Pathophysiology of Type 2 Diabetes

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Insulin resistance:
Insulin resistance is defined as a reduced physiological response to insulin – the effects of the circulating insulin is inadequate. The insulin sensitive tissues (eg skeletal muscle) have a reduced sensitivity to the effects of insulin on glucose uptake. Insulin resistance is associated with hyperinsulinaemia and normal or hyperglycaemia. Insulin resistance is not symptomatic. Insulin resistance is the predominant and central feature in the pathophysiology of type two diabetes.

Cluster of cardiovascular risk factors comprises the insulin resistance syndrome – type 2 diabetes (or impaired glucose tolerance); insulin resistance; hyperinsulinaemia; hypertension; visceral/central obesity; dyslipidaemia; hyperleptinaemia; hyperuricaemia; endothelial dysfunction; hypercoaguable state; microalbuminuria; early/accelerated atherosclerosis; polycystic ovary syndrome

WHO definition of the insulin resistance syndrome:
Insulin resistance (insulin sensitivity below the lowest quartile for the population)
Glucose intolerance (2 hour OGTT >7.8mmol)
Central obesity (waist/hip ratio for female >0.85 and male >0.95)
Hypertension (>160/95mmHg)
Hypertriglyceridaemia (triglycerides >1.7mmol)
Lower level of high density lipoprotein-cholesterol (female < 1.1mmol; male <0.9mmol)Insulin resistance closely associated with increase in visceral fat. Insulin resistance is exacerbated by physical inactivity and cigarette smoking.Insulin resistance is of two types – insulin insensitivity & insulin unresponsivenessCan be due to: 1) Abnormality in insulin molecule 2) Defects in target cells/tissues (most common cause) 3) Excessive amounts of antagonists Type 2 is considered a heterogenous disease due to inter-individual variability in these three defects.Beta cell failure: The secretion of insulin becomes abnormal once type 2 diabetes is well established. Initially, the beta cells secrete sufficient insulin to prevent ketosis, but not sufficient to maintain normal glucose levels.No initial decrease in mass of beta cells, but later get amyloid deposits  role in pathogenesis is unclear. Eventually get failure of beta cell secretion of insulin.Endothelial dysfunction and leptin physiology also plays important roles in Type 2 diabetes. Leptin is the hormone that signals when appetite is satisfied. Nearly all obese people are resistant to leptin and high levels of circulating levels of leptin.

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