Page 576 - Concise Pathology for Exam Preparation ( PDFDrive )

20 Endocrinology 561

Role of obesity in insulin resistance
• Inverse correlation exists between fasting plasma nonesterified fatty acids (NEFA) and
insulin sensitivity. Central fat is more lipolytic. Excess circulating NEFA generated there-
fore get deposited in the liver and muscle. Intracellular NEFA overwhelms the fatty acid
oxidation pathways leading to accumulation of toxic intermediates like diacylglycerol
(DAG) and ceramide. These activate the serine/threonine kinases, which cause aberrant
serine phosphorylation of insulin receptor and IRS proteins, reducing insulin signalling.
• Adipocytes release prohyperglycaemic adipocytokines (including retinol-binding pro-
tein 4 or RBP 4 and resistin) as well as antihyperglycaemic adipocytokines (leptin and
adiponectin). Obesity is associated with a decrease in adiponectin contributing to in-
sulin resistance. Excessive resitin and RBP-4 are also associated with insulin resistance.
• Adipocytes also release proinflammatory cytokines which induce insulin resistance by
increasing cellular stress.
• PPARg activation promotes secretion of antihyperglycaemic adipocytokines (leptin and
adiponectin).
Clinical Features of DM

Type I DM
• When hyperglycaemia exceeds the renal threshold for reabsorption, glycosuria occurs.
Glycosuria induces osmotic diuresis and polyuria causing loss of water and electrolytes.
Depletion of intracellular water due to water loss and hyperosmolarity (resulting from
increased blood glucose levels) triggers osmoreceptors of the thirst centres of brain re-
sulting in intense thirst or polydipsia.
• Deficiency of insulin leads to a catabolic state (as insulin is an anabolic steroid). Ca-
tabolism of proteins and fat causes a negative energy state, which leads to increased
appetite or polyphagia.
• The catabolic state dominates over the polyphagia and causes progressive loss of weight
and muscle weakness.
• Insulin deficiency coupled with glucagon excess decreases peripheral utilization of
glucose and induces abnormally high levels of blood glucose, which result in severe
osmotic diuresis and dehydration as well as increased ketone synthesis leading to
ketonaemia, ketonuria and ultimately diabetic ketoacidosis (presents with severe nau-
sea, vomiting and respiratory difficulty).
Type II DM
• High portal insulin levels in Type II DM prevent unrestricted hepatic fatty acid oxidation
and keep ketone body production in check.
• Osmotic diuresis and resulting dehydration can induce hyperosmolar nonketotic coma
especially in case of poor fluid intake.

Complications of DM
• Macrovascular disease (affects large- and medium-sized muscular arteries): Acceler-
ated atherosclerosis leading to increased myocardial infarction, stroke and lower extremity
gangrene.
• Microvascular disease (causes capillary dysfunction in target organs): Most pro-
found effects on retina, kidneys and peripheral nerves resulting in diabetic retinopathy,
nephropathy and neuropathy.
Pathogenesis of Complications

1. Formation of advanced glycation end products (AGE): Nonenzymatic reaction
between intracellular glucose with amino group of intra- and extracellular proteins leads to
formation of AGEs. AGEs bind to a specific receptor (RAGE) expressed on inflammatory
cells (macrophages and T cells), endothelium and vascular smooth muscle.
Chemical properties of AGEs
• AGE crosslink polypeptides of same protein (crosslinking between collagen Type I
molecules in large vessels decreases their elasticity and predisposes the vessel to shear
stress and endothelial injury)
• Trap nonglycated proteins (trapping of LDL retards its efflux from the vessel wall and
enhances the deposition of cholesterol in the intima. In capillaries, albumin binds to the

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