people without the condition. twice as much as diabetes.
While patients with diabetes who do come with TIA are more likely to progress to
a full-blown ischemic stroke in the following two days as predicted by the ABCD2
Intermediate Hyperglycemia And Other Danger Signs
score, this may indicate that patients with diabetes are more likely to present with
While forms of intermediate hyperglycemia are not as well identified as risk
completed infarct rather than reversible ischemia. This score divides TIA patients
factors for ischemic stroke as diabetes, it is generally known that it is a significant
into groups according to their age, blood pressure, clinical symptoms of speech or
risk factor. Selvin et al. assessed HbA1c values obtained at a specific visit, not
motor involvement, duration greater than 60 minutes, and diabetes.
necessarily connected to the time of incident stroke, and looked at participants
with and without diabetes in the Atherosclerosis Risk In Communities (ARIC)
Diabetes raises the risk of coronary artery disease (CAD), which in turn raises the risk
experiment. The risk of stroke increased with rising tertiles of HbA1c across the
of MI and the subsequent emergence of atrial fibrillation. In an examination of over
normal distribution within each group in both those with and without diabetes, but
850 000 charts over a 10-year period for one significant retrospective investigation
only in those with diabetes did the difference reach statistical significance.
on the relationship between diabetes and atrial fibrillation or atrial flutter, diabetes
was revealed to be a strong independent predictor for atrial arrhythmias following
In contrast, Myint et al. associated the risk of stroke with data on HbA 1c levels in
logistic regression. Diabetes was associated with an odds ratio of 2.13, with a 95%
patients without known diabetes that were extracted from the European Prospective
confidence interval (CI) of 2.10 to 2.16. Atrial fibrillation, on the other hand, has
Investigation into Cancer (EPIC). Compared to patients with HbA1c less than
consistently been shown to be a significant risk factor for cardioembolic stroke,
5.0% (31 mmol/mol), an elevated risk of stroke was only seen in this cohort if
with an estimated 75 000 strokes per year being linked to the arrhythmia.
HbA1c levels were higher than 7.0% (53 mmol/mol). Given the high likelihood of
undiagnosed diabetes in these individuals, this finding may not specifically identify
Diabetes also makes cardiac embolization more likely. An approach for validating persistent hyperglycemia as the main risk factor for stroke.

496 497
 Another kind of diabetes called insulin resistance (IR) has also produced compelling
evidence linking it to stroke. According to the ARIC study, there is a little increase
in the risk of stroke of 1.19 for every 50 pmol/L increase in fasting insulin in people
without diabetes. The increase in risk was less clear after other risk variables like
age, systolic blood pressure, and smoking were taken into account.
Numerous epidemiologic studies have also connected obesity, a surrogate for
insulin resistance and intermediate hyperglycemia, to stroke. For instance, the
Copenhagen City Heart Study discovered a direct correlation between body mass
5 index (BMI) and a higher risk of stroke. Similar to the Nurses’ Health Study, ARIC
was unable to show a connection between BMI and stroke or between waist:hip
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
ratio, a better indicator of abdominal obesity, and stroke. The Nurses’ Health Study
also found, as expected, an increasing risk of stroke with increasing BMI, with a
relative risk of stroke of 2.37 (95% CI 1.60 - 3.50) seen in patients with BMI > 32
kg/m 2. Additionally, the relative risk of BMI for stroke was once again decreased
when cardiovascular factors were taken into account.
Although it hasn’t been proven beyond a reasonable doubt that these specific types
of intermediate hyperglycemia increase the risk of stroke, metabolic syndrome as a
group of illnesses has. A milieu that is especially vulnerable to vascular injury and
ischemic sequelae is created by the interaction of hypertension, hyperlipidemia,
insulin resistance, and abdominal obesity.
In a Finnish cohort, metabolic syndrome without diabetes or cardiovascular
disease (CVD) was linked to a relative risk of about 2 for stroke after accounting
for a number of additional risk variables. Similar to this, a group from the ARIC
research that was also free of diabetes, coronary heart disease (CHD), or stroke
exhibited a 1.5–2.0 increase in risk for ischemic stroke. A synergistic effect from
the combination over the proportionate hazards inherent in each component was
also seen when separating out each risk factor.
Diabetes And The Pathophysiology Of Ischemic Stroke
Patients with diabetes are more likely to experience vascular thrombo-occlusive
events for a variety of reasons. Atherosclerosis has increased in both big and
medium-sized arteries. The endothelial response is disturbed, and the blood of the
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diabetic patient is hypercoagulable.
Due to the simplicity of Doppler measurement, carotid intima-media thickness
(cIMT) is a helpful indicator for early atherosclerosis. Additionally, cIMT raises the
risk of primary stroke by 1.57 times every standard deviation (0.163 mm) among
patients who have never had a stroke before. Additionally, each 0.1 mm rise in
cIMT is associated with an 18% higher risk of recurrent stroke. Increased cIMT is
related to diabetes. The IR Atherosclerosis Study showed that patients with chronic
diabetes experienced an increase in common cIMT, whereas those with recently
diagnosed diabetes did not. Additionally, there was no correlation with internal
cIMT. 5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
On the other hand, it has been discovered that people with diabetes and stroke
had higher cIMT. Even after adjusting for age, BMI, and smoking status in a
study of 438 Japanese individuals with T2DM, common cIMT was significantly
higher in those who experienced stroke. In a Czech cohort, stroke patients with
diabetes had higher cIMT levels. The endothelium’s capacity to release nitric
oxide (NO), a strong vasodilator, is also impacted by atherosclerosis. The diabetic
blood vessel either produces less NO or changes how NO is metabolized. NO also
prevents platelet aggregation and makes the blood vessel resistant to ischemic
circumstances, in addition to its vasodilator actions. The vessel will lean more
toward vasoconstriction with lower NO activity, which will result in a predictably
subpar response to ischemia.
It has been shown that stroke patients had lower levels of NO in their blood as well
as higher levels of the reactive oxygen species peroxynitrite (ONOO). The larger
the stroke, the more accurate these results were. Because the measurements were
made for an acute stroke, it is likely that these levels reflect the result of ischemia
rather than its cause. Nevertheless, the correlation suggests that decreased NO may
play a role in the consequences of stroke.
Inhibition of NO synthase (NOS) results in a decreased response from the cerebral
vasculature. The blood flow via the internal carotid artery was significantly lower
in men with diabetes treated with the synthetic NOS inhibitor NG - monomethyl
- L - arginine (L - NMMA) than in control patients treated similarly.The fact that
3 - hydroxy - 3 - methyl - glutaryl coenzyme A (HMG - CoA) reductase inhibitors
499
 (statins) have other positive effects beyond their most typical, which is reducing
plasma cholesterol, serves as more indirect proof of the function of NO in stroke.
Increased endothelial NOS expression and decreased Rho - kinase activity, a
proconstrictor enzyme, are two of these consequences. In numerous sizable trials,
statins have been shown to reduce the incidence of recurrent stroke. It is exceedingly
difficult to determine whether statins’ beneficial effects on stroke are due to their
ability to decrease cholesterol, their capacity to stabilize atherosclerotic plaques,
their impact on vascular function, or—more likely—a combination of all of the
above.
5 5
In addition to the aforementioned risk factors, a patient with diabetes has
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
hypercoagulable blood. Increased thrombin production, prothrombin fragments, and
thrombin-antithrombin III complexes have all been seen in studies. Furthermore,
the microangiopathic consequences were significantly linked with the higher
prothrombotic levels. Platelet hyperreactivity in the blood of the diabetic patient
further encourages thrombus development. By measuring closure time with the
platelet function analyzer (PFA-100), increasing fibrinogen binding after exposure
to ADP, suggesting activation of the GPIIa/IIIb receptors, and expressing activated
ligands on the platelet surface, it has been demonstrated that platelets in patients
with metabolic syndrome have increased activity. Platelets were hyperreactive in
patients with full-blown diabetes as shown by light transmittance aggregometry
and the expression of surface ligands. As a result, the vascular environment of the
diabetic person is more sensitive to thrombo-occlusive problems. These disorders
are susceptible to thrombophilia because they have early atherosclerosis and an
abnormal endothelial response.
At the time of diagnosis and at least once a year after that, all diabetics should undergo
rigorous screenings for hypertension and signs of hypertensive tissue damage. Values
persistently over the World Health Organization/International Society of Hypertension
limits defined for hypertension in the general population—130–140/80–85 mmHg—
require treatment. Additionally, the blood lipid profile ought to be examined.
The blood is much more likely to clot due to its hypercoagulable state and the
presence of platelets, which are already very active. Smaller parenchymal vessels
500
are harmed in lacunar strokes. Microatheroma is the most frequent cause, as shown
in pathologic case series written by Fisher, the neurologist who named the lacunar
syndromes. Microangiopathies are also brought on by lipohyalinosis and fibrinous
necrosis, both of which are most frequently observed alongside chronic hypertension
or extreme acute BP spikes, such as those seen in hypertensive encephalopathy.
The Primary Prophylaxis Of Stroke In Diabetic Patients
Given the severity of stroke-related disabilities and the high costs of both acute and
long-term care, primary stroke prevention is of utmost importance. The prevention
strategy for diabetic patients must, by necessity, be multidimensional.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
The cornerstone is medical treatment aiming at establishing normoglycemia. In
patients with T1DM, the Diabetes Control and Complications Trial (DCCT)
examined rigorous insulin regimens that included external insulin pumps and
subcutaneous insulin injections. Less than 6.05% (42 mmol/mol) HbA1c levels
were the target for treatment. The comparison group’s only objectives were the
avoidance of hyper- or hypoglycemia.
The combined outcomes of non-fatal MI or stroke, cardiac mortality, or
revascularization procedure were reduced by 57% in the intensive therapy group.
The reduction in HbA1c was mostly responsible for this improvement. When
compared to standard treatment, metformin has been found to reduce diabetes-related
endpoints, such as stroke, by 32% and diabetes-related mortality, such as stroke,
by 42%. Additionally, it was superior to other intensive therapy like sulfonylureas
(such as chlorpropamide or glibenclamide) or insulin in terms of lowering these
outcomes. The benefits were not explainable on the basis of improved glycemic
control because the HbA1c levels were comparable between the treatment groups.
A thiazolidinedione called rosiglitazone has been connected to a higher risk of MI
and cardiovascular mortality. The meta-analysis that produced these results did not
evaluate stroke individually. The use of rosiglitazone was linked to a non-significant
decrease in stroke in a more recent multicenter, open-label trial that evaluated the
impact of the drug directly on cardiovascular events (HR 0.72, 95% CI 0.49 - 1.06).
Another drug in the same family, pomiglitazone, did not result in worse cardiovascular
events, including stroke, and it actually decreased by 16% the secondary outcome
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 of all-cause mortality, non-fatal MI, and non-fatal stroke.
Despite an 11% decrease in HbA 1c in the intensive treatment group, the UK
Prospective Diabetes Study (UKPDS) failed to demonstrate any reduction in
macrovascular consequences of T2DM.
Retinopathy and neuropathy, two microvascular consequences, were significantly
decreased. After attempts to preserve treatment differences had failed, a 10-year
follow-up analysis of the same cohort revealed that the original treatment cohort
had consistent declines in microvascular complications, MIs, and deaths from any
5 cause but not CVA. Therefore, glycemic management has not been associated
with a lower risk of stroke, at least in people with T2DM. The therapeutic regimen
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
must also address these conditions since patients with diabetes are particularly
vulnerable to the impact of additional vascular risk factors including hypertension
and hyperlipidemia. The kinds of drugs that affect the renin-angiotensin system
tend to be most beneficial for treating hypertension in diabetics.
The Hypertensive Old People in Edinburgh (HOPE) experiment looked at
people who had either diabetes plus one other cardiovascular risk factor, such as
hypertension, tobacco use, or increased low density lipoprotein levels, or vascular
illness (including CAD or stroke). Angiotensin-converting enzyme inhibitor
(ACEi) ramipril decreased the risk of mortality from cardiovascular causes with a
relative risk of 0.74 and the risk of stroke with a relative risk of 0.68 in this high risk
cohort. Because the mean drop in blood pressure was only 3/2, the benefits could
not be attributed to the medication’s ability to lower blood pressure. Whether or not
the patients had experienced a stroke before enrolment, the outcome was the same.
Patients with diabetes, hypertension, and left ventricular hypertrophy were evaluated
in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE)
experiment. Losartan, an ARB (angiotensin receptor blocker), or atenolol were
the treatment options for the participants. The primary endpoint of cardiovascular
mortality, MI or non-fatal stroke was lowered with a relative risk of 0.76 in the
Losartan group, despite the fact that both drugs once more reduced blood pressure
equally. Notably, only 40% of patients in this experiment had systolic blood pressure
that was less than 140 mmHg, suggesting that additional benefits would probably
result from more careful management.
502
In individuals with diabetes and microalbuminuria, rigorous multifactorial
medical care has recently been shown to reduce all-cause mortality, cardiovascular
mortality, and cardiovascular events. The following objectives were intended to be
attained by the regimen: Fasting total serum cholesterol less than 175 mg/dL (4.5
mmol/L), systolic and diastolic blood pressure less than 130 mmHg, and HbA 1c
levels less than 6.5% (48 mmol/mol). Stroke was not a pre-specified endpoint in
this trial, although six patients in the intensive medical group experienced a stroke,
compared to 30 individuals in the control group who experienced 30 strokes.
5
Note: There is a strong link between congestive heart failure (CHF), and diabetes
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
and both conditions are becoming increasingly more common. The prevalence of the
combination of CHF and diabetes was 0.5% in men and 0.4% in women increasing by
age in a recent population - based study. Diabetes was found in 12% of those with CHF
compared with only 3% of the controls without CHF
The Anti-Thrombotic Trialists’ Collaboration meta-analysis was unable to show a
significant improvement in the primary prevention of ischemic stroke in patients
with diabetes, even though antiplatelet therapy is advised for the primary prevention
of CAD. Only 7% fewer severe vascular events occurred overall among the almost
5000 individuals who received aspirin treatment. The confidence interval was large
enough to account for a potential 25% risk reduction, which is consistent with the
population’s ability to avoid secondary strokes. The potential benefits of prophylactic
aspirin may outweigh the hemorrhagic risks in this high-risk population.
Early antithrombotic drug studies tended to only be conducted on men. Low dose
aspirin (100 mg every other day) was linked to a 17% risk reduction in stroke in
the Women’s Health Study, a study conducted among female health professionals
without a history of coronary or cerebrovascular disease. This was due to a 24%
risk reduction in ischemic stroke and a non-significant increase in hemorrhagic
stroke risk. These results were particularly noticeable in the subgroup of women
with diabetes and in women who were older than 65 at the time of enrollment.
Diabetes Patient Receiving Acute Stroke Treatment
Because of the neuron’s susceptibility to ischemia injury, acute stroke treatments
503
 are only partially effective. It becomes less likely for the parenchyma to recover
from even brief periods of ischemia when cerebral blood flow (CBF) declines.
Neurologic impairment starts to show up when CBF is below 200 mL/kg of tissue,
but irreversible ischemia doesn’t happen for many minutes until CBF is below 100
mL/kg of tissue.
As long as the medicine is administered within the first three hours of symptom
onset, as determined by the last time the patient was seen at their neurologic
functional baseline, thrombolysis has been shown to be successful in the treatment
5 of acute stroke.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
In the intravenous tissue plasminogen activator (t-PA) trial conducted by the National
Institute of Neurologic Disorders (NINDS), there was a 30–50% greater chance of
having little to no disability three months after therapy. The risk of symptomatic
cerebral hemorrhage following thrombolysis was 6.4%, however mortality data at
3 months did not show a statistically significant difference between the treatment
and placebo groups.
Table 5.5: Acute ischemic stroke treatment
This trial’s findings led to the early adoption of intravenous t-PA therapy as regular
medical practice. It has not yet become routine procedure, despite recent evidence
504
from the ECASS - III study suggesting that giving intravenous t - PA in the window
between 3 and 4.5 hours is not only safe but also mildly clinically effective in a
restricted number of patients. Additionally, participants with diabetes who had a
prior stroke based on their medical history or imaging results were disqualified
from the experiment. The series was too little to clearly show a difference of any
significance. There was a tendency for patients with diabetes to be less likely
to see considerable neurologic improvement in another trial that looked at the
characteristics that would predict this improvement in patients receiving intravenous
t-PA.
5
In addition to intravenous thrombolysis, individuals up to 6 hours following
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
the start of stroke symptoms have been studied with intra-arterial thrombolysis.
According to the PROACT II trial, intra-arterial urokinase treatment resulted in a
58% relative risk decrease for patients to have minimal or no functional disability
90 days following treatment. Comparable mortality rates were observed, and
the drug significantly reduced the rate of recanalization. Although intra-arterial
thrombolysis is recommended for usage between 3 and 6 hours in accordance with
current standards, the US Federal Drug Administration (FDA) has not yet given the
drug its blessing for this use. Diabetes was linked to a poor functional outcome at 3
months in one case study of 100 patients who underwent intra-arterial thrombolysis
with urokinase. Although diabetes is independently linked to worse outcomes after
an acute ischemic stroke, it is unclear whether these findings have any clinical
significance given that it was not related with symptomatic cerebral bleeding.
When receiving therapy for a stroke, hyperglycemia is linked to worsening results.
Age, diabetes, admission glucose greater than 140 mg/dL (7.8 mmol/L), and early
reocclusion on transcranial Doppler imaging were all significantly associated with
worsened functional outcome in a series of 73 patients treated with intravenous t-PA;
however, after logistic regression, only hyperglycemia remained as an independent
predictor of poor outcome. In particular, if recanalization was successful, it was
linked to a bigger infarct size, a poorer degree of neurologic recovery, and a worse
clinical prognosis.
Similar to this, baseline hyperglycemia increases the risk of intravenous
thrombolysis-induced symptomatic intracranial hemorrhage. The likelihood of
505
 hemorrhaging and serum glucose levels appear to be correlated in a dose-response
manner. In particular, 25% of patients experienced symptomatic cerebral bleeding
when levels were greater than 11.1 mmol/L (200 mg/dL). When the occurrence
of diabetes was substituted for blood glucose levels in a second analysis, diabetes
was linked to odds ratios of 3.61 for all hemorrhages and 7.46 for symptomatic
hemorrhages. Additionally, patients who both abruptly deteriorated and exhibited
no improvement after 24 hours were more likely to have baseline blood glucose
levels that were increased. Unsurprisingly, intracerebral hemorrhage and a lack
of recanalization were related with hyperacute worsening in patients treated with
5 either intravenous or intra-arterial thrombolysis, or both. However, greater serum
glucose levels were also associated with this condition. The chances ratio for
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
a worse outcome was 1.50 and the odds ratio for mortality was 1.38 for every
increment of 50 mg/dL glucose. Higher blood glucose levels predicted worse results
even in those who did achieve recanalization. Similar to the previous example,
blood glucose levels higher than 144 mg/dL, cortical involvement, and time to
therapy were all independent predictors of lack of improvement 24 hours following
intravenous thrombolysis treatment. Hyperglycemia had an odds ratio of 2.89. A
poor functional result at three months was also predicted by the absence of progress
at 24 hours.
These results are naturally depressing, but in no way should they be interpreted to
infer that patients with diabetes and acute stroke shouldn’t receive thrombolysis or
that they don’t benefit from it. Furthermore, it is unclear whether the hyperglycemia
reported in patients with acute stroke and diabetes is a stress response to the ischemic
insult or if it is merely a complication of the chronic diabetic state.
It’s interesting to note that one study looked at the functional results and mortality
of chronic hyperglycemia compared to transient hyperglycemia. When present at
baseline and measured 24 hours after admission, hyperglycemia was negatively
correlated with neurologic progress in the first 7 days, functional result at 30 days,
and insignificant dependency at 90 days. At the same time, parenchymal hemorrhage
and greater 90-day mortality were both strongly correlated with persistent
hyperglycemia. Similarly, when hyperglycemia was missing at baseline but present
24 hours after admission, it was positively associated with death and parenchymal
hemorrhage and inversely associated with 90-day minimal dependency. In this
506
investigation, persistent baseline hyperglycemia (without persistence at 24 hours)
was not linked to unfavorable results. These findings imply that the damage in the
acute stroke situation may not be brought on by stress-induced hyperglycemia.
As shown in the cardiac literature for MIs, intensive management of hyperglycemia
may be linked to better outcomes. The results of a tiny pilot trial showed that
hyperglycemic individuals could be safely treated with insulin infusions, but the
sample size was insufficient to compare the functional results at one month. In
a different study, patients with acute ischemic stroke who received insulin drips
to keep their blood sugar levels between 5.0 and 7.2 mmol/L (90 and 130 mg/ 5
dL) no later than 12 hours after the onset of symptoms showed a trend toward
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
better functional outcomes and little to no neurologic symptoms as measured
by the National Institutes of Health (NIH) stroke scale. In the group receiving
continuous infusion therapy, there were hypoglycemia episodes, but most of them
were asymptomatic. It is obvious that more research is needed on this topic. For
some of the aforementioned reasons as well as the fact that severe hyperglycemia
might result in localized neurologic deficits that resemble stroke, hyperglycemia,
as defined by serum glucose > 400 mg/dL, was a contraindication for inclusion in
the NINDS trial. According to current recommendations, rigorous glycemic control
should be initiated if serum glucose levels are above 200 mg/dL, while values
between 140 and 185 mg/dL may still be hazardous. This strategy hasn’t been tried,
but it may be reasonable to try to lower the glucose level first to see if any focal
symptoms get better or go away, and if not, to treat with thrombolysis.
One study examined the role of sulfonylureas given prior to the stroke and
throughout the acute hospitalization in relation to oral hypoglycemics in the acute
stroke situation. Like pancreatic cells, which only open during ischemia events,
sulfonylureas have an effect on the ATP-sensitive Kir6.2 potassium channels
that are controlled by the SUR1 receptor. This results in cell death. So, in theory,
sulfonylurea therapy should be neuroprotective during ischemia. The patients
on the medication were more likely to have a score of 0 or a decrease of four
points on the NIH stroke scale, and they were also more likely to have made an
excellent functional recovery at discharge, despite the fact that the numbers were
small and patients with more severe strokes (NIH stroke scale greater than 9) were
excluded. The outcome was especially evident in non-lacunar strokes. A certified
507
 stroke unit is the best place to continue treating acute stroke patients because it
offers multidisciplinary treatment from a staff that includes vascular neurologists,
registered nurses with stroke-specific training, physical therapists, occupational
therapists, and speech and swallow experts. A 25% decrease in mortality is seen as
a result of this therapy.
The management of blood pressure in acute ischemic stroke is still up for dispute.
Permissive hypertension during the peri-stroke period is still a concept that is
supported by current thought. Most vascular neurologists would wait to treat high
5 blood pressure until it reached a systolic pressure > 220 mmHg or a diastolic
Diabetes Secondary Stroke Prevention
As mentioned above for primary prevention, the management of the diabetic
patient after a stroke is comparable (Table 5.6). According to the Joint National
Committee’s eighth report on the prevention and management of hypertension, it
will probably take many antihypertensive drugs to keep blood pressure in adults
with diabetes at or below 130/80 mmHg. According to the studies mentioned above,
ACEi and ARB offer better defense against cardiovascular events, such as stroke.
Similar to this, the National Cholesterol Education Program and later the Endocrine
Society have released recommendations for managing cholesterol in diabetics. 5

pressure > 120 mmHg. Cholesterol should be actively reduced since diabetes should be seen as an identical

Management Of Comorbidities/Complications/ Dm In Extremes Of Age

Management Of Comorbidities/Complications/ Dm In Extremes Of Age

CHD risk. This is especially valid for people with diabetes who have experienced a
It is also debatable how long permissive hypertension should be permitted. The stroke. These patients should have their levels reduced to at least 100 mg/dL, with
bulk of health issues following a stroke are related to the incapacity brought on 70 mg/dL being preferable because they are at high risk for CHD. All people with
by neurologic impairments. Therefore, the two problems that stroke units must diabetes and stroke should begin taking statins in light of the information on statins
avoid are deep vein thrombosis (DVT) and aspiration pneumonitis. Subcutaneous and stroke that was previously discussed.
anticoagulation with heparin or low molecular weight heparin, along with or
without external compressive devices, is used to prevent DVT. Regardless of the
magnitude of the infarct, treatment usually starts as soon as the patient is admitted.
A low molecular weight heparin was observed to reduce thrombosis in one unblinded
research comparing it to enoxaparin. Aspiration prevention is more difficult. In the
immediate aftermath of a stroke, the protection of the airway is frequently impaired.

Aspiration can be avoided by posture and routine suctioning. Before starting oral
feeding for any patient with suspected dysphagia, swallow assessments should be
conducted.
Nasogastric tubes (NGT) must commonly be implanted, and patients frequently
need percutaneous endoscopic gastrostomies (PEG) tubes for long-term nutrition Table 5.6: Preventing ischemic stroke in diabetic patients
delivery. To avoid dehydration and aberrant electrolytes, hydration is required,
All individuals who have suffered a non-cardioembolic ischemic stroke should
either intravenously before enteral access is established or by NGT or PEG tubes.
begin antiplatelet medication. The Clopidogrel versus Aspirin in Patients at Risk
Any patient who is suspected of having an infection should start taking antibiotics,
of Ischemic Events (CAPRIE) study found that people with diabetes treated with
and a fever should trigger an intensive course search. Antipyretics should be given
clopidogrel had a decreased risk of stroke, MI, or death of 15.6% compared to
because hyperthermia itself weakens the nervous system.
17.7% risk in those treated with aspirin, despite the Antithrombotic Trialists’
Collaboration meta-analysis failing to show benefit in patients with diabetes.

