PATHOPHYSIOLOGY &

MANAGEMENT OF DIABETES
MELLITUS
DR. EDWARD O. AMPORFUL FGCPharm, FPCPharm, Pharm D
CHIEF PHARMACIST
COCOA CLINIC.
CASE 1
Maame Yaa is 56 yr old diabetic (5 yrs) and hypertensive (6 yrs) on Tab.
Glimepiride 4mg daily, Tab. Metformin 1g twice daily, Tab. Amlodipine
10mg daily, Tab. Losartan 50mg daily. Her last HBA1c was 6.0% and
B.P. 120/70mmHg. Maame Yaa was rushed to a hospital after
complaints of weakness, fatigue.
On presentation RBS 24.9mmol/L, Ketones +++, B.P. 110/70mmHg
with severe dehydration. She has stopped taking her usual medicines
for diabetes and now taking Linagliptin 5mg daily upon advise of a
relation who is a health care provider abroad.
1. Describe Maame Yaa’s current condition
2. Suggest interventions for the management of Maame Yaa.
LEARNING OBJECTIVES
1.Understand the classification of diabetes
mellitus
2. Understand the pathophysiology of diabetes
mellitus
3. Understand the management options for
diabetes mellitus
4. Understand complications of diabetes
mellitus
PRESENTATION OUTLINE
 GENERAL OVERVIEW
 EPIDEMIOLOGY
 NORMAL PHYSIOLOGY
 PATHOPHYSIOLOGY
 GUIDELINES
 MANAGEMENT 1
 MANAGEMENT OF SPECIAL CASES-HPT + DM
 CONCLUSION
GENERAL OVERVIEW
Diabetes- 1°ly defined by the level of
hyperglycaemia giving rise
• to risk of microvascular damage (retinopathy,
nephropathy and neuropathy).
• reduced life expectancy, significant
morbidity due to specific diabetes related
microvascular complications,
• increased risk of macrovascular complications
(ischaemic heart disease, stroke and
peripheral vascular disease),
• diminished quality of life.
GENERAL OVERVIEW
 Complications of uncontrolled diabetes
include kidney failure, neuropathy, heart
disease (DCM), stroke, periodontal disease,
impaired immune response, blindness,
hypertension, amputations, and sexual
dysfunction.
Abnormalities associated with diabetic
cardiomyopathy.
FA, fatty acid; LV, left ventricular
DIABETIC FOOT ULCER
DIABETIC FOOT ULCER
EPIDEMIOLOGY
 2000- 171 million people
 2030- projected to increase to 366 million
 more than 70% live in low and middle income

countries,
 About 4mil DM in Ghana(NDA, 2012)
 rising killer disease

- one life every 8sec, one limb lost every 30

sec (WHO & IDF).
COST BURDEN OF DIABETES
 The American Diabetes Association (ADA)
estimated the national costs of diabetes in
the USA for 2002 to be $US 132 billion,
increasing to $US 192 billion in 2020
NORMAL PHYSIOLOGY
 Plasma glucose concentration
 - a function of

rate of glucose entering the circulation (glucose appearance)

vrs
rate of glucose removal from the circulation (glucose
disappearance).

 Circulating glucose derived from three sources:

-intestinal absorption during the fed state,
-glycogenolysis, and gluconeogenesis.
-major determinant of how quickly glucose appears in the
circulation during the fed state is the rate of gastric
emptying.
GLUCOREGULATORY HORMONES
 Glucoregulatory hormones include insulin,
glucagon, amylin, GLP-1, glucose-dependent
insulinotropic peptide (GIP), epinephrine,
cortisol, and growth hormone.
 Insulin & amylin- from the β-cells,
 Glucagon- from the α-cells of pancreas
 GLP-1 and GIP- from the L-cells of the
intestine.
GLUCOSE REGULATION-POST-FEEDING (NON-DIABETIC)

