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Research Article

The Genetics and Pathophysiology of Type II and Gestational Diabetes

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Pages 509-550 | Published online: 27 Sep 2008
 

Abstract

The development of both type II diabetes and gestational diabetes is probably governed by a complex and variable interaction of genes and environment. Molecular genetics has so far failed to identify discrete gene mutations accounting for metabolic changes in NIDDM. Both beta cell dysfunction and insulin resistance are operative in the manifestation of these disorders. Specific and sensitive immunoradiometric assays found fasting hyperproinsulinemia and first-phase hypoinsulinemia early in the natural history of the disorder. A lack of specificity of early radioimmunoassays for insulin resulted in measuring not only insulin but also proinsulins, leading to overestimation of insulin and misleading conclusions about its role in diabetes. The major causes of insulin resistance are the genetic deficiency of glycogen synthase activation, compounded by additional defects due to metabolic disorders, receptor downregulation, and glucose transporter abnormalities, all contributing to the impairment in muscle glucose uptake. The liver is also resistant to insulin in NIDDM, reflected in persistent hepatic glucose production despite hyperglycemia. Insulin resistance is present in many nondiabetics, but in itself is insufficient to cause type II diabetes. Gestational diabetes is closely related to NIDDM, and the combination of insulin resistance and impaired insulin secretion is of importance in its pathogenesis.

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