508 509
 Similar to this, people with diabetes had a lower rate of recurrent stroke on the drug
when compared to placebo, with a relative risk reduction of 41.7%, according to
a post hoc subgroup analysis of a cilostazol research. This observation held true
particularly for lacunar stroke patients. Additional tests are required to confirm
these results.
Carotid endarterectomy is still the therapy of choice for carotid artery stenosis
greater than 70% in patients who have experienced an ischemic stroke as a result of
5
extracranial carotid stenosis (Figure 5.15). The benefits of surgery are substantially
smaller for degrees of stenosis between 50 and 70%, and the decision to treat will
be based on the local hospitals’ complication rates. Studies are still being conducted
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
on carotid artery stenting for symptomatic carotid artery stenosis. Currently, carotid
endarterectomy is still preferred unless there is a significant risk of undergoing
the procedure, such as clinically significant cardiac disease or pulmonary disease,
contralateral carotid artery occlusion, history of prior radical neck surgery, or neck
radiation therapy.
Stenting the carotid arteries is not less effective than surgery in these high-risk
circumstances. Diabetes alone does not qualify a patient as high risk.
Figure 5.15: Iodinated contrast computed tomography angiography of the
neck. At the right internal carotid artery’s origin, there is a little stenosis.
At the left internal carotid artery’s origin, which corresponds to severe
atherosclerotic plaque, there is critical stenosis (also known as the “string
sign”)
510
Warfarin should be used to prevent thrombosis in people with diabetes who
experience paroxysmal or persistent atrial fibrillation with an International
Normalized Ratio (INR) target range of 2.0 to 3.0. Anticoagulation therapy results
in a 68% risk reduction, and the annual stroke rate is reduced from 4.5% to 1.4%
in absolute terms. A patient would need to fall 295 times in a year, according to
one study’s estimate, for the danger of a subdural hematoma owing to trauma to
outweigh the benefits of anticoagulation.
5.2 Antiplatelet Therapy in Diabetes 5
The primary cause of morbidity and mortality in diabetic people is cardiovascular
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
disease. In diabetic people, the simultaneous presence of numerous traditional
cardiovascular risk factors raises the atherothrombotic risk. However, additional
risk factors, like poor platelet function, might be significant. In reality, platelets
play a significant role in the development of atherosclerosis, and interventions
that reduce the risk of ischemic stroke in diabetes patients by blocking one or
more mechanisms that regulate platelet activation and aggregation are essential.
The pro-thrombotic condition that is characteristic of DM patients is caused by
a variety of mechanisms, underlining the significance of antiplatelet medications
used for secondary prevention in these patients. For many years, patients having
percutaneous coronary interventions (PCI) or receiving dual antiplatelet therapy
(DAPT) with aspirin and the P2Y12 inhibitor clopidogrel have been treated
primarily with these medications. Even though DAPT lowers the frequency of
atherothrombotic recurrences, the high rates in DM patients highlight the need for
more effective treatments. Patients with DM may benefit from antiplatelet therapies
like vorapaxar, which inhibits the thrombin-mediated platelet signaling pathway,
as well as oral platelet P2Y12 receptor inhibitors with enhanced potency like
prasugrel and ticagrelor. These treatments have been linked to a greater reduction
in ischemic recurrences, though at the expense of more bleeding. ADP P2Y12
receptor antagonists (thienopyridines), cyclooxygenase-1 (COX-1) inhibitors
(aspirin), and platelet glycoprotein (GP) IIb/IIIa inhibitors are the three different
classes of medications that inhibit platelets and are primarily used to prevent and
treat atherothrombotic disorders (Figure 5.16). The COX-1 enzyme is inhibited
by aspirin, which prevents the production of platelet thromboxane A2. Patients
using aspirin, especially those at high risk, may nonetheless experience recurrent
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 thrombotic episodes. High-risk patients undergoing percutaneous coronary
interventions (PCI) have shown that GP IIb/IIIa inhibitors, which are very potent
antiplatelet agents that work by inhibiting the final common pathway that mediates
platelet aggregation processes, are effective in preventing thrombotic complications.
5 5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.16: The ways in which antiplatelet drugs work. Through inhibition of
the COX-1 enzyme, aspirin prevents thromboxane A2 (TXA2) synthesis. Both
TXA2 synthase and TXA2 receptors are inhibited by picotamide, ramatroban,
and ridogrel. ADP P2Y12 receptor inhibitors including thienopyridines,
ticlopidine, and clopidogrel stop intracellular pathways that activate platelets.
Current clinical studies on P2Y12 receptor antagonists include prasugrel,
ticagrelor, cangrelor, and elinogrel. Aspirin and P2Y12 receptor antagonists
work together to block the GP IIb/IIIa receptor, the last common pathway
leading to platelet aggregation. Intravenous GP IIb/IIIa receptor antagonists
may also directly inhibit this pathway. Cilostazol is a phosphodiesterase (PDE)
III inhibitor that prevents platelets from forming by raising intraplatelet cAMP
levels. The PAR-1 subtype is blocked by the thrombin receptor antagonists
E5555 and SCH 530348.
However, due to their brief duration of action and availability for parenteral use, these
medicines are not suitable for long-term protection. The examination of the results
512
achieved from a combination of oral antiplatelet medicines inhibiting additional
platelet-activating pathways was prompted by the need for alternate antiplatelet
treatment options. A first-generation thienopyridine called ticlopidine permanently
inhibits the platelet ADP P2Y12 receptor. Compared to aspirin monotherapy or
aspirin plus warfarin, its combination with aspirin is linked to a more improved
suppression of platelet activity and superior clinical results in patients undergoing
coronary stenting. However, ticlopidine’s poor safety profile and slow onset of
antiplatelet actions have made clopidogrel, a second-generation thienopyridine, the
preferred ADP P2Y12 receptor antagonist.
By preferentially acetylating the COX-1 enzyme, aspirin prevents platelet
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
thromboxane A2 synthesis. Because platelets are enucleate and can’t produce
COX-1 again, this effect is permanent. Aspirin may also be utilized for primary
prevention of ischemic events in addition to being the antiplatelet drug of choice
for secondary prevention of ischemic events in patients with atherosclerotic disease.
Although there is debate over this indication in the general population, aspirin use
in the primary prevention setting for diabetes patients is generally agreed upon.
Using aspirin as the main method of diabetes prevention
In patients with type 1 or type 2 diabetes who are at increased cardiovascular risk,
including those over 40 or who have additional risk factors (family history of
cardiovascular disease, hypertension, smoking, dyslipidemia, or albuminuria), the
American Diabetes Association (ADA) advises the use of low-dose aspirin (75-162
mg/day) as a primary prevention strategy. However, as Reye’s syndrome risk may
be increased, aspirin therapy should not be suggested for individuals under the age
of 21. Due to a lack of research, the function of aspirin in diabetes patients less than
30 years of age is yet unknown.
The effectiveness of aspirin in diabetic individuals has been assessed in a number
of clinical trials. The majority of these research found that aspirin helped diabetic
individuals. These trials weren’t especially created for diabetes individuals, hence
these results relied on post hoc analyses. Additionally, the results were based on a
small number of participants, which may help to explain why aspirin wasn’t always
demonstrated to be helpful for diabetes patients in the primary prevention scenario.
The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes
513
 (JPAD) trial (clinical trial registration number NCT00110448) was the country’s
first prospective trial to assess the use of aspirin (81 mg or 100 mg) in the primary
prevention of cardiovascular events in patients with type 2 diabetes (n = 2,539)
aged 30-85 years. The primary end point showed a 20% difference between the
aspirin and nonaspirin groups at a median follow-up of 4.37 years (5.4 vs. 6.7%,
respectively), although this difference was not statistically significant (P = 0.16).
Aspirin was linked to a 32% lower risk of the primary end point (6.3 vs. 9.2%; P =
0.047) among individuals older than 65 (n = 1,363). The appropriateness of aspirin
use in the primary prevention scenario for diabetic participants will be further
5 clarified by other ongoing research, though. These include Aspirin and Simvastatin
Combination for Cardiovascular Events Prevention study in Diabetes (ACCEPT-D)
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
and A Study of Cardiovascular Events in Diabetes (ASCEND) (clinical study
registration numbers NCT00135226 and ISRCTN48110081, respectively).
The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial
results have recently been released. Patients (n = 1,276) with type 1 or type 2 diabetes
who were older than 40 years old, with an ankle-brachial pressure index 0.99, but
no symptoms of cardiovascular disease, were randomized to receive aspirin (100
mg) and antioxidants in a double-blind, 2 2 factorial, placebo-controlled study. The
primary prevention of cardiovascular events with aspirin or antioxidants was not
successful in this experiment in demonstrating any effect. The results of the study
may have been impacted by the overall small patient population with low incident
rates. Despite the fact that participants in this experiment were asymptomatic, it
should not be viewed as a primary prevention research because there was some
peripheral artery disease among the participants.
Aspirin as a supplementary diabetes preventive measure.
All diabetic patients should take low-dose aspirin (75–162 mg/day) to help avoid
cerebrovascular and cardiovascular problems in the secondary preventive phase.
The findings of two significant meta-analyses of significant secondary prevention
trials conducted by the Antithrombotic Trialists’ Collaboration (ATC) support this
assertion. These analyses revealed that oral antiplatelet medications, primarily
aspirin, are protective in patients at high risk for cardiovascular disease, including
those with diabetes. 287 secondary prevention trials including 212,000 high-risk
patients with recent or past vascular disease or another condition that raised their
514
chance of developing vascular disease were included in the meta-analyses. The
most widely used antiplatelet drug was aspirin, which was administered daily in
doses ranging from 75 to 325 mg.
Antiplatelet therapy decreased the incidence of vascular events by 23% in the
key high-risk groups (acute myocardial infarction, prior history of myocardial
infarction, prior history of stroke or transient ischemic attack, acute stroke, and any
other relevant history of vascular disease). It’s important to note that lower daily
doses of aspirin (75–150 mg) were proven to be at least as beneficial. The smaller
doses also resulted in less bleeding problems. The incidence of vascular events 5
decreased in more than 4,500 diabetic patients evaluated by the ATC from 23.5 in
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
the control group to 19.3% in the group receiving antiplatelet medication (P 0.01)
and from 17.2 to 13.7% in the almost 42,000 nondiabetic individuals (P 0.00001).
Antiplatelet therapy was consistently beneficial in both diabetic and nondiabetic
patients, despite the fact that the overall incidence of vascular events was much
higher in diabetic patients (42 vascular events were prevented for every 1,000
diabetic patients and 35 events for every 1,000 nondiabetic patients).
P2Y12 receptor antagonists
Because it has a better safety profile than ticlopidine, clopidogrel is currently the
preferred thienopyridine. In the Clopidogrel versus Aspirin in Patients at Risk
of Ischemic Events (CAPRIE) trial, patients with a history of recent myocardial
infarction, recent ischemic stroke, or established PAD (n = 19,185) were divided
into two secondary prevention populations to compare the effects of clopidogrel
(75 mg/day) and aspirin (325 mg/day). Clopidogrel was associated with an 8.7%
relative risk reduction compared to aspirin, with the annual incidence of the major
end event (combined incidence of vascular mortality, myocardial infarction,
or ischemic stroke) being 5.32% with clopidogrel and 5.83% with aspirin (P =
0.043). The results of the diabetic subgroup in the CAPRIE study, which made
up 20% of the study population, were retrospectively examined by Bhatt et al.
15.6 and 17.7%, respectively, of the patients randomly assigned to clopidogrel and
aspirin experienced the composite vascular primary end point (P = 0.042). This
averted 21 vascular incidents for every 1,000 diabetes individuals treated, rising
to 38 for those receiving insulin treatment. It should be noted that among non-
diabetic individuals, the difference between clopidogrel’s (11.8%) and aspirin’s
515
 (12.7%) reduction in the composite vascular primary endpoint was not statistically
significant. The American Diabetes Association presently advises using clopidogrel
medication in very high-risk diabetic patients or as an alternate therapy in those
who are aspirin-intolerant. Patients (n = 12,562) with unstable angina or non-ST-
elevation myocardial infarction (NSTEMI) were enrolled in the Clopidogrel in
Unstable Angina to Prevent Recurrent Events (CURE) research to compare the
effectiveness of clopidogrel combined with aspirin with aspirin alone. In addition
to conventional aspirin therapy (75-325 mg/day), patients were randomized to
receive either clopidogrel (300 mg loading dose and 75 mg/day maintenance
5 dose) or a placebo for up to a year. When compared to patients only receiving
aspirin (9.3 vs. 11.4%, respectively; P 0.001), patients assigned to dual antiplatelet
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
therapy (aspirin and clopidogrel) had a significant 20% relative reduction in the
first primary outcome (composite vascular death, myocardial infarction, or stroke).
Dual antiplatelet medication increased the degree of platelet inhibition, which
decreased ischemic events but was linked to a higher frequency of severe bleeding
(3.7 vs. 2.7%; P = 0.001). Life-threatening hemorrhage, however, did not differ
significantly (2.2 vs. 1.8%; P = 0.13). Aspirin and clopidogrel therapy resulted in a
17% reduction in the first primary outcome for 2,840 diabetic patients in the CURE
study when compared to aspirin alone (14.2 vs. 16.7%). Although dual antiplatelet
therapy with aspirin and clopidogrel had positive effects in the diabetic subgroup
(as it did in the entire trial population), the CI 0.70-1.02 indicates that this therapy
just barely reached statistical significance.
It is significant to note that, despite more aggressive antiplatelet medication with
concomitant clopidogrel use, the incident rate was significantly greater in the
diabetes cohort than in the nondiabetic category. In fact, diabetes patients’ rates of
the key composite cardiovascular endpoint were nearly twice as high as nondiabetic
patients’ rates (14.2 vs. 7.9%, respectively). These findings highlight the need for
more specialized antiplatelet therapy regimens for diabetic patients, which may
include stronger medicines or a combination of antiplatelet medications. The
addition of clopidogrel (300 mg loading dosage and 75 mg/day maintenance dose)
to aspirin in patients presenting with unstable angina and NSTEMI is advised by the
most recent American College of Cardiology (ACC)/American Heart Association
(AHA) recommendations for the therapy of these conditions. The U.S. Food and
Drug Administration recently approved the use of clopidogrel in patients with ST-
516
elevation myocardial infarction (STEMI), and the current ACC/AHA guidelines
on the care of STEMI patients both support this usage. Clopidogrel should be
administered in acute coronary syndrome (ACS) patients regardless of the chosen
treatment approach (invasive or noninvasive), and should preferably be continued
for up to one year. The prognostic consequences of adhering to supplementary
clopidogrel medication are highlighted by a rebound rise in fatalities and myocardial
infarctions after its discontinuation. This phenomenon is more pronounced in people
with diabetes and may be explained by a more pronounced increase in platelet
reactivity in these patients after stopping clopidogrel.
5
The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization,
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Management, and Avoidance (CHARISMA) trial results showed that in high-risk
but non acute patients (n = 15,603) with clinically evident cardiovascular disease
(n = 12,153) or multiple cardiovascular risk factors (n = 3,284), treatment with
clopidogrel did not appear to be as beneficial as dual antiplatelet therapy across
the spectrum of patients with ACS, including those undergoing PCI. Although dual
antiplatelet therapy showed a 17% relative risk reduction (P = 0.01) in a subgroup
analysis in a higher-risk population (n = 9,478) with prior myocardial infarction,
ischemic stroke, or symptomatic PAD (the “CAPRIE-like” population), the
opposite results were seen in patients in the lower-risk cohort who were enrolled
in the study based on the presence of multiple cardiovascular risk factors, in which
an increase in mortality was seen. Importantly, diabetes diagnosis was one of the
primary inclusion criteria, and a high percentage of patients enrolled in this latter
grouping had the disease. Aspirin and clopidogrel dual antiplatelet treatment is
therefore contraindicated in the context of primary diabetes prevention.
Currently available antiplatelet medications have some drawbacks.
Patients, including those with diabetes, who have either stable or unstable
atherosclerotic cardiovascular disease should take aspirin and clopidogrel as the
cornerstone of their secondary prevention program. Despite the usage of these
antiplatelet medications, a sizable portion of patients continue to have recurrent
atherothrombotic episodes. The concept of antiplatelet medication resistance has
emerged in recent years as a result of these results. The word “resistance” comes
from a laboratory discovery that an antiplatelet drug was unable to sufficiently
block its particular target on the platelet.
517
 If the effectiveness of the antiplatelet agent was not assessed in the afflicted patients,
thrombotic events cannot be attributed to drug resistance. Resistance to aspirin is
caused by insufficient or absent suppression of the COX-1-mediated thromboxane
A2 pathway, whereas resistance to clopidogrel is brought on by P2Y12 receptor
activation. It is important to distinguish between antiplatelet drug resistance and
treatment failure, which is the recurrence of an ischemic event in spite of treatment.
Although not all treatment failures can be ascribed to antiplatelet drug resistance,
antiplatelet drug resistance can certainly contribute to a treatment failure. This is
consistent with atherothrombosis’ multifactorial nature, which denotes the existence
5 of several pathways that can cause events to repeat themselves.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Aspirin resistance
Numerous studies have linked aspirin resistance to long-term unfavorable clinical
outcomes in patients with coronary artery disease, ischemic stroke, and peripheral
arterial disease in addition to patients with coronary artery disease. The prevalence
of aspirin resistance reported in the literature varies significantly (in 0% of patients
in some studies and >50% of patients in others); the inconsistent results can be
attributed to variations in the definition of resistance, type of assay used, aspirin
dose, and patient population under consideration. Numerous studies employed
non-COX-1 specific tests (such as PFA-100 and light transmittance aggregometry
utilizing agonists other than arachidonic acid), and the outcomes may have been
influenced by a number of different platelet-signaling pathways. However, there is
growing evidence that aspirin resistance occurs relatively rarely (in 5% of patients)
when tests that specifically measure COX-1 activity are used to identify aspirin
responsiveness. Meta-analyses utilizing diverse laboratory assays corroborate the
unfavorable prognostic implications of insufficient aspirin-induced effects, even
though the relevance of different assays measuring aspirin sensitivity (specific and
nonspecific for COX-1 inhibition) still needs to be better established. There aren’t
any published trials, nevertheless, that were made particularly to assess the effects
of biochemical aspirin resistance in diabetic individuals.
Poor patient compliance is the main cause of aspirin resistance when employing
COX-1-specific tests. Effects of aspirin may be insufficient or nonexistent due to
interactions with medications like ibuprofen, which prevent COX-1 from becoming
acetylated as a result of aspirin. Despite using aspirin, the latter may also be to
518
blame for a higher risk of ischemic events. Additionally, the patient group under
study can have an impact on the overall prevalence of inadequate aspirin effects.
Platelet hyperreactivity is a characteristic feature of diabetic patients. As shown
by COX-1-specific assays, aspirin may completely block COX-1, but substantial
residual platelet reactivity may still exist in these patients due to activation of
other signaling pathways that aspirin does not block. When non-COX-1 specific
assays are employed, it is easier to see this since diabetic patients are more likely
to exhibit resistance to these tests. Studies that have looked into possible aspirin
resistance intrinsic to diabetes patients are few and far between. Diabetics are more
likely to have inadequate aspirin-induced effects because of their increased platelet 5
reactivity and elevated levels and activities of prothrombotic clotting factors. It
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
is possible to see hyperglycemia as a diabetes-specific mechanism for ineffective
aspirin-induced effects. In fact, it has been frequently demonstrated that glycation
and acetylation interact. Additionally, the acetylation process of platelet and
coagulation factor proteins may be hindered by increased glycation, which would
explain why diabetes patients’ aspirin-induced antiplatelet effects are insufficient.
It is still unclear, nevertheless, whether better glycemic control increases aspirin’s
effectiveness or whether higher aspirin doses are advantageous when glycemic
control is subpar.
Clopidogrel resistance
As a selective, permanent antagonist of the platelet P2Y12 ADP receptor, clopidogrel
suppresses platelet activation in a completely different way than aspirin does.
Similar to aspirin, there are significant variations in the prevalence of clopidogrel
resistance described in the literature, which can be attributed to varying definitions,
assay types, clopidogrel doses, and patient populations. However, interindividual
variation in platelet responsiveness to clopidogrel is a topic that has been well
proven. Inadequate clopidogrel response can have genetic, biological, and clinical
reasons. Through a variety of ways, hyperglycemia may make clopidogrel’s
actions less effective. individuals needing insulin therapy are more likely than
non-needing individuals to experience clopidogrel non responsiveness (Figure
5.17). These findings could help to explain why diabetic individuals continue to
experience recurrent atherothrombotic events, such as stent thrombosis, even when
their condition is at its most advanced stage (requiring insulin, for example). Even
though type 2 diabetic patients have higher levels of platelet reactivity than non-
519
 diabetic subjects, platelet-function profiling done specifically on these patients
taking aspirin and clopidogrel medication has indicated that there is still a wide
range of responsiveness. Importantly, among this cohort of just diabetic individuals,
those with high platelet reactivity had a risk of long-term adverse outcomes that
was more than three times higher.
those with high platelet reactivity had a risk of long-term adverse outcomes that
was more than three times higher (Figure 5.18). The presence of significant platelet
reactivity when testing for several signaling pathways with agonists revealed that
these patients also had generally dysfunctional platelets.

