Saikat Sen · Raja Chakraborty

Biplab De

Diabetes
Mellitus in
21st Century
Diabetes Mellitus in 21st Century
Saikat Sen • Raja Chakraborty
Biplab De

Diabetes Mellitus in
21st Century
Saikat Sen Biplab De
Department of Pharmacy Department of Pharmaceutical
Assam Down Town University Chemistry
Guwahati, Assam Regional Institute of Pharmaceutical
India Science and Technology, Abhyonagar
Agartala, Tripura
Raja Chakraborty India
Department of Pharmacy
Assam Down Town University
Guwahati, Assam
India

ISBN 978-981-10-1541-0 ISBN 978-981-10-1542-7 (eBook)

DOI 10.1007/978-981-10-1542-7

Library of Congress Control Number: 2016947467

© Springer Science+Business Media Singapore 2016

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Preface

In the twenty-first century, diabetes mellitus became an epidemic in all cor-

ners of the world. Currently, more than 382 million people are suffering from
diabetes mellitus, and the number is set to reach in a stunning figure of 592
million by 2035. A huge number of people are in prediabetic stage or unaware
about their diabetes. Diabetes mellitus is also responsible for several compli-
cations affecting all parts of the human body. Diabetes mellitus and its com-
plications are not only responsible for morbidity, disability, and mortality but
also financial burden at individual, family, community, and national levels.
In the last few years, India became the home of a large number of diabetic
people and the number is increasing gradually. Keeping all the above in mind,
we felt it is necessary to write this book entitled Diabetes Mellitus in 21st
Century. The first few chapters include the general basic consideration about
the pancreas, the pancreatic hormone, and diabetes mellitus. Chapters on pre-
diabetes and prevalence will help to understand the current diabetes situation.
Special attention has been given to highlight the effect of diabetes on preg-
nancy and role of obesity and oxidative stress on diabetes. Chapters empha-
sizing in detail about the complication of diabetes and role of biomarkers in
diabetes are the key content of the book. Besides the management of diabetes
mellitus, we have also highlighted the role of Indian traditional medicine and
herbal medicine for diabetes treatment and stated the recent and upcoming
treatment strategies for diabetes mellitus.
We are very sure this book will have a long-lasting effect and will help
graduate students, undergraduate students, teachers, researchers, physicians,
and other people to understand the current scenario, to know about the cur-
rent approaches for diagnosis and treatment, and to increase their
awareness.

Guwahati, Assam, India Saikat Sen

Guwahati, Assam, India Raja Chakraborty
Agartala, Tripura, India Biplab De

v
Acknowledgment

We are greatly indebted to our parents and teachers who played an instrumen-
tal role in our life. We are also thankful to our friends, colleagues, and well-
wishers who were all the time with us during the journey of our education and
professional life. We want to express our thanks to our students, who are one
of the important sources of motivation to acquire sufficient knowledge to
complete this book. In the writing of this book over a long period, we have
consulted a large number of publications. We are thankful to all of them and
acknowledged some of them in the reference section.
We want to express our sincere thanks to the authorities/managements of
Assam Down Town University, Guwahati, and the Regional Institute of
Pharmaceutical Science And Technology, Agartala, for providing the profes-
sional backbone while writing the book.
Most importantly for us, we are personally indebted to our family mem-
bers, for their motivation, support, and tolerance, without which this book
would have never been finished.
Finally, we would like to thank Springer Publishers and their staff mem-
bers, specifically Dr. Abhinav Shrestha, for taking up this project.
However, for any errors that remain, despite our best efforts to catch them,
we take responsibility. Authors would welcome suggestions from the reader
through electronic mail (saikat.pharm@rediffmail.com/dr_rchakraborty@
rediffmail.com) for further improvement.

vii
Contents

1 Pancreatic Hormones and Control of Blood

Glucose: A Glance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Pancreatic Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Regulation of Glucose Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Insulin and Glucose Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2 Diabetes Mellitus: General Consideration . . . . . . . . . . . . . . . . . . . 13
What Is Diabetes Mellitus? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Classification of Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Type 1 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Etiology and Pathophysiology of T1DM . . . . . . . . . . . . . . . . . . . . 14
Type 2 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Etiology and Pathophysiology of T2DM . . . . . . . . . . . . . . . . . . . . 15
Other Specific Types of Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . 17
Gestational Diabetes Mellitus (GDM) . . . . . . . . . . . . . . . . . . . . . . . . 18
Symptoms and Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Prediabetes: IFG and IGT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Screening and Diagnostic Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3 Impaired Glucose Tolerance and Impaired
Fasting Glycemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
“IGT” Versus “IFG”: Clinical Characteristic . . . . . . . . . . . . . . . . . . . 23
Innervations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Approaches to Manage Prediabetes . . . . . . . . . . . . . . . . . . . . . . . . 25
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
4 Prevalence of Diabetes and Its Economic Impact . . . . . . . . . . . . . 27
Prevalence of Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Prevalence of Impaired Glucose Tolerance. . . . . . . . . . . . . . . . . . . . . 31
DM and Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Morbidity and Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Economic Impact of DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5 Pregnancy and Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Gestational Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

ix
x Contents

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Screening and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Complications of GDM. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Postpregnancy Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Diabetes in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Preexisting DM in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
6 “Diabesity”: Current Situation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Overweight and Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Some Important Causes of Obesity and Overweight . . . . . . . . . . . 47
Measurements of Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Obesity: Impact on Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Diabesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Possible Correlation Between Obesity and Diabetes . . . . . . . . . . . 50
Management of Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
7 Oxidative Stress and Diabetes Mellitus. . . . . . . . . . . . . . . . . . . . . . 55
Oxidative Stress and Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Biological Roles of Free Radicals. . . . . . . . . . . . . . . . . . . . . . . . . . 55
Antioxidant Protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Oxidative Stress and Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Relation Between Oxidative Stress and DM. . . . . . . . . . . . . . . . . . . . 58
ROS and Cell Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Mitochondrial Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Reactive Species, Antioxidant Enzyme, and Antioxidant Gene
Polymorphisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Obesity, Oxidative Stress, and DM . . . . . . . . . . . . . . . . . . . . . . . . . 61
Influence of Ketone Body, Nutrient Availability, PTEN,
and Sleep Restriction on Insulin Signaling . . . . . . . . . . . . . . . . . . . 62
Oxidative Stress and Diabetic Complications . . . . . . . . . . . . . . . . . . . 62
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
8 Complications of Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . 69
Acute Metabolic Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Diabetic Ketoacidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Hyperglycemic Hyperosmolar State . . . . . . . . . . . . . . . . . . . . . . . . 69
Lactic Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Vision Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Diabetic Retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Cataract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Macular Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Keratopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Ischemic Optic Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Other Eye Disorders During DM . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Contents xi

Foot Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Foot Ulcer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Foot Gangrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Lower Extremity Amputation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Cardiovascular Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Congestive Heart Failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Digestive Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Gastric Nerve and Motility Abnormalities . . . . . . . . . . . . . . . . . . . 76
Anorexia, Nausea, Vomiting, Dysphagia, Early Satiety,
Reflux, and Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Candida Esophagitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Diarrhea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Constipation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Celiac Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Megasigmoid Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Gastropathy and Gastroparesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Fatty Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Gallstones and Cholecystitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Hyperamylasemia, Pancreatitis, and Abnormalities
of Pancreatic Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Carcinoma of GIT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Skin Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Acanthosis Nigricans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Bullosis Diabeticorum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Calciphylaxis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Diabetic Dermopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Diabetic Thick Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Xanthelasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Eruptive Xanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Erysipelas-Like Erythema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Granuloma Annulare . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Necrobiosis Lipoidica Diabeticorum . . . . . . . . . . . . . . . . . . . . . . . 80
Perforating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Periungual Telangiectasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Pigmented Purpura . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Rubeosis Faciei and Red Skin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Skin Tags or Acrochordons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Yellow Nails . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Kaposi’s Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Bacterial Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Fungal Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
xii Contents

Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Macro- and Microangiopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Oral and Dental Complications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Periodontal Disease (Gingivitis and Periodontitis) . . . . . . . . . . . . . 83
Salivary Gland Dysfunction and Xerostomia . . . . . . . . . . . . . . . . . 84
Tooth Loss or Edentulousness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Dental Caries. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Burning Mouth Syndrome and Test Disturbance . . . . . . . . . . . . . . 84
Candidiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Oral Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Acute Oral Infections or Other Oral Infections . . . . . . . . . . . . . . . 85
Traumatic Ulcers and Irritation Fibromas . . . . . . . . . . . . . . . . . . . . 85
Kidney Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Diabetic Glomerulosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Diabetic Nephropathy and Renal Papillary Necrosis . . . . . . . . . . . 86
Bladder Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Urinary Tract Infection and Pyelonephritis . . . . . . . . . . . . . . . . . . 86
Sexual Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Erectile Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Ejaculatory Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Retrograde Ejaculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Balanitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Aspermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Low Quantity of Seminal Fluid . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Testosterone Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Disorder of Libido or Desire . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Defects in Arousal and Vaginal Lubrication . . . . . . . . . . . . . . . . . . 88
Menstrual Problem, Amenorrhea, and Disturbed
Ovarian Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Polycystic Ovarian Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Dyspareunia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Anorgasmia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Vaginal Infection and Discomfort . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Pregnancy-Related Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Congenital Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Fetal Macrosomia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Shoulder Dystocia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Neonatal Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Spontaneous Abortion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Neonatal Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Stillborn Infant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Respiratory Distress Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Hyperbilirubinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Polycythemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Hypomagnesemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Perinatal Asphyxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Other Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Contents xiii

Diabetic Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Infective Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Hepatitis C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Bacteremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Malignant External Otitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Surgical Wound Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Respiratory Tract Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
CNS-Related Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Alzheimer’s Disease and Dementia . . . . . . . . . . . . . . . . . . . . . . . . 95
Thyroid Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Autoimmune Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Disability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
9 Biomarkers of Diabetes and Diabetic Complications . . . . . . . . . 101
Biomarkers to Predict and Monitor DM and Its Complications . . . . 102
Hemoglobin A1c . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Albumin and Glycated Albumin . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Fructosamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
1,5-Anhydroglucitol (1,5-AG) . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Adipokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Fetuin-A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Cystatin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
C-Reactive Protein (CRP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Type IV Collagen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Transforming Growth Factor β1 (TGF-β1) . . . . . . . . . . . . . . . . . . 109
Fibronectin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Laminin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
N-acetylglucosaminidase (NAG) and Kidney
Injury Marker-1 (KIM-1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Angiopoietin-Like Proteins (ANGPTLs) . . . . . . . . . . . . . . . . . . . 110
α1 Microglobulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Transferrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Glycosaminoglycans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Osteoprotegerin (OPG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Podocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Vascular Endothelial Growth Factor (VEGF) . . . . . . . . . . . . . . . . 113
Ceruloplasmin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Adhesion Molecule (ICAM-1 and VCAM-1) and
von Willebrand Factor (vWF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Apolipoprotein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Monocyte Chemoattractant Protein-1 (MCP-1) . . . . . . . . . . . . . . 114
Neutrophil Gelatinase-Associated Lipocalin (NGAL) . . . . . . . . . 114
Lipocalin-Type Prostaglandin D2 Synthase (L-PGDS) . . . . . . . . 114
xiv Contents

Microvesicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
2-AminoAdipic Acid (2-AAA) . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
AGEs and RAGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Skin Autofluorescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Advanced Oxidation Protein Products . . . . . . . . . . . . . . . . . . . . . 116
F2-Isoprostanes (F2-ISOPS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Nitrotyrosine (NT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
8-Hydroxydeoxyguanosine (8-OHdG) . . . . . . . . . . . . . . . . . . . . . 117
8-Oxo-7,8-Dihydro-2′-Deoxyguanosine (8-oxodG) . . . . . . . . . . . 117
Oxidative Stress-Related Biomarkers . . . . . . . . . . . . . . . . . . . . . . 117
Retinal Vascular Caliber and Retinal Thickness . . . . . . . . . . . . . . 118
Microaneurysm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Biomarkers That Influence Retinal Macroglial Activity. . . . . . . . 118
Biomarkers Related to Later Pregnancy Complications . . . . . . . . 118
MicroRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Genetic Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Biomarkers as Essential Tool for Treatment . . . . . . . . . . . . . . . . . . . 119
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
10 Indian Traditional Medicinal Systems, Herbal Medicine,
and Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Ayurveda and Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Nidan (Etiology) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Samprapti (Pathogenesis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Rog Pariksha and Nidan (Examination and Diagnosis) . . . . . . . . 128
Upadravas (Complications). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Diabetes Mellitus in Siddha, Unani, and Homeopathy . . . . . . . . . . . 129
The Importance of Yoga and Naturopathy in Diabetes . . . . . . . . . . . 130
Traditional Medicinal Plants and DM . . . . . . . . . . . . . . . . . . . . . . . . 131
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
11 Management of Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . 153
Pharmacological Treatment of DM. . . . . . . . . . . . . . . . . . . . . . . . . . 153
Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Amylin Analog . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Glucagon-Like Peptide-1 (GLP-1) . . . . . . . . . . . . . . . . . . . . . . . . 154
Sulfonylureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Meglitinides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Biguanides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Thiazolidinediones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
PPARα and PPARγ Agonist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
α-Glucosidase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors . . . . . . . . . . . . . . . . . . 163
Sodium-Glucose Co-transporter 2 (SGLT) Inhibitor . . . . . . . . . . 164
Intestinal Lipase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Non-pharmacological Treatment of DM. . . . . . . . . . . . . . . . . . . . . . 166
Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Self-Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
Contents xv

12 Recent Developments in Diabetes Therapy . . . . . . . . . . . . . . . . . 175

Gene Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
Islet Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
Stem Cell Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
Diabetes “Vaccines” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Possible New Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
About the Authors

Saikat Sen, MPharm, PhD

Dr. Saikat Sen is working as an Associate
Professor at the Department of Pharmacy,
Assam Down Town University, Guwahati,
India. Dr. Sen basically is from Tripura, India,
and is the son of Mr. Pramathes Sen and Ms.
Gopa Gupta Roy (Sen). He gained his bache-
lor degree (B.Pharm) from JSS College of
Pharmacy, Ooty, and master degree (M.Pharm
in Pharmacology) from the College of
Pharmacy, SRIPMS, Coimbatore, in 2008 and
Ph.D. in Pharmaceutical Sciences from JNT
University, Anantapur, Andhra Pradesh, in
2014. He has authored a book and contributed
different peer-reviewed edited books published by the American Chemical
Society (USA), Springer Publishers, and Studium Press LLC. Nearly 50
research and review articles in reputed national/international journals were
added to his credit, and he presented several scientific papers, attended a
number of national and international conferences, and delivered invitee lec-
ture in an international forum. Dr. Sen is working as editorial board/advisory
board member and reviewer of several international and national journals.
His name was selected for the bibliography published by Marquis Who’s Who
in the World 2016; he also received monetary reward from J For Res in col-
laboration with the government of China to continue his research in herbal
medicine. He is a member of different professional bodies around the world
and involved enthusiastically in scientific research on traditional/folk medici-
nal system and developing an active research culture.

xvii
xviii About the Authors

Raja Chakraborty, MPharm, PhD

Dr. Raja Chakraborty is working as an
Associate Professor at the Department of
Pharmacy, Assam Down Town University,
Guwahati, India. He has received his M.Pharm
(2008) in Pharmaceutical Chemistry from the
College of Pharmacy, SRIPMS, Coimbatore,
affiliated with the Tamil Nadu Dr. MGR
Medical University, Chennai, and Ph.D.
(2014, Pharmaceutical Sciences) from
Jawaharlal Nehru Technological University,
Anantapur, India. He has nearly 50 research
and review articles published in several
national and international journals. He
authored a book and also contributed 3 book chapters published by ACS
Publication, Studium Press LLC, and Springer Publishers. He serves as
reviewer of several reputed journals and is working as editorial board mem-
ber for different international journals.
Dr. Chakraborty is the first son of Mr. Bijan Chakraborty and Ms. Chinu
Chakraborty. He was born and brought up in Tripura, India, and completed
his basic education in Tripura. He experienced the environment of utilizing
plants and herbs by the peoples of Tripura for their health needs. He wants to
contribute his research hand in the field of natural chemistry in respect to
traditional knowledge aimed to serve a beneficiary and economic
healthcare.

Biplab De, MPharm, PhD, AIC, FICCE, FIBR

Dr. Biplab De is currently working as
Associate Professor at the Regional Institute
of Pharmaceutical Science and Technology,
Agartala, Tripura. He holds an M.Pharm in
Pharmaceutical Chemistry (JSS College of
Pharmacy, Ooty, 1997) and a Ph.D. in
Pharmacy (Jadavpur University, Kolkata,
2006). With a teaching experience of over 17
years, he authored more than 100 research and
review papers in reputed journals, seven arti-
cles in reference books, and two books. Dr. De
was awarded and praised for his research
works in different levels including the “Bharat
Excellence Award” and “Dr. R.L. Nicore Award.” His name has also been
recognized and included in several bibliographies published by national and
international agencies. He obtained an AICTE (India) grant and is working as
reviewer/member of editorial board/editor of different national and interna-
tional journals. He guided a number of students in graduate, postgraduate,
M.Phil, and Ph.D. level.
Abbreviations

•
OH Hydroxyl radical
1,5-AG 1,5-Anhydroglucitol
1
O2 Singlet oxygen
2-AAA 2-Aminoadipic acid
8-OHdG 8-Hydroxydeoxyguanosine
8-oxodG 8-Oxo-7, 8-dihydro-2′-deoxyguanosine
ACC Acetyl-coenzyme A carboxylase
ACE Angiotensin-converting enzyme
ACTH Adrenocorticotrophic hormone
ADA American Diabetes Association
ADMA Asymmetric dimethylarginine
ADP Adenosine diphosphate
AGEs Advanced glycation end products
AIDS Acquired immunodeficiency syndrome
AL Aldose reductase
ALT Alanine transaminase or alanine aminotransferase
AMP Adenosine monophosphate
AMPK Activated protein kinase
ANGPTLs Angiopoietin-like proteins
AOPPs Advanced oxidation protein products
AP-1 Activating protein-1
aP2 Adipocyte fatty acid-binding protein
ApoAI Apolipoprotein AI
ApoB Apolipoprotein B
AQP Aquaporin
ASC Adult stem cell
Ask1 Apoptosis signal-regulating kinase 1
AST Aspartate transaminase or aspartate aminotransferase
AT1 Angiotensin II type 1 receptor
ATP Adenosine triphosphate
BMI Body mass index
CAD Coronary artery disease
cAMP Cyclic adenosine monophosphate
CAT Catalase
CCK Cholecystokinin
CHD Coronary heart disease
CNS Central nervous system

xix
xx Abbreviations

COX Cyclooxygenase
CRP C-reactive protein
CVD Cardiovascular diseases
DAG Diacylglycerol
DCCT Diabetes Control and Complications Trial
DHAP Dihydroxyacetone phosphate
DI Diabetes insipidus
DM Diabetes mellitus
DNA Deoxyribonucleic acid
DPP-IV Dipeptidyl peptidase IV
EMA Endomysial antibodies
eNOS Endothelial NOS
ERK Extracellular signal-regulated kinases
ESC Embryonic stem cell
ESRD End-stage renal disease
ET-1 Endothelin-1
ETC Electron transport chain
F2-ISOPS F2-isoprostanes
FADH Flavin adenine dinucleotide (reduced)
FAS Fatty acid synthase
FDXR Ferrodoxin reductase
FFA Free fatty acid
G6Pase Glucose-6-phosphatase
GAD Glutamic acid decarboxylase
GAG Glycosaminoglycan
GAP GTPase-activating protein
GAPDH Glyceraldehyde-3-phosphate dehydrogenase
GDM Gestational diabetes mellitus
GFAP Glial fibrillary acidic protein
GFAT Glutamine fructose-6-phosphate amidotransferase
GH Growth hormone
GIP Glucose-dependent insulinotropic polypeptide
GIPR Glucose-dependent insulinotropic polypeptide receptor
GIT Gastrointestinal tract
GLCANAC N-Acetylglucosamine
GLP Glucagon-like peptide
GLP-1R Glucose-dependent insulinotropic polypeptide-1 receptor
GLUT Facilitative glucose transporters
GPCR G-protein-coupled receptor
GPx Glutathione peroxidase
GR Glutathione reductase
GSH Glutathione
GSIS Glucose-stimulated insulin secretion
GSK Glycogen synthase kinase
GSSH Oxidized glutathione
GST Glutathione-S-transferase
GTP Guanosine-5′-triphosphate
GβL G-protein β-subunit-like
Abbreviations xxi

H2O2 Hydrogen peroxide

Hb Hemoglobin
HbA1C Hemoglobin A1c
hCS Human chorionic somatomammotropin
HDL High-density lipoprotein
HHS Hypoglycemic hyperosmolar state
HIF-1 Hypoxia-inducible factor 1
HLA Human leukocyte antigen
HMG-CoA 3-Hydroxy-3-methylglutarylcoenzyme A
HNF Hepatocyte nuclear factor
HNO2 Nitrous acid
HOCl Hypochlorous acid
hPL Human placental lactogen
IAPP Islet amyloid polypeptide
ICAM-1 Intracellular adhesion molecule-1
IDDM Insulin-dependent diabetes mellitus
IDF International Diabetes Federation
IDL Intermediate-density lipoprotein
IFG Impaired fasting glucose
IFN Interferon
IgA Immunoglobulin A
IgG Immunoglobulin G
IgM Immunoglobulin M
IGT Impaired glucose tolerance
IKK IkB kinase
IKKβ Inhibitor of NF-kappaB kinases beta
IL Interleukin
iNOS Inducible NOS
INS gene Insulin gene
IPF Insulin promoter factor
IR Insulin receptor
IRR IR-related receptor
IRS Insulin receptor substrate
JAK Janus kinase
JNK c-jun-NH2-terminal kinase
KIM-1 Kidney injury marker-1
LDL Low-density lipoprotein
LGA Large or obese for gestational age
LOO• Lipid peroxyl radical
LOOH Lipid peroxide
LOX Lipoxygenase
L-PGDS Lipocalin-type prostaglandin D2 synthase
MAPK Mitogen-activated protein kinase
MCP-1 Monocyte chemoattractant protein-1
MHC Major histocompatibility complex
miRNAs MicroRNAs
MODY Maturity-onset diabetes of the young
xxii Abbreviations

mTOR Mechanistic target of rapamycin/mammalian target of

rapamycin
MVs Microvesicles
N2O3 Dinitrogen trioxide
NAD Nicotinamide adenine dinucleotide
NADH Nicotinamide adenine dinucleotide (reduced)
NADP Nicotinamide adenine dinucleotide phosphate
NADPH Nicotinamide adenine dinucleotide phosphate (reduced)
NADPH oxidase Nicotinamide adenine dinucleotide phosphate-oxidase
NAG N-Acetylglucosaminidase
NCDs Noncommunicable diseases
ncRNA Non-(protein)-coding RNAs
NEFAs Non-esterified fatty acids
NFAT Nuclear factor of activated T cells
NF-kB Nuclear factor kappa-light-chain-enhancer of activated B
cells
NGAL Neutrophil gelatinase-associated lipocalin
NIDDM Non-insulin-dependent diabetes mellitus
NO Nitric oxide
NO• Nitric oxide radical
NO2• Nitrogen dioxide radical
NOS Nitric oxide synthase
NPH Neutral protamine Hagedorn
Nrf2 Nuclear factor erythroid 2-related factor (or NFE2L2)
NT Nitrotyrosine
O2•− Superoxide radical
O3 Ozone
OGTT Oral glucose tolerance test
ONOO•- Peroxynitrite radical
OPG Osteoprotegerin
PAI-1 Plasminogen activator inhibitor-1
PDK 3-Phosphoinositide-dependent protein kinase
PEPCK Phosphoenolpyruvate carboxykinase
PG Prostaglandin
PH Pleckstrin homology
PI3K Phosphatidylinositol 3-kinase
PIP2 Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]
PIP3 Phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3]
PKB Protein kinase B
PKC Protein kinase C
PLA2 Phospholipase A2
PPAR Peroxisome proliferator-activated receptor
PPRE Peroxisome proliferator response elements
PTEN Phosphatase and tensin homolog
PTK Protein tyrosine kinases
PTPs Protein tyrosine phosphatases
RaB-GAP Rab-GTPase-activating protein
Abbreviations xxiii

RAGEs Receptor for AGEs

RBC Red blood cell
RBP4 Retinol binding protein-4
REED1 Regulated in development and DNA damage responses 1
RNA Ribonucleic acid
RNS Reactive nitrogen species
RO• Alkoxyl radical
ROO• Peroxyl radical
ROS Reactive oxygen species
rT3 Reverse T3
RXR Retinoic X receptor
SAPK Stress-activated protein kinase
SDH Sorbitol dehydrogenase
SERCA2a Sarcoplasmic reticulum Ca2+-ATPase 2a
SGK Glucocorticoid-inducible kinase
SGLT Sodium-glucose linked transporter or sodium-dependent
glucose cotransporters
SH2 Src homology 2
SHIP SH2 domain containing inositol 5-phosphatase
SIRT1 Sirtuin 1
SOD Superoxide dismutase
SREBP-1 Sterol regulatory element-binding protein-1
SSTR Somatostatin receptor
STAT Signal transducer and activator of transcription
SUR Sulfonylurea receptor
T1DM Type 1 diabetes mellitus
T2DM Type 2 diabetes mellitus
TBARS Thiobarbituric reactive substances
TCA Tricarboxylic acid cycle
TCF7L2 Transcription factor-7 like 2
TGF Transforming growth factor
Th T helper
TNF Tumor necrosis factors
Trx1 Thioredoxin-1
tTG Tissue transglutaminase
UCP Uncoupling protein
UDP Uridine diphosphate
USA United Sates of America
VCAM-1 Vascular cell adhesion molecule-1
VEGF Vascular endothelial growth factor
VLDL Very-low-density lipoprotein
VNTR Variable number of tandem repeat
VSMC Vascular smooth muscle cell
vWF Von Willebrand factor
WHO World Health Organization
WHR Waist-to-hip ratio
XO Xanthine oxidase
List of Figures

Fig. 1.1 Location of the pancreas and islet cell

Fig. 1.2 Synthesis of insulin from proinsulin
Fig. 1.3 Biphasic response of insulin secretion
Fig. 1.4 Pathway involved in glycogenolysis, gluconeogenesis, and glyco-
gen synthesis [UDP uridine diphosphate, ADP adenosine diphos-
phate, ATP adenosine triphosphate]
Fig. 1.5 Release of insulin and glucose transportation [ATP adenosine tri-
phosphate, IRS insulin receptor substrate, PI3K phosphatidylinosi-
tol 3-kinase, PI(4,5)P2 phosphatidylinositol 4,5-bisphosphate,
PI(3,4,5)P3 phosphatidylinositol (3,4,5)-trisphosphate, SHIP2
SH2 domain containing inositol 5-phosphatase 2, PTEN phospha-
tase and tensin homology, PDK 3-phosphoinositide-dependent
protein kinase, GLUT facilitative glucose transporters]
Fig. 2.1 Mechanism involved in the pathogenesis of T1DM and T2DM
Fig. 4.1 Estimated number of diabetic people in different regions of the
world in 2000 and 2030 as per WHO
Fig. 4.2 Top ten countries in comparative prevalence of diabetes (20–79
years group) in 2010 and 2030
Fig. 4.3 Global projection of the diabetic people (20–79 years) in different
IDF region
Fig. 4.4 Top ten estimated diabetic-affected countries in a number of peo-
ple in 2010 and 2030
Fig. 4.5 Mortality caused by DM in different regions of the world
Fig. 5.1 Pathogenesis of GDM and its common complications (GH growth
hormone, GDM gestational diabetes mellitus, FFA free fatty acid)
Fig. 5.2 Gestational period and risk of diabetes-induced birth defect
Fig. 6.1 The potential role of some adipokines in insulin resistance and
insulin sensitivity. TNF α tumor necrosis factor α, FFA free fatty
acid, NEFA nonesterified fatty acid
Fig. 6.2 Obesity and its treatment approaches
Fig. 7.1 Schematic representation of involvement of oxidative stress and
pathway leading to diabetes mellitus. ATP adenosine triphosphate,
JNK c-jun-NH2-terminal kinase, MAPK mitogen-activated protein
kinase, DAG diacylglycerol, CRP C-reactive protein, PKC protein
kinase C, NO• nitric oxide radical, ONOO•− peroxynitrite radical,
O2•− superoxide radical, NOS nitric oxide synthase, eNOS endothe-
lial NOS, XO xanthine oxidase, H2O2 hydrogen peroxide, SOD

xxv
xxvi List of Figures

superoxide dismutase, CAT catalase, GSH glutathione, GSSH oxi-

dized glutathione, GR glutathione reductase, •OH hydroxyl radi-
cal, UCP uncoupling protein, IKKB inhibitor of NF-kappaB
kinases beta, GPx glutathione peroxidase, NF-kB nuclear factor
kappa-light-chain-enhancer of activated B cells, iNOS inducible
NOS, IRS insulin receptor substrate, PI3K phosphatidylinositol
3-kinase, TNF-α tumor necrosis factor α, IL-6 interleukin-6, ROS
reactive oxygen species, LOX lipoxygenase, COX
cyclooxygenase
Fig. 7.2 Mechanism involved in diabetic-induced complications. DAG dia-
cylglycerol, PKC protein kinase C, NOS nitric oxide synthase,
eNOS endothelial NOS, GSH glutathione, GR glutathione reduc-
tase, GPx glutathione peroxidase, NF-kB nuclear factor kappa-
light-chain-enhancer of activated B cells, ROS reactive oxygen
species, SOD superoxide dismutase, ET-1 endothelin-1, VEGF
vascular endothelial growth factor, NADPH reduced nicotinamide
adenine dinucleotide phosphate, NADP nicotinamide adenine
dinucleotide phosphate, NAD nicotinamide adenine dinucleotide,
NADH reduced nicotinamide adenine dinucleotide, ROS reactive
oxygen species, UDP uridine diphosphate, GFAT glutamine fruc-
tose-6-phosphate amidotransferase, VCAM-1 vascular cell adhe-
sion molecule-1, ICAM-1 intracellular adhesion molecule-1, AGE
advanced glycation end product, RAGE receptor for AGE, TGF
transforming growth factor, PAI-1 plasminogen activator inhibi-
tor-1, DHAP dihydroxyacetone phosphate, AL aldose reductase,
SDH sorbitol dehydrogenase, GlcNAc N-acetylglucosamine
Fig. 9.1 Process of diabetes mellitus and some of its complications, show-
ing opportunities of identifying biomarkers. HbA1C hemoglobin
A1c, 1,5-AG 1,5-anhydroglucitol, 2-AAA 2-aminoadipic acid,
AGEs advanced glycation end products, RAGE receptor for AGE,
8-OHdG 8-hydroxydeoxyguanosine, 8-oxodG 8-oxo-7, 8-dihydro-
2′-deoxyguanosine, TNF-alpha tumor necrosis factor α, IL-6
interleukin 6, CPR C-reactive protein, ANGPTLs angiopoietin-like
proteins, AOPPs advanced oxidation protein products, ApoAI apo-
lipoprotein AI, ApoB apolipoprotein B, AQP aquaporin, DPP-IV
dipeptidyl peptidase IV, F2-ISOPS F2-isoprostanes, GAG glycos-
aminoglycan, GFAP glial fibrillary acidic protein, VEGF vascular
endothelial growth factor, KIM-1 kidney injury marker-1, L-PGDs
lipocalin-type prostaglandin D2 synthase, MCP-1 monocyte che-
moattractant protein-1, ICAM-1 intracellular adhesion molecule-1,
T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus,
VCAM-1 vascular cell adhesion molecule-1, NAG
N-acetylglucosaminidase, miRNAs microRNAs, MVs microvesi-
cles, NGAL neutrophil gelatinase-associated lipocalin, NT nitroty-
rosine, OPG osteoprotegerin, vWF von Willebrand factor
Fig. 10.1 Phytoconstituents investigated in preclinical study for hypoglyce-
mic and antidiabetic effect
Fig. 11.1 Biological role of GLP-1 and DPP-4
List of Figures xxvii

Fig. 11.2 Mechanism of action of sulfonylureas and meglitinides

Fig. 11.3 Mechanism of action of metformin. ACC acetyl-coenzyme A car-
boxylase, HMG-CoA 3-hydroxy-3-methylglutarylcoenzyme A,
SREBP-1 sterol-regulatory-element-binding-protein-1, G6Pase
glucose-6-phosphatase
Fig. 11.4 Mechanism of action of thiazolidinediones
Fig. 11.5 Glucose reabsorption in the kidney and site of action of SGLT2
inhibitors in the proximal tubule
Fig. 11.6 Chemical structure of different antidiabetic drugs
Fig. 11.7 Approaches to manage diabetes mellitus
 Pancreatic Hormones and Control
of Blood Glucose: A Glance
The pancreas, a retroperitoneal gland (12–
15 cm long, 2.5 cm thick), lies within the poste-
rior area of the greater curvature of the human
stomach. The pancreas is formed by the small
clusters of glandular epithelial cells. About
99 % of the clusters, called acini, and the
remaining 1 % of the clusters make the pancre-
atic islets. It is an elongated gland that contains
both exocrine and endocrine tissue. Acini
(grape-like clusters of secretory cells) are the
exocrine part of the pancreas, while the smaller
endocrine part consists of isolated islands of
endocrine tissue. The exocrine pancreas
secretes pancreatic juice (1200–1500 mL/day)
into the small ducts that finally combine to
form two larger ducts which are known as the
pancreatic duct and accessory duct (Tortora and
Derrickson 2009; Sherwood 2010). The compo-
nents of pancreatic juice are:
• Pancreatic enzymes: Secreted by the acinar
cells. Pancreatic enzyme includes several
digesting enzymes, such as proteolytic
enzymes (trypsin, chymotrypsin, carboxypep-
tidase, elastase) for protein digestion, amylase
for carbohydrate digestion, pancreatic lipase
for fat digestion, and nucleic acid-digesting
enzymes called ribonuclease and deoxyribonu-
clease.
• Aqueous alkaline solution: Secreted by the
duct cells that lie in the lines of the pancreatic
ducts. These solutions are rich in sodium
© Springer Science+Business Media Singapore 2016
S. Sen et al., Diabetes Mellitus in 21st Century, DOI 10.1007/978-981-10-1542-7_1
1
bicarbonate (NaHCO3) solution and neutralize
the acidic chime.
The endocrine pancreas synthesizes and
secretes several hormones which play a direc-
tive role in glucose, protein, and lipid metabo-
lism (Tortora and Derrickson 2009; Sherwood
2010).
Pancreatic Hormones
The islets of Langerhans (in a cluster) form the
endocrine pancreas, which are scattered through-
out the pancreas and embedded in the exocrine
tissue. About 106 islets present in the pancreas,
each of these which is composed of 2000–3000
epithelial cells. The cells (epithelial) are arranged
in a dense manner that is pervaded by a capillary
network. Thin reticular fiber layer divides the
exocrine tissue from the islets. The presence of
pancreatic artery makes the islets highly vascu-
larized. The pancreatic artery drained directly
into the portal vein, which transports the entire
pancreatic hormone discharge into the liver.
Nerve fibers of the autonomic nervous system
(vagus nerve of parasympathetic and middle
splanchnic nerve of sympathetic nervous system)
innervate the islet on or near the secretory cells.
Four principal types of cell in the islets of
Langerhans are α cell (produces glucagon), β cell
(produces insulin and amylin), D cell (produces
1
2 1
somatostatin), and PP cell (produces pancreatic
polypeptide). The presence of ε-cell is also found
in the islet which is responsible for ghrelin
production (Fig. 1.1; Table 1.1) (Davis 2006;
Torlińska 2014; Thompson 2014).
Glucagon Glucagon is a peptide hormone (sin-
gle chain of 29 amino acid, MW 3500 Da), pro-
duced by α cells of the pancreatic islet. It acts via
a cAMP pathway and opposes the action of insu-
lin. α cells release the hormone when blood
sugar level falls. It is synthesized from a larger
A- cell
PP cell
Pancreas
Fig. 1.1 Location of the pancreas and islet cell
Pancreatic Hormones and Control of Blood Glucose: A Glance
160 amino acid precursor (proglucagon), and
concentration of glucagon in blood is 10−anM
normally. Glucagon by activating glycogen phos-
phorylase increases glycogenolysis in the liver,
inactivates glycogen synthase, and thus prevents
glucose-1-phosphate from being recycled back
into glycogen and promotes the conversion of
pyruvate to phosphoenolpyruvate (gluconeogen-
esis) in the liver, therefore increasing blood glu-
cose level and decreasing glycogen level. It also
takes part in lipid metabolism, where it increases
lipolysis in the adipose tissue and ketogenesis in
D cell
Acinar cell
Beta cell
Islet
Acinar cell
Pancreatic Hormones
Table 1.1 Hormones secreted by the pancreatic islet (islets of Langerhans)
Regulation of glucagon
Hormones Secretes from secretion
Glucagon α (A) cells [consists Glucagon secretion stimulated
of ~15 % endocrine by several factors, including
cells and are located metabolic factors
around periphery of (hypoglycemia, amino acids
the islets] especially arginine and lysine),
hormonal factors
(catecholamines,
cholecystokinin, gastrin,
cortisol), nervous factors (β
adrenergic receptor, vagal
nerves – acetylcholine), and
other factors (stress, exercise,
infection), while its release is
inhibited by metabolic factors
(increase in blood glucose,
free fatty acid, ketones level,
urea production), hormonal
factors (insulin, somatostatin,
secretin), and nervous factors
(α2 adrenergic receptor)
Insulin β (beta) cell [consists Secretion of insulin stimulated
of ~75 % endocrine by metabolic factors (increase
cells and are located in glucose, amino acids, β-keto
at center of the islets] acids), hormonal factors
(glucagon, gastrointestinal
hormones, growth hormone,
cortisol, progesterone,
estrogen), and nervous factors
(β2 adrenergic and M4
cholinergic receptor), while
metabolic factors (K+
depletion), hormonal factors
(insulin, somatostatin,
catecholamines), and nervous
factors (α2 receptor) inhibit its
release
Amylin Glucose, arginine, and
carbachol increase the
secretion of amylin, while
somatostatin acts as an
inhibitory factor
3
Major role
Generally oppose insulin
action. Regulate
carbohydrate metabolism
(enhances blood glucose
concentration and reduces
glycogen level) and lipid
metabolism (increase free
fatty acid level in blood).
Increases cardiac output and
bile secretion. Stimulates
insulin, somatostatin, and
growth hormone secretion.
Inhibits gastric acid
secretion
Regulate carbohydrate
metabolism (reduces blood
glucose level and increases
glycogen level), lipid
metabolism (decreases free
fatty acid level and fat
storage), and protein
metabolism (reduces amino
acid level in blood and
increase in protein
formation)
Plays a key role to maintain
the blood glucose level by
suppressing secretion of
postprandial glucagon. It
also slows down the gastric
emptying, decreased intake
of food, and body weight
(continued)
4 1
Table 1.1 (continued)
Hormones Secretes from
Somatostatin δ (D) cells [consists
of ~5 % endocrine
cells]
Pancreatic polypeptide PP (γ) cells [consists
of trace amount of
endocrine cells]
Ghrelin Epsilon (ε) cells
the liver (Watkins 2003; Kitabchi 2009; Torlińska
2014).
Insulin Preproinsulin (110 amino acid) is a pre-
cursor of insulin synthesized in the rough endo-
plasmic reticulum and transported to the Golgi
apparatus where it undergoes proteolytic break-
down. Proinsulin is formed by cleavage of
N-terminal signal peptide (24 amino acid) of pre-
proinsulin. Thereafter, during the synthesis of
insulin from proinsulin, four basic amino acids
and C-peptide (residual connector) are separated
by proteolysis. Two distinctive Ca2+-dependent
endopeptidases play a significant role in the con-
version of proinsulin to insulin. These endopepti-
dases are located in the graduals of the pancreatic
islet and in other neuroendocrine cells. Insulin is
a polypeptide hormone made up of two peptide
chains (named as A and B) that are joined by two
disulfide bonds. A chain is made up of 21 amino
acid residues, while B chain has 30 (Davis 2006;
Haevey and Chanpe 2009; Kitabchi 2009).
Insulin is essential for normal working and sur-
vival of the cell. Insulin is a key regulator of metab-
olism of carbohydrate, lipid, and protein in the
Pancreatic Hormones and Control of Blood Glucose: A Glance
Regulation of glucagon
secretion Major role
Secretion is stimulated by Reduces the secretion of
increased blood glucose, insulin and glucagon;
increased amino acid, reduces the motility of the
increased fatty acids, and stomach, duodenum, and
increased cholecystokinin gallbladder; inhibits the
(CCK) level secretion and absorption of
gastrointestinal tract; and
increases the period of time
over which the food
nutrients are digested into
the blood
Stimulated by protein meal. Inhibits insulin,
The secretion of pancreatic somatostatin, pancreatic
polypeptide also increases due zymogen, and gastric acid
to excitation of the vagus secretion; reduces
nerve and administration of gallbladder contractility and
gastrin, secretin, or CCK gastrointestinal motility
Recently investigated in ice as well as in human islet. Ghrelin
may involve in appetite stimulation. Recent evidence
suggested that it decreases food intake
tissues which are sensitive to insulin, where at phys-
iologic concentrations (10−11 to 10−10M) insulin
impart its effect. Though glucose is a foremost stim-
ulus to insulin secretion from beta cell of pancreatic
islet cell, the release of insulin also can increase by
several endogenous stimuli like enteroglucagon-,
cholecystokinin-, secretin-, gastrin-, and gastrin-
releasing peptide. Intake of glucose stimulates
release of gastrointestinal hormones (gastrointesti-
nal inhibitory peptide and glucagon-like peptide 1)
and vagal activity, which in turn promote insulin
secretion. Blood glucose level significantly regu-
lates the extent of insulin release. It was observed
that blood glucose threshold level for release of the
insulin is ~ 50 mg/dL; for half maximum response
of insulin, it should be ~ 150 mg/dL, and maximum
release of insulin takes place when blood glucose
reaches to ~ 300 mg/dL. Glucose also imparts nega-
tive feedback mechanism on insulin release, as
insulin secretion reduces if blood glucose level
reaches below normal. Insulin secretion is biphasic:
In the first phase, insulin level reaches at its highest
after 1–2 min but it is short lived, while insulin
secretion in the later phase has a delayed start but a
longer period. Insulin flows in blood as a monomer,
and in fasting condition, islet secretes about 1 unit
(40 μg) of insulin per hour into the portal vein to
Pancreatic Hormones 5

attain an insulin level in the portal blood about Amylin It is a 37-residue peptide hormone
50–100 μunits/mL, and in peripheral blood circula- secreted from pancreatic β cell but in very less
tion, insulin concentration reaches 12 μunits/ amount compared to insulin. Amylin is synthe-
mL. After intake of food, insulin level increases rap- sized by posttranslational modifications from
idly. The t1/2 of insulin in plasma is ~5–6 min nor- its precursor proislet amyloid polypeptide. It
mally but may be increased in diabetics. Insulin reduces the food intake and body weight and is
degradation mainly occurs in the liver, kidney, and involved in the maintenance of blood glucose
muscle. Half of insulin reaches to the liver through level. Along calcitonin and calcitonin, gene-
the portal vein and destroyed (Figs. 1.2 and 1.3; related peptide amylin also regulates bone
Table 1.2) (Davis 2006; Kitabchi 2009; Rang et al. metabolism (Aronoff et al. 2004; Rang et al.
2012; Torlińska 2014). 2012).

Sites of action of the 55 53 51

57 49
endopeptidases PC2 (PC3) 59 LEU PRO GLN LEU SER GLY
ALA ALA
LEU GLY 47
61 GLY GLU PRO
GLY
SER
GLY
45
63 LEU
GLN GLY
NH2 65 LYS LEU
43
ARG
1 GLU
GLY
COOH VAL
1 PHE ILE
41
3 VAL GLN
VAL ASN 21
GLU GLY
CYS
3 ASN S S VAL 39
5 GLN TYR
GLN ASN
CYS 19 GLN
GLU
5 HIS CYS GLN LEU LEU
THR SER ILE CYS SER LUE TYR 37
17
LEU 7 15
ASP
9 11 13
GLU
7 CYS S S S 35
ALA
GLY GLU
ARG 33
SER S
9 ARG
HIS THR 31
LEU LYS
11 VAL THR PRO 29
GLU THR
PHE 27
13
ALA LEU GLY PHE Sites of action of
TYR LEU VAL CYS GLU GLU ARG 25
15 23 endopeptidases PC3
17 19 21

Proinsulin

Proteolytic cleavage
[removal of four basic amino acids
NH2 (residues 31, 32, 64, and 65) and the
1 connecting peptide]
GLY COOH
1 PHE ILE
3 VAL
VAL ASN 21

3 ASN
GLU
S
S
CYS (A- chain)
5 GLN TYR
GLN ASN
CYS 19
5 HIS CYS
THR SER ILE TYR GLN LEU
GLU
C- peptide
CYS SER LUE 17
LEU 7 15
9 11 13
7
CYS S S S
GLY

9
SER S
HIS THR

11
LEU
VAL THR PRO
LYS
(B- chain)
29
GLU THR
PHE 27
ALA GLY PHE
13 LEU TYR LEU VAL CYS GLU GLU ARG 25
15 23
17 19 21

Insulin

Fig. 1.2 Synthesis of insulin from proinsulin

6 1
Fig. 1.3 Biphasic response
of insulin secretion
80
Insulin release (mg/ml)
60
40
20
Somatostatin Somatostatin is a cyclic tetradeca-
peptide hormone produced in two active forms.
Among them one consists of 14 amino acids and
the other contains 28 amino acids. Somatostatin
(MW 1640 da) is synthesized from a larger precur-
sor called pro-somatostatin; it is also known as a
growth hormone-inhibiting factor or somatotropin
Table 1.2 Effects of insulin on carbohydrate, fat, and
protein metabolism
Tissue Effects of insulin
Liver Suppresses hepatic glucose synthesis
(decreases gluconeogenesis and
glycogenolysis)
Increases glycolysis and glycogenesis
Stimulates hepatic glucose uptake
Muscle Increases glucose uptake
Increases glycolysis and glycogenesis
Restrains the flow of gluconeogenic
precursors like alanine, lactate, and
pyruvate to the liver
Increases protein synthesis and amino
acid uptake
Adipose Stimulates glucose uptake
tissue Increases glycerol synthesis and inhibits
flow of gluconeogenic precursor
(glycerol) to the liver, thus decreasing
energy substrate for gluconeogenesis in
the liver
Stimulates synthesis of triglycerides and
fatty acid
Decreases lipolysis
Pancreatic Hormones and Control of Blood Glucose: A Glance
First phase
(insulin secrection reaches a
peak, but shor live)
Second phase
(a delayed onset but a
longer duration)
Normal
Type 2 DM
Type 1 DM
Time
release-inhibiting factor and produced by the wide
variety of cells including neuroendocrine (D cell of
islet, in CNS and PNS), inflammatory, and immune
cells. It regulates several functions related to the
endocrine system. It apparently acts locally and
inhibits the secretion of glucagon, insulin, and pan-
creatic polypeptide. Somatostatin acts as a neuro-
transmission in the brain and also regulates cell
proliferation. It is also involved in several other
functions including regulation of different hor-
mones when produced in the gut, thyroid, adrenals,
submandibular glands, kidneys, prostate, and pla-
centa. Somatostatin mediates its action through a
family of seven transmembrane domain GPCR
(G-protein-coupled receptors) that include five dis-
tinct subtypes (SSTR1–5) (Patel 1999; Kitabchi
2009; Torlińska 2014).
Pancreatic Polypeptide Pancreatic polypeptide
(36 amino acids, MW 4200 Da.) is secreted by PP
cells of the islet and may have influence on pan-
creatic exocrine secretion. The release of pancre-
atic polypeptide increases after a protein meal;
some recent pieces of evidence suggested that
pancreatic polypeptide decreases the food intake.
The distribution of PP cells enhances signifi-
cantly after the onset of diabetes (Adeghate and
Ponery 2003; Kitabchi 2009; Torlińska 2014).
Regulation of Glucose Homeostasis
Regulation of Glucose Homeostasis
Glucose concentration in plasma is normally
preserved within a narrow range reflecting a
balance between the utilization and produc-
tion of glucose. Postprandially, carbohydrates
from diet serve as the principal external source
of glucose. Glucose is considered as the
foremost fuel for energy and considered as a
starting material for almost all varieties of
biosynthetic reactions. Thus, the appropriate
concentration of glucose is indispensable to
guarantee proper function and survival of
every cells, tissues, and organ. Disturbance or
improper glucose metabolism may cause
physiological problems and warrants appro-
priate management (Aronoff et al. 2004;
Haevey and Chanpe 2009; Shrayyef and
Gerich 2010; Rang et al. 2012).
Plasma glucose level is preserved by the rate
in which glucose enters and is removed from the
circulation (glucose appearance and glucose
disappearance). The amount of circulating glu-
cose mainly depends on the following three
factors:
• Intake of food followed by intestinal absorp-
tion: When glucose in plasma comes from
dietary sources, then glucose emptying time
acts as a key factor which determines how
swiftly glucose appears in blood
circulation.
• Glycogenolysis: Breakdown of the glycogen
to glucose by glycogen phosphorylase enzyme
in the liver and muscle is called as glycoge-
nolysis. The process of glycogenolysis plays a
distinctive role in the fight-or-flight response
and in the preservation of glucose levels in
circulation.
• Gluconeogenesis: Gluconeogenesis is the
metabolic process that results in the forma-
tion of glucose from noncarbohydrate car-
bon substance like lactate, pyruvate, amino
acids, and glycerol in the liver (major) and
kidney (in a lesser extent). It is a key mecha-
nism in the human which maintains the
glucose level normal by preventing
hypoglycemia.
7
Fact sheet
Glucose Normal blood glucose level 60–100 mg/
level dL (in fasting condition), <140 mg/dL
(postprandial, after 2 h of meal/
glucose), 80–100 mg/dL (random)
Arterial plasma glucose values
approximately 90 mg/dL (throughout a
24-h period average)
After a meal, maximal concentrations
generally do not cross 165 mg/dL
After exercise or a moderate fasting
(60 h), the usual arterial plasma glucose
found more than 55 mg/dL
Insulin The pancreas releases approximately
40 mg insulin/h into the portal vein
under fasting conditions, to attain an
insulin level in the portal blood of
50–100 μunits/mL and in peripheral
circulation of 12 μunits/mL
A rapid rise in the level of insulin in the
portal blood was observed after
ingestion of a meal, followed by a
parallel but a smaller rise in the
peripheral circulation
The liver is the chief metabolic regulatory organ
and supplies nearly 90 % of all circulating glucose.
The liver stores significant amounts of glycogen
which can be utilized for rapid release into glucose
circulation and also synthesizes a large quantity of
glucose from amino acids, lactate, and glycerol dis-
charged by other tissues. In the initial fasting con-
dition, glucose is liberated from the liver through
the process glycogenolysis, whereas in prolonged
fasting condition, gluconeogenesis in the liver trig-
gers the release of glucose. During the post-absorp-
tive state, the kidney may also take part in the
overall endogenic glucose formation. During the
hepatic phase of liver transplantation surgery, sus-
tained glucose production is maintained by the kid-
ney only. Glucose is an obligated metabolic fuel for
the brain under physiologic environment as the
brain is unable to produce glucose or accumulate
excess glucose. Thus, the brain is reliant on a con-
stant glucose supply from plasma. Reduced plasma
glucose concentration below 55 mg/dL may induce
impaired cerebral function. During prolonged star-
vation, both glucose and ketone bodies are pro-
duced by the liver. In the time of starvation, ketone
8 1 Pancreatic Hormones and Control of Blood Glucose: A Glance
bodies partially replace glucose and are utilized as
fuel for the brain. The liver utilizes glycolysis
mainly as a source of intermediates produced by
biosynthetic reactions, with breakdown of amino
acid and fatty acid supplying the larger part of its
fuel. The muscle has also an imperative role in the
maintenance of glucose in blood despite the fact
that the muscle cannot release glucose into circula-
tion. The muscle can increase glucose uptake rap-
idly – that is, decisive for dealing with hasty raise in
plasma glucose. Skeletal muscle liberates free
amino acids into blood circulation that act as a sub-
strate for gluconeogenesis in the liver, thus regulat-
ing glucose homeostasis (Brandt 1999; Aronoff
et al. 2004; Davis 2006; Haevey and Chanpe 2009;
Shrayyef and Gerich 2010; Rang et al. 2012).
Removal of glucose from plasma may have
dissimilar fates depending upon the tissues and
environment (e.g., postabsorptive vs. postpran-
dial) though the pathways for its removal are rel-
atively limited.
• Glucose can be stored as glycogen
immediately.
• Glucose may undergo non-oxidative glycoly-
sis to produce pyruvate or through oxidative
glycolysis glucose convert to acetyl CoA
which is again oxidized in the tricarboxylic
acid (TCA) cycle to produce CO2 and water.
Non-oxidative glycolysis carbons may go
through gluconeogenesis to form new glucose
molecule, which either accumulates as glyco-
gen or goes back into plasma.
The mechanisms of glucose homeostasis are
maintained by a complex interaction of hor-
monal and metabolic regulatory processes.
Several hormones such as glucagon, amylin,
glucagon-like peptide-1 (GLP-1), catechol-
amines, growth hormone, adrenocorticotropic
hormone (ACTH), and thyroxin along with insu-
lin maintain glucose homeostasis. Table 1.3 dis-
cusses the individual effect of these hormones.
Nutritional factors like diet composition, exer-
cise, physical fitness, and diseases state also can
be important for maintenance of glucose homeo-
stasis (Fig. 1.4) (Aronoff et al. 2004; Shrayyef
and Gerich 2010).
Insulin and Glucose Transport
Insulin usually plays a central role to maintain glu-
cose homeostasis by suppressing blood glucose
level. Digestive enzymes that induced breakdown of
carbohydrates result in the increased level of glu-
cose, which stimulates the β cells to release insulin.
Glucose is hydrophilic in nature; thus, glucose is
unable to diffuse through the lipid bilayer of cell
membrane. Membrane transporters thus play the
vital role for glucose transport across the cell. In
humans, mainly two types of glucose transporters
exist, namely, sodium-dependent glucose transporter
family (SGLT) and facilitative glucose transporters
(GLUT). SGLT comprises sodium-dependent glu-
cose co-transporters (SGLT1 and SGLT2), glucose
sensor (SGLT3), inositol, and multivitamin trans-
porter (SGLT4 and SGLT6). SGLTs usually regulate
absorption in the intestine and in the kidneys, while
transporters of GLUT family are considered as facil-
itative glucose transporters. Till now, 14 gene coding
was identified for individual proteins of the GLUT
family which named as GLUT1 to GLUT14. Among
them, GLUT14 are well characterized (Medina and
Owen 2002; Ducluzeau et al. 2002; Scheepers et al.
2004; Karlsson 2005).
• GLUT1: It is widely distributed in all tissues.
In the adult, it is expressed at the highest lev-
els in erythrocytes and the brain. Generally it
is involved in the low level of basal glucose
uptake, transport of glucose across the blood–
brain barrier, and in growing cells.
• GLUT2: It is a bidirectional transporter, per-
mitting glucose to flow in both directions. It is
mostly expressed in the pancreatic islet (β
cell), liver, intestine, kidney, and retina.
• GLUT3: It is expressed in the brain mainly in
neurons and in the placenta.
• GLUT4: It is expressed in the fat (adipose tis-
sues), skeletal muscle, and heart. It is involved
in insulin-sensitive uptake of glucose and cru-
cial in postprandial glucose clearance.
Glucose enters β cells via a membrane
transporter called GLUT2 and immediately
phosphorylated to glucose-6-phosphate which is
oxidized by β cell to produce adenosine
Insulin and Glucose Transport 9

Table 1.3 Hormones regulating blood glucose level

Hormones Actions Effects of blood glucose level
Insulin Stimulates glycogen synthesis in the liver Decreases blood glucose
Suppresses glycogenolysis and level
gluconeogenesis in the liver
Stimulates storage of hepatic glycogen by
decreasing hepatic glucose output
Increases uptake of glucose by adipose
tissue and muscle
Glucagon Stimulates glycogenolysis Increases blood glucose
Increases gluconeogenesis level
Amylin Suppresses secretion of postprandial Reduces blood glucose level
glucagons
Slows down the gastric emptying
Glucagon-like peptide-1 (GLP-1) [an Increases glucose-dependent insulin Reduces blood glucose level
incretin hormone] secretion
Suppresses secretion of postprandial
glucagon
Slows gastric emptying
Promotes β-cell health
Growth hormone Increases hepatic glucose production Increases blood glucose
Stimulates lipolysis and ketogenesis level
Glucocorticoids Stimulate gluconeogenesis Increase blood glucose level
Reduce peripheral glucose utilization
Enhance the concentration of plasma free
fatty acid and ketone
Increase insulin resistance
Adrenocorticotropic hormone (ACTH) Stimulates secretion of glucocorticoids Increases blood glucose
level
Thyroxin Increases release of glucose from Increases blood glucose
glycogen level
Increases absorption of sugar from
intestine
Catecholamines (norepinephrine and Hepatic glycogenolysis Increase blood glucose level
epinephrine) Suppress peripheral glucose uptake

triphosphate (ATP). Glucokinase and glycolysis
raise the intracellular ATP level. β cell has two types
of channels: ATP-sensitive K+ channel (KATP) and
voltage-gated Ca2+ channel. Due to increase con-
centration of ATP, it binds with KATP and blocks this
channel resulting in depolarization of β cell.
Subsequently, voltage-dependent calcium channels
open which leads to Ca2+ influx and trigger exocyto-
sis of secretory vesicles containing insulin to release
insulin. Insulin influences the glucose metabolism
in most tissues. In the liver, insulin stimulates glyco-
gen synthesis while suppressing glycogenolysis and
gluconeogenesis. Insulin increases storage of
hepatic glycogen by decreasing hepatic glucose
output. Insulin also has effects on peripheral tissues,
with an increase in glucose uptake by adipose tissue
and muscle. Furthermore, insulin increases fatty
acid as well as triglyceride synthesis in the adipose
tissue and liver and restrains lipolysis, protein
catabolism, and oxidation of amino acids in the liver
(Haevey and Chanpe 2009; Sherwood 2010; Rang
et al. 2012).
A complex mechanism and multiple path-
ways are involved in the insulin that initiated
the process of glucose uptake in fat and muscle
cell. Insulin receptor (IR), a tetrameric protein,
contains two insulin-binding extracellular
α-subunits (MW 130000) and two transmem-
brane β-subunits (MW 90000) with tyrosine
kinase activity. IR is considered as a subfamily
of tyrosine kinases receptor; several other
receptors like insulin growth factor-1 receptor
10 1 Pancreatic Hormones and Control of Blood Glucose: A Glance

Glucokinase Phosphoglucomutase
Glucose Glucose-6-phosphate Glucose-1-phosphate
Glucose 6-
phosphatase
UDP- glucose
Hexokinase phosphorylase

Gluconeo Glycolysis
UDP-glucose Phosphorylase
Glucose genesis
Glycogen
synthase
Protein/
amino acid Pyruvic acid Glycogen

Lactate
Nitrogen pool Tissue protein Aminoacid biosynthesis
Fatty acid biosynthesis Fat and lipid
Acetyl CoA Neocleotide biosynthesis

Ammonia CO2
Fatty acid spiral

Urea Citric
acid Lipgenesis
cycle
cycle
ADP ADP ADP
2e– O2
Urea CO2
+ Electron transport chain
2H
H2O

ATP ATP ATP

Fig. 1.4 Pathway involved in glycogenolysis, gluconeogenesis, and glycogen synthesis [UDP uridine diphosphate,
ADP adenosine diphosphate, ATP adenosine triphosphate]

and the IR-related receptor (IRR) also belong
to the same subfamily of receptor. Insulin on
release binds to IR at the cell surface plasma
membrane and thus phosphorylates insulin
receptor substrate proteins (IRS proteins),
which in turn is responsible to activate two key
signaling pathways:
• Phosphatidylinositol 3-kinase (PI3K)–Akt/
protein kinase B (PKB) pathway regulates
most of the metabolic actions of insulin.
• Ras-/mitogen-activated protein kinase
(MAPK) pathway is responsible to regulate
cell growth and cell differentiation by express-
ing few genes and cooperating with the phos-
phatidylinositol 3-kinase pathway.
IR substrates present in skeletal muscle (IRS-1
and IRS-2) get phosphorylated by stimulated IR on
tyrosine moiety. Interaction between Src homology
2 (SH2) domains of PI3K regulatory subunit (p85)
with phosphorylated IRS molecules leads to the
enzyme activation (by activating p110 catalytic
subunit of the enzyme). Subsequently, several
phosphoinositide moieties, i.e., phosphatidylinosi-
tol-3-monophosphate, phosphatidylinositol-3,4-bi-
phosphate, and a lipid second massager
phosphatidylinositol3,4,5-trisphosphate (PIP3), are
generated which involve in the localization and
activity of numerous proteins. Activation of PI3-
kinase is attenuated by the dephosphorylation of
PIP3 through the 3'-phosphatases such as phospha-
tase and tensin homology (PTEN) or 5'-phospha-
tases like SH2 domain enclosing inositol
5-phosphatase 2 (SHIP2). Pleckstrin homology
(PH) domain-holding proteins (such as cytoskeletal
proteins, adapter molecules, various enzymes, and
their substrates) bind with PIP3 and localized to the
area where their activation initiates. Among
them the most important is the activation of
3-phosphoinositide-dependent protein kinase 1
(PDK1), which activates a number of downstream
kinases such as Akt/PKB, protein kinase C (PKC),
serum, and glucocorticoid-inducible kinase (SGK)
after phosphorylation. Among them, activation of
Akt and PKC is vital for glucose transportation
Insulin and Glucose Transport 11

(Karlsson 2005; Chang et al. 2004; Taniguchi et al. recommended that PDK2 is complex among the
2006; Henriksen 2007). rapamycin-insensitive companion of mTOR
The serine/threonine kinase Akt or protein (RICTOR) and mammalian target of rapamycin
kinase B (PKB) imparts a significant role by act- (mTOR). It is believed that a number of reputed
ing as central intermediate for growth factor and substrates of Akt actively regulates glucose trans-
insulin responses downstream of PI3-kinase. port; few of them include PKC, isoforms and
Expression of three Akt isoforms (Akt1, Akt2, glycogen synthase kinase 3 (GSK3), Rab-
Akt3) was reported in the skeletal muscle. PIP3 GTPase-activating protein (Rab-GAP), and a
appears to mediate the relocation of Akt to the newly discovered molecule, AS160, which has
plasma membrane, via interaction of its appeared as a supplementary distal step vital in
N-terminal of PH domain. Activation of Akt takes the commencement of glucose transport. Another
place by two phosphorylation steps. PDK1 signaling protein downstream of PI3-kinase
induces the phosphorylation of Akt at Thr308 in important for glucose transport on insulin stimu-
the catalytic domain. Phosphorylation of Akt also lation includes the two PKC isoforms (PKC-ζ/λ).
takes place at Ser473 residue in a hydrophobic PKC-ζ/λ is from the divergent family of PKCs
motif at the C-terminal end, though kinase respon- that are phosphorylated and stimulated by PDK1.
sible for this is still debated. Some studies have The commencement of these processes finally
suggested that DNA-dependent protein kinase induces GLUT4 translocation to the sarcolemmal
(DNA-PK) or TOR–RICTOR–GßL complex may membrane, where transportation of glucose
induce Akt phosphorylation at the Ser473. It is occurs via a facilitative diffusion process (Fig. 1.5)
also postulated that PDK1 is unable to phosphory- (Chang et al. 2004; Karlsson 2005; Taniguchi
late Ser473, and some new evidence has et al. 2006; Henriksen 2007).

