UNIT - 2

CLASSIFICATION AND PATHOGENESIS

OF DIABETES MELLITUS

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 LEARNING OBJECTIVES OF THIS MODULE
• Be able to classify diabetes based on the
pathogenesis (etiology)
• Describe the role of endocrine pancreas in glucose
homeostasis.
• Understand the autoimmune mediated pathogenesis
the of type 1 Diabetes
• Understand the role of the various factors in the
pathogeneses of type 2 Diabetes

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 Diabetes Mellitus (DM)
Introduction
• Diabetes Mellitus is a metabolic disorder characterized by
persistent hyperglycemia
• Glucose level in the blood is controlled by several hormones
• Insulin secreted by beta-cells of Islet of Langerhans of
pancreas is the major hormone which controls the level of
glucose in blood
• Diabetes mellitus results either from an inadequate
secretion of insulin, an inadequate response of target cell to
insulin or combination of these factors
• Several other mechanisms including the glucagon level,
hepatic glucose production, renal glucose reabsorption and
the incretin hormones play significant role in the
pathogenesis particularly of type two diabetes
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 The Pancreas and Glucose Homeostasis

07/08/2023 Essential Endocrinology and Diabetes,6th Edition 4

 Islets of Langerhans
1. β-cells: Synthesize Insulin
2. α-cells: producing glucagon,
3. δ-cells: producing somatostatin,
4. ε-cells: producing ghrelin and
5. pancreatic polypeptide (PP) cells: producing
pancreatic polypeptide.
• The β-cells are the most numerous, tend to
be located more centrally in islet structures
and are surrounded by the other cell types.
Characteristic Biphasic release of insulin

Essential Endocrinology and Diabetes,6th Edition

Regulation of blood glucose concentration

Essential Endocrinology and Diabetes,6th Edition

MAJOR INSULIN ACTION IN GLUCOSE HOMEOSTASIS
 Normal insulin action in different human tissues :

Muscle tissue  glucose uptake and utilization

Liver  glycogen storage, glycolysis
 glycogenolysis, gluconeogenesis

Fat tissue  synthesis,  lipolysis (ketogenesis)

 The plasma glucose concentration is determined by a
balance between glucose entry from the gastrointestinal
tract and hepatic glucose production Vs tissue glucose
uptake and metabolism

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DM is classified into four general categories

Is based on the etiology (pathogenesis) not the treatment type

or age of onset:
Type 1 diabetes : due to B-cell destruction, usually leading to
absolute insulin deficiency
Type 2 diabetes : results from a progressive insulin secretory
defect on the background of insulin resistance
Gestational diabetes mellitus (GDM) : hyperglycemia
diagnosed in the second or third trimester of pregnancy that is not
clearly overt diabetes
Specific types of diabetes : DM due to specific causes e.g. drug
(such as steroid induced DM)
9
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 Spectrum of glucose homeostasis and diabetes
mellitus (DM.

HPIM 19th edition

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 CLASSIFICATION OF DM IN AN INDIVIDUAL PATIENT

Type 1 DM
(1) onset of disease prior to age
30 years;
(2) lean body habitus;
(3) requirement of insulin as the
initial therapy;
(4) propensity to develop
ketoacidosis; and
(5) an increased risk of other
autoimmune disorders such as
autoimmune thyroid disease,
adrenal insufficiency, pernicious
anemia, celiac disease, and
vitiligo.
Type 2 DM
(1) Onset of disease after the age
of 30 years;
(2) are usually overweight or
obese (up to 80%, but elderly
individuals may be lean);
(3) may not require insulin
therapy initially; and
(4) may have associated
conditions such as insulin
resistance, hypertension,
cardiovascular disease,
dyslipidemia, or PCOS.

07/08/2023 Harrison’s Principles of Internal Medicine 19th edition, page 2407 11

CLASSIFICATION OF DM IN AN INDIVIDUAL PATIENT…
• Some patients cannot be clearly classified as having
either type 1 or type 2 DM.
• Exception to the above guideline happens frequently
i.e. Young people developing Type 2 DM and Older
individuals developing Type 1 DM.
• Also presentation with diabetic ketoacidosis is not
necessarily limited to type 1 DM.
• Hence difficulties in diagnosis may occur in children,
adolescents, and adults, with the true diagnosis
becoming more obvious over time.