5 5

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

Figure 5.18: Cumulative cardiovascular event-free survival in 173 diabetic

individuals with and without high platelet reactivity (n = 73). Using receiver
operating characteristic analysis, the threshold value for high platelet reactivity
Figure 5.17: Platelet aggregation in response to ADP (20 mol/l) stimuli in non-
was 62% maximal ADP (20 mol/l)-induced platelet aggregation (Aggmax).
diabetic patients (NDM) (n = 65), diabetic patients who have not received
When compared to patients with platelet reactivity below the threshold value,
insulin (NITDM) (n = 133), and diabetic patients who have received insulin
those with platelet reactivity beyond the cutoff value had a substantially greater
(ITDM) (n = 68). Diabetes patients have higher levels of platelet aggregation
probability of major adverse cardiac events (37.7 vs. 13.3%, respectively; odds
than non-diabetic patients do, and diabetes patients receiving insulin have
ratio 3.96 [95% CI 1.8-8.7]; P 0.0010). High platelet reactivity was identified by
the highest levels of platelet reactivity. Patients who are not diabetic, who are
multivariate Cox regression analyses as the most potent independent predictor
not taking insulin, and who are taking insulin all see an increase in platelet
of severe adverse cardiac events (HR 3.35; 95% CI 1.68-6.66; P = 0.001).
aggregation with time.
Inadequate clopidogrel response in diabetic individuals, especially type 2 diabetic
These findings could help to explain why diabetic individuals continue to
subjects, may be caused by a variety of causes. Insulin binds with its own receptor
experience recurrent atherothrombotic events, such as stent thrombosis, even when
on the surface of human platelets, which results in a reduction of Gi function. As
their condition is at its most advanced stage (requiring insulin, for example). Even
a result, P2Y12 signaling is inhibited, cAMP is suppressed, and platelet reactivity
though type 2 diabetic patients have higher levels of platelet reactivity than non-
is decreased. However, the insulin resistance phenomenon that distinguishes these
diabetic subjects, platelet-function profiling done specifically on these patients
individuals, which results in lower sensitivity to insulin, also has an impact on the
taking aspirin and clopidogrel medication has indicated that there is still a wide
platelets of type 2 diabetic patients. As a result, the P2Y12 pathway is activated,
range of responsiveness. Importantly, among this sample of just diabetic individuals,
increasing platelet reactivity. ADP exposure, calcium levels in the cytosol,

520 521
 and platelet turnover are all factors that have been associated with clopidogrel
nonresponsiveness in diabetic individuals.
Future directions
More specialized antiplatelet therapy regimens are required, especially for diabetic
patients, as a result of the drawbacks of currently available antiplatelet medications
used to prevent atherothrombotic events and which have been demonstrated to
be more severe in these individuals. To do this, three approaches are suggested,
including dose adjustment, supplementary antiplatelet medication use, and the use
5 in diabetes individuals also lowers thrombin production. Nevertheless, a sizable
of more recent drugs.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
The justification for raising the dose of already available antiplatelet medications
is that doing so may boost platelet inhibition by potentially enhancing the drug’s
bioavailability. In clinical practice, aspirin is typically taken in doses ranging from
75 to 325 mg daily. The ATC clearly demonstrates that larger aspirin dosages
are not connected with improved clinical results, despite the fact that there is no
randomized research examining which of these levels is most effective. On the
other hand, taking more aspirin is linked to an increased risk of side effects, chiefly
bleeding in the gastrointestinal tract. The degree of COX-1 blockade, which
necessitates that low dosages of aspirin be fully blocked, is unaffected by aspirin
dosage, despite functional studies suggesting that this may be the case for its COX-
1-independent actions, the importance of which is unknown. It has been suggested
that numerous daily doses rather than an increase in a once-day dose may be more
advantageous in people with diabetes given that diabetic platelets are characterized
by greater turnover rates. Since aspirin actually has a relatively short half-life, it
cannot prevent the formation of new platelets. The functional and clinical effects
of taking aspirin only once per day as opposed to several times per day remain
unknown.
Increasing the dose has been the focus of several research to treat clopidogrel non
responsiveness. In the chronic phase of clopidogrel therapy, type 2 diabetic patients
with high platelet reactivity were specifically investigated in the Optimizing Anti-
Platelet Therapy in Diabetes MellitUS (OPTIMUS) trial. A maintenance dose
of 150 mg of clopidogrel caused more platelet inhibition than a dose of 75 mg.
Recent research has demonstrated that high-dose clopidogrel’s improved P2Y12
522
inhibition in diabetes individuals also lowers thrombin production. Nevertheless,
a sizable proportion of patients continued to have post treatment platelet reactivity
levels above the therapeutic threshold, which was used in this investigation.
Increasing the dose has been the focus of several research to treat clopidogrel non
responsiveness. In the chronic phase of clopidogrel therapy, type 2 diabetic patients
with high platelet reactivity were specifically investigated in the Optimizing Anti-
Platelet Therapy in Diabetes MellitUS (OPTIMUS) trial. A maintenance dose of
150 mg of clopidogrel caused more platelet inhibition than a dose of 75 mg. Recent
research has demonstrated that high-dose clopidogrel’s improved P2Y12 inhibition
5
proportion of patients continued to have post treatment platelet reactivity levels
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
above the therapeutic threshold, which was used in this investigation.
PCI guidelines offer a class I recommendation (level of evidence C) for high (600
mg) clopidogrel loading dosages notwithstanding the absence of large-scale clinical
trial data powerful enough to assess the safety and efficacy of high-dose clopidogrel.
There is 150 mg of maintenance dose available with class IIb level of proof C.
In the ongoing Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent
EveNTs/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS7)
trial (clinical trial registration number NCT00335452), it will be examined whether
high loading and maintenance doses of clopidogrel lead to better clinical outcomes
than standard dosing in ACS patients undergoing PCI. All participants will also be
randomly assigned to receive either low (75–100 mg) or high (300–325 mg) aspirin
dosages.
Using additional antiplatelet medications
Enhancing platelet inhibition in diabetic individuals may be accomplished by
using extra antiplatelet therapy on top of treatments now utilized for secondary
prevention of ischemic events. There are, however, few solutions available to
accomplish this. Inhibitors of GP IIb/IIIa are only used during the acute phase
of therapy. These medications have been demonstrated to be especially helpful
in ACS patients undergoing PCI, especially diabetic ones. However, GP IIb/IIIa
inhibitors failed to demonstrate any clinical advantage in non-ACS conditions,
especially in diabetic patients, in the current era of high-dose clopidogrel use.
However, it has recently been proposed that GP IIb/IIIa inhibitors may be helpful
523
 in non-ACS circumstances for patients having nonurgent PCI who are resistant to
aspirin or clopidogrel. The Tailoring Treatment with Tirofiban in Patients Showing
Resistance to Aspirin and/or Resistance to Clopidogrel (3T/2R) study’s subgroup
analysis, however, was unable to detect any appreciable changes related to this
approach in participants with diabetes. With the supplementary use of cilostazol, a
PDE III inhibitor, diabetic individuals can benefit from improved platelet inhibition.
Aspirin, clopidogrel, and cilostazol triple antiplatelet medication has been found
to be beneficial in numerous studies, notably in diabetic patients receiving bare-
metal or drug-eluting stent treatment (55–56). These results could be explained by
5 a higher level of platelet inhibition obtained with cilostazol adjunctive therapy in 5

diabetic patients, as demonstrated by the OPTIMUS-2 research.

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

According to the results of this study, cilostazol, which raises intraplatelet cAMP
levels, also increases the phosphorylation of vasodilator-stimulated phosphoprotein
(VASP), which amplifies the inhibitory effects of P2Y12. The high frequency of
adverse effects (such as migraine, palpitations, and gastrointestinal disorders),
which commonly result in drug withdrawal, is the main disadvantage of cilostazol
therapy.
Figure 5.19: Patients with diabetes mellitus have a mechanism that contributes
to platelet dysfunction and prothrombotic state. ADP is for adenosine
Diabetes & Atherothrombosis
diphosphate; Ca++ stands for calcium; GP stands for glycoprotein; IRS
The accelerated atherogenesis and increased atherothrombotic risk in people with
diabetes are caused by a variety of factors. Endothelial dysfunction and metabolic stands for insulin receptor substrate; NO stands for nitric oxide; PGI2, or
abnormalities, such as obesity, hyperglycemia, dyslipidemia, insulin resistance, prostacyclin; PKC stands for protein kinase C; ROS/NOS, or reactive oxygen
and elevated oxidative stress, are present in patients with DM. Patients with and nitrogen species; TF stands for tissue factor; water, or H2O
diabetes mellitus (DM) have prothrombotic and inflammatory states that accelerate
Hyperglycemia And Platelet Reactivity
the development of atherosclerosis and increase their risk of thrombosis in the
Platelet reactivity can be elevated in diabetic people for a variety of reasons. One
event that an atherosclerotic plaque bursts. Patients with diabetes mellitus have
of the most distinctive symptoms of DM is hyperglycemia, which might cause the
hyperactive platelets that exhibit enhanced adhesion, activation, and aggregation.
adhesion molecule P-selectin to express itself on the cell surface. There has also
The outcome of this elevated platelet reactivity is the prothrombotic state. Other
been evidence of a connection between P-selectin expression and fasting glucose
factors, such as high levels of procoagulant substances (such as fibrinogen, tissue
levels.
factor, von Willebrand factor, factor VII, and platelet factor 4), impaired endogenous
fibrinolysis (such as elevated levels of plasminogen activator inhibitor-1), and low
There have been several hypothesized methods through which hyperglycemia
levels of endogenous anticoagulants (such as antithrombin III and protein C), also
could increase platelet reactivity. These include the osmotic action of glucose,
play a role in this condition (Figure 5.19).
the glycation of platelet surface proteins, which reduces membrane fluidity and
increases platelet adhesion, and the activation of protein kinase C, a mediator of

524 525
 platelet activation.
In patients with ACS presenting with hyperglycemia, early intensive glucose
management with insulin was reported to reduce platelet reactivity. After 3.4 years
of follow-up, the Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial
Infarction (DIGAMI) trial demonstrated that intensive glucose-lowering treatment
can reduce mortality in DM patients who report with an ACS.
Platelet Reactivity And Insulin Resistance
Type 2 diabetes is brought on by a confluence of insulin resistance in the target tissues
5 5
and insufficient compensatory insulin production, which results in insulin deficit.
One of the causes of platelet dysfunction in DM is decreased insulin secretion and
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
tissue responsiveness. Insulin and insulin-like growth factor-1 (IGF-1) receptors
are both expressed on platelets. Insulin stimulates the surface expression of the
adenylate cyclase-linked prostacyclin receptor when it binds to platelets. The bulk
of the insulin receptor’s subunits heterodimerize with those of the IGF-1 receptor to
generate an insulin/IGF-1 hybrid receptor, which avidly binds IGF-1 but not insulin.
As a result, the expression of the insulin receptor tends to be relatively low. IGF-1 is
found in platelet granules, and its receptor is expressed on the platelet surface, which
helps DM patients’ prothrombotic condition by amplifying platelet responsiveness.
IGF-1 also promotes the tyrosine phosphorylation of IRS-1 and IRS-2, which in
turn causes them to bind to the p85 subunit of the phosphoinositide-3 kinase and
phosphorylate protein kinase B. This results in a variety of cellular responses to
insulin, IGF-1, and the modulation of platelet reactivity.
Increased intracellular calcium due to insulin resistance encourages increased platelet
degranulation and aggregation. The precise method by which the concentration of
calcium is raised is not yet known. It has been proposed that IRS-1 uses the inhibitory
G-protein Gi to mediate insulin’s suppression of Ca2+ mobilization. Patients with
type 2 diabetes who carry the C allele of the IRS-1 gene’s rs956115 marker exhibit
hyperreactive platelets and are more likely to experience ischemic episodes. Platelet
hyperreactivity brought on by insulin resistance also involves IRS independent
pathways, which affects platelet sensitivity to prostacyclin and nitric oxide (NO).
These mediators lessen platelet activation and are secreted by the endothelium.
Consequently, greater platelet reactivity is linked to poor responsiveness to NO and
prostacyclin. The thiazolidinedione rosiglitazone, an insulin sensitizer, has been
526
linked to decreased P-selectin expression in non-DM patients and better platelet
sensitivity to NO. Clinical studies have also demonstrated that insulin-sensitizer
therapy has an advantage over insulin-providing therapy in slowing the progression
of atherosclerosis and improving cardiovascular outcomes in DM patients.
However, the supplementary use of pioglitazone in DM patients receiving aspirin
and clopidogrel therapy was not connected to increased suppression of platelet
P2Y12 mediated signaling.
Platelet Reactivity And Related Metabolic Issues
Type 2 DM is frequently accompanied by a number of metabolic disorders, including
obesity, dyslipidemia, and systemic inflammation. Other factors, however, such as
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
high mean platelet volume and elevated platelet count, increased systolic calcium
concentration, increased oxidative stress, and high blood leptin concentrations,
which cause an enhanced effect for platelet activation and adhesion, can contribute
to platelet dysfunction in obese people. In DM individuals, abnormalities in the lipid
profile are frequently observed. A higher level of platelet activation may result from
hypertriglyceridemia. It has been hypothesized that the presence of apolipoprotein
E in the triglyceride-rich very-low-density lipoprotein particles mediates this action.
Increased platelet reactivity may also be influenced by systemic inflammation.
Inflammation has been demonstrated to alter platelet FcgammaRIIA receptor
expression, which is elevated in DM patients and engaged in platelet activation.
Additional Conditions Linked To Platelet Reactivity
In DM platelets, there is a condition called dysregulation of calcium metabolism,
and the mechanisms underlying aberrant calcium signaling are still not completely
understood. Increased oxidative stress, insulin resistance, a change in the activity of
calcium ATPases, and an excessive inflow of calcium through the sodium/calcium
exchanger are a few of the potential reasons that could be at play. Oxidative stress
is a disease that is frequently linked to diabetes mellitus (DM), particularly when
there is an excess of reactive oxygen and nitrogen species and a decrease in platelet
antioxidant levels, which results in decreased platelet function. Atherosclerosis has
been linked to the activation of the receptor for advanced glycation end products,
which is increased by the rise in reactive oxygen species. Advanced glycation
end products are also produced in greater quantities as a result of the increase
in ROS. Additionally, the oxidative stress experienced by DM patients worsens
527
 endothelial dysfunction by lowering prostacyclin and NO production, increasing
platelet reactivity, and boosting the prothrombotic state by increasing tissue factor
synthesis.
Greater numbers of reticulated platelets are indicative of patients with DM who have
faster platelet turnover. Due to their increased size and sensitivity, these platelets
are more reactive and less responsive to antiplatelet medications like aspirin and
clopidogrel. In addition to this mechanism, platelet ADP P2Y12 receptor signaling
is upregulated, which suppresses cAMP and results in a diminished sensitivity to
5 insulin as well as increased adhesion, aggregation, and a pro-coagulative state.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
5.3 Microvascular Complications And Foot Care In Individuals
Diabetic Peripheral Neuropathy
A demonstrated disease, either clinically obvious or preclinical, has been defined
as diabetic neuropathy when it develops in the presence of diabetes and no other
known causes of peripheral neuropathy. It contains symptoms in the somatic and/
or autonomic regions of the peripheral nervous system that are being categorized
according to clinical criteria; nevertheless, there is no classification that is universally
recognized due to the wide range of clinical syndromes that may overlap. Thomas’s
most popular classification of diabetic neuropathy has since undergone some
changes. This approach distinguishes between focal or multifocal neuropathies and
fast reversible, chronic symmetric polyneuropathies.
A demonstrated disease, either clinically obvious or preclinical, has been defined
as diabetic neuropathy when it develops in the presence of diabetes and no other
known causes of peripheral neuropathy. It contains symptoms in the somatic and/
or autonomic regions of the peripheral nervous system that are being categorized
according to clinical criteria; nevertheless, there is no classification that is universally
recognized due to the wide range of clinical syndromes that may overlap. Thomas’s
most popular classification of diabetic neuropathy has since undergone some
changes. This approach distinguishes between focal or multifocal neuropathies and
fast reversible, chronic symmetric polyneuropathies.
528
The management of chronic painful DPN remains a challenge for the doctor, who should
take into account the following practical guidelines: the right drug must be tried and
identified in each patient by carefully titrating the dosage based on effectiveness and side
effects; lack of efficacy should be judged only after 2 to 4 weeks of treatment using an
adequate dosage. Given the common polypharmacy in diabetics, analgesic combination
treatment may be helpful, and potential medication interactions must be taken into
account.
5
Affected by 30% of diabetics living in the community, diabetic distal symmetrical
sensory or sensorimotor polyneuropathy (DPN) is the most significant clinical
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
symptom. A growing body of research indicates that intermediate hyperglycemia
is linked to a higher risk of DPN. The prevalence of DPN was 28.0% in subjects
with diabetes, 13.0% in subjects with impaired glucose tolerance (IGT), 11.3% in
subjects with impaired fasting glucose (IFG), and 7.4% in subjects with normal
glucose tolerance (NGT) in the general population in the Augsburg region of
southern Germany. DPN affects 2% of people annually on average.
Poor glycemic control, visceral obesity, long-term diabetes, height, hypertension,
age, smoking, hypoinsulinemia, and dyslipidemia are the main etiologic variables
that have been linked to DPN. Figure 5.20 depicts how DPN has an effect on
clinical outcomes. DPN is linked to both functional constraints like walking ability
and lower extremity deficits like weakened position sensing. There is mounting
data that suggests DPN and DPN-related measures, such as nerve conduction
velocity and vibration perception threshold (VPT), as well as surrogate markers of
microangiopathy, such as albuminuria, may all be useful in predicting mortality in
diabetics. The development of neuropathic foot ulceration, one of the most frequent
reasons for hospital admission and lower limb amputations among diabetic patients,
is also predicted by elevated VPT.
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5 mentioned high prevalence of painful neuropathy in individuals with diabetes and
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.20: Diabetic distal symmetric polyneuropathy’s clinical effects
Table 5.7: Classification of diabetic neuropathies
As a subjective symptom that frequently drives patients to seek medical attention,
pain has significant clinical significance. Even though 96% of diabetic patients
reported having neuropathic pain to their doctor, only 65% of them received
530
treatment for it. Diabetic neuropathy pain has a significant negative impact on
quality of life, particularly because it interferes with sleep and enjoyment of life.
Antidepressants, anticonvulsants, opiates, and alternative therapies were used to
alleviate pain in 43.5%, 17.4%, 39%, and 30% of cases, respectively. While 77% of
the patients reported having chronic pain for more than 5 years, 23% had pain-free
periods of at least one year. As a result, neuropathic pain lasts for several years in
the majority of diabetic patients.
Up to 26% of diabetic people have chronic painful DPN. In addition to the previously
5
intermediate hyperglycemia, persons with macrovascular disease appear to be
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
especially susceptible to neuropathic pain. The prevalence of neuropathic pain was
21.0% in persons with diabetes, 14.8% in people with IGT, 5.7% in people with
IFG, and 3.7% in people with NGT among myocardial infarction (MI) survivors
from the Augsburg MI Registry. Age, obesity, and a lack of physical activity were
the most significant risk factors for DPN and neuropathic pain in these surveys,
whereas peripheral arterial disease was the most common comorbidity, underlining
the critical involvement of cardiovascular risk factors and disorders in DPN.
Clinical Signs And Symptoms
Distal symmetric polyneuropathy
The phrase “hyperglycemic neuropathy” has been used to describe sensory
complaints that are quickly relieved after the onset of near-normoglycemia in
persons with poorly controlled diabetes; nevertheless, the most prevalent form is
DPN, which is frequently linked to autonomic involvement. It has a subtle onset, and
if nothing is done to stop it, it progresses slowly over time. According to a length-
related distribution, the longer axons leading to the lower limbs appear to be more
susceptible to the nerve damages brought on by diabetes. The association between
the presence of DPN and height that was discovered lends credence to this idea.
The most distal extremities (toes) are often affected first by DPN, which typically
manifests as a “ dying-back “ neuropathy. The neuropathic process then spreads
laterally over the trunk and proximally up the limbs. Later, it may also damage
the anterior abdominal wall. When the upper limbs are afflicted, the fingertips are
typically the first to be affected (“glove and stocking” distribution; Figure 5.21).
531
 then larger fibers, or if small or large fiber participation refers to either end of a
continuous spectrum of fiber damage. However, there is data that suggests small-
fiber neuropathy may manifest early, frequently with pain and hyperalgesia prior to
the detection of sensory impairments or nerve conduction slowing.
Pain that is either chronic or episodic and usually gets better while you’re
moving around is mostly restricted to your feet. The discomfort is sometimes
described as a deep-seated aching, but there may also be lancinating stabs
or a searing thermal feel to it. The sites of pain that were most frequently re-
5 ported in a clinical study of 105 patients with painful DPN were as follows: 5

96% feet, 69% footballs, 67% toes, 54% foot dorsum, 39% hands, 37% foot

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

plantum, 37% calves, and 32% heels. Patients most frequently described
their pain as “burning/hot,” “electric,” “sharp,” “achy,” and “tingling,” and
they noted that it was worst at night and when they were exhausted or under
stress.

It is possible to experience allodynia (pain from a stimulation that does not

typically induce pain, such as stroking). Although sensory loss may accompany the
symptoms, persons who are in great agony may show minimal clinical indicators.
In some people, pain might last for many years, leading to significant impairment
and lowered quality of life, whereas in others, it can subside partially or entirely
despite continuing declines in small-fiber function. Sudden metabolic changes,
short-term pain or diabetes, prior weight loss, and less severe sensory loss are
frequently linked to pain remission.

Figure 5.21: The characteristic “glove and stocking” distribution of

sensorimotor or sensory-motor polyneuropathy in diabetes
Atactic syndrome (diabetes pseudotabes) and painful small-fiber or pseudo
syringomyelic syndromes are examples of variations. Large fiber myelinated (A
ɑ, Aβ ) neurons as well as small fiber unmyelinated (C) and thinly myelinated
(A σ) fibers are frequently engaged. It is yet unknown if the different fiber types
are damaged in a predictable order, with smaller fibers being harmed first and

532 533

5 5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.22: An illustration of how sensory deficits often appear in a patient
with distal symmetric sensory or sensorimotor polyneuropathy (dots: reduced
temperature sensibility; lines: reduced pain sensation; crossing lines: reduced
touch feeling)
Motor involvement is typically less pronounced and limited to the distal lower
limbs, leading to muscular atrophy and weakness at the toes and foot in comparison
to sensory deficiencies.
There are typically diminished or missing ankle reflexes. The danger of callus
and foot ulcers is increased at the foot level by the loss of the protective sense
(painless feet), motor dysfunction, and reduced sweat production, which is brought
on by autonomic involvement and results in dry and chapped skin. As a result, the
neuropathic patient has a significant chance of developing serious and perhaps fatal
foot problems include ulceration, osteoarthropathy (Charcot foot), osteomyelitis,
medial arterial calcification, and neuropathic edema.
534
Early diagnosis of DPN by screening is crucial since it is the main contributing
factor for diabetic foot ulcers and because persons with diabetes have a 15 times
greater rate of lower limb amputation than the general population without diabetes.
This is especially important because many DPN patients are asymptomatic or
only have minor symptoms. If effective screening and preventative measures were
implemented, the majority of amputations should be potentially avoidable in light
of these causation pathways.
Acute Painful Neuropathy
A distinct clinical entity has been identified for acute painful neuropathy. It is a rare
complication of type 1 (T1DM) and type 2 diabetes mellitus (T2DM) that manifests
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
as a constant burning pain, especially in the soles (“like walking on burning sand”)
and is worse at night. A cutaneous contact discomfort with clothing and bedding
that can be objectively defined as hypersensitivity to tactile (allodynia) and painful
stimuli (hyperalgesia) is a distinguishing trait. The ability to move is not affected,
and there may be a little loss of sensory perception—thermal sensitivity is more
affected than vibration sense. Precipitous and severe weight loss occurs prior to
and concurrent with the beginning. Impotence and depression are recurring issues.
It has been demonstrated that proper glycemic control can cause weight loss, and
in every case, the severe signs disappear within 10 months. After up to 6 years of
follow-up, there were no recurrences. According to Ellenberg, the state of acute
painful neuropathy is comparable to diabetic cachexia. It has also been mentioned
in connection with weight loss in girls with diabetes and anorexia nervosa. Caravati
coined the term “insulin neuritis” to characterize a situation in which the onset of an
acute painful neuropathy occurred several weeks after the start of insulin therapy.
In a recent study, all patients’ unpleasant symptoms gradually got better, enabling
them to stop taking their analgesics in 3 to 8 months. Thus, people with long-term
uncontrolled diabetes should think about carefully correcting their glucose levels.
Upon doing a sural nerve biopsy, it was discovered that the nerve had chronic
neuropathy with prominent regeneration activity, epineurial arteriovenous shunting,
and a fine network of vessels that resembled the new blood vessels in the retina.
This could have the effect of making the endoneurium ischemic. This could occur
analogously to the temporary worsening of a pre-existing retinopathy after a quick
improvement in glycemic management.
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 Focal And Multifocal Neuropathies
Most focal and multifocal neuropathies tend to affect long-term diabetic patients
who are in their middle years or older. The majority of them have a good chance
of making a full or partial recovery and eventually getting relief from the pain that
commonly goes along with them. In light of this, medical professionals should
constantly adopt a positive approach when treating patients who suffer from these
conditions.
Cranial neuropathy
5 5
About 50% of the time, diabetic ophthalmoplegia, a palsy of the third cranial
nerve, is unpleasant. Usually, the start is abrupt. The discomfort is felt behind and
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
above the eye, and it can occasionally appear days before diplopia and ptosis (with
pupillary dysfunction in 14–18% of patients). Within a day or at most a few days,
oculomotor findings reach their lowest point, endure for several weeks, and then
start to gradually improve. Full resolution is the norm and typically occurs in 3
to 5 months. The following in frequency are the fourth, sixth, and seventh cranial
nerves.
Mononeuropathy of the limbs
In addition to entrapment neuropathies like carpal tunnel syndrome, which is
accompanied by severe paresthesia, focal lesions affecting the limb nerves, most
frequently the ulnar, median, radial, and peroneal, may also be painful, especially
if they have an immediate onset.
Diabetic truncal neuropathy
Pain or dysesthesia may be the first symptom of mononeuropathy of the trunk
(also known as thoracoabdominal neuropathy or radiculopathy), which can also
occasionally be followed by cutaneous sensory impairment or hyperesthesia. In
addition to the adjectives jabbing, scorching, sensitive skin, or tearing, pain has also
been characterized as deep, agonizing, or boring. Almost always, the neuropathy is
unilateral or predominantly unilateral. As a result, discomfort from the pulmonary,
cardiac, or gastrointestinal systems may be mistaken for pain felt in the chest or
the abdomen. Sometimes it may have a radicular or girdling character, partially
surrounding the trunk in a distribution resembling a root. One or more dermatomal
distributions may experience pain, and it is almost always severe at night. Rarely,
536
3–5 neighboring nerve roots between T6 and T12 may be affected by an abdominal
muscle herniation; this condition is more common in middle-aged males (Figure
5.22). Most of the time, it takes only a few days from the onset of the first symptom
to the height of the pain syndrome, but in rare occasions, the pain may spread to
nearby dermatomes and last for several weeks or even months. More than 50%
of people lose 15–40 pounds (7–18 kg) of weight. Truncal neuropathy has a good
prognosis; the pain goes away in a few months to a maximum of 1.5 to 2 years.
Diabetic amyotrophy
Asymmetric or symmetric proximal muscle weakness and muscle wasting
(iliopsoas, obturator and adductor muscles) are easily recognized clinically
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
in the syndrome of lower limb proximal motor neuropathy (synonyms: Bruns -
Garland syndrome, diabetic amyotrophy, proximal diabetic neuropathy, diabetic
lumbosacral plexopathy, ischemic mononeuropathy multiplex, femoral - sciatic
neuropathy, femoral neuropathy). Figure 5.23 depicts a quadriceps muscle that has
had clear bilateral atrophy and paresis. The illness almost only involves pain.
It frequently worsens at night and has a searing, raw sensation. It is deep, agonizing,
continuous, and terrible. Most of the time, it isn’t blatantly cutaneous or dysesthetic.
The afflicted side’s buttock or lower back are frequently the first places where pain
is reported to begin, however it can also reach the hip and knee.
Figure 5.23: Oblique abdominal muscle herniation as a result of diabetic
truncal neuropathy (also known as radiculopathy or thoracoabdominal
neuropathy)
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 5 5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.24: Quadriceps muscle paresis and significant bilateral atrophy are
symptoms of diabetic amyotrophy (proximal neuropathy)
The prognosis of proximal motor neuropathy pain is favorable despite its
severity and tenacity. There is commonly concurrent distal sensory polyneu-
ropathy. Another often seen trait is weight loss, which can range from 35 to
40 pounds (16 to 18 kg). In most cases, the weight is gained again during the
recovery stage.
Central nervous system dysfunction
The central nervous system (CNS) dysfunction in DPN patients has received
very little study. Previous autopsy studies on diabetic patients have shown diffuse
degenerative lesions in the central nervous system (CNS), including demyelination
and loss of axon cylinders in the posterior columns, degeneration of cortical neurons,
and abnormalities in the midbrain and cerebellum that have been labeled as diabetic
myelopathy and diabetic encephalopathy. However, the author has demonstrated
that the degree of dysfunction along the somatosensory afferent pathways in
patients with T1DM depends on the stage of the disease. Studies that evaluated CNS
function in people with diabetes using evoked potentials in response to stimulation
of peripheral nerves, event-related potentials, and neuropsychological tests have
produced variable results regarding the existence of spinal or supraspinal (central)
conduction deficits or cognitive dysfunction.
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Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.25: PET and [18 F]- 2 - deoxy - 2 - fluoro- D- glucose (FDG) imaging
reveals decreased cerebral glucose metabolism in a patient with T1DM with
polyneuropathy as compared to a healthy person
Patients with T1DM with DPN had a higher frequency of subcortical and brainstem
lesions, according to magnetic resonance imaging (MRI). Additionally, at C4/5 and
T3/4, individuals with DPN displayed a decreased cross-sectional chord area. We
have shown lower cerebral glucose metabolism in individuals with T1DM with DPN
in comparison to newly diagnosed people with diabetes and healthy participants
using positron emission tomography (PET) and [18F]-2-deoxy-2-fluoro-D-glucose
(FDG) (Figure 5.25).
When brain metabolites like N-acetyl aspartate (NAA) were measured via
spectroscopy in the thalamus, the ratio of NAA to creatine was lower than expected,
pointing to possible thalamic neuronal dysfunction in DPN. Accordingly, there is
growing evidence that neuropathic involvement at the central and spinal levels is a
characteristic of DPN, albeit it is unclear whether these are primary or subsequent
occurrences.
Diagnostic Assessment
Numerous consensus conferences have been held to address the current issues
brought on by the lack of consensus regarding the definition and diagnostic
assessment of neuropathy. These conferences have been convened as a result of the
539
 growing recognition of diabetic neuropathy as a significant contributor to morbidity
and the recent flurry of clinical trials in this field. The following five measurements
should be used in the diagnosis of diabetic neuropathy, according to the Consensus
Development Conference on Standardized Measures in Diabetic Neuropathy:
Clinical measurements, morphologic and biochemical examinations,
electrodiagnostic evaluation, quantitative sensory testing, and autonomic nervous
system examinations are all included in the list.
Disability Score, which all appear to be sufficiently reproducible. Once a year,
a neurologic history and examination should be conducted. According to the
Neuropathy Symptom Score and Neuropathy Disability Score, the following
conditions must be met in order to make a clinical diagnosis of neuropathy:
• Moderate signs with or without symptoms; or
• Mild signs with moderate symptoms.