Liver
Pancreatic β-Cell

Glucogenolysis Glucose
Pancreatic islet
Gluconeogenesis

Pancreatic
D-Cell PP-Cell polypeptide
I Glucose
n Amino acid Somatostatin
t –
Glucose Glucose ATP
ATP sensative
e Fatty acid 6-phosphate
s K+ chanel
Digested food β-Cell α-Cell
t
i Glucagon
n Intracelluar
+
e Blood K+
Ca+2
+

Amylin Insulin
(Insulin)
Ca+2

(Glucose)

Cell membrane

P Akt Akt -Tyrosine

P P
P
PI(4,5)P2
Translocation P110 P85

PTEN IRS IRS-I

P PDK1 PDK1
PI(3,4,5)P3 P

P110 P85
SHIP2
PKC
P PKC PI3K
PI(3,4)P2
GLUT4 Containing vesicle

Fig. 1.5 Release of insulin and glucose transportation [ATP (3,4,5)-trisphosphate, SHIP2 SH2 domain containing inosi-
adenosine triphosphate, IRS insulin receptor substrate, PI3K tol 5-phosphatase 2, PTEN phosphatase and tensin homol-
phosphatidylinositol 3-kinase, PI(4,5)P2 phosphatidylinosi- ogy, PDK 3-phosphoinositide-dependent protein kinase,
tol 4,5-bisphosphate, PI(3,4,5)P3 phosphatidylinositol GLUT facilitative glucose transporters]
12 1 Pancreatic Hormones and Control of Blood Glucose: A Glance

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 Diabetes Mellitus: General
Consideration
Over the past decade, it has been evident that the
global diabetic burden is increasing sharply as a
result of the evolving diabetes pandemic.
Diabetes mellitus (DM) is becoming one of the
world’s leading health problems that affect indi-
viduals of all ages including children, young,
adults, and pregnant women. DM and complica-
tions resulting from DM impose quite a substan-
tial burden on individuals, as well as on
healthcare system (World Health Organization
1999a).
The word diabetes in Greek means “to run
through” or “asiphon” – describing the excessive
urination. The term mellitus is derived from the
Latin and Greek ancestry for “honey,” which was
added later to the name of this disorder, when it
was known that the taste of diabetic urine is
sweet. This condition has been recognized by
ancient traditional medicinal systems like
Egyptian medicine or Ayurveda in India (Scobie
2007; Anjana et al. 2011).
What Is Diabetes Mellitus?
DM is a group of metabolic disorder of numer-
ous etiology characterized by hyperglycemia
and glucose intolerance. The condition arises
from the metabolic disturbance of carbohy-
drate, fat, and protein caused by imperfection
in insulin release, insulin action, or both
(World Health Organization 1999a, 2006).
© Springer Science+Business Media Singapore 2016
S. Sen et al., Diabetes Mellitus in 21st Century, DOI 10.1007/978-981-10-1542-7_2
2
Thirst, blurring of vision, polyuria, and loss of
weight are the general symptoms of DM. In
severe diabetic progression, complications like
ketoacidosis or a nonketotic hyperosmolar
state may lead to stupor, and lack of effective
treatment can increase the risk of coma and
death.
Classification of Diabetes Mellitus
In 1980, World Health Organization (WHO)
has published the categorization of diabetes
mellitus and subsequently revised in 1985. The
first WHO report named two major classes of
diabetes mellitus; one is insulin-dependent dia-
betes mellitus (IDDM) or type 1 diabetes and
non-insulin-dependent diabetes mellitus
(NIDDM) or type 2 diabetes. In the year 1985,
the Expert Committee of WHO included
another class “malnutrition-related DM” along
with the classes IDDM and NIDDM, though
they omitted the terms type 1 and type 2. In
both the 1980 and 1985 reports, WHO also
emphasized another classes of diabetes such as
other types, impaired glucose tolerance (IGT)
and gestational diabetes mellitus (GDM). The
classification of 1985 was widely accepted and
is used internationally (World Health
Organization 1999a, 2006; Davis 2006;
Tripathi 2008; American Diabetes Association
2013a, b).
13
14
The diagnostic label “diabetes mellitus”
viewed as “high glucose level” in the blood due
to deficiency of insulin, tissue resistance toward
insulin, or both can lead to several complications.
This condition is thus referred as multiple
disorders of different causations rather than a
unique disease. Increasing knowledge toward the
cause and facts of DM allowed us to classify DM
in a different form. Currently, based on etiology
DM is classified into four types:
1. Type 1 diabetes mellitus (IDDM)
2. Type 2 diabetes mellitus (NIDDM)
3. Other specific drugs
4. Gestational diabetes mellitus (GDM)
Fact sheet
Diabetes mellitus (DM) Diabetes insipidus (DI)
DM is a group of DI is characterized by a
metabolic disorders with condition result from the
hyperglycemia (high partial or complete
blood glucose), due to deficiency of vasopressin
deficiency of insulin, or an insensitivity of renal
impaired effectiveness of tubules to vasopressin. The
insulin action, or both main symptoms of DI
include excessive thirst
and excretion of frequent
and large diluted urine
Though the name of both conditions is almost similar,
diabetes mellitus is not related to diabetes insipidus
apart from the similar symptoms like increased
volume of urine and thirst. The word diabetes means
“to go through” – explaining the excessive urination.
While the word “insipidus” means “tasteless urine,”
“mellitus” indicated “sweet taste of urine”
Type 1 Diabetes Mellitus
Type 1 diabetes mellitus (T1DM) was also referred
as IDDM. Earlier it was also called as “juvenile-
onset diabetes,” as it mostly afflicts individuals in
puberty or youngsters, but some latent forms can
occur later in life. Type 1 DM caused by the com-
plete deficiency of insulin resulted from the
destruction of pancreatic β cell. Recent epidemio-
logical studies revealed that the frequency of type
1 diabetes increased among children and young-
aged people. Annually about 70,000 children are
2 Diabetes Mellitus: General Consideration
likely to be affected by type 1 diabetes worldwide,
and incidences are increasing more sharply in the
low diabetic prevalence countries such as Central
and Eastern Europe countries. T1DM represents
about 5–10 % of all DM in developed countries
and the number is even higher in developing coun-
tries. T1DM is further classified again in type 1A
and type 1B (Mohan 2003; Sperling 2003; Davis
2006; Scobie 2007; Tripathi 2008):
• Type 1A DM, also known as immune-
mediated diabetes, is a condition resulting
from autoimmune pancreatic β-cell destruction.
Autoantibodies to islet cells, insulin, glutamic
acid decarboxylase 65 (GAD65), and tyrosine
phosphatases IA-2 and IA-2b are usually consid-
ered as markers of the immune destruction of β
cell. Though this condition has numerous genetic
predispositions and is also linked to environmen-
tal factor that are still inadequately described.
• Type 1B or idiopathic diabetes is the type of
NDDM with no known etiologies. Type 1B
DM is strongly inherited, although a less num-
ber of people (maximum from African or
Asian ancestry) have this type of DM. People
with type 1B DM have permanent insulinope-
nia and are more susceptible to ketoacidosis,
but evidence of autoimmunity is lacking.
Etiology and Pathophysiology
of T1DM
The beginning of T1DM represents the end-stage
destruction of β cell. Though the exact etiology and
pathogenesis of T1DM is still unknown, the role of
genetic factor and environmental factor which
includes infection and disease is well acknowledged
as a causative factor which influences the islet auto-
immunity (Khardori and Pauza 2003; Achenbach
et al. 2005; Atkinson 2012; Ozougwu et al. 2013).
Genetic T1DM susceptibility genes are discov-
ered within the human leukocyte antigen (HLA)
class II region on chromosome 6 (IDDM1). HLA
genes are responsible for as much as half of the
total genetic risk for T1DM. In general, it was
Type 2 Diabetes Mellitus
observed that an individual with T1DM lacks
aspartic acid at position 57 of HLA class II mol-
ecules of the β cell. Several other genetic suscep-
tibility loci have been identified by a variable
number of tandem repeat (VNTR) in the pro-
moter region of INS gene (insulin gene).
Environmental Factors Environmental
agents are also known as a triggering agent of
β-cell autoimmunity. Several factors including
dietary factor, change in environment, etc.,
have shown involvement in T1DM. Some
researchers found that breastfeeding may pro-
tect against T1DM whereas early feeding of
supplementary milk/cow’s milk intake may
induce the generation of islet autoantibodies
and can promote T1DM, though, controversy
exists on the findings.
Viral Infections Virus infections (like mumps)
may promote the autoimmunity against β cell by
molecular mimicry between viral peptides, amino
acid sequences, and antigens of islet that can trig-
ger autoreactive T cells.
Maternal Transfer of Islet Autoantibodies
Recent findings have showed that transmission of
islet autoantibodies maternally on the advance-
ment of islet autoimmunity and T1DM has the
good connection.
Humoral and cellular islet autoimmunity and
faulty immunoregulation appear to be a key fac-
tor for T1DM. The following factors are respon-
sible for T1DM by destroying β cell (Khardori
and Pauza 2003; Achenbach et al. 2005; Atkinson
2012; Ozougwu et al. 2013):
• The existence of immunocompetent and
accessory cells in islets of pancreas through
infiltration
• Involvement of vulnerability to disease with
the class II genes of the major histocompati-
bility complex (MHC, HLA)
15
• The presence of autoantibodies which is spe-
cific to islet cell
• Modification immunoregulation which medi-
ates through T cell, mainly in the CD4+ T-cell
compartment
• Association of monokines and interleukins
produced from T-helper 1 (Th1) cells generat-
ing interleukins in the disease progression
• As a specific reaction against any other auto-
immune diseases in individual or in their fam-
ily members
• Molecular mimicry (i.e., antigenic property
sharing, including sequences of amino acid
between β cells and probable environmental
factors) which results in β-cell autoimmunity
• Breakdown of the development of immunity
to self-antigens in early life
• Immunotherapy
• Deadly trafficking of dendritic cells from pan-
creatic islet β cells to pancreatic lymph nodes
which are responsible for autoimmunity
Type 2 Diabetes Mellitus
Type 2 diabetes mellitus (T2DM) is also known as
NIDDM, which is exemplified by resistance of tis-
sue toward the action of insulin or relative decrease
in insulin secretion. Type 2 DM is related with obe-
sity and usually occurs later in life (after an age of
40). T2DM can remain undetected (asymptomatic)
for several years, which can lead to different dia-
betic complications. People suffering from T2DM
are not reliant on insulin from an exogenous source.
This type of diabetes represents 90–95 % of total
DM case. In this form of diabetes, ketoacidosis is
less likely but possible (Mohan 2003; Davis 2006;
New Zealand Guidelines Group 2006; Scobie
2007; Tripathi 2008).
Etiology and Pathophysiology
of T2DM
T2DM is characteristically a multifactorial dis-
ease relating to multiple genetic factors and fac-
tors related to the environment.
16
Genetics Family history generally considered as a
key risk factor for T2DM. High concordance rate
among monozygotic twins than between dizygotic
twins was also reported. These observations clearly
indicated the involvement of genetics in
T2DM. Recently, researchers discovered some
candidate genes for T2DM though most of their
connection to human diabetes is not certain.
Mutation of several genes including multiple forms
of glucokinase genes like HNF-4-α, HNF-1-β and
IPF-1, and NeuroD1 is found to associate with
maturity-onset diabetes of the young (MODY), one
of the forms of T2DM. Transcription factor-7
like-2 (TCF7L2) gene expression in β cell may
increase the risk of T2DM. Mutation in the KCNQ1
gene causes abnormality of insulin release as a sig-
nificant disease-susceptible gene connected with
the pathogenesis of DM in Japanese and other
Asian ethnic groups (Kitabchi 2009; Kaku 2010).
Environmental Factor Physical inactivity and
unhealthy diet (consumption of more fat) are the
key inducers of obesity. Obesity (particularly vis-
ceral fat obesity) can induce insulin resistance;
thus in recent time, it has emerged as a key cause
of T2DM. Insufficient calorie consumption,
smoking, excessive alcohol drinking, etc., are
independent risk issues of the pathogenesis of
T2DM (Kaku 2010).
There are three major problems associated
with T2DM which include diminished secretion
of insulin, impaired insulin action, and increased
in production of hepatic glucose. A number of the
factors are also involved in the pathogenesis of
T2DM. Disturbance of the cross talk between the
pancreas, adipose tissue, liver, skeletal muscle,
and, presumably, central nervous system and gut
may be responsible for the alteration of glucose
homeostasis in type 2 diabetes.
Impaired Insulin Secretion IGT due to dimin-
ished glucose response in early-phase insulin release
from islet cell and reduction in further insulin secre-
tion after intake of meals is responsible for postpran-
dial hyperglycemia. Impaired insulin secretion is
usually progressive and induces secondary failure of
pancreatic β cell as a result of hyperglycemia
2 Diabetes Mellitus: General Consideration
(glucose toxicity) and high free fatty acid (lipotoxic-
ity), frank T2DM. Evidence has suggested that glu-
cotoxicity and lipotoxicity are the acquired defects
that can also induce impaired insulin secretion. The
progression of this condition may result in impair-
ment of pancreatic islet β-cell function and decrease
in pancreatic β-cell mass, which alters long-term
control of blood glucose. Genetic defect is consid-
ered as a cause of β-cell dysfunction. For example,
Finnish families with T2DM have inherited trait-
impaired insulin secretion which may be due to its
susceptibility locus on chromosome 12. Age, amy-
lin, decrease incretin effect, hexosamines, and insu-
lin resistance can induce impairment in β-cell
function (Scheen 2003; Kitabchi 2009; Kaku 2010).
Insulin Resistance Insulin resistance is a situa-
tion when insulin does not show enough action par-
ticularly in reducing blood glucose level despite its
sufficient concentration in blood. The impairment
of insulin action mainly occurs at the liver and
muscles. Genetic factors and environmental factors
are the contributors of the situation. Polymorphisms
of the gene which regulated insulin receptor and
IRS-1 can directly affect insulin signals. GLUT2
gene (expressed in liver and β cells) and GLUT4
gene (expressed in adipose tissue and skeletal mus-
cle) are key target genes for the genetic susceptibil-
ity of T2DM. Polymorphisms of β3 adrenergic
receptor and uncoupling protein (UCP) gene are
responsible for visceral obesity and insulin resis-
tance. Obesity is a key determinant of insulin resis-
tance and sensitivity; distribution of body fat seems
to be a critical aspect in this regard. Long-term
positive energy balance is responsible for surplus
triglyceride store in the adipocyte and ectopic tri-
glyceride storage. Recent studies highlighted the
role of adipocytokines (leptin, resistin, TNF-α, adi-
ponectin) in insulin resistance. Glucolipotoxicity
and release of inflammatory mediators are also
involved in such process (Scheen 2003; DeFronzo
2004; Kaku 2010).
The current evidence suggested that imperfec-
tion in glucose uptake medicated by insulin, dys-
regulation of adipocyte as a secretory organ,
β-cell dysfunction, and liver dysfunction
are together or in combination inducing
Other Specific Types of Diabetes Mellitus 17

Table 2.1 Comparison between T1DM and T2DM

Feature
General
Type of population affected
Incidence
B-cell
Genetic predisposition
Concordance in identical twins
Antibodies to ß-cells
Inflammatory cell in islet
Family history of diabetes
HLA association
Metabolic ketoacidosis
Body habitus
Obesity at onset
Plasma insulin/C-peptide
Sign and symptoms
Risk factor
Drugs
Type 1 DM Type 2 DM
Absolute insulin deficiency Insulin resistance or decrease insulin
production
Generally in the age of puberty and to Generally middle-aged to old-aged
youngsters people
In people age <35 years In people age >35 years
About 5–10 % among all DM case About 90–95 % among all DM case
Reduced Variable
Low High
30–50 % 90–95 %
Yes (90–95 %) No
Present initially Absent
Uncommon Common
Yes No
Frequent Rare (except in African-Americans)
Normal/wasted Obese
Uncommon Common
Low/absent Near to normal/high
Sudden and dramatic, abnormal thirst Polyuria, polydipsia, polyphagia,
and a dry mouth, frequent urination, hyperglycemia, glycosuria, frequent
intense tiredness, hyperglycemia, infections, sexual dysfunction, dry/itchy
constant hunger, blurred vision, skin, fatigue
recurrent infections, slow-healing
wounds, weight loss
Blood group incompatibility, Race/ethnicity, obesity, unhealthy
maternal viral infections during lifestyle, diet, physical inactivity, insulin
pregnancy, early exposure to cow’s resistance, family history, intrauterine
milk components and other environment, history of GDM, smoking,
nutritional factors, lifestyle, weight increased alcohol intake, hypertension,
and growth abnormal lipid profile, IFG/IGT, history
of vascular diseases
Insulin Oral hypoglycemic drugs and insulin in
some extent

T2DM. Oxidative stress may be caused by the
variety of factors that also contribute to T2DM by
inducing β-cell dysfunction and altering insulin-
induced glucose transport (Table 2.1; Fig. 2.1)
(Homsi and Lukic 1993; Lin and Sun 2010).
Other Specific Types of Diabetes
Mellitus
This category includes hyperglycemia due to
other specific causes, like chronic pancreatic or
chronic drug therapy with glucocorticoids and
thiazide diuretics. The recent publication of
American Diabetes Association (ADA) includes
different causes of this type of DM (Davis 2006;
Scobie 2007).
• Genetic defects of β-cell function: This may
occur due to modification/defect in genetic
level like MODY 1 (chromosome 20, HNF-4a),
MODY 2 (chromosome 7, glucokinase),
MODY 3 (chromosome 12, HNF-1a), MODY
4 (chromosome 13, insulin promoter factor-1),
MODY 6 (chromosome 2, NeuroD1), MODY
7 (chromosome 9, carboxyl ester lipase), ZAC/
HYAMI imprinting defect on 6q24 (results
transient neonatal DM), KCNJ11 gene encod-
ing Kir6.2 subunit of β-cell KATP channel
(results permanent neonatal diabetes), and
mitochondrial DNA defect.
• Genetic defects in action of insulin: This
includes type A insulin resistance, lepre-
chaunism, Rabson–Mendenhall syndrome,
and lipoatrophic diabetes.
18 2 Diabetes Mellitus: General Consideration

Genetic susceptibility Environmental factors Constitution/environmental factor

• Concordane in identical tweens - • Genetic and seasonal variation. • High fat diet
50 % • Early exposure to bovine milk • Lack of physical activity
• Suceptibility in gene on HLA region protein • Stress and depression Genetic factor
of chromosome
• Ethinic factor
• Family history
Hypertension and other
Obesity cardiovascular disease

Infection and disease

• Viral infection (mumps)

• Pancreotropic virus Decrease insulin secretion
Autoimmune process
• Presence of other autoimmuno Insulin resistance
• Islet cell antibody disease (gravis disease)
• Hyperinsulinemia • Failure of cell functioning
• Insulitics • Impaired glucose utilization • Lipo-Gluco toxicity
• T-Lymphocyte - CD4-IN γ • Receptor, Post receptor defect
• Macrophase - antigen-peptide (IL-I, • Lack of sensitivity in peripheral tissue
TNF-α) • Lipo-Gluco toxicity

Increase in hepatic glucose synthesis

Type I diabetes mellitus Postprandial hypoglycemia
Destruction of β -Cell
over working of β-Cell

Type 2 diabetes mellitus Progression of

β-Cell apoptosis

Fig. 2.1 Mechanism involved in the pathogenesis of T1DM and T2DM

• Exocrine pancreas diseases: Pancreatitis, neo- Gestational Diabetes Mellitus (GDM)

plasia, trauma/pancreatectomy, cystic fibrosis,
fibrocalculous pancreatopathy, and hemochro-
matosis are some disorder which may cause
DM.
• Endocrinopathies: Disorders like Cushing’s
syndrome, acromegaly, glucagonoma, hyper-
thyroidism, pheochromocytoma, aldoster-
onoma, and somatostatinoma also can lead to
β-cell damage.
• Drug or chemical induced: DM also can occur
by the toxic effect of different drugs like nico-
tinic acid, pentamidine, glucocorticoids,
diazoxide, thyroid hormone, thiazides, Dilantin,
β-adrenergic agonists, and g-interferon.
• Infections: Several infections like congenital
rubella and cytomegalovirus are also respon-
sible for β-cell damage.
• Uncommon forms of immune-mediated diabe-
tes: This form of DM includes “stiff-man” syn-
drome and anti-insulin receptor antibodies.
• Other genetic syndromes sometimes associated
with diabetes: A number of syndromes like the
Klinefelter syndrome, Down syndrome, Turner
syndrome, Friedreich ataxia, Huntington cho-
rea, Wolfram syndrome, Laurence–Moon–
Biedl syndrome, porphyria, myotonic dystrophy,
and Prader–Willi syndrome are also linked with
DM.
GDM is a situation of carbohydrate intolerance of
varying severity that begins or is first identified in
the time of pregnancy. Hyperglycemia during preg-
nancy is one of the most frequent complications of
pregnancy and responsible for increased risk of
preeclampsia, premature delivery, and caesarean
section delivery. Few cases of GDM also lead to
DM to mother after pregnancy (GDM discussed on
detail in Chap. 5) (American Diabetes Association
2004; Davis 2006; Scobie 2007; Murphy 2010).
Symptoms and Risk Factors
T2DM has a long asymptomatic preclinical phase
which regularly goes undetected. Though both
T1DM and T2DM have several common signs and
symptoms and risk factors, but due to their dissimi-
lar pathogenesis, it is essential to understand the
difference in risk factor and symptoms. Table 2.2
includes signs and symptoms and risk factors of
these two types of DM. Apart from these, diabeto-
genic drugs like steroid, thiazide diuretic, etc. are
aslo considered as risk factor of DM (Mohan 2003;
Loghmani 2005; World Health Organization 2006;
Rotella and Mannucci 2013; American Diabetes
Association 2013a; Whiting 2013).
Prediabetes: IFG and IGT 19

Fact sheet Fact sheet

High morning Somogyi effect (Somogyi rebound)
blood sugar It is also recognized as “rebound
Somogyi hyperglycemia” and named after the
effect and physician Dr. Michael Somogyi who
Dawn speculated that hypoglycemia during
phenomenon the midnight (usually blood glucose
cause high >70 mg/dL in between 2 and 3 a.m.).
blood sugar This condition results in activation of
levels, counter regulatory hormone
especially in mechanism. The release of hormones
the early (i.e., cortisol, growth hormone, and
morning catecholamines) helps to overturn the
before low blood sugar level but may lead to
breakfast, in hyperglycemia (<200 mg/dL) in the
people who early morning. Generally, this
have DM situation is a result of poor diabetes
management
Dawn phenomenon
This condition is named after the
time of day when it takes place. It is a
regular phenomenon where blood
sugar increases during waking up. In
the early morning time, release of
several hormones like cortisol,
growth hormone, and catecholamines
increases induces the liver to release
a large quantity of sugar into the
bloodstream. In diabetic people
lacking enough circulating insulin to
maintain glucose level under normal
level, as a result there is a high level
of blood glucose in the morning
before breakfast
Postprandial It is a medical term used to describe
hypoglycemia the recurrent occurrence of
or symptomatic hypoglycemia within
reactive 4–5 h after a meal (generally
hypoglycemia high-carbohydrate meal) in an
individual who do not have DM. The
situation occurred as a consequence
of extreme insulin release triggered
by carbohydrate meal. This type of
hypoglycemia is usually divided into
two types: (1) early, with onset within
2 h, and (2) late, occurring between 2
and 5 h after a meal. The first can be
considered as a reflection of
abnormal rapid gastric emptying,
whereas the late type is frequently
believed to be a precursor to the onset
of T2DM
Prediabetes: IFG and IGT
Prediabetes is referred as a state in which the
blood glucose levels found are more than the
normal value, although not yet highly suffi-
cient to be diagnosed as T2DM. Prediabetes
condition also can be described as impaired
fasting glucose (IFG) or impaired glucose tol-
erance (IGT), depending on the test used to
diagnose it. IFG and IGT represent impaired

Table 2.2 Symptoms and risk factor of T1DM and T2DM

Feature Type 1 DM
Sign and symptoms Sudden and dramatic, abnormal thirst
and a dry mouth, frequent urination,
intense tiredness, hyperglycemia,
regular hunger, loss of weight,
slow-healing wounds, recurrent
infections, blurred vision
Risk factors Blood group incompatibility, maternal
viral infections during pregnancy, early
exposure to cow’s milk components
and other nutritional factors, lifestyle,
weight, growth, genetic
Type 2 DM
Polyuria, polydipsia, polyphagia,
hyperglycemia, glycosuria, frequent
infections, sexual dysfunction, dry/
itchy skin, fatigue
Race/ethnicity (i.e., Blacks, Hispanics,
Native Americans, and Asians),
obesity, unhealthy lifestyle, diet,
physical inactivity, insulin resistance,
family history, intrauterine
environment, history of GDM,
smoking, increased alcohol intake,
hypertension, abnormal lipid profile,
IFG/IGT, history of vascular diseases,
history of delivering very healthy
(overweight) infant, toxemia, stillbirth,
polycystic ovarian syndrome,
depression
20
Table 2.3 Indication to screen T2DM in asymptomatic
patient or in children
Asymptomatic Age ≥30 years
individuals (the Body mass index ≥23 kg/
individual fulfills the m2 (overweight) of any
criteria may screened for age
DM) Obesity (primarily central
obesity) [waist/hip ratio in
man, >0.90 and in women
>0.85]
Family history of DM
Sedentary lifestyle
[without physical activity
and intake of high-fat
diet]
Previous history of IGT,
IFG
History of GDM, recurrent
fetal loss, or delivery of
more healthy (≥3.5 kg)
baby
Hypertension and/or
dyslipidemia
Women with polycystic
ovarian syndrome
People without risk factors
by more than 45 years age
Children and adolescents Overweight (usually
>120 % of normal body
weight) and any of the
following factors
History of T2DM in
first- or second-degree
relative
Sign related to insulin
resistance like
hypertension,
dyslipidemia, acanthosis
nigricans, polycystic ovary
syndrome
Maternal history of
diabetes or GDM during
child’s gestation
glucose homeostasis; the condition described
as in between states of abnormal glucose regu-
lation exists between normal glucose homeo-
stasis and diabetes. IFG is defined as a fasting
plasma glucose (measured at least after 8 h of
fasting) which is lower than those needed to
detect DM but comparatively higher than nor-
mal reference range. While, IGT represents
plasma glucose level in between normal and
diabetes condition during OGTT (carried out
as per WHO guideline) (American Diabetes
2 Diabetes Mellitus: General Consideration
Association 2004, 2013a; Nathan et al. 2007;
World Health Organization 2006, 2013).
Screening and Diagnostic Criteria
In clinical observation, the diagnosis of diabetes
is generally prompted by several symptoms like
increased urine volume, thirst, recurrent infec-
tions, sudden loss of weight, and, in severe cases,
drowsiness and coma. In general blood/plasma
glucose analysis (fasting plasma glucose, random
plasma glucose, 2-h plasma glucose), oral glu-
cose tolerance test (OGTT), or estimation of
hemoglobin A1c (HbA1C) is used to detect
DM. Diagnostic criteria differ among different
organizations. Determination of blood glucose
level is still considered as a key marker for the
diagnosis of diabetes. Usually, the common and
widely used criteria to diagnose DM and predia-
betes were suggested by WHO and ADA. Plasma
glucose level is still a key criterion for the diag-
nosis of diabetes.
In undiagnosed diabetes, alone fasting
plasma glucose fails to identify nearly 30 %
cases; OGTT is then useful to find the disturbed
glucose tolerance in asymptomatic people. ADA
modified its 2003 recommendations and
included HbA1C for estimation of diabetes.
WHO also in their 2011 report suggested that
HbA1c can be utilized as a diagnostic test for
DM, but the test should follow the standard pro-
cedure and reference value. Estimation of A1C
is a predominant marker for assessment of dia-
betes, which also play a key role in monitoring
DM. Estimation of HbA1C is reflecting an aver-
age level of blood glucose over a period of 2–3
months. Table 2.3 includes the criteria/indica-
tion which can be used to screen T2DM in an
asymptomatic patient or in children, while
Table 2.4 includes the diagnostic criteria for
DM recommended by WHO and ADA
(American Diabetes Association 2013b, 2014;
World Health Organization 1999a, b, 2006;
Reinauer et al. 2002; Indian Council of Medical
Research 2005).
The people who have some problems like undue
tiredness, burning feet, pruritis, recurrent infection,
References 21

Table 2.4 Diagnostic criteria for DM and prediabetes

WHO Diabetes
recommendation Fasting plasma glucose: ≥126 mg/dL (7.0 mmol/L) or
(2006) 20-h plasma glucosea: ≥200 mg/dL (11.1 mmol/L)
Prediabetes
Impaired glucose tolerance (IGT):
Fasting plasma glucose: <126 mg/dL (7.0 mmol/L) and
2-h plasma glucosea : ≥140 and <200 mg/dL (≥7.8 and <11.1 mmol/L)
Impaired fasting glucose (IFG):
Fasting plasma glucose: 110–125 mg/dL (6.1–6.9 mmol/L), and (if measured) 2-h
plasma glucosea: <140 mg/dL (7.8 mmol/L)
WHO in 2011 addendum the diagnostic criteria for diabetes of 2006 and suggested
HbA1c of 6.5 % as the cut point for screening diabetes. HbA1c <6.5 % does not exclude
diabetes diagnosed using glucose tests
ADA recommendation Diabetes
(2014) HbA1C ≥ 6.5 % [the test method should be National Glycohemoglobin Standardization
Program certified and standardized to the DCCT assay]b
Or
Fasting plasma glucosec: ≥126 mg/dL (7.0 mmol/L)b
Or
2-h plasma glucose:d ≥200mg/dL (11.1 mmol/L) during an OGTT
Or
A random plasma glucose: ≥200 mg/dL (11.1 mmol/L) in those patients who have
typical symptoms of hyperglycemia or hyperglycemic crisis
Prediabetes
Impaired fasting glucose (IFG):
Fasting plasma glucose: 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L)
Or
Impaired glucose tolerance (IGT):
2-h plasma glucose in the 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0
mmol/L)
Or
HbA1C: 5.7–6.4 %
a
Venous plasma glucose 2 h after intake of 75 g glucose orally. If 2-h plasma glucose is not measured, status is uncertain
as diabetes or IGT cannot be excluded
b
In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing
c
Fasting is defined as no caloric intake for at least 8 h
d
Test should be performed as described by the WHO

tingling and numberless, delayed and nonhealing
wound, balanitis, impotency, and premature cata-
ract also should undergo DM screening as these
may occur as a result of undetected DM.
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tory of type 1 diabetes. Diabetes. 2005;54(Supply
2):S25–31.
American Diabetes Association. Gestational diabetes
mellitus. Diabetes Care. 2004;27(supply 1):S88–90.
American Diabetes Association. Diagnosis and classi-
fication of diabetes mellitus. Diabetes Care. 2013a;
36(supply 1):S67–74.
American Diabetes Association. Standards of medical
care in diabetes – 2013. Diabetes Care.
2013b;36(supply 1):S11–66.
American Diabetes Association. Standard medical care in
diabetes – 2014. Diabetes Care. 2014;37(supply
1):S14–79.
Anjana RM, Ali MK, Pradeepa R, et al. The need for
obtaining accurate nationwide estimates of diabetes
prevalence in India – Rationale for a national study on
diabetes. Indian J Med Res. 2011;133:369–80.
Atkinson MA. The pathogenesis and natural history of
type 1 diabetes. Cold Spring Harb Perspect Med.
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Davis SN. Insulin, oral hypoglycemic agents, and the
pharmacology of the endocrine pancreas. In: Brunton
LL, Lazo JS, Parker KL, editors. Goodman & Gilman’s
the pharmacological basis of therapeutics. 11th ed.
New York: McGraw-Hill; 2006.
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DeFronzo RA. Pathogenesis of type 2 diabetes mellitus.
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Homsi MFA, Lukic ML. An update on the pathogenesis of
diabetes mellitus. Inter J Diabetes Metab.
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Indian Council of Medical Research. Guideline for man-
agement of type 2 diabetes. New Delhi: Indian Council
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Kaku K. Pathophysiology of type 2 diabetes and its treat-
ment policy. Japan Med Assoc J. 2010;53:41–6.
Khardori R, Pauza ME. Type 1 diabetes mellitus: patho-
genesis and advances in therapy. Inter J f Diabetes Dev
Ctries. 2003;23:106–19.
Kitabchi AE. Physiology of endocrine pancreas and
pathophysiology of diabetes mellitus (DM). 2009.
Available from: http://www.2ndchance.info/diabetescat-
endocrinepancreas.pdf. Assessed on 23 Mar 2014.
Lin Y, Sun Z. Current views on type 2 diabetes.
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Loghmani E. Diabetes mellitus: type 1 and type 2. In:
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nutrition services. Minneapolis, MN, 2005. Available
from: http://www.epi.umn.edu/let/pubs/img/adol_
preface_materials.pdf.
Mohan H. Text book of pathology. 4th ed. New Delhi:
Jaypee Brothers Medical Publishers; 2003.
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2010;38(12):676–8.
Nathan DM, Davidson MB, DeFronzo RA, Heine RJ,
Pratley R, Zinman B. Impaired fasting glucose and
impaired glucose tolerance. Diabetes Care.
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genesis and pathophysiology of type 1 and type 2 dia-
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Informa Healthcare; 2007.
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 Impaired Glucose Tolerance
and Impaired Fasting Glycemia
Impaired glucose tolerance (IGT) and impaired
fasting glycemia (IFG) are recognized as an
intermediate group of people who have higher
blood glucose level than the recognized normal
value but not sufficiently high as described in
diabetes mellitus. In 1979, IGT was introduced
to change the word “borderline diabetes” and
other situations of increased level of blood
sugar that did not produce risk of a microvas-
cular complication. WHO in 1985 recognized
IGT as a clinical class of glucose intolerance
and subsequently categorized it as a state in the
natural history of disturbed carbohydrate
metabolism. The people with IFG and/or IGT
have a high chance toward diabetes state in the
future. Though IFG and IGT should not be
considered as clinical entities in their own,
they should be considered as risk factors for
DM and cardiovascular disease (CVD). This
prediabetes condition are usually connected
with obesity (though abdominal obesity or vis-
ceral obesity is mainly connected with this sit-
uation), hypertension, and dyslipidemia with
higher level of triglycerides and/or reduced
quantity of high-density lipoprotein (HDL)
cholesterol (Petersen and McGuire 2005;
Nathan et al. 2007; NHS Lanarkshire 2011;
American Diabetes Association 2013a, b).
© Springer Science+Business Media Singapore 2016
S. Sen et al., Diabetes Mellitus in 21st Century, DOI 10.1007/978-981-10-1542-7_3
3
“IGT” Versus “IFG”: Clinical
Characteristic
IGT and IFG generally refer to impaired glucose
regulation, though these terms are stated unequiv-
ocally, but IFG and IGT are not the same and
symbolize dissimilar abnormalities of regulation
of glucose, IFG in the fasting state and IGT in
postprandial. IFG is defined as a level of fasting
plasma glucose (after 8 h of fasting) which is
higher than the normal reference range but below
than those required to diagnose DM. As per ADA
2013 criteria, fasting plasma glucose levels
between 100 and 125 mg/dL are considered as
IFG, while the WHO considers IFG if the plasma
glucose level found is between 110 and 125 mg/
dL. IGT reflects a plasma glucose level higher
than the normal reference range but below than
those required to diagnose DM after 2 h of 75-g
oral glucose administration (during OGTT as per
WHO guideline). Plasma glucose value between
140 and 199 mg/dL after 2 h of glucose adminis-
tration during OGTT is considered as
IGT. Currently, ADA recognized HbA1C value to
determine the prediabetes condition. HbA1C
value in between 5.7 and 6.4 % is considered as
prediabetes (Reinauer et al. 1999; Rao et al.
2004; American Diabetes Association 2013b).
23
24 3 Impaired Glucose Tolerance and Impaired Fasting Glycemia
The metabolic determinants of plasma glu-
cose values during fasting and after 2 h of glu-
cose load in an oral glucose tolerance test are not
entirely similar. Therefore, the people catego-
rized under IGT may not have IFG or vice versa.
In general, capacity of the human body to main-
tain sufficient basal insulin secretion reflects the
fasting glucose level. The normal value of fasting
glucose level indicates appropriate insulin sensi-
tivity toward the tissue especially the hepatocytes
to control hepatic glucose output. While after
administration of glucose during an OGTT, the
body works effectively in response to carbohy-
drate absorption and suppresses hepatic glucose
output, glucose uptake in the liver and muscle
increases. An instant rise in insulin secretion and
sufficient sensitivity of the muscle and liver
toward the insulin are essential in this regard
(Schianca et al. 2003; Rao et al. 2004; Nathan
et al. 2007).
Several conflicting reports exist on the physi-
ological basis of IFG and IGT. Some researchers
suggested that increased hepatic glucose output
and an abnormality in early secretion of insulin
are the features of IFG, while insulin resistance
in the peripheral tissue most significantly at the
skeletal muscle (foremost depot for glucose
removal postprandially) is the important charac-
teristic of IGT. In short, the physiological basis of
IFG and IGT is considerably different. While
some have found that insulin resistance is more
prevalent in IFG than IGT, IGT is related mostly
with the deficiency of β cell which is responsible
for the elevated post-load glucose level. It was
also reported that disorders of insulin secretion
from the islet cell can be confirmed in IFG
patients than in normal individuals at both the
early and late phases of insulin secretion follow-
ing a glucose administration. Currently, the dif-
ference in pathophysiology between IFG and
IGT is not sufficient to differentiate individuals
with predominant dysfunction of β cell from the
persons with insulin resistance. In particular, it
could be suggested that both IFG and IGT exhibit
features of both impaired release of insulin and
insulin resistance, but in different levels. Current
understandings suggested that individuals classi-
fied under isolated IFG principally have insulin
resistance in hepatic tissue and normal insulin
sensitivity in muscle; however IGT in people
symbolizes normal to slightly reduced insulin
sensitivity in hepatic tissue and muscle insulin
resistance in moderate to severe level. Although
people with both IFG and IGT are manifesting
both muscle and hepatic insulin resistance, along
with the consequence of insulin resistance, the
way or pattern of insulin secretion also varies
between IFG and IGT. IFG in an individual
shows to be decreased in first-phase (0–10 min)
insulin secretion in response to intravenous glu-
cose challenge and decreased in early- or first-
phase (first 30 min) insulin response to glucose
administration through oral route. On the other
hand, the late or second phase (60–120 min) of
plasma insulin response is normal during the
OGTT in isolated IFG. Individual with isolated
IGT also has faulty insulin secretion in the first
phase due to oral glucose load along with a severe
shortfall of insulin secretion in late phase. In iso-
late IFG, excessive fasting hepatic glucose pro-
duction takes place due to the combination of
faulty release of insulin and hepatic insulin resis-
tance which accounts for fasting hyperglycemia.
In the first hour of OGTT, an extreme early rise of
plasma glucose takes place as a result of early
insulin response impairment and hepatic insulin
resistance. However in isolated IFG, the mainte-
nance of late insulin release along with normal
insulin sensitivity in muscle permits glucose lev-
els to come back in preload value. In comparison,
alteration in late insulin release along with insu-
lin resistance in hepatic tissue and muscle is
responsible for prolonged hyperglycemia after
glucose challenge in isolated IGT (Unwin et al.
2002; International Diabetes Federation 2006,
2009; American Diabetes Association 2013a, b).
IFG and IGT from early metabolic distur-
bance and then its progression to diabetes may
take a long time. A proper innervation and health
management can avert the progression of diabe-
tes from prediabetes. However, several reports
have predicted that many individuals suffering
from prediabetes eventually convert to diabetic
state, and several others revert to a normal state.
Individuals who are older, overweight, and suf-
fering from inadequate insulin secretion and
Innervations
resistances are more likely to develop diabetes.
People with both IFG and IGT possess nearly
double risk of developing DM compared with
people with just any one of them. In addition to
diabetes, the state of IGT also represents a
foremost public health crisis, both because of its
connection with incidence of diabetes and its
own involvement with an amplified risk of the
advancement of the cardiovascular disease.
Currently, IFG is acknowledged as being a state
in the transition from normal stage to diabetes,
and people with IGT are at high risk of progress-
ing to T2DM. Although such development is not
inevitable, and probably more than 30 % of indi-
viduals with IGT will return to normal glucose
tolerance over a period of several years. IFG and
IGT are not only considered as a risk factor of
T2DM but also associated with other metabolic
syndromes like increased blood pressure, abdom-
inal obesity, dyslipidemia, endothelial dysfunc-
tion, microalbuminuria, hypercoagulability, and
inflammation (Heldgaard et al. 2004; National
Diabetes Education Program 2009).
Innervations
The sixth edition of IDF Diabetes Atlas assumed
that the prevalence of IGT is 6.9 % and 316 mil-
lion people have IGT in 2013 (in people aged
between 20 and 79 years). It was predicted that
the number of individuals with IGT will cross
471 million by 2035. A major problem related to
IGT/IFG is the diagnosis. Individuals with
impaired glucose tolerance/impaired fasting gly-
cemia usually have no symptoms. Therefore, a
large number of people are still unaware of pre-
diabetes condition which increases the risk for
diabetes. Screening for IFG/IGT is characteristi-
cally not different from the diagnosis method for
diabetes, and similar risk factors connected with
diabetes are also associated with IFG/IGT. Early
detection and modification in lifestyle are the
most important approach to averting the progres-
sion of diabetes. The lifestyle modifications are
also useful and confer a benefit to the normal
individual (Unwin et al. 2002; Schianca et al.
2003; Heldgaard et al. 2004; Petersen and
25
McGuire 2005; National Diabetes Education
Program 2009; American Diabetes Association
2013b; International Diabetes Federation 2013).
Approaches to Manage Prediabetes
Physical Activity and Weight Loss Physical
activity in moderate intensity (nearly 30 min
daily) and modest loss of weight (5–10 % of body
weight) are considered as the basic treatment for
individuals with IFG/IGT.
Healthy Balanced Food Healthy balanced and
timely intake of food in correct proportions is
important during IFG/IGT. At least three meals
are essential to maintain the appetite and steady
blood glucose levels. Starchy carbohydrate foods
(like pasta, rice, bread, cereals, potatoes) with a
limit can be taken during a meal, though con-
sumption of high-fiber food is good for the health.
Consumption of sugar/sweet, more salt, and fried
and fatty foods should be restricted. Daily intake
of plenty of fruits and vegetable could be benefi-
cial. Oily fish which contains omega 3 may be
helpful to protect from cardiovascular disease.
Most commonly weight loss diets should con-
tain a minimum of 1,000–1,200 kcal/day for
women and 1,200–1,600 kcal/day for men. In
daily calories the proportion of the different com-
ponents of food could be like this: <25–30 % of
fat, <7–10% of saturated fat, 50–60 % of carbo-
hydrates, 15–20 % of protein, and >15 g/day fiber
intake for every 1,000 cal consumed.
Stop Smoking Smokers should stop smoking.
Behavior Therapy It includes (i) self-
monitoring through observing and recording the
different characteristics of daily life followed by
analysis, rectification, and stick self-management,
(ii) stimulus control and management of stress,
(iii) positive approach to solve the problem, (iv)
cognitive restructuring by changing the thinking
in a positive way, and (v) support of society and
26 3 Impaired Glucose Tolerance and Impaired Fasting Glycemia
people surrounding the individual. These things
eventually help the individual for a stress-free life
and to change diet and activity accordingly.
Follow-Up Monitoring of physical condition,
modified lifestyle, and diet is essential.
Drug Therapy Though in general drug therapy
is not essential for IFG/IGT state, metformin can
be given to the individual with IFG/IGT and any
one of the risk factors (like age more than 60
years, BMI ≥ 35 kg/m2, history of DM in first-
degree relatives, increased triglycerides level,
reduced level of HDL cholesterol, increased
blood pressure, HbA1C > 6.0 %) along with mod-
ification in lifestyle. Though acarbose and orlistat
are also effective in this condition but because of
their few limitations, they are not used widely.
Difference between prediabetes and diabetes
in terms of physical condition and diagnostic cri-
teria should be clear based on established guide-
lines so that proper treatment could be continued.
Physician and health professionals should take
special precaution and need to consider this situ-
ation seriously. They should avoid describing the
“IFG/IGT” condition as “borderline diabetes,”
“sugar is a little high,” or “a touch of diabetes”
with patients and their families. Otherwise, the
individual will take this condition seriously
which increase the risk of diabetes. IFG and IGT
continue to be helpful in identifying individuals
at enlarged risk to develop DM and CVD. These
parameters can help the researchers to investigate
the reason behind varying impaired glucose
metabolism in different communities, which can
help further in the discovery of new drugs. The
multi-faceted approach including awareness to
individual about the condition and treatment/
management of impaired metabolism of glucose
across the range of IGT, IFG, and T2DM has
increased acknowledgment as an imperative clin-
ical objective. As a consequence, regular moni-
toring of blood glucose level to identify the
people with IFG/IGT can be used on a population-
wide basis; moreover such approaches will be
useful to avert the clinical consequences of type 2
diabetes mellitus (Unwin et al. 2002; Schianca
et al. 2003; Petersen and McGuire 2005; National
Diabetes Education Program 2009; American
Diabetes Association 2013b).
References
American Diabetes Association. Diagnosis and classifica-
tion of diabetes mellitus. Diabetes Care.
2013a;36(supply 1):S67–74.
American Diabetes Association. Standards of medical
care in diabetes – 2013. Diabetes Care.
2013b;36(supply 1):S11–66.
Heldgaard PE, Olivarius NF, Hindsberger C, Henriksen
JE. Impaired fasting glycaemia resembles impaired
glucose tolerance with regard to cardiovascular risk
factors: population-based, cross-sectional study of risk
factors for cardiovascular disease. Diabet Med.
2004;21:363–70.
International Diabetes Federation. Diabetes atlas. 3rd ed.
Brussels: International Diabetes Federation; 2006.
International Diabetes Federation. Diabetes atlas. 4th ed.
Brussels: International Diabetes Federation; 2009.
International Diabetes Federation. IDF diabetes atlas. 6th
ed. Brussels: International Diabetes Federation; 2013.
Nathan DM, Davidson MB, DeFronzo RA, Heine RJ,
Pratley R, Zinman B. Impaired fasting glucose and
impaired glucose tolerance. Diabetes Care.
2007;30:753–9.
National Diabetes Education Program. Guiding principles
for diabetes care: for health care professionals. The
U.S. Department of Health and Human Services (NIH
Publication No. 09–4343, NDEP-16, Revised April
2009), 2009.
NHS Lanarkshire. Impaired Glucose Tolerance (IGT)
Impaired Fasting Glycaemia (IFG). NHS Lanarkshire
PIL.IMPTOL.77991.L, 2011.
Petersen JL, McGuire DK. Impaired glucose tolerance
and impaired fasting glucose ─ A review of diagnosis,
clinical implications and management. Diab Vasc Dis
Res. 2005;2:9–15.
Rao SS, Disraeli P, Mcgregor T. Impaired glucose toler-
ance and impaired fasting glucose. Am Fam Physician.
2004;69:1961–9.
Reinauer H, Home PD, Kanagasabapathy AS, Heuck
C. Laboratory diagnosis and monitoring of diabetes
mellitus. Geneva: World Health Organization; 1999.
p. 1–26.
Schianca GPC, Rossi A, Sainaghi PP, Maduli E, Bartoli
E. The significance of impaired fasting glucose versus
impaired glucose tolerance. Diabetes Care.
2003;26:1333–7.
Unwin N, Shaw J, Zimmet P, Alberti KGMM. Impaired
glucose tolerance and impaired fasting glycaemia: the
current status on definition and intervention. Diabet
Med. 2002;19:708–23.
 Prevalence of Diabetes and Its
Economic Impact
DM is considered as the most widespread chronic
disease of the world, and the figure of diabetic
population is mounting worldwide along with a
raise in population, aging, urbanization, and pol-
lution. Increase in the occurrence of obesity and
reduced physical activity are also responsible for
such situation. Computing the prevalence of peo-
ple affected by diabetes and its complications, at
the present and in the future, is essential to find
out the rational strategy and allocation of
resources. Estimates of the future burden of DM
and prevalence of death due to DM and its com-
plications are significant with the intention of
even distribution of community and health
resources. Emphasis on diabetes education, high-
light on the role of daily life, and promoting the
healthy process are essential to counteract the
trends for rising prevalence of diabetes.
Prevalence of Diabetes Mellitus
A WHO report estimated 135 million people
affected by diabetes in 1998 (King et al. 1998),
while, in 2004, another WHO report estimated
171 million people are affected by diabetes in all
age group, which was estimated to increase by
300 million by 2025 (Wild et al. 2004). Figure 4.1
represents the approximate number of diabetic
people in the different region of the world in
2000 and 2030 as per WHO. The report men-
tioned that the diabetes prevalence will increase
from 2.4 % in 2000 to 4.0 % in 2030 among all
© Springer Science+Business Media Singapore 2016
S. Sen et al., Diabetes Mellitus in 21st Century, DOI 10.1007/978-981-10-1542-7_4
4
age group. According to this report, between
2000 and 2030, the total population of the world
will rise by 37 %, but the figure of diabetic people
will amplify by 114 % (Wild et al. 2004).
According to a report by WHO on noncommuni-
cable diseases (NCDs), in 2008, the prevalence
of diabetes was assessed to be 10 % worldwide in
adults with more than 25 years of age (World
Health Organization 2011).
The International Diabetes Federation (IDF)
periodically estimates the diabetic prevalence
worldwide. According to the IDF Diabetes Atlas,
estimate of the number of diabetic people was
151 million in 2000, 194 million in 2003, 246
million in 2007, and 285 million in 2010. The
IDF Diabetes Atlas of 2009 estimated that the
number of diabetes will increase to 438 million
by 2030. The report also estimates that the preva-
lence of diabetes is about 6.4 % in 2010, which
will increase to 7.7 % by 2030 (in people of
20–79 year age group). According to this report,
between 2010 and 2030, the total population of
the world will rise by 20 %, the number of adult
population (20–79 years) will increase by 30 %,
but figure of diabetic people (20–79 years) will
increase by 54 %. Though the latest sixth edition
of IDF Diabetes Atlas (2013) revised the number
and showed that the problem is more serious. It is
estimated that in 2013, about 382 million people
are affected by DM, and it will reach a stunning
592 million by 2035 (age group, 20–79 years),
and the number of diabetic people will rise by
55 % by 2035. This implies about three new cases
27
28 4 Prevalence of Diabetes and Its Economic Impact

400 2000 2030

350

300

250
Millions

200

150

100

50

0
World Americas Europe South-East Western Eastern Africa
Asia Pacific Mediterra
-nean

Fig. 4.1 Estimated number of diabetic people in different regions of the world in 2000 and 2030 as per WHO

Table 4.1 Prevalence of diabetes mellitus according to

several reports published by IDF and WHO diseases. Table 4.1 compiles data of diabetes
Current Estimated prevalence according to several reports published
Report prevalence prevalence by IDF and WHO (International Diabetes
IDF Diabetes 151 million in – Federation 2000, 2003, 2006, 2009, 2013).
Atlas (2000) 2000 (4.6 %)a
About 80 % of diabetic patients live in low-
IDF Diabetes 194 million in 333 million by
income and middle-income countries. A vast
Atlas (2003) 2003 (5.1 %)a 2025 (6.3 %)a
IDF Diabetes 246 million in 380 million by
diversity in the prevalence of diabetes exists in
Atlas (2006) 2007 (6.0 %)a 2025 (7.3 %)a different countries of the world, with the world’s
IDF Diabetes 285 million in 438 million by highest found in the Tokelau (37.5 % of the adult
Atlas (2009) 2010 (6.4 %)a 2030 (7.7 %)a population), followed by Federated States of
IDF Diabetes 382 million in 592 million by Micronesia (35 %), Marshall Islands (34.9 %),
Atlas (2013) 2013 (8.3 %)a 2035 (10.1 %)a Kiribati (28.8 %), and Cook Islands (25.7 %)
King et al. 135 million in 300 million by (Fig. 4.2) (International Diabetes Federation
(1998) [A WHO 1995 (4.0 %)b 2025 (5.4 %)b
report] 2009).
Wild et al. 171 million in 366 million by Developing countries are facing a severe
(2004) [A WHO 2000 (2.8 %) 2030 (4.0 %) threat due to diabetes as the number of diabetic
report] people will increase by 150 % in the next 25
a
The estimation in the people of 20–79 year age group years. In African regions, the number of diabetic
b
The estimation in the people more than 20 years people will increase by 109 % in the next 22
years. In the Middle East and North American
region, the figure will be 96 %. However, in
in every 10 s or roughly ten million cases of dia- Europe only 22 % increase will be observed in
betes per year. The prevalence of T2DM is this period (Fig. 4.3).
increasing tremendously, and people aged India, China, and the USA are the topmost
between 40 and 59 are more affected by the countries in numbers of people with diabetes.
Prevalence of Diabetes Mellitus 29

40
2013 2035
35

30
Prevalance of DM (%)

25

20

15

10

0
u of ds ati ds tu ia ur
u it ar
ke
la
es lan rib an a ab wa at
To at I s Ki Isl nu Ar Na Ku Q
t
S sia ll ok Va ud
i
d ha Co
a te one a rs Sa
r r M
de Mic
Fe

Fig. 4.2 Top ten countries in comparative prevalence of diabetes (20–79 years group) in 2010 and 2030

56.3 Million
Increase by 22 %
by 2035 Europe

138.2
North America Million
& Caribbean Increase by
Middle East &
North America 46 % by
36.7 2035
Million
34.6 Million
Increase by Western
Increase by
37 % by 2035 Pacific
96 % by South East
2035 Asia

South & Central Africa

72.1 Million
24.1 America
Million 98.8 Million Increase by
71 % by
Increase by
Increase by 2035
60 % by
109 % by
2035
2035
Zones are divived as per IDF Atlas 2013
Mentioned Only estimated figure of diabetic people in 2013

Fig. 4.3 Global projection of the diabetic people (20–79 years) in different IDF region

It was estimated that in the year 2013, about 65.1 Figure 4.4 shows the top ten countries with the
million people was affected by diabetes in India, most number of diabetic people.
which will cross 109.0 million by 2035. In China Several studies related to the prevalence of
and the USA, the figure was 98.4 million and diabetes in India have been reported. The reports
24.4 million in 2003, respectively, but likely to clearly indicate that the prevalence of diabetes in
cross 142.7 million and 29.7 million by 2030 India is also rising. The population-based surveys
(International Diabetes Federation 2009). completed in the early 1970s in several states of
30 4 Prevalence of Diabetes and Its Economic Impact

150 142.7

130
87.0
110 98.4
Person in million

90
65.1
70

50
36.0
24.4
30 12.8
19.2 15.7
10.9 11.9 12.0 11.8 13.1
7.6 7.6 7.2 7.0 8.7 11.2
10

Turkey
USA

USA
India

India
Brazil

Brazil
Japan
Egypt

Egypt
China

China
Russia

Maxico

Mexico
Pakistan

Russian
Germany

Indonesia

Indonesia
–10

2013 2035

Fig. 4.4 Top ten estimated diabetic-affected countries in a number of people in 2010 and 2030

India reported the prevalence of diabetes ranging But recent statistics suggested that prevalence of
from 1.0 to 3.0 %. But every study had shown that T2DM in children is rising. Ethnicity, insulin
the prevalence of diabetes is more in urban parts resistance, obesity, diet, physical inactivity, fam-
of India than the rural areas. The current surveys ily history, and intrauterine environment are con-
reported that the prevalence of diabetes in urban sidered as major risk factor for T2DM in children.
areas ranges from 3.7 to 20.1 %, whereas in rural Variation in the incidence of DM between genders
areas it was found to be 1.7–13.2 %. A recent is not significant presently as DM. The reports
multicenter survey reported that in urban areas, suggested that 184 million women were affected
the prevalence of diabetes ranges 10.9–14.2 %, by DM in 2013, whereas the count was 198 mil-
but in rural areas it was 3.0–7.8 % only (Anjana lion for men. However, it was expected that the
et al. 2011; Sandeep et al. 2010). variation will rise to 15 million by 2035 (303 mil-
Though the T2DM constitutes the majority of lion men compared to 288 million women).
diabetes, T1DM is rapidly increasing primarily in Effects of fast food, physical inactivity, and stress
children and adolescents in various parts of the are also the contributing factor of DM. Currently,
world, and evidence also suggests that the number 246 million diabetic people live in urban areas,
of T2DM in children is increasing with the while in rural areas the number is 136 million. In
increase of obesity. The incidence of T1DM in low- and middle-earnings countries, 181 million
childhood (mainly the children under 15-year age people in urban areas are affected by DM, whereas
group) is growing in several countries. Though 122 million DM-affected people live in rural
there is evidence of regional and geographic dis- areas. By 2035, the variation is expected to extend
similarities in trends, the annual increase is as the count will be 347 million in urban region
approximately 3 % when taken as a whole. and 145 million in rural region. It was also esti-
Currently, it is estimated that annually some mated that a large number of people nearly 175
79,000 children (under 15 years of age) are million (46 %) are still unaware about the diabetic
affected by T1DM worldwide. Of the estimated state. Generally, people with T2DM can remain
497,000 children living with T1DM, 26 % are undiagnosed for several years and thus increases
from the Europe Region. It was figured out that the possibility of long-term damage being caused
0.2 % of the whole global diabetic population of by the disease (International Diabetes Federation
118 million was less than 15 years of age in 1990. 2009, 2013).
Morbidity and Mortality
Prevalence of Impaired Glucose
Tolerance
People with IGT or IFG are at significant risk
factor for diabetes. In addition to DM, the state
of IGT also represents a key health problem of
people. IGT is associated with the increased risk
of advancement of the cardiovascular disease
(CVD) and also with the diabetes occurrence. IFG
is now accepted as being a stage in the shift from
nondiabetic stage to diabetes; the people with
IGT are considered under the high-risk group
toward the advancement of T2DM. Although
these development is not inevitable, and probably
more than 30 % of people with IGT will come
back to nondiabetic (normal glucose tolerance)
stage after a time of some years (International
Diabetes Federation 2006, 2009; Rao et al. 2004;
Schianca et al. 2003).
IDF Diabetes Atlas (2003) estimated that the
number of people with IGT is 314 million
(8.2 %), but in 2010 IDF revised the number as
344 million (7.8 %). However, the current IDF
Diabetes Atlas (2013) estimated that the number
of people with IGT is 316 million (6.9 %) in 2013
and projected it to increase by 471 million (8.0 %)
by 2035. The highest prevalent IGT country is
Kuwait; the prevalence of IGT in Nauru is 17.9 %,
followed by Qatar (17.1 %) and UAE (116.6 %)
in 2013. While in 2035 it is expected that Poland
will lead as the more IGT prevalent country
(19.3 %) followed by Kuwait (18.1 %) and Qatar
(17.4 %) and UAE (116.6 %).
DM and Pregnancy
About 21.4 million incidences of high blood glu-
cose in pregnancy was estimated which was
equivalent to 16.8 % of live births in 2013 (in age
group 20–49 years). Nearly 16 % of those
incidences were due to DM in pregnancy and
would need cautious supervision during and after
the pregnancy. In the Southeast Asian region, the
condition is more serious with the highest preva-
lence at 25.0 % compared to the North American
and Caribbean regions with 10.4 % prevalence. In
31
low- and middle-income nations, the problem is
epidemic and affecting almost all pregnancy
(91.6 %), where availability and accessibility of
maternal care is limited. The risk of hyperglyce-
mia in pregnancy rises hastily with age, and the
incidence of maternal diabetes is almost 47.7 %
in women with more than 45 years of age
(International Diabetes Federation 2013).
Morbidity and Mortality
DM is one of the foremost reasons of premature
illness and death in most of the parts of the world.
CVD results in the death of 50 % or more number
of individuals living with DM depending on the
population. Diabetes complications are mainly
responsible for the death of people with diabetes.
Assessing and documenting the mortality burden
has been difficult. It is believed that though mor-
tality due to diabetes is higher, it was underesti-
mated as straight connection between death and
diabetes is lacking. Over a third of the countries
around the world lack any proper statistics on
diabetes-related mortality; moreover statistics of
morbidity are frequently based on hospital reports
which bear a possibility of bias in the manner that
only diabetic patient with moderate to severe
complications will come to the hospital, and
probably a larger section of diabetic people with
minor morbidity will miss out (International
Diabetes Federation 2006, 2009).
WHO estimated that during 2008, a sum of 57
million deaths occurred globally; 36 million
(63 %) deaths were related to NCDs, mainly
CVD, DM, chronic respiratory illness, and cancer.
The majority of these deaths (nearly 80 %) are
observed in low- and middle-income nations. A
report on NCDs also projected global 15 %
increase in death due to NCDs between 2010 and
2020 (to 44 million deaths). This report also sug-
gested that the diabetes is responsible for 4 % of
death due to NCDs (World Health Organization
2011). Though the figure may not represent the
actual situation as a large number of death caused
cardiovascular diseases, other diseases are actu-
ally related to diabetes complications.
32
Recent statistics suggest that nearly 5.1 mil-
lion people (20–79 years) died worldwide due to
diabetes-related causes in the year 2013, which is
about 8.4 % of all-cause mortality in the world in
people 20–79 years of age. Approximately 48 %
of deaths due to diabetes are reported in individu-
als (<60 years). Maximum figure of deaths
related to diabetes and its complications is
expected to take place in nations with large popu-
lations as higher number of diabetic people lives
in these nations like India, China, the USA, and
the Russian Federation. A higher number of
female than male are estimated to die due to
diabetes-associated causes, reaching up to a quar-
ter of all deaths in middle-aged women in some
regions. IDF current statistics suggests that about
11 % increase in figure of deaths are attributable
to DM in 2013 from the number of the death esti-
mates for the year 2011 (International Diabetes
Federation 2013). It was estimated that in 2013,
one person dies every 6 s due to DM. Figure 4.5
represents the data regarding diabetes mortality
in the different regions of the world according to
IDF in 2010.
2000 WP - Western Pacific
SEA - South East Asia
1800 SCA - South and Central America
NAC - North America and Caribbean
MENA - Middle East & North Africa
1600
1400
Population in thousand
1200
1000
800
600
400
200
0
Africa Europe
Fig 4.5 Mortality caused by DM in different regions of the world
4 Prevalence of Diabetes and Its Economic Impact
Economic Impact of DM
Diabetes inflicts a huge economic burden on each
individual, family, society, and healthcare system
of a nation and is considered as one of the costli-
est healthcare problem. Costs toward DM are cal-
culated as both direct and indirect expenditure.
Direct costs account medical costs for long-term
care of diabetes and its complications, and indi-
rect costs include coping mechanisms, productiv-
ity loss, and costs of the value of life, which
influences individual persons, family, and nations
and is infinite (Siegel and Narayan 2008).
Healthcare expenditures on diabetes and its
complication are increasing in a high rate. It was
estimated that about 11.6% of total global
expenditure spent for the management of diabe-
tes and its complication in 2010. About 80 % of
the 216 countries mentioned by the IDF Diabetes
Atlas (2009) spend 5–13 % of their total health-
care expenditure on DM. It was estimated that
global expenditures toward healthcare to treat
and/or avert DM and its complications are about
ID 418 billion (USD 376 billion) in 2010, and
Total number of death
Total number of male death
Total number of female death
MENA NAC SCA SEA WP
Economic Impact of DM
by 2030, it is projected to exceed ID 561 (USD
490) billion. The average estimated expenditure
on diabetes is ID 878 (USD 703) per person in
2010 globally (International Diabetes Federation
2009).
The sixth edition of IDF Diabetes Atlas pre-
dicted that nearly 548 billion will be spent to treat
diabetes and manage complications in 2013
(11 % of the total spent worldwide), which was
expected to reach USD 627 billion by 2035. It
was estimated that USD 1,437 per diabetic per-
son (in average) was spent globally due to the
consequence of DM (International Diabetes
Federation 2013).
Allocations of resources are not evenly dis-
tributed for the diabetes care across different
areas (countries/states), age, and gender groups.
As the prevalence of diabetes increases with the
age, global statistics showed that more than
three-quarters of overall expenditure will be
spent for relatively old-aged individuals (50
and 80 years); in 2010, high proportion of funds
is required for women compared to men for dia-
betes care. The expenditure on diabetes is also
evenly distributed across the different countries
and the regions. The world’s economically rich
countries spent huge proportion (>80 %) of
total estimated global expenditures on DM,
whereas more number of diabetic people (about
70 %) lives in low- and middle-income nations
but spent very less proportion. It was projected
that the USA spent USD 198 billion (52.7 % of
global expenditure) in 2010, while India with
the largest proportion of diabetic people spent
only USD 2.8 billion (less than 1 % of the
global total). According to WHO, net losses in
national income in China from DM and CVD is
557.7 billion, while it was ID 303.2 billion in
Russian Federation, ID 236.6 billion in India,
and ID 49.2 billion in Brazil, between 2005 and
2015. While in the American Diabetes
Association, it was estimated that in 2007, the
US economy lost USD 58 billion, which was
equivalent to about half of the diabetes-related
direct healthcare expenditure. It was also esti-
mated that healthcare costs of diabetes-related
illness ranges from 2.5 to 15.0 % of a country’s
annual healthcare budget, but in high preva-
33
lence countries, this may increases up to 40.0 %
also (International Diabetes Federation 2006,
2009).
The economic burden borne by Indian indi-
vidual and their families due to DM and its com-
plications is related to the economic status of the
individual/family and the area they live. A recent
survey conducted in urban and rural areas of
India had shown that overall median spent on
healthcare was INR. 10,000 (USD 227) in urban
(annual family income USD 2,273) and INR.
6,260 (USD 142) in rural (family income USD
818) people. The survey also calculated that
lower-income groups spent a higher percentage
of their earnings on diabetes care (urban poor
34 % and rural poor 27 %). The secular raise
(113 %) in expenses was reported in the total
expenses by the urban people between 1998 and
2005. Another study in India found that total
mean expenditure by the individual with diabe-
tes was about INR. 20,000 annually. The same
report also estimated that the average direct cost
per year toward the outpatient care for all dia-
betic people was INR 4724, though the patient
without any complications had an 18 % lesser
cost, while the people with three or more dia-
betic complications had a 48 % higher cost. The
mean indirect cost was calculated to be INR
12,756; among this loss of productivity
accounted for INR 9166, and loss related to per-
sonal and family income loss was about INR
1811 and INR. 1779, respectively. Complications,
hospitalizations, surgery, insulin therapy, and
duration of diabetes are also contributed toward
the increase in the annual expenditure (Kapur
2007; Ramachandran et al. 2007).
The principal financial burden, therefore, is
the monetary assessment connected with the dis-
ability and sometimes loss of life as consequences
of the disease and its linked complications. This
financial burden, however, can be abridged by
maintaining a healthy lifestyle, early detection of
diabetes, regular health checkup, and executing a
number of inexpensive, comprehensible inter-
ventions; most of them are associated with eco-
nomic traditional approaches, even in the poorest
nations. However, these interventions are not
used widely worldwide.
34 4 Prevalence of Diabetes and Its Economic Impact

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 Pregnancy and Diabetes
Diabetes mellitus is a disorder related to altered
carbohydrate metabolism which warrants
proper modification of lifestyle and medica-
tions if necessary. In its chronic forms, DM is
responsible for short- and long-term complica-
tions and also contraindicated in pregnancy.
Diabetes is the usual medical situation compli-
cating pregnancy, which results in several
complications to the baby and mother.
Pregnancy is associated with decreased sensi-
tivity or insufficient secretion of insulin in nor-
mal pregnant women condition also. Thus,
diabetes in pregnancy can possess severe prob-
lem if not managed properly. Based on the cur-
rent literature and reports, maternal diabetes
can be classified in three major groups:
1. Gestational diabetes mellitus
2. Diabetes mellitus in pregnancy (T1DM or
T2DM occurring first during pregnancy)
3. Pregestational diabetes mellitus (preexisting
T1DM or T2DM)
It is estimated that DM is a frequent problem
in 6–7 % of pregnancy and GDM is the most
common form, accounting for almost 90 % of
diabetic pregnancies (Murthy et al. 2002; Murphy
2010; World Health Organization 2013; American
College of Obstetricians and Gynecologists
2013).
© Springer Science+Business Media Singapore 2016
S. Sen et al., Diabetes Mellitus in 21st Century, DOI 10.1007/978-981-10-1542-7_5
5
Gestational Diabetes Mellitus
Gestational diabetes mellitus (GDM) is a frequent
metabolic disorder in pregnant women and can be
described as any situation of glucose intolerance
with beginning or first detected in pregnancy time.
Based on the current understanding and analysis
of large pool of data on DM in pregnancy, Based
on the current understanding and analysis of large
pool of data on DM in pregnancy, WHO suggested
that, GDM should include pregnant women with
diabetes and women with intermediate hypergly-
caemia (IGT/IFG) (World Health Organization
2013). Though, ADA and Canadian Diabetes
Associations don’t have any guideline to screen
GDM and diabetes in pregnancy separately. GDM
is a common metabolic disorder affecting large
pool of pregnant women. But nearly all women
(≥90 %) with GDM come back to normal glucose
level after delivery. However, women with GDM
are at risk for future GDM, abnormal glucose tol-
erance, and obvious diabetes. At the same time,
GDM is also responsible for significant harms,
which includes maternal and perinatal compli-
cations and metabolic disorders in offspring of
women with GDM. Long-time consequences of
DM during pregnancy include amplified adiposity
and body weight at birth that is high for gesta-
tional age. The extent of adverse outcome of GDM
related to the mother and fetus is often linked with
35
36
obesity, as the majority of the adverse effect can
be seen in obese pregnant women with GDM
compared to those who have GDM but are non-
obese (Sathyapalan et al. 2010; Sugiyama 2011;
Simmons 2011).
Risk Factors
Obesity, ethnicity, genetic factor, and unhealthy
lifestyle including lack of physical exercise are
the major contributing factor for GDM. Although
large percent of women have no known risk fac-
tors, some of the specific risk factors for GDM
include (First Nations Centre Des Premieres
Nations 2009; Murphy 2010; Sweeting et al.
2013):
• Increased body mass index (>30 kg/m2)
• History of large or obese for gestational age
(LGA) infant > 4.5 kg
• History of GDM in a previous pregnancy
• Family history of diabetes particularly in first-
degree relative
• Ethnicity (who have high risk of T2DM) like
South Asian (mainly Indian, Bangladeshi, and
Pakistani), Middle Eastern, and Black
Caribbean
• Polyhydramnios (high level of amniotic fluid
in the womb)
• Iatrogenic: glucocorticoids and antipsychotic
medication
• Past history of polycystic ovary syndrome and
acanthosis nigricans
• Previous unexplained stillbirth
Pathophysiology
During pregnancy, a series of metabolic altera-
tion occurs in mother. Secretion from adipose tis-
sue takes place in early phase of gestation; while
insulin resistance and facilitated lipolysis was
observed in late phase. During the first few
months of gestation period, insulin secretion
enhances, while sensitivity of insulin may remain
unchanged or altered (increase/decrease).
However, during the late phase of pregnancy, adi-
5 Pregnancy and Diabetes
pose tissue depots reduce in mother, postprandial
free fatty acid (FFA) level rises, and glucose dis-
posal induced by insulin deteriorates by 40–60 %
in contrast with prepregnancy time. Insulin resis-
tance and hyperinsulinemia are the common
problem during pregnancy. During pregnancy,
the release of placental diabetogenic hormones,
including cortisol, growth hormone, human pla-
cental lactogen (hPL), and progesterone,
increases. As pregnancy progresses, several hor-
mones like cortisol, human chorionic somato-
mammotropin (hCS), prolactin, progesterone,
and estrogen level increase which cause insulin
resistance in peripheral tissues. Secretions of pro-
lactin and estradiol became instant at 10th and
26th week of gestation, respectively, but have
weak to very weak diabetogenic potency. The
level of hCS (moderate diabetogenic potency)
and cortisol (very strong diabetogenic potency)
reaches the peak at 26th week, while at 32nd
week, the peak elevation of progesterone (strong
diabetogenic potency) was observed. Human pla-
cental lactogen during pregnancy period also
increases up to 30-fold that is responsible for the
release of insulin. Some studies have shown that
hPL can induce peripheral insulin resistance,
even though the consequences have been incon-
sistent. Increase in maternal adipose deposition,
reduced exercise, and rise in caloric consumption
are the common consequence of pregnancy.
These physiological metabolic alterations are
essential for sufficient supply of energy and
nutrients to the fetus, but responsible for a “dia-
betogenic” environment. Human placental lacto-
gen is responsible for the breakdown of
triglycerides which contributes to the maternal
energy while sparing nutrition from carbohydrate
for the fetus. These changes in the hormonal
milieu induce insulin resistance state as such hor-
mones are antagonizing insulin action and also
create glucose intolerance. In the late phase of
pregnancy, capability of insulin to restrain lipoly-
sis in the whole body is also decreased, which is
more common in women with GDM. This situa-
tion causes a few-fold increase in postprandial
FFAs, increased production of hepatic glucose,
and severe insulin resistance. Insulin-induced
glucose uptake into the skeletal muscle is reduced
Gestational Diabetes Mellitus
in pregnancy. C-peptide response to intravenous
glucagon is also considerably decreased in preg-
nant women with IGT, while concentration of
proinsulin in serum is increased. GDM happens
when maternal β cell of the pancreas is insuffi-
cient to compensate increased demand of insulin
or due to increased insulin resistance during
pregnancy. In general, during the pregnancy
period, insulin resistance progressively enhanced
and is most prominent late in the third trimester.
The pre-obese women are more susceptible to
develop diabetes during pregnancy as such
women have elevated plasma triglycerides and
nonesterified fatty acid level and reduced plasma
adiponectin levels. Obesity is a most vital risk
factor of GDM, as maternal body mass index is
directly proportional to GDM (Carr and Gabbe
1998; Barbour et al. 2007; Sathyapalan et al.
2010; Marcinkevage and Narayan 2011; Sweeting
et al. 2013).
The role of human placenta is found complex
in diabetic pregnant women. Human placenta
expresses several adipokines like tumor necrosis
factor-α (TNF-α), resistin, and leptin. Current
researches found that these cytokinins exhibit
key role in the controlling of insulin action and
DM. These cytokinins also link inflammation to
metabolic alteration by increasing insulin resis-
tance to the mother. Depending on the nature and
extent, the placenta undergoes an assortment of
functional and structural changes in diabetic con-
dition. GDM also can lead to short-term modifi-
cations in several molecules for essential
functions including expression of gene (Desoye
and Mouzon 2007).
Screening and Diagnosis
Screening of GDM is usually performed at 24–28
weeks of gestation. In early stage of pregnancy,
screening should be carried out for undiagnosed
T2DM. Women with prior history of GDM or
with obesity should also be diagnosed in early
stage to confirm whether previous GDM/obesity
changed to T2DM (American College of
Obstetricians and Gynecologists 2013; Thompson
et al. 2013).
37
Screening of GDM is a high task, especially
in rural areas. It also suggested that other than
the monitoring of blood glucose level, suscepti-
ble women also should undergo regular physical
and biochemical screening which is essential for
early detection and management of GDM. Some
of these examinations includes (1) regular moni-
toring of blood pressure, heart rate, and weight;
(2) measurement of height of the uterine fundus
possibly once per week; (3) pelvic examination
to find the risk of premature birth; (4) general
blood examinations such as blood sugar, HbA1c,
glycoalbumin, and lipid profile; (5) specific anti-
body like anti-GAD antibody, anti-insulin anti-
body, and islet cell antibody testing (early in the
pregnancy); (6) urine analysis which includes
uric acid, protein, glucose, ketone bodies, pro-
tein, albumin, urinary N-acetylglucosaminidase
(NAG), urinary β2MG, creatinine, and urinary
C-peptide; (8) fetal ultrasound which includes
examination of fetal development, assessment
of fetal congenital malformations, estimation of
amount of amniotic fluid, and evaluation of fetal
well-being; and (9) screening of ocular fundus
(Sugiyama 2011) (Table 5.1).
Complications of GDM
DM is a serious condition with potentially devas-
tating complications that affects type of people.
GDM is responsible for complication in the
mother and baby which may include both short-
and long-term complications (Sugiyama 2011;
Sweeting et al. 2013; First Nations Centre Des
Premieres Nations 2009; Sathyapalan et al. 2010)
(Table 5.2, Fig. 5.1).
Management
Non-pharmacological methods like diet
and exercise are the key part of managing
GDM. These types of approaches in women
with GDM are useful to achieve normal blood
glucose level, avert ketosis, and cause suffi-
cient weight gain and useful to fetal well-being.
Though weight loss is not recommended dur-
38 5 Pregnancy and Diabetes