- Glucose removal into skeletal muscle and adipose

tissue driven mainly by insulin.
- At the same time, endogenous glucose production
is suppressed by
 1) the direct action of insulin, delivered via the
portal vein, on the liver, and
 2) the paracrine effect or direct communication
within the pancreas between the α- and β-cells,
which results in glucagon suppression
GLUCOSE REGULATION-POST-FEEDING (NON-DIABETIC)
POST-FEEDING (DIABETIC)
FASTING STATE (NON-DIABETIC)
FASTING STATE (DIABETIC)
Insulin Control Of Postprandial Gucose

 signals the cells of insulin-sensitive

peripheral tissues, primarily skeletal muscle,
to increase their uptake of glucose.
 acts on the liver to promote glycogenesis.
 Simultaneously inhibits glucagon secretion

from pancreatic α-cells, thus signalling the

 liver to stop producing glucose via

glycogenolysis and gluconeogenesis

Other Insulin Stimulators
 While glucose is the most potent stimulus
of insulin, other factors stimulate insulin
secretion :
 increased plasma concentrations of some

amino acids, especially arginine, leucine,

and lysine;
 GLP-1 and GIP released from the gut

following a meal;
 parasympathetic stimulation via the vagus

nerve.
AMYLIN
 Amylin, amino acid peptide,
 neuroendocrine hormone coexpressed and

cosecreted with insulin by pancreatic β-cells

in response to nutrient stimuli
 insulin-to-amylin molar ratio in the portal

circulation is approximately 50:1. Because of

hepatic extraction of insulin, this ratio falls to
~ 20:1 in the peripheral circulation.
AMYLIN
 In healthy adults, fasting plasma amylin
concentrations range from 4 to 8 pmol/L rising
as high as 25 pmol/L postprandially.
 In subjects with diabetes, amylin is deficient

in type 1 and impaired in type 2 diabetes.

α-CELL HORMONE: GLUCAGON

 Glucagon is a key catabolic hormone .

 Secreted from pancreatic α-cells.
 Glucagon opposes effects of insulin.
 Plays a major role in sustaining plasma

glucose during fasting conditions by

stimulating hepatic glucose production.
INCRETIN HORMONES GLP-1 AND GIP

 By the late 1960s, Perley and Kipnis and

others demonstrated that ingested food
caused a more potent release of insulin than
glucose infused intravenously.
INCRETIN HORMONES GLP-1 AND GIP

 This effect, termed the “incretin (Intestinal

seCRETion of Insulins) effect,” suggested
that signals from the gut are important in
the hormonal regulation of glucose
disappearance.

 Additionally, these hormonal signals from

the proximal gut seemed to help regulate
gastric emptying and gut motility.
PANCREAS α-cells
Glucagon•stimulates breakdown of
stored liver glycogen • Promotes
hepatic gluconeogenesis •promotes
hepatic ketogenesis
PANCREAS β-cells
Insulin • Affects glucose metabolism
and storage of ingested nutrients•
Promotes glucose uptake by cells •
Suppresses postprandial glucagon
secretion • Promotes protein and fat
synthesis • Promotes use of glucose as
an energy source
INTESTINE L-cells
GLP-1 • Enhances glucose-
dependent insulin secretion •
Suppresses postprandial glucagon
secretion • Slows gastric emptying •
Reduces food intake and body
weight
PANCREAS β-cells
Amylin • Suppresses postprandial
glucagon secretion • Slows gastric
emptying • Reduces food intake and
body weight
PATHOPHYSIOLOGY
 Diabetes is the result of imbalances between
glucoregulatory hormones leading to
hyperlycaemia.
 Mono-hormonal concept 1920
 Bi-hormonal concept 1950
 Multi-hormonal concept 1970
CLASSIFICATION OF DIABETES
 type 1 diabetes
 type 2 diabetes
 others, e.g., genetic defects( β-cell

function, in insulin action, diseases of the

exocrine pancreas (such as cystic fibrosis),
and drug or chemical-induced (such as Rx
of AIDS or after organ transplantation)
 ● gestational diabetes mellitus (GDM)
 MODY
TYPE 1 DM
 autoimmune-mediated destruction of
pancreatic β–cells= deficiency in insulin= deficiency in
the other co-secreted and β-cell hormone, amylin.