5 5
Clinical Actions
Clinical assessments encompass:

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

1. Thorough general and neurological medical histories;

2. Neurological evaluation covering:
- Sensation (pain, light touch, vibration, position);
- Muscle strength (graded: normal = 0, weak = 1 – 4 [25 – 100%]);
- Reflexes (presence or absence); and
- Autonomic function (tests like heart rate variation during deep breathing and
postural blood pressure response).

The fundamental neurological appraisal involves overall medical and neurological

histories, foot inspection, and sensory assessment utilizing simple semi-quantitative
tools like the 10 g Semmes – Weinstein monofilament (touch), Neuropen (touch),
NeuroQuick (temperature), calibrated Rydel – Seiffer tuning fork (vibration),
pinprick (pain), and tendon reflexes (knee and ankle). Evaluation of joint position
and motor function may also be necessary. The tuning fork on the dorsal distal joint
of the great toe has a typical range of 5/8 scale units in people under the age of 20,
4.5/8 scale units in people between the ages of 41 and 60, 4/8 scale units in people
between the ages of 61 and 71, and 3/8 scale units in people between the ages of
72 and 82. The Neuropad is a diagnostic tool for the identification of sudomotor
dysfunction. It measures plantar sweat production by changing from blue to pink
as it measures it. Anhydrous cobalt-II chloride, a complicated salt, is present in the
patch.
Clinical evaluation should be standardized using validated scores for the degree
of neuropathic impairments and the severity of symptoms, such as the Michigan Figure 5.26: (A) Bedside examinations to evaluate the function of big fibers.
Neuropathy Screening Instrument, Neuropathy Symptom Score, and Neuropathy (b) Bedside examinations to evaluate the function of tiny fibers

540 541
 This indicates that the diagnosis of DPN cannot be made only based on the regeneration may be connected to these symptoms rather than the degree of nerve
existence of neuropathic symptoms. Early stages of DPN or a painful small-fiber fiber destruction). Therefore, it has been advised that symptom or pain ratings
neuropathy, then, can only be confirmed with more complex procedures, including should only be used to measure pain intensity rather than to evaluate the overall
heat thresholds or skin biopsies. existence or advancement of diabetic neuropathy.

An 11-point Likert scale or a visual analog scale should be used to rate the intensity
(severity) of neuropathic pain and its progression. To diagnose neuropathic pain,
a number of screening methods (with or without limited bedside testing) have
been created, including the PainDetect, LANSS, NPQ, DN-4, and ID-Pain. The
5 following findings should prompt the doctor to think about DPN causes other than
diabetes and to send for a thorough neurologic work-up:
Electrodiagnostic Measures
In many neurophysiologic laboratories across the world, electrophysiologic
techniques have the benefit of being the most objective, sensitive, specific, and
reproducible procedures (Figure 5.27).
5
The following electrodiagnostic measures have limitations as well:
• Measure only function in the largest, fastest-conducting myelinated fibers;

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

• Have comparatively low specificity in detecting diabetic neuropathy;

A family history of non-diabetic neuropathy, pronounced asymmetry of the
neurologic deficits, predominant motor deficits, mononeuropathy, cranial nerve
involvement, rapid development or progression of the neuropathic impairments,
symptoms that are primarily in the upper limbs, progression of the neuropathy
despite optimal glycemic control. Clinical examination cannot determine the
diagnosis of DPN.
• Show relatively high intra-individual variability for some variables (amplitudes);
• Are susceptible to external factors like electrode locations or limb temperature;
and
• Provide only indirect information about symptoms and deficits.

From the standpoint of general medicine, the most significant differential diagnoses
are neuropathies brought on by alcoholism, uremia, hypothyroidism, vitamin B12
deficiency, peripheral artery disease, paraneoplastic syndromes, immune- and
infectious-system disorders, and neurotoxic medications.

Establishing the presence or absence of neurologic dysfunction in diabetes, ruling

out non-neuropathic causes of neurologic dysfunction, eliminating non-diabetic
causes of neuropathy, differentiating and classifying the various types of diabetic
neuropathy, monitoring progression, and providing a clinical correlate of outcome
in trials are all done using clinical measures.

The limitations of clinical measurements include:

• Limited reliability and repeatability;
• Limited sensitivity to change once they become aberrant.
Positive symptoms, such as pain or paresthesia, may reflect a different Figure 5.27 (a): Measuring the speed of nerve transmission in the motor and
pathophysiology than negative symptoms (i.e., the degree of compensatory sensory systems

542 543

5 They help distinguish between the relative deficiency of tiny vs. large fibers, and
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.27 (b): Quantitative sensory testing
The “determination of the absolute sensory threshold, defined as the minimal energy
reliably detected for a particular modality” is known as quantitative sensory testing
(QST). The detection thresholds of touch, such as pressure, vibration (Figure 5.27
b), coolness, warmth (Figure 5.27 b), heat pain, cold pain, and mechanical pain,
should be used to describe cutaneous sensation, according to the Peripheral Nerve
Society.
The following techniques are employed in QST: The method of limits (constant
544
increase or decrease in intensity to appearance or disappearance threshold);
Threshold tracking (combination of appearance or disappearance threshold);
Titration method (graded steps to appearance and disappearance threshold); and
Two Alternative Forced Choice Method (pairs of Stimulus and Null Stimulus
Phases).
The benefits of QST approaches include their high sensitivity, relative simplicity,
lack of invasiveness, and lack of aversiveness; their ability to precisely alter
stimulus intensity and testing algorithms; and their lack of aversiveness.
5
they’re very useful for screening massive populations or long-term studies.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
The following factors are among the QST procedures’ limitations:
• Constitute psychophysical methods susceptible to the effects of alertness, mood,
concentration, ambient noise, etc.;
• Show a relatively high intra-individual variability;
• Have not been adequately standardized; and
• May be time-consuming (forced-choice methods), which could result in diagnostic
errors because the test subject loses interest or becomes bored.
The method of limitations has drawn criticism since it might result in a response
delay due to subject-to-subject variation in reaction time, however it has been
shown that this method produces results with sensitivity and reliability that are
on par with forced-choice procedures. Although less favorable than that of nerve
conduction, the repeatability of the QST indices is still within acceptable bounds.
Morphologic Assessment
Sural nerve biopsy
Sural nerve biopsy is not a commonly used technique to identify diabetic
neuropathy. When the cause of the neuropathy is unclear, it may be utilized to make
the diagnosis (Figure 5.28). The drawbacks of this method include the fact that the
patient receives no immediate benefit from the biopsy results and that the process
carries some morbidity and carries a risk of complications.
545
 5 5
Figure 5.28: Axonal loss in mild and severe diabetic polyneuropathy (DPN) is
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
seen in the right panel compared to normal sural nerve pathology in the left
panel
Skin biopsy
In peripheral neuropathies and other disorders, skin biopsy has become a
popular method for examining small diameter sensory nerves, including somatic
unmyelinated intra-epidermal nerve fibers (IENF), dermal myelinated nerve
fibers, and autonomic nerve fibers (Figure 5.29). Numerous methods have
been employed for evaluating nerve fibers and processing tissues. Guidelines
for the use of skin biopsies in the diagnosis of peripheral neuropathies were
recently issued by a task group of the European Federation of Neurological
Societies. According to the guidelines, performing a 3 mm punch skin biopsy at
the distal leg and measuring the linear density of IENF in at least three 50 mm
thick sections of each biopsy fixed in 2% periodate-lysine-paraformaldehyde
(PLP) or Zamboni solution using bright-field immunohistochemistry or
immunofluorescence with antiprotein gene product 9.5 antibodies are the best
methods for diagnosing peripheral neuropathies (level A recommendation).
546
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.29: Skin biopsy taken from the lateral lower leg of a patient with
diabetic polyneuropathy shows less intra-epidermal nerve fibers (IENF) than
skin biopsy taken from a healthy individual (red arrows indicate IENF).
Bright-field immunohistochemistry using PGP 9.5 (anti-protein gene product)
antibody.
In comparison to sensory nerve conduction studies and sural nerve biopsy,
quantification of IENF density appeared to be more sensitive in the diagnosis of
small-fiber sensory neuropathy. This approach had extremely excellent diagnostic
effectiveness and predictive values (level A recommendation).
Treatment
Treatment and prevention of diabetic neuropathy by comprehensive
diabetes therapy
There have been a number of published long-term prospective studies that evaluated
the impact of rigorous diabetes therapy on the development and progression of
chronic diabetic problems. The purpose of the large randomized trials, including
the Diabetes Control and Complications Trial (DCCT) and the UK Prospective
Diabetes Study (UKPDS), was to examine the effects of intensive diabetes therapy
on the onset and progression of chronic diabetic complications rather than the
effects of such therapy on DPN. Thus, only a small portion of the participants in
these trials showed DPN symptoms at enrollment.
547
 Studies on T1DM patients demonstrate that aggressive diabetic medication delays
the onset of DPN but does not entirely stop it. Similar to the findings for diabetic
retinopathy and nephropathy, the Epidemiology of Diabetes Interventions and
Complications (EDIC) study found that the benefits of 6.5 years of intensive
therapy on neuropathy status persisted for at least 8 years after the conclusion of
the DCCT despite equal HbA 1c levels (hyperglycemic memory). After 3 to 4 years
of normoglycemia following pancreas transplantation, the progression of nerve
conduction deficiencies is stopped in T1DM patients with the most severe stages of
peripheral neuropathy, but there is no effect on autonomic neuropathy.
5 intensive diabetic treatment or a target-driven, intensified intervention directed at
Observational research has suggested a glycemic threshold for the onset and
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
progression of T1DM’s long-term consequences, but the DCCT findings refute this
theory. Therefore, efforts to achieve optimum glycemic management should focus
on establishing normal glycemia as soon as is safely practicable in as many T1DM
patients as possible rather than aiming at a specific HbA1c threshold within the
diabetic range. The risk of weight gain and hypoglycemia is generally moderately
elevated with intense diabetes medication. The outcomes were mostly unfavorable
among individuals with T2DM, who make up the great majority of those who have
diabetes.
However, the only additional time point at which VPT reached a significant
difference between intensive and conventional therapy was the 9-year follow-
up, whereas the rates after 3, 6 and 12 years did not differ between the groups.
The UKPDS showed a lower rate of impaired VPT (VPT > 25 V) after 15 years
for intensive vs. conventional therapy (31 vs. 52%). Additionally, there were no
differences in the frequencies of missing knee and ankle reflexes or heart rate
responses to deep breathing. In the ADVANCE study, 11 140 T2DM patients were
randomized to either standard or intensive glucose control, and after a median of
5 years of follow-up, the relative risk reduction for new or worsening neuropathy
for intensive vs. standard glucose control was 4% ( 10% to 2%), with no significant
difference between the groups. Similarly, no differences between the two groups
on intensive or standard glucose control were seen for DPN or microvascular
complications in the Veterans Affairs Diabetes Trial (VADT) study, which included
1791 military veterans (mean age 60.4 years) who had a suboptimal response to
therapy for T2DM. In the Steno 2 study, patients with microalbuminuria received an
548
intensified multifactorial risk intervention that included intensive diabetes treatment,
ACE inhibitors, antioxidants, statins, aspirin, and smoking cessation; however,
this intervention had a beneficial effect on other microvascular complications
like diabetic nephropathy and retinopathy. Only autonomic neuropathy (increase
in heart rate variability) showed a benefit from this strategy. The same after 7.8
(range 6.9 - 8.8) years. Peripheral neuropathy advanced in 44 and 46 patients in the
two groups, respectively (relative risk 0.97; 95% CI 0.62 - 1.51; P = 0.89), while
autonomic neuropathy advanced in 39 patients in the intensive therapy group and
in 52 patients in the conventional therapy group. Therefore, there is no proof that
5
several risk variables has a positive impact on the onset or progression of DPN in
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
T2DM patients.
Using Pathogenetic Principles To Treat Disease
Recent experimental research indicates a multifaceted development of diabetic
neuropathy. Clinically, it’s crucial to recognize that diverse causative mechanisms
could lead to various therapeutic avenues. Certain of these have undergone
assessment in randomized clinical trials, encompassing aldose reductase inhibitors
(alrestatin, sorbinil, ponalrestat, tolrestat, epalrestat, zopolrestat, zenarestat,
fidarestat, ranirestat), the antioxidant α-lipoic acid (thioctic acid), essential fatty
acid (γ-linolenic acid), ACE inhibitors (trandolapril), prostacyclin (PGI2) analogs
(iloprost, beraprost), prostaglandin derivatives (PGE1αCD), NGF, PKC β inhibitor
(ruboxistaurin), C-peptide, vascular endothelial growth factor, and benfotiamine
(vitamin B1 derivative). Instead of treating symptomatic pain, these medications
have been created to positively influence the underlying neuropathic process. The
benefit of the aforementioned therapy options is that they may act despite existing
hyperglycemia, which is advantageous because normoglycemia will not be achieved
in the majority of diabetics in the near future. An improved pharmacological
efficacy may be caused by drug interactions that operate as facilitators, according
to experimental trials of low-dose combination drug therapy.
Despite recent significant improvements in the quality of controlled trials,
medications based on current pathogenetic theories have not significantly slowed
the course of diabetic neuropathy over the long term. Some of the more recent
medications have had encouraging benefits in phase II studies, but confirmation
549
 will come through sizable phase III studies. Drugs that interfere with the etiology of
diabetic neuropathy may be more helpful in preventing the disease than at treating
it. Only benfotiamine and -lipoic acid have clinical licenses for the treatment of
symptomatic DPN in a number of nations; epalrestat is sold in Japan and India.
Weak evidence is currently available to support the use of benfotiamine in DPN.
Infusions of -lipoic acid (600 mg/day IV) on the other hand, according to a meta-
analysis involving 1258 patients, improved neuropathic symptoms and deficits
after 3 weeks. The SYDNEY 2 study also indicates that therapy for 5 weeks with
600 mg of lipoic acid taken orally four times a day decreases the primary symptoms
5 of DPN, such as pain, paresthesias, and numbness, to a clinically significant degree.
interactions must be taken into account.
Table 5.8 provides a summary of a reasonable therapy protocol that takes into
account the numerous causative and symptomatic choices. While opioids are
advised as second-line therapy, some antidepressants (tricyclics, duloxetine) and
anticonvulsants (pregabalin, gabapentin) are regarded first-line alternatives. Table
5.9 provides a summary of the benefits and drawbacks of the various medications
and pharmacological types used to treat painful diabetic neuropathy in light of the
many co-morbidities and problems related to diabetes. It is important to diagnose
the underlying neuropathic manifestation in order to estimate its natural history 5

460 individuals with stage 1 or stage 2a DPN were randomly allocated to receive before making a choice on the best course of action. Agents utilized for symptomatic

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

oral therapy with 600 mg of lipoic acid four times per day (n = 233) or a placebo (n
= 227) for four years in a multicenter double-masked parallel group clinical study
(NATHAN 1). Some neuropathic symptoms and deficits, but not nerve conduction
velocity, improved after 4 years, and the medication was well tolerated throughout
the experiment. Studies conducted during clinical trials and after the product was
launched have shown a very good safety profile.
The Use Of Medications To Alleviate Painful Neuropathy
Painful DPN symptoms are a significant treatment challenge. Simple analgesics
are typically insufficient to manage the pain, and the efficacy of a single therapeutic
drug is not the norm.
treatment were created to control pain without favorably affecting the underlying
neuropathy, in contrast to those that have been produced from the pathogenetic
processes of diabetic neuropathy. In clinical trials, the relative benefit of an active
treatment over a placebo treatment is typically expressed as the relative risk, the
relative risk reduction, or the odds ratio; however, to estimate the magnitude of a
therapeutic effect (such as pain relief) that can be applied in clinical practice, it
is helpful to apply a straightforward metric that helps the doctor choose the best
course of action for the specific patient. The number required to treat (NNT; i.e., the
number of patients who need to receive a certain therapy in order to see a clinically
significant effect or adverse event in one patient) is one such useful metric.

There is consensus that patients should be provided with the various treatments
gradually. Without indicating a maximal impact, effective pain management takes
into account a good balance between pain relief and adverse effects. When using
medications to treat neuropathic pain, the following general factors need to be
taken into account:
• By carefully titrating the dosage depending on efficacy and adverse effects, the
right medication must be attempted and identified in each patient.
• Failure to achieve efficacy should only be assessed after 2 to 4 weeks of therapy
with a sufficient dosage.
• Analgesic combinations may be helpful because the data from clinical studies
only support a maximum response of 50% for any monotherapy.
• Given that diabetic patients frequently use many medications, potential drug