Table 5.1 Proposed criteria for GDM by different agencies

Fasting plasma 1-h plasma 2-h plasma 3-h plasma
Organization Glucose challenge glucose glucose glucose glucose
WHO 2013 75 g OGTTa 5.1–6.9 ≥10.0 mmol/L 8.5–11.0 –
mmol/L (180 mg/dL) mmol/L
(92–125 g/ (153–199 mg/
dL) dL)
Canadian Approach no 1:
Diabetes 50 g GTT and check the plasma glucose level after 1 h [plasma glucose level < 7.8 mmol/L,
Association normal; plasma glucose level 7.8 to 11.0 mmol/L, perform 75 g OGTT; plasma glucose
2013 level ≥ 11.1 mmol/L, GDM]
[Approach 1 is 75 g OGTTa ≥5.3 mmol/L ≥10.6 mmol/L ≥9.0 mmol/L –
more preferred
Approach no 2:
than Approach 2]
75 g OGTTa ≥5.1 mmol/L ≥10. mmol/L ≥8.5 mmol/L
ADA 2014 Step 1:
[Two-step 50-g GLT (non-fasting) in women at 24–28 weeks of pregnancy period but not previously
(NIH identified with overt diabetes: if 1-h plasma glucose level after the load is ≥140 mg/dLa (≥7.8
consensus)] mmol/L), proceed to step 2.
[1-h 50-g Step 2:
glucose load 100 g OGTT (Carpenter/ 95 mg/dL 180 mg/dL 155 mg/dL 140 mg/dL
test (GLT) Coustan)a (5.3 mmol/L) (10.0 mmol/L) (8.6 mmol/L) (7.8 mmol/L)
followed by a
100 g OGTT (NDDG)a 105 mg/dL 190 mg/dL 165 mg/dL 145 mg/dL
3-h 100-g
(5.8 mmol/L) (10.6 mmol/L) (9.2 mmol/L) (8.0 mmol/L)
OGTT]
a
One or more values required for diagnosis
GDM screening is suggested at 24-48 weeks in women who were not previously diagnosed with overt diabetes

ing pregnancy, it is always recommended that
pregnant women should manage excessive
weight gain. Maximum women with GDM
will respond to exercise and diet; in such case,
medicine is not required. Strategy involved
in the GDM includes (National Collaborating
Centre for Women’s and Children’s Health
2008; International Diabetes Federation 2009;
Refuerzo 2011; Simmons 2011; Sweeting et al.
2013; American College of Obstetricians and
Gynecologists 2013):
Monitoring of Blood Glucose Levels
Examining the level of blood glucose is useful
to detect the presence of GDM and to moni-
tor or achieve the treatment targets. In general
women with GDM should restrict their fasting
blood glucose below 3.5 mmol/L, 1-h postpran-
dial blood glucose below 7.8 mmol/L, and 2-h
postprandial blood glucose below 6.7 mmol/L
during pregnancy. In the second and third tri-
mesters of pregnancy, HbA1c level may not be
utilized regularly for assessing the level of gly-
cemic control. Examining capillary blood glu-
cose during labor and birth on an hourly basis
is essential in women with DM (any type) and
required to maintain blood glucose level in
between 4 and 7 mmol/L.
Diet Dietary intervention is considered as one of
the key points of treatment of GDM. In general
women with GDM should take 2000–2500 kcal/
day which includes 150–180 g of total carbohy-
drate per day with an even distribution (3–4
times) of preferably complex carbohydrates/
lower glycemic index food. But if risk exists for
small for gestational age infants, then caloric or
carbohydrate restriction should be avoided. If the
diet is composed of more than 50 % of carbohy-
drates, then the risk of obesity and postprandial
hyperglycemia will increase.
Exercise Exercise is the mainstay of treatment
for women with GDM, which improves insulin
Gestational Diabetes Mellitus
Table 5.2 Some common complications of GDM
Type of complications
Diabetes complications (maternal
complications)
Obstetric complications (maternal
complications)
Perinatal complications (fetal complications)
Offspring’s complications (fetal
complications)
sensitivity and decreases the risk of gestational
weight gain. Moderate-intensity exercise (like
20–30-min walk or 10–15-min walk after a meal)
in a regular basis is beneficial to maintain the glu-
cose level.
Drug Treatment In general hypoglycemic
treatment should be considered in case where
exercise and diet did not succeed to preserve the
normal target of blood glucose during a period
of 1–2 weeks. If ultrasound examination recom-
mends incipient fetal macrosomia, then hypo-
glycemic treatment is required. Metformin, an
oral hypoglycemic drug, is usually prescribed in
women with GDM, but the strategy remains
controversial as it may have long-term effects
39
Name of specific problem
Diabetic ketoacidosis
Worsening of diabetic nephropathy
Deterioration of diabetic retinopathy
Hypoglycemia (when using insulin)
Spontaneous abortion
Pregnancy-induced hypertension
Premature birth
Shoulder dystocia
Hydramnios
Caesarean section delivery
GDM recurrence in subsequent pregnancies
Increased risk of developing type 2 diabetes
Bradytocia due to macrosomia
Induction of childbirth
Fetal distress/fetal death
Macrosomia
Congenital malformations
Birth injury due to shoulder dystocia
Bone fracture
Nerve palsy
Delayed fetal development
Neonatal hypocalcemia
Neonatal hyperinsulinemia
Neonatal hypoglycemia
Neonatal hyperbilirubinemia
Neonatal polycythemia
Newborn respiratory distress syndrome
Hypertrophic cardiomyopathy
Delayed intrauterine fetal development
Obesity/diabetes
Impaired fine and gross motor functions
Increased incidence of inattention and/or hyperactivity
due to placental transfer of metformin to the
fetus. It is considered as category B drug in
pregnancy and may cause neonatal hypoglyce-
mia. The treatment with oral sulfonylureas (gly-
buride, glibenclamide) is attractive in pregnancy,
and the use of glyburide is popular in women
with GDM due to its patient compliance, satis-
faction, and overall maternal and neonatal out-
come. Glyburide is relatively safe and the
overall incidence of hypoglycemia from the
drugs is only 1–5 %. Insulin secretagogues of
the meglitinide class and α-glucosidase inhibi-
tors (acarbose) may confer theoretical benefit in
controlling postprandial glucose levels but have
not been subject to either historical usage or
prospective studies. Insulin sensitizers of the
thiazolidinedione class are believed to contrain-
40 5 Pregnancy and Diabetes

In pregnancy
Hepatic glucose
Increased secretion of GH, Cortisol,
Prolactin, Progesterone, Placental lactogen Free fatty acid

Insuficient insulin secretion/insulin Obesity/ In Mother

resistance in late phase of pregnancy Lae of exercise/
Unhealthy diet Spontaneous
GDM abortion
Fetus
Hypertension
Increased glucose
Increased FFA Caesarean
section
Oxygen uptake; Oxidative stress; Fetal substrate delivery

Delayed organ maturity; Endothelial dysfunction GDM

Fat amount
Reocuurance
Hyperinsulinism
Increased
risk of T2DM
Polycythemia, Neonatal asphyxia,
Neonatal Still birth, Shoulder dystocia, Ratinopathy
hypoglycemia Respiratory distress problem,
Microsomia, Other birth problem, Nephropathy
Obesity/Diabetes in
baby & child Dysmorphogenesis
Ketoacidosis

Fig. 5.1 Pathogenesis of GDM and its common complications (GH growth hormone, GDM gestational diabetes mel-
litus, FFA free fatty acid)

dicate in pregnancy. Insulin is also used in these Postpregnancy Management

situations but should be monitored regularly.
Generally, if the blood glucose levels are tend-
ing to be elevated despite correct diet and exer-
cise, then insulin therapy can be initiated. Some
reports estimated that nearly 15 % of women
with GDM are advised for insulin treatment
because in such patients blood glucose levels
are tending to be elevated despite correct diet
and exercise. Some cases of combination ther-
apy (insulin + metformin/glyburide) are also
used, but effects of such treatment strategy were
not examined systematically in pregnancy.
Obstetric Management Assessment of fetal
growth particularly measuring the fetal abdomi-
nal circumference through ultrasonography
might be helpful to find the effect of GDM on
baby or to evaluate the effectiveness of treat-
ment. Ultrasound monitoring to examine the
fetal growth and volume of amniotic fluid is
recommended in every 4 weeks in between 28
and 36 weeks of pregnancy.
Administration of dextrose through intravenous
route and/or insulin infusion is recommended in
the time of labor and birth in women with DM
whose blood glucose level is not maintained in
between 4 and 7 mmol/L. Treatment for hypergly-
cemia should be stopped after birth. GDM is
increasingly acknowledged as a contributing fac-
tor for the progression of T2DM. In general
majority of women with GDM will be normogly-
cemic in the immediate postpartum stage. But
some of women with GDM displayed evidence of
IGT and frank diabetes at 6–12 weeks postdeliv-
ery, while a section had transformed to T2DM
during 10 years of postpregnancy. Thus careful
postpregnancy surveillance is required to monitor
any sign of T2DM. It is generally proposed to
monitor/screen IGT for 6–12 weeks following
delivery and then at a minimum of every 3 years
thereafter. Along with regular screening physical
activity, healthy lifestyles are essential to reduce
the chance of developing T2DM. The mother with
GDM should be encouraged for adequate breast-
Preexisting DM in Pregnancy
feed starting from delivery to at least 3 months of
postpartum, as this may be useful to decrease the
risk of hypoglycemia to neonate and offspring
obesity and will avert the development of meta-
bolic disease and T2DM in the mother (National
Collaborating Centre for Women’s and Children’s
Health 2008; American Association of Diabetes
Educators 2013; Thompson et al. 2013).
Diabetes in Pregnancy
Generally women with GDM go back to normal
state after pregnancy. Although the prevalence is
less than the incidence, DM in pregnancy also
exists. This type of DM in pregnancy should be
screened by the WHO (2006) criteria or by other
recognized criteria which is similar to the diag-
nosis of DM in normal individual. Criteria for
diagnosing DM in pregnancy (WHO, 2006 crite-
ria) include [one or more of the following criteria
should match] (World Health Organization
2013):
• Fasting plasma glucose ≥ 7.0 mmol/L
(126 mg/dL)
• 2-h plasma glucose ≥ 11.1 mmol/L (200 mg/
dL) following a 75 g oral glucose load
• Random plasma glucose ≥ 11.1 mmol/L
(200 mg/dL) if diabetes symptoms exist
It was also proposed that the pregnant women
with fasting plasma glucose more than ≥ 7 mmol/L,
HbA1c ≥ 6.5 % (DCCT/UKPDS standardized)
and random plasma glucose ≥11.1 mmol/L can be
overt diabetes in pregnancy (Murphy 2010).
Preexisting DM in Pregnancy
Women suffering from pregestational diabetes
(both T1DM and T2DM) are high-risk pregnan-
cies. Pregestational diabetes especially T1DM is
still responsible for high morbidity rate. As
already elaborated, the physiology of glucose
metabolism alters during pregnancy. A reduction
in fasting glucose level was observed as a result
of increased renal clearance and decreased glu-
41
coneogenesis. This situation increases the risk in
women suffering from T1DM especially in the
first trimester of pregnancy. Insulin requirement
and insulin resistances in pregnant women
increase as pregnancy progresses due to placen-
tal hormones like cortisol, hPL, and progester-
one. Pregnant women who are not suffering from
preexisting DM enhance their postprandial insu-
lin secretion by 50 % to counteract this. But
pregnant women with DM fail to produce a suf-
ficient reaction to increased blood glucose level
due to absence of β cell (T1DM) or reduction of
β cell/insulin resistance state (T2DM). Thus
pregnant women with T1DM will require high
dose (up to three times) of insulin compared to
their normal dose, while T2DM women will
require an adequate quantity of insulin or oral
hypoglycemic agents to attain normoglycemia
during pregnancy. Once the baby is delivered,
women with diabetes can come back to their pre-
pregnancy state. Women with DM whose HbA1c
is more than 10 % should be strongly recom-
mended to avoid pregnancy (Kitzmiller et al.
2008; National Collaborating Centre for
Women’s and Children’s Health 2008; Lambert
and Germain 2010).
Higher frequency of congenital abnormali-
ties, macrosomia, preeclampsia, stillbirth, infec-
tion, and other complications in the fetus
associated with preexisting DM is also respon-
sible for long-term complications in the mother.
The risk of maternal complications associated
with GDM is greatest in the presence of preexist-
ing microvascular disease like retinopathy and
nephropathy. Diabetic ketoacidosis is a com-
mon, severe problem which is virtually found in
women with T1DM and also responsible for
high perinatal mortality rate. The problem of
diabetic retinopathy is only linked with preexist-
ing diabetes. If the DM exists for long time
before pregnancy, this may lead to several com-
plications like retinopathy and renal impairment,
and pregnant women with the complications are
not monitored and diagnosed properly.
Miscarriage is another problem in pregestational
diabetic women. A study reported that in such
women (HbA1c > 11.5 %) the incidence of mis-
carriage is very high. Diabetic ketoacidosis due
42
to pregnancy-induced lipolysis is more common
in pregnant women with T1DM (Murthy et al.
2002; Kitzmiller et al. 2008; Lammbert and
Germain 2010).
The incidence of birth defect is more common
in women with pregestational DM compared to
mother with GDM. Some studies have shown
that about 6–13 % of children of mother with pre-
gestational diabetes have various type of dysmor-
phogenesis or irregular tissue formation. In
women with pregestational DM, birth defects
start during the first 8 weeks of pregnancy
(embryonic stage), but in this time, a large num-
ber of women may be unaware about their preg-
nancy. Moderate and transient high blood sugar
can also trigger the series of events that are
responsible for birth defects. If pregestational
DM is not managed properly, it may cause long-
term adverse effects on the development of the
placenta. These adaptive reactions like increased
maternal glucose transport or increased vascular
resistance of the plasma may also limit the growth
of fetus within a normal range. While develop-
ment of GDM is observed after the 20th week of
gestation, after the completion of embryogenesis,
by that time, the incidence of birth defect is less.
Thus, precaution and measurement before the
pregnancy who already have DM are essential to
Pre-existing diabetes
First trimester Second trimester
(1–12 week) (13 – 28 week)
Skin begins to form
Proliferation
Formation of more
Formation of all major complete skeleton
organ starts Meconium develops
Sex organ begin to form Bone marrow starts
Development of Eye blood cell production
Nerve-muscle starts Organ development
work together continues
Gestational period
Fig. 5.2 Gestational period and risk of diabetes-induced birth defect
5 Pregnancy and Diabetes
reduce birth defect (Desoye and Mouzon 2007;
Clapes et al. 2013) Fig. 5.2.
Management
Care and proper counseling are essential for
diabetic women considering pregnancy. In gen-
eral folic acid supplements (5 mg daily until 12
weeks of pregnancy period) along with proper
glycemic control in prepregnancy period is
essential. Maternal hyperglycemia in the first
few weeks after conception may induce sponta-
neous abortions (excess) and major congenital
malformations. Hyperglycemia generally after
12 weeks’ gestations can cause fetal hyperinsu-
linemia, speedy growth, and surplus adiposity.
Postprandial glucose level was most importantly
connected with high birth weight. Poor mater-
nal control of blood glucose level is associated
with macrosomia (birth weight > 4.0–4.5 Kg)
which may be responsible for increased inci-
dence of operative delivery and trauma at birth,
fetal death, and several complications in neonate
like hypoglycemia, polycythemia, hyperbilirubi-
nemia, and hypertrophic cardiomyopathy. Poorly
controlled diabetic women are in more increased
risk for fetal hypoxia and acidosis, which may be
Increased risk of birth
defect/dysmorphogenesis
GDM
Less incidance of
birth defect
Third trimester
(29 – 40 week)
Bone maturation
almost complete
Fetus begins to store
vital minerals
Eye sense changes
in light
Lanugo begins to fall off
Organ maturation
Preexisting DM in Pregnancy
associated with increased risk of stillbirth. The
optimum blood glucose level in women with
preexisting DM during pregnancy should be
(Kitzmiller et al. 2008; National Collaborating
Centre for Women’s and Children’s Health 2008):
• Premeal, bedtime, and overnight glucose:
60–99 mg/dL
• Peak postprandial glucose: 100–129 mg/dL
• Mean daily glucose: ≥ 110 mg/dL
• HbA1C: ≥ 6.0
Screening for complications (diabetic neurop-
athy, retinopathy, nephropathy, dyslipidemia,
hypertension, depression, and thyroid disease) is
also considered as a key approach as a part of the
prepregnancy review. In such patient with high
blood pressure, hyperlipidemias are the common
problem which also may be responsible for sev-
eral complications. Diabetic women should avoid
ketosis during pregnancy. Thus, the following
test should be required to avert such problems
(Kitzmiller et al. 2008; Balaji and Seshiah 2011;
Thompson et al. 2013):
• Blood glucose level and HbA1C estimation
(in every month till 28th week of gestation,
one in 15 days till 32nd week, and thereafter
in every week)
• Lipid profile estimation (triglycerides, total,
HDL, and LDL cholesterol (as required)
• Urine test for microalbuminuria and creati-
nine clearance (in every 1/3 months)
• Liver enzymes like aspartate aminotransfer-
ase–alanine aminotransferase (ALT/AST)
ratio and creatinine level in serum estimation
(in every 1/3 months or as required)
• Possible liver ultrasound (as required)
• Hemoglobin and serum ferritin level estima-
tion (to monitor treatment)
• Test for cardiac autonomic neuropathy and
peripheral arteriosclerotic vascular disease
(carotid ultrasound, ankle/brachial blood pres-
sure) (as required)
• 2-D or Doppler echocardiogram or tissue
Doppler imaging with indication of diabetic
cardiomyopathy or systolic or diastolic heart
failure (as required)
43
• Evaluation of risk factors for coronary heart
disease (CHD) (as required)
• Dilated retinal examination (in every 1–6
months)
• Anti-tissue transglutaminase antibody (anti-
tTG) or anti-endomysial antibodies (anti-
EMA) plus IgA level estimation in T1DM to
diagnose celiac disease (to monitor treatment/
as required)
• Thyroid peroxidase antibodies (to monitor
treatment)
Thus, antihypertensive medications are usu-
ally prescribed which also help to prevent or slow
diabetic nephropathy. Pregnant women should
not take the medications without consulting the
physician and should take extra care as these are
commonly used medications for the treatment of
diabetes and its complications. For example,
some hypertensive drugs like statin, antagonists
of angiotensin II receptor, and angiotensin-
converting enzyme (ACE) inhibitors should be
discontinued before pregnancy or as soon as con-
ception is confirmed. Thus, regular follow-up,
proper medications, tight management of diet
and weight, and low-intensity exercise are essen-
tial. Exercise from prepregnancy period will be
helpful to reduce weight gain, decrease of fetal
adiposity, better control glucose, and improve
tolerance of labor. Psychological disorders,
stress, and depression can affect glycemic con-
trol; thus, emotional well-being is also required
for diabetes management (Kitzmiller et al. 2008;
National Collaborating Centre for Women’s and
Children’s Health 2008; Lambert and Germain
2010; Thompson et al. 2013).
Nutritional therapies are also important to
manage the weight and blood glucose level. In
young women with T1DM, eating disorders are a
usual problem, and thus unhealthy weight control
may increase the misuse insulin to control the
obesity/body weight. T2DM also has similar
problem but often binge eating. The pregnancy in
these women may lead to preterm delivery, fetal
growth restriction, hyperemesis, and postpartum
depression. A proper meal pattern can offer
adequate calories and nutrients to achieve the
requirement of pregnancy (Kitzmiller et al. 2008).
44
Key Facts
• Diabetic women should attain HbA1c
value > 7 % before pregnancy.
• Diabetic women with HbA1c
value > 10 % should avoid pregnancy.
• ACE inhibitors, AT1 antagonist, and
statin should not be used during
pregnancy.
• Women with preexisting DM who are
preparing to become pregnant should
consume folic acid (5 mg/day) until 12
weeks of pregnancy to decrease the risk
of having a baby with a neural tube
defect.
• Diabetic obese women (BMI > 27 kg/
m2) who are planning to become preg-
nant should lose their weight.
• Women with GDM whose prepregnancy
BMI was > 27 kg/m2 should be restricted
with calorie consumption (up to 25 kcal/
kg/day or less) and should have moder-
ate exercise (of at least 30 min/day).
• Women should be diagnosed for GDM
(generally OGTT) at 24–28 weeks of
pregnancy.
• Women with pervious history of GDM
should be diagnosed (regular blood glu-
cose level or OGTT) in early weeks of
the next pregnancy (16–18 weeks) and a
further OGTT at 28 weeks if the conse-
quences are normal.
References
American Association of Diabetes Educators. Gestational
diabetes mellitus AADE Practice advisory. 19 Dec
2013. https://www.diabeteseducator.org/docs/default-
source/legacy-docs/_resources/pdf/inpractice/aade_
gdm_practiceadvisory.pdf?sfvrsn=2
American College of Obstetricians and Gynecologists.
Gestational diabetes mellitus. Practice Bulletin No.
137. Obstet Gynecol. 2013;122:406–416.
5 Pregnancy and Diabetes
Balaji V, Seshiah V. Management of diabetes in preg-
nancy. JAPI. 2011;59:33–6.
Barbour LA, Kirwan JP, McCurdy CE, et al. Cellular
mechanisms for insulin resistance in normal preg-
nancy and gestational diabetes. Diabetes Care.
2007;30 Suppl 2:S112–9.
Carr DB, Gabbe S. Gestational diabetes: Detection, man-
agement, and implications. Clin Diab. 1998;16:2.
Clapes S, Fernandez T, Suarez G. Oxidative stress and
birth defects in infants of women with pregestational
diabetes. MEDICC Rev. 2013;15:37–40.
Desoye G, Mouzon SH. The human placenta in gestational
diabetes mellitus. Diabetes Care. 2007;30:S120–6.
First Nations Centre Des Premieres Nations. Gestational dia-
betes and first nations women a literature review. First
Nations Centre, National Aboriginal Health Organization;
2009. http://www.naho.ca/documents/fnc/english/gesta-
tional_diabetes_first_nations_women.pdf.
International Diabetes Federation. Global guideline on
pregnancy and diabetes. Brussels: International
Diabetes Federation; 2009.
Kitzmiller JL, Jovanovic LB, Block JM, et al. Managing
preexisting diabetes for pregnancy. Diabetes Care.
2008;31:1060–79.
Lambert K, Germain S. Pre-existing type I and type II dia-
betes in pregnancy. Obstet Gynaecol Reprod Med.
2010;20:353–8.
Marcinkevage JA, Narayan KMV. Gestational diabetes
mellitus: Taking it to heart. Prim Care Diabetes.
2011;5:81–8.
Murphy HR. Gestational diabetes: what’s new? Medicine.
2010;38:676–8.
Murthy EK, Pavliæ-Renar I, Metelko Z. Diabetes and
pregnancy. Diabetol Croat. 2002;31:131–46.
National Collaborating Centre for Women’s and Children’s
Health. Diabetes in pregnancy management of diabetes
and its complications from preconception to the post-
natal period. London: RCOG Press; 2008.
Refuerzo JS. Oral hypoglycemic agents in pregnancy.
Obstet Gynecol Clin North Am. 2011;38:227–34.
Sathyapalan T, Mellor D, Atkin SL. Obesity and gestational
diabetes. Semin Fetal Neonatal Med. 2010;15:89–93.
Simmons D. Diabetes and obesity in pregnancy. Best
Pract Res Clin Obstet Gynaecol. 2011;25:25–36.
Sugiyama T. Management of gestational diabetes melli-
tus. JMAJ. 2011;54:293–300.
Sweeting AN, Rudland VL, Ross GP. Gestational diabetes
towards new diagnostic criteria. Med Today.
2013;14:46–53.
Thompson D, Berger H, Feig D, et al. Diabetes and preg-
nancy. Can J Diabetes. 2013;37:S168–83.
World Health Organization. Diagnostic criteria and clas-
sification of hyperglycaemia first detected in preg-
nancy (WHO/NMH/MND/13.2). Geneva: WHO;
2013.
 “Diabesity”: Current Situation
Obesity has become the leading metabolic dis-
ease, with more than 1.5 billion overweight
adults, and a minimum of 200 million men and
about 300 million women were found to be clini-
cally obese. Obesity is considered as a chief con-
tributor to the global chronic disease and
disability burden. Overweight and obesity are the
fifth leading risk for global fatality. The death
rate per year is not less than 2.8 million adults
due to overweight or obese. The recent statistics
also showed that about 44 % of the diabetes, 23 %
of the ischemic heart disease, and 7–41 % of cer-
tain cancer burdens are attributable to overweight
and obesity. The relationship between obesity
and diabetes, particularly T2DM, has been known
for thousands of years. Prevalence of diabetes
and obesity is continually rising, and the associa-
tion between these two has been demonstrated
constantly in both cross-sectional and prospec-
tive studies. Obesity plays a key role in the etiol-
ogy of T2DM. Diabetes and obesity are
independent and in combination can substantially
diminish the quality of life, can increase health-
care costs, can decrease life expectancy, and can
increase the risk of morbidity and mortality due
to cardiovascular disease. Often in developing
countries, undernutrition with obesity exists as a
complex physiological condition, with serious
social and psychological facets, affecting practi-
cally in socioeconomic groups of all ages. The
epidemic of obesity is not restricted to industrial-
ized areas or developed countries; in developing
countries this increases often faster than in the
© Springer Science+Business Media Singapore 2016
S. Sen et al., Diabetes Mellitus in 21st Century, DOI 10.1007/978-981-10-1542-7_6
6
developed world. Increased intake of poor nutri-
ent, more energy dense foods with high sugar
level and saturated fats, collectively with abridged
physical activity, led to increased obesity rates in
the UK, Eastern Europe, North America, Middle
East, Australia, Pacific Islands, China, and India.
Obesity is becoming a synonym for T2DM in
several countries and has reached in an alarming
situation (World Health Organization 2000, 2003,
2011; Formiguera and Canton 2004; Lau 2010;
Pandya et al. 2011).
Consumption of excess calories and reduced
physical activity to use up the intake calories
cause energy imbalance resulting obesity and
overweight. Environmental and societal changes,
lack of well-developed infrastructure and poli-
cies, and individual ignorance are responsible for
such situation. Generally, an increased energy-­
rich food intake (food high in fat, sugars, and salt
but low in minerals, vitamins, and other micronu-
trients); easy availability of lower-cost processed
foods; reduced physical activity; increasing
urbanization, globalization, pollution of environ-
ment, and industrialization with wider access to
the market economy; and modern lifestyle com-
pound the risk of overweight and obesity. The
situation became critical for children also; mainly
in developed countries and upper society, there is
an increase in the prevalence of obesity (World
Health Organization 2000, 2011; Formiguera and
Canton 2004; Leong and Wilding 1999;
U.S. Department of Health and Human Services
2000).
45
46
Obesity: Key Statistics
• The number of obese people became
double since 1980.
• In 2008, >1.4 billion adults (20 years
and older) were diagnosed as over-
weight. Of these more than 200 million
men and approximately 300 million
women were obese.
• In 2008, 35 % of adults (20+ years) were
overweight, and 11 % were obese.
• Over 40 million children (<5 years)
were overweight in 2011.
• By 2015, more than 2.3 billion people
will be overweight, and of them, 700
million will be obese.
• Overweight and obesity are the fifth
leading risk for global deaths.
• Nearly 2.8 million people die each year
globally due to the consequence of over-
weight/obesity. In the Southeast Asia
Region, it was 300,000.
• In India, the prevalence of overweight
(BMI >25 kg/m2) is 24 % and 25 % in
females and males, respectively.
Prevalence of overweight (BMI >30 kg/
m2) is 1.3 % and 2.5 % in males and
females, respectively.
The data given is as per:
1. WHO Media Center fact sheet “Obesity
and Overweight.” Accessed on
November 2013. (http://www.who.int/
mediacentre/factsheets/fs311/en/ and
http://www.searo.who.int/entity/non-
communicable_diseases/media/non_
communicable_diseases_obesity_fs.
pdf)
2. WHO report on “Noncommunicable
Diseases in the Southeast Asia Region.
2011 Situation and Response.” WHO
Regional Office of Southeast Asia
6 “Diabesity”: Current Situation
Overweight and Obesity
Obesity is a complex, multifactorial disease
caused by accumulation of excessive and abnor-
mal fat in the adipose tissue to such extent that
can cause impaired health. Despite of the instance
of physiological regulation when intake of energy
became more than the energy intake, it promotes
energy stores, and if the condition continues for a
long time, this may lead to weight gain. In gen-
eral the weight gain process in an individual can
be categorized in three phases (World Health
Organization 2003).
1. Pre-obese static phase: The situations arise
due to long-term energy balance, and weight
remains steady.
2. Dynamic phase: In this phase due to the con-
sequence of exceeding energy intake over
energy expenditure for a long time, the indi-
vidual gains weight.
3. Obese static phase: In such situation weight
increases compared to pre-obese static phase
though the energy balance regains.
Obesity develops from the genotype and the
environmental factor interactions. In addition to
the obese or overweight, the fat distribution
around the body is also significant. However,
obese people are different in the amount of
excess stored fat and the regional fat distribution
in the body. In general two types of fat distribu-
tion are considered (World Health Organization
2003):
1. The android (central-type obesity or apple
shape): distribution of fat around the viscera
and abdomen (truncal obesity).
2. The gynoid (peripheral-type obesity or pear
shape): fat is distributed more peripherally,
especially located subcutaneously in the lower
body (around the hips, buttocks, and lower
extremities).
Overweight and Obesity
The former type is more common in men
while the latter in women. Weight gain induced
by distribution of fat affects the risks linked with
obesity. An excess abdominal fat is considered as
huge risk issue for diseases as is excess body fat
per se. It was observed that “truncal obesity” is
often associated with ill-health.
 ome Important Causes of Obesity
S • Waist circumference
and Overweight
The primary cause of overweight and obesity is
an energy inequality between calories expended
and calories consumed. Few underlying causes of
obesity and overweight are (World Health
Organization, 2003):
• Increased consumption of energy-rich foods
(e.g., high in fat, sugars, and salt but low in
minerals, vitamins, and other micronutrients).
• Reduced in physical activity.
• Changes in dietary patterns and altered physi-
cal activity, due to social or environmental
changes. The lack of must needed supportive
strategies in health, transport, agriculture,
urban planning, food processing, environ-
ment, distribution, marketing, and education
sector is also linked with the problem.
Measurements of Obesity
Obesity is a chronic disease associated with the
raise in body fat stores. Therefore, measurement
of body fat and assessment of degree of obesity
are significant for better management of obesity.
However, determination of body fat needs quite
sophisticated methods and instruments that are
expensive and not readily available to most clin-
ics, therefore almost impossible to perform in
general or poor population. Consequently, there
are no literatures available that can precisely
47
define normal level of body fat. Hence, in practi-
cal approach, two surrogate determinants are
used to calculate body fat and determine the
degree of obesity (Leong and Wilding 1999;
World Health Organization 2000, 2003, 2011;
Formiguera and Canton 2004; U.S. Department
of Health and Human Services 2000).
• Body mass index (BMI)
Body mass index (BMI) is a simple method of
estimating adiposity and is suggested as a practical
method for estimating body fat in the clinical set-
ting. Calculation of BMI is carried out by dividing
the individual mass by the square of the height and
characteristically expressed either in US “custom-
ary” units or metric. It offers a more correct mea-
sure of total body fat contrast with the body weight
assessment alone. The method is also useful to
find the prevalence of obesity within inhabitants
and the risks linked with it. However, BMI does no
accounts for the wide variation in the body fat dis-
tribution or varying degrees of truncal obesity
within the same BMI range. Increased BMI levels
are linked with growing risks for developing
T2DM (Leong and Wilding 1999; World Health
Organization 2000, 2003, 2011; Formiguera and
Canton 2004; U.S. Department of Health and
Human Services 2000).
BMI = Weight ( kg ) / Height squared ( m 2 )
or
BMI = Weight ( pounds ) × 703 / Height squared
( inches )2
Waist circumference is the most simple, useful
practical method, which can be used by a clini-
cian to estimate abdominal fat of an individual
before and during the weight loss therapy or
approach. It is generally calculated halfway
48 6 “Diabesity”: Current Situation

between the lowest ribs and the iliac crest.
Magnetic resonance imaging and computed
tomography can give more accurate result in this
regard but are impractical for daily clinical use.
Furthermore, abdominal fat emerges as an inde-
pendent risk analyst when BMI has not notice-
ably increased. Therefore, measurement of waist
or abdominal circumference, including BMI,
gives not only for the evaluation of obesity in ini-
tial stage but also for scrutinizing the effective-
ness of the weight loss therapy for patients with a
BMI <35. A waist circumference of over 94 cm
in men and 80 cm in women forecasts that BMI is
>25 in such people with a sensitivity and speci-
ficity of 96 %. The ratio of the waist circumfer-
ence to the hip circumference (the waist-to-hip
ratio, WHR) is calculated at the greater trochan-
ters. The normal value of WHR is <0.95 for men
and <0.80 for women, and an increased WHR has
been connected with an amplified risk of cardio-
vascular mortality (Leong and Wilding 1999;
World Health Organization 2000, 2003, 2011;
Formiguera and Canton 2004; U.S. Department
of Health and Human Services 2000). However,
the ethnic communities differ in the level of risk
associated with a particular waist circumference.
Classification of obesity in adults according to
BMI is given in Table 6.1.
Obesity: Impact on Health
Increased in obesity is a most important risk fac-
tor for numerous noncommunicable diseases.
The significance of obesity appears from being a
life-threatening situation since it is a valid risk
for many life-threatening diseases. Besides being
a shortening life factor, obesity and precisely
central-type obesity are frequently connected
with several other diseases like metabolic dis-
eases, cardiovascular diseases, and cancer. The
epidemic of obesity is not limited to industrial-
ized areas; this rise is often rapid in developing
countries than in the developed world. Obesity
and overweight emerge as a foremost risk for
serious diet-related chronic diseases, including
T2DM, CVD, and certain types of cancer. Obesity
is also associated with various nonfatal but debil-
itating health problems like chronic
musculoskeletal problems, respiratory difficul-
­
ties, skin diseases, and infertility. Some recent
literature also showed that obesity is also consid-
ered as an important risk factor for renal diseases
like glomerulomegaly and focal segmental glo-
merulosclerosis (World Health Organization
2003, 2011; Formiguera and Canton 2004;
U.S. Department of Health and Human Services
2000). Table 6.2 includes several health problems

Table 6.1 Classification of adult underweight, overweight, and obesity according to BMI
BMI(kg/m2)
Classification Principal cutoff points Additional cutoff points Risk of comorbidity
Underweight <18.50 <18.50 Low risk of obesity-related
Severe thinness <16.00 <16.00 diseases (but it may
produce other clinical
Moderate thinness 16.00–16.99 16.00–16.99
problem)
Mild thinness 17.00–18.49 17.00–18.49
Normal range 18.50–24.99 18.50–22.99 Average
23.00–24.99
Overweight ≥25.00 ≥25.00 Increased
Pre-obese 25.00–29.99 25.00–27.49
27.50–29.99
Obese ≥30.00 ≥30.00 Moderate
Obese class I 30.00–34.99 30.00–32.49
32.50–34.99
Obese class II 35.00–39.99 35.00–37.49 Severe
37.50–39.99
Obese class III ≥40.00 ≥40.00 Very severe
Diabesity 49

Table 6.2 Obesity-related health problems according to months. They also found that this situation is
their relative risk accompanied with reversible increase in fasting
Relative risk score Diseases insulin, glucose, and triglycerides level along
Slightly increased Several types of cancers with impaired glucose tolerance. In general,
(relative risk 1–2) (endometrial, breast, and colon) maximum individual suffering from T2DM has
Reproductive hormone a BMI >23 kg/m2, the risk of DM being very
abnormalities
much amplified by a family history of DM or
Polycystic ovary syndrome
GDM and early increase in body weight. Based
Impaired fertility
on the observation and to emphasize the rela-
Anesthesia complications
tionship between obesity and T2DM, the term
Fatal defects in maternal obesity
Low back pain
“diabesity” was coined in the 1970s. Along
Moderately Cardiovascular diseases (heart
with the degree of obesity, history of weight
increased (relative disease and stroke) gain and location of body fat are also impera-
risk 2–3) Hypertension tive predictors of DM. Usually, visceral adipos-
Osteoarthritis ity is associated with hyperinsulinemia and is a
Hyperuricemia and gout foremost risk factor for T2DM. A number of
Greatly increased Insulin resistant and T2DM reports have suggested accumulation of excess
(relative risk >3) Dyslipidemia and visceral fat linked with insulin resistance,
atherosclerosis reduced sensitivity of insulin-mediated glucose
Gallbladder diseases (mainly uptake, and decrease rate of FFA reesterifica-
cholelithiasis and gallstones)
tion. The constant resistance to glucose uptake,
Breathlessness
in spite of the activation of several compensa-
Sleep apnea
tory mechanisms like increased glycemia and
insulinemia, progressively leads to T2DM dur-
connected with obesity according to their relative ing longtime obesity. During obesity there is a
risks (as per WHO report). shift in glucose uptake in spite of these com-
Health consequences of obesity range from pensatory mechanisms, which leads to insulin
amplified risk of premature death to severe resistance in the muscles. Chronic reduction in
chronic diseases that decrease the overall expec- the utilization of glucose from glycogen limits
tancy and quality of life. Therefore, a special the additional glucose uptake. The continuous
concern is the escalating occurrence of child obe- physiological modification between the stages
sity. The risk for these noncommunicable dis- of glycogen depletion and repletion depending
eases rises with the increase in BMI and waist to meals in that condition ultimately alters the
circumference. Childhood obesity is related with normal physiology and may result in permanent
a higher possibility of obesity, premature death, increased plasma glucose and insulin levels
and disability in adulthood. But this condition in (Mooradian 2001; Golay and Ybarra 2005;
obese children is also associated with increased Haslam 2010).
future risks like experience of breathing difficul- Obesity is considered as risk factor for
ties, increased risk of fractures, hypertension, GDM. Obesity and diabetes in pregnancy have
early markers of cardiovascular disease, insulin independent and additive effects on several fetal
resistance, diabetes, and psychological effects. complications like fetal wastage from early preg-
nancy loss or congenital anomalies, macrosomia,
shoulder dystocia, stillbirth, growth restriction,
Diabesity and hypoglycemia. However, GDM is connected
with enhanced possibility of early obesity, T2DM
Sims and his colleagues observed that BMI of during adolescence, and the occurrence of meta-
young individual with no family history of DM bolic syndrome in early childhood (Yogev and
increases to 28.0 kg/m2 when overfed for 6 Visser 2009).
50
 ossible Correlation Between Obesity
P insulin-­stimulated glucose uptake (mainly in the
and Diabetes
Though association of obesity and DM is well
documented, the specific biochemical pathways
connecting obesity to glucose intolerance are not
described clearly. Several molecular pathways
are believed to be involved in obesity-related
T2DM.
Insulin is involved in the several functions of
the liver, adipose tissue, and muscle which are
necessary for the normal regulation of blood
sugar. Insulin resistance is considered as key
pathogenesis in T2DM which can be explained as
reduced function of insulin on uptake, metabo-
lism, and storage of glucose. Impaired insulin
signaling or GLUT4 downregulation is responsi-
ble for reduced glucose uptake induced by insulin
in the adipose tissue and skeletal muscle and
impaired hepatic glucose output. Normally insu-
lin causes activation of the tyrosine kinase of the
insulin receptor, which regulates the phosphory-
lation of several tyrosine residues. But in obese
individual or animal, increased expression and/or
action of several protein tyrosine phosphatases
observed in the muscle and adipose tissue, which
dephosphorylate and terminate signaling, propa-
gated through tyrosine phosphorylation. Some
researchers also found the decrease expression of
diverse insulin-signaling molecules in the skele-
tal muscle in morbid obesity. Though in the skel-
etal muscle of obese and diabetic individual,
GLUT4 expression was found normal, faulty glu-
cose transport comes into view due to impair-
ment of translocation, docking, or fusion of
GLUT4-containing vesicles within the plasma
membrane (Mooradian 2001; Golay and Ybarra
2005; Haslam 2010).
Insulin promotes the differentiation of preadi-
pocytes to adipocytes. In the adipose tissue, insu-
lin increases lipogenesis by the conversion of
glucose to glycerol-3-phosphate, which is then
collected with nonesterified fatty acids (NEFAs)
to generate triglycerides. Insulin also decreases
lipolysis (breakdown of triglycerides) and thus
inhibits release of excess NEFAs. In normal peo-
ple, NEFAs stimulate insulin production. But
increases in the NEFA are responsible for
impaired glucose metabolism by reducing
6 “Diabesity”: Current Situation
skeletal muscle) and increasing hepatic glucose
output by interfering the Randle (glucose–fatty
acid) cycle. Several reports confirmed the ele-
vated level of NEFA in obese and T2DM patients.
Hence, it may be suggested that in obese indi-
vidual the increased level of NEFA may be
responsible for impaired glucose metabolism and
insulin resistance, which contribute in the patho-
genesis of T2DM (Mooradian 2001; Golay and
Ybarra 2005; Haslam 2010).
It has been observed that productions of sev-
eral cytokines from adipose cell are associated
with obesity and reduced sensitivity of insulin in
the skeletal muscle and liver. TNF-α has para-
crine effects on adipose cells and decreases the
action of insulin in the skeletal muscle. In obese
individual TNF-α produced from adipose cells is
double than that of nonobese individuals.
Increased secretion of TNF-α can produce
impairment of insulin function in fat and muscle
by decreasing the tyrosine kinase activity of the
insulin receptor. Only in chronic case, TNF-α has
shown to induce insulin resistance in the skeletal
muscle which is thought to occur via a reduced
GLUT4 level. The level of another cytokinin
resistin was also found more in obese and dia-
betic individual suggesting that resistin also may
have a role in obesity-induced DM (Mooradian
2001; Golay and Ybarra 2005; Haslam 2010).
Lipolytically active intra-abdominal adipo-
cytes release FFA which results to glucose intol-
erance and insulin resistance in the skeletal
muscle and liver by altering the intracellular
insulin-signaling cascade. FFAs after release
transported into the liver via the portal circulation
and can provoke hepatic insulin resistance,
mainly by increasing gluconeogenesis. In obese,
nondiabetic individuals, high level of plasma
FFA induces increase in lipid oxidation which is
indirectly responsible for insulin resistance. In
muscles, the constant reduction in glucose oxida-
tion due to the preferential utilization of lipids as
a source of energy that limits the glucose utiliza-
tion from the glycogen stores and, a retro, inhib-
its glycogen synthase activity. Inhibitory activity
of FFAs on insulin-stimulated glucose transport
is also observed. Generally, in obese individual
particularly when visceral fat mass is large, the
Diabesity 51

plasma FFA is found more than normal. This
condition may be accountable for the two major
imperfections in glucose homeostasis of T2DM,
namely, insulin resistance and impaired β-cell
function. Recent research on rodent found that
adipocyte fatty acid-binding protein (aP2) may
play a key role in this regard as mice lack aP2 and
do not produce insulin resistance, while obesity
is induced with high-fat diet (Mooradian 2001;
Golay and Ybarra 2005; Haslam 2010).
Adiponectin, another adipokinin, improves
insulin sensitivity in the skeletal muscle and liver
by enhancing intracellular insulin signaling.
Some reports confirmed that the level of serum
adiponectin was decreased in obesity. Though
several other researchers reported a normal level
of serum adiponectin in obese individual, they
suggested that subcutaneous rate of secretion of
adiponectin is reduced in obese individual com-
pared with nonobese individual. In fact, the
insulin-­resistant subjects have lesser values of
both rate of adipose secretion and serum concen-
tration than the individuals with elevated insulin
sensitivity. These reports indicate that in obesity,
the extent of hypoadiponectinemia is linked to
insulin resistance (Mooradian 2001; Golay and
Ybarra 2005; Haslam 2010).
Adipocytes produced leptin that generally
reduces food intake and increases outflow of
sympathetic nervous system so that it maintains
the energy expenditure and induces weight loss.
Reduction of neuropeptide Y level in the hypo-
thalamus is important in this regard. Several
researchers demonstrated the positive corre-
lation between the leptin level with BMI and
percentage body fat, insulin resistance, TNF-α
in both humans and animals. It was suggested
that leptin inhibits insulin-induced tyrosine
phosphorylation of IRS-1 that is responsible for
insulin resistance. Some in vivo study reported
that increased level of plasma leptin within
physiological range may hold back insulin
secretion. Several in vitro and animal studies
found that insulin production can be impaired
by leptin and decreased the effects of insulin on
the liver, though the role of leptin regarding the
insulin effect on human adipocytes and muscle
is unclear. The stimulation of sympathetic ner-
vous system by leptin also may be involved
in insulin resistance. Thus, it may be possible
that obesity results to the increase in leptin pro-
duction which in turn causes insulin resistance
(Mooradian 2001; Golay and Ybarra 2005;
Haslam 2010) (Fig. 6.1).

Preadipocyte Lipogenesis in adipose tissue

+

Insulin NEFA in obase individual

-
Adipocyte Lipolysis in adipose tissue
(In obase people)

Hepatic glucose output

Resistain Impaired insulin signaling action

TNFα Insulin resistance

FFA
Impaired β-cell function

Leptin Sympathetic nervous system activity

Adiponectin (may be) Insulin sensitivity

Fig. 6.1 The potential role of some adipokines in insulin resistance and insulin sensitivity. TNF α tumor necrosis factor
α, FFA free fatty acid, NEFA nonesterified fatty acid
52
Management of Obesity
Prevention and treatment of overweight and obe-
sity can play a significant role to keep away the DM
or for its successful management. Promoting a
healthy lifestyle in the family will decrease the risk
of diabetes and its complications (World Health
Organization 2000, 2011; Mooradian 2001).
Diet and Physical Activity Control in diet and
proper physical activity is the cornerstones for
the management of obesity. Some studies have
found that reducing more than 5 % of weight
could be good in this regard. Nearly 10 % reduc-
tion in body weight in reasonable time could be
more helpful. Restriction in caloric consumption
per se decreases insulin resistance and improves
glycemic control. Lifestyle and dietary modifica-
tion to continue a reduced caloric diet of between
500 and 600 kcal/day, less than the baseline calo-
rie intake, could be useful in obesity. Consumption
of vegetables and fruits, as well as nuts and whole
grains, need to be increased, while intake of fatty,
sugary foods especially saturated animal-based
fats in the diet should be avoided. Intake of salt
also needs to be reduced in such case, while
intake of fiber should be increased. Along with
instance exercise, longtime slow-intensity exer-
cise (such as walking) can be equally beneficial
6 “Diabesity”: Current Situation
for weight loss. Moderate levels of physical
activity for 3–5 days per week with 30–45 min
per day may be useful.
Behavioral Therapy Self-monitoring of physi-
cal activity and food habits, stress management,
problem solving, contingency management, and
social support are important components for
weight loss treatment. The significance of indi-
vidualizing behavioral strategies must be high-
lighted for behavior therapy, as it was for exercise
and diet strategies.
Anti-obesity Drugs Several drugs like amphet-
amine (increase the availability of norepineph-
rine), orlistat (inhibitor of pancreatic lipase), and
sibutramine (noradrenaline and serotonin reup-
take inhibitor) are also used to decrease food
intake.
Surgical Innervations In some extreme cases
and when other nonsurgical methods failed to
show any effect than “bariatric surgery,” “Roux-­
en-­
Y gastric bypass,” “laparoscopic gastric
band,” and “sleeve gastrectomy” are also recom-
mended for weight loss (Fig. 6.2).
References
Genetic
Physio- factor
logical
factor
Behavi-
oral
factor
Social
factor Energy
expenditure
Treatment strategy
Non-pharmacological approches
Amphetamine, Orlistat, Bariatric surgery, Roux-en-Y
& Behavioral therapy including self-monitoring
Fig. 6.2 Obesity and its treatment approaches
References
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 Oxidative Stress and Diabetes
Mellitus
Evolution is driven by heritable biological adap-
tations in this changing nature and environment.
Amalgamation of evolutionary and mechanistic
physiology is important for us to understand our
complex phenotype and how and its structure.
Oxygen is obligatory for most organisms but,
paradoxically, damages vital biological sites.
Oxygenic threat is met by antioxidants that devel-
oped in parallel with our oxygenic atmosphere.
Our effective antioxidant defense system is well
equipped to protect our body when it is exposed
to these oxidants, but this is not infallible in cer-
tain conditions. Reactive oxygen species (ROS)
or reactive nitrogen species (RNS) can breach
antioxidant defenses and causes a variety of path-
ological changes. Oxidative stress is recognized
as a vital risk factor involved in the onset, pro-
gression, and several complications of diabetes.
Several frequent risk factors, such as obesity,
unhealthy diet and habits, increased age, pollu-
tion, stress, etc., contribute to an oxidative envi-
ronment, which may modify the sensitivity of
insulin either by impairing glucose tolerance or
increasing insulin resistance. Excessive free radi-
cal generation is also responsible for degradation
of pancreatic beta cell. The mechanisms through
which oxidative stress contributes in the patho-
genesis of diabetes are often multifactorial and
relatively complex, relating different cell signal-
ing pathways. Hyperglycemia, a usual condition
in both T1DM and T2DM, also contributes to the
development and upholding of overall oxidative
environment. Various life-threatening complica-
© Springer Science+Business Media Singapore 2016
S. Sen et al., Diabetes Mellitus in 21st Century, DOI 10.1007/978-981-10-1542-7_7
7
tions including macro- and microvascular com-
plications in diabetic patients are also well linked
to oxidative stress (Benzie 2003; Valko et al.
2007; Sen et al. 2010; Rains and Jain 2011; Sen
and Chakraborty 2011).
Oxidative Stress and Health
Biological Roles of Free Radicals
Oxidative characteristic of oxygen plays a vital
role in different biological phenomena. The
capacity to utilize oxygen has offered humans
with the benefit of metabolizing fats, proteins,
and carbohydrates for energy; however being
crucial for life, oxygen can also magnify the
injury inside the cell by oxidative proceedings.
Oxygen is an extremely reactive atom that is
competent of generating several active damaging
molecules usually called “free radicals” as a
result of mitochondrial ATP production. These
reactive species like ROS and RNS are the by-
products generated from the cellular redox pro-
cess, and they play a dual role as both beneficial
and toxic substances. ROS and RNS are the terms
jointly described as free radicals, and other non-
radical reactive substances are also called oxi-
dants; though radicals are less stable, their
reactivity is usually more than non-radical spe-
cies. Examples of ROS include hydroxyl (•OH),
superoxide (O2•−), peroxyl (ROO•), alkoxyl (RO•)
radicals, and lipid peroxyl (LOO•), and nitrogen
55
56
free radicals include nitrogen dioxide (NO2•) and
nitric oxide (NO•). These free radicals can be
readily converted to different non-radical reactive
species like hydrogen peroxide (H2O2), singlet
oxygen (1O2), ozone (O3), hypochlorous acid
(HOCl), peroxynitrite (ONOO−), nitrous acid
(HNO2), lipid peroxide (LOOH), and dinitrogen
trioxide (N2O3) which are also dangerous for
health and easily initiate free radical reactions in
living cells. ROS and RNS exert key role in sev-
eral beneficial physiological effects such as
defense against infectious organisms, killing of
tumor or cancer cells, xenobiotic detoxification
by cytochrome P450, mitochondrial ATP genera-
tion, cell growth, mitogenic responses induction,
several cytokines activation and growth factor
signaling, activation of tyrosine kinases, activa-
tion of protein tyrosine phosphatase, activation of
nuclear transcription factors, discharge of cal-
cium from intracellular storage area, gene tran-
scription, activation of nuclear transcription
factors, and soluble guanylate cyclase activity
regulation in cells at low/moderate concentra-
tions. Nitric oxide (NO) generated by endothelial
cells also plays a vital role in the maintenance of
blood pressure, leukocyte adhesion, aggregation
of platelet, angiogenesis, and thrombosis and acts
as an important neurotransmitter. Moreover,
recent studies also found that superoxide radicals
and H2O2 may work as second messengers. But
these oxidants are harmful in high concentration
and can induce oxidative damage to cellular
macro- and micromolecules (Fang et al. 2002;
Valko et al. 2007; Sen et al. 2010; Sen and
Chakraborty 2011).
Reactive metabolites also participate in the
production of thiyl radicals and their derivatives
like sulfinyl and disulfide anion radical.
S-glutathionylation induced by reactive species
occurs either by oxidative/nitrosative modifica-
tion of protein thiol or in the presence of protein
thiyl radical, sulfinic acid, and S-nitrosothiol.
Thiyl radicals are also involved in the oxidization
of biological electron donors including ascorbic
acid, reduced nicotinamide adenine dinucleotide
(NADH) and ferricytochrome c. Thus concentra-
tion of thiyl radicals can be a detrimental factor
for redox balance. S-glutathionylation has been
7 Oxidative Stress and Diabetes Mellitus
suggested as a posttranslational alteration which
can protect proteins from over-oxidizing environ-
ments in a wide variety of disorders including
diabetes mellitus (Rains and Jain 2011; Banerjee
and Vats 2014).
These reactive species can be formed from
both exogenous and endogenous sources under
physiologic and pathologic conditions, which
include immune system (in response to patho-
gens), metabolic process (during arachidonic
acid, macrophages, platelets, and smooth muscle
cell metabolism), inflammatory responses, lipid
peroxidation, stress, pollution (different chemical
solvents and air, water pollutants), burning of
organic substances in the time of cooking, fire in
the forest, volcanic activities, different types of
radiation (i.e., UV radiations, gamma rays, medi-
cal and dental X-rays and microwave radiation),
diet-related factors (coffee, alcohol, foods from
animal origin, broiled fried, foods that have been
barbecued, grilled food, hydrogenated vegetable
oils, herbicides, pesticides, etc.), several drugs
and toxins, and smoking of tobacco products
(Sen et al. 2010; Sen and Chakraborty 2011).
Antioxidant Protection
Human body has developed an extremely sophis-
ticated antioxidant defense mechanism to guard
the human cells and organ systems against oxi-
dants. A highly multifaceted network of antioxi-
dant metabolites and enzymes are working jointly
to avert the oxidative damage to cellular compo-
nents such as proteins, DNA, and lipids.
Antioxidant defenses include both exogenous
and endogenous in origin and are composed of
several enzymatic and molecular components;
however, the system distinctly differs, in terms of
concentration and components, in dissimilar
environments. Both endogenous and exogenous
antioxidant defense mechanisms act synergisti-
cally and interactively to counterbalance free
radicals. Defense mechanisms of antioxidant
against oxidative stress involve (i) preventative
action, (ii) repair process, (iii) physical defenses,
and (iv) antioxidant protection. Generally, anti-
oxidant systems either avert these reactive
Oxidative Stress and Health
oxygen or nitrogen species from being generated
or eliminate them before they can initiate free
radical reaction to injury to cellular components.
Since reactive species do have valuable role in
cells at low/moderate level, the function of anti-
oxidant systems to keep them at an optimum
level is not to remove oxidants entirely. The prin-
cipal biological defense systems against oxidants
generally comprise array of endogenous antioxi-
dant enzymes and different nonenzymatic endog-
enous antioxidant defense factors. Superoxide
dismutase (SOD), glutathione reductase (GR),
glutathione peroxidase (GPx), and catalase
(CAT) are the endogenous enzymatic antioxidant
defenses, while nonenzymatic antioxidants are
α-tocopherol (vitamin E), ascorbic acid (vitamin
C), carotenoids, glutathione (GSH), flavonoids,
and other antioxidant nutrients. In normal physi-
ological conditions, cells are defended against
oxidative stress by an interrelating antioxidant
network, and thus the redox equilibrium and nor-
mal cellular function are maintained. Dietary
antioxidants and phytoconstituents are consid-
ered as a major source of exogenous antioxidants,
which directly quenches the free radicals or pro-
vides support to the endogenous antioxidants
against oxidative stress. It was assumed that a
typical meal/food supplies > 25,000 bioactive
constituents and several of them may adjust a
multitude of processes that are associated to
diverse diseases. Antioxidants are plentiful in
food grains, fruits, vegetables, and in other food
products. Vitamin C, vitamin E, and beta-carotene
are among the most important dietary antioxi-
dants. Different phytoconstituents like polyphe-
nols, flavonoids, flavones, flavonols, and
proanthocyanidins are also considered as most
biologically important antioxidants (Fang et al.
2002; Pham-Huy et al. 2008; Sen et al. 2010; Sen
and Chakraborty 2011).
Oxidative Stress and Diseases
The “steady state” level of free radicals is decided
by the delicate balance between two opposite
effects such as rates of production of free
radicals/oxidants and their removal by various
57
antioxidants, and this is considered undoubtedly
as a key aspect of life. Though at low/moderate
concentrations, reactive species exert construc-
tive results on cellular redox signaling and
immune activities, at high level, they induce oxi-
dative stress, an injurious process that can alter
the function and structures of cell. The term “oxi-
dative stress” has been coined to symbolize a
shift of the redox balance through oxidative
potentials. The condition can begin when cells
cannot sufficiently obliterate the surplus of free
radicals generated due to the overproduction of
free radicals or decrease activity/quantity of anti-
oxidants. In another way, oxidative stress can be
described as an imbalance between generation
and neutralization of ROS/RNS. Oxidative stress
at the cellular level can arise as a consequence of
several factors, including disease condition,
infection, cold, exposure to alcohol, medication,
poor diet, radiation, toxins, or strenuous physical
activity. Oxidative stress is responsible in the
pathogenesis of several diseases via four crucial
steps: (i) membrane lipid peroxidation, (ii) pro-
tein oxidation, (iii) DNA damage, and (iv) distur-
bance in reducing equivalents of the cell, which
induce destruction of cell, altering signaling
pathways. The recent researches also suggest that
long-lasting exposure to free radicals, even at a
low/moderate concentration, may cause the dam-
age to biologically vital molecules and poten-
tially induce toward the tissue injury. The recent
evidences recommended that free radicals impli-
cated in the pathogenesis of almost all the
diseases and aging process. Some diseases where
free radicals play important role include (Fang
et al. 2002; Valko et al. 2007; Sen et al. 2010; Sen
and Chakraborty 2011):
• CVDs like atherosclerosis, ischemia, hyper-
tension, cardiac hypertrophy, cardiomyopa-
thy, shock, and trauma
• Diabetes mellitus, both T1DM and T2DM
• Neurodegenerative diseases such as
Parkinson’s disease, Alzheimer’s disease,
cognitive dysfunction in the elderly, schizo-
phrenia, Huntington’s disease, tardive dyski-
nesia, amyotrophic lateral sclerosis, multiple
sclerosis, depression, and memory loss
58
• Rheumatoid arthritis
• Gastrointestinal diseases like peptic ulcer,
colitis, ulcerative colitis, small intestinal isch-
emia, gastric ulcer, pancreatitis, inflammatory
bowel disease, and alcoholic and nonalcoholic
liver diseases
• Liver disease, pancreatitis
• Renal diseases like glomerulonephritis and
tubulointerstitial nephritis, proteinuria,
chronic renal failure, uremia, vasculitis, glo-
merulonephritis, and pyelonephritis
• Diseases of respiratory tract like chronic
obstructive pulmonary disease and asthma
• Fatal growth, preeclampsia
• Several diseases like periventricular leukoma-
lacia, bronchopulmonary, dysplasia, intraven-
tricular hemorrhage, retinopathy of
prematurity, and necrotizing enterocolitis in
premature infants
• Male and female infertility, including poly-
cystic ovarian disease, endometriosis, unex-
plained infertility, recurrent pregnancy loss,
and tubal infertility
• Tumors and cancer like leukemia, lung cancer,
ovary, breast cancers, etc.
• Cataract and maculopathy (eye diseases)
• Skin diseases
• Immunodepression
• Acquired immunodeficiency syndrome
(AIDS)
• Aging process
Relation Between Oxidative Stress
and DM
ROS and Cell Signaling
ROS in low concentration is involved in the sev-
eral normal cellular signaling pathway including
differentiation and proliferation of cells. ROS can
be generated in nonphagocytic cells by the vari-
ety of cytokines (i.e., TNF-α, IL-1, and IFN-γ)
and growth factors that attach to receptors of
diverse classes. ROS produced as a result of acti-
vation of such growth factor/cytokines receptor
signaling can act as true second messengers and
initiate several key cellular activities such as
7 Oxidative Stress and Diabetes Mellitus
proliferation and apoptosis. Several non-receptor
protein tyrosine kinases (PTKs) belonging to the
Src family (Src kinases) and JAK-STAT can be
activated by ROS. Then, through myristoylation
process, stimulated Src binds to cell membranes
and induces MAPK, nuclear factor kappa-light-
chain-enhancer of activated B cells (NF-kB), and
PI3K signaling pathways. ROS also induces
reversible inactivation of protein tyrosine phos-
phatases (PTPs), which is a key factor for the
redox control and cell signaling. O•– and H2O2 are
found to excite stress-related signaling mecha-
nisms such as NF-kB, p38-MAPK, and JAK-
STAT particularly resulting in vascular smooth
muscle cell (VSMC) migration and proliferation.
Cysteine residues in the active site of tyrosine
phosphatases are most vulnerable to oxidative
damage by H2O2 and other oxidants, thus induc-
ing inaction of PTP disulfides. H2O2 found to
induce apoptosis and pathological angiogenesis
in endothelial cells. In normal condition, ROS
plays a key role in the mammalian glucoregula-
tory system. H2O2 is found to control glucose-
stimulated insulin secretion from islet β cells and
to alter proximal and distal insulin signaling
(Valko et al. 2007; Perez-Matute et al. 2009;
Banerjee and Vats 2014).
Experimental evidences suggested that trans-
forming growth factor-beta 1 (TGF-β1) (receptor
serine/threonine kinases) stimulates ROS pro-
duction in several cells, restrains the growth of
various target cells, and suppresses antioxidant
enzyme expression in few cells. Vascular endo-
thelial growth factor (VEGF) activation by ROS
in rodent muscle cells demonstrated through
PI3K/Akt pathway. Akt (a serine/threonine
kinase) activation induces growth pathway stim-
ulation and apoptotic pathway inhibition.
Alternatively, inhibition of Akt may cause apop-
tosis. ROS also can stimulate the calcium libera-
tion from intracellular stores, ensuing the
activation of PKCs. Several studies have shown
that serine/threonine kinases of the MAPK fam-
ily can be controlled by oxidants. The effect of
ROS on MAPK pathways, especially through
c-jun-NH2-terminal kinase (JNK) and p38
MAPK, has been accepted as the key effect of
ROS. This results in commencement of nuclear
Relation Between Oxidative Stress and DM
transcription factors, which regulate the expres-
sion of protective genes that are involve in repair-
ing of DNA damage, powering the immune
system, arresting proliferation of damaged cells,
and causing apoptosis. ROS have been impli-
cated in the activation of nuclear transcription
factor NF-kB via TNF-α and IL-1, which are
involved in inflammatory responses. Activating
protein-1 (AP-1) is found to be vital for cell
growth and differentiation. p53, a nuclear factor,
is important in the protection of a cell from
tumorigenesis. Ferredoxin reductase (FDXR)
and REDD1/HIF-1 are found to involve in ROS-
mediated apoptosis. The nuclear factor of acti-
vated T cells (NFAT) controls the production of
cytokine, angiogenesis, adipogenesis, muscle
growth, and differentiation. Different ROS are
involved in the increase of intracellular calcium,
which may be a possible mechanism by which
ROS/metals stimulate NFAT (Valko et al. 2007;
Perez-Matute et al. 2009). Additional stress-
sensitive kinases like isozymes of PKC such as
PKCβ, PKCγ, and inhibitor of NF-kappaB
kinases beta (IKKβ)-NF-kB is involved in IRS-
mediated insulin resistance. After activation,
these kinases can phosphorylate the insulin
receptors and IRS proteins such as IRS-1 and
IRS-2. Oxidative stress causes phosphorylation
of serine in IRS which involves several molecular
mechanisms and thus induces insulin resistance.
In T2DM activation of stress-sensitive pathways
and increase in glucose and free fatty acid levels
are responsible for both insulin resistance and
impaired insulin secretion (Banerjee and Vats
2014).
In high concentration, ROS (mainly superox-
ide radical and H2O2) is also involved in the alter-
ation of several signaling pathways which can
modify the signal transduction and gene expres-
sion permanently, characteristics for disease con-
dition (Perez-Matute et al. 2009; Valko et al.
2007). In spite of the several mechanisms pro-
posed, a most commonly accepted one suggested
that oxidative stress induces stress-signaling
MAPKs, such as JNK, that in turn induce inhibi-
tion of insulin signaling. ROS can activate JNK
(a key mechanism of pathogenesis of T2DM and
insulin resistance) by oxidation and can inactivate
59
JNK through inhibiting MAPK phosphatases, by
glutathione-S-transferase, or by oxidizing thiore-
doxin-1 (Trx1) leading to apoptosis signal-regu-
lating kinase 1 (Ask1) dissociation and
subsequent Ask-mediated activation of JNK
(Styskal et al. 2012).
Several stress-sensitive signaling pathways,
such as NF-kB, JNK/SAPK, and p38 MAPK can
be induced in chronic oxidative stress condition.
Phosphorylation of the inhibitory subunit IkB by
IKK (an active serine kinase that exerts a nega-
tive effect on insulin signaling) can activate
NF-kB. Oxidative stress is also responsible for
activation of other MAPKs (JNK, ERK, and p38
MAPK), a family of related serine/threonine pro-
tein kinases. On activation, these MAPKs pro-
voke the serine/threonine phosphorylation of key
substances (i.e., IR and IRS) in insulin signaling
pathway. Serine/threonine phosphorylation of
IRS or IR damages the ability of proteins to
employ and activate downstream SH-2-
containing signaling molecules and disturbs the
interaction of IRS protein to insulin receptor.
Other serine/threonine kinases like PKC, PKB,
mTOR, and GSK-3 can be directly activated by
ROS and can work synergistically to desensitize
the insulin signal by phosphorylating IR or IRSs
on select serine/threonine residues (Rains and
Jain 2011).
Mitochondrial Dysfunction
Glucose autooxidative can also stimulate ROS
generation. Excess generation of superoxide by
the mitochondrial electron transport chain (ETC)
is considered as a main contributing factor for
insulin resistance. Oxidation of glucose starts in
the cytoplasm, where glucose undergoes glycoly-
sis, which results in the generation of NADH and
pyruvate. Pyruvate takes part in tricarboxylic
acid (TCA) cycle and produces NADH and
reduced flavin adenine dinucleotide (FADH2).
Both NADH and FADH2 supply the electrons
that provide energy to ETC and ATP generation.
Glucose oxidation and TCA cycle result in the
generation of NADH, which donates electrons to
complex I of the ETC. On the other hand, FADH2
60
donates its electrons to complex II of the
ETC. Both the complexes transfer the electrons
to ubiquinone, which again donate the electrons
to complex III, cytochrome c, complex IV, and
lastly to molecular oxygen. The ETC requires
energy to transport the protons across the mem-
brane, which forces synthesis of ATP. In hyper-
glycemic environment, the quantity of substrates
goes to the TCA cycle and is amplified highly,
and accordingly the number of reducing equiva-
lents contributing electrons to the ETC is also
amplified. Consequently, ETC attains a threshold
voltage across the membrane the electrons start
to back up at complex III. These electrons are
then supplied to molecular oxygen, and produc-
tion of mitochondrial superoxide increases.
Glucose and its metabolites can react with hydro-
gen peroxide in metal (iron and copper) ions’
presence to produce OH–•. Xanthine oxidase
(XO) is also considered as a crucial source of
ROS. In low antioxidant environment, β cells are
highly sensitive to ROS. Therefore, phenomena
like oxidative stress induce mitochondrial dam-
age, and marked reduction of insulin secretion is
not surprising (Perez-Matute et al. 2009; Rains
and Jain 2011). Generation of ROS also increases
in mitochondrial dysfunction condition, thus may
lead to oxidative stress situation. Antioxidant
enzyme expression in islet cells is very little, and
pancreatic β cells have a high oxidative energy
requirement, and thus risks of β cells are increased
in such environment. Oxidative stress conditions
damage glucose-stimulated insulin release,
reduce gene expression of key β-cell genes, and
provoke cell death (Simmons 2006).
ROS like H2O2 produced through glucose
metabolism also mediate signal for glucose-
stimulated insulin secretion (GSIS) in β cells.
Thus, adequate quantities of antioxidant enzymes
are required minimizing the oxidative damage-
linked impairment of insulin release. On the other
side, the stimulation of antioxidant enzymes by
the activation of nuclear factor erythroid 2-related
factor (Nrf2) blunts glucose-triggered ROS sig-
naling, thus reducing GSIS (Perez-Matute et al.
2009; Rains and Jain 2011). Mitochondria
also can play a great role in the influx of fatty
acids and stress-related kinases activation.
7 Oxidative Stress and Diabetes Mellitus
Experimental evidences have suggested that
insulin-stimulated glucose transport activity inhi-
bition is an important mechanism in fatty acid-
induced insulin resistance. Dysfunction of
mitochondria or reduced mitochondrial biogene-
sis and density is responsible for reduction in
mitochondrial fatty acid oxidation, which is
responsible for increases in the levels of fatty
acyl-CoA and diacylglycerol (DAG). These
changes trigger the activation of stress-related
Ser/Thr kinase activity and hold back glucose
transport. Increased UCP2 activity also may con-
tribute to mitochondrial dysfunction. Uncoupling
proteins act as mitochondrial transporters of the
inner membrane, which on activation results pro-
tons to leak across the inner membrane, produc-
ing heat without contributing to the production of
ATP. UCP2 may reduce the production of ATP
produced and thus will influence insulin signal-
ing in diverse cell (Rains and Jain 2011).
Endothelial dysfunction can be considered as
a contributing factor for progression of
DM. Glucose results in increase production of
superoxide radical within endothelial and smooth
muscle cells which subsequently generates reac-
tion with nitric oxide to generate the reactive
intermediate ONOO•-. Superoxide also enhances
the generation of asymmetric dimethylarginine
(ADMA). Both ONOO•- and ADMA are respon-
sible for NOS III inhibition and NOS III uncou-
pling, which may contribute to endothelial
dysfunction leading to DM (Sydow and Munzel
2003).
Reactive Species, Antioxidant
Enzyme, and Antioxidant Gene
Polymorphisms
Endogenous antioxidant enzymes like SOD,
CAT, GPx, glutathione-S-transferase (GST), and
nitric oxide synthase (NOS) are involved in scav-
enging of reactive species and are important to
maintain redox balance. Functional polymor-
phisms of these antioxidant enzymes may signifi-
cantly involve in pathogenesis of T2DM. Reduced
levels of antioxidant enzymes or nonfunctional-
ity of antioxidant gene may lead to oxidative
Relation Between Oxidative Stress and DM
stress and initiate stress-related pathways,
thereby leading to insulin resistance and T2DM
(Banerjee and Vats 2014).
SOD family of antioxidant enzymes includes
SOD1, intracellular (CuZn-SOD); SOD2, mito-
chondrial (Mn-SOD); and SOD3, extracellular
(EC-SOD) enzymes. Gene for SOD1, SOD2, and
SOD3 is located on chromosome 4p 15.1–15.3,
6q25 and 1q22.11, respectively. A functional poly-
morphism in exon2 of SOD2 gene A16V(C/T)
(rs4880) is responsible for structural changes in
the mitochondrial targeting domain, involving its
reduced antioxidant potential to limited posttran-
scriptional transport. Posttranslational covalent
changes in SOD, e.g., nitration, phosphorylation,
glutathionylation, and glycation, are also reported
due to increased oxidative stress condition, thus
causing decreased enzyme activity. Polymorphic
of SOD1 35A/C (rs2234694) and SOD2
A16V(C/T) showed that serum SOD activity was
more in individuals with “CC” genotype than
“TT” genotype of SOD2 gene and more in “AA”
as contrast to “CC” genotype of SOD1 gene
(Banerjee and Vats 2014).
Deficiency of CAT can lead to the development
of T2DM. CAT gene is located on chromosome
11p13. Exon2 and neighboring introns of the CAT
gene were considered as mutation hot spots for
T2DM susceptibility. In oxidative stress condition,
modification of cysteine to cysteic acid leads to
tyrosyl nitration of catalase and thus reduces
enzyme activity. The exon 9-262C/T polymorphism
in CAT gene was examined in different types of dia-
betic and its associated complication. A study on
North Indians found that “AT” genotype of -21A/T
polymorphism of CAT gene may increase the risk
of T2DM (Banerjee and Vats 2014).
GPx is mainly available in five forms like
GPx-1 (cellular), GPx-2 (gastrointestinal),
GPx-3 (plasma), GPx-4 (phospholipid), and
snGPx (sperm). Deficiency of GPx-1 can induce
endothelial dysfunction, heart failure, and abnor-
mal structural changes in the vasculature and
myocardium. GPx-1 gene is located on chromo-
some 3p21.3, and suppression of expression of
same can be considered as a one of the mecha-
nisms through which hyperhomocysteinemia
enhances vascular oxidative stress. Several other
61
polymorphisms in GPx-1, GPx-3, and GPx-4 are
also involved in diabetic complications (Banerjee
and Vats 2014).
GST polymorphisms are found to be involved
in the reduced enzymatic activity. Increased level
of plaque DNA damage and several markers of
inflammatory reactions such as C-reactive pro-
tein (CRP), fibrinogen, and adhesion molecules
were noticed in individuals with GST M1*0 null
allele. GSTs M1, T1, and P1 are found to play a
vital role in the development of T2DM and its
associated complications. In North Indian peo-
ple, Val105Val of GSTP1 gene and multiple
blending GST isoforms boost the risk of having
T2DM, while in Pima Indians, Caucasian, and
Chinese individuals, microsomal GST3 encoded
by MGST3 gene, which maps to chromosome
1q23, is a possible susceptibility gene linked
toT2DM (Banerjee and Vats 2014).
Three isoforms of NOS include inducible
nitric oxide synthase (NOSI/iNOS), neural NOS
(NOS II/nNOS), and endothelial NOS (NOSIII/
eNOS). Clinically, eNOS uncoupling has been
related with diabetes mellitus and other diseases.
Impairment of NO production results in endothe-
lial dysfunction which induces insulin resistance,
T2DM, and other complications. Several studies
have found that eNOS or NOSIII gene, mapped
to chromosome 7q36, is highly polymorphic. In
T2DM patients, eNOS Glu298Asp can interact
with gene polymorphisms of other endogenous
antioxidant enzymes (Banerjee and Vats 2014).
Obesity, Oxidative Stress, and DM
Intake of high caloric food is considered as a key
reason for obesity. Consumption of high-fat or
high-carbohydrate diet (glucose and fatty acids)
may result in the generation of more substrates
that are inflowing into mitochondrial respiration.
Therefore, the amount of electrons donated to the
electron transport chain may rise, which results in
excessive production of highly reactive superoxide
radical. Thus, risk of diabetes is increased. Obesity,
in turn, is also responsible for a pro-inflammatory
environment. In in vivo condition, inflammation
can induce oxidative stress due to a large boost in
62
free radical generation by immune cells as part of
the immune response. Amplified generation of dif-
ferent pro-inflammatory cytokines by immune
cells, mature adipocytes, and preadipocytes was
observed in obese condition. Obesity and ROS can
also activate signal transduction pathways gener-
ally through NF-kB and can promote production
of TNF-α and interleukin-6 (IL-6). Experimental
evidences have suggested that obesity and high-fat
feeding may increase NADPH oxidase activity,
mainly in the adipose tissue. Decreased mRNA
expression of SOD1, GPx-1, and CAT in the adi-
pose (not in the liver or skeletal muscle) was also
reported in obese condition. Thus, it can be
assumed that in obese condition, superoxide pro-
duction is increased by NADPH oxidase and
reduced expression/function of antioxidant
defense system components. In high-glucose envi-
ronment, NADPH oxidase production increases
by advanced glycation end products (AGEs)
(Styskal et al. 2012).
Production of H2O2 is also stimulated by insu-
lin oversecretion which increases the insulin cas-
cade by reducing PTP activity, thus causes basal
phosphorylation of IR and the IRS proteins. In
oxidative stress condition, normal glucoregula-
tory mechanism alters by stimulation of stress-
responsive pathways, due to cellular dysfunction
or by inducing apoptosis/death of cells that are
vital for glucose/insulin regulation such as pan-
creatic β cells (Styskal et al. 2012). Obesity and
T2DM have shown to activate the protein product
of JNK1, at least in part due to lipotoxic stress,
which triggers the phosphorylation of IRS-1 at
inhibitory sites that avoid recruitment of this pro-
tein to the activated insulin receptor. Thus, IRS-1
phosphorylation through JNK disturbs the insulin
signaling pathway guiding to insulin resistance.
Influence of Ketone Body, Nutrient
Availability, PTEN, and Sleep
Restriction on Insulin Signaling
An increased serum level of ketone bodies is
known as ketosis. Investigations have showed
that cellular oxidative stress condition may
amplify in oxidative stress condition, which may
7 Oxidative Stress and Diabetes Mellitus
play a vital character in progression/development
of the insulin resistance (Rains and Jain 2011).
Excessive intake of nutrients may be responsible
for insulin resistance in the liver and skeletal
muscle. Several key modulators such as regula-
tory subunits of PI3K, the protein deacetylase
sirtuin 1 (SIRT1), and mTOR, a serine/threonine
protein kinase, may be involved in modulating
insulin action (Rains and Jain 2011).
PI3K signaling pathway is important for meta-
bolic responses to insulin, and alteration in PI3K
signaling have been observed in T2DM. Current
experimental evidence suggested that PTEN in
in vivo condition plays a vital role in glucose
metabolism regulation by negatively regulating
insulin signaling (Butler et al. 2002)
Sleep is considered a key regulator of the nor-
mal homeostasis of glucose metabolism and sen-
sitivity of insulin. Decrease in sleep increases
insulin resistance and risk of T2DM. Increase in
sleep loss is directly linked with obesity and dia-
betes. Sleep loss increases evening cortisol,
nighttime growth hormone, and leptin level but
decreases ghrelin level. This, in turn, increases
food intake and thus contributes to obesity, oxi-
dative stress, and production of pro-inflammatory
cytokines or other inflammation markers, which
are already discussed as contributing factor of
diabetes (Rains and Jain 2011) (Fig. 7.1).
Oxidative Stress and Diabetic
Complications
Activation of PKC isoforms, increased hexos-
amine, polyol pathway flux (conversion of glu-
cose to sorbitol through aldose reductase and
surplus sorbitol is responsible for oxidative dam-
age and activates stress genes), and increased
production of AGE (after binding to specific
receptors present in cell surface AGE leads to
postreceptor signaling and generates ROS) are
the four major mechanisms by which hypergly-
cemia increases the risk of diabetic complica-
tions (Choi et al. 2008).
Sequential glycation followed by free radical-
mediated oxidation produces early glycosylation
products. Irreversible AGE is produced by the
Oxidative Stress and Diabetic Complications 63