Effect

 Increase in postprandial glucose concentrations due

to lack of insulin stimulated glucose disappearance,
poorly regulated hepatic glucose production, and
increased or abnormal gastric emptying following a
meal.
TYPE 2 DM
 postprandial β-cell action becomes abnormal,
as evidenced by the loss of immediate insulin
response to a meal.
 Peripheral insulin resistance
 Progressive β-cell failure and decreased

availability of insulin, amylin, and GLP-1

contribute to the clinical picture of
hyperglycemia in diabetes.
TYPICAL FEATURES OF TYPE 1 & TYPE 2 DIABETES
MELLITUS
Type 1 diabetes Type 2 diabetes
If young onset, always obese. Rare
Young patient < 30 yrs pre adolescence

Thin patient Obese (85% of cases)

Family of history of T2DM (45 -

80% cases) High-risk ethnic group
Family history absent or of type (African-American, Hispanic, or
1 DM Native American decent)

Features of metabolic syndrome:

(hypertension,
No features of insulin resistance hypercholesterolaemia, acanthosis
(although can be overweight) nigricans, NAFLD, PCOS)

Frequent ketosis and severe Mild DKA possible; 33% with

acidosis ketonuria

C-peptide low C-peptide higher or recovers

Two or more +ve antibodies (anti-May have low positive anti-GAD as

GAD, anti-IA2, anti-ICA) additional risk

Auto-immune absolute lack of insulin resistance, insufficient

insulin ICA 85% of cases production of insulin

Acute onset of symptoms More gradual in onset

GESTATIONAL DIABETES
 form of insulin resistance in which the onset
or initial recognition of impaired glucose
tolerance occurs during pregnancy.
 combination of anti-insulin hormones

secreted by the placenta, increased caloric

intake, and decreased exercise can
overwhelm the mother's ability to naturally
regulate glucose metabolism.
MATURITY ONSET DIABETS OF THE YOUNG (MODY)

 a heterogeneous group of disorders that lead to

β-cell dysfunction.
 rare, 1%–2% of all diabetes.
 often misdiagnosed as T1DM or T2DM, due to
difficulty in separating MODY fro these two forms.
 diagnosis allows appropriate individualized care,
depending on the genetic etiology, and allows
follow-ups in family members.
SIGNS & SYMPTOMS
 polyuria (excessive urination),
 polydipsia (excessive thirst), and
 polyphagia (extreme hunger).
 unusual weight loss, fatigue, irritability.
 frequent skin, gum, or bladder infections

( impaired immune response).

 Blurred vision and tingling or numbness in

the hands and feet are also common.

DIAGNOSIS
CRITERIA FOR DM SCREENING
1. Adults overweight (BMI 25 kg/m2) with one or more additional risk factors:

•physical inactivity •first-degree relative with diabetes •high-risk race/ethnicity

(e.g., African American, Latino, Native American, Asian American, Pacific
Islander)
•women who delivered a baby weighing .9 lb or who were diagnosed with
GDM • hypertension (blood pressure $140/90 mmHg or on therapy for
hypertension) •HDL cholesterol level ,35 mg/dL (0.90 mmol/L) and/or a
triglyceride level .250 mg/dL
(2.82 mmol/L)
•women with PCOS •A1C $5.7%, IGT, or IFG on previous testing • history of CVD
other clinical conditions associated with insulin resistance (e.g., severe obesity,
acanthosis nigricans) • Central obesity: abdominal waist circumference greater
than 77cm (35 inches) in women; greater
than 88cm (40 inches) in men
2. In the absence of the above criteria, testing for diabetes should begin at age
45 years

3. If results are normal, testing should be repeated at least at 3-year intervals,

with consideration of more-frequent testing depending on initial results (e.g.,
those with prediabetes should be tested yearly) and risk status
Criteria for testing for diabetes in
asymptomatic adult individuals
1. Adults overweight (BMI 25 kg/m2) with one or more additional risk factors:

•physical inactivity •first-degree relative with diabetes •high-risk race/ethnicity

(e.g., African American, Latino, Native American, Asian American, Pacific
Islander)
•women who delivered a baby weighing .9 lb or who were diagnosed with
GDM • hypertension (blood pressure $140/90 mmHg or on therapy for
hypertension) •HDL cholesterol level ,35 mg/dL (0.90 mmol/L) and/or a
triglyceride level .250 mg/dL
(2.82 mmol/L)
•women with PCOS •A1C $5.7%, IGT, or IFG on previous testing • history of CVD
other clinical conditions associated with insulin resistance (e.g., severe obesity,
acanthosis nigricans) • Central obesity: abdominal waist circumference greater
than 77cm (35 inches) in women; greater
than 88cm (40 inches) in men
2. In the absence of the above criteria, testing for diabetes should begin at age
45 years