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5 5
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Table 5.8: Methods for managing uncomfortable diabetic neuropathy
Table 5.9: Painful neuropathy should be treated differently in light of common
comorbidities and adverse effects
This measurement is given as the reciprocal of the absolute risk reduction, or NNT
= 1/ [Pc - Pi], which is the difference between the proportion of incidents in the
control group and the intervention group. The reciprocal value of the 95% CI for
the absolute risk reduction may be used to calculate the 95% CI of NNT. Table
552
5.8 provides the NNT and number needed to harm (NNH) for each drug used to
treat painful diabetic neuropathy. Because of issues with heterogeneity, several
scientists have issued a warning that summary NNT estimations may only have
a limited therapeutic value. The most valuable information that can be gleaned
from systematic reviews that have been published thus far is the identification of
medicines that have shown efficacy for particular forms of neuropathic pain and the
quality of the supporting data.
Tricyclic antidepressants
Since more than 30 years ago, psychotropic drugs have played a significant role
in the treatment of chronic pain syndromes, with tricyclic antidepressants (TCAs)
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
having received the most thorough evaluation. Antidepressants may reduce pain
by blocking norepinephrine and/or serotonin reuptake at synapses of the central
descending pain control systems and by antagonistically binding to the N-methyl-D-
aspartate receptor, which mediates both hyperalgesia and allodynia. Desipramine is
a somewhat selective norepinephrine inhibitor, whereas imipramine, amitriptyline,
and clomipramine provide a balanced reuptake inhibition of both norepinephrine
and serotonin. The NNT (CI) for a TCA-induced pain reduction of 50% or more is
2.4 (2.0 - 3.0). For moderate adverse events, the NNH is 2.8, while for significant
adverse events, it is 19 (Table 5.8). As a result, among 100 patients with diabetes and
neuropathic pain receiving antidepressant therapy, 30 will report pain alleviation
of at least 50%, 30 will suffer minor side effects, and five will stop taking the
medication due to serious side effects.
In contrast to noradrenergic agents, which have a mean NNT of 3.6, medicines with
balanced reuptake inhibition have a mean NNT of 2.2.
The most prevalent side effects of TCAs are dry mouth and fatigue. A single
nighttime dosage of 25 mg (10 mg in fragile individuals) should be administered 1
hour before bedtime. It should be raised by 25 mg per week until pain relief is seen
or unfavorable side effects appear. The daily maximum dosage is typically 150 mg.
Since both types of neuropathic pain are responsive to TCAs, it is evident that
the idea that the nature of the pain would determine how it will be treated—i.e.,
that scorching pain should be treated with antidepressants and shooting pain with
anticonvulsants—is false. Many people continue to have pain relief for months or
553
 years after taking antidepressants, however this is not always the case. The majority
of evidence supporting the effectiveness of antidepressants comes from trials that
have only been done over a few weeks. TCAs should be used with caution in patients
with orthostatic hypotension and are contraindicated in those who have long QT
syndrome, unstable angina, a recent (within six months) MI, heart failure, a history
of ventricular arrhythmias, and significant conduction system dysfunction. TCAs
are regarded by many authors as the preferred medication for treating neuropathic
pain, but their usage is restricted by their relatively high rates of adverse effects and
numerous contraindications. Therefore, there is a need for drugs with effectiveness
5 that is on par with or greater than that produced by TCAs but that also have a more
manageable adverse effect profile.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Selective Serotonin Reuptake Inhibitors (SSRI)
It has been argued that individuals who cannot tolerate TCA due to adverse events
may instead be treated with selective serotonin reuptake inhibitors (SSRI) due to
the relatively high rates of side effects and numerous contraindications of TCA.
The presynaptic reuptake of serotonin is specifically inhibited by SSRIs, but not
that of norepinephrine. Additionally, unlike tricyclics, they do not have the same
postsynaptic receptor blocking actions or membrane stabilization as quinidine.
Fluoxetine, paroxetine, citalopram, and escitalopram therapy had either marginal
or no impact on neuropathic pain. SSRIs have not been approved for the treatment
of neuropathic pain due to these scant efficacy data.
Serotonin Noradrenaline Reuptake Inhibitors (SNRI)
Recent research has been focused on antidepressants with dual selective inhibition
of serotonin and noradrenaline such as duloxetine and venlafaxine since SSRI
have been proven to be less effective than TCAs. In three controlled trials, the
efficacy and safety of duloxetine were assessed using daily doses of 60 and 120
mg for 12 weeks. In all three investigations, the difference between active and
placebo therapy reached statistical significance after one week, and the average
24-hour pain intensity was significantly decreased with both dosages compared
with placebo treatment. The response rates defined as a 50% decrease in pain were
48.2% (120 mg/day), 47.2% (60 mg/day), and 27.9% (placebo). These response
rates resulted in an NNT of 4.9 (95% CI 3.6 - 7.6) for 120 mg/day and 5.3 (3.8 - 8.3)
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for 60 mg/day.
The effects of duloxetine on diabetic peripheral neuropathic pain are predicted by
pain intensity but not by diabetes or neuropathy-related factors. Patients who are
experiencing more pain often react more favorably than those who are experiencing
less discomfort. Duloxetine (60/120 mg/day) has a number of adverse effects,
although nausea (16.7/27.4%), somnolence (20.2/28.3%), dizziness (9.6/23%),
constipation (14.9/10.6%), dry mouth (7.1/15%), and decreased appetite (2.6/12.4%)
are the most common ones. These negative effects are often mild to moderate and
momentary. The initial dose should be 30 mg/day for 4–5 days in order to reduce
them. Duloxetine does not increase body weight, in contrast to TCAs and other 5
anticonvulsants, however it may slightly raise fasting blood glucose levels. The
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
analgesic response rates in a 6 week experiment with 244 patients were 56%, 39%,
and 34% for patients given 150-225 mg of venlafaxine, 75 mg of venlafaxine, and
placebo, respectively. The impact of venlafaxine (150-225 mg) was attributed to
an analgesic, rather than an antidepressant, effect since individuals with depression
were eliminated. Tiredness and nauseousness were the most frequent side reactions.
Venlafaxine has not been given a license to treat painful diabetic neuropathy; only
duloxetine has.
Calcium Channel Modulators (α2 - δLigands)
Gabapentin is an anticonvulsant that shares structural similarities with GABA,
a neurotransmitter involved in the transmission and regulation of pain. It is still
unclear exactly how this medication works to treat neuropathic pain.
Involved in them are, among other things, interactions with the system’s L-amino
acid transporter and high affinity binding to the 2A voltage-activated calcium
channel subunit. In an 8-week multicenter dose-escalation experiment with 165
patients who had severe diabetic neuropathy, 60% of the gabapentin-treated patients
(3600 mg/day attained in 67%) reported at least some pain reduction, compared
to 33% of the placebo-treated patients. About 23% of the patients reported that
dizziness and somnolence were the most prevalent side effects.
Pregabalin has a six times greater binding affinity than gabapentin and is a more
specific 2 - ligand. Pregabalin’s effectiveness and safety were reported in a pooled
analysis of 6 trials conducted in 1346 individuals with excruciating diabetic
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 neuropathy over a period of 5 to 11 weeks. With an NNT of 4.2, 5.9, and 20.0, the
response rates defined as 50% pain reduction were 46% (600 mg/day), 39% (300
mg/day), 27% (150 mg/day), and 22% (placebo). Dizziness (22.0%), somnolence
(12.1%), peripheral edema (10.0%), headache (7.2%), and weight gain (5.4%) are
the most prevalent adverse effects for 150-600 mg/day. Pregabalin has far better
dosage titration than gabapentin, and there is greater evidence in favor of a positive
impact in painful diabetic neuropathy.
Sodium channel blockers
5 capsaicin cream (0.075%), several studies have shown a significant reduction in
Despite being often used to treat neuropathic pain, there is not enough evidence to
suggest carbamazepine for painful diabetic neuropathy. Its replacement medication,
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
oxcarbazepine, and other sodium channel blockers such valproate, mexiletine,
topiramate, and lamotrigine had only marginally better results and were not
approved for the treatment of uncomfortable diabetic neuropathy. In a controlled
research with 15 patients who had chronic painful diabetic neuropathy, a single IV
infusion of lidocaine (5 mg/kg body weight over 30 minutes under continuous ECG
monitoring) led to a significant pain reduction after 1 and 8 days.
The topical lidocaine patch 5% (Lidoderm), a targeted peripheral analgesic, has
been developed in response to potential detrimental systemic effects associated
with IV lidocaine. The lidocaine patch 5% has shown to reduce pain and tactile
allodynia in individuals with post-herpetic neuralgia with a low risk of systemic
side effects or drug-drug interactions. There are studies being conducted on DPN
sufferers.
Lacosamide
In contrast to sodium channel blockers, lacosamide preferentially accelerates the
slow inactivation of voltage-dependent sodium channels while leaving the rapid
sodium channel inactivation unaffected. The collapsin response mediator protein 2,
a neuronal cytosolic protein that is crucial for nerve sprouting and excitotoxicity,
is involved in its second potential mechanism. Lacosamide has been tested in a
number of studies for painful diabetic neuropathy; however, neither the Food and
Drug Administration (FDA) nor the European Medicines Agency (EMEA) have
authorized the medication for this condition. Additional clinical trials might yet be
conducted.
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Topical Capsaicin
The most potent component of the red pepper is capsaicin, which is an alkaloid with
the chemical name trans - 8 - methyl - N - vanillyl - 6 - nonenamide. It decreases
neurogenic plasma extravasation, the FLARE response, and chemically produced
pain while depleting tissues of substance P.
Substance P is regarded as the principal neurotransmitter of painful impulses from
the periphery to the central nervous system. It is found in afferent neurons that
innervate skin, primarily in polymodal nociceptors. After 8 weeks of therapy with
5
pain and increase in quality of life in individuals with severe diabetic neuropathy. A
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
double-blind strategy has been criticized as being impractical for topical capsaicin
due to the temporary local hyperalgesia (often a slight burning sensation that occurs
in >50% of instances). Treatment should be limited to no more than 8 weeks, since
no negative effects on sensory function (caused by the mechanism of action) were
seen in diabetic individuals during this time.
Opioids
Both opioid and monoaminergic receptor systems are used by tramadol to exert
its direct and indirect effects. Tramadol is an alternative to powerful opioids in the
treatment of neuropathic pain since the occurrence of tolerance and dependency
during long-term tramadol treatment is unusual, and because its misuse potential
seems to be minimal. In a six-week multicenter study with 131 patients, tramadol
(up to 400 mg/day orally, mean dose: 210 mg/day orally) has been evaluated for
the painful symptoms of diabetic neuropathy. Tramadol reduced pain by 44%
compared to 12% with a placebo. Constipation and nausea were the most typical
side reactions. Drop-outs due to adverse events had a comparatively low NNH of
7.8, which indicated significant toxicity.
Tramadol significantly reduced pain (NNT 4.3) and mechanical allodynia in a
4-week research including patients with painful neuropathy of various causes, with
diabetes accounting for one-third of the patients. A postsynaptic opioid receptor-
mediated hyperpolarization of postsynaptic neurons is one potential explanation
for the beneficial effects of tramadol. Tramadol’s capacity to reduce cerebral
hyperexcitability can also result from a monoaminergic impact or from a synergistic
557
 opioid and monoaminergic effect. classes have to be used in patients with pain may benefit from wearing comfy shoes.
resistant to monotherapy. Several add - on trials have demonstrated significant
pain relief and improvement in quality of life following treatment with controlled
Acupuncture
- release oxycodone, a pure μ - agonist in patients with painful DPN whose pain
In a 10-week uncontrolled trial of diabetic patients receiving conventional pain
was not adequately controlled on standard treatment with antidepressants and
management, 77% reported significant pain alleviation after as many as six sessions
anticonvulsants.
of traditional Chinese acupuncture without experiencing any negative side effects.
Only 24% of patients needed additional acupuncture treatments over the follow-
Non-pharmacologic treatment of painful neuropathy up period of 18 to 52 weeks, and 67% were able to quit or significantly reduce
Non-pharmacologic treatment methods should always be taken into consideration their pharmaceutical use. To confirm these findings, controlled research employing
5 5
because there is no fully effective pharmacotherapy for painful diabetic neuropathy. placebo needles should be conducted.
In addition to making significant efforts to create efficient non-pharmacologic

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

treatments, there is also a need for pharmacologic therapy. Recent systematic

Electrical stimulation
reviews of complementary and alternative treatments for the treatment of
Transcutaneous electrical nerve stimulation
neuropathic and neuralgic pain evaluated the data from rigorous clinical trials and
Transcutaneous electrical nerve stimulation (TENS) affects the speed and
meta-analyses. We found information on acupuncture, electrostimulation, herbal
transmission of neuronal afferents, raises the threshold for nociceptive flexion
medicine, magnets, nutritional supplements, visualization, and spiritual healing,
reflexes, and modifies somatosensory evoked potentials. In a 4-week research using
among other complementary and alternative medical practices.
TENS administered to the lower limbs, each for 30 minutes a day, 83% of patients
reported pain alleviation, compared to 38% in a control group. individuals who
The finding was that most complementary and alternative medicine methods are
very slightly reacted to amitriptyline experienced much less pain after receiving
not completely effective in treating neuropathic or neuralgic pain. The data for
TENS for 12 weeks compared to individuals who received sham therapy. TENS
cannabis extract, magnets, carnitine, and electrostimulation may be categorized as
can therefore be used in conjunction with pharmaceuticals as an adjuvant modality
encouraging and calls for more research.
to enhance pain alleviation.

Psychological support
Mid-frequency external muscle stimulation
It is important to recognize that pain has a psychological component. Therefore,
Mid-frequency external muscle stimulation had a better effect on neuropathic
it is important to explain to the patient that even extreme pain might subside,
symptoms than TENS after one week, according to one randomized controlled
especially in patients with acute painful neuropathy or painful symptoms brought
research, although longer-term controlled studies are lacking.
on by aggressive insulin therapy. Therefore, neuropathic pain patients’ fears and
anxieties must be addressed emphatically if they are to be successfully managed.
Frequency-modulated electromagnetic nerve stimulation
In comparison to placebo stimulation, frequency-modulated electromagnetic nerve
Physical measures
stimulation administered over 10 sessions over three weeks significantly reduced
Arteriovenous shunting may raise the temperature of the painful neuropathic foot.
pain. A bigger, multicenter investigation is now being conducted.
Immersion in cold water can lower shunt flow and ease discomfort. Silk pajamas
or the use of a bed cradle may help to reduce allodynia. Patients who report their
symptoms as being unpleasant when walking and comparing it to walking on stones

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 Electrical spinal cord stimulation
Electrical spinal cord stimulation (ESCS) is frequently used to treat neurogenic
types of pain. Studies show that after electrical stimulation, the excitatory amino
acids glutamate and aspartate in the dorsal horn decrease. GABAergic pathway
mediates this action. 8 out of 10 patients who had ESCS with electrodes placed
between T9 and T11 experienced pain alleviation more than 50% in cases of painful
diabetic neuropathy that was refractory to medication therapy. Additionally, there
was a noticeable improvement in exercise tolerance. Infection of the superficial site
in two patients, lead migration necessitating reinsertion in two patients, and “late
5 failure” after four months in a patient who initially had pain alleviation were all
complications of ESCS.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Monochromatic infrared energy
In uncontrolled investigations, monochromatic infrared radiation was found to
lessen the neuropathic symptoms and indicators in diabetic individuals. Contrarily,
two controlled trials revealed that monochromatic infrared energy had no more
effect on improving sensation in patients with DPN than a placebo, highlighting
the necessity for controlled investigations in this area to enable an evidence-based
therapy decision.
Surgical decompression
For individuals with symptomatic DPN, surgical decompression at the location
of anatomic constriction has been advocated as an alternate therapy. Only Class
IV studies on the usefulness of this therapy strategy were found after a thorough
examination of the literature. This treatment option should be regarded as unproven
(Level U) based on the present body of evidence. To evaluate the efficacy of this
therapy intervention, prospective randomized controlled trials using accepted
definitions and performance indicators are required.
Diabetic Retinopathy
Capillary aneurysms were noted by Mackenzie and Nettleship in one of the earliest
pathologic findings on diabetic retinopathy (DR) in 1877. Over the following
century, the average life expectancy for males increased to 76.0 years and for
women to 80.6 years from 48.5 years for men and 52.4 years for women in 1900.
560
Insulin was discovered by Banting and Best at Dr. J. MacLeod’s laboratory in
1921. Banting and MacLeod received the Nobel Prize in Medicine in 1923. When
Ballantyne and Loewenstein examined flat, unstained retinas in 1943, they saw
many capillary aneurysms and were the ones who first used the term “diabetic
retinopathy.” In 1953, based on research on postmortem retinas, Ashton revealed
alterations in the arterioles in DR.
The Normal Eye
The retina, which is the eye’s interior surface and contains specialized photoreceptor
5
cells, is roughly shaped like a globe (Figure 5.31).
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
The necessary supply is given by diffusion from the capillaries of the innermost
vascular layer of the underlying choroid through contact with the retinal pigment
epithelium in the central foveal area, which is thinner and devoid of retinal blood
supply. The retinal vascular circulation delivers oxygen to the bulk of the retina
(Figure 5.32).
Tight connections between neighboring cells are present in the blood vessels of
the retina, preserving the blood-retinal barrier. Figure 5.33 depicts the retinal
vessels’ typical structure. Small spaces (fenestrations) exist between the cells of the
choroidal circulation in the walls of the smaller choroidal vessels, which allow the
transport of small molecules and other necessary nutrients, supporting the nutrition
and oxygenation of the foveal region through the retinal pigment epithelium.
Risk Factors For Diabetic Retinopathy
Risk Factors That Are Modifiable
Blood glucose
Numerous early investigations supported the relationship between poor glucose
management and faster DR development. The Diabetes management and
Complications Trial (DCCT) was the research that confirmed that strict blood
glucose management lowers the chance of developing DR and delays the course of
pre-existing DR in people with type 1 diabetes mellitus (T1DM).
At the 6 and/or 12 month visits of the DCCT, 13.1% of patients allocated to intense
561
 therapy reported an early worsening of their diabetes; nevertheless, the long-term
benefits of intensive insulin treatment exceeded the risks of an early worsening
significantly.

5 5

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

Figure 5.31: (a) Cross - section diagram of the eye and major structures.
(b) Normal human fovea. This shows the inner and outer
nuclear cell layers at the edge of the fovea and the concentration of cones
centrally
(c) Color photograph of the left central retina, including the
macula and disc

Figure 5.30: Diabetic retinopathy displaying a vein on the right and an artery
on the left. Microaneurysms and hemorrhages may be detected on an arteriole
in the middle of the image. Significant atrophies have occurred on the arteriolar
side of the circulation. Figure 5.33: (a) This figure shows a retinal structure cross - section diagram.

Indian ink was injected. Schiff stain with periodic acid: 44 (b) A histologic section showing the ganglion cell layer, the bipolar layer, the
nuclei of the
cones and rods, the pigment epithelium, Bruch’s membrane and choroidal
vessels.

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5 Unchangeable Risk Factors
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.34: A tube of basement membrane, which is encircled by pericytes,
encloses an inner layer of endothelial cells
Similarly, type 2 diabetes (T2DM) patients with rigorous blood glucose management
had a lower likelihood of developing DR and see a slower rate of advancement of
their pre-existing DR, according to the UK Prospective Diabetes Study (UKPDS).
Blood pressure & lipid levels
It has been demonstrated that systemic hypertension management lowers the chance
of developing DR and slows the development of pre-existing DR. There is evidence
linking macular exudates and mild vision loss to increased blood lipid levels, and
lowering elevated lipid levels may be able to partially reverse hard exudates.
564
Note: In the Wisconsin research, 67% of those with type 1 diabetes mellitus (T1DM)
for 35 or more years experienced proliferative diabetic retinopathy (PDR). Therefore, it
stands to reason that two thirds of T1DM patients will eventually require laser therapy for
PDR.
The incidence of panretinal photocoagulation during a 4-year period was 2.5 times
greater in the same research than the incidence of macular laser.
5
Age, genetic disposition and ethnicity
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
The Wisconsin Epidemiological Study showed that the severity of retinopathy was
related to older age at examination in those whose age at diagnosis was less than
30 years and who had diabetes of 10 years’ duration or less, whereas the severity of
retinopathy was related to younger age at diagnosis in those whose age at diagnosis
was 30 years or more. Among the UKPDS, advancement was linked to greater age
among individuals who already had retinopathy.
Early research on diabetic identical twins points to a genetic clustering of DR.
Human leukocyte antigens have been linked to human leukocyte severity in a
number of investigations, albeit this has not always been agreed upon. Where
connections have been found, they have not been confirmed across several groups,
and the bulk of potential genes under study show little or no relationship with
retinopathy status.
According to Emanuele et al., Latin Americans (36%) and African-Americans
(29%) had a greater incidence of DR scores > 40 than whites of Northern European
descent (22%). In Auckland, New Zealand, Simmons et al. evaluated the frequency
of DR across European, Maori, and Pacific Islander peoples with diabetes. They
showed that Polynesians experience mild to severe DR more frequently than
Europeans. The disparities in these two investigations could not be explained by an
imbalance in conventional risk variables such age, the length of time since diabetes
was diagnosed, HbA1c, or blood pressure.
Pathophysiologic Events In Diabetic Retinopathy
Basement membrane thickening
The thickening of the basement membrane is an early histopathologic indicator of
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 DR (Figure 5.35).
5 5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.35: (a) Basement membrane thickening (arrow) in a retinal arteriole.
Periodic acid – Schiff stain, original magnification × 250. (b) Pericyte loss, in a
flat - mounted tryptic digest of retina. Pericytes (small, dark nuclei) normally
occur in a 1 : 1 ratio with the endothelial cells (pale, elongated nuclei). Original
magnification × 400
Pericyte loss
An early and significant event in DR is the fallout of pericytes, which are susceptible
to high glucose concentrations and experience apoptosis (Figure 5.35 b). Acellular
capillaries are formed shortly after pericyte loss, which is followed by the loss of
retinal capillary endothelial cells.
Greater capillary permeability
In order to maintain the inner blood-retinal barrier, which may become compromised
566
in DR and result in the leaking of plasma proteins, endothelial cells create a
continuous sheet with each cell being joined to neighbors by tight junctions. A
smaller amount of leakage is seen near microaneurysms, although this is more likely
due to endothelial cell injury brought on by inflammatory mediators produced by
adhering leukocytes.
Microaneurysms
The microaneurysm is the telltale sign of diabetic patients’ retinal microvascular
dysfunction (Figure 5.36). The loss of the supporting pericytes (Figure 5.35 b) and
localized increases in hydrostatic pressure have been linked to the development of
microaneurysms, which may be asymmetric dilatations of the capillary wall when
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
it is weak or injured. Monocyte and polymorphonuclear cell counts may be quite
high in early stage microaneurysms (Figure 5.36).
Figure 5.36: Tryptic digest of diabetic retina, showing two large microaneurysms
in an area of acellular capillaries. One aneurysm (left) appears to be filled with
clotted blood, while the second is hypercellular. Hematoxylin and eosin stain,
original magnification × 400.
Smooth muscle death
It has been demonstrated in the diabetic human retina that vascular smooth muscle
cells in the retinal arteries and arterioles gradually die.
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 Capillary weakening
Intraretinal microvascular abnormalities (IRMA) may be associated with increased
capillary closure. These formations, which are associated with acellular capillaries
near to the arterial side of the circulation, include a significant number of cells that
resemble endothelial cells.
Retinal blood flow
The majority of clinical hemodynamic research in diabetes come to the conclusion
that DR is characterized by increased blood flow and poor autoregulation. A well-
5 5
known complication of diabetes is persistent retinal arteriole dilation. Larger and
more extensive patches of retinal ischemia are created when DR worsens as a result
periphery and posterior area. Compared to slit-lamp biomicroscopy, a
broader area may be seen, although the vision is not as magnified.
It is crucial for an ophthalmologist to be informed of how each patient’s risk factors
are being managed and to work well with the general practitioner or diabetes
specialist who is in charge of this area of the patient’s care.
Investigative Techniques To Assess Diabetic Retinopathy
Retinal photography
As a way to document retinal lesions, digital color retinal photography is becoming

Management Of Comorbidities/Complications/ Dm In Extremes Of Age

Management Of Comorbidities/Complications/ Dm In Extremes Of Age

more and more popular.

of capillary blockage and intravascular coagulation, which some studies suggest is
aided by increased platelet stickiness but not others.
Fundus fluorescein angiography
This is a diagnostic process that involves quickly injecting sodium fluorescein into
The Consultation the arm. The fluorescence of the dye in blue light allows for the taking of pictures
A thorough history and clinical examination are essential parts of the treatment of of the condition as it appears in the retina (Figure 5.37). Some adverse reactions
any patient with DR. to fluorescein dye include nausea, vomiting, infrequent syncope, skin rashes, and
● Past ocular, diabetic, medical, familial, drug, and psychological histories. itching. Anaphylactic shock, cardiac arrest, and other more severe adverse effects
● An eye exam, including a red reflex examination with an ophthalmoscope, are exceedingly uncommon.
slit-lamp biomicroscopy of the anterior eye, assessment of visual acuity
and, when necessary, color vision, examination of external structures,
visual fields to confrontation, ocular movement, pupillary reactions to
light, and accommodation.
● Both pupils are dilated with 1% tropicamide and, in many patients, 2.5%
phenylephrine as well.
● Direct ophthalmoscopy has been demonstrated to have a low sensitivity
and specificity for the identification of sight-threatening DR, although it is
beneficial for ad hoc detection of DR. It also has a limited two-dimensional
field of vision.
● The most popular technique used by ophthalmologists to diagnose and track
retinal illness using condensing lenses or fundus contact lenses (contact
lens biomicroscopy) is slit-lamp biomicroscopy of the retina.
● Binocular indirect ophthalmoscopy is helpful for assessing the retinal

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5 5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.37: Fundus fluorescein angiography. (a) Choroidal flush. (b) Retinal
arterial stage with very early signs of fluorescein in veins. (c) Arteriovenous
phase. (d) Venous phase
Optical coherence tomography
The imaging method known as optical coherence tomography (OCT) uses
interferometry to analyze reflected optical pulses. OCT images can be shown as
topographic maps or as cross-sectional pictures (Figure 5.38).
Ultrasound B scan examination
High frequency ultrasound is used in an ultrasound B scan examination to assess
the density and size of a vitreous hemorrhage as well as the presence or absence of
a retinal detachment in cases when the retinal vision is occluded.
Perimetry
Perimetry, which typically involves testing each eye separately but binocularly
for driving field assessment, is the systematic measurement of differential light
sensitivity in the visual field by the detection of the presence of test targets on a
570
defined background in order to map and quantify the visual field.
Screening For Diabetic Retinopathy
The World Health Organization (WHO) defined screening as “the presumptive
identification of unrecognized disease or defect by the application of tests,
examinations, or other procedures which can be applied rapidly” in 1968. Screening
tests separate people who appear healthy from those who likely do not have an
illness. A screening test is not meant to provide a diagnosis. The diagnosis and
required care for those with positive or questionable findings must be directed to
their doctors.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.38: (a) Normal cross - sectional optical coherence tomography
(OCT) image. (b) Topographic map of macular area. (c) Topographic map
superimposed on red free image of macular area. (d) Measurements of
thickness in macular area.
This definition, when applied to DR, shows that it is an excellent candidate for
screening:
• A significant issue in terms of public health is sight-threatening DR.
• The International Diabetes Federation (IDF) has forecast a global rise in diabetes
and DR, making the occurrence of sight-threatening DR an even bigger public
health issue.
571
 • Laser therapy for sight-threatening DR is successful and well accepted. • Sight-
threatening DR has a distinct latent stage. Positive long-term visual outcomes have
been documented, and there is evidence that rigorous blood glucose management
and systemic hypertension control lower the risk of developing new cases of
diabetes and limit the course of existing cases of diabetes.

• Digital photography is a viable and trustworthy screening method for sight-

threatening DR that is acceptable to both the public and medical experts.
• When compared to the whole cost of healthcare, including the effects of leaving
5 the illness untreated, the expenses of screening and effective treatment of sight- 5

threatening DR balance economically.

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

Lesions And Classifications Of Diabetic Retinopathy

Microaneurysms and retinal hemorrhages
The lesions that the Early Treatment Diabetic Retinopathy Study (ETDRS)
identified as being crucial to the phases of DR development were as follows:
● Microaneurysms, which are defined as red spots with sharp borders and a
vein width of around 125 m. Figure 5.40: An illustration of more oval, darker red blot hemorrhages and
● Small retinal hemorrhages are defined as red spots with uneven edges and/ more elongated, lighter red flame hemorrhages
or densities, especially when they surround a smaller center lesion thought
to be a microaneurysm.

Figure 5.39: An illustration of the venous phase of a fluorescein angiography

revealing microaneurysms that are fluorescing and some of them are leaking
as indicated by the fluffy edge Figure 5.41: An example of exudates in the right macular area

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 5 5

Figure 5.42: An example of cotton wool spots

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

Other significant retinal hemorrhages

Just below the nerve fiber layer are flame hemorrhages, which are superficial
hemorrhages (Figure 5.40).
In the region of the retina where they occur, blot hemorrhages—deeper Figure 5.43: An example of intraretinal microvascular abnormality (IRMA)
hemorrhages—are a symptom of retinal ischemia. in the temporal retina of the right eye (the right macula is seen in the right side
of this red free photograph)
Hard exudates
Hard exudates are defined as tiny, white or yellowish-white deposits with sharp
corners that are normally seen in the outer layers of the retina, however they may
be more prominent, especially in the presence of retinal edema (Figure 5.41).

Cotton wool spots

Cotton wool spots are fluffy white opaque areas that are caused by an accumulation
of axoplasm in the nerve fiber layer of the retina, which is caused by an arteriolar
occlusion in that area of retina that is visible on a fluorescein angiogram (Figure
5.42). Cotton wool spots are also known as soft exudates in the ETDRS, but this
term is now rarely used.

The length of diabetes, blood glucose and blood pressure control, as well as the availability
of screening and preventative laser therapy, all have an impact on the prevalence of
blindness. The danger of becoming blind can be reduced to extremely low levels by Figure 5.44: An example of a venous loop
achieving great compliance, as was done in Iceland.

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 Fibrous proliferation elsewhere
Fibrosis and new vascular regression are the two main causes of fibrous proliferation
elsewhere (FPE).
New vessels on and/or within 1 disc diameter of the disc
See Figure 5.46 for information on new vessels on or near the disc (NVD) by 1 disc
diameter (DD).
A hemorrhage that occurs in the vitreous gel is called a vitreous hemorrhage (VH).
In the area just anterior to the retina or underneath the internal limiting membrane,
preretinal hemorrhages (PRH) include boat-shaped hemorrhages and approximately
5 5
circular, confluent, or linear patches of hemorrhage (Figure 5.48).