↑Lipid Mitochondria (through mitocondrial respiration)

Excess ADMA production
↑Glucose PKC
.–
NADPH oxidase ONOO
.
NO
NADPH NADP+
NOS III inhibition / uncoupling
LOX, COX Fenton
O2 Through increased production of O2.– reaction .
inflammatory mediators from arachidonic acid OH
eNOS GR
Fe+2
SOD GSH
XO Fe+3 GSSH
GPx
Hypgenthine/ Uric acid H2O2 H2 O
Xanthine CAT

Decreased endogenous
antioxidant production Incresed concentration of O2.–, H2O2
and other reactive species
Endothelial dysfunction

(↑UCP2 activity & ↑Mitochondrial ROS)

Oxidative stress Mitochondrial dysfunction

Enhance engagement OBESITY ↑Fatty acid ↑ATP

oxidation in generation
mitochondria
IKKB MAPK (JNK, P38) Pro-inflammation
other serine kinase (↑macrophage inflammation ↑Fatty acetyl CoA
NFKB ↑CRP, ↑NFKB, ↑TNE-α,↑IL-6)
iNOS expression Activation of Serine/
Threonine kinase ↑DAG
.
↑NO ↓Insulin stimulated
Serine/Threonine phosphorylation
glucose transport
S-nitrosylation
- -

Insulin receptor IRS P13K ATK GLUT-4

Increase glucose resistant and

After insulin signaling reduces glucose transport activity and metabolism decrease glucose tolarance

Diabetes mellitus

Fig. 7.1 Schematic representation of involvement of oxi-
dative stress and pathway leading to diabetes mellitus.
ATP adenosine triphosphate, JNK c-jun-NH2-terminal
kinase, MAPK mitogen-activated protein kinase, DAG
diacylglycerol, CRP C-reactive protein, PKC protein
kinase C, NO• nitric oxide radical, ONOO•− peroxynitrite
radical, O2•− superoxide radical, NOS nitric oxide syn-
thase, eNOS endothelial NOS, XO xanthine oxidase, H2O2
hydrogen peroxide, SOD superoxide dismutase, CAT
catalase, GSH glutathione, GSSH oxidized glutathione,
GR glutathione reductase, •OH hydroxyl radical, UCP
uncoupling protein, IKKB inhibitor of NF-kappaB kinases
beta, GPx glutathione peroxidase, NF-kB nuclear factor
kappa-light-chain-enhancer of activated B cells, iNOS
inducible NOS, IRS insulin receptor substrate, PI3K phos-
phatidylinositol 3-kinase, TNF-α tumor necrosis factor α,
IL-6 interleukin-6, ROS reactive oxygen species, LOX
lipoxygenase, COX cyclooxygenase

chemical rearrangements of some early glycosyl-
ation products. Under normal conditions, AGE
produced but their production accelerated in
diabetic condition. AGE generally accumulates
structural proteins, such as the collagens,
inducing increased covalent cross-linking result-
ing in hardening of the vessel walls and thus
increases the risk of vascular complications. In
diabetic condition, low-density lipoprotein
(LDL) has been found to be more prone to oxida-
64
tion (Catella-Lawson and FitzGerald 1996).
AGEs are also found to play a key role in the
pathogenesis of diabetic nephropathy. Increased
level of AGEs in chronic hyperglycemic condi-
tion also accumulates within the glomeruli and
may induce diabetic nephropathy. In T2DM
patients enhanced levels of erythrocyte aldose
reductase may be responsible for active prolifera-
tive retinopathy through erythrocyte polyol path-
way (Kuyvenhoven and Meinders 1999).
AGEs also can activate NF-kB (an intracellu-
lar transcription factors) which can stimulate sev-
eral intracellular molecules [e.g., PKC, sorbitol,
transcription of vascular cell adhesion molecule-
1 (VCAM-1), intracellular adhesion molecule-1
(ICAM-1)]. These activated molecules play an
important role for production of ROS. Production
of AGE is almost certainly an important contrib-
utor in diabetic complication, mainly atheroscle-
rosis. Recent studies have suggested that NADPH
oxidase could play a dual role. In response to
excessive ROS generation, NADPH oxidase
offers a feedback defense by the starting of recep-
tor tyrosine kinases and the redox-sensitive Nrf2-
Keap1 signaling pathway, whereas prolonged
activation of NADPH oxidase causes eNOS
uncoupling, mitochondrial dysfunction, and
damaged antioxidant defenses owing to the
reduction of intracellular NADPH and, thus, is
responsible for oxidative stress in DM (Wolff
et al. 1991; Perez-Matute et al. 2009).
Aldose reductase is considered as a limiting
enzyme of polyol pathway. Hyperglycemia is
responsible for the saturation of hexokinase, and
excess glucose is entered into the polyol pathway.
In the tissue of diabetic people, polyol pathway
enhances what do not need insulin for glucose
uptake in cellular level, such as the kidney, retina,
blood vessels, and peripheral nerves. Eventually,
polyol pathway causes shortage of intracellular
NADPH and excess of NADH, i.e., a reductive
imbalance. At the time of the conversion of sorbi-
tol to fructose, NADH generation increases
which offers substrate for NADH oxidase to pro-
duce ROS. Activation of poly (ADP-ribose)
polymerase occurs by the response of superoxide
and peroxynitrite-induced DNA damage. This
7 Oxidative Stress and Diabetes Mellitus
enzyme reduces the glyceraldehyde-3-phosphate
dehydrogenase (GAPDH) activity by ADP-
ribosylation, which results in the rise in triose
phosphate pool, upstream of GAPDH, and
enhanced flux of intermediates into the damaging
pathways of complications of DM. The reduced
bioavailability of NADPH as a consequence of
polyol pathway can affect adversely by depleting
GSH concentration. In the retina polyol pathway
acts as a main source of ROS. In addition, accu-
mulation of sorbitol has been implicated in some
eye diseases like osmotic swelling of the eye lens
and cataractogenesis (Ayepola et al. 2014).
Activation of PKC is responsible for prolifera-
tion, vasoconstriction, and overgrowth of smooth
muscle cells. In the same time, synthesis of extra-
cellular matrix proteins is accelerated by PKC
activation and thus confers significant role in the
beginning and progression of vascular cell dys-
function DM. Several researchers found that
interaction between AGEs and their receptors
present in cell surface can result in increased
activity of PKC isoforms. Activation of eNOS,
NADPH oxidase, endothelin-1 (ET-1), phospho-
lipase A2 (PLA2), VEGF, NF-kB, and TGF-β
may be responsible for several diabetic complica-
tions which are likely regulated by
PKC. Alteration of gene expression through
diacylglycerol-activated PKC can be considered
as key mechanism which is responsible for blood
flow reduction, inflammation, capillary occlu-
sion, production of free radical, and cellular mac-
romolecule damage. In vitro study demonstrated
that ROS production can increase via PKC-
dependent activation of NADPH oxidase in cul-
tured smooth muscle cells, aortic endothelial
cells, and renal mesangial cells due to high glu-
cose level. Experimental evidences suggested
that NADPH oxidase-dependent production of
ROS may be responsible for several diseases like
nephropathy, coronary artery disease, retinopa-
thy, etc. (Ayepola et al. 2014).
Loss of the vasoprotective effects of
endothelium-dependent relaxations arbitrated by
nitric oxide and on endothelial cells increased
expression of adhesion molecules which may
result in the activation of platelets. In diabetic
Oxidative Stress and Diabetic Complications
patients, platelets showed increased sensitivity to
aggregating agents, thus can play important role
in dyslipidemia (Catella-Lawson and FitzGerald
1996).
Alteration of cell signaling pathway and
induction of DM increase the risk of diabetic
complication. Insulin resistance generally
reflects decreased activity of NO, amplified
activity of angiotensin II and endothelin-1,
and elaboration of VEGF. Extracellular matrix
abnormalities can result to an irreversible rise
in vascular permeability. Reactive metabolite-
induced damage induces several metabolic and
structural changes in the body. Oxidation of
low-density lipoprotein which is taken up by
scavenger receptors in macrophages results in
atherosclerotic plaques and foam cell formation.
ROS-induced lipid peroxidation leads to abnor-
mality of the structure and fluidity of biological
membranes which eventually affects cellular
function. Insulin resistance and hyperglycemia
may be responsible for endothelial dysfunction
and dyslipidemia. Atherosclerotic macrovas-
cular complication generally affects arteries,
which supply the blood to the brain, heart, and
lower extremities. Thus, diabetic patients have
enlarged risk of stroke, myocardial infarction,
and limb amputation. Hyperglycemia decreases
the expression of heparan sulfate proteogly-
can and perlecan on hepatocytes resulting in
increased levels of atherogenic cholesterol-
enriched apolipoprotein B-containing remnant
particles. Hyperglycemia particularly increased
glucose level in postprandial condition is more
predictive of atherosclerosis than fasting blood
glucose level or HbA1c. These changes can
induce ischemia, edema, and hypoxia-induced
neovascularization in proteinuria, retina, mesan-
gial matrix expansion and glomerulosclerosis,
and multifocal axonal degeneration in periph-
eral nerves (Perez-Matute et al. 2009). It was
also found that activated monocytes and poly-
morphonuclear leukocytes in diabetic patients
produce significantly more oxidants like H2O2
than those of healthy individual, suggesting their
character in pathogenesis of CVDs and vascular
complications in diabetes. The apolipoprotein
65
moiety of LDL is also found to modify oxida-
tively in diabetic condition as a consequence of
generation of more ROS (Lipinski 2001).
DM is also responsible for depletion of endog-
enous antioxidant defense system components
including GSH, vitamin C, and vitamin E. Insulin
resistance and DM are also found to decrease the
total antioxidant, SOD, GPx, and GR activity.
Increased glucose level in the blood may be
responsible for downregulation of antioxidant
activity as it has been found that glycation of
SOD1 and Trx causes considerable deduction in
these enzyme activities. Strong evidence between
degree of oxidative stress and metabolic dysfunc-
tion was found in obese patients (Styskal et al.
2012). Polymorphism of antioxidant gene is also
involved in the increased risk of complications of
diabetes. For example, variant R213G in heparin-
binding domain of EC-SOD found to increase the
risk of CVDs. In Danish people it was observed
that this type of polymorphism was correlated to
increased risk of ischemic heart disease (Banerjee
and Vats 2014). Polymorphism of CAT gene par-
ticularly 9-262C/T polymorphism was examined
in several diabetic complications like retinopa-
thy, nephropathy, ischemic heart disease, and
CVD, which also contributed to the progression
of T2DM complications (Banerjee and Vats
2014). Polymorphism of polyalanine sequence of
GPx-1 (at least one 6-alanine repeat) is also
involved with the increased risk of coronary
artery disease (CAD). In Japanese individual
with T2DM, Pro198 LeuC/T polymorphism in
GPx-1 gene increased carotid intima-media
thickness, prevalence of CVDs, and peripheral
vascular disease. Seven polymorphisms of GPx-3
are also involved in hypoxic conditions, arterial
thrombotic stroke, and cerebral venous thrombo-
sis. Reduction in oxidized phospholipids, choles-
terol hydroperoxides, and pro-inflammatory lipid
peroxides caused by overexpression of GPx-4
involved oxidative stress and progression of
atherosclerosis. Polymorphism of GST is also
associated with atherosclerosis and other diabetic
complications (Banerjee and Vats 2014).
Ketosis is a common problem in DM due to
insulin deficiency, though it is severe in patient
66 7 Oxidative Stress and Diabetes Mellitus

with T1DM compare to patient with fructose-6-phosphate to glucosamine-6-phos-

T2DM. Result of several investigations suggested
that hyperketonemia may modify glucose uptake
at the time of metabolic stress and could be a con-
tributing factor to cardiomyopathy in diabetic
patients (Rains and Jain 2011).
Oxidative stress also plays a central role in
birth defect in diabetic mother and can certainly
affect embryonic development. Oxidative stress
can alter the sufficient expression of a few genes
characteristic of the different stages of embryonic
development. Every gene affected has precise
sensitivity to hyperglycemic situation and modi-
fies in cellular redox condition; the whole conse-
quence depends on some sort of molecular
signals (Clapes et al. 2013).
Hexosamine pathway also appeared as
important factor for diabetic complications. In
this pathway, fructose-6-phosphate is diverted
from glycolysis into this signaling path-
way where the enzyme glutamine fructose-
6-phosphate amidotransferase (GFAT) converts
phate and finally to UDP N-acetylglucosamine. It
is proposed that hyperglycemia-induced damage
increased flux of fructose-6-phosphate through
the hexosamine pathway and may increase the
gene transcription for several key genes like
TGF-α, TGF-β1, and plasminogen activator
inhibitor-1 (PAI-1), which may be responsible
for the complication related to diabetic blood
vessels. Inhibition of eNOS in arterial endo-
thelial cells by O-GlcNAcylation may lead to
diabetic vascular complications. In diabetic con-
dition GFAT activity increases in aortic smooth
muscle cells, which is responsible for O-GlcNAc
alteration of different proteins. Increased glucose
level is responsible for impairment of cardiomyo-
cyte calcium cycling through increased nuclear
O-GlcNAcylation, which decreased sarcoplasmic
reticulum Ca2+-ATPase 2a (SERCA2a) mRNA
and protein expression, and reduced SERCA2a
promoter activity (Brownlee 2005; Giacco and
Brownlee 2010) (Fig. 7.2).

SOD; GPx; GR; GSH; Vit C; Vit E; Hyperglycemia

Polyol pathway
Polymorphism of antioxidant gene NADPH & NADP; ROS
AL SDH
Glucose Sorbitol Fructose GSH; accumulation of sorbitol

Different diabetic NAPH NADP+ NAD NADH

O2
complecations related
Glucose-6-phosphate Vascular and Eye complecations,
to oxidative stress
Cataractogenesis
Hexosamine pathway
PKC Pathway
GFAT
Glucosamine
NADH NAD+ Fructose-6-phosphate -6-phosphate
UDP-GLCNAC
Vascular complecations,
a-glycerol-P DHAP GIn GIu Cardiomyocyte dysfunction

Glyceraldehyde-3-phosphate Detoriation of beta cell function: mRNA and protein expression

DAG
cNOS; ET-1; A11; VEGF; PAI-1,
NF-kB; NADPHoxidase; ROS; NOS
PKC
Gene transcription for TGF-α, TGF-β1, PA1; Nuclear O-GlcNAcylation
Modification of several protein in arterial endothelial cell
Age pathway

1,3-Diphosphoglycerate Methyglyoxal AGEs Yascular complecations.

Atherosclerosis, Nephropathy
Cardiomyopathy, Blood flow abnormality,
Macular edema, Vascular abnormality
Pyruvate Collagen cross linking accumulate in glomeruli; NF-kB; VCAM-I; ICAM-1;
Capillary occlusion, Neovascularization,
Vascular occlusion, Renal failure, Neuropathy, RAGE; Sorbitol; Chemokinin; adhesion molecule; NADPH oxidase
Amputation, Pro-inflammatory gene expression

