TYPE 2 DM Pathogenesis

INTRODUCTION
• T2DM is characterized by 1) hyperglycemia, 2)
insulin resistance, and 3) relative impairment
in insulin secretion.
• Although only hyperglycemia is measured for
a diagnosis, T2DM is a heterogenous disease
with each patient have varying degrees of
insulin resistance and defective insulin
secretion
 Impaired insulin secretion
• Largely a result of genetic influences and the programming of
the beta cell mass and function in utero.
• Additionally, hyperglycemia itself can impair pancreatic beta
cell function and exacerbate insulin resistance
("glucotoxicity"), leading to a vicious cycle of hyperglycemia.
• In a cohort study of 6500 british servants which 505 of them
become diabetics within 9.7 years follow-up, beta cell-function
increase 3-4 years before T2DM (likely a compensatory
mechanism for decrease insulin sensitivity), and then
decrease until diagnosis.
• Abnormal beta-cell function is readily observed in pts with FPG
>100 mg/dL
 Impaired insulin processing
• Normal insulin production involves cleavage of insulin from
proinsulin; 10-15% of secreted insulin is proinsulin and its
conversion intermediates.
• In diabetes, there is considerable increase in proinsulin at
basal state (>40%). This is even more pronounced after
stimulation of insulin secretion by injecting arginine or
glucagon.
• The increase in proinsulin secretion persists after matching
for degree of obesity, suggesting that it represents beta cell
dysfunction and not merely the response to the increased
secretory demand imposed by the insulin resistance
Role of islet amyloid polypeptide (amylin)

• Amylin is stored in insulin secretory granules in the

pancreatic beta cells and is cosecreted with insulin,
resulting in serum concentrations approximately
1/10 those of insulin
• It seems that amylin may tonically inhibit insulin
secretion based on observation that administration
of an amylin antagonist to rats results in a fall in
blood glucose and an increase in insulin secretion,
whereas administration of physiologic amounts of
amylin has no acute effect on insulin secretion.
 Genetic susceptibility
• T2DM is a polygenic disease, with likely thousands of
genetic factors contributing to disease risk together with
complex interaction with environmental factors.
• In contrast to monogenic causes of diabetes, where
inheriting a given causative mutation imparts a substantial
risk of developing disease (typically odds ratios [ORs]
>10), the genetic variants associated with type 2 diabetes
each have small impact on risk (typically ORs <1.2)
• Genetic variants can be combined together to generate
polygenic risk scores that allow greater prediction of
disease risk than individual variants.
 Genetic susceptibility (cont’d)
• The contribution of genetic factors is based on the following
findings :
1. 39% of patients with type 2 diabetes have at least one parent with
the disease.
2. Among monozygotic twin pairs with one affected twin,
approximately 90% of unaffected twins eventually develop the
disease .
3. The lifetime risk for a first-degree relative of a patient with T2DM
is 5-10 times higher than that of age- and weight-matched
subjects without a family history of diabetes
• Among groups with increased genetic risk for diabetes,
environmental factors still play a major role in the development of
diabetes.
 Insulin resistance
• Predominantly "environmental" factors related to overeating,
sedentary lifestyle, and resulting overweight and obesity, with
less prominent contributions from aging and genetics.
• T2DM is often accompanied by other metabolic syndrome,
including hypertension, dyslipidemia (raised triglycerides and
lowered HDL cholesterol), and central obesity
• Insulin resistance may play an important role in the genesis of
these conditions.
• ↑ free fatty acid levels, inflammatory cytokines from fat, and
oxidative factors have all been implicated in the pathogenesis
of metabolic syndrome, T2DM, and their cardiovascular
complications
 ROLE OF DIET, OBESITY, AND INFLAMMATION

• Upper-body obesity, so-called "central adiposity," has

a much greater association with insulin resistance and
impaired glucose tolerance than lower-body obesity
• Obesity causes peripheral resistance to insulin-
mediated glucose uptake and may also decrease the
sensitivity of the beta cells to glucose
• The mechanisms by which obesity induces insulin
resistance are poorly understood, The c-Jun amino-
terminal kinase (JNK) pathway may be an important
mediator linking these 2 condition.
 Factors released from adipose tissue
• Leptin – Leptin is produced by adipocytes and is secreted in
proportion to adipocyte mass. It signals the hypothalamus
about the quantity of stored fat (induced satiety perception).
Leptin deficiency and resistance are associated with obesity
and insulin resistance
• Adiponectin – an adipocyte-derived cytokine, reduces levels
of blood free fatty acids and has been associated with
improved lipid profiles, better glycemic management, and
reduced inflammation in patients with diabetes
• Resistin – resistin decreases insulin-mediated glucose uptake
by adipocytes and also enhances glucose production,
independent of changes in glucoregulatory hormones
 Subclassification of diabetes based on
pathophysiology
• These 6 diabetes-related clinical parameters is used in
studies for better characterization of T2DM
1. Glutamic acid decarboxylase (GAD) antibody
2. Age
3. Body mass index (BMI)
4. Glycated hemoglobin (A1C)
5. Homeostatic model assessments of beta cell function
(HOMA2-B)
6. Insulin resistance (HOMA2-IR) based on C-peptide
concentrations
 Subclassification of diabetes based on
pathophysiology
• Based on these 6 parameters, T2DM can be
subclassified into 5 subgroups, 1 of them is T1DM
and the rest 4 are T2DM :
1. Severe autoimmune form (capturing type 1
diabetes and latent autoimmune diabetes of adults)
2. Severe insulin deficiency
3. Severe insulin resistance
4. Mild obesity related
5. Mild age related