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

Figure 5.45: A fluorescein angiogram showing venous beading adja-

cent to an ischemic area of retina
Intraretinal microvascular abnormalities
Retinal ischemia is indicated by IRMA, which are defined as tortuous intraretinal
vascular segments of various diameters that are the result of remodeling of retinal
capillaries and tiny collateral arteries in sites of microvascular occlusion (Figure
5.43).
Venous abnormalities
• Venous loops, which are sharply curved vein departures from their regular course
(Figure 5.44).
• Venous beading: According to the ETDRS, venous beading is a localized increase
in vein diameter, and the severity depends on both the magnitude of the increase
and the length of the affected vein. Retinal ischemia is linked to it (Figure 5.45).
The following are some vascular alterations related to DR:
Venous dilatation, narrowing, opacification of the venous wall, and perivenous
exudate are all symptoms of vein disease.
Figure 5.46: An example of new vessels on disc (NVD)
Arteriolar abnormalities
Arteriolar constriction, opacification of the arteriolar walls, and arteriovenous
pinching are further alterations to the arteries that develop in DR.
Fibrous proliferation at the disc
Fibrosis and new vessel regress at the disc are the two main causes of fibrous
proliferation at the disc (FPD).

576 577
 Preventing Diabetic Retinopathy
A few simple lifestyle adjustments can enhance your overall well-being and lower
your chance of getting retinopathy.
These consist of:
● Eating a nutritious, balanced diet; in particular, attempt to reduce salt, fat,
and sugar intake
● To lose weight, you should aim for a BMI of 18.5-24.9. To calculate your
BMI, use the BMI calculator. To exercise regularly, you should aim to do
5
at least 150 minutes of moderate-intensity activity each week. Aiming to 5
complete 10,000 steps each day can help you reach this goal.

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

● Giving up smoking if you smoke while abstaining from drinking in excess

- It’s recommended that neither men nor women habitually consume more
than 14 alcohol units each week.
● Maintaining and monitoring blood sugar levels and blood pressure regularly
Figure 5.47: An example of new vessels elsewhere (NVE)
● Aim for a blood pressure reading of no more than 140/80 mmHg if
you have diabetes; if you have complications such eye damage, aim
for a reading of less than 130/80 mmHg.
● Attend your yearly diabetic eye test even if you believe your diabetes is
under control because this can spot warning signals before you even realize
there is a problem.
● The likelihood that retinopathy will respond to therapy and not worsen
improves with early identification.
● Additionally, if you experience any issues with your eyes or eyesight,
including but not limited to:
● progressive eyesight deterioration
● abrupt loss of eyesight and the appearance of floating objects in your range
of view
● eyesight that is hazy or painful or inflamed eyes
● having trouble seeing in the dark

Laser Treatment
Figure 5.48: An example of preretinal hemorrhage
If laser therapy is administered before the retina has suffered significant damage, it

578 579
 typically prevents vision loss rather well. As for macular edema, it could be helpful.
Scatter (pan-retinal) photocoagulation is a more intense laser treatment that
can be used to treat severe proliferative retinopathy. It enables your doctor
to control the expansion of fresh blood vessels over the retina’s dorsum.
Proliferative retinopathy may not always respond favorably to laser therapy.
Surgical Removal Of The Vitreous Gel (Vitrectomy)
If the retina has not suffered significant damage, this operation could aid with
5 major non-specialist journal had focused on this widespread issue, but there are still
visual improvement. When the retina is detached or there is bleeding (vitreous
hemorrhage), it is performed. In persons with early-stage retinopathy, these two
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
issues are uncommon.
When extensive scar tissue has developed, this operation is also performed.
It is a treatment option for macular edema.
Anti-Vegf (Vascular Endothelial Growth Factor) Or An Anti-
Inflammatory Medicine
The development of aberrant blood vessels in the retina is slowed by anti-VEGF
medications. Vascular endothelial growth factor (VEGF), a protein, stimulates this
growth. Anti-VEGF medications stop VEGF’s effects.
Injections of these medications have occasionally been shown to reduce the number
of new blood vessels in proliferative diabetic retinopathy.
If the macula has been harmed by macular edema, an anti-VEGF medica-
tion, such as aflibercept (Eylea) or ranibizumab (Lucentis), may be utilized.
The eye may receive a steroid injection. In some cases, an implant like Ilu-
vien may be inserted into the eye. Over time, the implant gradually releases
a little quantity of corticosteroid.
As the problem worsens, many persons with diabetic retinopathy require many
treatments.
Foot Problems in Diabetic Patients
“Superior doctors prevent the disease. Mediocre doctors treat the disease
580
before evident. Inferior doctors treat the full - blown disease.”
According to a Chinese saying, subpar physicians should only handle fully
developed illnesses; regrettably, this was the situation with diabetic foot disease
until recent years. The International Diabetes Federation (IDF) focused on the
diabetic foot throughout 2005 as a result of realizing the importance of diabetic
foot disease on a global scale. During this time, there was a global campaign to “put
feet first” and draw attention to the all-too-common issue of amputation among
patients with diabetes worldwide. The Lancet published a nearly entire issue on the
diabetic foot to coincide with World Diabetes Day in 2005. This was the first time a
5
significant obstacles to communicating vital information about the diabetic foot.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
The most frequent reason for hospital admissions for diabetic individuals in Western
nations continues to be diabetic foot issues.
Up to 50% of elderly type 2 diabetic individuals have risk factors for foot issues.
Foot ulcers can occur prior to lower limb amputations in up to 85% of cases.
All diabetic patients should have an annual foot risk assessment; those who have risk
factors need ongoing podiatrist care as well as patient education and self-care training.
Up to 25% of diabetic people will get foot ulcers throughout their lifetime.
2 In western nations, diabetes continues to be the most prevalent reason for non-
traumatic amputation, with foot ulcers being the cause of more than 85% of lower
limb amputations.
3 The first step in addressing diabetic foot issues is prevention. A more significant
statistic is that up to 85% of all amputations in diabetes should be avoided, despite
estimates that a limb is amputated somewhere in the globe every 30 seconds.
4 Reducing amputations will only be possible if medical professionals from all
specialties understand that, as Brand once said, “Pain is God’s greatest gift to
mankind.” Patients with neuropathy are able to develop ulcers and walk on them
despite the presence of a frequently overwhelming infection because they are no
longer experiencing pain.
If more attention is paid to patients who have known risk factors for developing
581
 foot issues, prevention strategies for foot ulcers are both cost-effective and may
even result in cost savings.
6 In Western nations, diabetes is currently the leading cause of Charcot
neuroarthropathy, a disorder that should be mostly avoidable.
Over the past 25 years, significant progress has been achieved in our knowledge of
the pathophysiology and treatment of the diabetic foot. An increase in publishing
in peer-reviewed journals has paralleled this. When viewed as a fraction of all
diabetes-related publications in PubMed, papers on the diabetic foot climbed from
5 0.7% between 1980 and 1988 to more than 2.7% between 1998 and 2004. Despite
the fact that the link between gangrene and diabetes was discovered in the middle
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
of the 19th century, no progress had been made prior to 1980. Following these
accounts, it was believed that diabetic foot issues were mostly vascular and made
worse by infection during the first 100 years.
Following these accounts, it was believed that diabetic foot issues were mostly
vascular and made worse by infection during the first 100 years. McKeown, who
had diabetes himself and was a co-founder of the British Diabetic Association,
which is now known as Diabetes UK, encouraged Lawrence to perform the first
ray excision on a patient with diabetes and osteomyelitis but good blood supply
during the Second World War. Numerous significant national and international
organizations, such as study groups for diabetic feet, were founded during the past
20 years. The worldwide working group on the diabetic foot was first created in
1991. Recent years have seen the publication of new editions of two of the top
worldwide textbooks on the diabetic foot, and other joint research groups are now
addressing many of the unresolved issues surrounding the pathophysiology and
treatment of diabetic foot disease.
The term “diabetic foot” will be used in this segment to refer to a wide range of
pathologic problems that may impact a person with diabetes’ feet.
The Economic And Epidemiological Aspects Of Diabetic Foot Disease
Due to the strong connection between foot ulceration and amputation in diabetes,
they will be discussed together in this section. Table 5.10 provides a collection
of epidemiologic data regarding foot ulceration and amputation, collected from
research in several different nations. All types of diabetes and all countries continue
582
to experience major medical, social, and economic problems related to diabetic
foot complications, but different diagnostic criteria and regional variations have a
significant impact on the reported frequencies of amputation and ulceration. With
rates up to 15 times greater than in the non-diabetic population, diabetes continues
to be a leading cause of non-traumatic amputation worldwide.
5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Table 5.10: Epidemiology of foot ulceration and amputation
Despite the fact that much of the research mentioned and included in Table 5.10
were competently done, methodological problems still exist, making it difficult
to establish direct comparisons between studies and/or nations. First of all, there
are different definitions of what defines a foot ulcer, and secondly, studies almost
always only include people who have already been diagnosed with diabetes, even
though foot issues may be the first sign of type 2 diabetes. For instance, 15%
of individuals undergoing amputation in a UK research had their first diabetes
diagnosis during their hospital stay. Third, the researchers working on the study
don’t always confirm reported foot ulcers by personal inspection. Finally, as can be
seen from the table, in those studies that assess the percentage of the population that
had risk factors for foot ulceration, 40 – 70% of patients fell into that category. Such
observations clearly indicate the need for all diabetes services to have a regular
screening program to identify such high risk individuals.
Health Economics Of Diabetic Foot Disease
Diabetes patients’ foot lesions not only have significant morbidity and even death
risks, but they also have significant economic costs.
US health care payers were reported to have spent $10.9 billion on diabetic foot
583
 ulcers and amputations in 2001. According to comparable UK estimates, the
total annual costs of diabetes-related foot complications were estimated to be £
252 million. However, when comparing data on the costs of diabetic foot lesions,
similar issues to those noted with epidemiology exist regarding methodology as
well as whether direct and indirect costs were included.
Furthermore, only a few studies have calculated the expenses of patients’ long-term
follow-up after foot ulcers or amputations.
According to the most recent statistics from the USA, $11.7 billion was spent
5 on lower extremity amputations in 2007 and $18.9 billion was spent on treating
the development of foot ulcers is necessary here. In diabetic individuals, PVD tends
to develop earlier and is more likely to affect distal arteries. PVD is a significant
contributing factor in the etiology of foot ulceration and consequent major
amputations, according to reports from the USA and Finland. As will be explained
for neuropathy, the etiology of ulceration is seldom caused by PVD alone; rather,
the combination of risk factors and mild trauma always results in ulceration (Figure
5.49). As a result, small injuries and subsequent infections cause blood supply
demands to exceed circulatory capacity, leading to ischemic ulceration and the
possibility of amputation. In diabetic foot clinics, neuroischemic ulcers—which
occur when neuropathy and PVD coexist in the same patient and are accompanied 5

diabetic foot ulcers. The authors calculated the entire cost of diabetic foot illness to by some sort of trauma—have become more prevalent in recent years.

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

be $30.6 billion in 2007, and then went on to project savings of up to $21.8 billion
based on actual reductions in ulceration and amputation. Such persuasive economic
justifications can encourage advancements in preventative foot care, which might
ultimately result in significant cost savings for healthcare systems.

Etiopathogenesis Of Diabetic Foot Lesions

“ Coming events cast their shadow before. ”
-[Thomas Campbell]
Understanding the mechanisms that lead to the formation of an ulcer is becoming
increasingly crucial if we are to be effective in lowering the high frequency of
foot ulcers and ultimately amputation. The deterioration of the diabetic foot can
be helpfully explained using the words of Scottish poet Thomas Campbell. The
formation of a lesion is the consequence of the interaction of the causative elements;
ulceration does not happen on its own. Numerous “shadows” or warning signals
can help identify people at risk before an ulcer develops. It is not a natural effect Figure 5.49: Diabetic foot ulceration risk factors
of diabetes that ulcers develop; instead, specific diseases in the lower leg interact
Diabetic neuropathy
with environmental dangers to produce ulcers. Traditionally, it has been thought
As was previously mentioned, diabetic neuropathies are the most prevalent type
that peripheral vascular disease (PVD), peripheral neuropathy, and some kind of
of long-term consequences of diabetes. They affect various sections of the nervous
trauma combine to cause the disintegration of the diabetic foot. There is also a brief
system and can have a variety of clinical presentations. Chronic sensorimotor distal
description of other reasons.
symmetrical polyneuropathy and autonomic neuropathies are the most prevalent
neuropathies. The pathophysiology of ulceration is significantly influenced
PVD by peripheral autonomic sympathetic neuropathy and common sensorimotor
Even though it has already been discussed, a quick note of PVD’s contribution to neuropathy.

584 585
 It has been noted that patients who have various late problems, notably nephropathy,
are at higher risk of developing foot ulcers. Patients who have recently begun
receiving dialysis as a kind of therapy for end-stage renal illness are those who are
most at risk. Additionally, it must be kept in mind that even when normoglycemic
as a result of the pancreatic transplant, patients who have had renal transplants
or more recently combined pancreas-renal transplants are often at high risk of
ulceration.
5 5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Table 5.11: Factors putting diabetic foot ulceration at risk. Bold font indicates
the more frequent contributing elements
Plantar callus
Due to dry skin (autonomic dysfunction), insensitivity, and recurrent mild stress
from high foot pressure, callus develops under weight-bearing regions. It induces
ulceration and behaves like a foreign body. A podiatrist or other qualified healthcare
provider should remove the callus if it is present on a patient’s insensate foot since
it puts that patient at a high risk of developing an ulcer.
Elevated foot pressures
The contributing role that aberrant plantar pressures play in the formation of foot
ulcers has been confirmed by several investigations.
586
Foot deformity
The “high risk” neuropathic foot, which has clawing of the toes, large metatarsal
heads, high arch, and minor muscle atrophy (Figure 5.50), is assumed to be the
outcome of a combination of motor neuropathy, cheiroarthropathy, and changed
walking patterns.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.50: The high risk neuropathic diabetic foot demonstrating high arch,
prominent metatarsal heads, clawing of toes and callus under first metatarsal
head
Ethnicity and gender
The prevalence of ulcers has been shown to be 1.6 times higher in men. The North-
West Diabetes Foot Care Study in the UK found that the age-adjusted prevalence
of diabetic foot ulcers (past or present) for Europeans, South Asians, and African-
Caribbean people was 5.5%, 1.8%, and 2.7%, respectively. This data from cross-
sectional studies in Europe suggests that foot ulceration is more common in Europid
subjects than other racial groups. There is definitely need for more research into
the causes of these racial disparities. In contrast, Latino and Native Americans in
the southern USA experienced ulceration considerably more frequently than White
individuals with Northern European heritage did.
Route To Ulceration
Diabetic foot ulceration is eventually caused by the interaction of two or more risk
587
 factors (Figure 5.49). The Rothman model for causality has been used by Pecoraro
as al. and later Reiber et al. to apply to amputation and foot ulcers in diabetes.
This model is predicated on the idea that while a component cause by itself is
not sufficient to induce ulcers, when the component causes operate jointly, they
produce a sufficient cause that will inevitably cause ulceration. A modest number of
causative pathways were identified when this model was applied to foot ulceration:
the most prevalent trio of component causes, present in almost two out of every
three incident foot ulcer cases, was neuropathy, deformity, and trauma. Edema and
ischemia were additional frequent contributing factors.
5 seen to be required.
drawbacks, it was decided that the 10 g monofilament had the most evidence in
favor of its usage. As a result, it was suggested that the 10 g monofilament be
used in combination with one additional test for the assessment of neuropathy.
Assessment of vibration perception threshold was one feasible test for neuropathy
in addition to the straightforward procedures indicated in Table 5.12.
Even though it is a semi-quantitative examination of feeling, it was included since
many facilities in North America and Europe have this technology. Although
significant evidence does support the use of vibration perception threshold as an
excellent predictor of foot ulceration, as can be shown from Table 5.12, this is not
5

Other straightforward examples of two-part causes of ulceration include loss of

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

sensation and mechanical trauma, like standing on a nail or wearing too-small

shoes; neuropathy and thermal trauma, like walking on hot surfaces or getting
burned in the bath; and, finally, neuropathy and chemical trauma, like improper use
of chemical “corn cures.” This model may also be used to explain neuroischemic
ulcers, which frequently have the three causes of ischemia, trauma, and neuropathy.

Preventing Diabetic Foot Ulcers

According to estimates, the great majority of foot ulcers may be prevented; the first
step in prevention is the identification of the group that is “at risk.” The “annual
review” idea, whereby each patient is checked at least once a year for signs of
diabetic complications, has now been adopted by many nations. Either a primary
care facility or a hospital clinic can do such an evaluation.

What should be included in the “comprehensive diabetic foot examination (CDFE)”

for the yearly review was recently discussed by a taskforce of the American
Diabetes Association. When feasible, the taskforce used evidence-based medicine Table 5.12: The essential elements of the diabetic foot examination
to determine what should be included in the CDFE for adult patients with diabetes. The ankle brachial index was advised with regard to the vasculature, despite the
The taskforce evaluated and succinctly described the most recent literature in this fact that many primary care clinics would not be able to execute this in regular
area. A quick history was thought to be vital, but a thorough examination of the clinical practice.
foot, particularly determining its neurologic and vascular condition, was thought
Intervention
to be crucial. A solid body of research supports the use of straightforward clinical
Any irregularity in the aforementioned screening test would place the patient in a
tests as indicators of the likelihood of developing foot ulcers. Table 5.12 lists the
group at an increased risk of developing a foot ulcer. The most significant of the
essential elements of the CDFE in brief.
several topics covered by potential treatments is education.
Although each prospective simple neurologic clinical test had benefits and

588 589

According to earlier research, persons at risk for foot ulcers lack the information and
skills necessary to properly care for their feet. Patients must be made aware of the
dangers of having insensate feet, the importance of routine self-inspection, proper
foot hygiene, and any necessary chiropodist or podiatrist care, as well as what to
do in the case of an accident or the discovery of a foot ulcer. According to recent
research compiled by Vileikyte et al., individuals frequently have false notions
regarding neuropathy, believing that this is a circulation issue and connecting
neuropathy directly to amputation.
5 5
Thus, if patients do not think that foot ulcers precede amputations, an education
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
campaign that concentrates on minimizing foot ulcers will be destined to failure.
If adequate education is to succeed in lowering foot ulcers and ultimately
amputations, it is evident that significant effort is needed in this area. Figure 5.51
depicts the possibility for education and self-care at several stages along the road
to neuropathic ulceration.
Figure 5.51: The potential for education and self - care in prevention of
neuropathic foot ulcers. t ° , temperature
590
This may involve using the given indicator plaster (Neuropad), which when placed
on the foot and exposed to normal perspiration, changes color from blue to pink.
Patients can recognize there is something odd about their feet because there is no
sweating, as would occur in a foot that is at high risk. The PressureStat (Podotrack)
is a comparable visual tool (Figure 5.52). This straightforward, reasonably priced
semi-quantitative footprint mat may detect excessive plantar pressures. The color
of the footprint gets darker the more pressure there is. Similar to that, it may be used
as a teaching tool to make the patient aware of certain foot regions that are more
vulnerable to ulcers.
This straightforward, reasonably priced semi-quantitative footprint mat may detect
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
excessive plantar pressures. The color of the footprint gets darker the more pressure
there is. Similar to that, it may be used as a teaching tool to make the patient aware
of certain foot regions that are more vulnerable to ulcers.
In conclusion, despite minimal evidence from randomized controlled studies, foot
care education is thought to be essential in the prevention of ulceration. Therefore,
it is vital that further research be done in this area.
Podiatry/chiropody
Regular nail and skin care by a podiatrist or chiropodist is crucial in the high-risk
neuropathic foot, however it is not always available. Self-care of calluses should
also be avoided because it has been documented that self-care in certain cases
results in ulceration. If possible, chiropodists and podiatrists should be part of the
foot care team since they can treat the patient’s feet while simultaneously educating
the patient.
Footwear/orthoses/hosiery
Insensitive feet are frequently subjected to foot ulcers, which can be prevented
by wearing suitable footwear. Randomized controlled trials back up this claim.
The use of specialty footwear may lessen foot pressures and provide all-around
protection for high-risk neuropathic feet, according to findings from the literature.
591
 Self-monitoring of skin temperature
It has long been understood that due to local inflammation, the affected region
of the foot tends to warm up prior to skin breakdown and ulceration. Lavery et
al. randomized patients with a history of neuropathic foot ulceration to one of
three groups in an appropriately designed, randomized controlled trial. The main
intervention was self-monitoring of skin temperature of both feet; patients who
received this skin temperature thermometer were advised to rest or contact their
foot clinic should there be a maintained difference in temperature between the two
feet. This study unequivocally showed that the incidence of recurrent ulceration Table 5.13: Meggitt – Wagner classification. Modified from Oyibo et al.
5 was significantly decreased in individuals who maintained their skin temperatures 5

and adhered to the recommendations (8% vs 30%). In order to prevent real skin

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

disintegration, infrared temperature home monitoring may assist to recognize

the “pre-ulcerative” foot. This idea has been further supported by a more recent
investigation.

Foot Ulcers: Diagnosis And Management

Foot ulcers remain a serious problem in diabetes treatment and may potentially
be the presenting characteristic of type 2 diabetes, despite increased efforts to
identify high risk patients early and educate them about preventative foot care. The
management guidelines hinge on a detailed evaluation of the contributing causes,
the existence or absence of infection, the level of neuropathy, and/or ischemia in
the foot. It’s necessary to think about how to categorize foot lesions before talking
about how to treat particular kinds of ulcers. Only a handful of the classification
schemes for diabetic foot ulcers that have been presented are discussed here.
At the time of writing, the Meggitt-Wagner grading, as illustrated in Table
5.13, is the system of foot ulcer classification that is most often used around
the world. Despite being widely used, this technique is not very specific and Figure 5.52: A black and white pressure distribution of one footstep using
does not mention if the ulcers are neuropathic, ischemic, or infected. PressureStat: the darkest areas represent highest pressures, in this case under
metatarsal heads 1 and 3 and the hallux

Healing Of The Diabetic Foot’s Wounds

Inflammation, chemotaxis, cellular proliferation, extracellular matrix deposition,
wound remodeling, and scarring are all stages of the tissue’s healing process after
an injury. Numerous factors, including impaired peripheral circulation, altered

592 593
 leukocyte activity, an unbalanced ratio of cytokines and proteases, and even
chronic hyperglycemia itself, can affect how quickly a foot lesion heals in people
with diabetes. Diabetes patients’ foot ulcers are therefore resistant to repair due
to several cellular and molecular abnormalities. Chronic foot ulcers frequently
experience reduced granulation tissue production in the chronic inflammatory
phase, in contrast to typical acute wound healing.
Therefore, a crucial issue is: Does diabetes fundamentally hinder wound healing?
If yes, what are the molecular/cellular impairments and are they unique to chronic
5 wounds? The tissue from chronic diabetic foot ulcers has abnormalities in cytokines
and growth factors, according to a number of studies. Most recently, it has been
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
proposed that matrix metalloproteinase (MMP) levels have a significant role in
predicting the likelihood of wound healing and that MMP-1 levels are crucial for
wound healing. The repeated application of pressure to the lesion appears to be
another component that contributes to poor wound healing in diabetes. Thus, the
following part examines the crucial function of off-loading.
Table 5.14: The University of Texas ulcer classification system
Offloading
It has long been recognized that neuropathic plantar foot lesions would heal
successfully when loaded in a Total Contact Cast (TCC). A typical person with a
foot wound will hobble. The fundamental idea of TCC management is that pressure
is reduced, but also that the device is fixed, requiring adherence to the prescribed
course of action. In several randomized controlled studies comparing the TCC with
alternative detachable off-loading devices for treating plantar diabetic foot ulcers,
individuals who were randomly assigned to the TCC therapy always saw the fastest
recovery. Although it is known that the Removable Cast Walkers (RCW) redistribute
pressure similarly to the TCC, the reason why the TCC often showed superiority
in terms of wound speed remained a mystery. In a research of 20 participants with
plantar neuropathic diabetic foot ulcers who were given RCWs, their total activity
594
was recorded both from the waist and from an activity monitor disguised in the
RCW, the most plausible explanation, which is that of patient non-compliance,
was verified. Patients only used the RCW for 28% of all stages, it turned out. After
making this discovery, it was suggested that an RCW might be made irremovable
by wrapping it in one or two bands of plaster of Paris, eliminating the majority
of the TCC’s drawbacks while maintaining irremovability. A second randomized
controlled experiment comparing the healing periods of this modified, permanent
RCW to the TCC revealed no differences.
5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Figure 5.53: Wagner grade I ulcer, UT1A foot ulcer, showing a rim of callus
and a punched out neuropathic ulcer in the metatarsal head region with no
evidence of infection
Piaggesi et al. reported on the effect of adequate off-loading on the histopathologic
characteristics of neuropathic diabetic foot ulcers. The foot wound, according to
these authors, now resembles an acute wound more due to reparative patterns,
angiogenesis, fibroblast proliferation, and the development of granulation tissue after
proper offloading. Biopsies from wounds that had not yet been offloaded, however,
confirmed the existence of hyperkeratosis, fibrosis, and persistent inflammation.
These findings undoubtedly imply that proper off-loading is linked to changes in
the histology of neuropathic foot ulcers, such as a decrease in inflammatory and
595
 reactive components and a faster rate of wound healing.
The impact of mental disturbance (such as sadness and anxiety) on wound healing
in diabetic patients is another crucial factor to take into account. Both direct and
indirect impacts on wound healing may result from such factors. Changes in
catecholamine and steroid release, as well as a cytokine imbalance, are examples of
the direct impacts, which may directly hinder wound healing. Indirectly, depressed
individuals, for instance, are less likely to follow treatment recommendations like
always walking with an RCW on. These crucial findings have historically gone
unnoticed by doctors, thus consideration should be given to compliance and the
5 prospect of making the RCW irremovable as mentioned above if any patient with 5

a plantar foot ulcer treated with an RCW exhibits no signs of healing. As may be

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

seen from the description above, off-loading is a crucial part of treating plantar foot
ulcers that are mostly neuropathic. This includes the majority of UT 1A and 2A
ulcers. In cases of localized infection in neuropathic foot ulcers, casts may also be
employed (Figure 5.54). In the therapy of neuroischaemic ulcers, there is evidence
to support the use of off-loading devices, but only if the ulcers are not clinically
infected.