Fig. 7.2 Mechanism involved in diabetic-induced com-
plications. DAG diacylglycerol, PKC protein kinase C,
NOS nitric oxide synthase, eNOS endothelial NOS, GSH
glutathione, GR glutathione reductase, GPx glutathione
peroxidase, NF-kB nuclear factor kappa-light-chain-
enhancer of activated B cells, ROS reactive oxygen spe-
cies, SOD superoxide dismutase, ET-1 endothelin-1,
VEGF vascular endothelial growth factor, NADPH
reduced nicotinamide adenine dinucleotide phosphate,
NADP nicotinamide adenine dinucleotide phosphate,
NAD nicotinamide adenine dinucleotide, NADH reduced
nicotinamide adenine dinucleotide, ROS reactive oxygen
species, UDP uridine diphosphate, GFAT glutamine
fructose-6-phosphate amidotransferase, VCAM-1 vascular
cell adhesion molecule-1, ICAM-1 intracellular adhesion
molecule-1, AGE advanced glycation end product, RAGE
receptor for AGE, TGF transforming growth factor, PAI-1
plasminogen activator inhibitor-1, DHAP dihydroxyace-
tone phosphate, AL aldose reductase, SDH sorbitol dehy-
drogenase, GlcNAc N-acetylglucosamine
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 Complications of Diabetes Mellitus
DM is connected with long-standing damage,
dysfunction, and malfunction of different organs
like the eyes, kidneys, skin, heart, nerves, blood
vessels, etc. DM has swiftly turned into a global
health problem because of its complications with
quickly rising in population, aging, urbanization,
and increase in the incidence of physical inactiv-
ity and obesity.
Acute Metabolic Complications
Diabetic Ketoacidosis
Diabetic ketoacidosis is a potentially life-
threatening complication in type 1 diabetic
patients with hyperglycemia (blood glucose lev-
els >200 mg/dL), but, also, can be seen in patients
with T2DM under certain circumstances like
stress of acute illness. Absolute shortage of insu-
lin combined with excess secretion of counter-
regulatory hormone (glucagon, growth hormone,
cortisol, catecholamines) results in lipolysis, aug-
mented production of ketone, hyperketonemia,
and acidosis (pH < 7.3 or bicarbonate <15 meq/L).
Morbidity due to diabetic ketoacidosis is related
to the harshness of the acid–base and disturbance
of electrolyte balance, which leads to coma and
death. Kussmaul respiration and a fruity odor on
the patient’s breath are classic symbols of dia-
betic ketoacidosis. Severity of the disorder results
in depression of the central nervous system
(CNS) and lethargy which may lead to coma.
© Springer Science+Business Media Singapore 2016
S. Sen et al., Diabetes Mellitus in 21st Century, DOI 10.1007/978-981-10-1542-7_8
8
Cerebral edema is an extremely serious compli-
cation of the disease which is rare but frequently
fatal in children. Lack of knowledge on DM, dif-
ferent acute illnesses, infection, noncompliance,
poor glucose control and self-care, psychological
disturbance, and indeterminate causes is some
precipitating factors for diabetic ketoacidosis.
Attention toward diabetes education and blood
glucose monitoring can help to reduce the fre-
quency of such complication and hospitaliza-
tions. If the condition became more severe, then
hospitalization and initiation of intravenous ther-
apy with insulin are the important approaches to
managing the situation. Awareness about hydra-
tion, maintenance of the balance between acid
and base, and management of electrolyte are nec-
essary to decrease the disturbance of electrolyte
(i.e., hypophosphatemia and hypokalemia) in
posttreatment period (Fishbein and Palumbo
1995).
Hyperglycemic Hyperosmolar State
Hyperglycemic hyperosmolar state (HHS) is a seri-
ous life-threatening acute metabolic complication
due to relative insulin deficiency and severe hyper-
glycemia in primarily T2DM. Hyperglycemic
hyperosmolar state is due to a constant osmotic
diuresis and is recognized by severe hyperglycemia
(plasma glucose level ≥ 600 mg/dL), serum hyper-
osmolarity (serum osmolality ≥ 320 mOsm/kg),
and deep dehydration (typically 8–12 L) with
69
70
increased serum nitrogen and creatinine ratio, but
without significant ketoacidosis. Bicarbonate con-
centration also found more (15 meq/L), tiny keto-
nuria, lack of low ketonemia with same alteration
in consciousness also can be observed. Polyuria,
weight loss, and diminished oral intake are associ-
ated with HHS which culminates in mental confu-
sion, lethargy, or coma. HHS is commonly
precipitated by concurrent myocardial infarction or
stroke. Infection (i.e., pneumonia, sepsis), mesen-
teric thrombosis, pulmonary embolism, gastroin-
testinal bleeding, acute pancreatitis, renal failure,
heat illness, thyrotoxicosis, Cushing’s syndrome,
acromegaly, and practices with glucose loading
(e.g., recent surgical operation, peritoneal dialysis)
can increase the chance of HHS and consider as
participating factors. Drugs like glucocorticoids,
thiazide diuretics, phenytoin, calcium channel
blocker, and beta-blockers which affect carbohy-
drate metabolism can contribute to the develop-
ment of HHS. Recent researches suggest that drugs
like clozapine, olanzapine, lithium, pentamidine,
immune-suppressant drugs, and cimetidine have
been connected with the advancement of hypergly-
cemia and also can cause HHS diabetic ketoacido-
sis. Alcohol and cocaine also are found to implicate
in the development of HHS. Sepsis, pneumonia,
and other infections are also occurring with the dis-
ease without the presence of ketosis or acidosis.
HHS is significantly less common than diabetic
ketoacidosis, but mortality rate is higher than those
associated with diabetic ketoacidosis (Fishbein and
Palumbo 1995; Nugent 2005).
Lactic Acidosis
Lactic acidosis is caused by increased pro-
duction or less utilization of lactic acid; this
situation is considered as broad-anion gap met-
abolic acidosis. Lactic acidosis is described as
the elevated level of lactic acid (lactic acide-
mia, ≥2.0 mmoL/L) with acidosis (pH ≤ 7.3)
and without ketoacidosis. It is also referred
as nonketotic acidosis occurring in diabetic
patients. The mortality rate due to lactic acido-
sis is high. Increased level of lactic acid along
with the acidosis increases the mortality rate.
8 Complications of Diabetes Mellitus
Morbidity due to lactic acidosis is associated
with neurologic impairment and probable cere-
bral edema. Biguanides are the drugs used for
the treatment of T2DM, may restrain oxidative
metabolism which results in the increase in the
level of NADH, decrease gluconeogenesis, and
restrain the gastrointestinal glucose absorption.
Biguanides especially phenformin therapy in
diabetes are one of the major reasons for fatal
lactic acidosis. Lactic acidosis is associated
with serious illness, hypotension, and high rate
of mortality. Although phenformin has been
banned by most of the countries, the report of
lactic acidosis result of metformin therapy was
anecdotal (Watkins et al. 1969; Fishbein and
Palumbo 1995; Luft 2001).
Hypoglycemia
Hypoglycemia is a very usual and alarming com-
plication during diabetic treatment and results in
sudden decrease in blood glucose level, and it is
one of the most important limiting conditions in
proper glycemic control in patients with T1DM
or T2DM. Mild hypoglycemia (60–70 mg/dL)
with no or least symptoms usually can be treated
with oral carbohydrate. Although if the condition
became more severe with extremely low glucose
level (<40 mg/dL) and neurologic impairment,
then it may need intrusion with either intravenous
glucose or glucagon, but the individual may be
adequately responsive to take oral carbohydrate
to alleviate the hypoglycemia. Hypoglycemia is
relatively more common in T2DM though the
patient with T1DM can also be familiar with
hypoglycemia and can experience nearly ten
symptomatic hypoglycemia episodes/week and
at least one severe temporarily disabling hypo-
glycemia/year. About 2–4 % mortality rate of
individual with T1DM have been accredited due
to hypoglycemia. The 90 % of patient receiving
insulin can also experience hypoglycemic epi-
sodes. Primarily, death connected with hypogly-
cemia is due to temporary neurologic deficit and
coma, permanent neurologic impairment and sei-
zures with CNS injury resulting from improper
treatment. The hypoglycemia-sensitive children
Vision Complications
with the occurrence of electroencephalographic
changes and seizure episodes are more prone to
death. Some factors involved in diabetic hypo-
glycemia include the use of insulin or oral hypo-
glycemic agent, mistakes in dosage and timing of
drug administered particularly insulin, not con-
suming meals at the right time, and comorbidity
such as adrenal insufficiency, renal insufficiency,
and pituitary insufficiency (Fishbein and Palumbo
1995; Briscoe and Davis 2006).
Vision Complications
Diabetic Retinopathy
Diabetic retinopathy is a microcirculatory com-
plication of both T1DM and T2DM. It is an ocu-
lar manifestation of systemic disease, occurs due
to damage of the tiny blood vessels inside the
retina, and can eventually lead to blindness. In
such conditions, the tiny blood vessels that sup-
ply nutrients and oxygen to the retina are dam-
aged due to high blood glucose level. This can
affect up to 80 % of all patients who have had
DM for more than 10 years. According to WHO,
diabetic retinopathy is responsible for 4.8 % of
cases of blindness from 37 million cases. Retinal
neurodegeneration is an early occurrence in the
pathogenesis of disease responsible for the
microcirculatory abnormalities in diabetic reti-
nopathy. The disease can be described into two
phases, proliferative and nonproliferative reti-
nopathy. Nonproliferative retinopathy is the pri-
mary stage and characterized by dilation of blood
vessels, microaneurysms, and small hemor-
rhages. Proliferative stage is the later stage with
frequent microaneurysms, hemorrhages, and
decrease in supply of nutrients and oxygen to the
retina. Proliferative retinopathy also can lead to
intravitreous hemorrhage condition. Duration of
diabetes, uncontrolled blood sugar, high choles-
terol level, high blood pressure, and smoking can
provoke diabetic retinopathy. Vision cannot be
reinstated if lost by diabetic retinopathy. But the
advancement of the disease and vision loss can
be minimized by better management of DM and
ongoing treatment of diabetic retinopathy.
71
Surgical procedures like laser surgery to assist in
shrinking the vessels or, in advanced serious situ-
ation, vitrectomy surgery to eliminate blood from
the center of the eye can be useful to treat such
condition (Kertes and Johnson 2007).
Cataract
Cataract is an opacification or cloudiness of the
lens that results in decreased visual acuity and
can lead to blindness. In Africa and in Asia, cata-
ract is the main reason behind blindness. Cataract
is one of the foremost causes of visual impair-
ment in diabetic affected patients. Research
showed that polyol pathway (aldose reductase
catalyzes the decrease of glucose to sorbitol) is
primarily linked with the development of diabetic
cataract and increase in the concentration of
intracellular sorbitol directs to osmotic changes
that leads in hydropic lens fibers which degener-
ate and cause sugar cataracts. Sorbitol accumula-
tion can result in osmotic stress which leads to
apoptosis in lens epithelial cells and also is
responsible for the development of cataract. In
addition, high level of glucose in the aqueous
humor may induce free radical generation (i.e.,
superoxide radicals) through glycation of lens
proteins, which is responsible for the formation
of AGEs. This process further leads the genera-
tion of superoxide radicals and hydrogen perox-
ide. Diabetic lenses also demonstrated a
weakened antioxidant capacity, which is not suf-
ficient against free radical-induced oxidative
damage. The concentration of NO• also increases
in the diabetic lens and in the aqueous humor,
which may cause generation of peroxynitrite in
high amount that causes cell damage. The use of
antioxidants and aldose reductase inhibitors is
found beneficial in the treatment of diabetic cata-
ract (Pollreisz and Schmidt-Erfurth 2010).
Glaucoma
Glaucoma is a painful disease that causes pro-
gressive optic neuropathy with characteristic
structural loss of optic nerve that leads to
72
blindness. This is generally associated with
raised intraocular tension (>21 mm of Hg) or
abnormal visual field and large or asymmetric
cupping of the optic nerve. Generally, it is classi-
fied into open- and closed-angle glaucoma.
People with diabetes mellitus have higher risk to
glaucoma. Diabetes mellitus is an important ocu-
lar risk factor of glaucoma with the incidence of
increase intraocular pressure and possibly open-
angle glaucoma (National Glaucoma Research
2009; Sakata et al. 2000).
Macular Edema
Macular edema is a frequent reason behind loss
of vision in diabetes due to the accumulation of
fluid behind the retina of the eye. It is a frequent
cause of blindness, especially in patients with
long-standing diabetes or with diabetic retinopa-
thy. Diabetic macular edema is due to upregula-
tion of vascular permeability factors, which
results in the breakdown of the blood–retina bar-
rier, allowing fluid to leak from abnormal retinal
capillaries and microaneurysms. Treatment of
macular edema includes resolving the edema,
improving visual acuity, and preventing recur-
rence, though control of blood sugar, hyperten-
sion, and body weight is included as the first-line
treatment of the disease (Spirn and Regillo 2008).
Keratopathy
Keratopathy can be described as the chronic
damage to the cornea with irritation, redness,
dry eye, and reflex watering of the eyes, which
can also result in impaired vision. Diabetic
keratopathy can be believed as a potentially
intimidating situation and must need suitable
clinical attention. Diabetic keratopathy includes
different symptomatic corneal conditions induc-
ing superficial punctate keratopathy and persis-
tent corneal epithelial erosion. After vitreoretinal
surgery, poor healing process of corneal epithe-
lial surface leads to persistent corneal epithelial
erosion. Poor healing process leads to microbial
attack and influences bacterial and fungal
8 Complications of Diabetes Mellitus
infective keratopathies. Increase in the polyol
metabolism in the cornea, advanced glycation of
end products, reduction in the corneal sensation,
and loss of nerve may implicate in the progres-
sion of diabetic keratopathy (Kaji 2005; Chous
2009).
Ischemic Optic Neuropathy
Anterior and posterior ischemic optic neuropathy
in diabetes is the medical condition characterized
by the damage of optic nerve which occurs after
ischemic lesions of anterior or posterior part of
the optic nerve in the area of diabetic micro- and
macroangiopathy. Different researches have
shown that the people with diabetes are more
prone to ischemic optic neuropathy than the nor-
mal people (Veselinovi and Jovanovi 2005;
Chous 2009).
Other Eye Disorders During DM
Dry eye is a disease condition of the eye surface
that includes dry, red, gritty, and even watery
eyes due to an imbalance in the quantity or qual-
ity of tears. This may result due to insufficient
tear production/flow. Reports suggested that poor
glycemic control can correlate with this as the
dry eye incidence is more common in diabetic
patient than normal (Kaiserman et al. 2005).
Retinitis pigmentosa is an eye disease that can
lead to incurable blindness. It is a type of pro-
gressive retinal dystrophy. Night blindness fol-
lowed by decrease of the peripheral visual field
and also vision loss can result in retinitis pigmen-
tosa. Though DM and retinitis pigmentosa occur
independently, few cases are reported where both
diseases are found simultaneously and diabetes
may be considered as a risk factor for the illness
(Al-Adsani and Gader 2010).
Myopia is a common refractive defect of the
eye. Far objects appear as blurred though near
objects are clear. Different researchers reported
that hyperglycemia led to the development of
myopia and myopia is associated with hypergly-
cemia (Srivastava 2003).
Foot Complications
Optic atrophy is the disorder related with loss
of some or most of the fibers of the optic nerve. It
may develop by the inflammation of the optic
nerve or due to glaucoma. Several reports sug-
gested that the cases of optic atrophy are more in
diabetic people and it is regarded as diabetic
complication (Shaw and Duncan 1958).
Some other complications of the eyes like
albinism, nystagmus, eye muscle palsy, and reti-
nal vascular occlusion are also important disor-
der. Though the direct relationship between these
diseases and diabetes is not clear, many research-
ers suggested that these diseases are more in dia-
betic patient than normal subject, indicating the
involvement of diabetes in the pathogenesis of
those diseases.
Foot Complications
Foot Ulcer
Foot ulcer is a common and major health prob-
lem of diabetic people. Different surveys showed
that a large number of people with diabetes have
a foot ulcer of varying sensitivity. About 15 % of
diabetic people are affected by foot ulcer during
their lifetime, and rate of morbidity associated
with diabetic foot ulcer is also considerable. DM
can cause peripheral arterial disease and neurop-
athy in the lower extremity, which can lead to
foot ulcer. Decreases in oxygen supply, nerve
impairment, and infection in diabetes are the
major causes of foot ulcer. Peripheral neuropathy
is considered as the greatest significant risk factor
for foot ulcer formation and lower extremity
amputation. Generally, foot ulcers in diabetic
people can be divided into two types: (i) neuro-
pathic ulcer, those in neuropathic feet recognized
as neuropathic ulcers, and (ii) neuroischemic
ulcer, those in the feet with ischemia frequently
coupled with neuropathy. Some studies reported
that in patient with neuropathy who develops foot
ulceration, 77 % will have had a minor traumatic
event and 63 % will have a foot deformity.
Moreover, once a foot ulcer is present and there is
poor arterial supply, a foot ulcer becomes more
difficult to heal if the blood sugar levels are not
73
controlled adequately and the risk of amputation
occurring significantly increases. Though treat-
ments with antibiotics, pressure relief, or some
traditional approaches are available to treat foot
ulcers, control of blood sugar is an important
measure to treat foot complications (Reiber et al.
1995; Jeffcate and Harding 2003; Oumeish
2008).
Foot Gangrene
Gangrene is defined as focal or extensive necro-
sis or death of the skin and underlying tissue of a
part of the body due to infection, injury, and/or
lack of blood supply. It is a type of irreversible
damage of body parts and related to lower
extremity arterial disease. As per recent report of
the World Health Organization, vascular disease
in individuals with diabetes is common, and the
word “lower extremity amputation” also includes
unoperated gangrene. Diabetic patient with foot
ulcers can progress to gangrene. Diabetic foot
gangrene and ulcers are most common complica-
tions in diabetes which can lead to amputation
(Palumbo and Melton 1995; Jeffcoate and van
Houtum 2004).
Lower Extremity Amputation
Microbial infection, tissue ischemia, continuing
trauma, and inappropriate/poor management of
foot ulcer and diabetes result in slow healing of
foot ulcers and transform readily into chronic
wounds which need amputation. DM is the most
frequent and primary cause of lower extremity
amputation. Amputations are referred as surgical
procedures performed in different heath condi-
tion including peripheral arterial occlusion, gan-
grene, non-healing ulcers, osteomyelitis, severe
soft tissue infections, trauma, deformities, and
tumors. Foot ulceration followed by amputations
is a key risk to individual suffering from DM, it is
a usual surgical procedure when healing is slug-
gish and uncertain, and the overall prognosis is
not as per expectation. Several epidemiologic
data also suggest that foot ulcers precede 50–85 %
74
of amputations though rates vary between coun-
tries and individuals with diabetes have a 15
times more risk of lower extremity amputation
than the healthy people without DM. Older
patients (>40 years of age) with DM for more
than 10 years had the highest risk of amputation.
An effective prevention of lower extremity ampu-
tation includes primary and secondary strategy.
Primary prevention includes diabetes manage-
ment, and the goal of secondary prevention is
proper and good care of foot ulcer. As the inci-
dence rate is more increasing, therefore ulcer
healing should be managed by a well-
synchronized program of secondary prevention
(Jeffcoate and van Houtum 2004).
Cardiovascular Complications
Cardiovascular complications are mainly respon-
sible for the increased rate of morbidity and mor-
tality in diabetic people. Cardiovascular disorders
are the most expensive complication of DM and
responsible for 86 % of deaths in diabetic indi-
viduals. The genetic background and lifestyle of
diabetic patient are also responsible for different
cardiovascular disease. Type 2 diabetic patient
has a two to four times greater risk of morbidity
from cardiovascular complications than the
patient without diabetes (Grundy et al. 1999;
Morrish et al. 2001).
Hypertension
Hypertension is a widespread cardiovascular
complication of DM, affecting 20–60 % of dia-
betic people. Hypertension is also considered as a
risk factor for different cardiovascular, macrovas-
cular, and microvascular complications including
stroke, myocardial infarction, peripheral vascular
disease, retinopathy, and nephropathy. Increase
in diastolic or systolic blood pressure (>5 mm of
Hg) results in 20–30 % concomitant increase in
cardiovascular disease. The incidence of hyper-
tension is 1.5–3.0 % higher in the diabetic than
that of nondiabetic. Hypertension developed in
generally 30 % of type 1 diabetic patient but is
generally found after several years of the disease;
8 Complications of Diabetes Mellitus
about 20–60 % of patients with T2DM are prone
to develop hypertension though it depends upon
age, ethnicity, lifestyle, and obesity. Hypertension
in T1DM may reflect the beginning of diabetic
nephropathy, and in T2DM, it is mainly due to
insulin resistance metabolic syndrome and also
includes obesity and dyslipidemia (Hamet 1993;
Arauz-Pacheco et al. 2002).
Atherosclerosis
Atherosclerosis is the most recurrent cause of
premature death in type 1 or type 2 diabetic
patients. Levels of plasma cholesterol and tri-
glycerides are significantly increased in diabetic
patient compared to nondiabetics. Insulin is not
only useful to decrease the blood glucose level
but also act as lipid-lowering hormone. Insulin
resistance generally reflects impaired insulin
action and manifests as an impaired effect of dif-
ferent lipid moieties like fatty acids and triglycer-
ide carrying lipoproteins. Generally, T2DM is
characterized by the increased level of triglycer-
ides, decreased level of high-density lipoprotein,
and normal level of low-density lipoprotein in
plasma. But, high triglycerides and low-density
lipoprotein are usually more susceptible to oxida-
tion, and chronic diabetes increases the glycation
of low-density lipoprotein, which may result to
atherogenesis. In T1DM, plasma lipid and lipo-
protein level may be normal, but oxidation and
glycation of the lipoproteins may harm their
function and/or augment their atherogenicity.
According to different researches, it was proved
that treatment of diabetes is useful to normalize
the abnormal lipid patterns. Thus, control of dia-
betes is the most important feature that helps to
normalize the lipids in diabetes (Hoogwerf 2005;
Canadian Diabetes Association 2006).
Stroke
Stroke is one of the major factors accountable
for morbidity, mortality, and permanent
disability worldwide. Diabetes significantly
enhances the risk of stroke; diabetic people have
1.5–3.0-fold risk of stroke compared with the
Cardiovascular Complications
nondiabetic individuals. Due to the inability of
insulin production, a patient with T2DM gener-
ally coexists with different cardiovascular dis-
eases including hypertension, obesity, and
hyperinsulinemia; these are also known as insu-
lin resistance syndrome and responsible for
stroke. DM is also one of the main regular pre-
dictors of recurrent stroke which leads to
increase in morbidity and mortality. Insulin
resistance and hyperinsulinemia in diabetes are
responsible for atherosclerotic changes.
Increased level of fasting plasma glucose (>5.5
mmoL/L) is strongly associated with ischemic
cerebrovascular events in individuals with pre-
existing atherothrombotic disease and stress
hyperglycemia, which may be responsible for
primary stroke. Chronic hyperglycemia is linked
with 17 % increase in the risk of stroke which is
because of elevated HbA1c levels. Diabetic
individuals have high risk of acute stroke, poorer
stroke outcome, and delayed recovery of neuro-
logical function followed by a stroke (Air and
Kissela 2007; Sander et al. 2008).
Myocardial Infarction
Myocardial infarction can be defined as isch-
emic necrosis of a portion of myocardium layer
of the heart due to sudden obstruction of a branch
of the artery. Epidemiological data suggest that
the number of morbidity, mortality, and early
disability due to ischemic heart disease repre-
sents a grave situation in several countries.
According to several researchers, the prevalence
of DM in acute myocardial infarction patients is
ranging from 8 to 18 %, and diabetes amplifies
the risk of acute myocardial infarction.
Myocardial infarction causes increase number of
morbidity in diabetic patient; according to a sur-
vey, diabetic patients with myocardial infarction
was accounted to 40 % mortality rate, which is
double than in patients without diabetes. In dia-
betic patient, production of ATP is less efficient
as relative insulinopenia causes increase in lipol-
ysis which increases plasma free fatty acid levels
and oxidation of fatty acid, while glucose oxida-
tion is suppressed. Diabetic patient with acute
myocardial infarction also increased the risk of
75
myocardial damage because in that condition
level of myocardial GLUT4 transporter protein
may be reduced which can induce increased pro-
duction of oxygen free radicals, myocardial con-
tractile dysfunction, and increased myocardial
oxygen consumption. Hypertension, atheroscle-
rosis, and other heart disorders in diabetes also
increase the risk of myocardial infarction.
Diabetic people also had the higher risk for fis-
suring and rupture of the atherosclerotic plaques.
Particularly during the periods of inadequate
control, platelet adhesiveness and aggregation,
increased level of plasma fibrinogen, increased
blood viscosity, and elevated levels of coagula-
tion factor VIII and procoagulant von Willebrand
factor were observed, which promote thrombus
formation. Fibrinopeptide A concentration also
increases in diabetic subjects that indicate
increased thrombin activity in vivo. Over-
production of thromboxane A2 leads to increased
platelet aggregation and vasoconstriction.
Endothelial dysfunction is linked with decreased
elaboration of prostacyclin and nitric oxide,
which are known as vasodilatory substances.
The levels of plasminogen activator inhibitors
are increased which leads to a decrease in fibri-
nolysis. The consequent events increase the risk
of blood vessel blocked and myocardial infarc-
tion in individuals with DM (Nesto and Zarich
1998; Alajbegovic et al. 2007).
Congestive Heart Failure
Congestive heart failure is a usual clinical disor-
der due to pulmonary vascular congestion or
decrease in cardiac output. Though the direct
relationship between diabetes and congestive
heart failure was not found, the disorder is com-
mon in people with heart disease, diabetes melli-
tus, hypertension, and coronary artery disease.
Different surveys suggest that diabetic people are
susceptible to congestive heart failure compared
to nondiabetic people, which is caused by a larger
amount of postinfarction myocardial necrosis.
Treatment of diabetes helps to control different
cardiac completions and ultimately can prevent
congestive heart failure (Figueroa and Peters
2006).
76
Cardiomyopathy
Diabetic cardiomyopathy may be described as a
broad range of structural abnormalities in the
myocardium ultimately which causes left ven-
tricular hypertrophy, diastolic and systolic dys-
function, or a combination of these. Diabetes can
direct to changes at the cellular level which may
play an important role in structural and functional
abnormalities of the heart. Hyperglycemia may
be responsible for the excess generation of AGEs
and generation of ROS which may lead to cardio-
myopathy. Some factors responsible for cardio-
myopathy include myocardial fibrosis, structural/
functional alterations of the small vessels, endo-
thelial dysfunction, different metabolic disorder
like altered supply of substrate and improper uti-
lization of it by cardiac myocytes, abnormality in
calcium homoeostasis, altered free fatty acid
metabolism, AGE accumulation, and activation
of PKC, which are directly linked with diabetes.
Poor diabetic management, chronic hyperglyce-
mia, prolonged hypertension, severe coronary
atherosclerosis, glycosylation of myocardial pro-
teins, microvascular disease, and autonomic neu-
ropathy amplify the risk of diabetic
cardiomyopathy. Better diabetic management
with adequate glycemic control, management of
hypertension, and prevention of atherosclerosis
with the specific therapy to reduce cholesterol
may avert or mitigate diabetic cardiomyopathy
(Grundy et al. 1999; Figueroa and Peters 2006).
Digestive Complications
The digestive tract executed a unique role relative
to diabetes. Diabetes can affect the entire diges-
tive system and causes mortality and morbidity.
About 75 % of diabetic patient reported for dif-
ferent digestive complications (Bjelakovic et al.
2005; Zhao et al. 2006).
Gastric Nerve and Motility
Abnormalities
Gastrointestinal tract is innervated by intrinsic
(constitute the enteric nervous system) and
8 Complications of Diabetes Mellitus
extrinsic (sensory and motor) nerves.
Gastrointestinal sensory–motor nerve abnormali-
ties are common in diabetic patients which may
lead to different complications. Diabetic auto-
nomic neuropathy can result in different abnor-
malities in afferent and efferent nerves.
Abnormalities of sensory and motor nerve may
result in increased vagal tones with abnormal
mechanical and electrical stimulation of the
esophagus, isovolumetric and isobaric disten-
sions of the proximal stomach, gastric distension
during euglycemia, and slow-transit, abnormal
motility, which are found more in diabetic patient
than the normal (Zhao et al. 2006).
Different researches on human and experi-
mental animals proved that gastric nerve abnor-
malities lead to gastrointestinal motility disorders.
Different motility complications due to diabetes
include esophageal dysmotility (excessive acid
exposure, spastic manometric pattern, low-
amplitude peristalsis, low lower esophageal
sphincter pressure), gastric dysmotility (delayed
gastric emptying, impaired adaptive relaxation),
biliary tract dysmotility (impaired gallbladder
emptying), small intestinal dysmotility (irregular
contractile activity and/or delayed small bowel),
and colonic and anorectal dysmotility (abnor-
mally low anal canal pressures, delayed colonic
transit) (Wingate et al. 2002).
Anorexia, Nausea, Vomiting,
Dysphagia, Early Satiety, Reflux,
and Pain
Anorexia, nausea, vomiting, dysphagia, early
satiety, and reflux are usual complaints of diabe-
tes. Anorexia, nausea, and vomiting are the early
indications of diabetic acidosis. Dysfunction or
abnormalities of afferent and efferent nerve in
diabetic patient are mainly responsible for these
types of complications. Dysphagia is a result of
motility disorder of the esophagus or impaired
esophageal transit. Early satiety is the most com-
mon symptom of diabetic gastroparesis.
Heartburn, chest pain, and abdominal pains are
also common with the diabetic patient. Heartburn
and chest pain in diabetes are mainly caused by
reflux or esophageal motor disorders. Abdominal
Digestive Complications
pain in diabetic patient may be the result of
diabetic gastroparesis, ketoacidosis, and severe
metabolic acidosis (Bjelakovic et al. 2005; Zhao
et al. 2006).
Candida Esophagitis
Poor glycemic control may contribute to GIT
infections by yeast. Yeast can infect the mouth,
exemplified by a thick tongue white coating, and
the throat along with burning sensation and pain.
Progression of the infection results in candida
esophagitis. It causes burning sensation in the
heart with difficulty in swallowing and also may
cause intestinal bleeding (Wolosin and Edelman
2000).
Diarrhea
Several factors like composition of food, irregu-
lar motility in the intestine, bacterial overgrowth
in the small intestine, extreme loss of bile acids,
and insufficiency of the pancreas are involved in
diarrhea of diabetic patients. Rapid or irregular
intestinal motility in diabetic patient may enhance
intraluminal contents that go to the cecum, and
delayed transit may result in overgrowth of bacte-
ria which may cause diabetic diarrhea. Abnormal
quick transit of fluids in the colon can lead to
increased urgency and frequency of stool.
Abnormal absorption and release of colonic fluid
may result in increased stool volume, frequency,
and water content. Diabetic diarrhea can occur
with or without steatorrhea, though exact patho-
genesis is still unknown (Wolosin and Edelman
2000; Zhao et al. 2006).
Constipation
Constipation is another gastrointestinal compli-
cation in diabetic patients. Though pathogenesis
of the disease is still not fully understood, abnor-
mality between the gut musculature and the
sphincters may be responsible for constipation.
Constipation results from autonomic dysfunction
and abnormalities in colonic myoelectric and
77
motor activity. Dietary manipulation with fibers
may be helpful in this condition (Bekele and
Kabadi 1996).
Celiac Disease
Celiac disease is a chronic autoimmune disease
of GIT, and commonly it causes atrophy in the
mucosa of small intestinal proximal segment.
Interaction between environmental factors, glu-
ten, genetic predisposition, and immune system
hyperactivity can trigger celiac disease. Current
studies showed that occurrences of celiac disease
in type 1 diabetic patient are approximately 20
times more than nondiabetic patient. There is evi-
dence of several autoimmune disorders in type 1
diabetes, which can correlate with celiac disease
(Pozgaj and Metelko 2003; Bjelakovic et al.
2005).
Megasigmoid Syndrome
Megasigmoid syndrome is a rare disorder of the
large intestine in diabetic patient. It can be
described as dilation of the colon, analogous to
gastric dilatation, which is generally related to
neuropathy and paralysis of ganglia in the large
intestinal wall. Erosions and ulcers in the sig-
moid colon are generally observed in this condi-
tion, which may be due to acute intestinal
pseudo-obstruction. Abdominal bloating, diar-
rhea, or obstipation is occurring as complication
due to megasigmoid syndrome in diabetic patient.
If obstipation progressed, it can be dangerous and
even fatal also (Bjelakovic et al. 2005).
Gastropathy and Gastroparesis
Diabetic gastropathy can be explained by com-
plex functional, contractile, electrical, and sen-
sory nerve dysfunction of the gastrointestinal
tract, mainly the stomach. It is related with
delayed gastric emptying. Diabetic gastroparesis
is a common complication in diabetic patient and
related with delayed emptying of food from the
stomach, which causes retention of contents in
78
the stomach. Bloating, distention, early satiety,
nausea, vomiting, abdominal pain, and anorexia
are general symptoms of gastroparesis. Gastric
emptying time is controlled by vagal nerve inner-
vations in the fundus and also dependent upon
the volume of the gastric content. A peptide moti-
lin regulates gastrointestinal motility, vagal nerve
control, and gastrointestinal secretion. Thus
impaired vagal nerve function causes prolong
emptying of fluid in diabetic patient. Dysfunction
of receptors involved in gastric relaxation causes
motility disorder in the stomach and duodenum.
Delayed gastric emptying may cause gastric
bezoars, and dysfunction of these nerves also is
responsible for mortality. Gastroparesis is mostly
common in type 1 diabetic patient with poor gly-
cemic control (Wolosin and Edelman 2000;
Emral 2002; Talley 2003; Zhao et al. 2006).
Fatty Liver
Fatty liver in diabetes is a result of microvascular
or macrovascular deposition of fat, nuclear vacu-
olization, cellular infiltration, and fibrosis in the
liver. The reports of diabetic fatty liver in T1DM
and T2DM range from 4 to 17 % and 21 to 78 %,
respectively. Most of the patients have asymp-
tomatic hepatomegaly and mild increased level
of alkaline phosphatase, though increase in
gamma-glutamyl transpeptidase level has also
been documented in some patient. Fatty meta-
morphosis in the liver can be managed by main-
taining optimal metabolic control (Bekele and
Kabadi 1996; Bjelakovic et al. 2005).
Gallstones and Cholecystitis
Several studies have shown that the incidence of
gallstone is more common in diabetic patient
than the normal. It causes significant problems in
diabetics when combined with acute cholecysti-
tis. Generally, cholecystectomy should be carried
out in diabetic patient with onset of acute chole-
cystitis due to autonomic dysfunction and which
may be secondary to gallstones (Bekele and
Kabadi 1996; Bjelakovic et al. 2005).
8 Complications of Diabetes Mellitus
Hyperamylasemia, Pancreatitis,
and Abnormalities of Pancreatic
Secretion
Pancreatic exocrine dysfunction is a common
complication in patient with T1DM and T2DM,
and it can affect up to 80 % of individuals with
T1DM. Diabetes mellitus results in decreased
pancreatic secretion. Pancreatitis is a common
complication in diabetes mellitus and one of the
major reasons for mortality. Alteration in carbo-
hydrate metabolism in diabetes is related to pan-
creatic lesions. Diabetes can more often be
observed with recurrent or chronic pancreatitis.
Some case of diabetes can arise from pancreati-
tis, which differs from the genetically determined
type. Degenerative complications of diabetes
mellitus are not generally found in pancreatic
diabetes (Wolosin and Edelman 2000; Bjelakovic
et al. 2005).
Carcinoma of GIT
Carcinoma of the pancreas is associated with
DM. The most frequent malignant lesion in
diabetes is pancreatic carcinoma, with massive
weight loss and deteriorated glycoregulation.
Patients with more than 5 years of diabetes
have twofold more risk of pancreatic cancer.
Researches have shown that T2DM was also
allied with an amplified risk of gallbladder and
biliary cancer, though other risk factors such as
pancreatitis, cholelithiasis, smoking, and obe-
sity are also related with gastrointestinal carci-
noma (Bjelakovic et al. 2005; Jamal et al.
2009).
Skin Complications
Skin manifestations are the common complica-
tions in DM. The structure and function of a pro-
tein depend upon the attachment of glucose to
protein and clinical appearances of the disease.
Both T1DM and T2DM account many complica-
tions of the skin (Huntley 1995; Sreedevi et al.
2002).
Skin Complications
Acanthosis Nigricans
Acanthosis nigricans is illustrated as thick and
highly pigmented upper layers of the skin that
causes a velvety appearance. It is a dermatologic
situation connected with hyperinsulinemia in few
cases. The pathogenesis may associate with
increased quantity of circulating insulin that
attach to growth factor receptors to augment
keratinocytes and dermal fibroblasts. It produces
asymptomatic lesions which are painful, mal-
odorous, or macerated. Generally this type of
complication is more found in patients with
T2DM (Sreedevi et al. 2002; Kong et al. 2007;
Hattem et al. 2008).
Bullosis Diabeticorum
Bullosis diabeticorum is characterized by multi-
ple dense bullae or blisters that occur primarily in
the lower extremities. It is a very rare complica-
tion of diabetes and can affect only 0.5 % of dia-
betic population and found more in T1DM. The
blisters can be of different types like spontaneous
lesions, nonscarring lesions, multiple tender non-
scarring blisters, and hemorrhagic blisters that
can heal with scarring and atrophy (Hattem et al.
2008; Oumeish 2008).
Calciphylaxis
Calciphylaxis is a small-vessel vasculopathy due
to mural calcification with intimal proliferation,
thrombosis, and fibrosis. It is caused by deposi-
tion of calcium and phosphate outside the bone.
Wound healing in calciphylaxis is slow and poor;
infection may progress to sepsis. It is found more
in patient with renal failure, those who are obese
or diabetic. The risk is more in T2DM (Hattem
et al. 2008).
Diabetic Dermopathy
It is one of the common cutaneous complications
mainly observed in the pretibial region of the
79
lower extremities. It is characterized by shiny
atrophic hyperpigmented macules or bilateral,
asymmetrical, irregular, or annular red papules or
plaques on the skin surface. Patients with T2DM
are more susceptible to this type of asymptomatic
lesions; it can occur in 7–70 % of diabetic patient.
Microvascular complication in diabetes can
aggravate diabetic dermopathy (Romano et al.
1998; Sreedevi et al. 2002; Hayat et al. 2010).
Diabetic Thick Skin
Diabetic patient commonly experienced thicker
skin generally in the dorsum of the fingers, palms,
soles, posterior thorax, and neck than normal
nondiabetic people. It can affect 8–50 % of
patient with T1DM. It may be due to abnormal
nonenzymatic glycosylation of collagen. The
thickness may be in different types: (i)
scleroderma-like changes of the hand allied with
stiff joints and restricted mobility, (ii) apparent
but quantifiable rise in skin thickness but clini-
cally insignificant, and (iii) scleredema adulto-
rum. Other signs of thickening of the skin include
pebbled or rough skin which is also called as
Huntley’s papules, over the interphalangeal
joints, predominantly the knuckles (Al-Mutairi
2006; Bhat et al. 2006; Hayat et al. 2010).
Xanthelasma
Xanthelasma is associated with yellowish discol-
oration of the skin of the palm, sole, and nasola-
bial fold. It is mainly observed in hyperlipidemic
state and in diabetes. Excess quantity of plasma
carotene results in deposition of carotene in
higher quantities, and the skin became yellowish
(Sreedevi et al. 2002).
Eruptive Xanthoma
Eruptive xanthoma is an uncommon complica-
tion of diabetes. The skin lesions are multiple,
firm, yellow, waxy papules with 1–4 mm in diam-
eter. Eruptive xanthomas are mainly associated
80
with hyperlipidemia and caused by the deposi-
tion of lipids in the histiocytes of dermal and sub-
cutaneous tissue. The decline in lipoprotein
lipase activity in insulin-dependent diabetics
causes increase of serum triglycerides, lipid, and
lipoprotein, which can initiate eruptive xan-
thoma. This type of complication is also found in
insulin-resistant diabetic patient (Al-Mutairi
2006; Oumeish 2008; Binic and Jankovic 2009).
Erysipelas-Like Erythema
Erysipelas-like erythema is another cutaneous
manifestation in diabetes appeared as red spot on
the feet and legs in aged patients. It is a microcir-
culatory problem that may cause demarcated ery-
thema on the dorsum of the foot or lower leg,
which linked with radiological proof of underly-
ing bone destruction, and early gangrene (Huntley
1995; Oumeish 2008).
Granuloma Annulare
Granuloma annulare is a degenerative condition
described by red spot in an initial stage, which
progressed to ringlike smooth, red lesions.
Though the pathogenesis is unknown, it can be
associated with diabetes. Granuloma annulare
can be characterized by the local degeneration
of collagen in the nearby areas of reactive
inflammation and fibrosis. Normally the lesions
appear in the dorsal surface of the feet, fingers,
and hand, but it can usually be observed in
extensors of the legs and arms; sometimes these
are also seen in the scalp (Sreedevi et al. 2002;
Oumeish 2008).
Lichen Planus
Lichen planus is characterized by pruritic, flat,
violaceous lesions in the forearms, wrist, lower
legs, lower back, mouth, and genitalia. It can
occur due to different autoimmune disorder or
metabolic disorder. Lichen planus is mainly clas-
sified into two types, i.e., immunogenic type and
8 Complications of Diabetes Mellitus
metabolic type. Both types of lichen planus are
associated with diabetes mellitus. About 1.6–
3.8 % of diabetic population has reported for this
type of complication. The occurrence of DM and
altered insulin response to glucose challenge has
been reported in patient with lichen planus
(Sreedevi et al. 2002; Al-Mutairi 2006).
Necrobiosis Lipoidica Diabeticorum
Necrobiosis lipoidica diabeticorum is a rare
inflammatory skin disease identified by irregular-
shaped, callous lesions with reddish-brown pig-
mentation and central atrophy. It is a manifestation
of diabetes and affects less than 1 % of diabetic
patient. But diabetes can be found in about 50 %
of patient with necrobiosis lipoidica (Huntley
1995; Wake and Fang 2006).
Perforating Disorders
Perforating disorders are chronic disorder con-
nected with DM or renal failure. It is illustrated
by pruritic, dome-shaped papules and nodules
with a hyperkeratotic plug (2–10 mm diameter),
found primarily on the trunk, limbs, hand (dorsal
surface), and face but in lesser extent. Perforating
disorders are distinguished by transepidermal
removal of collagen, elastic tissue, or necrotic
connective tissue. Different perforating diseases
include reactive perforating collagenosis, perfo-
rating folliculitis, elastosis perforans serpiginosa,
and acquired perforating dermatosis (Al-Mutairi
2006; Oumeish 2008).
Periungual Telangiectasia
Periungual telangiectasia is a frequent compli-
cation of DM with prevalence of up to 49 % in
diabetic patient. The lesions in periungual tel-
angiectasia appeared as red, dilated capillary
veins, which is the result of the loss of capillary
loops and dilation of the residual capillaries.
Periungual vessel changes cause connective
tissue disorder but these changes are
Skin Complications
morphologically different. Venous dilation of
periungual microcirculation appears as an indi-
cation of microangiopathy. Periungual telangi-
ectasia in diabetes is allied with nail fold
erythema, accompanied by “ragged” cuticles
and fingertip tenderness (Oumeish 2008;
Hattem et al. 2008).
Pigmented Purpura
Pigmented purpura is a skin disorder generally
found in most of the older patient affected by dia-
betic dermopathy. Skin lesions in pigmented pur-
puric dermatosis characterized as multiple tan to
reddish small macules which coalesce into tan to
orange patches in the skin of the lower extremi-
ties frequently extend below the ankles and the
dorsum area of the feet. It generally resulted from
RBCl extravasations from the superficial vascu-
lar plexus (Huntley 1995; Bhat et al. 2006).
Psoriasis
Psoriasis is a multifunctional inflammatory skin
disorder and may be considered as complications
of DM. Psoriasis is attributed to alterations in the
immune system involving T lymphocytes and
linked with an amplified risk of comorbidity and
mortality. Different studies have found the exis-
tence of higher incidence of psoriasis in diabetic
patent. Higher risk of psoriasis is connected with
insulin resistance, obesity, and an adverse cardio-
vascular risk profile. Several studies have also
suggested increased risk of diabetes and hyper-
tension in patient with psoriasis (Sreedevi et al.
2002; Qureshi et al. 2009).
Rubeosis Faciei and Red Skin
Diabetic rubeosis can be described as prototype
functional microangiopathy. Red, flushed area
appeared on the neck, face, and extremities par-
ticularly in the feet and hands due to engorge-
ment of the superficial venous plexus. Chronic
diabetes causes slow microcirculation and
81
develops a functional microangiopathy that is
clinically apparent by venous dilatation. This
venous dilatation and red colorization can be
observed in the skin and eye grounds, which are
marked in recently diagnosed individuals with
hyperglycemia, and this condition usually
comes back to normal when the blood glucose is
managed properly (Huntley 1995; Oumeish
2008).
Skin Tags or Acrochordons
The small, pedunculated, soft, generally pig-
mented lesions present on the neck, axillae, and
eyelids are so-called skin tag. Generally skin
tags are ignored but occasionally it became irri-
tant and painful. It is generally associated with
abnormalities of glucose metabolism, glucose
intolerance, hyperglycemia specifically in
T2DM, hyperinsulinemia, and obesity. Skin
tags are consequence of proliferation of dermal
fibroblasts through the activation of insulin-like
growth factor-1 receptors. Skin tags generally
appeared on the neck and it may associate with
acanthosis nigricans. The occurrence of skin
tags varies depending on the population and
area, but different studies showed it as a compli-
cation of diabetes (Romano et al. 1998; Hattem
et al. 2008).
Vitiligo
Vitiligo is described as acquired cutaneous
achromia with skin depigmentation character-
ized by single or multiple patches of milk white
color and tendency to expand peripherally. The
condition results in reduced or no function of
melanocytes that causes macular depigmenta-
tion; the skin presents no textural changes
except the absence of pigment with absence of
sensitivity to solar irradiation. Vitiligo is associ-
ated with T1DM, T2DM, autoimmune disorder,
thyroid disease, pernicious anemia, carcinoma
of the stomach, and Addison’s disease (Macaron
et al. 1977; Al-Mutairi 2006; Hattem et al.
2008).
82
Yellow Nails
Yellow colorization and lesion in the distal end of
the hallux nail of diabetic patient are mostly seen
in patients with T2DM. The prevalence of yellow
nail is 50–60 % in type 2 diabetic patient.
Glycosylation end product may be responsible
for yellowing of the nail of the hand and toe.
Protein–glucose reaction most probably contin-
ues to develop in the aging of nail which causes
yellow pigment at the distal segment of the slow-
est growing nail. It is also considered as one of
the important markers of diabetes (Huntley 1995;
Sreedevi et al. 2002; Hattem et al. 2008).
Kaposi’s Sarcoma
Kaposi’s sarcoma is a multiple idiopathic hemor-
rhagic sarcoma which is evident as primarily
multiple vascular nodules in the skin and other
organs. The lesions are initially observed in the
legs as several purple macules, nodules, or
plaque, which generally spread to other parts of
the body. According to some author, diabetes
mellitus is reported in higher frequency in
Kaposi’s sarcoma than normal, but still it is con-
troversial and needs more research (Sreedevi
et al. 2002; Hayat et al. 2010).
Bacterial Infection
Patients with hyperglycemia are prone to dif-
ferent cutaneous bacterial infections. Different
surveys reported that the prevalence of bac-
terial infection in diabetic patient is about
14–19 %. Uncontrolled and prolong duration
of diabetes increases the chances of bacte-
rial manifestation in diabetes. Staphylococcus
aureus and beta-hemolytic streptococci are
mainly responsible for different bacterial infec-
tions like folliculitis, furunculosis, carbuncles,
ecthyma, cellulites, erysipelas, abscesses, and
styes. Corynebacterium minutissimum causes
erythrasma which takes place with increased
occurrence in obese diabetic patients. Otitis
8 Complications of Diabetes Mellitus
externa is another bacterial infection caused by
Pseudomonas aeruginosa, which can advance
from cellulites and osteitis to nerve damage and
meningitis and causes high rate of mortality.
Another bacterial infection, anaerobic cellulitis,
is caused by Clostridium species in individuals
whose diabetes is not well managed properly
(Sreedevi et al. 2002; Al-Mutairi 2006; Bhat
et al. 2006; Oumeish 2008; Hattem et al. 2008;
Ahmed et al. 2009).
Fungal Infection
Fungal infections in diabetes include candida and
dermatophyte infections. Different surveys sug-
gested the occurrence of different fungal infec-
tions in about 9–19 % in diabetic patients.
Candida albicans, Vulvovaginal candidiasis,
Trichophyton rubrum, Trichophyton mentagro-
phytes, Tinea unguium, Tinea manuum, Tinea
cruris, Tinea corporis, and Microsporum and
Epidermophyton species commonly manifests
different fungal infections. The common fungal
infections include tinea pedis, onychomycosis,
candidal angular cheilitis, and candidal inter-
trigo. Candida generally infects the mouth, nail
folds, and intertrigo. Vulvovaginitis with itching,
soreness, and thick creamy white discharge is
generally common among women with long-
term diabetes. Candidiasis is most common
where the skins are moist; different candida
infections are generally found in the groins,
perineum, breasts, and axillae. Balanitis is
another common infection in diabetes with itch-
ing, pain, erosions, crack, and white scales.
Dermatophytosis is ringworm infections and
infects the skin, skull, and nails. Different tinea
species infects the foot, toenails, palms, groin,
and hand. Phimosis is also widespread among
individual with uncontrolled diabetes, where cir-
cumcision is frequently considered as a preven-
tive measure. General pruritus is common in
diabetic patient, but its frequency is unknown
though it is believed that candidiasis or dermato-
phytosis may cause pruritus in diabetic patient.
Most of the fungal infections cause the itching,
Oral and Dental Complications
red spot in the different parts of the body
(Sreedevi et al. 2002; Bhat et al. 2006; Hattem
et al. 2008; Ahmed et al. 2009).
Viral Infections
Viral infections are less common or rare manifes-
tation in diabetes, though several surveys have
suggested the occurrence of viral infections is
about 2–3 % in diabetic patient (Bhat et al. 2006;
Ahmed et al. 2009).
Macro- and Microangiopathy
Diabetic angiopathy is a vascular cutaneous com-
plication during diabetes. Diabetic patients have
slightly higher prevalence of large vessel disease
or macroangiopathy. Low-density lipoprotein,
very-low-density lipoprotein, and cholesterol are
considered as risk factor of macroangiopathy.
Angiopathy in larger vessel or atherosclerosis of
arteries of the legs results in skin atrophy, cold-
ness of the toes, hair loss, nail dystrophy, mot-
tling on dependence, and pallor upon elevation.
Microangiopathy is the foremost complication of
diabetes. Changes in small blood vessel or thick-
ening of vessel walls and vascular deposition
type IV collagen within and around blood vessel
affect the retinal and renal vasculature, which are
accountable for kidney failure, blindness, and
diabetic neuropathy. The sign of diabetic micro-
angiopathy includes dermopathy, pigmented pur-
pura, erysipelas, periungual telangiectases, and
diabetic foot complications. The presence of
microaneurysms is found in microangiopathy.
Gangrene of the foot is also considered as delayed
manifestation of microangiopathy (Huntley
1995; Sreedevi et al. 2002; Oumeish 2008).
Oral and Dental Complications
Diabetes is a most prevalent disease worldwide
with concomitant oral manifestations that
impact on dental and oral care. Uncontrolled
83
hyperglycemia results in oral complications in
diabetes and is devastating. Patients suffered
from DM represent a higher susceptibility to dif-
ferent infections due to a deficiency in polymor-
phonuclear leukocytes, as a result of vascular
alterations (Lyle 2001; Vernillo 2003; Hirsch
2004; Bakhshandeh et al. 2007).
Periodontal Disease (Gingivitis
and Periodontitis)
Periodontal diseases are the group of chronic dis-
eases, mostly caused by gram-negative bacterial
infections which damage the tissue of periodon-
tium and cell active in the inflammatory cascade.
This includes gingivitis and periodontitis.
Polymorphonuclear leukocytes which reduce in
diabetes play an active role in the inflammatory
process and in the upholding of gingival and peri-
odontal health. On exposure to bacterial toxin,
upregulation of chemical mediators like interleu-
kin (IL-1 and IL-6), prostaglandin E2, and TNF
takes place which plays a key role in periodontal
diseases. Periodontal diseases are commonly
seen in patients with both T1DM and T2DM.
Change in host response, vascularity, collagen
metabolism, subgingival microflora, gingival cre-
vicular fluid, and heredity patterns are said to be
involved in increased susceptibility to periodon-
tal diseases. Chances of periodontal problems
like as gingivitis and periodontitis can also
increase by the presence of plaque formation.
Salivary hyperglycemia is also considered as a
contributory factor to periodontal disease.
Diabetic people are two to five times more sus-
ceptible to develop periodontal diseases (Lyle
2001; Ship 2003; Vernillo 2003).
Gingivitis is characterized by pain, swelling,
or redness around the gums and considered as the
first stage of gum disease. Children with DM and
adults with less than optimal metabolic control
exhibit a higher incidence of gingivitis (Ship
2003; Vernillo 2003). Periodontitis is the inflam-
matory disorder of the periodontium and spe-
cially the periodontal membrane. The prevalence
of periodontitis is more in people with moderate
84
and poorly controlled diabetes. Hyperglycemia
and increased glucose in the saliva of people with
DM could modify the environment of the micro-
flora of the oral cavity, promoting periodontitis.
Periodontitis frequently coexisting with diabetes
is considered a usual complication in individual
with both T1DM and T2DM (Hirsch 2004;
Bakhshandeh et al. 2007).
Gingivitis is initiated generally by deposition
of microbial plaque on the dentogingival inter-
face, but its progression to periodontitis is modi-
fied by different environmental, behavioral,
biological, and healthcare factors. Though
chronic gingivitis is a frequent inflammatory dis-
order in the gingival tissues and commonly pro-
ceeds to the development of periodontitis, chronic
gingivitis does not certainly progress to peri-
odontitis (Hirsch 2004; Ojehanon and Akhionbare
2006).
Salivary Gland Dysfunction
and Xerostomia
Salivary gland dysfunction and dry mouth or
xerostomia are reported as a common compli-
cation of diabetes. This complication may be a
result of polyuria or an underlying metabolic
or endocrine problem. Poor glycemic control
and long-term diabetes cause salivary gland
dysfunction and xerostomia. Different surveys
suggested that about 40–80 % of populations
suffering from diabetes experienced xerosto-
mia. Studies have reported asymptomatic,
bilateral growth of the parotid glands in
24–48 % of people with diabetes, and individu-
als with uncontrolled hyperglycemia have
showed a greater tendency for enlargement of
the salivary gland. Decrease in saliva makes
the oral cavity became more susceptible to
dental caries and tooth deterioration.
Xerostomia causes damage of the oral tissue
by trauma and then the tissue became more
susceptible to different infections. Depression
and anxiety are significantly connected with
hyposalivation. Wettability, surface tension,
viscosity, and muscle control are some feature
that increases denture retention (Lyle 2001;
Lalla and D’Ambrosio 2001; Ship 2003).
8 Complications of Diabetes Mellitus
Tooth Loss or Edentulousness
Edentulousness or loss of all natural teeth in dia-
betes is another complication of diabetes melli-
tus. Progression of periodontitis results in tooth
loss in diabetic patient, which is difficult to con-
trol. Diabetes causes vascular changes in all tis-
sue including oral vessels causing membrane
disruption along with intramembranous presence
of collagen and endothelium in diabetic patients
leads to tooth loss. Inadequate metabolic control,
long-lasting diabetes, and risk of periodontitis
increase the chance of tooth loss (Cukovic-Bagic
et al. 2004; Hirsch 2004).
Dental Caries
Dental caries (tooth decay) is considered as an
infectious disease relating multiple factors like
existence of the causal microorganism, substrate
(diet), host (tooth), and immune capacity of the
individual. Different studies have suggested that
diabetic individual have more active dental caries
than control patient though the association
between DM and dental caries has had not been
clarified. Poor metabolic control of diabetes, ele-
vated salivary glucose levels, and presence of
periodontal diseases in diabetes increase the
chance of dental caries. Low-carbohydrate dia-
betic diets may be beneficial to reduce dental car-
ies prevalence. Dental plaque can eventually
increase the chance of dental caries (Lalla and
D’Ambrosio 2001; Lyle 2001; Ship 2003).
Burning Mouth Syndrome and Test
Disturbance
Taste is a critical element of oral health.
Dysfunction of taste and burning mouth syn-
drome (glossodynia/stomatopyrosis) are reported
in numerous diabetic patients that could result in
hyperphagia and obesity. Dry, atrophic, and
cracking oral mucosa is the result of inadequate
production of saliva and leads to burning mouth
syndrome. Mucositis, desquamation, ulcers, and
a depapillated and inflamed tongue are also
frequent problems in diabetic patient. These
Kidney Complications
complications are considered as sensory dysfunc-
tion, can restrain the capability to preserve a
proper diet, and can direct to poor glycemic man-
agement (Lalla and D’Ambrosio 2001; Ship
2003; Vernillo 2003).
Candidiasis
Oral candidiasis is a common, frequent fungal
infection connected with hyperglycemia.
Candida albicans and Candida pseudohyphae
are generally involved in this type of oral compli-
cation. Candidiasis is associated with oral lesions
which include atrophic glossitis, median rhom-
boid glossitis (central papillary atrophy), denture
stomatitis, angular cheilitis, and pseudomembra-
nous candidiasis (thrush). Different main caus-
ative factors for oral candidiasis in diabetic
patients include compromised immune function,
salivary dysfunction, and salivary hyperglycemia
that offer a potential substrate for growth of fun-
gus (Ship 2003; Vernillo 2003).
Oral Lichen Planus
Occurrence of oral lichen planus is significantly
higher in diabetic patient than the normal. It is a
comparatively common, chronic mucocutaneous
disease. Oral lichen planus causes atrophic or
erosive lesions in the mucosal membrane. The
exact etiology of oral lichen planus is still
unknown, but some factors like genetic, psycho-
logical, and infectious factors are associated
with it. Oral lichen planus is now considered as
an autoimmune disease illustrated by an epithe-
lial basal cell lesion that provokes an autoim-
mune response, particularly mediated by the T
lymphocyte population (Lalla and D’Ambrosio
2001; Vernillo 2003).
Acute Oral Infections or Other Oral
Infections
The prevalence of aphthous stomatitis and other
bacterial or viral infections is found relatively
more in diabetic subjects than the normal.
85
Aphthous ulcer is a type of painful oral ulcer,
characterized by a break in the mucous mem-
brane. The different bacterial infections mainly
gram-negative bacterial infection in the oral cav-
ity are also one of the reasons of periodontal dis-
ease. Lengthening the time for healing and
increasing the risk of infection in diabetes
increase the chance of different infections (Ship
2003; Loo et al 2009)
Traumatic Ulcers and Irritation
Fibromas
Traumatic injuries are the lesions of the oral cav-
ity that may typically lead to the formation of
surface ulcerations, and irritation fibroma is a fre-
quent submucosal reaction to trauma from the
teeth or dental prostheses. Recently a survey
reported that T1DM has a higher incidence of
oral traumatic ulcers and irritation fibromas than
the people without DM (Lalla and D’Ambrosio
2001).
Kidney Complications
Kidney disease and failure due to diabetes is the
most familiar, accounting for about 44 % of new
cases. According to WHO, about 10–20 % of
individual with diabetes dies of renal failure.
Both T1DM and T2DM are responsible for the
development of different kidney complications
though different factors like sex, ethnic
background, genetic factors, and presence of
other diseases also may contribute in the patho-
genesis of kidney diseases (Morrish et al. 2001;
Dabla 2010).
Diabetic Glomerulosclerosis
Diabetic glomerulosclerosis is exemplified by
thickening of the membrane of glomerular base-
ment with increased permeability, and the mesan-
gial space becomes expended by deposits of
proteins. It results in increase in albumin or pro-
tein excretion and glomerular filtration rate also
rises and subsequently falls. The progression of
86
glomerulosclerosis was considerably associated
with the proper management of blood glucose
level, type of DM, onset age, kind of treatment
received, and presence of obesity. We have dis-
cussed the clinical factors accountable for the
progression of DM. Successful management of
blood glucose may stop or slow down the pro-
gression of diabetic glomerulosclerosis (Morrish
et al. 2001; Dabla 2010).
Diabetic Nephropathy and Renal
Papillary Necrosis
Diabetic nephropathy is a disorder described by
persistent albuminuria, reduce in glomerular fil-
tration rate, and increase in blood pressure.
Pathogenesis of diabetic nephropathy is multifac-
torial with the involvement of metabolic abnor-
malities, various growth factors, homodynamic
alteration, genetic factors, and infections. The
pathology of diabetic nephropathy is evident as
diabetic glomerulosclerosis, which can be exem-
plified by glomerular basement membrane thick-
ening and mesangial expansion with augmented
extracellular matrix deposition. Diabetic
nephropathy is the major life-threatening compli-
cation in T1DM. Expansion of mesangial and
clinical severity of the disease in type 1 diabetes
showed its direct relation with diabetes. Diabetic
nephropathy, also a common disorder in type 2
diabetic patients, according to different surveys,
occurs in approximately one third of individuals
with T2DM (McLaughlin et al. 2005; Dabla
2010).
Renal papillary necrosis is a one type of
nephropathy connecting with the necrosis of the
renal papilla, which is supplied by the vasa recta.
Renal papillary necrosis is associated with diabe-
tes due to the infection and vaso-occlusive sickle
cell crisis (Smith and Godwin 1964).
Bladder Dysfunction
Bladder dysfunction in man and women
is one of the widespread complications of
DM. Pathophysiology of bladder dysfunction is
complex and can be caused by modification in
8 Complications of Diabetes Mellitus
the physiology of detrusor smooth muscle cell,
innervations of the neuronal component, or uro-
thelial dysfunction. Several of clinical surveys in
diabetic people (women and men) have reported
39–61 % of bladder instability or hypersensitiv-
ity as the most common bladder dysfunction. In
diabetic women, bladder dysfunction results in
involuntary urine loss with a feeling of urgency
during physical activity. Poor glycemic control
and microvascular complications caused damage
to innervations of the bladder. In diabetic man,
bladder complications also may cause benign
prostatic hyperplasia and lower urinary tract
symptoms (Brown et al. 2005).
Urinary Tract Infection
and Pyelonephritis
Urinary tract infections are common in individuals
with diabetes. Different infections by different
microorganisms in the renal tract which include
pyelonephritis, cystitis, perinephric abscess, can-
didiasis, and bacteriuria showed close involvement
with diabetes mellitus. Maximum urinary tract
infection in diabetic patient is comparatively
asymptomatic, and presence of diabetes and its
other complications makes the infection more
severe. Bacteriuria can be described as a presence
of bacteria in urine and very common in diabetic
patient, which is also responsible for low-grade
foci of inflammation, which can result in renal
damage. Bacteriuria leads to cystitis and other
upper urinary tract infections. Perinephric abscess
mainly developed in renal parenchyma, and
according to a survey, diabetes is present in
30–40 % of cases of perinephric abscess.
Candidiasis is a fungal infection of the urinary
tract, and diabetes is commonly found in the
patient suffering from urinary tract infection than
normal (Balachandar et al. 2002).
Pyelonephritis is the most common and major
urinary tract complication in diabetic patient, and
it is found that it is five times more common in
diabetic patient than nondiabetics. Acute pyelo-
nephritis in a diabetic can cause the greatest dan-
ger as it can result in diabetic coma, the
impairment of renal function, and acidosis, which
is more difficult to treat. Emphysematous
Sexual Complications
pyelonephritis is associated with high mortality
rate due to renal destruction and a major compli-
cation of diabetes due to bacterial intestinal
nephritis (Prkacin et al. 2001).
Sexual Complications
DM is known to provoke numerous medical, psy-
chological, and sexual problems. Sexual dys-
functions are frequent in diabetic patients. Sexual
dysfunction of diabetic patient was considered an
inevitable, irreversible complication. Sexual
complications in diabetes include sexual dys-
function in male and female.
Erectile Dysfunction
Erectile dysfunction is a steady inability to
achieve and maintain erection of the penis to per-
mit adequate sexual intercourse in man. Total
incapability to have an erection and the lack of
ability to sustain an erection are considered as
erectile dysfunction. It was estimated that diabetic
patients are two to three times more likely to have
erectile dysfunction compared to normal people.
Diabetes causes autonomic neuropathy and
peripheral neuropathy; it is also responsible for
penile arterial narrowing and arteriolar closure
that lead to “penile hypotension” and cavernous
arterial insufficiency. Endothelial dysfunction,
disturbance in local neuro-regulatory mediators,
high blood pressure, high cholesterol, and lower
levels of testosterone are also linked with diabe-
tes, and thus diabetes increases the chance of
erectile dysfunction. Good glycemic control,
maintenance of blood pressure, and lipid control
minimize the risk of developing this complication
(Penson and Wessells 2004; Hatzimouratidis and
Hatzichristou 2009).
Ejaculatory Problems
Different types of ejaculatory problem like
delayed ejaculation and anejaculation (inability
to ejaculate) are also associated with diabetes.
Different physical or psychological factors are
87
responsible for impaired ejaculation. Type 2 dia-
betic men can experience altered sexual function
due to mechanical trouble. In diabetic men, auto-
nomic neuropathy is the possible cause of ejacu-
latory failure. Traumatic injury is also considered
as the important cause of an ejaculation by dis-
ruption of the nerve supply. Erectile impotence is
more frequent in DM that affects young diabetic
patients and is frequently related with ejaculatory
problems (Taylor 2002; Anonymous 2007).
Retrograde Ejaculation
Retrograde ejaculation is a situation where the
patient fails to see any fluid (semen) after orgasm,
because semen enters into the bladder instead of
going out through the penis tip at the time of ejac-
ulation. Retrograde ejaculation is a complication
in diabetes and reported as a consequence of dia-
betic neuropathy. This condition takes place
when internal muscles (sphincters) fail to func-
tion normally. In this condition, semen goes
inside the bladder, mixes with urine, and comes
out during urination without any bladder injury.
Retrograde ejaculation is responsible for infertil-
ity in 2 % of male and a foremost cause of
aspermia (Taylor 2002; Anonymous 2007;
National Diabetes Information Clearinghouse
2008).
Balanitis
Balanitis is a bacterial infection that causes
inflammation of the glans penis. It is character-
ized by itchiness, rashes, redness, swelling, dis-
charge from the penis, and inability to pull back
the foreskin of the penis. Moist area in the fore-
skin of the penis and poor glycemic control
increase the chance of bacterial infection and
causes balanitis (Allan 2008).
Aspermia
Aspermia is the condition with complete lack of
semen, and it is generally associated with infertil-
ity. Damage to the sympathetic nerve supply is
88
responsible for aspermia. This condition is gener-
ally observed in patients with autonomic neurop-
athy due to diabetes or from other neurological
conditions (Ralph and Wylie 2005).
Low Quantity of Seminal Fluid
Low volume of seminal fluid is an uncommon
complication and is mostly observed during the
infertility management associated with low vol-
ume or, infrequently, absent ejaculate. Ejaculatory
duct obstruction, urethral strictures, congenital
anomalies of the seminal vesicles, or limited neu-
rological lesions from DM or surgery can be
responsible for this type of problems (Ralph and
Wylie 2005).
Testosterone Deficiency
Testosterone deficiency, or hypogonadism, is
now recognized as a common occurrence in dia-
betic patient, which increases with age.
Testosterone is the most important male sex hor-
mone and plays a significant role in reproductive
and sexual function. It is one of the main factors
responsible for libido. T2DM mainly affects the
production of testosterone. High blood glucose
levels can reduce the amount of luteinizing hor-
mone, which trigger the testosterone production,
and thus testosterone level was reduced. Obesity
also can reduce the testosterone levels.
Testosterone is also produced naturally in the
female ovaries and adrenal glands and associated
with female sexual function. Testosterone is a
precursor of estrogen and involved in increasing
blood flow, either directly or via estrogen. Thus,
diabetes causes sexual problems by decreasing
the testosterone level in man and women (Allan
2008; Miocic et al. 2008).
Disorder of Libido or Desire
Libido (sexual desire) is a complex condition
regulated by a combination of biological, per-
sonal, and relationship factors. Androgen plays a
8 Complications of Diabetes Mellitus
vital role in preservation of sexual interest and
motivation. Libido is a frequent complication in
DM, which affects both man and woman.
Diabetes causes nerve damage and vascular trou-
bles which may induce decreased libido.
Testosterone is known to boost blood flow, either
directly or via estrogen. Diabetes results in
decrease quantity of testosterone/androgens
which is also responsible for disorder of libido
(Allan 2008; Miocic et al. 2008; Ozcan and Sahin
2009).
Defects in Arousal and Vaginal
Lubrication
Arousal is the main problem in diabetic women.
Arousal comprises the psychological condition
and physical reaction of vaginal alteration,
including the vaginal lubrication, the pelvic floor
muscle relaxation, and the engorgement of the
labia and clitoris. Physiologically, arousal is
characterized by vasodilation and engorgement
of the female external genitalia. Diabetes causes
vascular damage and reduces blood flow during
arousal, which results in decrease in the vaginal
lubrication and clitoral stimulation (Jovanovic
2002; Enzlin et al 2002).
Menstrual Problem, Amenorrhea,
and Disturbed Ovarian Function
Type 1 diabetic women are at greater risk for
menstrual dysfunction and linked irregularities.
Prevalence of secondary amenorrhea (abnormal
absence or suppression of menstruation) is more
in diabetic women in contrast with nondiabetic
women. Low body mass index and high HbA1C
are reported in diabetic women with amenor-
rhoea, which represents poor glycemic control
and less body weight in such women. Women
with diabetes may also have amplified dopami-
nergic tones, which may contribute to the patho-
genesis of amenorrhea. Type 1 diabetic women
showed early menopause than women without
diabetes. A survey reported 17 % decrease in the
childbearing period of women with this state.
Pregnancy-Related Complications
Though both T1DM and T2DM are responsible
for troubled ovarian function and if diabetes is
not controlled properly, anovulatory infertility
may occur. Type 1 diabetes may be linked with
premature menopause due to ovarian autoimmu-
nity by altering hypothalamic–pituitary function
(Taylor 2002; Ozcan and Sahin 2009).
Polycystic Ovarian Syndrome
Polycystic ovarian syndrome is mainly connected
with T2DM and impaired glucose tolerance. It is
an endocrine disease which causes enlargement
of the ovaries with multiple cysts scattered
around or through an echo-dense thickened cen-
tral stroma with connected symptoms of hyper-
androgenization, menstrual irregularity,
endocrine abnormalities, or obesity. Women suf-
fering from polycystic ovarian syndrome are
reported to be insensitive to insulin or insulin
resistant (Taylor 2002; Ozcan and Sahin 2009).
Dyspareunia
Dyspareunia (painful intercourse) is also a com-
mon problem in diabetic women; according to
several surveys, dyspareunia is reported in about
10–21 % of women with diabetes and in 4–8 % of
control subjects. Vaginal dryness is found to be
one of the reasons of dyspareunia (Enzlin et al
2002; Miocic et al. 2008).
Anorgasmia
Reduced or absent sexual response in diabetes
includes the failure to become or stay aroused,
decreased or complete loss of sensation in the
genital area, and the steady or infrequent inability
to reach orgasm. Anorgasmia (failure to achieve
orgasm) is another problem in diabetes.
According to one survey carried out in women
with diabetes aged 18–42, anorgasmia was
reported in about 35 % of patients reported as
compared with 6 % in the control group (Miocic
et al. 2008; Ozcan and Sahin 2009).
89
Vaginal Infection and Discomfort
Vaginal thrush is a fungal (candida) infection in
the vagina. It is an asymptomatic and a common
complication in diabetic women. Different sur-
veys reported vaginal discomfort in large number
of diabetic women (Ozcan and Sahin 2009).
Pregnancy-Related Complications
Poor glycemic control or improper care during
pregnancy increases morbidity and mortality to
infant of diabetic mother. Maternal hyperglyce-
mia or DM significantly increases the risks of
adverse perinatal outcomes during pregnancy.
The etiologies of those diseases are numerous
and heterogeneous, but these adverse effects, at
least in part, are related to periconceptional care,
especially the level of glycogenic control.
Congenital Malformations
Congenital malformations are expressed as phys-
ical body or organ malformations/defect present
in a baby next to birth. Different organs like the
heart, brain, lungs, bones, liver, and intestinal
tract are affected. The occurrence of congenital
malformations is higher in pregnant diabetic
women. Type 1 diabetic pregnant women are
associated with an increased risk of congenital
malformations. Major congenital malformations
include defect in the cardiovascular, central ner-
vous, skeletal, and genitourinary systems.
Congenital malformations are a foremost cause
of neonatal morbidity and mortality and found in
7–18 % of pregnancies of diabetic women. Proper
glycemic control reduces the risk of congenital
malformations (Chia et al. 1996; Russell and
Coustan 2005).
Fetal Macrosomia
Macrosomia or fetal obesity is a condition when
the birth weight of the baby is above 4000 g; it
is a common complication of pregnancy in
90
diabetes. Fetal macrosomia is a condition of
fetal overgrowth. Mother with GDM or T1DM
is more prone to deliver overweight infants.
Macrosomic infants have increased chance of
developing obesity, glucose intolerance, and
diabetes during childhood or even in adulthood.
Pancreatic islet cells get stimulated during fetal
hyperglycemia, leading to hyperinsulinemia,
which results in increased liver glycogen con-
tent, fat tissue, and total body size. The problem
in maternal metabolism is also affecting growth
and an important factor of macrosomia
(Merzouk et al. 2000; Russell and Coustan
2005).
Shoulder Dystocia
Shoulder dystocia, a condition where, after deliv-
ery of the head of the new born, the anterior
shoulder cannot pass underneath the pubic sym-
physis, requires major manipulation to get
through the pubic symphysis. A number of sur-
veys reported the increased risk of shoulder dys-
tocia in infant of diabetic women. It is an
obstetrical emergency, with fetal demise occur-
ring if the newborn is not delivered in 5 min, due
to compression of the umbilical cord in the birth
canal. Shoulder dystocia is also seen more in
macrosomic infants (Keller et al. 1991; The
HAPO Study Cooperative Research Group
2008).
Neonatal Hypoglycemia
Neonatal hypoglycemia or low blood glucose in
the newborn is another complication of preg-
nancy for women with high blood sugar level.
The risk of neonatal hypoglycemia is associated
with the degree of maternal glucose control in the
period preceding delivery. Neonatal hypoglyce-
mia generally is due to glycogen depletion,
immature gluconeogenesis, or hyperinsulinism.
Hyperinsulinism is related to abnormality of
β-cell function and principally caused by mater-
nal diabetes (Russell and Coustan 2005; Torpy
et al 2008).
8 Complications of Diabetes Mellitus
Spontaneous Abortion
Poor glycemic control during embryogenesis
has been associated with spontaneous abortion
or miscarriage. Two types of spontaneous abor-
tions can be seen in diabetic patient; this
includes early abortion (9–14 weeks), which is
associated with a blighted ovum or early embry-
onic death, and late abortions (16–25 weeks)
with normal fetus. Uncontrolled diabetes greatly
increases the risk of miscarriage. High level of
glycosylated hemoglobin which reflects overall
blood glucose level is connected with spontane-
ous abortion (Wright et al. 1983; Russell and
Coustan 2005).
Neonatal Deaths
The prevalence of high perinatal mortality
remains among newborns of mothers with T1DM
and T2DM. Perinatal deaths are mainly in two
types, neonatal deaths and stillbirth. A number of
surveys showed the increased risk of neonatal
death in diabetic pregnant mother. Hyperglycemia
is one of the important causes of fetal macroso-
mia and also responsible for angiopathy that gen-
erally affects the uteroplacental blood vessels,
resulting in fetal hypoxia. The cases of neonatal
death were doubled in women having a mean
prepregnancy body mass index (Cundy 2008;
Rackham et al. 2009).
Stillborn Infant
Stillbirth occurs when a fetus has died in the
uterus, during labor or delivery. It is a condition
of fetal death that occurs greater than 20 weeks.
All forms of diabetes during pregnancy are
linked with an elevated risk for stillbirth.
Hyperglycemia in pregnant mother causes fetal
anaerobic metabolism with hypoxia and acido-
sis which results in stillbirth. Proper glycemic
control and intensive multidisciplinary prenatal
care of pregnant diabetic mother can decrease
the risk of stillbirth (Dudley 2007; Torpy et al.
2008).
Pregnancy-Related Complications
Respiratory Distress Syndrome
Respiratory distress syndrome in infant is caused
by the insufficient or immature development of
the lungs. Maternal diabetes is one of the fore-
most reasons of respiratory distress syndrome in
infant. Poor glycemic control in diabetic preg-
nancies, delayed fetal lung maturation, and respi-
ratory distress syndrome may complicate the
neonatal course. Different studies showed that
the prevalence of respiratory distress syndrome is
about 25–30 % in maternal diabetes compared to
1 % in nondiabetic group (Robert et al. 1976;
Russell and Coustan 2005).
Hyperbilirubinemia
Hyperbilirubinemia is the most common perina-
tal problem found in infant when the bilirubin
level is reported to be 20 mg/deciliter (342 μmol/l)
or more. Infant of diabetic mother can be affected
by this problem. This type of problem is more in
infant of type 1 diabetic mother, and reasons for
hyperbilirubinemia often are conjectural and usu-
ally are multifactorial (Gamsu 1978; Mangala
et al. 1991).
Polycythemia
Polycythemia is a condition where venous hema-
tocrit rises above 65 %, and the proportion of
blood volume occupied by red blood cells is ele-
vated; this condition occurs due to increased
mass of red blood cells or decrease in plasma vol-
ume. Diabetes in pregnant mother is one of the
risk factors of polycythemia. This condition also
results in other complicated events like respira-
tory distress and cardiovascular problems in
infants (Gamsu 1978; Mangala et al. 1991).
Preeclampsia
Preeclampsia is a disorder in which blood pres-
sure rises during pregnancy with significant
amount of protein in urine. Chronic hypertension
91
is generally found in women with T2DM, but the
incidence of preeclampsia is more common in
women with T1DM. Increasing plasma glucose
levels increases the risk of preeclampsia and need
of neonatal intensive care (Cundy 2008; The
HAPO Study Cooperative Research Group
2008).
Hypomagnesemia
Hypomagnesemia or decreased level of magnesia
in blood of infant of diabetic mother is another
complication of diabetes in pregnancy. According
to a survey, decreased level of magnesium in
serum was found in 37.5 % of infant of diabetic
mother. Reduced level of serum magnesium in
neonate was related to severe maternal diabetes
which results in reduced level of maternal serum
magnesium, decreased neonatal ionized and total
calcium, increased serum phosphorus, and
decrease in parathyroid function (Tsang et al
1976; Gamsu 1978).
Perinatal Asphyxia
The newborn of diabetic mother is having an ele-
vated risk of perinatal asphyxia. The risk factor
for perinatal asphyxia included poor glycemic
control, diabetic nephropathy, diabetic retinopa-
thy, hypertension in pregnancy, smoking, fetal
macrosomia, maternal diabetes, and hypoglyce-
mia in 6 h preceding delivery. Diabetic vascu-
lopathy is considered as one of the important risk
factors for asphyxia in infant (Gamsu 1978;
Mimouni et al. 1988).
Other Complications
Diabetes in pregnant woman is dangerous for the
health of the mother and child. T1DM, T2DM,
and GDM during pregnancy required proper care
and glycemic control. Infant of diabetic mother
is also found to have increased risk of hypo-
calcemia, trauma, intrauterine growth restric-
tion, infection, thrombosis, and hemorrhage. A
92
number of studies have suggested that diabetes
also increases the risk of premature delivery and
caesarean delivery (Gamsu 1978; Mimouni et al.
1988; Russell and Coustan 2005; The HAPO
Study Cooperative Research Group 2008).
Diabetic Neuropathy
Diabetic neuropathy is a nerve disorder caused
by diabetes and can affect up to 70 % of the dia-
betic population. Diabetic neuropathy can be
seen in 50 % of patients suffering from diabetes
for 25 years, more recognizing it as one of the
most widespread diseases of the nervous system.
Diabetic neuropathy is a heterogeneous disease
that can affect any part of the body; this includes
mononeuropathies and polyneuropathies as well
as plexopathies and radiculopathies. The patho-
genesis of neuropathy is multifactorial, caused by
metabolic, vascular, neurovascular, autoimmune,
and lifestyle factors and by mechanical injury.
Diabetic neuropathy is generally found more in
elderly individuals in the form of polyneuropathy
as distal and symmetrical affecting both motor
and sensory nerves. Different types of neuropa-
thy in diabetes include vascular neuropathy, blad-
der neuropathy, sweat gland neuropathy,
radiculopathy, cranial mononeuropathy, neuropa-
thy in the eye, proximal motor neuropathy, sexual
neuropathy, distal symmetrical polyneuropathy,
etc., which affects the toes, feet, thighs, hands,
arms, buttocks, cardiovascular system, digestive
system, urinary tract, sex organs, sweat glands,
eyes, lungs, facial muscles, pelvis, ears, lower
back, chest, and abdomen (Verrotti et al. 2001;
Oumeish 2008; National Diabetes Information
Clearinghouse 2009).
Different types of diabetic neuropathies are
classified as follows (Bhadada et al. 2001):
1. Diffuse neuropathy
(a) Distal symmetric sensory–motor
polyneuropathy
(b) Autonomic neuropathy
(i) Sudomotor
(ii) Cardiovascular
(iii) Gastrointestinal
(iv) Genitourinary
8 Complications of Diabetes Mellitus
(c) Symmetric proximal lower limb motor
neuropathy (amyotrophy)
2. Focal neuropathy
(a) Cranial neuropathy
(b) Radiculopathy/plexopathy
(c) Entrapment neuropathy
(d) Asymmetric lower limb motor neuropa-
thy (amyotrophy)
Distal symmetric sensory–motor polyneurop-
athy or peripheral neuropathy is the most fre-
quent. Neuropathy includes both small and large
fibers and has an insidious onset. Distal parts of
the extremities are affected first and cause sen-
sory disturbance. This type of neuropathy affects
the feet, legs, arms, and hands. The symptoms of
this type of neuropathy may be positive or nega-
tive and are tremendously changeable, ranging
from very painful in some cases and completely
painless in other. Negative symptoms include
deadness and numbness in the lower limbs, while
uncomfortable and altered temperature percep-
tion, burning pain, paresthesia, stabbing, shoot-
ing, lancinating pain, allodynia, and hyperesthesia
are considered as positive symptoms. The feet
and legs are more susceptible than the upper
limbs (Bhadada et al. 2001; Verrotti et al. 2001;
National Diabetes Information Clearinghouse
2009). Autonomic neuropathy affects the body
organ which is regulated by autonomic nerves
like the heart and other internal organs which are
responsible for different problems associated
with respiratory function, urination, digestion,
vision, and sexual response. Autonomic neuropa-
thy is a serious complication of diabetes and
affects a large number of diabetic patients. Nearly
65 % of individuals with T2DM with >10 years
of diabetes experienced parasympathetic dys-
function and combined parasympathetic and
sympathetic neuropathy in 15 %. Sign and symp-
toms of autonomic neuropathy include cardio-
vascular problems (i.e., postural hypotension,
resting tachycardia, painless myocardial infarc-
tion, prolonged QT interval), gastrointestinal dis-
turbances (gastric dysrhythmia, esophageal
motor incoordination, hypomotility, diabetic
diarrhea, pylorospasm, constipation, spasm, ano-
rectal dysfunction, diabetic cholecystopathy),
genitourinary problems (atonic bladder, impaired
Infective Disorders
bladder sensation, post micturition dribbling,
male impotence, detrusor hyporeflexia or hyper-
reflexia, ejaculatory disorders, dyspareunia,
reduced vaginal lubrication), eye problems (mio-
sis, disturbances of dilatation, Argyll Robertson
pupil), and respiratory and thermoregulatory
complications. Disturbances in sweating, edema
and atrophy, and peripheral hyperemia with ery-
thema are the results of skin manifestations of
autonomic neuropathy in diabetic patients, and
motor neuropathy of the feet causes inequity
between the flexor and extensor muscle, displace-
ment of foot pads, and subluxation of the digit
(Bhadada et al. 2001; Sreedevi et al. 2002;
National Diabetes Information Clearinghouse
2009). Proximal lower limb motor neuropathy
may be symmetrical or asymmetrical, with or
without loss of sensation. Symmetric proximal
lower limb motor neuropathy generally causes
disturbance more in the elderly males (>50 year)
suffering from T2DM compared to females and
patients with T1DM (Bhadada et al. 2001;
National Diabetes Information Clearinghouse
2009).
Focal neuropathy emerges unexpectedly and
affects precise nerves in the body. Cranial neu-
ropathy involves the third, fourth, and sixth cra-
nial nerves and affects elderly patient mostly.
Truncal neuropathy is symptomatic and less
common, mostly seen in long-standing DM with
other microvascular complications particularly
peripheral neuropathy. Entrapment neuropathy or
pressure palsy is an uncommon complication in
diabetes; the median nerve is mostly affected and
associated with limited joint mobility.
Asymmetric lower limb motor neuropathy is
focal neuropathy; anorexia may persist.
Paresthesia and hyperesthesia are relatively com-
mon in this type with weakness and pain in the
upper legs. Several hypotheses of diabetic neu-
ropathy based upon the animal model are sug-
gested, but still it remains obscure. Diabetic
neuropathy is a multifactorial disease, and it is
believed that hyperglycemia, nonenzymatic gly-
cation, polyol pathway, free radical, and oxida-
tive stress are primarily associated with its
pathogenesis. Generally, glycemic control,
hyperglycemia-induced metabolic derangements
and neurophysiological alterations, serum lipid
93
changes, vascular coagulation, and thrombotic
abnormalities are correlated with the nerve
involvement, and optimum glycemic control is
essential for the treatment of neuropathy and
regeneration of nerves (Asbury 1987; Bhadada
et al. 2001).
Infective Disorders
The incidence of the different infective disorder
is also seen in DM. The infection in the lower
extremities, gastrointestinal tract, skin, mouth,
kidney, or urinary tract and in sexual organ has
already been discussed. Diabetes generally
increases the risk of bacterial infection like
bacteriuria, fungal infection, and cystitis. But
some other infections like tuberculosis, hepati-
tis, and respiratory tract infection are also asso-
ciated with diabetes, and these are discussed
below.
Tuberculosis
Tuberculosis is considered as a main threat to the
health of the world population, with an expected
eight to ten million new incidence and three mil-
lion deaths per year. The respiratory system espe-
cially the lungs is affected by Mycobacterium
tuberculosis. The occurrence of tuberculosis is
found more in diabetic patient and causes a sig-
nificantly greater mortality. Increased reactiva-
tion of lesions due to tuberculosis has also been
recorded in diabetics. DM is considered as a sov-
ereign risk factor for increasing lower respiratory
tract infections. An association between diabetes
mellitus and tuberculosis is well recognized and
also reported in several surveys. According to a
number of surveys, it was found that, in about
85 % of the patients, the occurrence of tuberculo-
sis was found after the onset of diabetes. The
incidence of pulmonary tuberculosis was consid-
ered the most common form found in diabetic
patients, and it showed a much higher proportion
than nondiabetic ones; high blood sugar level and
increased duration of diabetes increase the chance
of occurrence of pulmonary tuberculosis.
Different studies reported that the occurrence of
94
tuberculosis is 10–25 times more frequent in
juvenile diabetics (Guptan and Shah 2000;
Nissapatorn et al. 2005).
Hepatitis C
Hepatitis C is an important infectious disease
responsible for acute and chronic hepatitis that
guides to the progression of cirrhosis and hepato-
cellular carcinoma. About 150–200 million peo-
ple have been infected by hepatitis C worldwide,
and around 85 % are chronically infected. The
associations of hepatitis with diabetes are well
known, and hepatitis infection is considered as a
risk factor of diabetes. Hepatitis C is responsible
for steatosis and insulin resistance and also
causes islet cell destruction, which may lead to
diabetes (Noto and Raskin 2006; Wilson 2004).
But now, emerging evidence has shown that dia-
betes acts as a risk factor for hepatitis C infection.
Chronic hepatitis C infection is connected with
an amplified risk of developing insulin resistance
and T2DM (Negro and Alaei 2009). High level of
serum glucose, hyperinsulinemia, and insulin
resistance are generally connected with increased
fibrosis in case of chronic hepatitis C. The quick
development of hepatitis C in patient with DM
has also been reported after liver transplantation
and kidney transplantation. Insulin resistance and
T2DM also impart a significant effect on the pro-
gression of hepatitis C and response to antiviral,
which warrants effective and specific actions to
rectify such metabolic anomalies (Negro and
Alaei 2009).
Bacteremia
Bacteremia is a condition when the presence of
bacteria is found in the blood. Pneumonia, men-
ingitis, surgery in the GIT, urinary tract infec-
tion, intravenous drug abuse, etc. are mainly
responsible for entering of bacteria in blood.
The prevalence of bacteriuria is found more in
diabetic individuals than nondiabetic subjects
than any other infections. The duration of diabe-
tes is associated with bacteriuria prevalence.
8 Complications of Diabetes Mellitus
The prevalence of bacteriuria increases 1.9-fold
with each 10-year of diabetes duration.
Bacteriuria is also associated with cystitis and
upper urinary tract infection (Boyko and Lipsky
1995).
Malignant External Otitis
Malignant or external invasive otitis is associ-
ated with extension of external ear infection to
nearby mastoid bone, soft tissue, and central
nervous system. It is a severely painful and irri-
tative condition. It is caused primarily by
Pseudomonas aeruginosa and hardly ever by
Aspergillus. Malignant external otitis is also
responsible for high mortality rate in about
33 %, but when it affects the cranial nerves, the
mortality rate may be as high as 80 %. This type
of disease is generally found in elderly diabetic
patient though it may occur in younger diabetics
and elderly people who have not suffered from
diabetes. According to one survey, the preva-
lence of diabetes was 89 % in patients whose
average age was 68.5 years (Mills 1986; Boyko
and Lipsky 1995).
Surgical Wound Infection
Unlike other infections, the incidence of surgical
wound infections is high in diabetic patient.
Different surveys have reported that the inci-
dence of infection after different surgical proce-
dures like coronary artery bypass grafting, open
heart surgery, spinal surgeries, and cardiothoracic
surgery is much higher in diabetic patient than
nondiabetic subjects. Postoperative hyperglyce-
mia and previously undiagnosed hyperglycemia
are associated with the development of surgical
infections. Screening for diabetes and hypergly-
cemia among patients and controlling them
before and during surgery are necessary to pre-
vent postoperative and chronic complications of
this metabolic abnormality. Therefore, DM is
recognized as a key risk factor for surgical site
infection (Boyko and Lipsky 1995; Chen et al.
2009).
CNS-Related Complications
Respiratory Tract Infection
Association between respiratory infections and
diabetes is also reported. Pneumonia, influenza,
bronchitis, and sinusitis are the different respira-
tory tract infections, and few cases are reported
describing that the prevalence of these diseases is
higher in diabetic people. Pneumonia is consid-
ered as a most frequent class of pneumococcal
infection. Some study reported that diabetic peo-
ple were more frequently to be hospitalized for
influenza and pneumonia. Some data suggested
that mortality rate due to pneumonia and influ-
enza is 1.7-fold higher than for nondiabetic indi-
viduals (diabetes diagnosed 30 years of age). The
National Health Interview Survey in America
reported that chronic bronchitis is 5.2 % for non-
diabetic subjects compared with 7.9 % of diabetic
subjects. Higher self-reported prevalence of
bronchitis and chronic sinusitis was also observed
in people with diagnosed diabetes compared with
nondiabetic persons (Boyko and Lipsky 1995).
But a detailed survey is required to establish
these diseases as complication of diabetes.
CNS-Related Complications
Depression
Depression is a most common psychiatric disor-
der with high prevalence worldwide. It is a mood
disorder characterized by depressed mood, guilt
feeling, decrease in appetite, suicidal thought,
insomnia, fatigue, loss of energy, and loss of
weight and function. In some diabetic persons,
neuropathy causes severe pain which leads to
depression. There is some evidence suggesting
the relationship between plasma glucose level
and mood in diabetics, which means that depres-
sion is more prevalent among diabetic patients
with poor glycemic control. Visual impairment
following blindness, sexual dysfunction, and
other chronic and severe complications in diabe-
tes may also contribute to depression. Conversely,
it is also believed that psychiatric disorders may
have a negative effect on glycemic control.
Therefore, effective control of diabetes is helpful
95
to treat diabetes, and effective management of
depression may promote better blood glucose
control. Different types of depressive disorders
include major depression, minor depression, and
dysthymia. Approximately 340 million people
worldwide suffer from depression. The inci-
dence of depressive disorder among persons
with T2DM is about 8.5–14.0 % which was
2–3 % more compared to nondiabetics. The life-
time risk was observed in between 11.0 and
32.5 % (Goodnick et al. 1995; Anderson et al.
2001). Another study reported the incidence of
depression in diabetes, though such incidence
depends upon the area and races. A number of
researches suggest a bidirectional relationship
between depression and T2DM. Both T1DM and
T2DM have increased risk of depression. Poor
glycemic control is considered as one of the
major risk factors of depression. It is suggested
that depression in patients with both T1DM and
T2DM may result from chronic psychosocial
stressors, having chronic medical state (Egede
and Ellis 2010).
Parkinson’s Disease
Parkinson’s disease, a degenerative disorder of
the CNS, is related to impaired speech, motor
skills, and other functions. The disease is charac-
terized by muscle tremor, rigidity, gait abnormal-
ities, postural abnormalities, bradykinesia, and a
loss of physical movement in extreme cases.
Different studies established the report of the
connection of diabetes and Parkinson’s disease.
T2DM was associated with elevated threat of
Parkinson’s disease; however, proper mechanism
involved behind the association between
Parkinson’s disease and diabetes is still unknown
(Hu et al. 2007).
Alzheimer’s Disease and Dementia
Diabetes mellitus is also linked with an increased
threat of dementia and cognitive dysfunction.
Increased threat of dementia worried both
vascular dementia and Alzheimer’s disease.
96
Alzheimer’s disease is a neurodegenerative disor-
der due to the loss of both cortical and hippocam-
pal neurons which retards the cognitive ability
and memory. Diabetes is connected with slowly
progressive end-organ brain damage. Mild to
moderate destruction of cognitive functioning
has been accounted in both T1DM and T2DM
patients. T2DM is mainly responsible for
Alzheimer’s disease. Hyperglycemia is con-
nected with toxic effects on brain tissue and the
growth of cerebral microangiopathy. Alterations
in insulin metabolism influence directly the brain.
Generation of reactive oxygen species and impor-
tant functional and structural proteins’ glycation
are also involved in microvascular changes.
Pathophysiological connection between insulin
and Alzheimer’s disease is well established.
Alzheimer’s disease is characterized by both
insulin resistance and low insulin within the
CNS. Insulin receptor in the CNS is involved
with learning and long-term memory. Insulin is
also involved in maintaining the growth of cells
including neurons in the brain. Thus, lack of
insulin or insulin resistance in diabetes contrib-
utes to degenerative process in the brain and
leads to Alzheimer’s disease (Biessels and
Kappelle 2005; Han and Li 2010).
Thyroid Diseases
DM and thyroid diseases are the two frequent
endocrinopathies observed in the adult popula-
tion. Thyroid disorders’ prevalence is higher
compared with the normal population. Both thy-
roid hormones and insulin are involved in cellular
metabolism, and, therefore, increase or deficit of
these hormones may be the consequence in the
functional derangement of the other. Patients
with one organ-specific autoimmune disease are
at risk of other autoimmune disorders. Both
T1DM and T2DM may decrease the serum free
and total T3 levels and increased reverse T3
(rT3), but serum TSH and T4 concentrations are
found near normal. Diabetes is also found respon-
sible for the loss of TSH response to thyrotropin-
releasing hormone. The patient with diabetes and
hypothyroidism may suffer from recurrent inci-
8 Complications of Diabetes Mellitus
dents of hypoglycemia. T1DM patients have a
high incidence of thyroid dysfunction with about
one third of all newly identified patients showing
thyroid autoimmunity. Thyroid dysfunctions are
more common in females, and up to 30 % of type
1 diabetic female patients have thyroid disease.
The rate of postpartum thyroiditis is three times
more in diabetic patients than in normal women.
Different surveys also indicated that type 2 dia-
betic patient also has higher prevalence of thy-
roid disorders. The prevalence of thyroid disorder
in the general population is 6.6 %, whereas the
prevalence of thyroid disease in diabetic patient
is 10.8–13.4 %. Graves’ disease is a general form
of hyperthyroidism symbolized by goiter and fre-
quently a slight protrusion of the eyeballs; it is a
common complication of diabetes. Dysthyroid
optic neuropathy causes blindness and is the most
threatening complication of Graves’ disease due
to diabetes. Autoimmune thyroiditis (Hashimoto
thyroiditis) is the common autoimmune dysfunc-
tion of the thyroid gland and is found to associate
with diabetes (Wu 2000; Sathish and Mohan
2003).
Autoimmune Disorders
Autoimmune diseases are caused by overre-
sponse of the body’s immune system against sub-
stances and tissues present in the body. Diabetes
mellitus especially T1DM is considered as an
autoimmune disorder and also associated with
other autoimmune complications. Association of
autoimmune disorders like psoriasis, vitiligo,
celiac disease, and autoimmune thyroiditis with
diabetes was discussed earlier.
Disability
The incidence of disability in diabetics is the
rising problem with the increased number and
the increased life expectancies of diabetics.
Disability is considered as a major social, eco-
nomic, public health, and political problem
associated with impairments, activity limita-
tions, and participation restrictions. Disability
References
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However, the spectrum of disability depends on
many determinants including environmental,
social, and family factors. The impact or sever-
ity of disability may be permanent or temporary
and its effects are variable. Ability to work and
other life activities are generally influenced by
it. Increased hospitalization, institutionaliza-
tion, and loss of economic self-sufficiency are
commonly seen as an effect of disability. DM is
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ability. Several complications related to diabe-
tes are also responsible for disability. For
example, hypoglycemia in diabetic patient
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to diabetes diminishes vision. Like all of these,
DM and its complications decrease the quality
of life and augmented disability. The incidence
of disability is also found more in diabetic
patient, and this is also found to affect their
social and normal life (Songer 1995; Gregg and
Caspersen 2005).
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 Biomarkers of Diabetes
and Diabetic Complications
Asymptomatic phase before the development of
chronic diseases offers an opportunity for pre-
vention of disease. In the twenty-first century,
research on biomarkers has gained immense sci-
entific momentum. A biomarker can be any bio-
logical substance like blood components, genetic
substances, and substances from saliva or urine,
which may have any clinical value and can be the
component of interest in the practice of medicine.
Biomarkers can play an imperative role for
screening and diagnosis, risk assessment, selec-
tion of therapy, and monitoring the therapy and
can be used as a therapeutic substance or to find a
new drug. An expert panel of National Institution
of Health, USA, defined biomarker as “a charac-
teristic that is objectively measured and evalu-
ated as an indicator of normal biological
processes, pathogenic processes, or pharmaco-
logical responses to a therapeutic intervention or
other health care intervention” (Atkinson et al.
2001). Biomarkers can be the reliable stuff to
monitor specific physiological or pharmacologi-
cal mechanisms, as a therapeutic target. The con-
centration of biomarker component is increased/
decreased in response to disease or by the dis-
eased organ and thus believed as “surrogate end
point” in epidemiological, therapeutic, and
pathophysiological investigation that can confer
a clinical benefit. These are helpful to physician/
researchers for screening and risk assessment
before diagnosis and to predict clinically useful
outcome for additional primitive condition of
© Springer Science+Business Media Singapore 2016
S. Sen et al., Diabetes Mellitus in 21st Century, DOI 10.1007/978-981-10-1542-7_9
9
disease. Urine, salivary, blood, genetic, protein,
and cerebrospinal fluid-derived markers offer the
essential biological information for the identifi-
cation of specific disease and may be valuable to
establish the biological fact or situation that rep-
resent a subclinical appearance and condition of
the disorder and surrogate manifestation of the
disease. Biomarkers generally reproduce the nat-
ural history of an exacting disease and helpful to
monitor recurrent diseases (Frank and Hargreaves
2003; Mayeux 2004; Caveney and Cohen 2011).
The pioneering research for DM and its com-
plications are the needs of twenty-first century as
the number of diabetic people and diabetic com-
plications increases exponentially over time. The
major problems that are associated with the treat-
ment of diabetes and prevention of diabetic com-
plications are social awareness and advance
research of DM and its complications. Estimation
of fasting plasma glucose, OGTT, determines the
level of insulin that is usually in practice for diag-
nosis of DM and for selection of treatment.
Recently, HbA1c estimation is suggested as a
useful tool for assessment of DM by WHO and
ADA. But still more effort is needed in this
regard. Hence, research on serum, genetic, pro-
tein, urinary, and salivary biomarkers can play a
significant role in early detection, screening and
risk assessment of DM, and monitoring the pro-
gression and treatment of DM and its complica-
tions, to find candidate biomarkers with potential
clinical value. Biomarkers of DM will also help
101
102
in understanding well the pathogenesis of the dis-
eases and to make well-informed, scientifically
sound decisions regarding the DM treatment.
Thus, identification and research on DM bio-
markers will help researchers, scientists, and
physicians to promote the excellence and expec-
tancy of human life in a better way.
Biomarkers to Predict and Monitor
DM and Its Complications
Hemoglobin A1c
In recent years, HbA1c emerged as a key marker
for diagnosis of prediabetes and diabetes.
Hemoglobin (Hb) is an important component of
red blood cell (RBC) involved in transportation
function. Each RBC usually has 280 million Hb
molecules and each Hb molecule is composed of
a protein called globin and a ringlike nonprotein
pigment called a heme. A ferrous ion (Fe+2) pres-
ents at the center of every heme ring and an oxy-
gen molecule can combine reversibly with that,
permitting each Hb molecule to bind four oxygen
molecules. Among the several forms of Hb (HbA,
HbA2, and HbF), HbA is the normal adult hemo-
globin and is available in two forms like HbA0
(94 %) and HbA1 (5 %). Glycosylated hemoglo-
bin is formed during the 120-day life span of the
erythrocyte as glucose attaches mainly to HbA1
by nonenzymatic pathway. Among the major
subtypes of HbA1 (HbA1a, HbA1b, and HbA1c),
HbA1c is the key glycohemoglobin, and the
quantity of glucose in the blood is directly pro-
portional to the quantity of HbA1c (Raval et al.
2011; True 2009). Currently, HbA1c is consid-
ered as a strong biomarker to predict the progres-
sion of DM. Determination of HbA1c reproduces
the mean level of blood glucose for the last 2–3
months. Although, along with DM several other
diseases/condition like anaemia, abnormalities of
hemoglobin, pregnancy and uremia also may
induce change in HbA1c level. The level of
HbA1c can be differed based on genetic factors
and ethnic groups such as Hispanic whites and
non-Hispanic blacks, though all the major orga-
nization including WHO and ADA recommended
9 Biomarkers of Diabetes and Diabetic Complications
the use of HbA1c content to determine prediabe-
tes or DM. HbA1c estimation also helps to diag-
nose diabetic microvascular and macrovascular
complications, retinopathy, nephropathy, and
neuropathy. Serum lipid profile in patients with
DM can be predicted by HbA1c level (Leslie and
Cohen 2009; Sen et al. 2015).
Albumin and Glycated Albumin
Albumin, a most rich plasma protein produced in
the liver, regulates a variety of functions, such as
(i) oncotic pressure regulation and (ii) transporta-
tion of hormones, metabolites, drugs, and vita-
mins and (iii) acts as an acid–base buffer.
Increased excretion of urine albumin is a key
indicator of glomerular damage and tubular dys-
function. In most of type 2 diabetic patient, base-
line albuminuria is the significant marker to
predict the end stage of renal disease. ADA also
advices screening of urine albumin excretion
level for both type 1 and type 2 diabetic patients.
Microalbuminuria is a key predictor of diseases
of the kidney, end-stage renal disease, cardiovas-
cular mortality, and cardiovascular morbidity in
people with DM. Albuminuria is a key risk indi-
cator for cardiovascular events in patients with
T2DM and nephropathy (Cohen-Bucay and
Viswanathan 2012).
Nonenzymatic glycation of albumin may begin
the generation of AGEs, which is further respon-
sible for generation of ROS and several diabetic
complications (as discussed in Chap. 7). Increased
glycated albumin level was observed in patients
with DM, which also is a key source to know the
condition of glycemic control over the preceding
2–3 weeks. The level of glycated albumin is linked
with HbA1 and fasting plasma glucose level.
Glycated albumin is thought to be a better bio-
marker over HbA1c in a diabetic patient to evalu-
ate glycemic excursion. Estimation of glycated
albumin along with regular blood checkup could
help to understand the condition of DM in a better
way. It is also an ideal biomarker for GDM, with
potential clinical uses for diabetic individuals
undergoing hemodialysis or have cardiac compli-
cations (Roohk and Zaidi 2008; Sen et al. 2015).
Biomarkers to Predict and Monitor DM and Its Complications
Fructosamine
Fructosamine, a product generated by the reac-
tion of a carbonyl group of glucose and an amino
group of protein, is used to determine glycated
serum protein (mainly albumin) level. The level
of fructosamine can give the information about
blood glucose levels for the previous 10–14 days.
Due to excess glucose level in plasma, glycosyl-
ation of serum protein increases; thus excess
fructosamine is formed. In diabetic pregnancy
and hemoglobin disorder, HbA1c is not a useful
biomarker, and fructosamine can give important
information in such cases (True 2009; Sen et al.
2015).
1,5-Anhydroglucitol (1,5-AG)
1,5-AG is a serum monosaccharide estimation
which is useful to know the carbohydrate metab-
olism status in diabetic patients. It is a marker for
postprandial hyperglycemia, short-term glucose
status, and glycemic variability and thus provides
important information about the reasons of DM
which is not understood by HbA1c assay (Kim
and Park 2013). 1,5-AG estimation is helpful for
short-term monitoring of glycemic control; it is
also suggested that in a diabetic patient (if blood
glucose levels are frequently observed above
180 mg/dL), determination of 1,5-AG could pro-
vide key information about blood glucose level
(True 2009; Juraschek et al. 2012).
Adipokines
Adipokines are large number of substances
secreted by the adipose tissue which also includes
several cytokines. These adipokines like leptin,
adiponectin, resistin, apelin, visfatin, chemerin,
interleukin-6, monocyte chemotactic protein-1,
retinol-binding protein, plasminogen activator
inhibitor-1, and TNF-α serve as key substances
which regulate different functions in the human
body. Current research highlighted their role in
the pathogenesis of DM and its complications. In
spite of some conflicting results, they emerged as
103
potential biomarker of diabetes and its associated
diseases (Berg et al. 2001; Kadowaki et al. 2006;
Rabe et al. 2008; Yamauchi and Kadowaki 2008;
Li et al. 2009; Sell et al. 2009; Castan-Laurell
et al. 2011; Hai-bing and Wei-ping 2012;
Dunmore and Brown 2013; Tousoulis et al. 2013)
(Table 9.1).
Fetuin-A
Fetuin-A earlier recognized as human protein α2–
Heremans-Schmid glycoprotein acts as circulat-
ing calcium-regulatory glycoprotein which
predominantly is synthesized in the liver. It is
also acknowledged for its powerful insulin-
stimulated insulin receptor tyrosine kinase inhib-
itory activity (Ramadan et al. 2011; Sen et al.
2015). Animal experiments showed that fetuin-A
administration inhibits tyrosine phosphorylation
of the IR and IRS-1 in the skeletal muscle and
liver stimulated by insulin and higher insulin sen-
sitivity in fetuin-A knockout mice. High level of
fetuin-A may result in insulin resistance and inhi-
bition of insulin action in humans. Thus, fetuin-A
can be considered as a sovereign risk factor of
T2DM (Stefan et al. 2008; Sen et al. 2015).
Fetuin-A is also considered as a key biomarker
for several diabetes complications. Decreased
level plasma fetuin-A level is connected with dia-
betic nephropathy, especially in uncontrolled dia-
betes patient. It is also considered as an ideal risk
factor for microvascular complication in diabetic
patients (Stefan et al. 2008; Ramadan et al. 2011).
Cystatin C
Determination of specific proteins could be help-
ful to determine the progression of diabetic com-
plications. It is a neuroendocrine basic
polypeptide or post-gamma globulin which is
encoded by CST3 gene. Cystatin C is usually
considered as a novel urinary marker of diabetic
nephropathy. CAD is one of the main reasons of
mortality and morbidity in people with T2DM, as
it is accompanied by other risk factors such as
hypertension, dyslipidemia, and pro-inflammatory
104
Table 9.1 Adipokines involved in the pathogenesis of diabetes and its complications
Name of adipokine Characteristics
Adiponectin It is a 244 amino acid collagen-like
protein, which acts as a hormone
and regulates glucose and energy
homeostasis. It exists in three
different forms in blood: (1) low
molecular weight (LMW) trimer,
(2) middle molecular weight
(MMW) hexamer, and (3) high
molecular weight (HMW) 12- to
18-mer adiponectin
Leptin It is a protein hormone and plays a
key role in regulation of appetite/
hunger, metabolism, and energy
intake and expenditure
9 Biomarkers of Diabetes and Diabetic Complications
Importance as biomarker (based on in vitro and in vivo
research)
Reduced level of plasma adiponectin is linked with
reduced whole-body insulin sensitivity in human and
high-fat diet or obesity-related insulin resistance in
animals
HMW adiponectin and adiponectin receptors
(AdipoR1 and AdipoR2) play a key role in obesity-
linked metabolic syndromes and insulin resistance. In
in vivo condition (in liver), AdipoR1 and AdipoR2
trigger the AMP kinase and peroxisome proliferatory-
activated receptor-α (PPARα) pathway, respectively,
which is responsible for amplified insulin sensitivity
and reduced inflammation
Reduced concentration of adiponectin may serve as a
powerful and sovereign predictor of future
development of DM in people with IGT
A meta-analysis found that higher level of adiponectin
is connected with decreased risk of T2DM
An acute rise in level of circulating adiponectin results
in transient reduction in basal glucose level by
restraining hepatic gluconeogenic enzyme expression
and reduces production rate of endogenous glucose in
both wild-type mice and mice with T2DM, though
authors suggested that adiponectin sensitizes the body
to insulin
Adiponectin is responsible for stimulation of insulin
synthesis and secretion and cell proliferation, while
insulin treatment can increase adiponectin level
Adiponectin also positively associated with
suppression of pancreatic β-cell apoptosis in
experimental animals
Interactions of genetic factors (i.e., single-nucleotide
polymorphisms 276 in the adiponectin gene) and
environmental factors (change in lifestyle, obesity,
high-fat diet) may reduce adiponectin, which plays a
vital role in the expansion of insulin resistance, T2DM
The level of leptin associated with inhibitory,
stimulatory, and null effects on insulin secretion.
Leptin showed variable and complex effect on
pathogenesis of DM
In Japanese American men, higher baseline level of
leptin is linked with increased risk of developing DM
but not in women
In Mauritius, higher leptin level is linked with
augmented risk of DM, with a propensity to plateau at
high levels
In middle-aged white adults, higher level of leptin is
useful to envisage the worsening of glucose
Increased plasma level of leptin was found in obese
diabetic individuals than the nonobese diabetic people,
which may connect with insulin resistance in the
obesity syndrome
Biomarkers to Predict and Monitor DM and Its Complications
Table 9.1 (continued)
Name of adipokine Characteristics
TNF-α It is a pro-inflammatory cytokine
and found to regulate immune
system-mediated cell death
105
Importance as biomarker (based on in vitro and in vivo
research)
Ex vivo study showed that insulin secretion stimulated
by the leptin exposure on glucose
A study reported that lower level of leptin inhibits
insulin release while high leptin level has
comparatively stimulatory effect
In lean animals, leptin inhibits insulin secretion.
Leptin protected the β cell and improves β-cell
function
Several scientists proposed that leptin improves insulin
sensitivity in hepatic and skeletal muscle and
modulates pancreatic β-cell function
Strong inverse connection between plasma leptin
receptor (sOB-R levels) and risk of T2DM was
observed on US women, which is independent of
leptin and adiponectin level
A number of researchers established that leptin
suppresses preproinsulin gene expression in islet β
cells, inhibits insulin secretion, and inhibits insulin
biosynthesis by its peripheral action
Leptin promotes weight loss and appetite regulation
and improves glucose tolerance
The role of TNF-α in pathogenesis of T1DM and
T2DM is well documented. It can regulate immune
system-mediated β-cell death which ultimately cause
type I DM. It also strongly inhibits insulin-stimulated
tyrosine phosphorylations on the islet β-chain of the
IR and IRS-1 in cellular level
In obese subjects, high level of circulating TNF-α has
been implicated in insulin resistance
TNF-α inhibits insulin secretion and induces the
expression of amylin from the pancreatic islet β cell
Expression of TNF-α in human adipose tissue or
increase in the level of TNF-α in circulation is
associated with BMI, body fat percentage, and
hyperinsulinemia, whereas decrease level of TNF-α
was observed with weight loss
Some researchers reported that TNF-α level was
increased before the onset of diabetes and further rise
in the level TNF-α was not associated with insulin
resistance. Some conflicting reports also exist. So
studies did not find any association between insulin
resistance and TNF-α in nondiabetic hypertensive and
insulin-resistant obese individuals, though maximum
researchers found the positive correlation between
TNF-α and insulin resistance
A study reported high level of TNF-α in obese than in
nonobese diabetic subjects
Another research concluded that TNF-α may have a
key role in the development of insulin resistance,
particularly in males and in people with high BMI
(continued)
106 9 Biomarkers of Diabetes and Diabetic Complications