3. If results are normal, testing should be repeated at least at 3-year intervals,

with consideration of more-frequent testing depending on initial results (e.g.,
those with prediabetes should be tested yearly) and risk status
CORRELATION OF A1C & AVERAGE
GLUCOSE
SCREENING FOR AND DIAGNOSIS OF
GDM
MANAGEMENT
Objectives:
 To relieve symptoms
 To correct associated health problems

 To reduce morbidity, mortality and economic costs of

diabetes
• To prevent acute and long-term complications
• To monitor the development of complications and to

provide timely intervention

• To improve the quality of life and productivity of the
individual with diabetes
Multi-disciplinary (doctors, pharmacists, nurses, dietitian ,
foot care experts)
NON-P’COLOGICAL & P’COLOGICAL

Non-pharmacological
 Education (DSME, SMBG)
 Diet- low glycaemic index preferable to high

glycaemic index
 Exercise
 BMI (≤ 24kg/m²)
ACTION OF PLOYPHENOL-RICH COCOA
DIET THERAPY
 ensuring weight control
 providing nutritional requirements
 allowing good glycaemic control with blood
glucose levels as close to normal as possible
 correcting associated blood lipid abnormalities
 ensuring consistency and compatibility with other
forms of treatment (e.g. oral agents or insulin).
DIET THERAPY
 Dietary fat should provide 25-35% of total intake of calories
with saturated fat intake ≤ 10% of total energy. Cholesterol
consumption ≤300 mg/day.
 Protein intake can range between 10-15% total energy (0.8-1
g/kg of desirable body weight).
 Protein from both animal and vegetable sources.
 Carbohydrates to provide 50-60% of total caloric content of
the diet.
 Reduce salt intake esply if hpt and those with nephropathy
 Moderate use of artificial sweeteners. Nutritive sweeteners
(sorbital and fructose) should be restricted.
 Reduce intake of alcohol
 A1C 6.5 – 7.5%** A1C 7.6 – 9.0% A1C > 9.0%
Drug Naive Under Treatment

Symptoms No Symptoms

Monotherapy Dual Therapy 8

MET † DPP4 1 GLP-1 TZD 2 AGI 3 GLP-1 or DPP4 1 GLP-1
or DPP4 1
*** MET + or TZD 2 INSULIN ± SU 7 INSULIN
2 - 3 Mos. ± Other ± Other
MET + TZD 2
SU or Glinide 4,5 Agent(s) 6 Agent(s) 6
Dual Therapy
GLP-1
± TZD 2
GLP-1 or DPP4 1 2 - 3 Mos.*** or DPP4 1

MET + TZD 2 *
May not be appropriate for all patients
Triple Therapy 9
5
**
For patients with diabetes and A1C < 6.5%,
Glinide or SU pharmacologic Rx may be considered
GLP-1 ***
If A1C goal not achieved safely
TZD + GLP-1 or DPP4 1 + TZD 2
or DPP4 1 † Preferred initial agent
Colesevelam 1 DPP4 if  PPG and  FPG or GLP-1 if  PPG
MET + GLP-1 AACE/ACE Algorithm for Glycemic
MET + 2 TZD if metabolic syndrome and/or
3 Control Committee
AGI or DPP4 1 nonalcoholic fatty liver disease (NAFLD)
+ SU 7
Cochairpersons: 3 AGI if  PPG
2 - 3 Mos.*** TZD 2 Helena W. Rodbard, MD, FACP, MACE 4 Glinide if  PPG or SU if  FPG
Paul S. Jellinger, MD, MACE
Triple Therapy 5 Low-dose secretagogue recommended
*** Zachary T. Bloomgarden, MD, FACE 6 a) Discontinue insulin
2 - 3 Mos. Jaime A. Davidson, MD, FACP, MACE secretagogue
TZD 2 Daniel Einhorn, MD, FACP, FACE with multidose insulin
MET + Alan J. Garber, MD, PhD, FACE b) Can use pramlintide
GLP-1 or + James R. Gavin III, MD, PhD with prandial insulin
DPP4 1 INSULIN George Grunberger, MD, FACP, FACE
Glinide or SU 4,7 Yehuda Handelsman, MD, FACP, FACE
7 Decrease secretagogue by 50% when added
*** ± Other to GLP-1 or DPP-4
2 - 3 Mos. Edward S. Horton, MD, FACE
Agent(s) 6 Harold Lebovitz, MD, FACE 8 If A1C < 8.5%, combination Rx with agents
Philip Levy, MD, MACE that cause hypoglycemia should be used with
Etie S. Moghissi, MD, FACP, FACE caution
INSULIN
Stanley S. Schwartz, MD, FACE 9 If A1C > 8.5%, in patients on Dual Therapy,
± Other insulin should be considered
Agent(s) 6
Available at www.aace.com/pub
© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE
Dyslipidemia/lipid management
 No overt CVD, LDL target 100mg/dL (2.6mmol/L).
 overt CVD, a LDL target 70 mg/dL (1.8 mmol/L),
 If drug-treated patients do not reach the above
targets on maximal tolerated
 statin therapy, a reduction in LDL cholesterol
of ;30–40% from baseline is an alternative
therapeutic goal.
 Triglycerides levels ,150 mg/dL (1.7 mmol/L) and
HDL cholesterol 40 mg/dL (1.0 mmol/L) in men
and 50 mg/dL (1.3 mmol/L) in women, are
desirable
HYPERTENSION & DIABETES-THE GAPS