It is advised that the cast be first removed once a week for wound assessment,
debridement, and cleaning for patients who are being treated with walkers that
cannot be removed. It is extremely advised that the cast be worn for an additional 4
weeks after the plantar wound has healed to allow the scar tissue to firm up. Healing
Figure 5.54: A deep neuropathic ulcer under the right fifth metatarsal head
may often be completed in a period of 6 to 12 weeks in a cast. After that, the patient
is shown on the patient’s radiograph. Radiographs of neuropathic foot ulcers
may progressively transition to suitable footwear that may require more depth or,
in the event of a severe deformity, custom-molded footwear. frequently show gas in the tissues because individuals with these ulcers are
able to walk despite their lack of pain perception, “pumping” gas into the
tissue. However, in this case, the gas makes it challenging to determine whether
osteomyelitis is present

Dressings
The risk with bandages and dressings is that some medical professionals may get
a false feeling of security from them and think that by bandaging an ulcer, they
are treating it. In the case of a neuropathic ulcer, nothing could be farther from the
truth. The absence of pressure, the absence of infection, and adequate vascularity

596 597
 are the three most crucial elements in the healing of a diabetic foot ulcer. Dressings
are used to protect wounds from minor damage, reduce the risk of infection, and
improve the wound environment, which is often wet. The body of data to support
the selection of any particular dressing is grossly insufficient, with the majority
of studies being constrained by small sample sizes, unsuitable comparators, and
subpar research designs.
Infection Management
Remember that all foot ulcers are colonized with potentially pathogenic organisms,
5 designed randomized controlled studies have been conducted and it was difficult to
and that the international working group on the diabetic foot generally accepts that
the diagnosis of infection in the diabetic foot ulcer remains a clinical one. This
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
is one of the first steps in managing a foot ulcer. Because of this, the presence of
symptoms including purulent discharge, erythema, localized warmth, and swelling
that indicate infection and call for proper care.
Clinically non - infected ulcers
The use of antibiotics may be avoided in cases where the ulcers are mostly
neuropathic and not infectious (UT grades 1A, 2A), since Chantelau et al.’s
randomized controlled experiment shown that patients treated with adequate
wound care fare as well with or without systemic antibiotics. However, regular
assessment, debridement, callus removal, and offloading are crucial components
of managing neuropathic foot ulcers, and antibiotics may be required if infection
symptoms appear. Since the combination of infection and ischemia in the diabetic
foot are a prevalent cause of eventual lower limb amputation, antibiotics should
probably be provided in the majority of instances for those ulcers with an ischemic
component but no obvious indications of infection (UT 1C, 2C).
Clinically infected ulcers
Infected ulcers (UT 1B, 1D, 2B, 2D) that do not pose a threat to the limb can
often be treated as an outpatient procedure. Oral broad-spectrum antibiotics should
be administered initially until findings of sensitivities are acquired. Two sets of
worldwide recommendations have recently been released, according to Lipsky’s
analysis. The creation of criteria to categorize the severity of a diabetic foot
infection is one of these latest recommendations’ key components. Mild infections
are often localized and relatively superficial, moderate infections affect deeper
598
tissues, and severe infections are accompanied by a variety of signs or symptoms
of infection or metabolic abnormalities. Any ulcer with clinically obvious infection
should have tissue removed and referred to the microbiology department for
culture and sensitivity testing. Although superficial swabs are frequently taken,
deep specimens—preferably tissue—are preferred in terms of diagnostic accuracy.
The majority of infectious ulcers are polymicrobial and frequently contain a mix
of anaerobes and aerobes. However, if there is any suspicion of osteomyelitis
(signs such as a sausage-shaped toe or the ability to probe to bone may suggest
this diagnosis), should have a radiograph taken. Unfortunately, few appropriately
5
give specific guidelines as to antibiotic regimens for specific infective organisms.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Sensitivities, which can be obtained from tissue samples, should be used to guide
the prescription of antibiotics for a clinically infected non-threatening foot ulcer
without signs of osteomyelitis. When sensitivities are known, targeted appropriate
narrow-spectrum agents should be prescribed. Clindamycin or the amoxicillin-
clavulanate combination are suitable broad-spectrum antibiotics to begin using as
soon as the clinical diagnosis of illness is obtained while awaiting sensitivity results
from the microbiology department.
Limb - threatening infection
Patients who have infections that might endanger a limb typically have systemic
symptoms and signs and need to be hospitalized with parenteral antibiotics. Deep
wound and blood cultures should be obtained, the circulation should first be
evaluated using non-invasive tests, and metabolic control is often attained with
intravenous insulin infusion.
In these circumstances, early surgical debridement is frequently recommended,
and unless sensitivities are identified through cultures, initial antibiotic regimens
should be broad-spectrum. Clindamycin and ciprofloxacin are two examples of first
antibiotic regimens, as are flucloxacillin, ampicillin, and metronidazole. Whether
the isolated organism is merely a colonizing bacterium or a real infecting organism
is one issue with interpreting sensitivities. One method, the polymerase chain
reaction (PCR) test, has proven useful for locating several pathogenic pathogens.
The potential benefits of adopting this novel approach in the quick differentiation
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 between colonizing and virulent infecting organisms were recently demonstrated
by a study from France.

Antibiotic-resistant infections like methicillin-resistant Staphylococcus aureus

(MRSA) are a growing issue in diabetic foot clinics. The majority of the time,
MRSA is identified as an opportunistic colonizing bacteria after being treated with
frequently ineffective long-term broad-spectrum antibiotics. There are helpful new
medications like linezolid, which may be administered parenterally or orally and are
effective against such germs, if it is determined that MRSA is an infectious agent.
5 Larval therapy has been proposed as a potential treatment for MRSA contamination 5

in diabetic foot sores.

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

Osteomyelitis
Numerous diagnostic procedures have been suggested, and the diagnosis of
osteomyelitis is a contentious subject. Plain radiographs are insensitive early in
the natural history of osteomyelitis, however “probing to bone” has been proven to
have a rather good prognostic value. However, a plain X-ray of the foot is finally
used to provide the diagnosis in the majority of clinical cases (Figure 5.55). Due
to its great sensitivity, magnetic resonance imaging (MRI) is playing a bigger part
in diagnosis. The best indicators of osteomyelitis in the diabetic foot are an ulcer
area larger than 2x 2 cm, a positive probe to bone test, an increased sedimentation
rate, and an abnormal radiograph, but a negative MRI renders a diagnosis far less
likely. According to the most recent review on the subject, combining clinical and
laboratory findings can significantly increase diagnostic accuracy for osteomyelitis
in diabetic feet. In particular, the combination of ulcer depth with serum inflammatory
markers seems to be particularly sensitive. Contrary to what is often believed, it is
now known that certain cases of localized osteomyelitis can be treated with long-
term (10 to 12 week) antibiotic therapy; nonetheless, localized bone resection
with proper antibiotic therapy still represents the majority of cases. Instances of
osteomyelitis that only affect one bone and do not involve a joint are most likely
to respond to antibiotic treatment, especially in the absence of peripheral vascular
disease. It must be made clear that there is a severe lack of information available
to guide treatment decisions in osteomyelitis of the diabetic foot for randomized
controlled trials.
Figure 5.55: The first metatarso-phalangeal joint of the great toe is affected
by changes of osteomyelitis and septic arthritis, which have destroyed the
distal first metatarsal and proximal area of the proximal phalanx; and the
first cuneiform/metatarsal region is affected by chronic changes of Charcot
neuroarthropathy.
Charcot neuroarthropathy
In a well-perfused insensate foot, Charcot neuroarthropathy (CN) is a non-
infectious arthropathy. Although the precise mechanism behind the onset of CN is
still unknown, in the past ten years, we have made strides in our comprehension of
the etiopathogenesis of this condition. It is evident that several important aspects
of the illness are not covered by the traditional neurotraumatic and neurotrophic
explanations for the development of acute CN in diabetes. Contrary to the earlier
notion, acute CN is relatively uncommon among individuals with neuropathy and
is often asymmetrical, however there is an increased chance of acquiring CN in the
contralateral foot years later. If the former theory were true, CN would be far more
prevalent and should be symmetrical.

600 601
 A well-perfused insensate foot experiences CN. Contrary to some of the previous
writings, patients frequently appear with a warm, swollen foot along with pain or at
the very least discomfort in the afflicted leg. The affected patient often appears with
a heated, swollen foot that may or may not be painful, and they tend to be a little
bit younger than the average patient who has a diabetic foot ulcer. Even though
there may be a history of trauma, the trauma is rarely severe enough to explain
the anomalies found during a clinical evaluation (Figure 5.55). Although increased
local bone resorption is a feature of CN, the precise cellular processes causing
this disease are yet unknown. A crucial modulator of osteoclast development and
5 activation has recently been identified as receptor activator of nuclear factor- кB
ligand (RANKL). The RANKL/osteoprotegerin (OPG) pathway may be crucial in
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
the development of acute CN, according to a popular theory. It has since been
established that, as compared to healthy and diabetically managed monocytes,
peripheral blood monocytes extracted from patients with CN and cultivated in the
presence of macrophage colony-stimulating factors led to an enhanced osteoclast
formation. These findings showed that acute CN exhibits osteoclastic resorption
that is mediated by RANKL.
As a result, the RANKL-dependent pathway plays a significant role in the
pathophysiology of acute CN, indicating that RANKL inhibition may one day be
helpful in managing the condition. The diagnosis stage of the illness affects how
the foot is treated in CN. There is evidence that immobilizing the injured foot with
a plaster cast during the acute phase is the most efficient way to lessen disease
activity and local inflammation. The cast should be worn until the hyperemia and
edema have subsided and the difference in skin temperature is 1 °C or less, at
which point custom-molded shoes with the proper insoles are advised. Intravenous
pamidronate has been demonstrated to be effective in lowering disease activity in
acute CN. Bisphosphonates are powerful osteoclast activation inhibitory agents.
These early findings need to be confirmed by larger randomized controlled studies.
5.4 Diabetes in Special Groups
Diabetes in Children
Type 1 diabetes in children is a medical condition where the child’s body stops
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producing a vital hormone called insulin. Insulin is crucial for the child’s survival,
and its absence requires either injections or an insulin pump to replace it. This
condition, previously known as juvenile diabetes or insulin-dependent diabetes,
necessitates a significant adjustment in both the child’s and the parent’s lives.
The diagnosis of type 1 diabetes in children can be quite overwhelming, particularly
at the outset. Suddenly, parents and their child, depending on the child’s age, must
acquire new skills like administering injections, calculating carbohydrate intake,
and monitoring blood sugar levels.
5
While there’s no outright cure for type 1 diabetes in children, effective management
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
is achievable. Advances in blood sugar monitoring techniques and insulin delivery
methods have considerably enhanced the management of blood sugar levels and the
overall quality of life for children dealing with this condition.
Note: Around the world, there are thought to be 700 000 children who have
diabetes; each year, 100 000 new cases are identified, and over many years, the
incidence has been rising by up to 5% yearly.
Nearly all instances of type 1a (autoimmune) diabetes mellitus (T1aDM) in children
under the age of 10, > 90% in older children of European ancestry, and 20–70% in
older children from other ethnic groups older than 10.
In most cases, the presence of two or more islet autoantibodies predicts the onset of
diabetes in people younger than 10 years; yet, prevention of T1aDM remains elusive
despite significant research efforts.
Type 2 diabetes in children is a persistent condition that impacts the way your
child’s body handles sugar (glucose) as a source of energy. If left untreated, this
condition results in the accumulation of sugar in the bloodstream, carrying the
potential for significant and lasting complications.
Initially more prevalent among adults, type 2 diabetes was formerly referred to as
adult-onset diabetes. Nevertheless, the rising prevalence of childhood obesity has
led to an increased incidence of type 2 diabetes among younger individuals.
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 There are various effective measures to aid in the management and prevention of
type 2 diabetes in children. Encouraging your child to adopt a diet rich in nutritious
foods, engage in regular physical activity, and maintain a healthy weight can make
a substantial difference. If implementing healthy eating habits and exercise routines
isn’t sufficient to regulate type 2 diabetes, there might be a requirement for oral
medications or insulin therapy.
Although it can happen to anybody at any age, type 1 diabetes most frequently
affects youngsters. Children who have type 1 diabetes are at risk for:
5 physical activity.
Family background. A person’s chance of getting type 1 diabetes is marginally
elevated if they have parents or siblings who have the disease.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Genetics. Type 1 diabetes is associated with certain genes that raise risk.
Race. White children of non-Hispanic ancestry are more likely to have type 1
diabetes than children of other races in the United States.
Certain viruses. The immune system’s destruction of the islet cells may start in
response to exposure to different viruses.
T1DM Complications
Type 1 diabetes has the potential to impact vital organs within the body. Maintaining
consistently normal blood sugar levels can significantly lower the likelihood of
numerous complications.
Potential complications encompass:
1. Cardiovascular Issues: Diabetes heightens the risk of future health problems like
narrowed blood vessels, hypertension, heart disease, and stroke.
2. Nerve Impairment: Elevated sugar levels can damage the delicate blood vessel
linings that supply nerves, causing sensations like tingling, numbness, burning, or
pain. This nerve damage typically evolves gradually over time.
3. Kidney Impairment: The kidneys’ tiny blood vessel clusters, responsible for
filtering blood waste, can suffer damage due to diabetes.
4. Eye Impairment: Diabetes can adversely affect the retinal blood vessels,
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potentially leading to vision difficulties.
5. Osteoporosis: Diabetes could decrease bone mineral density, thereby increasing
the risk of osteoporosis later in life.
Preventing complications involves:
1. Collaborating with your child to maintain stable blood sugar levels.
2. Educating your child about the significance of a nutritious diet and regular
5
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
3. Arranging regular appointments with your child’s diabetes healthcare specialist.
Children with type 1 diabetes are also vulnerable to other autoimmune conditions,
such as thyroid and celiac diseases. Your child’s healthcare provider might
recommend tests to identify these conditions.
Preventing T1DM
There is presently no surefire strategy to stop type 1 diabetes, however research in
this area is quite active.
Children who are at high risk for developing type 1 diabetes may show signs of the
disease’s antibodies months or even years before their first symptoms. Preventing
or postponing the onset of type 1 diabetes in those who are at high risk for the
condition is a research focus. Halting additional islet cell deterioration in newly
diagnosed patients.
Researchers do not have a complete understanding of why some children develop
type 2 diabetes while others do not, even when faced with similar risk factors.
Nonetheless, specific elements contribute to an increased risk, including:
1. **Weight:** Excess weight is a significant risk factor for type 2 diabetes in
children. The greater the amount of fatty tissue, particularly around the abdomen
and within muscle and skin, the more resistant the body’s cells become to insulin.
2. **Physical Inactivity:** Reduced physical activity heightens the risk of type 2
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 diabetes in children.
3. **Dietary Habits:** Consuming red and processed meats, as well as sugar-
sweetened beverages, is linked to an elevated risk of type 2 diabetes.
4. **Family History:** If a child has a parent or sibling with type 2 diabetes, their
own risk of developing the condition increases.
5. **Race and Ethnicity:** Certain racial and ethnic groups, such as Black, Hispanic,
American Indian, and Asian American individuals, have a greater likelihood of
5
developing type 2 diabetes, though the reasons are not fully understood.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
6. **Age and Gender:** While many cases emerge in early adolescence, type 2
diabetes can manifest at any age. Adolescent girls are more susceptible to developing
it compared to boys.
7. **Maternal Gestational Diabetes:** Children born to mothers who experienced
gestational diabetes during pregnancy face a higher risk of developing type 2
diabetes.
8. **Low Birth Weight or Preterm Birth:** A low birth weight is associated with an
increased risk of type 2 diabetes. Babies born prematurely, before 39 to 42 weeks
of gestation, also have a heightened risk.
Type 2 diabetes in children often has connections with conditions like metabolic
syndrome and polycystic ovarian syndrome.
Metabolic syndrome in T2DM
Obesity-related diseases are linked to insulin resistance, which can raise the risk of
diabetes as well as heart disease and stroke. The metabolic syndrome is a term used
to describe the following disorders in combination:
● Elevated blood pressure
● Having insufficient amounts of HDL, the “good” cholesterol
● Elevated triglycerides
● High amounts of blood sugar
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Polycystic ovary syndrome
Young ladies who have PCOS experience it after puberty. A hormonal
imbalance underlies PCOS, which manifests as weight gain, irregular
menstruation cycles, and an overabundance of facial and body hair. Metabolic
issues are common in people with PCOS and can lead to insulin resistance
and type 2 diabetes.
Complications in T2DM
Type 2 diabetes can impact nearly all the organs within your child’s body, 5
encompassing blood vessels, nerves, eyes, and kidneys. The gradual emergence of
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
long-term complications over several years characterizes this condition. Ultimately,
these complications can become severe and even life-threatening.
The complications associated with type 2 diabetes stem from elevated blood sugar
levels and encompass:
1. Elevated Cholesterol Levels
2. Heart and Cardiovascular Disease
3. Stroke
4. Nerve Impairment
5. Kidney Dysfunction
6. Eye Problems, potentially leading to blindness
Maintaining your child’s blood sugar within the optimal range for most of the time
can significantly diminish the risk of these complications. To prevent diabetes-
related complications, you can take the following steps:
1. Collaborate with your child to consistently manage their blood sugar levels.
2. Educate your child about the importance of adopting a healthy diet and
engaging in regular physical activity.
3. Arrange regular appointments with your child’s diabetes care team.
Preventing T2DM
Making healthy lifestyle choices can aid in protecting children from type 2 diabetes.
Assist your youngster in:
Eat nutritious foods. Give your youngster calorie- and fat-free meals. Put an
emphasis on whole grains, veggies, and fruits. In order to avoid boredom, strive
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 for diversity.
Get moving more often. Encourage your youngster to start moving about. Enroll
your kid in dancing classes or a sports team.
Even better, involve the entire family. The same lifestyle decisions that can prevent
type 2 diabetes in kids can also prevent it in adults.
Diabetes in Geriatric Population
97% of the 124 million persons with diabetes in the globe in 1997 had type 2
5 5
diabetes. This figure is anticipated to reach 285 million by the time this edition is
released. Aging has a significant role in the T2DM epidemic’s explosive global
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
growth. In the USA, those 65 to 79 years of age saw five times as many new cases
of diabetes as those under 45. The data in Figure 5.56, which come from the Third
National Health and Nutrition Examination Survey (NHANES III) in the USA, are
indicative of most industrialized nations. The prevalence of diabetes starts to climb
slowly in early adulthood and reaches a plateau in those aged 60 or older.
Figure 5.56: Prevalence of diabetes in men and women in the US population
aged ≥ 20 years, based on the NHANES III study
608
Note: Age-related declines in glucose tolerance are primarily caused by
impairments in skeletal muscle glycogen synthesis and insulin-stimulated glucose
absorption.
Infections, myocardial infarction, stroke, and medications like thiazides or
glucocorticoids are among the causes of hyperosmolar hyperglycemic syndrome.
Episodes of hypoglycemia brought on by insulin or sulfonylureas may be severe and
protracted, in part because elderly people have weak counter-regulatory responses.
The incidence rates of diabetes among elderly persons vary significantly by
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ethnicity and region. Diabetes affects 9–17% of white persons over 65 in the
UK and other industrialized nations, as well as up to 25% of non-white peo-
ple. Curiously, the incidence of diabetes in senior care facilities in the UK is
similarly 25%. Mexican Americans continuously had a greater prevalence of
diabetes than non-Latino white and black respondents among NHANES III
participants over the age of 60 (Figure 5.57).
Figure 5.57: Prevalence rates for diabetes among elderly non - Hispanic white,
non - Hispanic black and Mexican - American subjects
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 Acute Metabolic Complications In Elderly People With Diabetes
Hyperglycemic State
Hyperosmolar hyperglycemic condition (formerly known as hyperosmolar non-
ketotic coma [HONK]), which predominantly affects persons over the age of 50,
can also arise in older diabetic subjects. In one research from Birmingham, UK,
22% of admissions with DKA were in patients 60 years of age or older, whereas in
Melbourne, Australia, 13% of instances of hyperglycemic coma in patients of all
ages were brought on by hyperosmolar hyperglycemia. Instead of developing DKA,
many persons with T2DM maintain adequate residual insulin secretion to block
5 5
lipolysis and ketogenesis. Hyperosmolarity can exacerbate insulin resistance and
may also inhibit lipolysis. Elderly individuals may be more prone to hyperosmolarity
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
since they frequently use diuretics and may not experience thirst or drink enough to
offset osmotic diuresis. Infection (which accounted for 55% of cases in one series
of hyperosmolar hyperglycemic states), myocardial infarction (MI), insufficient
hypoglycemic therapy, or diabetogenic medication therapy are also potential
causes of hyperglycemia. Blood glucose levels can rise and trigger DKA with
the use of thiazide diuretics and glucocorticoids; furosemide (frusemide) is more
likely to result in a hyperosmolar hyperglycemic condition. In many situations,
there is no clear reason for DKA, as in 38% of cases in Birmingham. Residents of
nursing homes are more likely to develop hyperosmolar hyperglycemia, which is
linked to significant mortality. Older patients experience greater death rates and
longer hospital admissions than younger ones; they are also less likely to have had
diabetes previously diagnosed, more likely to have renal impairment, and require
higher insulin regimens. Death may result from the metabolic imbalance or other
conditions like MI and pneumonia.
Examining and treating hyperglycemic coma
Prior diabetes symptoms, medication use, any triggering infections (MI), potential
MIs, signs of heart failure, and the degree of dehydration should all be given careful
consideration throughout the history and examination. Initial evaluations include
arterial blood gasses and plasma osmolality, just as they would be for younger
patients. When treating elderly patients, intravenous saline can typically be infused
at a rate of 500 milliliters per hour for four hours before being reduced to 250
milliliters per hour. A central line is invaluable for monitoring filling pressure
during this time if the patient has been shocked and is experiencing cardiac failure
or a recent MI. In order to lower plasma glucose levels in certain elderly patients
610
with hyperosmolar hyperglycemia, relatively low doses of insulin are required;
however, greater doses are needed in cases of hypercatabolic or extremely insulin-
resistant conditions.
In order to prevent thrombotic consequences, preventive anticoagulation with low
dosage subcutaneous heparin is advised, especially in patients with hyperosmolar
hyperglycemia.
Hypoglycemia
Older individuals are more prone to hypoglycemia, and this issue is sometimes
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
made worse since older persons may not have received adequate education
regarding the symptoms and warning indications of hypoglycemia. As seen in the
case history below, even medical experts have misdiagnosed hypoglycemia as a
stroke, transient ischemic attack, inexplicable perplexity, or epileptic fit.
Case Study
A 76-year-old guy with a left-sided hemiplegia was hospitalized.
He was unconscious when the emergency room professionals informed his family that
he had suffered a stroke and that his prognosis was not good. No one had considered
measuring his glucose levels up to this point. The medical registrar asked for it, and it was
discovered to be 1.4 mmol/L. The man recovered consciousness after receiving IV glucose
therapy, and an hour later, he was permitted to leave the hospital. Although he had taken
his insulin, he put off eating.
Patients who suffer from cognitive impairment or loss of the hypoglycemia warning
signals are particularly at risk because they may not notice imminent hypoglycemia
and/or fail to express their thoughts to their caregivers. The increased sensitivity
to hypoglycemia in the elderly is caused by a number of circumstances, including
recent hospital discharge with changed sulfonylurea doses, renal and hepatic
impairment, excess alcohol use, and insulin therapy. Furthermore, older patients
had a weaker counter-regulatory response to hypoglycemia, which might prolong
recovery. Although persistent hypoglycemia is a significant clinical issue for
older people on glibenclamide and chlorpropamide, the risk of hypoglycemia is
highest with insulin. Because the medication builds up inside the cell and some
611
 of its metabolites still have some hypoglycemic effect, glibenclamide-induced
hypoglycemia could be more intense. Chlorpropamide accumulates with prolonged
administration due to its lengthy elimination half-life (about 35 hours); steady-state
is not reached for 7–10 days. Hypoglycemia brought on by sulfonylureas, which
are eliminated through the kidneys, is further prolonged by impaired renal function.
Although some people believe that glipizide should not be used in senior patients,
short-acting sulfonylureas like gliclazide and tolbutamide are less likely to result
in hypoglycemia. The risk of hypoglycemia in the elderly may be reduced by more
recent oral medications including thiazolidinediones, meglitinides, and both fast
5 and longer acting insulin analogs.
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
Serious hypoglycemia appears to have a poorer prognosis and increased mortality
among the elderly; it may also result in irreversible neurologic impairment,
most likely as a result of already weakened cerebral circulation. The majority of
sulfonylureas, most frequently chlorpropamide or glibenclamide, have resulted in
fatal hypoglycemia. Other risk factors for deadly hypoglycemia include drinking
alcohol, eating poorly, having impaired kidney function, and using other medicines
that might make hypoglycemia worse. Many elderly adults are unable to self-
treat hypoglycemia. The instructional program should concentrate on identifying
hypoglycemia and treating it, as well as providing guidance on how to handle
situations when hypoglycemia is not responding. Due to the increased susceptibility
of elderly persons to hypoglycemia, more care must be taken when a patient has
a history of recurring symptoms, is drowsy, is taking relatively high doses of
insulin, or has their diabetes care given to an informal caregiver. A lower bar for
hospital admission when hypoglycemia is suspected must be used to counteract this
increased risk. A glucose level of less than 4 mmol/L may call for hospitalization
in this situation.
Complications of long-term diabetes in the elderly
Diabetes causes a significant amount of morbidity in elderly people, mostly due
to its long-term consequences. For instance, 188 people over the age of 60 who
participated in a 6-year research in Oxford reported incidence rates of peripheral
vascular disease (PVD) of 56, 22 and 146 instances per 1000 person-years,
respectively. Due to the greater age of the Oxford patients, they were somewhat
higher than the rates in the Framingham research. In comparison, proteinuria
612
(albumin concentration > 300 mg/L) occurred at a rate of 19 cases per 1000
person-years, retinopathy at a rate of 60 cases, and cataract at a rate of 29 cases. A
cross-sectional research of T2DM patients aged 53 to 80 years looked at the age-
dependence of chronic diabetes problems. Independent of the effects of metabolic
management, illness duration, and other risk factors, the prevalence of retinopathy
significantly increased with aging, according to the results of logistic regression.
Erectile dysfunction, hypertension, and peripheral neuropathy were all more
common as people aged. However, neither Ballard et al. from Minnesota, USA (who
found a positive relationship with persistent proteinuria only), nor Knuiman et al.,
who studied patients with both type 1 diabetes (TIDM) and type 2 diabetes (T2DM) 5
and found independent associations of age with renal impairment, macrovascular
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
complications, and sensory neuropathy only, reported an independent contribution
of age per se to retinopathy.
Coronary Heart Disease and Arterial Disease
Elderly people with diabetes had significantly higher rates of angina, MI, heart
failure, stroke, and intermittent claudication than do age-matched control groups
without diabetes. Because of early pump failure and the delayed development of
left ventricular failure, mortality is extremely high after MI.
A significant number of senior diabetic people may exhibit unusual symptoms,
such as “silent ischemia” (which has a poorer prognosis than in the non-diabetic
population); even MI may be painless and manifest non-specifically as a fall,
dyspnea, lethargy, or hypotension.
Erectile Dysfunction
After age 60, erectile dysfunction becomes more prevalent in older individuals
and develops earlier and more frequently in men with diabetes; between 55 and
95% of men with diabetes have the condition, compared to 50% of men without
diabetes. It is frequently disregarded or blamed on a poor quality of life or a mental
disorder. Vasculopathy, autonomic neuropathy, hormonal dysregulation, endothelial
dysfunction, psychogenic variables, certain medications (particularly cimetidine,
beta-blockers, and spironolactone), and excessive alcohol use have all been linked
to the condition.
In general, the investigation should continue as it would for younger males, starting
613
 with an interview of the patient and, if applicable, his spouse. Numerous elderly
people are frequently spared from comprehensive examination. One research found
that oral sildenafil, a vacuum tumescence device, misoprostol urethral pellets,
and self-administered intracorporeal injections of vasoactive medicines (such as
prostaglandin E1) are all effective treatments. Although the latter is comparatively
effective, up to 50% of men eventually give it up due to discomfort, loss of impact,
or boredom.
Disability
5 5
Older persons who have chronic diabetes problems frequently have significant
handicap. For instance, a community-based survey from Nottingham, UK, reported
Despite the multiple health issues they might face, around two-thirds of elderly
individuals with diabetes can benefit from strategies to enhance or optimize blood
sugar control (as depicted in Figure 5.59). It is crucial to identify “frail” patients who
are particularly vulnerable to a variety of adverse outcomes due to aging, diabetic
complications, physical and cognitive decline, and other medical conditions. The
Frailty Model of Diabetes serves as a tool to guide clinical decision-making by
identifying factors (such as recurring hypoglycemia, heart disease, and impaired
recovery from metabolic imbalances) that might lead to disability and jeopardize
independence. These factors often have modifiable or reversible components.
In real-world practice, the presence of mobility issues, severe limitations in daily