Table 9.1 (continued)

Importance as biomarker (based on in vitro and in vivo
Name of adipokine Characteristics research)
Increased level of TNF-α in DM may be responsible
for vaso-regulatory response alteration, leukocyte
adhesion to endothelium, and facilitation of
procoagulant activity. Thus, TNF-α may participate in
atherogenesis
Resistin It is from cysteine-rich protein In rodents, resistin level increases due to obesity.
family Resistin plays a vital role in hepatic or skeletal muscle
insulin resistance
In mice, resistin downregulates insulin receptor
expression which is significant in maintenance of
clonal β-cell mass
In Lep ob/ob mice, level of circulating resistin was
increased and positively connected with high levels of
insulin, glucose, and lipids
Several in vitro and in vivo studies showed the positive
involvement between resistin levels and insulin
resistance
Though research on animals clearly indicated that
resistin was responsible for insulin resistance, the
effect was not successfully reproduced in humans. A
study on T2DM or insulin-resistant patients did not
detect any association between serum resistin levels
and markers of insulin resistance
These researchers indicated the diversity of resistin
action in rodents and humans
Interleukin (IL) ILs are the pro-inflammatory An in vitro study (in primary hepatocytes and HepG2
cytokine, which is produced from a cell lines) showed the insulin resistance effect of IL-6
wide variety of cells including at cellular level, which may relate for insulin
adipocytes resistance and type 2 DM
IL-6 decreases insulin-dependent glycogen synthesis
in hepatocyte and glucose uptake in adipocyte. Though
several contradictory reports are available regarding
the effect of IL-6 on insulin resistance and hepatic
glucose production
IL-6 may relate with c-Jun N-terminal kinase
1-mediated serine phosphorylation of IRS-1, IkB
kinase-mediated activation of nuclear factor-kB, and
induction of SOCS-3, which can modulate insulin
resistance
IL-6 may in some extent be accountable for DM but
may not be essential nor sufficient for type 1 and type
2 DM development
Increased level of IL-6 in DM may be responsible for
vaso-regulatory response alteration, leukocyte
adhesion to endothelium, and facilitation of
procoagulant activity. Thus, IL-6 may participate in
atherogenesis
Omentin Omentin found in the bloodstream Omentin initiates insulin-stimulated glucose transport
and also expressed in visceral fat and Akt phosphorylation – which may regulate insulin
tissue action and sensitivity toward tissues
Biomarkers to Predict and Monitor DM and Its Complications 107

Table 9.1 (continued)

Importance as biomarker (based on in vitro and in vivo
Name of adipokine Characteristics research)
Level of serum omentin-1 found less in type 2 diabetic
individual
Level omentin-1 in serum negatively associated to
BMI, insulin resistance index, fasting insulin, TNF-α,
IL-6, plasma glucose, and obesity-induced insulin
resistance and glucose intolerance
Dipeptidyl It is a membrane-bound peptidase In rodent, genetic inactivation of DPP-IV or DPP-IV
peptidase IV and also expressed in other tissues. inhibition showed better glucose tolerance, increased
(DPP-IV) It is encoded by DPP4 gene quantity of incretin hormones, i.e., glucagon like
peptide-1 and glucose-dependent insulinotropic
hormone (incretin increases glucose-dependent insulin
secretion), and resistance to increased blood glucose
level and diet-induced obesity
Preclinical studies confirmed that DPP-IV inhibition
stimulates insulin, inhibit glucagon secretion, and
preservation of β-cell mass
It is a protein component of urinary microvesicles, and
its concentrations might represent a number of
microvesicles, released by tubular epithelial cells.
DPP-IV also considered as biomarker in diabetic
kidney disease
Visfatin A protein principally expressed in Visfatin has insulin-like action and mimic the action of
(previously visceral adipose tissues insulin
recognized as Visfatin found helpful for the growth of β-cell
pre-β-cell precursors
colony-enhancing
It stimulates glucose uptake and lipogenesis,
factor)
suppresses glucose production, and increases insulin
sensitivity thus reduce blood glucose level
Level of visfatin increases in patients with T2DM in
spite of the degree of adiposity; this condition arises
due to enhanced insulin resistance and insufficient
insulin action. The similar consequence was also
reported with progressive β-cell deterioration
Though some researchers in their community-based
investigation did not recommend visfatin as a clinical
biomarker, the sample size in those studies is
intermediate
Vaspin An inhibitor of serine protease Increase in body weight and worsening of DM results
derived from visceral adipose tissue decrease in vaspin expression
In obese rodent, vaspin treatment found beneficial to
improve insulin sensitivity and glucose tolerance and
to reduce intake of food
Level of serum vaspin was decreased significantly in
previously diagnosed type 2 diabetic women in China
than in newly diagnosed T2DM and healthy individual
Increased serum vaspin and expression of vaspin
mRNA in adipose tissue of human were connected
with insulin resistance, obesity, and T2DM
Increased serum level of vaspin was found in nonobese
and obese type 2 diabetic Libyan individuals
(continued)
108 9 Biomarkers of Diabetes and Diabetic Complications

Table 9.1 (continued)

Name of adipokine Characteristics
Retinol binding RBP4 is a novel adipokine of
protein-4 (RBP4) lipocalin family. It is key
transporter of retinoic acid in body
Apelin It is a bioactive peptide, regulate
feeding behavior and glucose
utilization
Chemerin A chemotactic substance which
may regulate adipogenesis,
inflammation, and glucose
metabolism
Importance as biomarker (based on in vitro and in vivo
research)
Vaspin level can correlate with BMI, insulin
resistance, and lipid profile
Plasma level of RBP4 found high in IGT, type 2
diabetic, or in insulin-resistant mice
Human RBP4 transgenic overexpression or
recombinant RBP4 administration in healthy mice
results insulin resistance, whereas genetic deletion of
RBP4 results increased sensitivity of insulin
Induction of increased serum RBP4 causes hepatic
expression of gluconeogenic enzyme
phosphoenolpyruvate carboxykinase and damages
insulin signaling in muscle
Some researchers did not observe any connection
between level of serum RBP4 and insulin resistance in
patient with T2DM but suggested the correlation
between RBP4 and TNF-α
Plasma level of RBP4 is related with insulin, glucose,
and homeostasis
Nutritional status, insulin, TNF-α regulates the
production of apelin
Activation of apelin receptor causes inhibition of
insulin secretion. In obese and hyperinsulinemic
humans, higher level of apelin was observed
Experimental evidence suggested lower expression of
apelin in experimentally induced diabetic mice
Current evidence suggested that apelin may regulate
glucose uptake and Akt phosphorylation
It regulates adipocyte differentiation and lipolysis and
improves insulin-dependent glucose uptake in
adipocytes
Chemerin and its expression of Chem R23 receptor
were observed in β cell and which may control islet
β-cell function through MafA expression
High level of chemerin may induce insulin resistance
at the level of lipogenesis and antilipolysis induced by
insulin in adipocytes
Chemerin level found more in obese/diabetic mice,
while administration of exogenous chemerin may
result in glucose intolerance, reduced insulin levels in
serum, and glucose uptake in obese/diabetic in
experimental animals
Altered chemerin expression and its receptors in white
adipose, skeletal muscle, and liver tissue of
experimental animal were also reported
Thus chemerin can be an underlying factor in
pathogenesis of T2DM
Biomarkers to Predict and Monitor DM and Its Complications
and prothrombic factors. Cystatin C is considered
as superior from serum creatinine or creatinine-
based estimating equations for estimation of all-
cause mortality, cardiovascular function, and
even congestive heart failure. Though a number
of researchers did not find the association of cys-
tatin C with diabetic CVD, they reported a higher
level of cystatin C in patients with diabetic
nephropathy in both CAD and non-CAD patients.
But some study found that prevalence of CVD-
like angina pectoris, myocardial infarction, and
stroke amplified with increasing cystatin C con-
centration. Serum cystatin C level was also
related with CRP, urine albumin/creatinine ratio,
and expected GFR thus serum level of cystatin C
is also helpful to find urinary complication in dia-
betes. Urinary cystatin C detection is helpful to
find the progression of diabetic nephropathy in
early stage. It is formed at a steady rate by all
nucleated cells and is liberally filtered by the
glomerulus. Urine cystatin C was found to link
with triglyceride, expected GFR, and albumin/
creatinine ratio. Estimation of cystatin C mea-
surement in urine is useful to find nephropathy in
diabetic people (Oh 2010; Jeon et al. 2011).
C-Reactive Protein (CRP)
CRP is a pro-inflammatory substance and recog-
nized as an indicator of systemic inflammation.
High level of CRP is reported in individuals with
impaired glucose tolerance and frank diabetes,
and high CRP level is found to increase the risk of
T2DM and insulin resistance. The high level of
CRP is also reported in diabetic adults with higher
HbA1c level. Several reports also found increased
level of CRP in people with T1DM and in preg-
nant women with amplified risk of developing
GDM (King et al. 2003; Chase et al. 2004; Sen
et al. 2015). CRP also emerged as a key biomarker
to determine vascular dysfunction in DM. CRP
especially high-sensitivity CRP increases quickly
(also long rising periods) and is stable in plasma.
It attenuates production of NO, reduces eNOS,
induces the oxidation of low-density lipoprotein
cholesterol, triggers PAI-1 expression, excites the
109
release of matrix metalloproteinase-1, causes acti-
vation of macrophages to secrete tissue factor, and
upregulates adhesion molecules expression in
endothelial cells (Tousoulis et al. 2013).
Type IV Collagen
Type IV collagen is the foremost component of
membranes of glomerular and tubular basement
as well as in mesangial matrix. Hyperglycemia
increases synthesis of type IV collagen and may
decrease the breakdown of type IV collagen by
producing advanced glycosylation of proteins.
Enhanced deposition of type IV collagen has
been observed in glomerular mesangial matrix of
kidneys of diabetic subjects with diffuse glomer-
ulosclerosis. Excretion of urinary type IV colla-
gen indicates mesangial expansion and
tubulointerstitial and glomerular injury and can
be correlated with the urinary excretion of sev-
eral tubular damage markers, like N-acetyl beta-
d-glucosaminidase and α1 microglobulin.
Increased urinary type IV collagen excretion was
observed in diabetic people compared to normal,
even in normoalbuminuric people, and is also
considered as a more sensitive marker than albu-
minuria to identify renal damaged individuals
with T2DM. Urinary excretion of type IV colla-
gen is related with the duration of diabetes. Thus,
urinary type IV collagen is a biomarker to fore-
cast the advancement of diabetic kidney disease
(Cohen-Bucay and Viswanathan 2012; Wang
et al. 2013a).
Transforming Growth Factor β1
(TGF-β1)
TGF-β1 is a profibrogenic cytokine found to
exhibit a vital role in the pathogenesis of chronic
kidney disease. It generally regulates the genera-
tion of vital extracellular matrix molecules
including type I and type IV collagen, laminin,
and fibronectin. TGF-β1 also supports cell–
matrix interactions by upregulating integrins. In
vitro cell culture studies showed that high
110
glucose level is responsible for hypertrophy of
proximal tubular cells and mesangial cells and
also stimulates the generation of matrix mole-
cules. Elevated ambient glucose upregulates the
expression and bioactivity of TGF-β1 in most of
the renal cell, and in few instances it is also
responsible for upregulation of TGF-β1 type II
receptor. A number of recent researchers (mainly
animal model) confirmed that both T1DM and
T2DM further implicate TGF-β1 as an impera-
tive mediator of kidney disease in diabetic sub-
jects (Ziyadeh 2004; Mehta et al. 2013).
Fibronectin
Fibronectin is formed in the liver, vascular endo-
thelia, and platelets and participated in several
functions like coagulation, platelet activity, and
tissue repair. Fibronectin is an intrinsic constitu-
ent of the glomerular extracellular matrix and in
diabetic condition reduces erythrocyte deformity
and filterability. In diabetic people, urinary excre-
tion of fibronectin is found higher and more effi-
ciently in macroalbuminuric patients. Level of
urinary fibronectin also can be linked with the
development of biopsy-proven glomerular dif-
fuse lesions. Urinary fibronectin excretion might
be a useful biomarker of diabetic nephropathy
(Cohen-Bucay and Viswanathan 2012).
Laminin
Laminin is a glycoprotein and normal compo-
nent of basement membranes. Excretion of uri-
nary laminin can be correlated with the urinary
excretion of type IV collagen. Several studies
have found that urinary excretion of laminin is
more in diabetic individuals compared to healthy
individuals. However, its excretion increases
with age, specifically in people over 60 years.
It can be also associated with the duration of
DM, hypertension, and glycemic control. Higher
urinary laminin excretion is reported in type
2 diabetic patients to compare to a nondiabetic
individual with nephropathy (Cohen-Bucay and
Viswanathan 2012).
9 Biomarkers of Diabetes and Diabetic Complications
N-acetylglucosaminidase (NAG)
and Kidney Injury Marker-1 (KIM-1)
NAG and KIM-1 are considered biomarkers of
proximal tubule injury. In normoalbuminuric
patient with diabetic urine, NAG can be increased
up to ninefold in comparison to controls. The
level of NAG further increases with development
and progress of microalbuminuria. Recently a
study on people with T1DM was found that
regression of microalbuminuria was connected
with a highly significant decrease in urine NAG
excretion. KIM-1 was also connected with
regression, though some study on type 2 diabetic
patients did not find any association of KIM-1
with the progression of microalbuminuria. Thus,
more research is required in this area (Anonymous
2011).
Angiopoietin-Like Proteins
(ANGPTLs)
ANGPTLs are the group of proteins which are
involved in energy metabolism. ANGPTL4 is a
member of ANGPTLs and it is recognized as
PPAR containing two ligands, PPARα and
PPARγ. ANGPTL4 is known as fasting-induced
adipose factor which is regulated by nutritional
state. ANGPTL4 expression is more in the liver,
followed by the adipose, thyroid gland, brain,
and intestine. ANGPTL4 is considered as a
hyperlipidemic agent, which is involved in the
inhibition of lipoprotein lipase. Lipid metabolism
increases in ANGPTL4 deficiency state and may
evade some cardiovascular problems like athero-
sclerosis. It also improves glucose tolerance by
reducing blood glucose level. ANGPTL4 was
observed to be upregulated in the adipose tissue
in people suffering from obesity which suggested
the key role of ANGPTL4 in the metabolism of
glucose and lipids in obese individuals. Increased
ANGPTL4 is also found to associate with high
triglycerides, cholesterol, LDL cholesterol, and
low HDL cholesterol level, which indicated that
ANGPTL4 could be a marker to find the progres-
sion of cardiovascular complications in diabetic
people (Abd-Allah et al. 2013).
Biomarkers to Predict and Monitor DM and Its Complications
α1 Microglobulin
α1 microglobulin is a glycoprotein, and unbound
form of α1 microglobulin is liberally filtered
through a glomerular filtration and reabsorbed
through the proximal tubule where the protein is
catabolized. Usually, urinary excretion of
unbound α1 microglobulin can be associated
with dysfunction of proximal tubule and can be
useful to find the early stage of tubular disorders
such as diabetic nephropathy, heavy metal intoxi-
cation, and urinary outflow disorders (Mehta
et al. 2013).
Transferrin
Transferrin is the main iron-binding protein
found in serum and involved in the transportation
of ferric ions to all proliferative cells of the
human body. Excretion of urinary transferrin is
found to increase considerably in individuals
with T2DM which can correlate with the pres-
ence of glomerular diffuse lesions, tubular atro-
phy, degree of interstitial fibrosis, and infiltration
of interstitial inflammatory cell. Greater excre-
tion of urinary transferrin indicates the develop-
ment of microalbuminuria in individuals with
T2DM with normoalbuminuria. High level of
urinary transferrin is also observed in primary
glomerulonephritis; thus, it cannot be a specific
biomarker only for diabetic kidney diseases.
Transferrinuria has been concerned as a cardio-
vascular risk factor; type 2 diabetic people with
both microtransferrinuria and microalbuminuria
have a superior risk of ischemic heart disease
compared to the subjects with microtransferrin-
uria only, indicating that microalbuminuria may
be considered as a superior predictor (Cohen-
Bucay and Viswanathan 2012; Wang et al.
2013a).
Glycosaminoglycans
Glycosaminoglycan (GAG) is a key constituent
of cellular membranes, extracellular matrix,
and endothelial glycocalyx. It regulates cell
111
proliferation and differentiation, cell-to-cell
interaction, cell-to-matrix binding, and
production of interleukin-1. GAGs are also a
key constituent of basement membranes.
Hyperglycemia reduces synthesis of GAGs and
content of heparan sulfate (glycosaminoglycan
in glomerular basement membrane) in the
mesangial matrix and glomerular basement
membrane, which is responsible for proteinuria
that indicates diabetic nephropathy. Several
researchers reported an increased excretion of
urinary GAGs than the controls, even in
normoalbuminuric patients, though several
contradictory results also exist. Diabetic indi-
viduals with manifest nephropathy have higher
excretion of urinary GAGs compared to indi-
viduals with incipient nephropathy. Urinary
GAG excretion estimation could be a high-
quality biomarker for diabetic nephropathy and
other diabetic complications (Cohen-Bucay
and Viswanathan 2012).
Osteoprotegerin (OPG)
OPG is a glycoprotein and also known as osteo-
clastogenesis inhibitory factor or TNF receptor
superfamily member 11b. It is involved in bone
metabolisms and in immune surveillance. This
glycoprotein is mainly expressed in the heart,
lung, kidney, liver, and bone marrow, formed in
the vascular endothelial and smooth muscle
cells, and then secreted in the circulation. OPG
level is found to be increased by TNF-α and
IL-1β, indicating that endothelial cell activa-
tion by pro-inflammatory cytokines might be a
potential basis of circulating OPG in people
with CVD. OPG is found to be responsible for
vascular calcification, in which a part of patho-
genesis involved in atherosclerosis process is
leading to clinical CVD. Polymorphism of
OPG gene (particularly T245G, T950C, and
G1181C) is reported to be linked with increased
OPG level in serum, which is generally
observed in subjects with carotid plaques or in
diabetic patients with a history of ischemic
stroke. A cohort study found a high level of
OPG in plasma and is related with increased
112
CV mortality in women above the age of 65.
Positive correlation of OPG level was observed
with coronary calcification, vascular stiffness,
and unstable atherosclerotic plaques. In dia-
betic patients initial lesion of atherosclerosis
involves changes in vascular endothelium
which are responsible for endothelial dysfunc-
tion, obesity, and cardiovascular diseases like
hypertension and dyslipidemia. High blood
glucose level increases formation of athero-
sclerosis and accelerates the progression of
acute myocardial infarction. Some studies
found high level of OPG in diabetic subjects
but not in nondiabetic controls. Children with
T1DM and T2DM patients with microvascular
complications had higher OPG levels than
healthy patients without complications. A fol-
low-up study found that high level of OPG is a
powerful predictor of all-cause mortality in
T2DM patients, independent of regular cardio-
vascular risk factors. Several contradictory
studies were also reported, and the precise
mechanism which can describe the relationship
between OPG level, diabetes, and cardiovascu-
lar disease are unknown. In spite of this situa-
tion, OPG can be used as a diagnostic biomarker
in diabetes-induced cardiovascular complica-
tions, and upregulation of OPG could be useful
to prevent further damage due to plaque rapture
(Bjerre 2013).
Podocytes
Podocytes are vital structural constituent of the
glomerular filtration barrier, and injury of podo-
cytes can induce diabetic kidney diseases.
Podocytes in urine were found in diabetic indi-
viduals with micro- and macroalbuminuria.
Nephrinuria is more common in diabetic subjects
with micro- and macroalbuminuria, compared
with normoalbuminuric patient, which indicated
that nephrinuria might be a biomarker of early
diabetic kidney diseases. Urinary podocalyxin
can be considered a useful marker to detect early
podocyte injury in diabetic individuals (Wang
et al. 2013a).
9 Biomarkers of Diabetes and Diabetic Complications
Antibodies
The presence of adaptive responses toward the
neuroendocrine proteins like glutamic acid
decarboxylase (GAD) is considered as a key
characteristic of autoimmune diabetes. Though
the distribution of GAD is extensive in neuroen-
docrine tissues, its precise role in DM has paral-
leled the progress in understanding the role of
cellular and humoral immunity in T1DM and in
a subset of T2DM. Estimation of autoantibodies
against GAD is a vital source to assess the risk
and progression to overt autoimmune diabetes.
GAD65 autoantibodies can precisely predict the
progression and development of T1DM along
with other humoral biomarkers. Though GAD65
expression is not exclusive to pancreatic β cell,
GAD65 can be considered as a specific bio-
marker in diabetes risk prediction (Towns and
Pietropaolo 2011).
Immunoglobulin G (IgG) is a protein released by
plasma which is involved in the secondary immune
response. High level of total urinary IgG level was
found in diabetic subjects compared to controls
who have not developed microalbuminuria. In nor-
moalbuminuric diabetic patient, elevated excretion
of urinary IgG predicts the development progres-
sion of microalbuminuria. It can be correlated with
urinary excretion of orosomucoid, ceruloplasmin,
and transferrin. IgG4, an isoform of IgG, was
reported as a more specific marker for glomerular
charge selectivity impairment. IgG and IgG4 excre-
tion was found to increase in patients with macroal-
buminuria (Cohen-Bucay and Viswanathan 2012;
Wang et al. 2013a).
Immunoglobulin M (IgM) is the biggest anti-
body in the circulatory system of humans and is
believed to be a key biomarker to predict the
declining kidney function. High level of urinary
IgM in nondiabetic patients indicates glomerular
disease like high degree of fibrosis and global
glomerulosclerosis. Thus, it is not considered as
early marker for diabetic kidney diseases. But in
macroalbuminuric type 2 diabetic individuals,
urinary excretion of IgM and IgG2/IgG4 ratio
found more compared to subjects with
T1DM. High level of urinary IgM excretion
Biomarkers to Predict and Monitor DM and Its Complications
indicates decline in kidney function in patient
with T2DM. Increased excretion of urinary IgM
is also useful to predict cardiovascular mortality
and advancement to end-stage renal disease in
diabetic individuals (Cohen-Bucay and
Viswanathan 2012; Wang et al. 2013a).
Vascular Endothelial Growth Factor
(VEGF)
VEGF (also known as the vascular permeability
factor or vasculotropin) is involved in angiogen-
esis. It is produced by endothelial cells, macro-
phages, CD4 lymphocytes, plasma cells,
myocytes, megakaryocytes, and neoplastic cells.
VEGF is involved in the proliferation and migra-
tion of endothelial cells, enhancement of vascular
permeability, production of tissue collagenase,
and enhancement of macrophage and monocyte
chemotaxis. VEGF contributes to the improved
permeability of blood–retina barrier and that it
excites the neovascularization process in the
advanced retinopathy. High level of VEGF was
reported in the early stages of nonproliferative
retinopathy in children and adolescents with
T1DM. It has been found that VEGF level was
increased in patients with T1DM diagnosed with
retinopathy, nephropathy, and hypertension as
compared to patients with T1DM, retinopathy,
and nephropathy but with no hypertension
(Zorena et al. 2013).
Ceruloplasmin
Ceruloplasmin is a protein involved in the carry-
ing of copper. It is highly negatively charged and
thus is not filtered by the glomerulus normally.
Urinary ceruloplasmin was observed in normoal-
buminuric diabetic people, and high level of
ceruloplasmin in urine indicated progression of
microalbuminuria in normoalbuminuric diabetic
patients. Higher ratio of ceruloplasmin and cre-
atinine was observed in diabetic people with kid-
ney disease (Cohen-Bucay and Viswanathan
2012; Wang et al. 2013a).
113
Adhesion Molecule (ICAM-1
and VCAM-1) and von Willebrand
Factor (vWF)
Along with CRP, TNF-α, and IL-6, different adhe-
sion molecules like ICAM-1 and VCAM-1 are con-
sidered as inflammatory markers which provide
prognostic information on the outcome and pro-
gression of the disease in diabetic patients. DM can
induce the endothelium to activate and express
VCAM-1 and ICAM-1, which are imperative medi-
ators for the adhesion of leukocytes to the surface of
endothelia and considerably related to the endothe-
lial dysfunction and risk of DM complications.
Serum VCAM-1 and ICAM-1 along with IL-6 and
vWF were significantly related with the progression
of albuminuria. Serum VCAM-1, serum ICAM-1,
and vWF are the key markers of endothelial dys-
function and observed as an independent predictor
of advancement of diabetic endothelial-related
complications (Tousoulis et al. 2013).
Apolipoprotein
Apolipoprotein AI (ApoAI) is a constituent of
HDL, while apolipoprotein B (ApoB) is present
in LDL, intermediate-density lipoprotein (IDL),
very low-density lipoprotein (VLDL), and lipo-
protein (a). Apo B can be considered a consistent
surrogate to find the definite number of low-
density lipoprotein particle irrespective of their
size. A study reported positive link between Apo
B levels and microvascular complications.
Researchers also observed that level of Apo B
was increased along with higher degree of
nephropathy. Level of Apo B was higher in peo-
ple with overt nephropathy than incipient
nephropathy, while in people with incipient
nephropathy Apo B level was more than in
patients without nephropathy. The presence of
more than one microvascular complication posi-
tively associates with high levels of Apo B. Thus
Apo B can be considered as a sensitive biomarker
to detect early diabetic microvascular complica-
tions. ApoAI, ApoB, and the ratio of ApoB to
ApoAI were considerably and independently
114
linked with diabetic retinopathy. Thus, serum
apolipoprotein levels can be a specific biomarker
of diabetic retinopathy than conventional mea-
surement of lipid profile (Sasongko et al. 2011;
Rizka et al. 2013).
Monocyte Chemoattractant Protein-1
(MCP-1)
MCP-1 is a chemokine which may exert vital role
in the pathogenesis of tubulointerstitial disease
through the activation of macrophage recruit-
ment in diabetic nephropathy. In people with dia-
betic nephropathy and advanced tubulointerstitial
lesions, the level of MCP-1 increases. Urinary
MCP-1/creatinine was more in individual with
macroalbuminuria than in the individuals with
normoalbuminuria and microalbuminuria. The
urinary excretion of MCP-1 is also associated
with decreased rate of eGFR. Several observa-
tions have recommended that MCP-1 might be a
prognostic marker to monitor the progression of
diabetic nephropathy (Mehta et al. 2013; Wang
et al. 2013a).
Neutrophil Gelatinase-Associated
Lipocalin (NGAL)
NGAL is a protease-resistant polypeptide which
is found to be involved in ischemic renal injury
and repair processes. NGAL level is found to
increase in diabetic people. A study also reported
five- to tenfold increase in the urine NGAL level
in individuals with normo- or microalbuminuria
compared with healthy subjects. A short-term
study on patients with T2DM indicated that uri-
nary NGAL has a negative association with
eGFR, which indicated that urinary NGAL might
be a hopeful early marker for screening renal
impairment in type 2 diabetic patients. In patients
with T1DM, level of urine NGAL can be associ-
ated with albumin/creatinine. It was also observed
that people with higher albuminuria had increased
level of urine NGAL, which indicated that high
urinary NGAL level can correlate with kidney
damage (Wang et al. 2013a).
9 Biomarkers of Diabetes and Diabetic Complications
Lipocalin-Type Prostaglandin D2
Synthase (L-PGDS)
L-PGDS is a secretory protein, involved in the
synthesis of prostaglandin D2. L-PGDS is found
in the peritubular interstitium but not in the tubu-
lar cells of nondiabetic subjects though, in dia-
betic individual, presence of L-PGDS is observed
in renal tubules. Increased urinary excretion of
L-PGDS was reported in patients with renal dis-
ease (exception, males with IgA nephropathy).
Several researchers considered L-PGDS as a
more sensitive marker than other urinary markers
like type IV collagen, NAG, β2 microglobulin,
and serum creatinine in diagnosing kidney dis-
ease. Higher urinary L-PGDS excretion was
reported in people with T2DM compared to con-
trols, even in those without albuminuria, and in
parallel associated with urinary protein excre-
tion. Excretion of urinary L-PGDS is helpful to
predict the progression of albuminuria in normo-
albuminuric patients. Urinary L-PGDS excretion
and albumin in combination raise the possibility
to identify diabetic nephropathy in individuals
with proteinuria. Proper glycemic control reduces
excretion of L-PGDS in normoalbuminuric indi-
vidual. Increased level of L-PGDS excretion is
associated independently with history of CVDs
in patient with T2DM (Cohen-Bucay and
Viswanathan 2012).
Microvesicles
Microvesicles (also known as microparticles)
(MVs) are small membrane vesicles. They are
released from a variety of cells including vas-
cular endothelial cells, blood cells, and smooth
muscle cells under different conditions. An
elevated level of circulating MVs from plate-
let, lymphocyte, monocyte, endothelial cells,
and granulocyte was observed in people with
T1DM, T2DM, and diabetic complications.
The presence of MVs was reported in urine,
blood, vitreous fluid, atherosclerotic plaques
present in vascular wall, and extracellular
spaces of solid organs. MVs show procoagu-
lant activity. Increased level of MVs derived
Biomarkers to Predict and Monitor DM and Its Complications
from monocyte, platelet, and endothelial cell
was observed in diabetic patients. People with
several diabetic complications like hyperten-
sion, hyperlipidemia, stable coronary disease,
myocardial infarction, angina with or with-
out symptomatic episodes, retinopathy, and
nephropathy have considerably high levels of
procoagulant MVs compared to no diabetic
complications. Significant effect of MVs in
leukocyte recruitment, endothelial activation,
and vascular inflammation was also reported,
which indicated its potential role in diabetic
cardiovascular complications. The role of
endothelial-derived, platelet-derived, and
CD31+/annexin V+ MVs in endothelial dys-
function was also reported. MVs also may be
responsible for reduced production of NO,
impairment of vasorelaxation induced by
acetylcholine, generation of superoxide, and
altered prostacyclin production, and adhesion
molecule expression increased in macrophage
infiltration. Pro- and antiangiogenic effect
of MVs was reported by several researchers
which may influence angiogenic activities.
MVs are also involved in the transferring of
biological messages between cells with char-
acteristics specially related to the type of
vascular complications. High level of circu-
lating MVs is considered as key indicator for
diabetic macrovascular complications. A few
researchers reported increased levels of circu-
lating monocyte-derived MVs and endothelial-
derived MVs in T1DM and T2DM people with
neuropathy, respectively. Monocyte-derived
MVs were found more in diabetic nephropathy
condition in the T2DM subjects with diabetic
microangiopathy, i.e., nephropathy, neuropa-
thy, or retinopathy. Recent investigation has
suggested that high levels of endothelial- or
monocyte-derived MVs may be considered
as biomarkers for nephropathy progression
in T2DM. In early tubular impairment condi-
tion, MV-associated DPP-IV (major form of
DPP-IV in urine) was found in urine. In T2DM
patients, MV-associated DPP-IV excretion in
urine was found more, and this can be posi-
tively associated with creatinine/albumin ratio
in urine. Therefore, MV-associated DPP-IV in
115
urine can be considered as an early biomarker
of renal damage before the beginning of albu-
minuria (Wang et al. 2014).
2-AminoAdipic Acid (2-AAA)
2-AAA is a metabolite biomarker investigated
for its potential role in investigation and treat-
ment DM. 2-AAA is an inadequately character-
ized product of lysine degradation, which is
found in the circulation from whole tissue or
plasma protein degradation. It is also produced
from circulating lysine by unidentified enzymatic
pathway. 2-AAA can be used to envisage the pro-
gression of diabetes in normoglycemic peoples.
A cohort study found that people with increased
plasma 2-AAA level had up to four times
increased risk of future DM. It is also assumed
that 2-AAA may be part of a carbonyl stress path-
way in DM. Recent investigations had also
showed that 2-AAA can be a promising tool to
treat DM (Wang et al. 2013b).
AGEs and RAGE
AGEs [e.g., N-(carboxymethyl) lysine, pentosi-
dine] are generated through nonenzymatic reac-
tion between reducing sugars and amine
residues of lipids, proteins, or nucleic acids and
are responsible for acting as pro-oxidants and
pro-inflammatory agents. Hyperglycemia
increases the production of AGEs which is
responsible for several diabetic complications
(as discussed in Chap. 7). Oxidative stress
induced by AGEs after its binding to membrane
receptors for advanced glycation end product
(RAGE) can be considered as a key mechanism
of diabetic complications; the expression of
RAGE also increases in hyperglycemic condi-
tion (Gillery 2001; Sen et al. 2015). Activation
of RAGE in diabetic condition increases the
production of ROS and further increases the
production of AGEs. AGE–RAGE interaction
responsible for upregulation of inflammatory
cell adhesion molecules and chemokines and
attachment of inflammatory cells to the vessel
116
wall thus induces activation of inflammatory
cell and release of RAGE ligands like S100/cal-
granulins and HMGB1. These substances are
responsible for increasing endothelial dysfunc-
tion and vascular permeability and polarizing
macrophages to a predominant “M1” versus
“M2” paradigm. These changes induce micro-
and macrovascular complications of DM
(Manigrasso et al. 2014). AGEs through gener-
ation of ROS are also found to increase VEGF,
MCP-1, and ICAM-1 expression in microvas-
cular endothelial cells and can activate NF-kB
and NADPH oxidase thus causing apoptosis of
pericytes and other retinal cells. Current
research showed that serum AGEs particularly
pentosidine levels are positively linked with
microvascular complications in T2DM retinop-
athy, hypertension, and hyperlipidemia
(Kerkeni et al. 2012). Urinary protein-bound
AGE level is closely related in albuminuria,
reflecting the stage of diabetic nephropathy and
thus considered as potential biomarker in this
regard (Coughlan et al. 2011).
Skin Autofluorescence
Skin autofluorescence can be considered as a
reproducible tool and noninvasive measure to
determine the level of AGE accumulation in
tissue, representing cumulative glycemic and
oxidative stress. Skin autofluorescence is found
to associate with high level of HbA1c,
increased body mass index, elevated triglycer-
ide levels, and lower HDL cholesterol level.
Age and duration of diabetes are positively
associated with skin autofluorescence. High
level of skin autofluorescence indicates
increased AGE content in tissue and also con-
sidered as useful predictor of diabetes mortal-
ity. Association between skin autofluorescence
in people with T2DM, degree of hyperglyce-
mia, adiposity, and metabolic syndrome was
established (Lutgers et al. 2006, 2009). Thus,
skin autofluorescence can be considered as a
useful marker in individuals with DM who are
at risk for developing diabetic complications
and to monitor glycemic control.
9 Biomarkers of Diabetes and Diabetic Complications
Advanced Oxidation Protein Products
Oxidative stress is believed to be an important
factor for the pathogenesis of diabetes and its
complications. ROS can attach different amino
acids which lead to the structural modification of
amino acids to generate carbonyl moieties, while
hypochlorous acid and chloramines produce dity-
rosine containing cross-linked protein products
known as advanced oxidation protein products
(AOPPs), both of which can be considered as
indicator for oxidative stress and can be used to
find the degree of protein damage. Plasma protein
carbonyls offer a global index to measure protein
oxidation, while in in vivo condition, level of
AOPPs in plasma closely associates with levels of
dityrosine, a characteristic of oxidized protein and
pentosidine. Thus, AOPPs which might be pro-
duced at the time of oxidative stress through the
reaction of plasma proteins with chlorinated oxi-
dants can be acknowledged as a novel indicator of
oxidant-mediated protein damage. Preservation
of protein redox status is important for cell func-
tion; therefore oxidative stress-induced structural
alteration in proteins is key molecular mecha-
nisms leading to diabetic complication. In dia-
betic subjects high plasma protein carbonyls and
AOPP level underlie the significance of the pro-
tein conformational alterations in the pathogene-
sis of diabetic nephropathy (Pandey et al. 2010).
F2-Isoprostanes (F2-ISOPS)
Conjugated dienes and lipid hydroperoxides are
the primary end products of lipid peroxidation,
while secondary end products formed during
lipid peroxidation include gaseous alkanes, thio-
barbituric reactive substances (TBARS), and a
group of prostaglandin (PG) F2-like products
known as F2-isoprostanes (F2-IsoPs). F2-IsoPs
are prostaglandin-like substances synthesized in
in vivo condition from free radical-catalyzed
peroxidation of arachidonic acid. The associa-
tion of F2-IsoPs was observed with hyperglyce-
mia, vasoconstriction, and diabetic nephropathy
condition. Estimation of urine/plasma level of
F2-IsoPs will help to measure oxidative stress
Biomarkers to Predict and Monitor DM and Its Complications
directly. In diabetic people (both T1DM and
T2DM) increased level of F2-IsoPs was reported.
8-iso-PGF2α (a major form of F2-IsoPs) was
found to enhance by threefolds in people with
T2DM than in control subjects. Several investi-
gations have found that impaired glycemic con-
trol results in increased level of F2-IsoPs in
patients with T2DM, and treatment with antidia-
betic drugs or proper metabolic control reduces
urinary IsoP levels. High level of 8-iso-PGF2α
was significantly associated with blood glucose
level and increased activation of platelet
(Kaviarasan et al. 2009; Laight et al. 1999).
Nitrotyrosine (NT)
Activation of PARP can be correlated closely with
nitrosative stress, manifested by accumulation of
NT. NT is considered as a stable footprint of per-
oxynitrite-induced damage. Peroxynitrite is a
potent oxidant responsible for lipid peroxidation,
DNA damage, impairment of mitochondrial func-
tion, alteration of signal transduction mechanisms,
and generation of hydroxyl radical. Nitrosative
stress plays a vital role in the pathogenesis of dia-
betic complications including diabetic neuropathy,
and accumulation NT has been observed in many
tissue sites. NT accumulation is also observed in
the circulation, myocardium, microvasculature,
loop of Henle, and renal proximal tubules of dia-
betic people. Level of plasma NT has been found
to associate with diabetes-associated endothelial
dysfunction (Drel et al. 2010).
8-Hydroxydeoxyguanosine (8-OHdG)
ROS is responsible for DNA strand breaks and
base alterations like oxidation of guanine resi-
dues to 8-hydroxydeoxyguanosine (8-OHdG), an
oxidized nucleoside of DNA. Increased level of
8-OHdG is detected in mononuclear cells from
diabetic patients. Level of urinary 8-OHdG is
regarded as a result of oxidative DNA damage,
which can be connected with severity of
tubulointerstitial lesions in diabetic nephropathy
condition. Thus, 8-OHdG is considered as a
117
sensitive biomarker of diabetic nephropathy (Pan
et al. 2007). Positive correlation between
8-OHdG with HbA1c means intima-media thick-
ness and coronary heart disease were observed in
people with T2DM. Urinary 8-OHdG/creatinine
ratio was found more in individuals with albu-
minuria and in those with retinopathy. These
observations clearly indicated that oxidative
stress is a vital mechanism of diabetic complica-
tions, and 8-OHdG could be a useful biomarker
of micro- and macrovascular complications in
individuals with T2DM (Nishikawa et al. 2003).
8-Oxo-7,8-Dihydro-2′-Deoxyguanosine
(8-oxodG)
High glucose level generally increases free radi-
cal generation and induce several complications.
8-oxodG is considered as key marker of intracel-
lular oxidative stress. Noninvasive assessment of
8-oxodG in urine could provide key information
about oxidative stress. High level of 8-oxodG in
urine can indicate the development of diabetic
nephropathy (Wang et al. 2013a).
Oxidative Stress-Related Biomarkers
Estimation of endogenous antioxidants like
catalase, superoxide dismutase, glutathione per-
oxidase, glutathione reductase, and glutathione
can offer key information about oxidative stress
in diabetes. Evidence of increased free radical-
induced oxidative stress and lipid peroxidation
in the pathogenesis of diabetes and its differ-
ent complications has been well recognized.
Monitoring the other marker of oxidative stress
such as lipid peroxidation, nitrite concentra-
tion, cholesterol oxides, ratio of glutathione,
and glutathione disulfide levels is also useful to
find the risk of diabetes and its complication.
Determination of total antioxidant capacity and
reduced protein thiols also provides useful infor-
mation on oxidative stress. Level of oxidative age
(a breath marker of oxidative stress) is also found
to increase in both T1DM and T2DM (Maritim
et al. 2003; Ferderbar et al. 2007).
118
Retinal Vascular Caliber and Retinal
Thickness
Retinal vascular changes like venular widening,
retinal arteriolar narrowing, hemorrhages, and
microaneurysms were found to be associated
with several systemic diseases, and current
researchers indicated that retinal measurement
concept may be useful to predict different sys-
temic diseases. Alteration in retinal vascular
caliber reflects a variety of disorders induced by
the response of hyperglycemia like inflamma-
tion, increased blood pressure, endothelial dys-
function, and hypoxia and also useful to predict
diabetes microvascular complications like coro-
nary heart disease and stroke. Changes in retinal
blood vessels may be monitored noninvasively
which can indicate the presence of early dia-
betic pathophysiology, supporting the thought
that these variations could translate as biomark-
ers for assessment of risk and as surrogate inten-
tion for preventive interventions. Several
investigations suggested that retinal vascular
calibers may be associated with the threat of
both occurrence and progression of T1DM- and
T2DM-related complication. Thus, retinal vas-
cular caliber serves as a possible biomarker for
the diabetic complications like retinopathy,
nephropathy, and neuropathy (Ikram et al.
2013). Percentage reduction in retinal thickness
is also a superior entrant for a prognostic bio-
marker for visual acuity reaction to anti-VEGF
therapy (Cunha-Vaz et al. 2014).
Microaneurysm
Rod dots consist of microaneurysms and hem-
orrhages are recognized as the initial changes
observed on ophthalmoscopic screening. These
are counted by fundus photography and con-
sidered as a key marker to observe retinopa-
thy progression. Formation and disappearance
of red dot are dynamic processes. Usually,
microaneurysm disappearance is not a revers-
ible procedure and signifies vessel closure and
progressive vascular damage. Disappearance
9 Biomarkers of Diabetes and Diabetic Complications
of microaneurysm because of thrombotic phe-
nomena leads to consequent rerouting of capil-
lary blood flow and continuous remodeling of
the retinal vasculature in diabetic patient. Thus,
formation and disappearance rates of microan-
eurysm can be considered as a suitable retinal
biomarker of disease state and development
of retinopathy to clinically important macular
edema, which can cause vision loss (Ribeiro
et al. 2013).
Biomarkers That Influence Retinal
Macroglial Activity
Aquaporin 1 (AQP1), aquaporin 4 (AQP4),
and glial fibrillary acidic protein (GFAP) are
considered as aqueous humor biomarkers of
retina macroglia activation in individuals with
DM. GFAP, AQP1, and AQP4 are recognized
as biomarkers of retinal macroglia activity.
GFAP, AQP1, and AQP4 enhanced significantly
in human eyes with diabetes, confirming that
retinal glia is a key factor in this disorder. A
study showed that GFAP increases 0.8-fold and
AQP1 increases 1.1-fold, while AQP4 increases
about 24-folds in diabetic patients versus con-
trols. Reduction of the markers in the eyes with
diabetic macular edema most likely represents
a sign of muller cell degeneration (Vujosevic
et al. 2013).
Biomarkers Related to Later
Pregnancy Complications
Several studies have proposed that mean arterial
pressure, maternal factors, placental growth fac-
tor, uterine artery Doppler pulsatility index,
b -human chorionic gonadotropin, pregnancy-
associated plasma protein A, fetal crown-rump
length, CRP, sex hormone-binding globulin, pla-
cental protein 13, fetal nuchal translucency,
metalloprotease, and disintegrin can be useful to
predict the later pregnancy complications like
preterm birth, preeclampsia, fetal growth restric-
tion, and GDM (Kane et al. 2014).
Biomarkers as Essential Tool for Treatment
MicroRNAs
In almost all mammalian genomes, non-
(protein)-coding RNAs (ncRNA) share ~98 % of
the transcribed genome. MicroRNAs (miRNAs)
represent an imperative subtype of ncRNA which
is found to be implicated in the pathogenesis of
DM and its complications. miRNAs are the key
gene regulators working at the posttranscriptional
level. Mature miRNAs at the posttranscriptional
level significantly act as a negative controller
of gene transcripts. Fresh findings showed the
imperative role of miRNAs in diabetes mellitus
through its effect on endocrine pancreas develop-
ment, pancreas regeneration, islet function, beta
cell proliferation, islet apoptosis, insulin secre-
tion, and insulin resistance. The role of miRNAs
in different complications is also well recognized.
Hence, microRNAs are also considered as vital
biomarkers for diabetes and its complications
(Ferland-Mccollough et al. 2010; Joglekar et al.
2011; Conserva et al. 2013; Rawal et al. 2014; Li
et al. 2014; Sen et al. 2015) (Table 9.2).
Genetic Biomarkers
Both T1DM and T2DM are associated with sev-
eral environmental and genetic risk factors.
Investigation toward the identification of suscep-
tibility genes, expression of gene, and/or protein
may serve as excellent biomarkers for assess-
ment of diabetes risk and to develop new drugs.
About 18 regions (IDDM1 to IDDM18) of the
genome have been recognized and are related to
the risk of T1DM. IDDM1, IDDM2, IDDM5,
IDDM10, IDDM12, and IDDM18 (genes related
to these are DRB1, DQA1, DQB1, INS, CTLA4,
PTPN22, PTPN11, IL-2Rβ, IL12B, SUMO4,
ITPR3) and are found to associate in the patho-
genesis of T1DM. It was found that DR gene and
certain alleles of the DQ gene are recognized as
risk factors for progression of DM, whereas other
alleles of DQ are defensive. The people who
inherit DR3 or DR4 to inherit DQ have advanced
risk of developing diabetes (Dean and McEntyre
2004; Sen et al. 2015). IDDM2 (locus INS gene)
119
is found to associate with T2DM. A number of
T2DM loci such as CDKAL1, CDKN2A/
CDKN2B, KCNQ1, CDC123, GLIS3, HNF1B,
DUSP9, GRK5, RASGRP1, PPARG, TCF7L2,
HNF1A, GCK, IGF1, IRS1, and IDE in different
genes were reported (Dean and McEntyre 2004;
Li et al. 2014). The relationship of different SNPs
across the genome was found to involve in the
pathogenesis of T2DM. The association of T2DM
with a variety of candidate genes which includes
CAPN10, PPARG, KCNJ11, ABCC8, HNF1A,
GCK, HNF4A, PC-1/ENPPI, PTPNI, PTPNI,
TCF7L2, and WFS1 was also reported. Genes
like TCF7L2, SLC30A8, IDE-KIF11-HHEX,
CDKAL1, CDKN2A-CDKN2B, IGF2BP2, and
FTO were found to be responsible for uncertain
function which can increase the risk of T2DM
(Rich et al. 2008; Singh 2011; Sen et al. 2015)
(Fig. 9.1).
Biomarkers as Essential Tool
for Treatment
Identifying the diabetes biomarker will not only
be useful in diagnosis/predicting diabetes and its
complications, or to gather useful information
about the pathogenesis of the diseases, but also
can be used as a drug to treat the same. Therefore,
the discovery of a specific, reliable diagnostic
and prognostic biomarker for DM is highly
essential. Adipokines also exert a key role in the
treatment of DM. Researches by targeting differ-
ent adipokines or use adipokines directly are
proven effective to find new therapies to manage
DM. Adiponectin gene therapy in experimental
animal improves insulin level, glucose tolerance,
and metabolic abnormalities due to high-fat,
high-sucrose diet. This therapy also reduced
decreases in blood glucose and decreased hepatic
gluconeogenesis. In patients with T1DM, leptin
alone or combined with low-dose insulin over-
turn the catabolic state by suppressing the hyper-
glucagonemia. Another study on rodent found
that neutralization of TNF-α and/or deletion of
TNF-α receptors results in significant increase in
insulin sensitivity or improves insulin resistance.
120 9 Biomarkers of Diabetes and Diabetic Complications

Table 9.2 Some miRNAs involved in the pathogenesis of diabetes and its complications
microRNA
Induction of diabetes mellitus
miR-495, miR-218, miR-124,
miR-375, miR-7
miR-15a, miR-15b, miR-16,
miR-195
miR-30d, miR-107, miR-296,
miR-484, miR-375, miR-9,
miR-124a, miR-96, miR-133a
miR-30 family
miR-21, miR-34a, miR-146,
miR-29a, miR-29b, miR-278
Cardiovascular complications
miR-1, miR-133, miR-126,
miR-208a, miR-499, miR-278,
miR-132
Diabetic renal complications
miR-192, miR-216a, miR-217,
miR-377, miR-29c, miR-21,
miR-200b/c, miR-215, miR-26b,
miR-200b
miR-192, miR-215, miR-25,
miR-29a, miR-29c, miR-21,
miR-132, miR-200a, miR-451,
miR-93
Specific pathological condition
Involved in the regulation of pancreas development, β-cell differentiation
and function
Activation of these miRs in pancreas during regeneration restrains Ngn3
translation and results neogenesis of islet
Involve in alteration of islet function through several path-like activation of
insulin transcription, inhibition insulin exocytosis, reduction of glucose-
mediated insulin secretion, insulin secretion inhibition, and inhibition of
insulin biosynthesis
Expression of miR-30 family reduced during in vitro mesenchymal
transition of human islet
Involve in islet apoptosis, change in insulin sensitivity in adipose tissue
These miR generally expressed in a variety of tissues like cardiac muscle,
skeletal muscle, endothelial cell, and neuron cell. They are reported in
several diabetic complications related to heart-like myocardial infarction,
cardiac hypertrophy, atherosclerosis, cardiomyopathy, cardiac remodeling,
arrhythmia, and cardiac regeneration
Upregulation of these involved in the diabetic nephropathy (based on
experiment on in vitro, animals, and human). They are responsible for
extracellular matrix accumulation in mouse renal mesangial cells, increased
Akt activation, mesangial expansion, hypertrophy, collagen synthesis,
increased fibronectin production in mesangial cells, fibrosis, cell
proliferation, and apoptosis
Downregulation in expression also involved in the diabetic nephropathy
(based on experiment on animals and human). They are responsible for
E-cadherin induction and increased oxidative stress

Dose-dependent inhibition of omentin-1 expres- therapies. GAD65 administration to nonobese

sion is observed after administration of glucose
and insulin to human omental adipose tissue.
Anti-obesity and antidiabetic activity of apelin
was also demonstrated. Recently discovery and
research on various DPP-IV inhibitors gain the
momentum as these drugs showed promising
effect to control DM. Sitagliptin, a DPP-IV
inhibitor, was developed which improves glyce-
mic control and reduces HbA1c levels, without
weight gain in type 2 diabetic people (Sen et al.
2015).
Few recent studies also confirmed that inter-
ventions to interrupt the activity of the renal
TGF-β1 system could be beneficial to halt the
progression of diabetic nephropathy (Ziyadeh
2004; Mehta et al. 2013). GAD65 is also consid-
ered as a potential avenue for immunoregulatory
diabetic mice was found to avert the autoimmune
loss of islet β cells. Currently, clinical trial of
“GAD-alum” vaccine (GAD65 formulated with
aluminum hydroxide, subcutaneous administra-
tion) on recent-onset T1DM patients was carried
out. Promising result of vaccine was observed in
the first two phases, though it is not continued in
the third phase. But such approaches show that
GAD65 has potential to be used in treatment
though a lot of research is still needed (Towns
and Pietropaolo 2011). Experimental investiga-
tion showed that 2-AAA administration decreases
fasting plasma glucose in rodents fed both stan-
dard chow and high-fat diets. Treatment with
2-AAA is also found to increase insulin release
from an islet β-cell line as well as murine and
human islets (Wang et al. 2013b). MVs are found
Biomarkers as Essential Tool for Treatment 121

Genetic biomarkers, miRNAs

Genetic factor
Constitutional factors
Environmental Oxidative (Diet, Physical activity, Stress) Genetic factor
factor stress
Autoimmune related
Adiopokines, Other
process biomarker,
miRNAs diseases
Infection & F-2IsoPs
Disease
Obesity
Oxidative
Destruction of beta cell stress Decrease insulin
Insulin resistance secretion

T1DM Adipokines, Fetuin-A,

CRP, miRNA, GAD

Increased hepatic Postprandial

AGEs, RAGE, Akin autoflurescence, glucose synthesis hypoglycemia
Lipid profile, Serum metabolites, 2-AAA

Progression of
beta cell apoptosis

Increased glucose level Reduced insulin

T2DM Hyperglycemia
in blood secretion

AGEs, RAGE, AOPPs,

8-OHdG, 8-oxodG, HbA1c, Glycated albumin, Albumin
Oxidative stress
Oxidative stress related 1,5-AG, Fructosamine
markers

Renal complications
Impairment of tissue or organ
function
DPP-IV, MVs, Ferutin A, Cystain C, Fibronectin,
Cardiovascular complications Type IV collagen, L-PGDs, FGF-betal, Laminin,
NAG, KIM-1, alpha-1 microglobulin, NT, MCP-1,
NAGL, Ceruloplasmin

TNF-alpha, IL-6, Vaspin, CRP,

Eye
Cystain-C, MVs, ANGPTLs, GFAP, AQPI, Microaneurysm, VEGF,
complications
OPG, ICAM-1, VCAM-1, vWF, ApoA1, ApoB, Retinal vascular caliber,
L-PGDs Retinal thickness

Fig. 9.1 Process of diabetes mellitus and some of its
complications, showing opportunities of identifying bio-
markers. HbA1C hemoglobin A1c, 1,5-AG 1,5-anhydro-
glucitol, 2-AAA 2-aminoadipic acid, AGEs advanced
glycation end products, RAGE receptor for AGE, 8-OHdG
8-hydroxydeoxyguanosine, 8-oxodG 8-oxo-7, 8-dihydro-
2′-deoxyguanosine, TNF-alpha tumor necrosis factor α,
IL-6 interleukin 6, CPR C-reactive protein, ANGPTLs
angiopoietin-like proteins, AOPPs advanced oxidation
protein products, ApoAI apolipoprotein AI, ApoB apolipo-
protein B, AQP aquaporin, DPP-IV dipeptidyl peptidase
IV, F2-ISOPS F2-isoprostanes, GAG glycosaminoglycan,
GFAP glial fibrillary acidic protein, VEGF vascular endo-
thelial growth factor, KIM-1 kidney injury marker-1,
L-PGDs lipocalin-type prostaglandin D2 synthase, MCP-
1 monocyte chemoattractant protein-1, ICAM-1 intracel-
lular adhesion molecule-1, T1DM type 1 diabetes mellitus,
T2DM type 2 diabetes mellitus, VCAM-1 vascular cell
adhesion molecule-1, NAG N-acetylglucosaminidase,
miRNAs microRNAs, MVs microvesicles, NGAL neutro-
phil gelatinase-associated lipocalin, NT nitrotyrosine,
OPG osteoprotegerin, vWF von Willebrand factor

to implicate in the different diabetic complica- ticlopidine), antihypertensive (efonidipine,

tions and MVs also appeared as potential nifedipine, losartan), antiatherosclerosis (pitavas-
therapeutic target. Several researchers found that tatin, atorvastatin, eicosapentaenoic acid), and
current medicines like antiplatelet (cilostazol, antihyperglycemic (glibenclamide, pioglitazone,
122
insulin) drugs are found to decrease MVs (Wang
et al. 2014). VEGF is the target to treat diabetic
retinopathy. Pegaptanib, ranibizumab, bevaci-
zumab, and VEGF Trap-Eye are the four anti-
VEGF agents available in the USA used in the
management of diabetic retinopathy (Zorena
et al. 2013).
Biomarker research in diabetes is the future
of diabetes management; thus, research on
identifying novel biomarker requires being
tested properly based on the information avail-
able from commonly measured variables in
clinical practice. Understanding of the particu-
lars of diabetes biomarker and their physiologi-
cal role will silhouette the future management
of DM and discovery of new drug/therapeutic
approach for the treatment of DM and its
complications.
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 Indian Traditional Medicinal
Systems, Herbal Medicine,
and Diabetes
The most precious, indispensable, and complex
system, which also shapes the backdrop for the
emergence, evolution, and existence of life, is
nature. Since time immemorial, nature has
bestowed incredible boons on mankind as it pro-
vides food, shelter, medicine, and animal
resources according to our needs. Folk or tradi-
tional systems of medicines always played an
imperative role in global healthcare system.
Traditional medicine is still playing a vital role,
especially in rural areas though the demand of
traditional medicines is increasing worldwide
and shall play a major role in the future as well.
Traditional medicine can be explained as the
diverse health practices and approaches, com-
plied knowledge, skills, and practices related to
animals, plants, and mineral – which is related to
the beliefs, spiritual remedies, manual practice/
procedures, and ancient indigenous experience
that used to maintain health and comfort as well
as to cure, diagnose, or prevent illness. Indian
civilization is comprehensive having multifac-
eted cultural aspects and one of the oldest heri-
tages of mankind. Indian traditional medicinal
system is a one of the oldest traditional medicinal
systems in the world. India has the unique char-
acteristic of having different well-acknowledged
traditional systems of medicine, such as
Ayurveda, Siddha, Unani, Yoga, naturopathy, and
homeopathy. Though homeopathy is not an
indigenous system and came to India in the eigh-
teenth century, it completely incorporated into
the Indian society and got improved like any
© Springer Science+Business Media Singapore 2016
S. Sen et al., Diabetes Mellitus in 21st Century, DOI 10.1007/978-981-10-1542-7_10
10
other traditional medicinal system; therefore, it is
believed as part of Indian Systems of Medicine.
Unani system originated in Greece, and later it
was introduced in India by Arabs. In Mughal
period, it spread and soon it took firm roots and
enriched in Indian soil. Apart from these systems,
folk (tribal) medicines are also important sources
for the indigenous healthcare system, though
they have not been organized under any category.
The classical transcripts of Indian traditional
medicine system Ayurveda include Rigveda,
Atharvaveda, Charaka Samhita, and Sushruta
Samhita (Joy et al. 1998; World Health
Organization 2002; Ravishankar and Shukla
2007).
Ayurveda and Diabetes
Ayurveda is deemed not just as an ethnomedicine
but also as a complete medical care system that
includes physical, psychological, philosophical,
ethical, and spiritual consideration for the well-
being of mankind; and causes, treatment, man-
agement, and prevention of almost every disease
in well-documented manner. DM is most likely
one of the well-described disorders in ancient
India as “Madhumeha kshaudrameha,” which
means too much urination with honey like sweet
taste. Epidemiology of DM in India has a very
old history. The oldest reference concerning dia-
betes in ancient Indian texts dates back to 4500
years. Historically, Ayurveda explains a set of
125
126 10 Indian Traditional Medicinal Systems, Herbal Medicine, and Diabetes
multifaceted clinical disorders with recurrent
abnormal micturition, collectively recognized as
Prameha (urine disorder), which correlate in sev-
eral ways with metabolic syndrome, obesity, and
DM. The etiology of Prameha is well discussed
in Sushruta Samhita; the text mentioned about
two types of Prameha: (i) sahaja, which is hered-
itary, and (ii) apathyanimittaja, which is acquired.
Charaka Samhita mentioned that Prameha occurs
due to genetic factors. Prameha if ignored or not
treated properly in time can convert into
Madhumeha and became untreatable; in several
occasions, Madhumeha is applying to all kind of
Prameha. This greatest ancient Indian medical
treatise succinctly explains about the etiopatho-
genesis, symptomatology, complications, and
treatment of Prameha (metabolic disorders) and
Madhumeha. Ayurvedic literature also suggests
that obesity was a major risk factor for diabetes,
and fat asymmetry impairs strength and decreases
life span; this may have been an indication of
increased incidence of diabetes among the asym-
metrically obese. The explanation on the etiol-
ogy, diagnosis, prognosis, and management of
diabetes in Ayurveda is principally the same to
those described by the modern allopathic medici-
nal system. The Ayurvedic approach in the man-
agement of diabetes includes a lifestyle
modification, exercise, dietary interventions, and
different herb and herbal formulation related to
the predominant dosa, though cleansing mea-
sures consider exclusive to the Ayurvedic
approach (Mishra and Adra 2004; Gupta and
Misra 2007; Weaver and Narayan 2008; Banani
et al. 2011; Sharma and Chandola 2011).
Basic philosophy of Ayurvedic approach in
management of diseases revolves around three
important factors (doshas) of life, viz., vata,
pitta, and kapha. The air, fire, and earth are the
primary dominant elements in vata, pitta, and
kapha, respectively. At macromolecular or
molecular levels, vata symbolizes the processes
like respiration, oxygen responsible for combus-
tion of nutritious substances throughout the met-
abolic process to release and mobilize energy.
Pitta represents the factors responsible for diges-
tion, absorption, and/or metabolism of nutritious
substances at any level of physiological activities
and may be considered as enzymatic activities,
etc. Kapha signifies nutritious regimens and may
be either of dietary origin or nutritious substances
at systemic and/or tissue level. Further, Ayurveda
describes DM as one of the Pramehas that may
occur in any of the three body constitutions such
as vata, kapha, or pitta. Ayurvedic texts have
explained 20 types of Pramehas based on the
predominant dosas (ten kapha types, six pitta
types, and four vata types). This classification is
mainly based on the physical features of urine
like volume, odor, color, taste, solid particles,
sediments, turbidity, temperature, presence of
seminal fluid, and mucus (Mishra and Adra 2004;
Tiwari 2005; Banani et al. 2011; Sharma and
Chandola 2011). A detail classification of
Pramehas with the factors responsible for it was
given in Table 10.1.
Ayurveda has described the advancement of
Prameha through different stages. In the early
stage, excess kapha leads to vitiate of meda (fat)
and kleda (body fluid), thereby resulting Kaphaja
Prameha. Further progression of such condition
leads in kshaya (loss) of kapha, which results in
predomination of pitta. In this condition, the
blood (rakta) vitiated, precipitating Pittaja
Prameha. In the next stage, loss of pitta results
vitiation of vata, which induces the elimination
of vital essence/vital substances from the body
through urine, resulting Vataja Prameha. This
oldest literature also specified that any of these
three major Pramehas can be involved directly,
based on genetic predisposition and inappropri-
ate lifestyle and diet. Associating the classifica-
tion and etiology, Kaphaja Prameha and Pittaja
Prameha are always Apathyanimittaja Prameha
(acquired), while Vataja Prameha can be either
hereditary or acquired. If Kaphaja Prameha and
Pittaja Prameha are not correctly treated, then
they lead to Madhumeha, which is untreatable.
Ayurvedic treatment is based upon the philoso-
phy that enforces the qualitative as well as quan-
titative appropriateness and balance of all these
factors to maintain normal mental and physiolog-
ical fuel homeostasis in order to live a healthy
life. Hence, Ayurveda recommends multiple
Ayurveda and Diabetes 127