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 PATHOGENESIS OF DIABETES MELLITUS

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I. Pathogenesis of Type 1 Diabetes Mellitus
• It is characterized by loss of the insulin producing
pancreatic beta-cells of islet of Langerhans
• Sensitivity and responsiveness to insulin are usually
normal
• Type 1 DM accounts for less than 10% of the general
diabetic population globally
• Type 1 DM affects children and adolescents
predominantly but can also occur in adults
• Loss of beta-cells leading to Type 1 DM is caused by
an autoimmune destruction i.e. antibodies directed
against insulin and Islet proteins
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 I. Pathogenesis of Type 1 DM….
• ~ 85% of T1DM patients have circulating islet cell antibodies
 Majority also have detectable anti-insulin
antibodies
• Most islet cell antibodies are directed against glutamic acid
decarboxylase (GAD) within pancreatic beta cells
• Three main factors are involved in type 1 DM pathogenesis
a) Genetic predisposition
b) Triggering environmental factor(s)
c) Development and progression of auto-Immunity
• Chronic autoimmune disorder occurring in genetically
susceptible individuals
– May be precipitated by environmental factors
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 I. Pathogenesis of Type 1 DM….
• Immune system is triggered to develop an autoimmune
response against
– Altered pancreatic beta cell antigens
– Molecules in beta cells that resemble a viral protein
 Is a slow T-cell mediated Auto-immune disease
 Destruction of the insulin secreting cell in the
pancreatic islets takes place over many years
 The pathological changes in the pre-diabetic
pancreas in Type 1 DM is characterized by
Insulitis which is the infiltration of Islet with
mono-nuclear cells containing activated
macrophages, helper cytotoxic T lymphocytes,
Natural Killer cells, B-lymphocytes
Models for Pathogenesis of T1DM

van Belle TL, et al. Physiol Rev. 2011;91:79-118.

II. Pathogenesis of Type 2 Diabetes Mellitus
• Type 2 DM is a heterogeneous disorder
• It encompasses a range of disorders with the common
phenotype of hyperglycemia.
• Accounts for more than 90% of diabetic cases in many
populations.
• It is characterized by impaired insulin secretion,
insulin resistance, increased hepatic glucose
production and abnormal fat metabolism.
• Insulin resistance is believed to be an early defect and
a root cause in Type 2 DM
• At the time of diagnosis, both impaired insulin
secretion and insulin resistance are already established.
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II. Pathogenesis of Type 2 DM……..
• Insulin resistance may be the result of genetic factors,
obesity, decreased physical activity or glucose toxicity
• Insulin resistance in the liver, muscle, and adipose tissue
leads to
 increased hepatic glucose production
 decreased glucose uptake in peripheral tissues
 increased lipolysis
• Several other important factors play significant role in the
pathogenesis of type 2 DM including abnormalities involving
the glucagon and incretin levels and effects
• There is no evidence of immune activation in type 2 DM

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 ACE/SLK/

Insulin resistance is a core defect in Type 2 DM 06/27261/1

> 90% of Type 2

diabetes patients
are insulin resistant

Genetic factors Environmental factors

• Family history • Age

• Ethnicity • Diet
• Obesity
• Lack of exercise

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 Insulin Resistance and Type 2 DM:
Causes and Associated Conditions

Physical
Central Obesity Inactivity Aging
Lipotoxicity

Geneticss Hormones
Medications
INSULIN
RESISTANCE

Hyperglycemia
Glucotoxicity Polycystic
Ovary Syndrome

Hypertension Atherosclerosis
Dyslipidemia
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 Type 2 DM is progressive and a continuum

• Insulin resistance leads to a compensatory increase in insulin

secretion by the β-cells of the pancreas (hyperinsulinaemia)
in order to achieve normoglycemia
• β-cell function eventually starts to decline, resulting in impaired
glucose tolerance (IGT) and Type 2 DM
• The -cells are also damaged by lipotoxicity and glucotoxicity.
• Mean β-cell function is < 50% at the diagnosis of Type 2 DM, and
keeps deteriorating over the years as seen in the United Kingdom
Prospective Diabetes Study (UKPDS)

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 ACE/SLK/
06/27261/1

At the time of diagnosis -cell function is already significantly reduced

100

80 Start of treatment
β-cell function (%)

60

40
50% β-cell function at
diagnosis

20 p < 0.0001

0
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6
Time (years)
UK Prospective Diabetes Study Group. Diabetes 1995; 44: 1249–1258.