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Management Of Comorbidities/Complications/ Dm In Extremes Of Age

that 80% of 98 senior inner-city diabetes patients (mean age 73 years) had significant activities, multiple co-existing health conditions, and/or advanced age (over 80
handicap; prevalent issues included visual impairment (particularly cataract) and years) significantly increases the risk of being confined to a chair or bed within a
prior amputation. span of two years by two to three times.
In the Welsh Community Diabetes Study, one in four respondents with diabetes
over the age of 65 required assistance with personal care, and older adults with
diabetes had significantly worse levels of wellbeing across most of the SF-36 health
status questionnaire’s areas. In addition, participants with diabetes had much higher
levels of both physical and cognitive impairment, with one in three of them having
spent the preceding 12 months in the hospital (twice the incidence of those without
diabetes).

Management Of Diabetes In The Elderly

The recommended approach for managing elderly individuals with diabetes is
to treat them with the same level of thoroughness as younger patients. Although
there have been limited studies focused on the elderly population, a comprehensive
collection of clinical guidelines based on evidence has been developed to guide
decision-making for treating Type 2 Diabetes Mellitus (T2DM) in older individuals.
These guidelines offer a systematic framework for making clinical choices for older
Figure 5.59: Matching treatment objectives to functional evaluations
patients.
in diabetic older patients
A more practical target HbA1c in frailer people is frequently 64 mmol/mol (8.0%)
Diabetes in the elderly can lead to significant physical and mental impairments,
due to the higher risk of hypoglycemia. This will still minimize hyperglycemic
necessitating targeted interventions to address individual challenges. A structured
malaise and may lower the risk of various vascular problems. Regarding the
approach, like the five-step assessment outlined in Table 5.14, can assist in
association between advancing age and HbA1c, conflicting results exist. In a French
determining the components of the care plan.

614 615
 study of telecom employees aged 18 to 80 years, HbA1c increased with age but
then decreased in men. However, in a smaller research of 93 participants, fasting
plasma glucose and rising age were not associated. Further research is necessary
in this area.
Modern diabetes care for older people
With the current movement in health care from hospitals to the community,
general practitioners (GPs) will play an increasingly essential role. Structured
diabetes treatment is particularly critical for elderly individuals who are currently
frequently overlooked. This will need a strong diabetes screening program, strong
5 5
GP encouragement, and good coordination with diabetes expert nurses. For elderly
patients, a shared-care strategy that involves GPs collaborating with hospital-based

Management Of Comorbidities/Complications/ Dm In Extremes Of Age

Management Of Comorbidities/Complications/ Dm In Extremes Of Age

surgical and diabetic experts and is based on established clinical guidelines is very
beneficial.

A “multidimensional intervention” concept serves as the foundation for

contemporary geriatric diabetes care. This underlines the need for early intervention
in diabetes complications as well as the establishment of rehabilitation programs for
patients who have been rendered incapacitated by a variety of problems, including
amputation, peripheral neuropathy, immobility, falls, stroke, and cognitive change.
“Critical event monitoring” refers to keeping an eye on instances of illness or social
care needed when patient vulnerability is high and the chance for action is crucial
(such as hospital admission, amputation, or stroke).
Due to diabetes’ high prevalence, long duration of effects, wide range of
complications, and emotional and psychological sequelae, healthcare must be cost-
effective, which is a difficult challenge. In older subjects, the challenge is even
more difficult due to the numerous other confounding factors.
Figure 5.60: Components of a contemporary diabetes management plan for
the elderly
Recent research suggests that elderly patients should not receive aggressive
diabetic treatment due to their shorter life expectancies; nonetheless, applying the
aforementioned measures is likely to minimize acute hospitalization, outpatient
expenditures, and long-term impairment. The optimum way to manage diabetes
in older persons can only be determined through well planned prospective clinical
studies.
5.5 Summary
The management of diabetes encompasses a holistic approach involving various
aspects such as assessment, non-pharmacotherapy, pharmacotherapy, metabolic
surgery, cardiovascular disease (CVD) and risk management, microvascular
complications, and diabetes in specific populations like children and the elderly.
Assessment forms the foundation of effective diabetes management. The focus
should mirror that of younger individuals, utilizing evidence-based clinical
guidelines developed for older adults with Type 2 Diabetes Mellitus (T2DM).
This approach helps guide clinical decisions by addressing the specific needs and

616 617
 vulnerabilities that come with aging. A systematic assessment, such as the five-step
evaluation, aids in crafting tailored care plans to meet individual challenges.
Non-pharmacotherapy plays a crucial role in diabetes management across all age
groups. Encouraging healthy lifestyle choices, including adopting a balanced diet
and engaging in regular physical activity, can substantially improve blood sugar
control. These interventions serve as cornerstones for diabetes management,
contributing to weight management and overall well-being.
5 Pharmacotherapy is often a vital component of diabetes treatment. Medications help
regulate blood sugar levels and mitigate the risk of complications. An individualized
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
approach is essential, considering factors such as age, overall health, and potential
interactions with other medications.
Metabolic surgery has emerged as a viable option for certain individuals with
diabetes, particularly those who are severely obese. This approach can lead to
substantial improvements in blood sugar control and overall health, providing an
alternative for those who have not responded well to other treatments.
Cardiovascular disease (CVD) management is paramount for diabetes patients due
to their heightened risk. Effectively addressing hypertension and coronary artery
disease (CAD) is essential. Blood pressure control and lipid management are
pivotal, reducing the risk of CVD events. Antiplatelet agents, while commonly used
for heart conditions, should be employed judiciously, considering their benefits and
potential drawbacks for individuals with diabetes and heart failure.
Microvascular complications are another facet of diabetes management. Conditions
like diabetic kidney disease, retinopathy, and neuropathy require vigilant monitoring
and intervention. Regular assessments, targeted treatments, and proactive foot care
play crucial roles in minimizing the impact of these complications.
Special populations, such as children and the elderly, warrant unique consideration.
Childhood diabetes necessitates careful management to ensure proper growth and
development, requiring coordination among healthcare providers, parents, and
schools. In the geriatric population, diabetes management becomes intertwined with
618
the challenges of aging, necessitating a tailored approach that addresses mobility
issues, cognitive decline, and the presence of multiple comorbidities.
In conclusion, diabetes management is multifaceted and comprehensive. It
involves thorough assessment, non-pharmacotherapy, pharmacotherapy, metabolic
surgery, cardiovascular risk management, microvascular complication mitigation,
and tailored approaches for specific populations. A holistic strategy that considers
individual needs and vulnerabilities is crucial for effective diabetes care across all
age groups.
5
5.6 Review Questions
Management Of Comorbidities/Complications/ Dm In Extremes Of Age
1. a. What are the key components of a comprehensive assessment for diabetes
management in older adults?
b. Explain the significance of non-pharmacotherapy interventions in diabetes
management and how they contribute to blood sugar control.
c. Discuss the challenges and benefits of tailoring non-pharmacotherapy
approaches for diabetes management in pediatric patients.
2. a. Compare and contrast the pharmacotherapeutic options available for type 2
diabetes management in the elderly versus younger individuals.
b. Analyze the criteria and considerations for selecting candidates for metabolic
surgery as a treatment for diabetes.
c. How does the management approach change when considering pharmacotherapy
in individuals with type 2 diabetes and established cardiovascular disease?
3 a. Outline the specific strategies for managing hypertension and coronary
artery disease in patients with diabetes, focusing on evidence-based approaches.
b. Explain the rationale behind lipid management strategies in diabetes
patients, highlighting the significance of individualized treatment plans.
c. Evaluate the role of antiplatelet agents in managing heart failure among
individuals with diabetes, considering both benefits and potential risks.
4. a. Describe the pathophysiology and clinical manifestations of diabetic kidney
disease, discussing the principles of management and prevention.
619
 b. Analyze the various stages of diabetic retinopathy and the available
interventions to prevent or slow its progression.
c. Explain the challenges in managing diabetic neuropathy and the importance
of foot care in preventing complications like ulcers and amputations.

5. a. Assess the unique challenges of diabetes management in pediatric patients,

discussing the impact on growth, development, and psychosocial well-being.
b. Compare and contrast the considerations for managing diabetes in geriatric
patients versus younger adults, considering factors such as comorbidities and
5
cognitive decline.
c. How does the approach to diabetes education and self-management differ
Management Of Comorbidities/Complications/ Dm In Extremes Of Age

between pediatric and geriatric populations, and what strategies are effective for
each?

620
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 https://www.ncbi.nlm.nih.gov/books/NBK567993/
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626 627
 Blockers of the angiotensin receptor
Index Blood glucose
Acquired Variables Blood pressure & lipid levels
Acupuncture Blood Pressure Measurement
Acute Metabolic Complications In Elderly People With Diabetes Blurred Vision
Acute myocardial infarction Calcium Channel Modulators (α2 - δLigands)
Acute Painful Neuropathy Canadian Diabetes Association
Acute Stroke Cancer
Administration Of Insulin Subcutaneously Capillary weakening
Aerobic Exercise Carbohydrate Metabolism
AGE binding proteins Cardiovascular Safety and RAS Inhibition
Age, genetic disposition and ethnicity Cellular Autoimmunity
Alcohol Central nervous system dysfunction
American Diabetes Association and American Association of Clinical Cerebral Edema in Childhood Diabetic Ketoacidosis
Endocrinologists 2006 Cerebrovascular Disease
Amylin Charcot neuroarthropathy
Anaerobic Exercise CHF and diabetes
Animal metabolism Chronic diabetes complications
Antigen-presenting cells Classic RAS
Antiplatelet Therapy in Diabetes Clinical Trials And Hyperglycemia
Anti-Vegf (Vascular Endothelial Growth Factor) Or An Anti-Inflammatory Clinically infected ulcers
Medicine Clinically non - infected ulcers
Arteriolar abnormalities Clopidogrel resistance
Artificial Pancreas Cognitive Impairment/Dementia
Aspirin resistance Combinations of prandial and basal insulins
Atherosclerosis and the Role Of Urotensin II Comorbidity Assessment
Autoimmune Diseases Complement Activation
Balance Of Energy And Body Weight Complications in T2DM
Bariatric Surgery Complications of long-term diabetes in the elderly
Basal only regimen Congestive Heart Failure
Basement membrane thickening Continuous Glucose Monitoring
Benefits and Limits of CGM Coronary Heart Disease and Arterial Disease
Beta-blockers Cost appraisal
Beverages Cotton wool spots
Biguanides Coupled processes and reactions

628 629
Cranial neuropathy
Cytokines
Deficiency of adiponectin
Dexcom Professional
Diabetes & Atherothrombosis
Diabetes And Cardiovascular Disease Risk Factors
Diabetes and Hypertension: Effects
Diabetes And The Pathophysiology Of Ischemic Stroke
Diabetes As A Stroke Risk Factor
Diabetes Diagnostic Procedures
Diabetes Hypertension Diagnosis
Diabetes Hypertension Screening
Diabetes in Children
Diabetes in Geriatric Population
Diabetes in Special Groups
Diabetes Patient Receiving Acute Stroke Treatment
Diabetes Secondary Stroke Prevention
Diabetes Type 2 Risk Factors
Diabetes-Related Hypertension Causes
Diabetic amyotrophy
Diabetic Ketoacidosis
Diabetic Macrovascular Problems and The Part of ET
Diabetic Neuropathy
Diabetic Peripheral Neuropathy
Diabetic Retinopathy
Diabetic truncal neuropathy
Diagnosis of diabetes
Diastolic congestive heart failure
Diet and Blood Glucose Response
Diet in diabetic children
Dietary Fat
Dietary Interventions of Type 1 Diabetes Patients
Dietary Protein
Differentiated stem or progenitor cells
Dimensions Of The Issue
630
Direct And Indirect Glycotoxicity
Discovery of insulin
Distal symmetric polyneuropathy
Distribution Of Macronutrients In Diets For Weight Loss
Diuretics and aldosterone antagonists
Downstream effects of RAGE activation
Dressings
Drug Treatment of Type 1 Diabetes
Drug Treatment of Type 2 Diabetes
Dyslipidemia
Early Childhood Malnutrition And Fetal Malnutrition
Eating disorders
Economic And Social Implications
Effects of consistent resistance training during rain in type 1 diabetes
Effects of Direct Vascular AGE Accumulation
Electrical spinal cord stimulation
Electrical stimulation
Electrodiagnostic Measures
Elevated foot pressures
Engineered non-β pancreatic cells
Engineering cells for improved in vivo survival
Environmental Risk Factors For Type 1 Diabetes: Insights From Epidemiological
Research
Erectile Dysfunction
Etiopathogenesis Of Diabetic Foot Lesions
Examination Of Diabetes And High Blood Pressure
Exercise’s Effects On Metabolism And Hormones In People With Diabetes
Eye presentations
Fibrates
Fibrous proliferation at the disc
Fibrous proliferation elsewhere
First insulins
Focal And Multifocal Neuropathies
Foot deformity
Foot Problems in Diabetic Patients
631
Foot Ulcers: Diagnosis And Management Hypoglycemia unawareness
Footwear/orthoses/hosiery Hypoglycemic Alarms
Formation of AGE Immunizations
Fractures Impact Of Diabetes
FreeStyle Libre Pro Impaired β- Cell Function Vs Insulin Resistance
Frequency By Gender Implications Of Hypoglycemia In Diabetes
Frequency-modulated electromagnetic nerve stimulation Incretin-Based Agents
Fundus fluorescein angiography Infection Management
Gene expression in glucose metabolism Infections
Genetic Factors Controlling Liver Function And Insulin Sensitivity Insufficient stimulation caused by incretins
Glitazones Insulin autoantibodies
Glucose lowering agents Insulin Dosage Plans
Glucose metabolism Insulin Resistance
Glucotoxicity Insulin resistance in adipose tissue
Glutamic Acid Decarboxylase Auto-Antibodies Insulin Resistance In Skeletal Muscle Pathogenesis
Glycemic index and glycemic load Interaction With The Renin Angiotensin System
Greater capillary permeability Intermediate Hyperglycemia And Other Danger Signs
Hard exudates International Diabetes Federation 2005
Healing Of The Diabetic Foot’s Wounds Intraretinal microvascular abnormalities
Health Benefits Of A Mediterranean Diet In Diabetes Investigative Techniques To Assess Diabetic Retinopathy
Health Economics Of Diabetic Foot Disease Islet Amyloid
Hepatic Insulin Resistance Islet antigen - 2 auto antibodies IA - 2Ab and IA - 2 βAb
Hepatitis C Infection Islet Histology In Type 2 Diabetes
High density lipoprotein cholesterol Islet of β-cell
HLA class II haplotypes Islet surface antibodies (ICSA)
Hormonal control of metabolism Issues With Blood Glucose Testing
Humoral Autoimmunity Lacosamide
Hyperglycemia And Platelet Reactivity Lactic Acidosis
Hyperglycemic Alarms Laser Treatment
Hyperglycemic Hyperosmolar State Lesions And Classifications Of Diabetic Retinopathy
Hyperglycemic State Limb - threatening infection
Hypertension And Diabetic Nephropathy Lipoprotein metabolism
Hypoglycemia Lipotoxicity
Hypoglycemia Long-lasting and soluble insulin patch repairs
Hypoglycemia in pregnancy Long-term Glycemic monitoring

632 633
Low density lipoprotein cholesterol Occurrence of T1DM By Age
Low density lipoprotein subfractions Occurrence Trends With Time
Low Testosterone in Men Occurrence Varies Between Nations, Notably By Ethnic Group
Major Burdens Offloading
Management Of Diabetes In The Elderly Omega-3-Fatty Acids
Mechanism of liver insulin resistance at the cellular level Opioids
Medical Nutrition Therapy Optical coherence tomography
Metabolic memory Organ systems involved in metabolism
Metabolic pathways Osteomyelitis
Metabolic Response To Surgery Osteoprotegerin and TNF-Related Apoptosis Inducing Ligand
Metabolic Syndrome And Hypertension Oxidative Stress and RAS
Metabolic syndrome in T2DM P2Y12 receptor antagonists
Metformin Pancreatic Substitute Cell Types
Microaneurysms Pancreatitis
Microaneurysms and retinal hemorrhages Patient-Centered Education
Micronutrients Pericyte loss
Microvascular Complications And Foot Care In Individuals Perimetry
Mid-frequency external muscle stimulation Periodontal Disease
Modern diabetes care for older people Peripheral Artery Disease
Modulators of Metabolism Pharmacologic Therapy of CHF
Monochromatic infrared energy Pharmacological Approaches
Mononeuropathy of the limbs Physical Activity For Patients With Type 1 & 2 Diabetes Mellitus
Morphologic Assessment Physical measures
Neuropathic Syndromes Plantar callus
New vessels on and/or within 1 disc diameter of the disc Platelet Reactivity And Insulin Resistance
Newly Discovered Risk Factors Platelet Reactivity And Related Metabolic Issues
Niacin Podiatry/chiropody
Nonalcoholic Fatty Liver Disease Polycystic ovary syndrome
Non-pharmacologic treatment of painful neuropathy Postnatal growth and perinatal influences
Normal Glucose Tolerance Potential Of Dietary Fiber
Novel aspects of the RAS : ACE 2 Power available to the system
Nutrition composition Precipitating Factors
Nutritional factors Preoperative Assessment
Obesity Prevalence By Nation
Obstructive Sleep Apnea Prevalence of CHF and glucose abnormalities

634 635
Preventing Diabetic Foot Ulcers Stroke In Diabetic Patients
Preventing Diabetic Retinopathy Studies reducing vascular AGE accumulation
Professional CGM Studies Using Twins And Familial Clustering
Prospective Mechanisms Subcutaneous Insulin Treatment Complications
Psychological support Sucrose And Other Sugars
PVD Sulfonylureas
Rapid and prolonged insulin analogs Sural nerve biopsy
RAS Activation And Endothelial Dysfunction Surgery For Diabetic Patients
RAS inhibition and vascular dysfunction Surgical decompression
Receptor for AGEs, RAGE Surgical Removal Of The Vitreous Gel (Vitrectomy)
Regular aerobic exercise’s effects on type 1 diabetes T1DM Complications
Repair of Regenerating Endothelial Cells and RAS Tests for Gestational Diabetes
Resistance to Insulin’s antilipolytic effect Tests for Type 1 and Type 2 Diabetes and Prediabetes
Retinal blood flow The Economic And Epidemiological Aspects Of Diabetic Foot Disease
Retinal photography The Fatty Liver And The Pathogenesis Of Hepatic Insulin Resistance
Risk factors for CHF and diabetes The Normal Eye
Risk Factors That Are Modifiable The postinsulin era
Role of RAS in Atherosclerosis The Primary Prophylaxis Of Stroke In Diabetic Patients
Role of the RAS in Macrovascular Disease The Reasons For Muscle Insulin Resistance
Route To Ulceration The System For Endothelin
Screening For Diabetic Retinopathy The Use Of Medications To Alleviate Painful Neuropathy
Seasonal Variations in T1DM Diagnosis Thirst, Polydipsia And Polyuria
Selective Serotonin Reuptake Inhibitors (SSRI) Topical Capsaicin
Self-Glucose Monitoring Transcutaneous electrical nerve stimulation
Self-monitoring of skin temperature Trans-Fats And Dietary Cholesterol
Sensory Impairment Treatment and prevention of diabetic neuropathy by comprehensive diabetes
Serotonin Noradrenaline Reuptake Inhibitors (SNRI) therapy
Skin biopsy Treatment To Reduce Blood Sugar
SLC30A8 gene Tricyclic antidepressants
Smooth muscle death Triglycerides
Sodium channel blockers UK Diabetes Services
Sodium-Glucose Co-Transporter 2 Inhibitors (SGLT-2 Inhibitors) Ultrasound B scan examination
Soluble RAGE Unchangeable Risk Factors
Soluble RAGE and diabetes associated atherosclerosis Urotensin II
Statins Using Pathogenetic Principles To Treat Disease

636 637
Venous abnormalities
Viral infections
Weight Loss In The Prevention Of Diabetes
ZnT8 Transporter (SLC30A8) Autoantibodies ZnT8Ab
β- Cell Alterations
β-Cell lines

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 MANAGEMENT OF DIABETES
4

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