Table 10.1 Classification of Pramehas and factors responsible for such conditions according to Ayurvedic literature
Types Subtypes Description Factors responsible
Kaphaja Udakameha Clear urine in large amounts without Dietary factors:
Pramehas odor resembles water; patients feels Yavaka (a type of barley), Atiyav
[Kapha cold sensation while passing urine (Avena sativa – a oats), Uddalaka
type] Iksumeha/ Urine is very sweet, like sugarcane (Paspalum scrobiculatum – kodo
Ikshuvalikameha juice, sometimes with slight turbidity, millet), Chanaka (Panicum
and slimy miliaceum – a millet grain),
Naishadha and Hayanaka (types of
Sandrameha Urine becomes thick if kept overnight
millet grain), Itkata (Saccharum
Surameha/ Urine look likes sura (beer) with a species), Harenu (Pisum sativum – a
Sandraprasadmeh clear top and a cloudy bottom portion green peas), Til Palal (a by-product
Pista meha/ Urine is white and thick, resembling to of Sesamum), Masha (Vigna
Shuklameha a solution of corn flour, while passing mungo – urad dal), Payasa (a milk
urine the patient get the sensation of preparation), milk, sugarcane
erection of body hairs preparations, fresh wine, immature
Sukrameha Urine looks like semen or mixed with curd, the meat of domesticated,
semen aquatic animals, marshy, and
Sitameha Urine is sweet and abundant but very different types of rice (such as
cold Mukundaka, Mahavrihi, Pramodaka,
Sugandhaka
Sikatameha Sand-like particles are observed in the
Lifestyle factors:
urine
Physical inactivity, excessive sleep
Sanairmeha Urine is passed very gradually, and and lying down, sitting too much,
patient may feel difficulty in passing sedentary habits
urine Psychological factors:
Laalameha Urine is slimy and contains threads Depression
similar to that of saliva
Pittaja Ksarameha Urine resembles to a solution of alkali Dietary factors:
Pramehas in smell, color, taste, and touch Consumption of hot (Ushna) foods,
[Pitta type] Kalameha Black color of urine foods with sour or pungent taste,
alkaline foods, extremely salty foods,
Nilameha Bluish color of urine
further eating before the complete
Haridrameha Yellowish color (similar to turmeric) of digestion of previous consumed food,
urine, with a severe burning sensation intake of mutually contradictory
Manjisthameha Urine is slightly reddish solution with foods (like – milk and salty foods,
foul smelling resembling manjistha milk and bananas, yogurt and sour
(Rubia cordifolia) fruits, etc.)
Raktameha/ Urine is slightly salty, is foul smelling, Lifestyle factors:
Lohitameha and contains blood Exposure to very intense heat of the
sun or fire, overexertion.
Psychological factors:
Anger
Vataja Majjameha/ Urine resembles like marrow or Dietary factors:
Pramehas Sarpimeha marrow mixed Excessive intake of food with
[Vata type] Ojasmeha/ Urine appears like honey. Urine is pungent, astringent, bitter taste.
Kshaudrameha/ astringent and sweet in taste, yellowish Consumption of cold, rough, and
Madhumeha to white in color, and nonunctuous very simply digested foods
Lifestyle factors:
Vasameha Urine appears like liquid muscle fat
Intense physical exercise, too much
and may be passed frequently.
sexual intercourse, extreme use of
Hastimeha Urine discharged continuously without Panchakarma (Ayurvedic purification
force, mixed with lymph and without process), injury, fasting, restraining
obstruction natural urges, extreme exposure to
the sun, and sleepless night
Psychological factors:
Anxiety, mental trauma, and grief
128 10 Indian Traditional Medicinal Systems, Herbal Medicine, and Diabetes
herbo-mineral preparations in the treatment of
diabetes that can have appropriate characteristics
to manipulate risk factors (doshas) in order to
bring physiological homeostasis back into the
state of normal equilibrium (Mishra and Adra
2004; Tiwari 2005; Banani et al. 2011; Sharma
and Chandola 2011).
On the basis of prognosis, the Prameha can
also be classified into three major types: (i) sad-
hya (curable), (ii) yapya (controllable), and (iii)
asadhya (difficult to manage). Kaphaja is sadhya
or curable type, which is mainly in obese patient
and acquired type. This is the early stage without
any complications. Clinical manifestation
showed that the stage is associated with mild
hyperglycemia due to disturbed carbohydrate and
fatty acid metabolism; hyperinsulinemia can also
be observed. Pittaja is yapya or controllable type
and consider as acquired manifestation. Moderate
hyperglycemia due to hyperadrenalism can be
observed in patients suffering from such type of
conditions. But Vataja is asadhya type, which is
difficult or impossible to cure. It may be heredity
or acquired type. Clinical manifestation showed
that this is a chronic, advanced state of diseases
with complications; severe hyperglycemia due to
hypoinsulinemia is also common in patient suf-
fering from Vataja (Sharma and Chandola 2011).
Nidan (Etiology)
According to Ayurvedic literature, the etiology of
Madhumeha is multifactorial which includes,
meda (fat), addiction to pleaser, laughing,
unwholesome sleep, sedentary habit, lying down,
lack of exercise, continuous cheerfulness, and
excessive mental and physiological work.
Ayurveda describes DM into two categories:
firstly, sahaja (genetic), generally found more in
young age, that has resemblances with juvenile
diabetes or insulin-dependent diabetes, and sec-
ondly, apathyaja (acquired), which results from
an unhealthy lifestyle more in old age and obese
people, that has resemblances with type non-
insulin DM. Charaka Samhita (100–400 A.D.)
also described diabetes in two categories: (a)
Krsa Prameha occurs in people with very low
weight and requires santarpan (restorative or
rejuvenation treatment); and (b) sthula occurs in
obese people, which requires apatarparna (fat-
reducing/removal treatment) (Mishra and Adra
2004; Banani et al. 2011).
Samprapti (Pathogenesis)
Ayurvedic texts described that Madhumeha can
arise by two ways: (1) aggravation of vata, due to
dhatukshya (body constitution) and (2) obstruction
of srotos (channels). Madhumeha and all Pramehas
initiated by the derangement of kapha that increases
throughout the body and mixes with meda that
resembles to kapha (mucus) when physical proper-
ties are considered. Kapha mixed with meda passes
through the urinary system and interferes with nor-
mal urine excretion. Vitiated condition of pitta,
vata, and other body fluids (malas) also may involve
in such condition. DM in Ayurveda is explained
both the conditions Madhumeha (sugar loss in
urine) and Ojameha (immunity and hormone loss)
for the treatment purpose (Mishra and Adra 2004;
Banani et al. 2011).
Rog Pariksha and Nidan (Examination
and Diagnosis)
The diagnosis of Madhumeha/Pramehas based
on Ayurveda was mainly based on identifying
some common sign and symptoms including the
sweetness of urine that was recognized by a
swarm of flies and ants over the urine. Some
characteristic which was commonly observed in
Ayurveda includes sweda (excessive sweating),
anga shidhilathwam (looseness the body), anga-
gandham (foul smell of the body), sayyasna
swapnasukhabhishangithwam (lethargy feeling),
hridayopadeham (feeling of some type of heavi-
ness of hridaya), netropadeham (sensation of
something coated on eyes), shravanopadeham
(sensation of coating on ears), jhwopadeham
(feeling of a coated tongue), anga ghanathwam
(heaviness of body parts), nakhathivridhi
(extreme growth of nails), keshathivridhi
(extreme growth of hairs), sheetha priyathwam
Diabetes Mellitus in Siddha, Unani, and Homeopathy
(attraction toward cold), thalu shosham (dryness
of palate), gala shosham (dryness of throat), asya
madhuryam (sweet taste in mouth), Pada daham
(burning sensation of soles), karadaham (burn-
ing sensation of palms), and moothra madhuryam
(sweetness of urine). The common characteristic
features of all types of Prameha are prabhootha
and aavila moothratha and medo dushti laksha-
nas (excessive urination and turbidity in urine
and symptoms of vitiated medo dhatu).
Nowadays, Ayurvedic doctors also use modern
testing of urine, blood sugar, and HbA1c levels to
confirm the predominant dosa (Mishra and Adra
2004; Banani et al. 2011).
Upadravas (Complications)
Traditional literature also discussed about the
complications of Prameha. Doshas are responsi-
ble in pathogenesis of the disease which can
make the problem more difficult in advance stage
that is called upadrava. Susrutha has explained
Prameha complications according to dosha pre-
dominance and mentioned that malabandhata
(constipation) as a common complication of dis-
eased person is loaded with meda, and in such
condition, common purgatives in usual doses are
not useful. Briha Thrayees have mentioned
Prameha pidaka (diabetic carbuncle) as a major
complication of Prameha. Kaphaja, pittaja, and
vataja describe different symptoms that are the
dominant element in a diabetic patient (Mishra
and Adra 2004; Tiwari 2005; Banani et al. 2011).
1. Kaphaja includes:
Avipakam (indigestion), chardi (vomiting
tendency), aruchi (loss of appetite), kasam
(cough), athinidra (excessive sleep), and
peenasam (cold with running nose)
2. Pittaja includes:
Vasthimehanyotoda (pain in the bladder
and urinary path), jwara (fever), mushkavath-
aranam (pain in the testes), daham (burning
sensation), amlika (acidity), trishna (thirst),
moorcha (giddiness), hridayashoola (pain in
heart region), vitbhedanam (loose motion),
and nidranasam (loss of sleep)
129
3. Vataja includes:
Udavartham (upward movement of vata),
hridgraham (gripping pain in chest region),
kambam (tremor), lolatha (affinity), anidratha
(insomnia), soolam (pain), sosha (wasting),
kasam (cough), badhapureeshathwa (consti-
pation), and swasam (difficulty to breath)
Diabetes Mellitus in Siddha, Unani,
and Homeopathy
DM is also well described in Siddha and Unani
system of medicine. Siddha system of medicine
originated and practiced in Tamil Nadu, a south-
ern state of India. This system has close similari-
ties with Ayurveda and recognizes the humoral
concept, viz., wind or vata, bile or pitta, and
phlegm or kapha (Karunamoorthi et al. 2012).
DM is described in Siddha literature as “madhu-
megam” or “neeazhivu,” which indicates sweet
urine. Siddha medicine uses herbs, metals, min-
erals, and animal products alone and in combina-
tion in the management of DM (Abhilash and
Augustine 2014).
Unani system of medicine was introduced in
India by Arabs and Persians in ancient time,
which also believes in “humoral theory” (Ahmad
2008). Unani system generally classifies the dis-
eases in two categories depending on their cause.
The first type is caused by the involvement of
four humors, which is known as “Meddi dis-
eases,” while the second class is known as “Ghair
Meddi diseases” caused by the change of organ
temperature only. Unani system described DM as
“Ghair Meddi diseases.” DM in this system is
described as a disturbed physiological condition
due to “hot” temperamental derangement of the
liver, along with the presence of excessive thirst
and increased volume and frequency of urine.
Several factors like mental tension, anxiety, frus-
tration, anger, fear, weakness of nervous system,
and intake of excessive hot or cold food/drinks
may alter the temperature of the liver (Ramaiah
2009). Several treatment strategies like (1) Ilaj-
bi-ghiza (dietotherapy) through the intake of
specific diet; (2) Ilaj-bil-tadbeer (regimental
therapy) through exercise, climate change,
130 10 Indian Traditional Medicinal Systems, Herbal Medicine, and Diabetes
massage, venesection, leaching, and cupping; (3)
Ilaj-bi-dawa (pharmacotherapy) that involves
prescription of medicine from herbal, mineral,
and animal sources; and (4) Ilaj-bil-Yad or sur-
gery are discussed in Unani system (Ahmad
2008).
Treatment of DM through homeopathy is
strictly based on individualizing every single
patient and examining the physical and mental
constitutional symptoms. In this system, T2DM
is believed to cause due to psora or sycosis or
both. Psora is responsible for functional defi-
ciency; sycosis causes incoordination. A number
of drugs like Abroma augusta, Syzygium jambo-
lanum, Gymnema sylvestre, Cephalandra indica,
thyroidinum and insulinum phosphorus,
Lycopodium clavatum, Arsenicum album,
Phosphoricum acidum, China officinalis,
Lacticum acidum, Calcarea carbonica, sulfur,
Nitricum acidum, Silicea, Aceticum acidum,
Chimaphila, Syzygium, Ignatia, Argentum nitri-
cum, Lachesis, Natrum sulphuricum, Arsenicum
iodatum, Argentum metallicum, bryony, Thuja,
and Aceticum acidum are used in homeopathy in
the management of DM (Zamora 2010; Dey
2013; Central Council for Research in
Homoeopathy 2014).
In recent time, pharmaceutical companies
marked different formulation in the treat-
ment of diabetes which is based on Ayurveda,
Siddha, or Unani. Some of these are Dia-
care (Admark Herbals Limited), Hyponidd
Tablet (Charak Pharma Pvt. Ltd), Mamajov
(Ambadas Vanaushadhalaya), Obenyl Tablet
(Charak Pharma Pvt. Ltd), Nishakathakadi
Kashaya, Nisamalaki Gutika, Seendhil
Tablet, Majoon E Falasifa (SKM Siddha and
Ayurvedha Company), Asanand, Triphala
Guggulu, Gokshuradi Guggulu, Trivang
Bhasma, Lohasava, Giloy Satva (Ayurveda
Rasashala, Pune), Diabetes Daily Care
(Nature’s Health Supply), Bitter gourd pow-
der, Gurmar powder (Garry and Sun natural
remedies), Diabecon (Himalaya), Epinsulin
(Swastik Formulations), Diasulin (Tobbest
Busindo), Diabetic powder (Rahul Pharmacy,
Gujarat), Diabecure (Nature beaute sante),
Synedrex (Plethico Laboratories).
The Importance of Yoga
and Naturopathy in Diabetes
Naturopathy is a system that has generated by
combing traditional practices and healthcare
measures. Diet therapy, mud therapy, fasting
therapy, hydrotherapy, acupressure, acupunc-
ture, massotherapy, chromotherapy, magnet
therapy, and air therapy are some important
approaches in naturopathy. Food or diet control
already emerged as a major parameter in the
management of diabetes. Different traditional
sciences also emphasized the positive role of
different naturopathic therapies for healthy life
and management of different diseases. The word
Yoga is coined from the Sanskrit word “Yuj”
which means a union of body, breath, and mind.
Yoga is an ancient, traditional, psychological,
physical, spiritual practice and is considered as
a rich heritage of Indian culture. Apart from its
spiritual and religious philosophy, Yoga is a
useful and essential tool to achieve good health
and treat disease. Yogic practice is useful to
achieve good health, which could be the result
of right thought and action. Yoga constitutes
asanas (different yoga positions), pranayama
(regulated breathing and meditation), and con-
sciousness of Yoga sutras (principles) that regu-
late the mind. Regular Yogic practice increases
the awareness of mind and body, which is essen-
tial to maintain the exercise and food habit in
DM condition. Several case studies have
reported the positive effect of Yoga on diabetes
mellitus and its complication. Yoga found to
improve glycemic control, reduce reaction time,
improve insulin level and sensitivity, decrease
insulin resistant, decrease elevated leptin level,
reduce depression and anxiety, decline the
weight and BMI in obese individual from fatty
people, improve lipid profile and oxidative
Traditional Medicinal Plants and DM
stress, improve nerve function in diabetic neuro-
pathic condition, and also reduce the risk of car-
diovascular complications in diabetes. It was
also reported that Sudarshan Kriya Yoga and
Pranayam program (nature walk and relaxing
music) had significant impact on gene expres-
sion in peripheral blood mononuclear cells
when compared with normal group (Sahay
2007; Kutty and Taju 2010; Leelayuwat 2013;
Jyotsna 2014).
Traditional Medicinal Plants
and DM
Traditional medicines include herbs, herbal
preparations, herbal materials, and finished
herbal products, which contain as active ingre-
dients parts of plants or other plant materials or
combinations thereof. Currently, folk and tra-
ditional medicinal plants have attracted the sci-
entists and researchers to find new drug
molecule or therapy which can useful to man-
age “diabetic epidemic.” Plants and phytocon-
stituents found to act via enhancing insulin
131
secretion, increasing uptake of glucose by adi-
pose tissue and skeletal muscle, reducing intes-
tinal glucose absorption, and reducing
production of hepatic glucose. Several phyto-
constituents have also been investigated for
hypoglycemic activity (Fig. 10.1). Tables 10.2
and 10.3 contain phytoconstituents and few
plants which are investigated/under investiga-
tion of researchers to find new diabetes treat-
ment (Grover et al. 2002; Bnouham et al. 2006;
Mukherjee et al. 2006; Jung et al. 2006;
Chauhan et al. 2010; Malviya et al. 2010;
Akhilesh et al. 2011; Prabhakar and Doble
2011; Dasgupta and De 2012; Patel et al. 2012;
Arif et al., 2014). A number of antidiabetic
herbal formulations have been granted patent
recently. Fenugreek, Rauvolfia vomitoria,
Citrus aurantium, Vitex leucoxylon, Pueraria
tuberosa, Dolichos biflorus, and many other
plants are used in such formulation to manage
diabetes. Looking into the number of patents
and researches, it can be easily understood that
antidiabetic treatment by plant products is
exploring successfully at a greater pace and
can be the future to manage diabetes mellitus.
132 10 Indian Traditional Medicinal Systems, Herbal Medicine, and Diabetes

HO HO

OH HO OH
O OH O O OH O

HO HO HO
OH OH

OH OH
HO O OH HO O O OH
OH
Mangiferin Mangiferin-7-O -b -d-glucoside
(Anemarrhena asphodeloides) (Anemarrhena asphodeloides )

OH
OH
HO O
HO

HO OH OH OH
O O
O O
OH

H3C OH OH HO
CH3 OH
H3C

Moracin M-3-O - b -d-glucopyranoside

Mulberrofuran U
(Morus insignis)
(Morus insignis)

Glu
CH3
O O Glu Glu
OH CH3
H
H3C H CH2
CH3 CH3 H
H
CH3
HO H3C COO Glu
H3C H
CH3 O
Glu
Stevioside
Senticoside A (Stevia rebaudiana)
(Acanthopanax senticosus)
O
O CH3
HO
NH

HO
7'-(3',4'-dihydroxyphenyl)-N-[(4-methoxyphenyl)ethyl]propenamide
(Cuscuta reflexa)
O CH3

HO
NH

HO
7'-(4'-hydroxy-3'methoxyphenyl)-N-[(4-butylphenyl)ethyl]propenamide
(Cuscuta reflexa).

Fig. 10.1 Phytoconstituents investigated in preclinical study for hypoglycemic and antidiabetic effect
Traditional Medicinal Plants and DM 133

CH2
CH3
HOOC CH3
H3C
CH3
OH CH3

CH3 CH3
CH3 COOH
H3C
CH3
CH3
HO
H3C CH3 HO
HO CH3
Dehydrotrametenolic acid
Corosolic acid
(Poria cocos)
(Lagerstroemia speciosa)

HO
H3C H3C OHC
CH3 CH3 CH3
H CH3

N N N

CH3 CH3
Boschniakine
Tecomine 5β-hydroxys kitanthine
(Tecoma stans)
(Tecoma stans) (Tecoma stans)

OCH3 H3CO
OCH3 H3CO
+ H
N N
OCH3 CH3 H H +
H3C - N N
O OH CH
H3C - 3
O O
O O
O O

CH3 O

CH3
Tetrandrine 2-N- β –oxide
(Stephania tetrandra) Fangchinoline 2'-N- α -oxide
(Stephania tetrandra)

OCH3 H3CO
H OCH3 H3CO
H
N NH
OH H H + -
H3C N N Cl
OCH3 CH3
O H3C CH3
O O
O O

CH3 O

CH3
2'-N-norfangchinoline
(Stephania tetrandra) 2'-N-methyltetrandrinium chloride
(Stephania tetrandra)

Fig. 10.1 (continued)

134 10 Indian Traditional Medicinal Systems, Herbal Medicine, and Diabetes

OH
R1
OH
R2
HO O
HO O

O
O
OH O O O 3
OH O R
HO
OHHO OH Astragalin: R1 = H; R2 = OH; R3 = β−D- glucopyranose
Isoquercitrin: R1 = OH; R2 = OH; R3 = β−D- glucopyranose
OH OH
Quercetin 3-O- α L-arabinopyranosyl-(1->2)- β glucopyranoside
(Eucommia ulmoides)

OH OH
OH OH
HO O
OH
HO O HO O
OH OH
O
OH O HO OH OH OH
O O
O OH O OH O
OH
HO HO
HO OH
OH OH
OH OH
Isorhamnetin-3-O-β-D-glucoside Isoaffineyin Isoorientin
(Salicornia herbacea) (Manikara indica) (Cecropia obtusifolia)

OH

H
H H
N O H
N N
H
N H
H O N O N O
H

Lupanine 13-α-OH-Lupanine 17-oxo-lupanine

(Lupinus perennis) (Lupinus perennis) (Lupinus perennis)
OH OAc OAc
OH OAc OAc

H H H
HO AcO AcO

N N N
HO AcO AcO

HO AcO OAc
OH OAc OAc
Javaberine A Javaberine A hexaacetate Javaberine B hexaacetate
(Talinum paniculatum) (Talinum paniculatum) (Talinum paniculatum)

Fig. 10.1 (continued)

Traditional Medicinal Plants and DM 135

CH3 CH2 CH3

H3C H2C
H3C

CH3 CH3
CH3 CH3 OH CH3 OH
OH
CH3 CH3
CH3 CH3

H3OCOC Caffeoyl-O HO
H3C CH3 H3C CH3 H3C CH3
Alpha-amyrin 23,28-dihydroxylupan-20(29)-ene-3-caffeate Betulin
(Ficus bengalensis) (Sorbus decora) (Euclea undulata)
CH3
OH CH2
O H3C
CH3

O H2C O
CH3
H3C CH3
CH3 H3C CH3 COOH
CH3 O CH3
H3C
O
HO
H3C CH3
H3C
O HO
O HO CH3
Palbinone Lactucain A Glucosol TM
(Paeonia suffruticosa) (Lactuca indica) (Lagerstroemia speciosa)

OH H3C CH3
HO H3C OH
CH3 CH3 OH H3C O OH
H3C OH
O
HO
O O O
CH3 CH3 O CH3 O
O O
O OH OH
OH OH O
H3C HO
CH3 O
HOOC O OH
3-hydroxy cacalolide HO
(Psacalium decompositum) O

Desmethoxysenegin II CH3
(Polygala senega) O

HO

O O OH

OH OH

O OH O OH

5,6,7-trihydroxy flavone
6-hydroxyapigenin
(Scutellaria baicalens)
(Origanum majorana)

Fig. 10.1 (continued)

136 10 Indian Traditional Medicinal Systems, Herbal Medicine, and Diabetes

OH
OH

HO O OH
CH3
O O
O
O H3C
OH O O
HO H
HO OH O
OH HO OH
1"(R)-5,4',1"-trihydroxy- 6,7-(3",3"-dimethylchromano) flavone
O OH (Eysenhardia platycarpa)
Quercetin 3-O-alpha-Larabinopyranosyl-(1->2) Beta-D-glucopyranoside
(Eucommia ulmoides) OH
OH
OH
OH
HO O HO O
OH
HO OH HO
HO O O
CH3 OH
O OH O
O OH O
HO OH
OH
OH O CH3 O Tectorigenin
O O HO (Pueraria thunbergiana)
Shamimin
Erigeroflavanone (Bombax ceiba)
(Erigeron annuus) H3C CH3
H3C CH3 O CH3
O
CH3 CH3

CH3
HO
CH3 CH3 COOH
CH3 HO O
O CH3
O CH3
CH3 HO
CH3 H3C CH3

OH
Salsones A Danshenols A
Centellsapogenol A (Salvia miltiorrhiza)
(Salacia chinensis)
O (Centella asiatica)

O OH
O OH
CH3 HO
O HO O
CH3 OH OH
O OH
HO HO
OH
CH3
O O O CH3 O HO
HO
HO
O OH
HO OH HO

OH Isoorientin Myricetin
Tinosporaside (Cecropia obtusifolia) (Parinari excelsa)
(Tinospora cordifolia)

Fig. 10.1 (continued)

Traditional Medicinal Plants and DM 137

-
O
OH
O S O O
O
HO

+
O OH HO O
+
S
OH
O
HO
Anthocyanin HO
(Vaccinium arctostaphylos) HO OH OH

Salacinol OH
(Salacia reticulatea) Kakonein
(Pueraria lobata)
HO OH
OH OH O OH
O OH
HO O
OH
HO H3C
O O
OH OH CH3
O
OH OH H3C
Leucopelargonidin
(Ficus bengalensis) Leucodelphinidin Swerchirin
(Ficus bengalensis) (Swertia chirayita)

HO + OH O OH
O
HO O
O O CH3
HO OH H
H3C
O O

O
CH3 Methylswertianin
β-D-O glucoside
(Swertia Punicea)
(Acosmium panamense)
OH
NH2
HO OH
OH O OH OH OH
HO O
CH3 O OH
O
N
OH H
CH3 H N CH3
HO O OH H3C CH3
Mangiferin
(Anemarrhena asphodeloides) CH3
Mahanimbin Mycominose
(Murraya koenigii) (Syzygium cumini)

O N
CH3 H CH3
H3C
O N H3C
O N
H
N O
H3C H CH3
CH3 O

Arecoline Tecomine
(Tecoma stans) Catharanthine
(Areca catechu)
(Catharanthus roseus)

Fig. 10.1 (continued)

138 10 Indian Traditional Medicinal Systems, Herbal Medicine, and Diabetes

OH OH

CH 3COO OH
O O
HO
O
CH3 OH

HO OCOCH 3 O
OCOCH 3 H3C
OH
Dihydroxy gymnemic triacetate CH3 CH3
(Gymnema sylvestre)
H O
H3C
O CH3 CH3

+ H3C O
N HO
O O OH

O
CH3 O CH3

CH3 Gymnemic acid V

O H3C CH3
(Gymnema sylvestre)
Berbine
(Tinospora cordifolia)

CH3 CH3 COOH

OH HO
O
NH
CH3
O O
H3C O H3C CH3
O HO O O
Aegeline 2
(Aegle marmelos) O
HO OH OH
OH
H OH OH
OH OH
Elatoside E
(Aralia elata) HO OH OH
O

O
O OH
H3C
H3C H3C H3C O OH
O

CH3
O CH3
OH
H3C CH3 Timosaponin A III
HO OH (Anemarrhena asphodeloides)

O O OH
CH3
HO OH
O
CH3CH3
O
O O
H3C CH3
OH
Momordin Ic
(Kochia scoparia)

Fig. 10.1 (continued)

Traditional Medicinal Plants and DM 139

- CH3
O O
O
HO OH
O HO
OH
+
N HO OH OH
H3C
O OH
CH3 OH
O
Trigonelline Pinitol 2-hydroxy-4-methoxy benzoic acid 4-hydroxy benzoic acid
Trigonelia foenum-graecum Bougainvillea spectabilis (Hemidemus indicus) Pandanus odorus

O OH
O OH OH
HO O
O H31C15 OH H3C
HO O O
OH O OH
OH
HO
Chlorogenic acid Anacardic acid Marsupsin
OH
Cecropia obtusifolia Anacardium occidentale Pterocarpus marsupium
OH
O O O HO O
H3C
H 2C S
S CH2 H3C
O
O OH
Allicin 6,7-dimethoxy-2H-1-benzopyran-2-one Moracin M
Allium sativum Cuscuta reflexa Morus alba
OH
OH

OH OH
OH OH

OH OH HO
OH
HO HO OH
HO OH
HO
OH
3-hydroxymethyl xylitol Masoprocol
HO Caseariae sculenta Larrea tridentata
OH

Scirpusin B
Callistemon rigidus
H3C
CH3 O OH O

H2N
H3C CH3 CH3 OH
CH3
H3C S
CH3 OH O OH
Shikonin
Lithospermumerythrorhizon CH2
HO
Gamma-sitosterol S-allyl cysteine sulfoxide
Lippianodi flora Allium sativum

Fig. 10.1 (continued)

140 10 Indian Traditional Medicinal Systems, Herbal Medicine, and Diabetes

O
H
+ N
N N
O N

O
CH3
H 3COOC CH3
CH3 COOCH 3
O N
CH3 H
Berberine Catharanthine Vindolinine
(Tinospora cordifolia) (Catharanthus roseus) (Catharanthus roseus)

H 3COOC OH
H COOCH 3
N

H3C O
CH3
N
O
N NH
H3C N
H CH3 N
Vindoline
H CH3
(Catharanthus roseus)
Harmane Pinoline
(Tribulus terrestris) (Tribulus terrestris)

Fig. 10.1 (continued)

Table 10.2 Some phytochemicals with antidiabetic potential

Alkaloids Piperin, pipernonaline, dehydropiperanonaline, berberine, catharanthine, vindoline,
vindolinine, casuarine 6-O-a-glucoside, tetrandrine 2-N-β-oxide, fangchinoline
2′-N-α-oxide, 2′-N-norfangchinoline, 2′-N-methyltetrandrinium chloride, lupanine,
13-α-OH lupanine, 17-oxo-lupanine, palmatine sulfate, palmatine chloride,
mycaminose, mahanimbine, arecoline, tecomine, egeline, catharanthine
Anthocyanidins Cyaniding, cyaniding 3-galactoside, delphinidin
Chalcones Davidigenin, gallotannins
Cinnamic acid derivative Caffeic acid
Curcuminoids Curcumin, demethoxycurcumin
Flavonoid Ferulic acid, 6-hydroxyapigenin, 6-hydroxyapigenin-7-O-β-d-glucopyranoside,
6-hydroxyluteolin-7-O-β-d-glucopyranoside, myrciacitrin, isoaffineyin, quercetin,
kaempferol 3-O-β-d-glucopyranoside, isoquercitrin, isoorientin, kaempferitrin,
genistein, catechins, epicatechins, phytoestrogens, kakonein, tectorigenin, shamimin
Glycosides Ginsenoside, anthocyanin, salacinol glycosides, leucopelargonidin, β-d-O-glucoside
Organic phenols Vanillic acid, gallic acid
Phenolics 1,3,4,6-Tetragalloylglucose, 1,2,3,4,6-pentagalloyl glucose, β-d-O-glucoside,
β-d-O-di (1–6)-glucoside, desmethylyangonin, ellagic acid and its derivatives,
trigonelline, pinitol, chlorogenic acid, allicin, marsupsin, piceatannol, scirpusin B,
moracin M, masoprocol
Phenylpropanoids Coumarin
Saponins Charantin, β-sitosterol, andrographolide, gymnemic acid, dihydroxygymnemic
triacetate, timosaponin A, momordin Ic, elatoside E
Sugars Salacinol, kotalanol
Tannins Ellagitannins, mallotinic acid
Terpenes Different sesquiterpenoid derivatives, enhydrin, salasones A, salaquinone A,
centellasapogenol A, dehydrotrametenolic acid, danshenols A and B, senticoside A,
stevioside, α-amyrin, palbinone, glucosol TM
Xanthones Mangiferin, bellidifolin, swerchirin, methylswertianin
Table 10.3 List of some potential plants investigated for their antidiabetic activity
Name of the plant with family
Acacia arabica (Lam.) Muhl.
[Family: Leguminosae]
Aegle marmelos (L.) Correa ex
Roxb.
[Family: Rutaceae]
Allium cepa L.
[Family: Liliaceae]
Allium sativum L. [Family:
Alliaceae]
Common name
Vabboola (S), kikar (H), babla (B), Indian
gum arabic (E)
Bilvam, sriphal (S), bel
(H & B), holy fruit (E)
Palandu (S), piyaj (H & B), onion (E)
Lasuna (S), lasan (H), rasun (B),
garlic (E)
Reported antidiabetic activity
Administration of powdered seeds (2, 3, and 4 mg/kg, oral route) in normal rabbits produced
hypoglycemic effect
Seed diet (94 %) in control healthy rats showed hypoglycemic activity but at the same dose
no hypoglycemic activity in alloxan-induced diabetic rats
Aqueous decoction of bark of root (1 ml/100 g) in healthy rats produced hypoglycemic
activity
Antidiabetic effect of aqueous extract of leaf in alloxan, streptozotocin (STZ), and glucose-
induced diabetic rats
Antioxidant and hypoglycemic activity of leaves in diabetic albino rats
Traditional Medicinal Plants and DM
Antioxidant and hypoglycemic effect of A. marmelos in alloxanized rats
Antidiabetic effect of aqueous extract of fruit (250 mg/kg) in STZ-induced female diabetic
rats
Ether-soluble fraction (0.25 mg/kg, orally) produced hypoglycemic activity in normal
rabbits
A positive response of the bulb A. cepa (2 g/kg) in rabbits in an OGTT
Diets that contain 3 % freeze-dried powder of onion-produced antihyperglycemic,
antioxidant and hypolipidemic activity on STZ-diabetic rats
S-Methyl cysteine sulfoxide, a sulfur containing amino acid isolated from the plant (200 mg/
kg) to alloxanized rats considerably controlled blood glucose
Fifty gram of juice expressed onion residue in single dose appreciably maintains
postprandial glucose levels to three diabetic patients
Ethanol, ethyl acetate, and petroleum ether extract showed antidiabetic potential in
alloxanized rabbits
Allicin, isolated from the plant (0.25 g/kg, p.o.), produced hypoglycemia in mildly diabetic
rabbits
Aqueous garlic homogenate (10 ml/kg/day, oral route) to sucrose-fed rabbits improved
content of hepatic glycogen and free amino acid, reduced fasting blood sugar level,
triglyceride content (in the liver, serum, and aorta), protein content (in the liver and serum)
Aged garlic extract (5, 10 ml/kg, p.o.) avert hyperglycemia and adrenal hypertrophy and
increase cortisone level without changing the level of insulin in serum in hyperglycemic
mice
(continued)
141
Table 10.3 (continued)
Name of the plant with family
Aloe vera (L.) Burm.f.
[Family: Aloaceae]
Amaranthus caudatus
[Amaranthaceae]
Andrographis paniculata Nees
[Family: Acanthaceae]
Annona squamosa L.
[Family: Annonaceae]
Areca catechu
[Family: Arecaceae]
Artemisia pallens Wall. ex
[Family: Compositae]
Asystasia gangetica
[Acanthaceae]
Azadirachta indica A.Juss.
[Family: Meliaceae]
Beta vulgaris L.
[Family: Chenopodiaceae]
Biophytum sensitivum (L.) DC
Family: Oxalidaceae]
Common name
Ghrita-kumari (S & B), ghi kanwar (H),
Indian aloe (E)
Kedari-chua, chawli (H), rajadri (S)
Bhunimba, mahatikta (S), kiryat (H),
kalmegh (B), green chiretta (E)
Shubha, suda (S), sitaphal (H), ata (B),
custard apple (H)
Kramuka pooga (S), supari (H & B), betal
nut (E)
Davanam (S & T), davana (H & K)
Parchorri, chorri, mekampokki (T),
valli-upu-dali (M)
Nimba (S), nim (H & B), margosa (E)
Chukander (H), beet (E)
Lajalu (H)
142
Reported antidiabetic activity
Plant extract at a dose of 200 and 300 mg/kg (orally) produced hypoglycemic activity on
different rat models (healthy fasted, oral glucose-loaded and STZ-induced diabetes)
Hypoglycemic potential of leaf pulp extracts in type I and type II diabetic rats
Plant and its bitter principal showed hypoglycemic activity in alloxanized mice
Antihyperglycemic effect of dried sap in type 2 diabetic patients and in alloxanized mice
Methanol extracts of leaves (200, 400 mg/kg) notably decreased the glucose level and
improve lipid profile in blood diabetic rats
The plant and andrographolide reduced blood glucose and produced antihyperglycemic
activity in normal and STZ-induced diabetic rodents
Antidiabetic activity of aqueous extract of leaf in STZ-nicotinamide-induced diabetic rats
Ethanolic extract of leaf exhibited hypoglycemic and antihyperglycemic activity at a dose of
350 mg/kg in normal, STZ-induced diabetic rats and alloxanized rabbits
Alkaloid fraction of the plant (0.05-/0.5 mg/kg) produced hypoglycemic effect in
alloxanized rabbits
Antihyperglycemic effect of aerial parts (100 mg/kg, p.o.) in hyperglycemic (induced by
glucose load) and alloxan-induced diabetic rodents. Fair hypoglycemic activity (1000 mg/
kg) in fasted normal rats
Treatment (28 days) with ethanolic extract at 100 and 200 mg/kg significantly reduced blood
glucose, HbA1C, and increased hemoglobin content. Extract also improved lipid profile and
exhibit in vivo antioxidant activity
Hydro alcoholic extract of the plant produced hypoglycemic activity in healthy, glucose-fed
and STZ-induced diabetic rats
Leaf extract reduced blood glucose and produces antihyperglycemic effect in normal and
STZ-induced diabetic rat
Ethanolic plant extract produced antidiabetic effect in alloxan-induced diabetic albino rats.
Hypoglycemic effect of betavulgarosides II–IV, isolated from plant root in an OGTT in rats
Leaf extract produced exert antihyperglycemic effect in alloxanized rabbits (only in mild
cases)
10 Indian Traditional Medicinal Systems, Herbal Medicine, and Diabetes
Boerhavia diffusa L.
[Family: Nyctaginaceae]
Bombax ceiba
[Family: Malvaceae]
Brassica juncea (L.) Czern.
[Family: Brassicaceae]
Caesalpinia bonducella (L.)
Roxb.
[Family: Caesalpiniaceae]
Cajanus cajan (L.) Millsp.
[Family: Fabaceae]
Camellia sinensis Kuntze
[Family: Theaceae]
Capparis decidua
[Family: Capparidaceae]
Casearia esculenta Roxb.
[Family: Flacourtiaceae]
Cassia auriculata L.
[Family: Leguminosae]
Catharanthus roseus (L.) G.
[Family: Apocynaceae]
Purnanava (S & B), mukaratee-kirei (T),
sant (H), hogweed (E)
Raktapuspa (S), semul (H), simul (B)
Rajika (S), asalrai (H), raisarisha (B),
Indian mustard (E)
Kuberakshi (S), kat-karanj (H), nata-
karanja (B), bonduc nut (E)
Adhaki (S), tavar (H), arhar (B), red gram
(E)
Symparani (S), cha (H & B), tea (E)
Gandha patra (S), kurrel (H), copper plant
(E), karyal (T)
Bairi (H), wid cowrie fruit (E)
Avaritaki (S), tarwar (H & B), Tanner’s
tea (E)
Sadabahar (H), shavam nari (M),
nayantara (B)
Antidiabetic activity of aqueous extract of leaf (100, 200, and 400 mg/kg) in alloxan-induced
diabetic rats
Hypoglycemic and antidiabetic effect of aqueous leaf extract (200 mg/kg, orally) in normal
and diabetic rats
A C-flavonol glucoside (shamimin) obtained from the plant leaves produced potent
hypoglycemic activity in rat at 500 mg/kg
Treatment with Brassica juncea diet (10 %, w/w) for 60 consecutive days produced
hypoglycemic activity in normal rats
Seed extracts (aqueous and 50 % ethanolic) produced hypoglycemic and antihyperglycemic
effect in normal and diabetic rats
Antidiabetic effect of the seed extracts in rats with T2DM
Traditional Medicinal Plants and DM
Extract (aqueous and ethanol) produced antidiabetic activity in chronic type II diabetic
model
Glucose tolerance enhancing effect of aqueous extract of leaf and stem in OGTT
Hypoglycemic activity of cooked diet was observed in healthy human volunteers.
Hot water extract of green tea showed antihyperglycemic activity in STZ-induced diabetic
rats.
Diet containing (30 %) fruit powder of the plant for 3 weeks showed significant
hypoglycemia in alloxan-induced diabetic rats
Oral administration of root extracts (300 mg/kg) decreases blood glucose level in normal and
STZ-induced diabetic rats
Aqueous extract reduces blood glucose and exhibited antihyperglycemic effect in normal,
glucose-loaded, and STZ-induced diabetic rats
Antidiabetic and antihyperlipidemic effect of aqueous extract of flower in diabetic rats
Aqueous leaf extract (400 mg/kg) reduced the glucose level in blood (fasting condition),
insulin level in plasma, hepatic hexokinase and phosphofructokinase and C-peptide level. It
also increased the number of islets and β cells but suppressed the activity of glucose-6-
phosphatase and fructose-1,6-bisphosphatase
Ethanolic extract of leaves produced hypoglycemic activity in normal, STZ-induced diabetic
rats and in OGTT
Blood glucose-lowering activity of leaves and twins extract (dichloromethane: methanol)
(500 mg/kg, p.o) in STZ-induced diabetic rat
Hypoglycemic and antihyperglycemic effect of leaf juice or water decoction of the plant in
normal and alloxanized diabetic rabbits
(continued)
143
Table 10.3 (continued)
Name of the plant with family
Citrullus colocynthis (L.)
[Family: Cucurbitaceae]
Coccinia indica Wight & Arn.
[Family: Cucurbitaceae]
Enicostemma littorale Blume
[Family: Gentianaceae]
Eucalyptus globulus
[Family: Myrtaceae]
Common name
Indravaruni (S), colocynth (E), indrayan
(B & H)
Vimboshta (S), kanduriki-bel (H),
telakucha (B)
Nagajibra (S), chota-chiretta (H)
Nilaniryasa (S), eukaliptas (H & B), blue
gum (E)
144
Reported antidiabetic activity
Aqueous extract (300 mg/kg, p.o.) in normal rabbits decreased plasma glucose after 1 h, and
the activity was more after 2, 3, and 6 h. Glycosidic extract produced better hypoglycemic
effect compared to alkaloidal extract
Graded doses of saponin also lowered the glucose level in alloxanized rabbits
Aqueous seed extract produced hypoglycemic activity in normal and STZ-induced diabetic
rats
Alcoholic leaf extract produced hypoglycemic activity in normoglycemic guinea pig
Hypoglycemic effect of the leaves in alloxanized dogs
Ethanolic extract of root produced hypoglycemic and antihyperglycemic activity in fasted
and glucose-loaded animal models
Leaf extract (95 % ethanol) showed hypoglycemic effect of in normal fed and 48 h starved
rats
Hypoglycemic activity of 60 % ethanol leaf extracts (200 mg/kg, oral route)
Leaf extract produced blood glucose-lowering activity in human tested through a double-
blind control trial
Dried extract produced antidiabetic activity (500 mg/kg, p.o.) in diabetic patients
Antidiabetic activity of extract of whole plant (aqueous) demonstrated in alloxan-induced
diabetic rats
Aqueous extract of plant produced insulin-enhancing activity experimentally diabetic
rodents
Blood glucose-lowering effect of aqueous extract (2 g/kg, p.o.) n type II diabetic rats
Aqueous extract produced reduction in the activity of glycosylated hemoglobin, glucose-6-
phosphatase in the liver, and improved the level of insulin the diabetic rats
Aqueous extract (0.5 g/l) reduced utilization of peripheral glucose observed in the abdominal
muscle of mouse and increased secretion of insulin tested on the clonal pancreatic beta cell
line
Leaf diet (6.25 % w/w) to healthy rats did not produce hypoglycemia but administration of
STZ to the pretreated rats found useful in inhibition of hyperglycemias, less polydipsia, and
loss of body weight
10 Indian Traditional Medicinal Systems, Herbal Medicine, and Diabetes
Eugenia jambolana Lam. (syn.
Syzygium cumini L.)
[Family: Myrtaceae]
Nilaprala (S), jaman (H), kala jam (B),
black berry (E)
Pulp extract of the fruits decreased blood glucose level in healthy and STZ-induced diabetic
rats
Antidiabetic activity of seed extracts (aqueous extract, 2.5 and 5.0 g/kg, p.o.) in diabetic rat
Antidiabetic activity of extract (alcoholic, oral route at dose of 100 mg/kg) in experimentally
induced diabetic rats along with decrease in the level of urine sugar and lipids in serum and
tissues
Blood glucose-lowering activity of alcoholic extracts, aqueous extract, and lyophilized
powder at a dose of 200 mg/kg demonstrated in hyperglycemic animals
Aqueous extracts (400 mg per day) produced antihyperglycemic and antihyperinsulinemic
activity in fructose-fed rats
Hypoglycemic activity by the extract (200 mg/kg) in STZ-induced diabetic mice
Traditional Medicinal Plants and DM

Ethanolic extract produced hypoglycemic activity in alloxan-induced diabetic rabbits

Eugenia uniflora
[Family: Myrtaceae]
Ficus benghalensis L.
[Family: Moraceae]
Ethanolic extract of whole seeds, kernel and seed in STZ-induced diabetic rats produced
antidiabetic effect
Inorganic trace elements, obtained from the seeds, produced antidiabetic activity in
STZ-induced diabetic rats
Seed powder (250, 500, or 1000 mg/kg) in STZ-induced female diabetic rats exhibited
hypoglycemic effect
Pitanga (E) Fractions isolated from the ethanolic leaf extract demonstrated good effects in OGTT in
mice
Vata, sriksha (S), vada (H), bot (B), Ethanolic bark extract and a glucoside isolated from the plant produced hypoglycemic
banyan tree (E) activity of in normal and alloxan diabetic rabbits
Hypoglycemic effect of extract of bark in STZ-induced diabetic animals and increase in the
serum level of insulin in normoglycemic and diabetic rats
A dimethoxy derivative of leucocyanidin 3-O-beta-d-galactosyl cellobioside isolated from
the bark showed hypoglycemic effect in normal and experimentally induced moderately
diabetic rats; improved level of serum insulin in diabetic rats is also observed
Antidiabetic activity of dimethoxy derivative of pelargonidin 3-O-alpha-l rhamnoside in
moderately diabetic rats. Increase in serum insulin and hypoglycemic effect in normal and
moderately diabetic dogs also reported
Hypoglycemic, hypolipidemic, and serum insulin raising activity of leucopelargonidin
isolated from the bark in diabetic rats
Hypoglycemic effect of leucodelphinidin derivative (250 mg/kg) in normal and alloxan-
induced diabetic rats
(continued)
145
Table 10.3 (continued)
Name of the plant with family
Gymnema sylvestre
[Family: Asclepiadaceae]
Helicteres isora L. [Family:
Sterculiaceae]
Hibiscus rosa-sinensis L.
[Family: Malvaceae]
Ipomoea batatas (L.) Lam.
[Family:
Convolvulaceae]
Lantana camara L.
[Family: Verbenaceae]
Common name
Sarpadarushtrika (S), chrota-dudhilata (H
& B)
Avatarini (S), marophali (H), atmora (B),
East Indian screw tree (E)
Rudhrapuspa (S), Jason (H), rakta Jaba
(B), Chinese rose (E)
Pindaluh (S), ratalu (H), ranga alu (B),
sweet potato (E)
Chaturangi (S), Chaturang (H); wild
sage (E)
146
Reported antidiabetic activity
Dried leaf powder produced hypoglycemic effect in alloxanized rabbits along with decrease
gluconeogenic enzymes activity
Powdered leaves significantly stop beryllium nitrate induced increase in blood glucose level
in rats
Aqueous extracts of leaves produced antidiabetic effect in STZ-diabetic rats and
hypoglycemic effect in normal rat
Different hypoglycemic principles such as gymnemosides and gymnemic acid were isolated
from the plant
Triterpene glycosides obtained from plant decreased utilization of glucose in muscles
Alcoholic extract increased release of insulin from the islet cell of rat and different beta cell
lines in the lack of other stimulus
Water-soluble leaf extract (400 mg/day) reduced fasting blood glucose, HbA1c, glycosylated
plasma protein, and requirement of insulin in IDDM patients who are on insulin treatment
but remained more than controls
Aqueous decoction (2 g thrice daily) to healthy people for 10 days and diabetic patients for
15 days appreciably decreased fasting and OGTT glucose level in all individual except
OGTT in normal group
300 mg/kg root extract (ethanol extract) showed plasma glucose-lowering effect in insulin
resistant and genetically modified diabetic mice
Antihyperglycemic effect of butanol extract of root (250 mg/kg) in glucose-loaded rats
Plant extract (ethanol) produced hypoglycemic effect in glucose-loaded rats at 2 h and
reduced blood after frequent dose of administration
Alcoholic leaf extract (250 mg/kg, orally) produced blood sugar lowering effect in glucose-
induced hyperglycemia model in rats
Ethanol extract of flower decreased blood sugar level in STZ-induced diabetic rats
Antidiabetic activity of the plant was observed against diabetic rats and inhibits
enhancement of the level of blood glucose in OGTT in rodents
Reduction of postprandial glucose level by peonidin 3-O-[2-O-(6-O-E-feruloyl-beta-d-
glucopyranosyl) -6-O-Ecaffeoyl-beta-d-glucopyranoside]-5-O-beta-d-glucopyranoside, a
diacylated anthocyanin, isolated from roots
Leaf juice of the plant (1500 mg/kg/day) showed significantly reduced blood glucose level in
rats
Methanol extract of the plant (200 and 400 mg/kg) leaves in alloxanized rats showed
reduction in the blood glucose concentration
10 Indian Traditional Medicinal Systems, Herbal Medicine, and Diabetes
Mangifera indica L. [Family:
Anacardiaceae]
Memecylon umbellatum
[Family: Melastomataceae]
Momordica charantia
[Family: Cucurbitaceae]
Momordica cymbalaria Fenzl
ex Naudin
[Family: Cucurbitaceae]
Morus alba L.
[Family: Moraceae]
Mucuna pruriens (L.) DC.
[Family: Leguminosae]
Murraya koenigii (L.) Spreng
[Family: Rutaceae]
Musa sapientum
[Family: Musaceae]
Amva (S), am (H & B), mango (E)
Anjan (H & S), kaayaabuu (M), keya (T)
Karavella (S), kerela (H); kerala (B),
bitter guard (E)
Kadvanchi (H)
Toola (S), tut (H & B), white mulberry
(E)
Atmagupta (S), kavach (H), alkushi (B),
cowhage (E)
Barsunga (B), meetha neem (H),
kariveppilai (M), girinimba (S)
Banana (E), kela (H), kala (B)
Hypoglycemic effect of aqueous leaf extract (1 g/kg p.o.), in STZ-induced diabetic rats
Mangiferin (10, 20 mg/kg, i.p.) isolated from the plant produced hypoglycemic activity in
experimentally induced diabetic rats and positive effect in oral glucose tolerance in
glucose-loaded healthy rats
Alcoholic extract of the leaves (250 mg/kg) caused reduction in blood glucose in normal and
alloxanized rats
A number of studies reported that fruit pulp, seed, leaves, and whole plant extracts exhibit
hypoglycemic and antihyperglycemic effect in various animal models
Pulp juice and saponin-free methanol extract of pulp juice decreased blood sugar level in
fasting and postprandial states of normal, type 2 diabetic rats
Charantin, a peptide similar to insulin (50 mg/kg) isolated from the plant, showed
Traditional Medicinal Plants and DM
hypoglycemic effect in rabbits
Oral supplementation with freeze-dried powder in the diet decreased serum glucose levels in
normal rats
Oleanolic acid 3-O-glucuronide and momordin, two other key constituents of the plant exert
antihyperglycemic effect
Hypoglycemic effect of fruit powder in fasting state of alloxanized diabetic rats
Aqueous fruit extract reduced blood glucose level in alloxanized diabetic rats
Hot water extract of leave (200 mg/kg, i.p.) exhibited antidiabetic effect in fasted and
non-fasted STZ-induced diabetic mice
Leaf extract produced degranulation effect on the pancreatic β-cells of rabbits upon chronic
administration through subcutaneous route
Powdered seed reduced blood glucose level in normal rabbits and alloxan-induced diabetic
rabbits
Plant extract (200 mg/kg) produced hypoglycemic effect in STZ-induced diabetic mice
Hypoglycemic effect of alcohol extract (100, 200 and 400 mg/kg/day) in alloxan induced
diabetic rats and but no prominent effect in STZ-diabetic mice.
Leaf powder produced antidiabetic effect in patients with T2DM after 1 month treatment
Hypoglycemic activity of the leaves in normal rats when given as a diet for 2 months
Decoction of fresh flower (4 ml/kg) to diabetic rabbits reduced the hyperglycemic peak and/
or the area under glucose tolerance curve
Cholesterol extract of flower (150, 200 and 250 mg/kg, p.o.) decreased blood glucose and
HBA1c, while total hemoglobin increased in alloxanized rats
(continued)
147
Table 10.3 (continued)
Name of the plant with family
Nelumbo nucifera
[Family: Nymphaeaceae]
Ocimum sanctum L.
[Family: Lamiaceae]
Phyllanthus niruri
[Family: Phyllanthaceae]
Picrorhiza kurroa
[Family: Plantaginaceae]
Pterocarpus marsupium
[Family: Fabaceae]
Punica granatum L. [Family:
Punicaceae]
148
Common name Reported antidiabetic activity
Lotus (E), kamala (S), kamal (H), tavare Ethanol extract of rhizome (400 mg/kg) produced hypoglycemic effect in normal, glucose-
(K) fed hyperglycemic and STZ-induced diabetic rats. Extract exhibit improved glucose
tolerance and potentiated the effect of injected insulin
Tulsi (B & H), thulasi (T), trittavu (M) Ethanol (70 %) leaf extract reduced blood glucose in normal, glucose-fed and STZ-diabetic
rats
Hypoglycemic effect of the leaf powder given along with food for 30 days in normal and
diabetic rats
Hypoglycemic activity of extract (200 mg/kg) in STZ-induced diabetic animals; extract also
produced significant effect on glucokinase, hexokinase, and phosphofructokinase
Glucose and cortisol reduction activity of the plant in male mice also reported
Keezha nelli (T), nila nelli (K), bhuiamla A preparation of the whole plant (5 g/day in divided doses) to mild hypertensives (among
(B & H) then few were suffering from diabetes mellitus) patient for 10 days decreased blood glucose
as well as nondiabetic subjects
Kutki (H), hellebore (E), katuka rohini Alcoholic extract (75 mg/kg) decreased serum glucose and produced antihyperglycemic
(T), katki (A) effect in alloxanized diabetic rats
Bija (H), vengai (T) Oral administration of the decoction and infusion of bark showed hypoglycemic activity in
different animal models
Pterostilbene, a chemical constituent from wood produced hypoglycemia in dogs
Flavonoid fraction of the plant produced islet β-cell regranulation
Epicatechin, a flavonoid and marsupin and a phenolic constituent such as from the plant, has
been shown to produce significant antidiabetic effect
The plant extract also found beneficial in newly diagnosed or untreated NIDDM patients
Dalim (B), pomegranate (E), anar (H), Antidiabetic effect of an ethanol extract of flower in glucose-fed and alloxanized diabetic
dhanimmapandu (T) rats
Seed extract (methanol) at an oral dose of 150, 300 and 600 mg/kg showed antidiabetic
effect in STZ-diabetic rats
Methanol extract of the flowering part demonstrated hypoglycemic activity in non-fasted
Zucker diabetic fatty rats
10 Indian Traditional Medicinal Systems, Herbal Medicine, and Diabetes
Salacia oblonga Wall
[Family: Celastaceae]
Salacia reticulata Wight
[Family: Celastaceae]
Scoparia dulcis L.
[Family: Scrophulariaceae]
Swertia chirayita (Roxb. ex
Fleming) H. Karst
[Family: Gentianaceae]
Tinospora cordifolia
[Family: Menispermaceae]
Salacia (E), ponkoranti (H)
Marking nut (E), saptharangi (H)
Sweet broom weed (E), mithi patti (H),
sarakkotthini (T), bon dhonya (B)
Chirata (E & B), chirayata (H)
Amrita (H), chindil (T)
Aqueous methanolic root extract exhibited hypoglycemic effect in rats loaded with sucrose
and maltose. Ethyl acetate and water-soluble fraction of same extract also produced aldose
reductase inhibitory and alpha-glucosidase inhibitory effect
Petroleum ether extract of root produced antihyperglycemic, antihypoinsulinemic, and
antioxidant activity in STZ-diabetic rats
Water extract produced antidiabetic activity in the obese Zucker rat
A clinical rail (double masked, randomized, and crossover) showed that plant extract at a
dose of 1 g/kg b.w. reduced plasma glucose and insulin response in postprandial time
Aqueous decoction showed hypoglycemic activity in fasted experimental animals with better
glucose tolerance
A single center clinical rail (double-blind crossover) showed that plant tea exhibited
Traditional Medicinal Plants and DM
antidiabetic activity in patient with T2DM
Antidiabetic activity of aqueous extract of leaf (0.15, 0.30 and 0.45 g/kg, orally) in diabetic
rats; extract also reduced HbA1c and increased total Hb
Aqueous plant extract at a dose of 200 mg/kg in STZ-induced diabetic rats reduced blood
glucose. Extract also found to reduce sorbitol dehydrogenase, islet glycosylated Hb,
hydroperoxides, and thiobarbituric acid reactive substance, while increased the level of
plasma insulin, glutathione S-transferase, and glutathione peroxidase
Aqueous extract (200 mg/kg, p.o.) enhanced plasma insulin and antioxidants in diabetic
animals
Plant extract showed insulin secretagogue activity in isolated mice pancreatic islets
Extract of the plant showed in vitro insulin secretagogue activity in rat insulinoma cell lines
(RINm5F cells)
Hexane fraction of 95 % ethanol extract (250 mg/kg) and swerchirin (isolated from the plant)
exhibited hypoglycemic effect in experimental animals
Hexane fraction (250 mg/kg, orally) in albino rats produced insulin-releasing effect and
significantly increased liver glycogen
Aqueous extract (400 mg/kg, p.o.) showed antidiabetic activity in experimentally induced
diabetic rats
Water extract of root (2.5, 5 and 7.5 mg/kg) produced hypoglycemic effect in alloxan-
induced diabetic rats. Extract decreased brain lipid level, serum acid phosphatase, content of
hepatic glucose-6-phosphatase, alkaline, and lactate dehydrogenase, while body weight, total
Hb, and hepatic hexokinase increased
(continued)
149
Table 10.3 (continued)
Name of the plant with family
Trigonella foenum-graecum
[Family:]
Vinca rosea
[Family: Apocynaceae]
A Assamese, S Sanskrit, H Hindi, B Bengali, E English, T Tamil, K Kannada, M Malayalam
Common name
Methi (H), Greek hay seed (E), vendayam
(T), uluva (M)
Nayantara (B), sadasawagon (H),
sudukadu mallikai (T), red periwinkle (E)
150
Reported antidiabetic activity
Seeds of the plant have been demonstrated hypoglycemic activity in experimentally induced
diabetic animals and healthy volunteers (both T1DM and T2DM patients)
Isolated phytoconstituents (i.e., saponins, fibers, and proteins) from seeds exhibited
antihyperglycemic and anti-glycosuric effect in alloxan-induced diabetic dogs along with
decrease in high plasma glucagon and somatostatin level
A novel amino acid, 4-hydroxyisoleucine from seeds enhanced insulin secretion induced by
glucose load, through a direct effect on the isolated islets in both humans and rats
Aqueous leaf extract produced antihyperglycemic and blood glucose-lowering effect in
normal and alloxan-induced diabetic rats, while ethanol extract (50 %) considerably
decreased blood glucose level
Water-soluble fraction (100, 250, 500 and 1000 mg/kg, p.o.) of ethanol extract of leaf
exhibited blood glucose-lowering effect in dose-dependent manner in normal rats. Extract
also produced effect toward OGTT in rats
10 Indian Traditional Medicinal Systems, Herbal Medicine, and Diabetes
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 Management of Diabetes Mellitus
DM is acknowledged as a serious medical prob-
lem since the last two centuries, but still repre-
sents a major medical challenge. Early detection
of DM/prediabetes condition offers an opportu-
nity to provide better management and to avert
consequences of DM. Modern treatments and
discovery of new medicines could be helpful to
stop the devastating condition DM and continue
to improve outcomes. But non-pharmacological
approaches are essential and considered as a key
strategy to remain healthy.
Pharmacological Treatment of DM
Pancreatic β cell is destroyed in T1DM which
causes an absolute deficiency of insulin in the
body. Thus, T1DM necessitates insulin treatment
soon after the detection of the disease, and subse-
quently insulin treatment should be continued
without interruption for lifelong. On the other
hand, T2DM results from the decrease in insulin
secretion or insulin resistance. Several oral hypo-
glycemic agents like sulfonylureas, biguanides,
meglitinides, thiazolidinediones, and
α-glucosidase inhibitors are the choice of drug to
treat T2DM along with insulin. But in last few
years, advancement of medical science gifted us
several other oral hypoglycemic agents (DPP-4
inhibitors, SGLT2 inhibitors) and injectable
(GLP-1 analog, amylin analog) antidiabetic drug
© Springer Science+Business Media Singapore 2016
S. Sen et al., Diabetes Mellitus in 21st Century, DOI 10.1007/978-981-10-1542-7_11
11
to treat T2DM, which offers an opportunity to
treat/manage DM and its complications in a bet-
ter way.
Currently available antidiabetic drugs are
classified as:
1. Injectable antidiabetic agents
(a) Insulin
(b) Amylin analog: Pramlintide
(c) Glucagon-like peptide-1 (GLP-1) analog:
Exenatide and liraglutide
2. Oral hypoglycemic agents
(a) Sulfonylureas:
First-generation sulfonylureas: Tolbutamide,
chlorpropamide, and acetohexamide
Second-generation sulfonylureas: Glimepiride,
glibenclamide, gliclazide, and glipizide
(b) Meglitinides: Repaglinide and nateglinide
(c) Biguanides: Metformin
(d) Thiazolidinediones: Pioglitazone and
rosiglitazone
(e) PPARα and PPARγ agonist: Saroglitazar
(f) α-Glucosidase inhibitors: Acarbose,
miglitol, and voglibose
(g) Dipeptidyl peptidase-4 (DPP-4) inhibi-
tors: Sitagliptin, saxagliptin, vildagliptin,
linagliptin, and alogliptin
(h) Sodium-glucose co-transporter 2 (SGLT2)
inhibitors: Canagliflozin, dapagliflozin,
empagliflozin, ipragliflozin, and
tofogliflozin
153
154
Insulin
Insulin treatment is the mainstay for the manage-
ment of not only for T1DM but also for T2DM. In
type 1 diabetic patients, insulin and insulin ana-
log are considered as an only treatment strategy,
while in type 2 diabetic individuals, insulin is
used along with other hypoglycemic agents.
Insulin can be given through intravenous or intra-
muscular route, but usual and long-term treat-
ment prefers subcutaneous injection of insulin.
Different insulin preparations available in the
market differ in a several way, including variation
in recombinant DNA production methods, a
sequence of amino acid, solubility, concentra-
tion, onset time, and duration of their biologic
effect. In a usual strategy, insulin injections are
given one or two times a day. About 2/3 of the
total daily dose is given before breakfast/morning
food, and remaining 1/3 is given before dinner. In
intensive insulin treatment, strategy includes
administration or insulin ≥ three times/day
through injection, external pump, or pen. Insulin
dose is adjusted as per premeal blood glucose
level. Insulin is absorbed quickly from the abdo-
men followed by the arms, thigh, and buttock. It
is appropriate to inject the insulin within one area
rather than administering to different areas, as its
day-to-day absorption differs. Exercise stimu-
lates the absorption rate from the site of injection.
Several new techniques like an artificial pancreas,
buccal and oral insulin, inhalable insulin, trans-
dermal insulin as patches, and intranasal insulin
are in the developing stage to deliver the insulin
other than the subcutaneous route. Hypoglycemia,
weight gain, allergy reaction, infection, injection
site abscess, lipoatrophy, insulin edema, lipohy-
pertrophy, and insulin resistance are the common
problems associated with insulin injection (Table
11.1) (Davis 2006; Yadav and Prakash 2006;
Joshi et al. 2007; Richard et al. 2009; Katzung
et al. 2012; Azad et al. 2013).
Amylin Analog
Amylin is a naturally derived peptide and is also
known as islet amyloid polypeptide (IAPP).
11 Management of Diabetes Mellitus
Amylin is mainly produced and synthesized by β
cells of islet of Langerhans and colocalized with
insulin. Amylin and insulin are released from β
cell in response to food intake in a molar ratio of
~1–100 in normal individuals. Expression of
amylin is also observed in the gut and sensory
nervous system. Amylin suppresses postprandial
glucagon secretion, induces satiety, delays gas-
tric emptying, and reduces intake of food and
body weight. Pramlintide is a soluble analog of
amylin used in the patient with T1DM and T2DM
as an adjunct treatment strategy. Usually, pram-
lintide is used in the patient to whom mealtime
insulin therapy or sulphonylurea and/or metfor-
min therapy failed to achieve expected antidia-
betic effect. Pramlintide acts through central
pathways by acting on the amylin receptors pres-
ent in the area postrema of the brainstem. Amylin
agonists also may exhibit few beneficial effects
of GLP-1. Pramlintide helps insulin to achieve
proper postprandial glucose homeostasis and
maintain the glucose level in blood. Pramlintide
suppresses glucagon secretion from α cell and
thus decreases hepatic glucose release, delays the
rate of gastric emptying, decreases release of gas-
tric acid and pancreatic juice, and thus retards the
digestion rate but not overall absorption of nutri-
ent. Pramlintide has moderate effect on HbA1C
reduction, but exerts favorable effect in reducing
food intake and body weight (Reda et al. 2002;
Day 2005; Messer and Green 2009).
Glucagon-Like Peptide-1 (GLP-1)
Incretins are a group of gastrointestinal hormones
that have a significant effect in the maintenance of
blood glucose levels. Glucagon-like peptide-1
(GLP-1) and glucose-dependent insulinotropic
polypeptide (GIP) are recognized as two main
incretin hormones. In response to carbohydrate-
and lipid-containing meals, GIP and GLP-1 are
secreted from the intestine and play a key role to
stimulate insulin release from the pancreas.
GLP-1 exists in two different molecular forms in
the circulation, GLP-1(7-37) and GLP-1(7-36)
amide, although the latter one is more copious in
the circulation after intake of food. The major
Pharmacological Treatment of DM 155

Table 11.1 Different types of insulin preparations

Insulin preparation Onset of action Peak action Duration of action Features
Rapid-acting insulin: These are clear solutions at neutral pH that contain crystalline zinc to increase the stability
and self-life. These agents increase prandial secretion of insulin, but not used alone, usually they prefer along with
long-acting insulin for better effect. They may also be used in external insulin pumps
Insulin lispro 5–15 min 30–90 min 3–5 h Usually given 15 min before a meal
or immediately after a meal
Insulin aspart 5–15 min 30–90 min 3–5 h Given just before the meal
Insulin glulisine 5–15 min 30–90 min 3–5 h Given either 15 min prior to a meal or
within 20 min after starting a meal
Short-acting insulin: Clear solutions at neutral pH contain crystalline zinc to increase the stability and self-life.
Phenol or m-cresol is added to prevent the growth of microorganism
Regular insulin 30–60 min 1–3 h 4–8 h Sustained infusion of insulin. May
also give through i.v. or i.m. route
Intermediate-acting insulin
Neutral 1–2 h 4–10 h 10–18 h Suspension of insulin in a complex
protamine with protamine and zinc in a
Hagedorn (NPH) phosphate buffer. Given through s.c.
insulin route only. Not recommended in
diabetic ketoacidosis or emergency
hyperglycemic condition. Usually
administered with rapid- or short-
acting insulin for mealtime control
Lente insulin 3–4 h 4–12 h 12–18 h Mixture of crystallized (ultralente,
extended insulin zinc) and amorphous
(semilente) insulin in acetate buffer
Long-acting insulin
Ultralente 6-10 h 10–16 h 18–24 h Cloudy suspension in acetate buffer
(pH 7.2–7.5), preferred before
breakfast/dinner
Insulin glargine 1–2 h Peakless 18–24 h Clear solutions at acidic pH. After
injection, acid is neutralized and
glargine precipitates
Insulin detemir 1–2 h 6–14 h 16–20 h Clear solutions
Insulin mixtures
70/30 human mix 30–60 Dual 10–16 h 70 % NPH, 30 % regular
min
75/25 lispro 5–15 min Dual 10–16 h 25 % lispro, 75 % intermediate
analog mix
70/30 aspart 5–15 min Dual 10–16 h 30 % aspart, 70 % intermediate
analog mix
50/50 human mix 5–15 min Dual 10–16 h 50 % NPH, 50 % regular

source of GLP-1 is enteroendocrine L cells of the In contrast, GLP-1R is expressed in pancreatic α

distal ileum and colon. Both GIP and GLP-1 bind
with of structurally distinct GPCRs such as GIP
receptor (GIPR) and GLP-1 receptor (GLP-1R).
Activation of these receptors result increase in
cAMP level in β cell, thereby stimulate glucose-
dependent insulin release. GIPR is mostly
expressed on pancreatic β cells and also in adi-
pose tissue and in the CNS but in a lesser extent.
and β cells and in several other tissues like the
CNS, heart, kidney, lung, and GIT. Incretin recep-
tor signaling is also related with pKA activation,
initiation of gene transcription, an increase in
insulin biosynthesis, and β-cell proliferation stim-
ulation. Activation of GLP-1R and GIPR endorses
resistance to apoptosis and increased survival of β
cell. GLP-1 also restrains secretion of glucagon,
156
gastric emptying, and ingestion of food and
causes glucose removal through neural mecha-
nisms. Type 2 diabetic people have distinctly
blunted incretin secretory action which may be
responsible for impaired postprandial insulin
release by up to 60 %. The α cell of the islet in the
pancreas downregulates glucagon secretion
through augmentation of incretin system. Thus, it
can be proposed that paralysis of incretin axis in
type 2 diabetic patient may result in high post-
prandial and fasting blood glucose level. GIP is
found comparatively ineffective in stimulating
release of insulin in people with T2DM, while
GLP-1 increases secretion of insulin in both non-
diabetic and diabetic individuals and promotes
glucose homeostasis beyond the enhancement of
insulin release. Thus, GLP and GLP-1 analog
have been pursued as a therapeutic agent (Drucker
and Nauck 2006; Seino and Yabe 2013).
Current researches have showed the impor-
tance of GLP-1 and the agonist of GLP-1R in the
management of T2DM. Very short half-life
(1.5 min) is the major limitation of endogenous
GLP-1. Dipeptidyl peptidase-4 (DPP-4) causes
proteolytic degradation of GLP-1 rapidly by
cleaving the active GLP-1 (7–36) to inactive
GLP-1 (9–36). Short-term intravenous adminis-
tration of GLP-1 reduces blood glucose level in
type 2 diabetic patient. But such measures are
helpful while controlling diabetic condition for
short term. Exenatide and liraglutide are the
examples of GLP-1R analog used to treat T2DM
(Drucker and Nauck 2006; Thompson and
Kanamarlapudi 2013).
Exenatide, a synthetic analog of exendin-4,
was approved by the US Food and Drug
Administration (FDA) and European Union (EU)
in 2005 and 2006, respectively. Exendin-4 is a
biologically active peptide of 39 amino acids dis-
covered from Heloderma suspectum (a lizard)
venom, bearing a 53 % homology to GLP-1 of
human. Exenatide and exenatide LAR (sustained
release) are the common forms available for
T2DM. Exenatide is a short-acting GLP-1R ago-
nist marked in 5–10 μg pen and prescribed twice
a day before meals. Treatment with exenatide is
11 Management of Diabetes Mellitus
found to reduce in HbA1c, decrease fasting and
postprandial plasma glucose level, and reduce
body weight (Drucker and Nauck 2006; Gupta
2013; Thompson and Kanamarlapudi 2013).
Liraglutide is an acylated analog of GLP-1
and also acts as DPP-4 resistant partly. It was
approved by the EU, Japan, and USFDA in 2009
and 2010. Liraglutide is a long-acting drug acting
on GLP-1R and administered subcutaneously
once a day. Liraglutide reduces postprandial
blood glucose and body weight without the risk
of hypoglycemia (Drucker and Nauck 2006;
Vilsboll et al. 2008; Lambert 2013; Gupta 2013).
In general, GLP-1R agonist is not responsible
for hypoglycemia on their own, but when admin-
istered with other antidiabetic drugs like sulpho-
nylureas, the risk of hypoglycemia may exist.
Nausea and vomiting are the usual adverse effect
of these drugs, but in case of transient nausea,
up-titrating the dose slowly is essential (Lambert
2013). Several other drugs like lixisenatide
(human GLP-1R agonist) developed by Sanofi
Aventis under license from Zealand Pharma are
undergoing phase 3 clinical trials. Albiglutide
(GLP-1 mimetic effect and resistant to DPP-4) is
under phase 3 clinical trial developed by
GlaxoSmithKline. Dulaglutide (long-acting
GLP-1 analog) is under investigation developed
by Eli Lilly (Gupta 2013; Thompson and
Kanamarlapudi 2013).
Current investigations also highlighted the
positive effect of GLP-1 agonist and several mac-
rovascular complications of diabetes. GLP-1 can
avert cerebrovascular disease, endothelial
dysfunction, peripheral artery disease, and coro-
nary artery disease, through their distinct mea-
sures on the brain, vascular endothelial cells, and
heart. Indirectly, GLP-1 also produces a positive
effect through regulation of blood pressure,
inflammation, and metabolism of lipid. GLP-1
agonist can also reduce the oxidative stress and
may be involved in controlling obesity or intake
of excessive food through meal enteroenteric
reflexes and across meal central signaling mecha-
nisms (Goyal and Kumar 2010; Dailey and
Moran 2013; Seino and Yabe 2013) (Fig. 11.1).
Pharmacological Treatment of DM
Increased secretion of
Intake of GLP-1 & GIP
food from intestine
↓ Glucagon secretion ↓ ROS production
↑ Insulin and somatostatin secretion ↑ Apoptosis
↑ β-call - mass and regeneration, ↑ Appetite, ↓ food intake
↓ β-cell apoptosis ↓ Satiety, ↓ water intake
Pancreas Brain
↑ Glucose uptake
↑ Glycogen synthesis
Liver, adipose and
muscle tissue
Fig. 11.1 Biological role of GLP-1 and DPP-4
Sulfonylureas
History and Chemistry Hypoglycemic effect
of synthetic sulfur compounds was investigated
in 1937 by Ruiz and his colleagues. In 1942, a
French physician Marcel Janbon and his col-
leagues found that sulfonylurea produces hypo-
glycemic effect in patients administered with
p-amino-sulfonamide-isopropylthiodiazole for
typhoid. Lobatieres and his colleagues in 1946
reported that this type of drugs stimulates β cell
and induces release of insulin. In between 1954
and 1956, tolbutamide (first generation of sulfo-
nylurea) was introduced in the USA and Germany
followed by chlorpropamide. In 1984, second-
generation sulfonylureas like glyburide and glipi-
zide were discovered. In 1995, glimepiride,
another potent second generation of a drug, was
introduced (Stingl and Schernthaner 2007;
Quianzon and Cheikh 2012).
Mechanism of Action Sulfonylurea receptor
(140-kDa) is associated with β cell which is con-
sidered as a subunit of the voltage-dependent
potassium ATP (KATP) channels on pancreatic β
cells. Sulfonylureas act on sulfonylurea receptor
1 (SRU1, a part of a transmembrane complex
with ATP Kir 6.2 potassium channels) and inhibit
the efflux of K+ through the channel, which
157
DPP-4
Inactivation of
GLP-1 & GIP
GLP-1
[act on GLP-1R]
↑ Gastric emptying time ↓ No production
↓ Acid secretion in stomach ↑ Glucose uptake
↓ Intestinal lipid absorption ↓ Apoptosis
↑ Sodium excretion through
kidney
Heart
↓ No production
↓ Fatty acid synthesis
↑ Fatty acid oxidation ↑ Proliferation
↓ Apoptosis
Liver Endothelial cell
induces depolarization. This depolarization
induces the opening of voltage-gated Ca2+ chan-
nels. Increase in the intracellular Ca2+ results in
the release of preformed insulin from the gran-
ules of β cell. There is some support that sulfo-
nylureas also enhance peripheral insulin
sensitivity, reduce the production of hepatic glu-
cose production, and reduce serum glucagon
level indirectly (Cheng and Fantus 2005; Nolte
and Karam 2007; Stingl and Schernthaner 2007).
Pharmacokinetic Profile Sulfonylureas are
absorbed from the GIT effectively though food
and hyperglycemia may retard the absorption.
They are more effective when administered
30 min before food. Sulfonylureas have high
(90–99 %) plasma protein (especially albumin)
binding capacity. Second-generation sulfonyl-
ureas are more effective than the first generation
of drugs. These drugs are metabolized in the
liver and excreted through urine. Tolbutamide is
absorbed rapidly and has an elimination half-
life of 4–5 h. Chlorpropamide is metabolized
slowly and has a half-life of 32 h. Half-life of
glipizide is about 2–4 h, shortest among the
potent agents. Among sulfonylurea compounds,
glimepiride required the lowest dose to produce
hypoglycemic effect (Davis 2006; Rang et al.
2003).
158
Uses, Adverse Effects, Contraindication, and
Precautions Sulfonylureas are used to control
blood sugar level in type 2 diabetic people. These
drugs are used as monotherapy (along with
proper diet) and in combination with insulin,
metformin, and other oral antidiabetic drugs.
Sulfonylureas, when used with metformin, may
reduce HbA1c very effectively. Sulfonylureas
should be introduced as low dose. Hypoglycemic
effect is the common side effect of sulfonylurea.
However, second-generation drugs have very dif-
fering frequency of hypoglycemia. Weight gain,
hyperinsulinemia, nausea, vomiting, agranulocy-
tosis, cholestatic jaundice, anemia (aplastic and
hemolytic), hypersensitivity, and dermatological
reactions are the other side effects of sulfonyl-
urea. Some sulfonylurea drugs like glyburide
may cause renal impairment (Davis 2006; Nolte
and Karam 2007; Richard et al. 2009).
Nonsteroidal anti-inflammatory drugs, cou-
marins, sulfinpyrazone, alcohol, monoamine oxi-
dase inhibitors, sulfonamides, trimethoprim,
SUR 1
Megkitinid
KATP Channel
K
+ ATP
Na+-K+
ATPade
+
Na
Glucose metabolism
Glucokinase
GLUT 2
Glucose
Fig. 11.2 Mechanism of action of sulfonylureas and meglitinides
11 Management of Diabetes Mellitus
chloramphenicol, and few imidazole antifungal
agents may reduce the blood glucose level when
administered with sulfonylureas. Thiazide diuret-
ics and corticosteroid may reduce the action of
sulfonylureas. Precaution has to be taken while
administering sulfonylureas in patients with renal
or hepatic insufficiency. These agents except
glibenclamide can cross the placenta and can ini-
tiate fetal islet to release insulin, which in turn is
responsible for severe hypoglycemia at birth
(Davis 2006; Rang et al. 2003; Richard et al.
2009) (Fig. 11.2).
Meglitinides
These drugs are known as non-sulfonylureas and
exert almost same mechanism of action like that
of sulfonylureas. However, they may attach to
sulfonylurea receptor at a distinct portion. These
drugs have a weaker binding affinity and quick
dissociation rate from the binding site. The first
drug of this group is repaglinide, which is
Sulfonylureas Block K+ channel
Depolarisation
+2 +2
Ca Ca
Proinsulin
biosynthesis
Exocytosis
Insulin
Pharmacological Treatment of DM
approved for clinical use in 1998. Meglitinides
are mainly considered as postprandial glucose
regulator in type 2 diabetic patient which produce
better effect in the early release of insulin after a
meal. These agents are metabolized in the liver
through the cytochrome P450 system and
excreted through bile. Meglitinides can be used
alone or along with other oral antidiabetic drugs
other than sulfonylureas. Repaglinide is quickly
absorbed from the GIT; half-life is about 1 h.
Nateglinide is also absorbed within 20 min after
oral administration, and half-life is about 1.5 h.
Major side effects of these drugs include hypo-
glycemia, weight gain, and diarrhea. Meglitinides
must be used with care in people with hepatic
impairment (Davis 2006; Nolte and Karam 2007;
Richard et al. 2009).
Biguanides
History and Chemistry Biguanides are the
class of oral antidiabetic drug introduced in 1957
for the treatment of T2DM. Phenformin and
buformin are withdrawn from the market of most
of the countries due to toxic effects. Metformin
(dimethylbiguanide) is a well-known antidiabetic
drug, the discovery of which is related to a tradi-
tional antidiabetic plant (Galega officinalis) from
Europe. Galega officinalis extract is used to treat
DM till the 1930s in France. Guanidine is a major
chemical constituent of the plant which possesses
hypoglycemic effect in animals, but the use of
guanidine is restricted due to its toxicity. In the
1920s, several natural and synthetic analogs of
guanidine like galegine (isoamylene guanidine),
decamethylene diguanide (Synthalin A), and
dodecamethylene diguanide (Synthalin B) were
discovered, which show antidiabetic effect and
exhibit less toxic effect. Several hypoglycemic
biguanides including dimethylbiguanide were
described in 1929. In 1957–1958, metformin was
found effective as an antidiabetic drug and intro-
duced in the market. But in the 1970s, metformin
was removed from market/not approved in sev-
eral countries due to its most common side effect
lactic acidosis. Metformin was used widely in
Canada and Europe; it was again approved in the
159
USA in 1995, when the drug satisfies the safety
criteria in Canada, Europe, and Asia (Bailey
1992; Bailey and Day 2004; Devis 2006).
Mechanism of Action Precise mechanism of
action of metformin is still not known. But met-
formin restrains gluconeogenesis, reduces fatty
acid and cholesterol synthesis, increases time for
gastrointestinal glucose absorption, decreases
food intake, and reduces body weight of type 2
diabetic obese individuals. Metformin activates
adenosine monophosphate (AMP)-activated pro-
tein kinase (AMPK) in hepatic and muscle tis-
sues. Activation of AMPK results in increase in
glucose uptake and glycogenesis in the muscle, a
key area for metformin effect. Metformin
increases AMP-ATP ratio and thus activates
AMPK which results in inhibition of the respira-
tory chain complex I. Hepatic AMPK activation
results in inhibition of acetyl-coenzyme A car-
boxylase (ACC) and 3-hydroxy-3-
methylglutarylcoenzyme A (HMG-CoA), thus
reducing expression of fatty acid synthase (FAS)
and activation of malonyl-CoA carboxylase.
These changes are responsible for cholesterol
and fatty acid synthesis inhibition. Activation of
hepatic AMPK is responsible for reduced expres-
sion of sterol-regulatory-element-binding-pro-
tein-1 (SREBP-1), which is playing a key role in
the pathogenesis of insulin resistance, DM, and
dyslipidemia. Reduced SREBP-1 expression is
also responsible for reduced synthesis of triglyc-
eride and hepatic steatosis through the reduced
gene expression of lipogenic enzymes. Another
key effect of metformin includes suppression of
gluconeogenesis in the liver through the inhibi-
tion of phosphoenolpyruvate carboxykinase
(PEPCK) and glucose-6-phosphatase (G6Pase)
transcription. Increase in hepatic SIRT1 (an
NAD+-dependent protein deacetylase) through
AMPK-mediated stimulation of nicotinamide
phosphoribosyltransferase also may involve in
suppression of liver gluconeogenesis. Metformin
may act on the hypothalamus and reduce
AMPK. Inactivation of AMPK results in inacti-
vation of phosphorylation of ACC and thus
increases the level of malonyl-CoA and sup-
presses food intake and reduces body weight
160 11 Management of Diabetes Mellitus

(Zhou et al. 2001; Cheng and Fantus 2005;
DiStefano and Watanabe 2010; Nakano and Inui
2012; Viollet et al. 2012).
Pharmacokinetic Profile Metformin is mainly
absorbed in the small intestine. Bioavailability of
metformin is 50–60 %, and plasma t1/t2 is about
2–5 h. Nearly 90 % of drugs are eliminated from
the body within 12 h. Metformin does not attach
to plasma proteins and is excreted through urine
in unchanged form (Bailey 1992; Cheng and
Fantus 2005).
Uses, Adverse Effects, Contraindication, and
Precautions Metformin is used to treat T2DM
alone or along with insulin or with other classes
of oral antidiabetic agent. Important side effect of
metformin includes lactic acidosis and megalo-
blastic anemia. Common side effects are diar-
rhea, vomiting, dyspepsia, flatulence, metallic
taste, and weight loss. Alcohol intake may poten-
tiate lactase metabolism. Metformin is contrain-
dicated in people with renal function impairment,
cardiac and respiratory insufficiency, liver dis-
eases, alcohol abuse, metabolic acidosis, or con-
dition related to hypoxia or reduced perfusion
(Reddy et al. 2000; Krentz and Bailey 2005;
Davis 2006) (Fig. 11.3).
Thiazolidinediones
History Thiazolidinediones are also known as
glitazones, act as an agonist of peroxisome
proliferator-activated receptor-γ (PPARγ), and
increase insulin sensitivity toward the body tis-
sue via multiple actions on gene regulation.
Antidiabetic effect of thiazolidinediones was
reported in early 1980, but introduced in the
market in the late 1990s. Troglitazone was the
first drug under this class marked in the UK
and USA in 1997 but withdrawn due to severe
hepatotoxicity reaction. Rosiglitazone and pio-
glitazone were introduced in USA and Europe
in the year 1999–2000 (Krentz and Bailey
2005).