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 ACE/SLK/
06/27261/1

The progressive nature of Type 2 DM

Normal Impaired Type 2 diabetes

glucose
tolerance
Insulin Microvascular complications
sensitive
Hypergly-
caemia

Normal
insulin
secretion Insulin
resistant
Normogly-
caemia β-cell
exhaustion

Fasting plasma glucose Insulin Insulin secretion

sensitivity
Adapted from DeFronzo R. Diabetes 1998; 37: 667–687.
Groop LC. In: Leslie RDS, Ed. Molecular pathogenesis of diabetes mellitus. Karger; 1997; 22: 131–156.
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 A range of Beta-cell functional abnormalities in Type 2 DM

 The normal pulsed oscillatory Mixed Normal subjects

meal
release of insulin is impaired * * Type 2 diabetics

 Pro-insulin levels are 500

increased 400
 The first-phase insulin

(pmol/L)
Insulin
300
response is essentially absent
 Slow and blunted second- 200

phase insulin response 100

0
 Progressive loss of beta-cell 0 60 120 180
functional mass Time (min)

*p<0.05 between groups.

Buchanan TA. Clin Ther. 2003;25(suppl B):B32–B46; Polonsky KS et al. N Engl J Med. 1988;318:1231–1239;
Quddusi S et al. Diabetes Care. 2003;26:791–798; Porte D Jr, Kahn SE. Diabetes. 2001;50(suppl 1):S160–S163;
Figure adapted from Vilsbøll T et al. Diabetes. 2001;50:609–613. 26
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 Other pathophysiologic changes in type 2 DM
• Decreased incretin effect
– Effect of food on secretion of GIT hormones mainly GLP-1 and GIP
which facilitate insulin secretion. This response is also defective in
Type 2 DM
• Altered glucagon-insulin dynamics in response to meals
– Delayed and suppressed insulin response and failed normal
postprandial decline in glucagon concentrations
– Insulin is not sufficient to drive glucose uptake in the body tissue
and the increased glucagon and decreased insulin cause the liver to
inappropriately release glucose into the blood.
– The resultant effect is fasting hyperglycemia or increasing
postprandial glucose
• Increased renal glucose re-absorption
– Increased SGLT-2 expression and activity in renal epithelial cells
from patients with DM compared with normoglycemic individuals
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 Insulin and Glucagon Dynamics in Response to Meals Are Abnormal in
Type 2 Diabetes
360 Meal
330
300
Glucose
270
(mg %) Type 2 diabetes
240
110 Normal subjects
80
120
Insulin 90
(µU/mL) 60
30 Delayed/depressed
0 insulin response

140 Nonsuppressed glucagon

130
Glucagon 120
(pg/mL) 110
100
90

-60 0 60 120 180 240 Time (min)

Normal subjects, n=11; Type 2 diabetes, n=12. 28
Adapted from Mü ller WA et al. N Engl J Med. 1970;283:109–115. 07/08/2023
 SUMMARY OF PATHOGENESIS OF HYPERGLYCEMIA IN TYPE-2 DM
The Ominous Octet

DeFronzo RA. Diabetes. 2009;58:773--‐795.

29
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 III. Pathogenesis of Gestational Diabetes
Mellitus
• It involves combination of inadequate insulin secretion
and responsiveness (see type 2 DM pathogenesis)
• Develops during pregnancy and improve or disappear after
delivery in most cases
• Individuals at higher risk for Gestational Diabetes include :
 Obese woman
 Those with previous history of glucose intolerance
 Any pregnant woman who has elevated fasting, or
random blood glucose level.
 Those with a history of gestational diabetes mellitus
 Those with a history of large for gestational–age-
babies(>4kg)
 First Degree relative with DM
 Maternal age >25 years of age
 Previous unexplained perinatal loss or birth of a
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malformed infant 30
IV. Pathogenesis of Specific types of
diabetes
DM due to specific causes such as :
 monogenic diabetes e.g. maturity-onset diabetes of the
young [MODY])
 endocrinopathies like thyrotoxicosis, Cushing’s syndrome
 diseases of the exocrine pancreas (e.g. cystic fibrosis)

 drug or chemical-induced diabetes (steroids, ART, Cytotoxic

drugs)

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 End of Unit-2

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