British HTN Guidelines 2011

 Urine strip test for blood and protein
 Blood electrolytes and creatinine, and eGFR
 Blood glucose
 Serum total and HDL cholesterol
 12 lead electrocardiogram.
DIABETES AND HYPERTENSION
 BP goal < 130/80
1. Ace-Is (or ARB).
2. Thiazide diuretic or CCB (avoid β-blockers alone or in
combination with Thiazides
DM with Nephropathy (alb:Cr≥2.0mg/mmol male, ≥ 2.8mg/mmol
female)
3. ACE-Is or ARB
4. Add Thiazide, or β₁-blocker, CCB
DM without Nephropathy (alb:Cr < 2.0mg/mmol male, 2.8mg/mmol
female)
5. ACE-I, ARB, Dihydropyridine CCB, Thiazide diuretic
6. Combination therapy
DEFINITIONS OF ABNORMALITIES IN ALBUMIN
EXCRETION

CATEGORY SPOT COLLECTION (µg/mg creatinine)

Normal < 30

Microalbuminuria 30 - 299

Macro (clinical)-
albuminuria ≥ 300
DIABETIC CARDIOMYOPATHY
 DM counters notion that the increase in
cardiovascular mortality is the result of accelerated
atherosclerosis.
 DM increases the risk for cardiac dysfunction and

heart failure independently of other risk factors

such as CAD and hypertension.
 Diabetic cardiomyopathy (DCM) is a well

characterized clinical disease manifested by

structural, functional, and metabolic changes.
(Heart metab. 2009)
Abnormalities associated with diabetic
cardiomyopathy.
FA, fatty acid; LV, left ventricular
 Diabetes in Pregnancy
Management of GDM:
 Lifestyle change is an essential component of
management of GDM and may suffice for the
treatment of many women. Medications should
be added to achieve glycemic targets. A
 Insulin is the preferred medication for treating
hyperglycemia in GDM as it does not cross the
placenta to a measurable extent. Metformin
and glyburide may be used, but both cross the
placenta to the fetus, with metformin likely
crossing to a greater extent than glyburide. All
oral agents lack long-term safety data. A
Management of Diabetes in Pregnancy:
Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S137-S143
RECAP
 GENERAL OVERVIEW
 EPIDEMIOLOGY
 NORMAL PHYSIOLOGY
 PATHOPHYSIOLOGY
 GUIDELINES
 MANAGEMENT 1
 MANAGEMENT OF SPECIAL CASES-HPT + DM
 CONCLUSION
 Our best bet in the fight against diabetes
mellitus is empowering health care at the
primary level (community).
 Pharmacists are clearly well positioned to

achieve this goal.

CASE 2
Mr. Patrick Nuamah, a 45 yr old man presented at the
Community Pharmacy at a very resource-challenged setting at
about 10p.m. Even though it was his turn to be seen, Mr.
Nuamah said he wanted a private discussion with the
Pharmacist. He complained excessive thirst, pangs of hunger,
frequent passing of urine, general bodily weakness and reduced
sexual appetite for about three months now. He is neither a
known diabetic or hypertensive.
His last food intake was about 2 hours ago.
The vitals at the Pharmacy:
RBS 17.5mmol/L, B.P. 128/72mmHg P 78bpm, T 36.8°C
RDT negative for malaria, Hb 15.8g/dL Wt 82kg Ht 1.72m
Suggest interventions for the care of Mr. Nuamah
ATHANK YOU.