Metformin

Hypothelamus LIVER Muscle

Inhibition of AMPK Activation of AMPK Activation of AMPK

Neuropeptide
SREB-1 Expression SIRT1
ACC
HMG-CoA and activity PEPCK Glucose uptake
G6Pase Glycogenesis
Fructose-1,6- Oxidative utilization
Food intake
Fatty acid synthase biphosphate
Body weight Activate Malonyl CoA carboxilase

Fatty acid activation

Fatty acid synthesis
Cholesterol synthesis Gluconeogenesis

Hepatic steatosis
Liver insulin sensitivity

Fig. 11.3 Mechanism of action of metformin. ACC acetyl-coenzyme A carboxylase, HMG-CoA 3-hydroxy-3-
methylglutarylcoenzyme A, SREBP-1 sterol-regulatory-element-binding-protein-1, G6Pase glucose-6-phosphatase
Pharmacological Treatment of DM
Mechanism of Action Nuclear hormone recep-
tors act by regulation of gene expression in
response to small ligands. Different type of
nuclear hormone receptors includes testosterone,
vitamin D, thyroid hormone, bile acids, and reti-
noic X receptor (RXR). PPARs are considered as
a significant subfamily of nuclear hormone
receptors which are found to regulate the storage
and catabolism of dietary fats in large extent.
PPARs regulate the transcription and expression
of a specific gene. Three subtypes of PPARs were
identified – α, δ, and γ. PPARα is expressed in the
liver, kidney, brown adipose tissue, skeletal mus-
cle, and heart tissue. PPARγ is mostly expressed
in adipose tissues and also found in the muscle,
kidney, colon, pancreas, liver, and intestine.
PPARδ is found in the brain, adipose tissue, and
skin and in wide range of tissue. Both PPARα and
PPARγ are also expressed in smooth muscle cells
of the blood vessel, endothelial cells, and mono-
cytes/macrophages and in human atherosclerotic
lesions (Singh et al. 2011; Javiya and Patel 2006).
Thiazolidinediones are lipophilic which enter
cells easily and act as ligand for PPARγ to stimu-
late insulin sensitivity particularly in the periph-
eral tissue. PPARγ acts in association with RXR
by producing heterodimer and then attached to
specific peroxisome proliferator response ele-
ments (PPRE) for activation. Their activation
results in the initiation of regulatory sequences of
DNA that regulate the expression of specific genes,
which is involved in carbohydrate and lipid metab-
olism. Metabolic effects of thiazolidinediones
include increase in glucose uptake in the skeletal
muscle and adipose tissue, increase in fatty acid
uptake and lipogenesis in the adipose tissue, pre-
adipocyte differentiation, increase in lipogenesis
in the liver, reduced glycogenolysis and gluconeo-
genesis in the liver, and increase in glycolysis and
glucose oxidation in skeletal muscle. Thus, thia-
zolidinediones play a key role for the treatment of
T2DM (Das and Panda 2004; Krentz and Bailey
2005; Chiarelli and Marzio 2008).
Pharmacokinetic Profile Rosiglitazone and
pioglitazone are absorbed completely and rap-
idly, though food may delay the absorption rate.
161
Drugs are metabolized through the liver exten-
sively (Cheng and Fantus 2005; Krentz and
Bailey 2005).
Uses, Adverse Effects, Contraindication, and
Precautions Rosiglitazone and pioglitazone can
be used as monotherapy in individual with T2DM
and can be used in combination of other drugs
and insulin. These drugs also lower the HbA1c
by 1 to 1.6 % in patients with DM. These drugs
also may be useful to reduce the CVS and other
complications related to DM. Pioglitazone may
be useful to improve lipid profile in diabetic sub-
ject. Retention of fluid, gain in body weight, con-
gestive heart failure, pulmonary edema, and
anemia are the side effects reported after thiazoli-
dinedione treatment. Caution should be taken
while using these drugs in acute liver diseases, in
heart failure, in patient receiving insulin, during
pregnancy and breastfeeding, and in polycystic
ovary syndrome (Krentz and Bailey 2005; Tack
and Smits 2006; Chiarelli and Marzio 2008)
(Fig. 11.4).
PPARα and PPARγ Agonist
People with T2DM are at risk of dyslipidemia
and overweight. CVS complications mainly mac-
rovascular disease is responsible for a huge num-
ber of mortality in diabetic patients. Currently
available antidiabetic thiazolidinediones act on
PPARγ receptor and mainly act via increasing
insulin sensitivity and confer very less/no effect
on CVS complications. PPARα regulates the
genes related to the fatty acid oxidation and
maintains energy homeostasis. PPARα agonists
reduce the plasma triglyceride level, increase
HDL level, and thus are useful to treat dyslipid-
emia. Thus, an agonist on PPARα and PPARγ
could be helpful to manage DM, dyslipidemia,
and atherosclerotic disorder. Saroglitazar is a
dual PPARα, PPARγ agonist (predominant
PPARα and moderate PPARγ agonist).
Saroglitazar, a non-thiazolidinedione and non-
fibrate molecule was approved in India in 2013.
The drug is mainly eliminated through enterohe-
patic route. Saroglitazar is found to reduce serum
162
Thiazolidinedione
Adipose tissue
- Increase glucose uptake through GLUT4
- Increase fatty acid uptake through FATP
- Increase a12, acyl CoA synthase
- Lipogenesis
- Adipocyle differenciation PPAR-γ RXR
- Decrease lypolysis DNA
- Decrease TNF-α and Leptin
- Increase adiponectin
- Improve insulin sensitivity
- Increase glucose uptake
- Increase glycolysis
- Increase oxidation
- Glycogensis
Fig. 11.4 Mechanism of action of thiazolidinediones
triglycerides, cholesterol, and LDL and improve
lipid clearance; the drug is also helpful to reduce
serum glucose level and improve oral glucose tol-
erance. During clinical trial pharmacokinetics,
safety and tolerability of the drug are found satis-
factory. Average plasma half-life of saroglitazar
was 2.9 ± 0.9 h after single-dose (4 mg) adminis-
tration. Pyrexia, dyspepsia and gastritis, itching,
abdominal pain, nausea, cough, cold, headache,
body pain, and diarrhea are the common side
effects of saroglitazar. The drug is approved in
India for the treatment of diabetic dyslipidemia
and to improve glycemic parameters.
Development of a number of other drugs under
the category like tesaglitazar, chiglitazar, sipogli-
tazar, aleglitazar, and naveglitazar was stopped
during clinical or preclinical trial due to adverse
effect, while muraglitazar (another dual agonist)
is withdrawn from the market due to heart failure
(Charbonnel 2009; Aggarwal 2014; Majumder
and Chatterjee 2014).
α-Glucosidase Inhibitors
α-Glucosidase inhibitors such as acarbose, vogli-
bose, and miglitol are the drugs used to manage
DM, but they lack target for a specific pathophys-
iologic aspect of DM. Acarbose is the first agent
11 Management of Diabetes Mellitus
Liver
- Decrease gluconeogenesis
- Decrease glycogenolysis
- Increase lipogenesis
- Increase glucose uptake
Transcription
mRNA
Specific protein
Muscle
of this class marketed in the 1990s; subsequently,
miglitol and voglibose were discovered. They
inhibit small intestinal brush border enzymes
competitively which are playing a key role for
breakdown of oligosaccharides and disaccharides
into monosaccharides and thus initiate absorp-
tion. Thus, intestinal absorption of carbohydrates
is retarded and moved to more distal portions of
the small intestine and colon. Acarbose restrains
both digesting enzyme α-glucosidases and
α-amylase, while voglibose and miglitol don’t
have any effect on α-amylase but inhibit the
disaccharide digesting enzymes. These drugs
mainly control postprandial hyperglycemia and
help to control both T1DM and T2DM (Reddy
et al. 2000; Cheng and Fantus 2005; Davis 2006).
Acarbose is absorbed poorly or not absorbed.
The drug is metabolized mainly by intestinal bac-
teria, in an unchanged form, acarbose is excreted
in feces, and some metabolites are absorbed and
excreted through urine. Miglitol is absorbed
nicely but doesn’t produce any systemic effects
and is excreted through the kidney in unchanged
form. In comparison to other hypoglycemic
agents, these drugs show lesser hypoglycemic
effect and have average HbA1c-lowering effect.
Little reduction in triglyceride concentration and
decrease in body weight were observed in patient
receiving α-glucosidase inhibitors. These drugs
Pharmacological Treatment of DM
Table 11.2 Different DPP-4 inhibitors available for the treatment of T2DM
DPP-4 inhibitors Dose and indications
Sitagliptin 100 mg once daily
Pregnancy category B drug can
enter in nursing baby through
breast milk and may cause harm
Saxagliptin 5 mg once daily
Vildagliptin 50 mg twice daily
Not recommended in end-stage
renal disease on hemodialysis
patients and in hepatic impairment
condition
Linagliptin 5 mg once daily
Alogliptin 25 mg once daily
Sitagliptin has high selectivity for DPP-4 and others have moderate selectivity
Linagliptin is excreted through biliary route; others are through renal route
Linagliptin binds extensively to plasma proteins
These drugs are used in combination with metformin, TZD, and sulfonylurea
are used rarely as monotherapy and not recom-
mended for initial treatment in people suffering
from moderate to severe hyperglycemia. They
are administered along with other oral hypogly-
cemic agents. α-Glucosidase inhibitors also may
produce positive effect by reducing the risk of
CVS complication in diabetic people by reducing
fibrinogen levels, activation of platelet, vascular
inflammation, and improving endothelial func-
tion. GIT disturbances like bloating, discomfort
in the abdomen, diarrhea, and flatulence are the
general side effect. These agents are contraindi-
cated in people with irritable bowel syndrome or
severe dysfunction of the liver and kidney. High
dose of acarbose may alter the concentration of
liver enzymes (Cheng and Fantus 2005; Krentz
and Bailey 2005; Richard et al. 2009).
Dipeptidyl Peptidase-4 (DPP-4)
Inhibitors
DPP-4 is an exopeptidase class of proteolytic
enzymes present on the different cell surface
including the small intestine, pancreas, kidney,
and liver and also present in plasma as soluble
163
Side effects
Upper respiratory tract infection, runny nose, headache,
stomach discomfort, and diarrhea
Sore throat, stuffed or runny nose, painful and burning
urination, pain in the stomach, nausea, headache,
vomiting, diarrhea, and bloating. Pancreatitis is reported
in some postmarketing study
Nausea, hypoglycemia, tremor, headache,
gastroesophageal reflux, and dizziness. Rarely
hepatotoxicity
Hypoglycemia (low), increase in body weight,
nasopharyngitis, diarrhea, infection in the urinary tract
and upper respiratory tract, back pain, headache, and high
blood pressure
Anxiety, blurred vision, cold, dizziness, headache,
increased hunger, nausea, slurred speech, weakness
form. DPP-4 is responsible for degradation of
several polypeptides like GLP-1 and GIP by
cleaving the N- or C-terminal amino acid por-
tions from peptides and proteins. Inhibition of
DPP-4 is a key target to treat T2DM, providing
enhanced GLP-1 level, with subsequent rise in
insulin secretion and decrease glucagon secre-
tion, which in turn exerts a beneficial effect to
people suffering from T2DM. DPP-4 inhibitors
represent a new class of drug available for treat-
ment of DM and its complications. DPP-4 inhibi-
tors presumably increase the serum level of
GLP-1 and GIP by averting the degradation of
such enzyme, leading to a net antihyperglycemic
effect. Generally, DPP-4 inhibitors have no effect
on body weight. A number of DPP-4 inhibitors
like saxagliptin, sitagliptin, and vildagliptin are
available in the market. Table 11.2 includes the
details of those drugs. These drugs not only
reduce blood glucose and HbA1c level but may
have significant role in neuropeptide signaling by
increasing the action of neuropeptide Y and
growth hormone-releasing hormone. These
agents possibly may exert a beneficial effect by
averting cardiovascular complications in
DM. Several studies and ongoing projects are
164
continuing in this area (Badyal and Kaur 2008;
Seshadri and Kirubha 2009; Cox et al. 2010;
Deacon 2011; Babu 2012; Guedes et al. 2013;
Mkele 2013).
Sodium-Glucose Co-transporter 2
(SGLT) Inhibitor
The kidneys play a major role in the mainte-
nance of glucose levels in the blood mainly
through the reabsorption of glucose by glomeru-
lar filtration. In normal condition, almost all fil-
tered glucose (approximately 180 g/day) is
reabsorbed by the kidneys and returned to the
blood. Less than 1 % of glucose is excreted
through urine after reabsorption. Glucose is a
hydrophilic molecule and crosses the cell mem-
brane through facilitative or active transport
mechanism. In facilitative system, molecule
crosses the membrane through concentration
gradient manner, while in active transport sys-
tem, sodium co-transport system plays the main
role. Sodium-glucose co-transporters (SGLTs)
belong to the family of membrane proteins
which are involved in the uptake and transport
of glucose across the brush border membrane of
the epithelium of the intestine and membrane of
the proximal tubule of the kidneys. A number of
SGLTs exist but SGLT1 and SGLT2 are the two
most studied SGLT. SGLT2 is a low-affinity but
high ability glucose transporter mostly
expressed in the earlier segments (S1) of the
proximal tubule and minimally expressed in
other tissues, while SGLT1 is a high-affinity,
low-capacity glucose transporter present in
enterocytes of the small intestine and in the dis-
tal part (S2, S3) of the proximal tubule. SGLT2
is the principal glucose transported in the kid-
ney and accountable for high glucose reabsorp-
tion (more than 90 %), while SGLT1 absorbs the
remainder. After reabsorption through SGLTs,
glucose is reabsorbed, entering in the circula-
tion through facilitative glucose transporters
(GLUTs). In diabetic individual, hyperglycemia
leads to hyperfiltration, and when the capability
11 Management of Diabetes Mellitus
for glucose reabsorption reaches saturation, sur-
plus glucose is excreted through urine, leading
to glucosuria. Genetically inherited SGLT1
mutations cause osmotic diarrhea, malabsorp-
tion, and dehydration, while genetically inher-
ited mutations of SGLT2 are responsible for
renal glucosuria. But glucosuria due to mutation
of SGLT2 is not associated with any alteration
of blood glucose level, intravascular volume, or
function of the kidney (Rajesh et al. 2010;
Tahrani and Barnett 2010; Valentine 2012;
Fujita and Inagaki 2014; Thynne and Doogue
2014).
Inhibition of SGLT2 and increase in excretion
of glucose are a key therapeutic approach to man-
age T2DM. SGLT2 inhibitors reduce the level of
blood glucose by inhibiting the reabsorption of
filtered glucose and may cause glucosuria. These
drugs are also associated with caloric loss, thus
reducing body weight. Activity of SGLT2 inhibi-
tors is not related with the presence of insulin,
magnitude of insulin resistance, or impairment of
islet β-cell activity. The incidence of hypoglyce-
mic effect is also low with SGLT2 inhibitors.
These drugs can be used along with other oral
hypoglycemic agents and insulin. But the effi-
cacy of these drugs depends on normal glomeru-
lar filtration mechanism and quantity of drugs
reaching to the proximal tubule. Thus, in moder-
ate to severe renal impairment condition, SGLT2
inhibitors are ineffective and not recommended.
Though short-term trials showed that SGLT2
inhibitors are not related with a decline in renal
function, concerns have been raised about the
long-term effects of these drugs on inhibition of
tubular glucose uptake. SGLT2 inhibitors are
responsible for urinary net glucose losses of
20–70 g/day in dose-dependent manner, though
this varies with the degree of hyperglycemia.
Different SGLT2 inhibitors are tabulated in
Table 11.3 (Nair et al. 2010; Tahrani and Barnett
2010; Kim and Babu 2012; London New Drugs
Group 2012; Donnelly 2013; Fujita and Inagaki
2014; Neumiller 2014; Poole and Dungo 2014;
Poole and Prossler 2014; Thynne and Doogue
2014) (Fig. 11.5).
Pharmacological Treatment of DM 165

Table 11.3 Different SGLT2 inhibitors available for the treatment of T2DM
SGLT2 inhibitors Characteristics
Phlorizin A glucoside obtained from the bark of apple trees and found to inhibit SGLT1 and SGLT2. But
due to low bioavailability, lack of specificity, and adverse effects, this drug is not developed as
an antidiabetic agent
Dapagliflozin Competitive, reversible inhibitor of SGLT2. Marketed in the UK in 2012, US FDA given final
approval in 2014.
Once a day (2.5–10 mg as monotherapy), with or without food. Designated category D drug
High bioavailability, high plasma protein bound property
Metabolized in the liver via glucuronidation
Reduces HbA1c in type 2 diabetic patients
Can be used as monotherapy or along with metformin, sulfonylureas, or insulin
Risk of hypoglycemia when given along with sulfonylureas or insulin
Risk of genital and urinary tract infections, may due to induced glycosuria. Rapid weight loss
and tiredness. Risk of hypotension
Canagliflozin Taken before first meal of the day
Approved in the USA in 2013
Once a day (2.5–10 mg as monotherapy), with or without food. Designated category C drug
High bioavailability, high plasma protein bound property
Metabolized in the liver via glucuronidation
Reduces HbA1c in type 2 diabetic patients
Can be used as monotherapy or along with metformin, sulfonylureas, or insulin
Risk of hypoglycemia when given along with sulfonylureas or insulin
Risk of genital and urinary tract infections, hypotension, headache, and symptoms suggestive
of hypovolemia
Empagliflozin It is a highly specific SGLT2 inhibitor, with >2500-fold selectivity toward SGLT2 compared to
SGLT1
Approved by the US FDA in 2014. Dose: 10 or 25 mg once a day
Side effects: urinary tract infection, hepatic injury. Other possible side effects include
headache, drowsiness, weakness, confusion, irritability, hunger, sweating, kidney problems in
old age people, and increased cholesterol
Should not be given in patients with an eGFR below 60 ml/min/1.73 m2 or CrCl <60 ml/min
and in patients with ESRD or on dialysis
During clinical development, the drug is used with metformin and other drugs like
sulfonylureas, insulin, thiazolidinediones, and DPP-4 inhibitors
Ipragliflozin and Both drugs got its first approval in this indication in Japan in the world
tofogliflozin Used as monotherapy or along with metformin, pioglitazone, a sulfonylurea, a α-glucosidase
inhibitor, DPP-4 inhibitor, or nateglinide

Intestinal Lipase Inhibitors lipase inhibitor), is isolated from bacterium

The pancreas secretes enzyme lipase in response
to fat ingestion. Intestinal lipase inhibitors
decreased the lipase activity and reduce gastroin-
testinal absorption of fats. High-fat foods are often
related with increased caloric intake and weight
gain. Obesity is a key factor responsible for T2DM
(discussed in detail in Chap. 6). Orlistat is an
inhibitor of gastrointestinal lipase that attached to
the active site of enzyme lipase. Orlistat, a satu-
rated derivative of lipstatin (lipstatin is pancreatic
Streptomyces toxytricini. By inhibiting lipase, orli-
stat reduces hydrolysis of triglyceride, slows down
fat/lipid digestion, reduces plasma free fatty acids,
and is thus responsible for weight loss. Orlistat
also increases incretin production or modulates the
secretion of cytokines by adipocytes. Orlistat is
found effective in obese people with T2DM as
adjuvant therapy to reduce body weight and
improve glycemic control and lipid profile
(Hollander et al. 1998; Mancini and Halpern 2008;
Olszanecka-Glinianowicz et al. 2013) (Fig. 11.6).
166 11 Management of Diabetes Mellitus

Fig. 11.5 Glucose SGLT2 inhibitors

reabsorption in the Tubular lumen
Blood
kidney and site of
action of SGLT2
Glucose Glucose
inhibitors in the
proximal tubule GLUT2 Glucose

SGLT2
Na+ (S1 part of Na+ 3Na+
Proximal
tubule) 3Na+

Na+/K+
2K+
2K+ Pump

Glucose Glucose

GLUT2 Glucose

Na+ SGLT1
(S2, S3 Na+ 3Na+
part of
Proximal 3Na+
tubule)
Na+/K+
2K+ Pump 2K+

Non-pharmacological Treatment Diet or total calorie intake should be depended on

of DM
Pharmacological interventions to treat DM are
not sufficient. Non-pharmacological interven-
tions like exercise, nutrition therapy, and stress
managements are important to achieve an opti-
mum goal for DM. These approaches help to
treat diabetes efficiently, increase the activity of
several antidiabetic agents, and prevent diabetic
complications (Alwan 1994; Indian Council of
Medical Research 2005; Flower 2007; Bibu et al.
2011; Jain et al. 2011a, b; Kumar et al. 2013;
Everat et al. 2014).
Diet
the physical activity, nutritional condition, and
presence of glycosuria. The main principle of
diet is to control the body weight. The ideal body
weight can be estimated by using the formula
Ideal body weight = ( height in cm 100 ) ´ 0.9.
If body weight is found > 120 % of ideal body
weight, then the people will be considered as
overweight, and weight < 90 % of ideal body
weight is considered as underweight.
Total calorie intake in diabetic patient should
not be more than 500 kcal/day. Intake of carbohy-
drate should be about 55–60 %, fat 20–25 %, and
protein 10–15 % (0.8–1 g/kg of desirable body
weight) of total calorie intake.

Dietary intervention should be based upon the • Sugar, honey, jaggery, and sweet should be
individual’s nutritional requirements, personal avoided.
choices, habit, cultural preferences, and mental- • Processed refinery foods (maida-based prod-
ity, to guarantee that quality of life is optimized. ucts) should be restricted.
Non-pharmacological Treatment of DM 167

O
O O
S R2
NH

R1
S ulfonylureas

Sulfonylurea R1 R2
Tolbutamide - CH3 - (CH 2)3CH3

Chlorpropamide - Cl - (CH 2)2CH3

Acetohexamide - COCH 3

Glyburide O

Cl .
NH

OCH3

Glipizide O
.
HN NH

NH
H3C

Glimepride NH NH
H3C .
O . CH3
H3CH2C O

CH3 O

H3C O OH O H

NH O CH3 NH
H3C
N HO O
CH3

Repaglinide Nateglinide

Fig. 11.6 Chemical structure of different antidiabetic drugs

168 11 Management of Diabetes Mellitus

NH NH
NH NH
H3C
N NH NH2
H2N NH NH2
H3C

Biguanides Metformin

NH
H3C
S
S O
O
O
Pioglitazone
O N
O
H

Thiazolidinedione CH3
NH
N S
O
O

Rosiglitazone
-
S

CH3 OH
HO
O
N O N
HO OH
OH
HO
CH3

S aroglitazar
O Miglitol

Fig. 11.6 (continued)

Non-pharmacological Treatment of DM 169

OH
HN
HO

HO NH H3C
OH
HO O

OH
OH
O
O
OH
OH
O
HO O
Acarbose
OH
OH

OH
CH 3

HO O
HO
S
OH

Canagliflozin

OH
Cl O

HO O
HO
O
OH

Empagliflozin

Fig. 11.6 (continued)

170 11 Management of Diabetes Mellitus

Cl O CH 3

O
HO

HO OH

OH
Dapagliflozin

F
F
F
NH N F N
NH N
N
N
N O N
NH2 O
N F
F Sitagliptin
Basic structure of cyanopyrrolidines

HO OH

O N
N
H2N N N
NH
O
N NH2
O F
N
F
Saxagliptin Denagliptin
Vildagliptin

Fig. 11.6 (continued)

• Complex and high in fiber and carbohydrate
foods (fiber-rich foods – ragi, jowar, oats,
whole pulse, green leafy vegetable) are more
preferable.
• Cereals, mixed course gains, whole pulses,
salad, and soybeans need to be consumed.
• Sparingly use root and tuber food.
• Protein from vegetable sources is more
preferable.
• Low-fat milk and milk product, fish, and lean
meat are allowed to take.
• Saturated fat intake should not be exceeding
7–10 % of total caloric intake, but ghee and
butter are not preferred.
• Dietary cholesterol should not be exceeding
300 mg/day.
• Oil containing linoleic acid (n = 6) like oil
from ground nut, sesame, cotton seed, rice
Non-pharmacological Treatment of DM
bran, and safflower can be consumed along
with oil with α-linoleic acid (n = 3) like oil
from soya bean, mustard, and canola. More
than one edible oil is recommended.
• Whole fruit is recommended in divided serv-
ings; very sweet fruit/fruit juice should be
avoided.
• Fish (particularly fatty fish containing
omega-3 fatty acids and omega-3 linolenic
acid) can be given at least two servings/week,
which help to reduce lipid profile. It is also
good for diabetic individuals.
• Artificial sweeteners can be consumed in lim-
ited quantity except during pregnancy and lac-
tation. Nutritive sweeteners (sorbitol and
fructose) should be limited.
• Common salt of up to 2300 mg/day is permit-
ted. Restrict processed salty food.
• Avoid the use of alcohol; if used, it must be in
moderation.
• Meal should not be skipped.
Usually, consumption of proper food and main-
tenance of diet provide us adequate vitamin and
endogenous antioxidants. Thus, except pregnancy
and lactation or if diet is not maintained properly
routinely, vitamin, mineral, and antioxidants are
not required in people. Vitamins, minerals, and
antioxidants have the important role for manage-
ment of DM. Several clinical trials and prelimi-
nary reports suggested that vitamins (vitamin B,
C, D, E), minerals (chromium, manganese, cop-
per, zinc, potassium, magnesium, vanadium, sele-
nium), amino acids (carnitine, taurine), and
antioxidant (alpha-lipoic acid, gamma-linolenic
acid, coenzyme Q10) are beneficial for the man-
agement of T1DM, T2DM, or different diabetic
complications. But detailed research or more clini-
cal trials are warranted before introducing these in
the main course of diabetic treatment. Meals
should be evenly distributed throughout the day.
Proper timing of food and energy should be under-
lined, especially by those taking insulin.
171
Physical Activity
Exercise is a key remedial modality in the treat-
ment of both T1DM and T2DM. Exercise
improves insulin sensitivity, increases glucose
uptake, reduces the risk of hypertension, and
decreases body adiposity. Regular scheduled
brisk walk for 30–60 min is found helpful. Yoga
also promotes physical and mental health.
Before the starting of physical exercise, a patient
should undergo proper medical checkup to find
the presence of other diseases. Diabetic people
with coronary artery diseases, retinopathy, and
nephropathy should avoid weight lifting.
Regular physical activity offers beyond glyce-
mic control, reduced HbA1c, and reduced mor-
bidity and mortality. Physical activity also at
large prevents the developing type 2
DM. Exercise decreases blood pressure, choles-
terol, body weight, and risk of heart disease and
stroke. It also helpful to relieve stress and
depression, improve blood circulation, increase
strength of muscles and bones, and increase
quality of life.
Self-Management
Self-management is very important to control
and prevent DM.
• Periodic checkup for screening of DM or pre-
diabetes is essential.
• Patient with DM should regularly screen for
blood sugar level (may be self-monitoring)
and need to find the presence of diabetic
complications.
• Patient should lead to stress-free life.
Physiological innervations are essential in this
regard.
• Patient should strictly follow self-care
activities including diet and exercise
(Fig. 11.7).
172 11 Management of Diabetes Mellitus

Fig. 11.7 Approaches to

Random/Fasting/Postprandial
manage diabetes mellitus blood glocose

Normal Value near to Value with in

value diagnose DM diagnostic range

Perform OGTT and

Unlikely DM
HbA1c test Diabetes mellitus
No action required

IGT/IFG
Life style
modification T2DM T1DM
(excercise, diet, etc.)

Life style modification + Metformin

Insulin + Life
style modification
If target not achieve sulfonylurea can be use
in place of metformin or in combination

Insulin and other antidiabetic drugs can

be used to achieve proper glycemic control

Dailey MJ, Moran TH. Glucagon-like peptide 1 and appe-

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 Recent Developments in Diabetes
Therapy
Gene Therapy
Gene therapy is a newer approach in the twenty-
first century which developed through the advance-
ment of molecular biology and Human Genome
Project. It has emerged as a key future strategy to
cure both T1DM and T2DM. Gene therapy is
accomplished by introducing DNA into cells,
which can be carried out by several methods. Viral
vectors (recombinant viruses) and non-viral vec-
tors (naked DNA or DNA complexes) are mostly
used in such process. Gene therapy usually targets
the β cells of pancreatic islet or the insulin sensitiv-
ity toward the peripheral tissues. Introduction of
DNA into target cells artificially should be stable
and functional; it is also necessary that the target
cells should accept the new DNA properly for nat-
ural reproduction function. Usually, ex vivo engi-
neering and in vivo delivery methods are used in
gene therapy. In ex vivo method, a cell will be iso-
lated from the host and used as a transgene factory,
and genetic manipulation is carried out in a labora-
tory. Cell expansion may or may not be part of it.
This strategy is mostly employed in gene therapy.
On the other hand, in vivo gene transfer method
genetic modification is carried out in situ using
vector-mediated delivery of genetic material into
specific target organ. It is a difficult method due to
selection of gene delivery vehicle that becomes an
issue (Welsh 2000; Giannoukakis and Trucco
2003; Creusot and Fathman 2004; Bertolaso et al.
2010).
© Springer Science+Business Media Singapore 2016
S. Sen et al., Diabetes Mellitus in 21st Century, DOI 10.1007/978-981-10-1542-7_12
12
A number of gene therapy approaches are in
investigation to confer benefit against DM.
Cloning of the insulin gene found useful in this
regard. Some of these approaches are:
• Modify non-insulin-producing cells geneti-
cally to insulin-producing cells mainly β cell
which could be helpful for both T1DM and
T2DM. This could be achieved by using an
appropriate promoter and insulin gene
construct.
• In prediabetic patient genetical modification
of islet cell.
• Manipulate the β cell genetically so that these
islet cells can produce a protection factor for
them, which could be beneficial to avert auto-
immune destruction of β cell.
• Genetically modify human/pig islet cell before
introducing them in a diabetic patient. This
process can minimize poor grafting and rejec-
tion problem.
Islet Transplantation
Islet transplantation is considered as the most
impressive and advanced option to cure T1DM. In
the 1970s, several researchers reported about
their successful experiments involving islet trans-
plantation in animal and human. In the 1990s first
islet transplantation is reported in patients with
T1DM. Pancreatic islet transplantation can be
175
176
carried out mainly in two ways: (1) islet
autotransplantation and (2) islet allotransplanta-
tion. Islet autotransplantation is mainly carried
out to maintain insulin secretory function of islet
so as to reduce/eliminate the need of exogenous
insulin treatment after a total pancreatectomy. In
this technique after removal of the whole pan-
creas, islets are purified and transfused into the
patient’s liver through a catheter. Pancreatic islet
allotransplantation involves the transfer of puri-
fied, processed islets from the pancreas to a
patient after receiving them from a pancreas of
deceased organ donor. Usually, 400,000–500,000
islets were infused in per infusion and patients
topically receive two infusions in such proce-
dure. Currently, several potential sources to sup-
ply the healthy and proper islet cell before
administering them in patient are under investi-
gation. Propagating islet cell in in vitro culture
after obtaining them from a donor has emerged as
a key approach. But several researchers have
reported decline insulin production by the cul-
tured cells. Proper propagation of islet cell in
in vitro condition is another problem. Islet cell
from pigs is another option to obtain islet cell.
Though insertion of pig islet may initiate hyper-
acute rejection response as humans express anti-
bodies against a galactose α (1,3) galactose
residue which is available in pigs cells mostly.
Pig contains endogenous retrovirus which may
infect human host after transplantation – which is
another limitation for such transplantation.
Generation of stem cell from embryonic stem
cell might be a promising strategy, but these war-
rants more research. The effort is also made in a
direction to produce genetically engineered
insulin-producing cell from non-β cell. However,
attaining glucose-dependent insulin secretion is a
key limitation of this approach. Currently, islets
are transferred in the portal vasculature and the
liver. Islet embolization in the liver confers sev-
eral physiological benefits as the liver is the key
organ for insulin action and is physiologically
reliable with insulin release from the pancreas
directly in the portal vasculature. More than 750
islet transplants have been carried out through the
world in last few decades. Still, this strategy can
be used to cure T1DM and can be very useful for
12 Recent Developments in Diabetes Therapy
proper glycemic control and maintenance of
HbA1c value; the strategy is also helpful to pre-
vent life-threatening hypoglycemia. Currently,
allotransplants can be carried out with the per-
mission of US FDA in hospitals for clinical
research purpose. Still, more clinical research is
required before labeling them therapeutic. In
Canada, islet transplantation became designated
as “non-research” in 2001 (Juang 2004; Rother
and Harlan 2004; Merani and Shapiro 2006; Ong
et al. 2009; Bruni et al 2014; NDIC 2014).
Stem Cell Therapy
Success of islet cell transplant depends on the
availability of functional insulin-producing β cell
of the pancreas. Stem cell therapy emerged as a
key technique that involves replacement or sub-
stitution of lost or unhealthy cells from progeny
of multipotent or pluripotent cells. Both embry-
onic and adult stem cells can be used to generate
β cell or insulin-producing β cell to restore the
normal level of insulin. Embryonic stem cells
(ESCs) can be used to produce more than 200
cell types in defined culture conditions. Thus,
ESC is also considered as key insulin-producing
cell generation for diabetes treatment. Mouse,
monkey, and human ESCs were used by different
scientist to isolate insulin-positive cells isolated
using various protocols. Human ESCs are gener-
ated from the inner cell layer of the blastocyst. A
method has been developed to direct human
ESCs through a specific pathway to endoderm
and after that to pancreatic and islet precursor
cells. Precursor cells are found to produce full-
fledged β cells after transplantation in mice.
However, concern to cause malignant tumors is a
major limitation of this. Another problem in this
technique includes human ESC obtained from
fertilization which has religious, spiritual, and
ethical opposition to some extent. Human ESCs
are also dissimilar from transplant recipient in
immunology. Induced pluripotent stem cells are
developed by reprogramming the mouse fibro-
blasts to an undifferentiated condition similar to
embryonic stem cells, which can be the future
answer for the problem associated with ESC.
Diabetes “Vaccines”
Adult stem cells (ASCs) are more preferred as a
substitute for the human ESC. Source of adult
stem cell includes the pancreas, pancreatic duct,
fresh fetal tissues, and other non-pancreatic stem
cells (enterocytes, hepatocytes, cord blood stem
cells, bone marrow, etc.). The pancreatic duct can
provide islet progenitor stem cells that are viewed
as a source to produce insulin-producing islet
cell. For the treatment of type 1 DM, identifica-
tion and use of pancreatic stem cell or precursor
cell could have an important role. Fetal tissue is
considered as source of islet progenitor stem
cells after grafting fresh fetal pancreatic tissue of
human, purified islets and cultured islet. Stem
cell derived from hepatocyte can distinguish into
insulin-producing cells under the specific condi-
tion (like high-glucose culture) or through genetic
reprogramming program. Bone marrow is a type
of tissue located in the interior of bones and
includes hematopoietic and mesenchymal stem
cells and endothelial progenitor cells.
Hematopoietic stem cell derived from the bone
marrow can produce insulin secretary cell in
in vivo condition (Hussain and Theise 2004;
Sameer et al. 2006; Yang et al. 2006; Weir 2008;
McCall et al. 2010; Li and Ikehara 2013).
Diabetes “Vaccines”
Vaccination to prevent diabetes is a new concept
that has developed and is under research. Diabetes
vaccines mainly apply only to T1DM. T1DM is
an autoimmune disease where the β cell is
destroyed by the body’s own “killer” T cells.
Diabetes vaccines are primarily used to stop the
T cells from destroying the β cells of the pan-
creas. Research on animals shows highly satis-
factory result. Animal diabetes vaccines initiate
the generation of protective “regulatory T cells,”
which can protect the mice from developing
T1DM when transferred to other rodents.
Interleukin 10 is released from these cells which
is useful to identify them. Currently clinical trials
are going on in different diabetes vaccines (Dayan
2005).
Glutamic acid decarboxylase (GAD) is an
enzyme that catalyzes the formation of GABA
177
from glutamate. GAD exists in two isoforms:
GAD65 and GAD67. Both GAD are isolated in
the brain, while GAD67 is mainly expressed in
the pancreas. GAD is considered as a key antigen
in autoimmune T1DM. GAD65 and/or tyrosine
phosphatase-like protein (IA-2) is the autoanti-
bodies to insulin present in most of the type 1
diabetic patient. Diamyd Medical AB (Swedish
Company) invented a diabetes vaccine Diamyd
(alum-formulated GAD65-based vaccine for
T1DM). In Europe, phase III study with Diamyd
did not show any significant effect after 15
months of study. Thus, complete follow-up of the
European Phase III study and US Phase III study
was discontinued. But further research on
Diamyd is underway. Currently, research was ini-
tiated to find the effect of GAD when combined
with other drugs and effect of GAD in healthy
children who are at increased risk of developing
T1DM. Currently, phase II study of DIAPREV-IT
by a Swedish researcher is going on in 50 chil-
dren. This study found that the effects of Diamyd
vaccine in children are at high risk for T1DM. The
first result is expected at the end 2015.
DIABGAD-1, another study to find the combined
effect of Diamyd with other drugs, was started in
2013. In this study, Diamyd is combined with
high doses of vitamin D and ibuprofen, and the
effect of this combination will be evaluated in
children and adolescents newly diagnosed with
T1DM (Hinke 2008; Anonymous 2011; Diamyd
Medical 2014).
Diapep277, a 24-amino-acid peptide obtained
from human heat shock protein 60, was discov-
ered first in 1990. Animal studies showed that
Diapep277 modulates immunological attack on β
cell and trigger regulatory T cell. Phase II trial
demonstrated that DiaPep277 inhibits the decline
in stimulated C-peptide secretion, preserves
endogenous insulin secretion, and slows the pro-
gression of T1DM. Phase III trial of DiaPep277
showed that the vaccine preserves the function of
islet β cell and improved glycemic control in the
individual with T1DM. However, in September
2014 the US company Hyperion Therapeutics
terminated the Diapep277 development program
for newly diagnosed T1DM due to alleged mis-
conduct (Larsen et al. 2009; Apple 2012;
178
Goa et al. 2012; Goldfine et al. 2013; Anonymous
2014; Raz et al. 2014).
Possible New Drugs
Several new drugs are under investigation and
preclinical/clinical investigations are going on
to develop them as antidiabetic agent. Some of
them are (Johnson et al. 2002; Larsen et al.
2002; Wagman et al. 2004; Anonymous 2007;
Kim et al. 2013; Patel et al. 2013; Ito et al.
2014):
• β3 adrenoreceptor agonist: Produce remark-
able anti-obesity and antidiabetic effects in
rodents. They exhibit an increase in lipolysis
and induce waste of metabolic energy.
Example: SR-58611, TAK-677, L-796568.
• Protein tyrosine phosphatase 1B inhibitors:
Protein tyrosine phosphatase 1B acts as a
negative regulator of IR signal transduction
and leptin signaling. Thus, inhibitor of pro-
tein tyrosine phosphatase 1B could be useful
to treat T2DM. Example: Safranal,
JTT-551.
• Glycogen synthase kinase-3 (GSK-3) inhibi-
tors: GSK-3 regulates phosphorylation of gly-
cogen synthase and has an important role in
several aspects of insulin signaling. GSK-3
inhibitors may play an important role in the
management of DM in the future, for exam-
ple, CT 99021 and CT 20026.
• Interleukin-1 (IL-1) receptor antagonist: IL-1
is responsible for the impairment of insulin
secretion and causes apoptosis of β cell. Thus,
antagonist of IL-1 receptor could be helpful
for type 2 DM. Example: recombinant human
IL-1Ra, nanakinra.
• A randomized trial found that salsalate
(NSAID drug from salicylate group) improves
glycemia in type 2 diabetic patient and reduces
inflammatory mediators.
• GSK5182 an inverse agonist of estrogen-
related receptor γ produced hypoglycemic
effect by inhibition of hepatic glucose produc-
tion in rodents.
12 Recent Developments in Diabetes Therapy
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immune diabetes. Curr Opin Mol Ther. 2008;10:1–10.
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mellitus. Lancet. 2004;364:203–5.
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T. Pharmacological effects of JTT-551, a novel protein
tyrosine phosphatase 1b inhibitor, in diet-induced
obesity mice. Journal of Diabetes Research. 2014;
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phosphatase 1B inhibitors for diabetes. Nat Rev Drug
Discov. 2002;1:696–709.
Juang J. Islet transplantation: an update. Chang Gung
Med J. 2004;27:1–15.
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Kim DK, Gang GT, Ryu D, et al. Inverse agonist of
nuclear receptor ERRγ mediates antidiabetic effect
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Larsen CM, Faulenbach M, Vaag A. Sustained effects of
interleukin-1 receptor antagonist treatment in type 2
diabetes. Diabetes Care. 2009;32:1663–8.
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28-d treatment with L-796568, a novel beta(3)-adren-
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Li M, Ikehara S. Bone marrow stem cell as a potential
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Raz I, Ziegler AG, Linn T, et al. Treatment of recent-onset
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 Index

A GAD65, 120
Acanthosis nigricans, 79 genetic biomarkers, 119, 121
Acute metabolic complications glycosaminoglycans, 111
diabetic ketoacidosis, 69 HbA1c, 102
HHS, 69–70 ICAM-1 and VCAM-1, 113
hypoglycemia, 70–71 IgG, 112
lactic acidosis, 70 IgM, 112–113
Acute oral infections, 85 KIM-1, 110
Adult stem cells (ASCs), 177 laminin, 110
Advanced glycation end products, 62–64 L-PGDS, 114
Advanced oxidation protein products (AOPPs), 116 MCP-1, 114
Alzheimer’s disease, 95–96 microaneurysm, 118
American Diabetes Association, 13 α1 microglobulin, 111
2-aminoadipic acid (2-AAA), 115 microRNAs, 119, 120
Amputation, 73–74 microvesicles, 114–115, 121–122
Angiopoietin-Like Proteins (ANGPTLs), 110 NAG, 110
1,5-Anhydroglucitol (1,5-AG), 103 NGAL, 114
Anorexia, 76 nitrotyrosine, 117
Apolipoprotein, 113–114 8-OHdG, 117
Atherosclerosis, 74 OPG, 111–112
Autoimmune diseases, 96 oxidative stress-related biomarkers, 117
8-oxodG, 117
podocytes, 112
B pregnancy complications, 118
β3 adrenoreceptor agonist, 178 retinal macroglial activity, 118
Balanitis, 82 retinal vascular caliber and retinal thickness, 118
Biguanides, 159–160 skin autofluorescence, 116
Biomarkers TGF-β1, 109–110
2-AAA, 115 transferrin, 111
adipokines, 103, 104–108 Type IV collagen, 109
adiponectin gene therapy, 119 VEGF, 113, 122
1,5-AG, 103 vWF, 113
AGEs and RAGE, 115–116 Bladder dysfunction, 86
albumin and glycated albumin, 102 Bullosis diabeticorum, 79
ANGPTLs, 110 Burning mouth syndrome, 84–85
AOPPs, 116
apolipoprotein, 113–114
ceruloplasmin, 113 C
CRP, 109 Candida esophagitis, 77
cystatin C, 103, 109 Cardiomyopathy, 76
fetuin-A, 103 Cardiovascular complications
fibronectin, 110 atherosclerosis, 74
F2-IsoPs, 116–117 cardiomyopathy, 76
fructosamine, 103 congestive heart failure, 75
GAD, 112 hypertension, 74

© Springer Science+Business Media Singapore 2016 181

S. Sen et al., Diabetes Mellitus in 21st Century, DOI 10.1007/978-981-10-1542-7
182 Index

Cardiovascular complications (cont.) kidney complications (see Kidney complications)

myocardial infarction, 75 Madhumeha (see Madhumeha)
stroke, 74–75 non-pharmacological treatment
Catalase (CAT) gene, 61 diet, 166, 170–171
Celiac disease, 77 physical activity, 171
Central-type obesity, 46 self-management, 171, 172
Chronic hyperglycemia, 75 obesity, 50–51
Congenital rubella, 18 oral and dental complications (see Oral and dental
Congestive heart failure, 75 complications)
Constipation, 77 oral hypoglycemic agents (see Oral hypoglycemic
C-reactive protein (CRP), 109 agents)
Cytomegalovirus, 18 Prameha (see Prameha)
prediabetes, 19–20
in pregnancy, 41–43
D pregnancy-related complications (see Pregnancy-
Dementia, 95–96 related complications)
Dental caries, 84 prevalence
Depression, 95 in 2000 and 2030, world, 27, 28
Diabesity, 49 global projection, 28, 29
Diabetes mellitus (DM) IDF and WHO reports, 28
action of insulin, 17 IDF Diabetes Atlas, 27
acute metabolic complications (see Acute metabolic morbidity and mortality, 31–32
complications) in pregnancy, 31
autoimmune diseases, 96 T2DM in children, 30
β-cell function, 17 T1DM worldwide, 30
biomarkers (see Biomarkers) top ten countries, 28–30
cardiovascular complications (see Cardiovascular sexual complications (see Sexual complications)
complications) Siddha medicine, 129
CNS-related complications skin complications (see Skin complications)
Alzheimer’s disease and dementia, 95–96 symptoms and risk factors, 18, 19
depression, 95 T1DM (see Type 1 diabetes mellitus (T1DM))
Parkinson’s disease, 95 T2DM (see Type 2 diabetes mellitus (T2DM))
definition, 13 thyroid diseases, 96
diabetic neuropathy, 92–93 traditional medicines, 131–150
diagnostic criteria, 20, 21 Unani system of medicine, 129–130
digestive complications (see Digestive vision complications (see Vision complications)
complications) yoga and naturopathy, 130–131
disability, 96–97 Diabetic glomerulosclerosis, 85–86
drug/chemical induced, 18 Diabetic ketoacidosis, 69
economic impact, 32–33 Diapep277, 177
endocrinopathies, 18 Diarrhea, 77
exocrine pancreas diseases, 18 Digestive complications
foot complications, 73–74 anorexia, nausea, and vomiting, 76
GDM, 18 candida esophagitis, 77
genetic syndromes, 18 carcinoma of GIT, 78
homeopathy, 130 celiac disease, 77
immune-mediated diabetes, 18 constipation, 77
infections, 18 diarrhea, 77
infective disorders dysphagia, 76
bacteremia, 94 early satiety, 76
hepatitis C, 94 fatty liver, 78
malignant external otitis, 94 gallstones and cholecystitis, 78
respiratory tract infection, 95 gastric nerve and motility abnormalities, 76
surgical wound infection, 94 gastropathy and gastroparesis, 77–78
tuberculosis, 93–94 heartburn and chest pain, 76
injectable antidiabetic agents megasigmoid syndrome, 77
amylin analog, 154 pancreatitis, 78
GLP-1 analog, 154–157 Dipeptidyl peptidase-4 (DPP-4) inhibitors, 163–164
insulin, 154, 155 DM. See Diabetes mellitus (DM)
Index 183

DNA-dependent protein kinase (DNA-PK), 11 Glucose-stimulated insulin secretion (GSIS), 60

Dysphagia, 76 Glutamic acid decarboxylase (GAD), 112, 177
Glutamine fructose-6-phosphate amidotransferase
(GFAT), 66
E Glutathione peroxidase (GPx-1) gene, 61
Early satiety, 76 Glutathione-S-transferase (GST) polymorphisms, 61
Electron transport chain (ETC), 59–60 Glycogen synthase kinase-3
Embryonic stem cells (ESCs), 176–177 (GSK-3) inhibitors, 178
Endocrine pancreas, 1 Glycosaminoglycan (GAG), 111
GSK5182, 178

F
Fatty liver, 78 H
Ferredoxin reductase (FDXR), 59 HAPO Study Cooperative Research Group, 91
Fetal macrosomia, 89–90 Heartburn and chest pain, 76
Fetuin-A, 103 Hemoglobin A1c (HbA1C), 102
Fibronectin, 110 8-Hydroxydeoxyguanosine (8-OHdG), 117
F2-Isoprostanes (F2-IsoPs), 116–117 Hyperbilirubinemia, 91
Flavin adenine dinucleotide (FADH2), 59 Hyperglycemic hyperosmolar state
Foot complications (HHS), 69–70
gangrene, 73 Hypertension, 74
lower extremity amputation, 73–74 Hypomagnesemia, 91
ulcer, 73
Free fatty acid (FFA), 50–51
I
Immunoglobulin G (IgG), 112
G Immunoglobulin M (IgM), 112–113
Gallstones and cholecystitis, 78 Impaired glucose tolerance/Impaired fasting glycemia
Gangrene, 73 (IGT/IFG)
Gastric nerve and motility abnormalities, 76 clinical characteristic, 23–25
Gastrointestinal sensory–motor nerve abnormalities, 76 prediabetes, 19–20
Gastroparesis, 77–78 behavior therapy, 25–26
Gastropathy, 77–78 drug therapy, 26
Gestational diabetes mellitus (GDM), 13 follow-up, 26
complications, 37, 39, 40 healthy balanced food, 25
long-time consequences, 35 physical activity and weight
management loss, 25
blood glucose levels monitoring, 38 stop smoking, 25
diet, 38 prevalence, 31
drug treatment, 39–40 screening for, 25
exercise, 38–39 Insulin-dependent diabetes mellitus (IDDM). See Type 1
obstetric management, 40 diabetes mellitus (T1DM)
postpregnancy, 40–41 Interleukin-1 (IL-1) receptor antagonist, 178
maternal and perinatal complications, 35 International Diabetes Federation
pathophysiology, 36–37 (IDF), 27, 28
risk factors, 36 Irritation fibromas, 85
screening and diagnosis, 37, 38 Islet amyloid polypeptide (IAPP), 154
Gingivitis, 83, 84 Islets of Langerhans
Glitazones. See Thiazolidinediones amylin, 3, 5, 6
Glucagon-like peptide-1 (GLP-1) analog ghrelin production, 2
Glucose homeostasis glucagon, 2–4
blood glucose level, 8, 9 insulin, 3–6
gluconeogenesis, 7 pancreatic polypeptide, 4, 6
glycogenolysis, 7 somatostatin, 4, 6
insulin and glucose transport, 8–11
intestinal absorption, 7
nutritional factors, 8 J
obligated metabolic fuel, 7 Juvenileonset diabetes. See Type 1 diabetes mellitus
plasma glucose level, 7 (T1DM)
184 Index

K overweight
Kaposi’s sarcoma, 82 causes of, 47
Kidney complications dynamic phase, 46
bladder dysfunction, 86 fat distribution, 46
diabetic glomerulosclerosis, 85–86 obese static phase, 46
nephropathy, 86 pre-obese static phase, 46
pyelonephritis, 86–87 truncal obesity, 47
renal papillary necrosis, 86 prevalence, 45
urinary tract infection, 86 O-GlcNAcylation, 66
Kidney Injury Marker-1 (KIM-1), 110 Oral and dental complications
acute oral infections, 85
Burning mouth syndrome, 84–85
L candidiasis, 85
Lactic acidosis, 70 dental caries, 84
Lipocalin-type prostaglandin D2 synthase (L-PGDS), 114 oral lichen planus, 85
periodontal disease, 83–84
salivary gland dysfunction and xerostomia, 84
M test disturbance, 84–85
Madhumeha tooth loss/edentulousness, 84
diagnosis of, 128–129 traumatic ulcers and irritation fibromas, 85
etiology of, 128 Oral glucose tolerance test (OGTT), 20
pathogenesis, 128 Oral hypoglycemic agents
“Madhumeha kshaudrameha,” 125 biguanides, 159–160
Mammalian target of rapamycin (mTOR), 11 DPP-4 inhibitors, 163–164
Maternal hyperglycemia, 42 α-glucosidase inhibitors, 162–163
Megasigmoid syndrome, 77 intestinal lipase inhibitors, 165, 167–170
Meglitinides, 158–159 meglitinides, 158–159
Metformin, 26, 160 PPARα and PPARγ agonist, 161–162
Monocyte chemoattractant protein-1 (MCP-1), 114 SGLT2, 164–166
Myocardial infarction, 75 sulfonylureas, 157–158
thiazolidinediones, 160–161
Oral lichen planus, 85
N Osteoprotegerin (OPG), 111–112
N-acetylglucosaminidase (NAG), 110 Oxidative stress
Nausea, 76 antioxidant protection, 56–57
Neonatal deaths, 90 diseases, 57–58
Neonatal hypoglycemia, 90 and DM
Neutrophil gelatinase-associated lipocalin (NGAL), 114 AGE, 62–64
Nitric oxide synthase (NOS), 61 aldose reductase, 64
Noncommunicable diseases (NCDs), 27, 31 birth defect, 66
Nonesterified fatty acids (NEFAs), 50 cell signaling pathway, 65
Non-insulin-dependent diabetes mellitus (NIDDM). endogenous antioxidant enzymes, 60–61
See Type 2 diabetes mellitus (T2DM) endothelium-dependent relaxations, 64
Nuclear factor of activated T cells (NFAT), 59 hexosamine pathway, 66
ketosis, 62, 65–66
mitochondrial dysfunction, 59–60
O nutrient availability, 62
Obesity obesity, 61–62
and DM, 50–51 PKC activation, 64
energy-rich food intake, 45 PTEN, 62
impact on health, 48–49 ROS and cell signaling, 58–59
management of sleep restriction, 62, 63
anti-obesity drugs, 52 free radicals, 55–56
behavioral therapy, 52 8-Oxo-7,8-Dihydro-2′-Deoxyguanosine (8-oxodG), 117
diet and physical activity, 52
surgical innervations, 52, 53
measurements of P
body mass index, 47, 48 Pancreatic duct and accessory duct, 1
waist circumference, 47–48 Pancreatic enzyme, 1
Index 185

Pancreatic hormones ejaculatory problems, 87

amylin, 3, 5, 6 erectile dysfunction, 87
ghrelin production, 2 libido, 88
glucagon, 2–4 menstrual dysfunction, 88
insulin, 3–6 polycystic ovarian syndrome, 89
pancreatic polypeptide, 4, 6 retrograde ejaculation, 87
somatostatin, 4, 6 seminal fluid, 88
Parkinson’s disease, 95 testosterone deficiency, 88
Perinatal asphyxia, 91 vaginal infection and discomfort, 89
Periodontal disease, 83–84 Shoulder dystocia, 90
Periodontitis, 83 Siddha medicine, 129
Peripheral-type obesity, 46 Skin autofluorescence, 116
Phimosis, 82 Skin complications
Polycythemia, 91 acanthosis nigricans, 79
Prameha bacterial infection, 82
classification of, 126, 127 bullosis diabeticorum, 79
complications, 129 calciphylaxis, 79
diagnosis of, 128–129 diabetic dermopathy, 79
types, 127 diabetic thick skin, 79
Prediabetes, 19–20 eruptive xanthoma, 79–80
Preeclampsia, 91 erysipelas-like erythema, 80
Pregnancy-related complications fungal infections, 82–83
congenital malformations, 89 granuloma annulare, 80
fetal macrosomia, 89–90 Kaposi’s sarcoma, 82
hyperbilirubinemia, 91 lichen planus, 80
hypomagnesemia, 91 macro-and microangiopathy, 83
neonatal deaths, 90 necrobiosis lipoidica diabeticorum, 80
neonatal hypoglycemia, 90 perforating disorders, 80
perinatal asphyxia, 91 periungual telangiectasia, 80–81
polycythemia, 91 pigmented purpura, 81
preeclampsia, 91 psoriasis, 81
respiratory distress syndrome, 91 rubeosis faciei and red skin, 81
shoulder dystocia, 90 skin tags/acrochordons, 81
spontaneous abortion, 90 viral infections, 83
stillborn infant, 90 vitiligo, 81
Protein tyrosine phosphatase 1B inhibitors, 178 xanthelasma, 79
Pyelonephritis, 86–87 yellow nails, 82
Sodium-dependent glucose transporter family (SGLT), 8
Sodium-glucose co-transporter 2 (SGLT2) inhibitors,
R 164, 165
Rabson–Mendenhall syndrome, 17 Spontaneous abortion, 90
Rapamycin-insensitive companion of mTOR Stem cell therapy, 176–177
(RICTOR), 11 Stiff-man syndrome, 18
Reactive nitrogen species (RNS), 55 Stillborn infant, 90
Renal papillary necrosis, 86 Stroke, 74–75
Respiratory distress syndrome, 91 Sulfonylureas
adverse effects, 158
contraindication, 158
S history and chemistry, 157
Salivary gland dysfunction, 84 mechanism of action, 157, 158
Salivary hyperglycemia, 83 pharmacokinetic profile, 157
Sexual complications precautions, 158
amenorrhea, 88 uses, 158
anorgasmia, 89 Superoxide dismutase (SOD) family, 61
arousal and vaginal lubrication, 88
aspermia, 87–88
balanitis, 87 T
disturbed ovarian function, 89 T1DM. See Type 1 diabetes mellitus (T1DM)
dyspareunia, 89 T2DM. See Type 2 diabetes mellitus (T2DM)
186 Index

Thiazolidinediones genetics, 16
contraindication and precautions, 161 impaired insulin secretion, 16
history, 160 insulin resistance, 16–18
mechanism of action, 161, 162 fatty liver, 78
pharmacokinetic profile, 161 gene therapy, 175
uses, adverse effects, 161 genetic biomarkers, 119
Thyroid diseases, 96 HHS, 69
Transforming growth factor β1 (TGF-β1), 58, 109 hypoglycemia, 70
Traumatic ulcers, 85 insulin treatment, 154
Tricarboxylic acid (TCA) cycle, 59, 60 ketoacidosis, 15
Truncal obesity, 47 microvascular complications, 112
Type 1 diabetes mellitus (T1DM), 13 neonatal deaths, 90
analog of amylin, 154 obesity, 48–50
autoimmune disorder, 96 orlistat, 165
CRP, 109 pancreatic exocrine dysfunction, 78
depression, 91 periodontal diseases, 83
diabetic nephropathy, 85 physical activity, 171
diabetic retinopathy, 71 polycystic ovarian syndrome, 89
etiology and pathophysiology postpregnancy, 40
environmental factors, 15 pregnancy, 41
genetic, 14–15 screening and diagnostic criteria, 20
humoral and cellular islet autoimmunity, 15 sleep restriction, 62
viral infections, 15 symptoms and risk factors, 18, 19
fatty liver, 78 vs. T1DM, 17
fetal macrosomia, 90 testosterone deficiency, 88
gene therapy, 175 thyroid diseases, 96
genetic biomarkers, 119 troubled ovarian function, 89
hypoglycemia, 70 vitiligo, 82
insulin-induced glucose transport, 17, 18 yellow nails, 82
insulin treatment, 154
islet transplantation, 175
menstrual dysfunction, 88 U
microvascular complications, 112, 115 Ulcer, 73
neonatal deaths, 90 Urinary tract infection, 86
NGAL, 114
pancreatic exocrine dysfunction, 78
periodontal diseases, 83 V
physical activity, 171 Vascular endothelial growth factor
preeclampsia, 91 (VEGF), 113, 122
pregnancy, 41 Vascular smooth muscle cell (VSMC), 58
in pregnancy, 41–42 Vision complications
prevalence, 14 cataract, 71
skin complications diabetic retinopathy, 71
bullosis diabeticorum, 79 dry eye, 72
diabetic thick skin, 79 glaucoma, 71–72
vitiligo, 81 ischemic optic neuropathy, 72
symptoms and risk factors, 18, 19 keratopathy, 72
vs. T2DM, 17 macular edema, 72
thyroid diseases, 96 myopia, 72
traumatic ulcers and irritation fibromas, 85 optic atrophy, 73
troubled ovarian function, 89 retinitis pigmentosa, 72
vaccination, 177 Vomiting, 76
VEGF level, 113 von Willebrand Factor (vWF), 113
Type 2 diabetes mellitus (T2DM)
acanthosis nigricans, 79
analog of amylin, 154 X
calciphylaxis, 79 Xanthelasma, 79
CAT gene, 61 Xerostomia, 84
depression, 91
diabetic retinopathy, 71
etiology and pathophysiology Y
environmental factor, 16 Yellow nails, 82