Insulin Resistance – Symptoms, Signaling Pathway, Obesity Mechanism & Genetic Defects in Insulin Action

Presentation Notes on Insulin Resistance in type 2 diabetes with symptoms & Treatment, metabolic syndrome in children, men & women for medical & Biology students in word / .doc / ppt format 

Insulin Resistance:

Insulin resistance is defined as resistance to the effects of insulin on glucose uptake, metabolism, or storage. Insulin resistance is a characteristic feature of most patients with type 2 diabetes and is an almost universal finding in diabetic individuals who are obese. The role of insulin resistance in the pathogenesis of type 2 diabetes can be gauged from the finding that

(1) insulin resistance is often detected 10 to 20 years before the onset of diabetes in predisposed individuals (e.g., offspring of type 2 diabetics) and

(2) in prospective studies, insulin resistance is the best predictor for subsequent progression to diabetes.

Insulin resistance leads to decreased uptake of glucose in muscle an adipose tissues and an inability of the hormone to suppress hepatic gluconeogenesis.

Genetic Defects of the Insulin Receptor and Insulin Signaling Pathway :

Loss of function abnormalities of either the insulin receptor or its downstream intermediates are obvious candidates for mediating insulin resistance in type 2 diabetes. In mice, tissue specific knockout of genes encoding various insulin signaling proteins has resulted in insulin resistance, hyperinsulinemia and hyperglycemia, recapitulating human type 2 diabetes. Unfortunately, the extrapolation of these single  gene knockout models to human disease has been less than gratifying. Point mutations of the insulin receptor are relatively rare, accounting for no more than 1% to 5% of patients with insulin resistance.

Analysis of candidate genes involved in insulin secretion or insulin action, as well as whole genome linkage studies of affected families, have yielded many polymorphisms that associate with the type 2 diabetic phenotype, but in most cases, the associations have been weak, or the studies were not reproducible .From these analyses, it appears that while the population risk associated with any particular genetic variant (polymorphism) may be significant, the increased risk for developing diabetes for a given individual harboring that variant is small at best.

Obesity and Insulin Resistance :

The association of obesity with type 2 diabetes has been recognized for decades, visceral obesity being a common phenomenon in the majority of type 2 diabetics. The link between obesity and diabetes is mediated via effects on insulin resistance. Insulin resistance is present even in simple obesity unaccompanied by hyperglycemia, indicating a fundamental abnormality of insulin signaling in states of fatty excess. The risk for diabetes increases as the body mass index (a measure of body fat content) increases. It is not only the absolute amount but also the distribution of body fat that has an effect on insulin sensitivity . Central obesity (abdominal fat) is more likely to be linked with insulin resistance than are peripheral (gluteal / subcutaneous) fat depots.

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