THE GENETICS AND PATHOPHYSIOLOGY OF TYPE-II AND GESTATIONAL DIABETES

The development of both type II diabetes and gestational diabetes is p robably governed by a complex and variable interaction of genes and en vironment. Molecular genetics has so far failed to identify discrete g ene mutations accounting for metabolic changes in NIDDM. Both beta cel l dysfunction and insulin resistance are operative in the manifestatio n of these disorders. Specific and sensitive immunoradiometric assays found fasting hyperproinsulinemia and first-phase hypoinsulinemia earl y in the natural history of the disorder. A lack of specificity of ear ly radioimmunoassays for insulin resulted in measuring not only insuli n but also proinsulins, leading to overestimation of insulin and misle ading conclusions about its role in diabetes. The major causes of insu lin resistance are the genetic deficiency of glycogen synthase activat ion, compounded by additional defects due to metabolic disorders, rece ptor downregulation, and glucose transporter abnormalities, all contri buting to the impairment in muscle glucose uptake. The liver is also r esistant to insulin in NIDDM, reflected in persistent hepatic glucose production despite hyperglycemia. Insulin resistance is present in man y nondiabetics, but in itself is insufficient to cause type II diabete s. Gestational diabetes is closely related to NIDDM, and the combinati on of insulin resistance and impaired insulin secretion is of importan ce in its pathogenesis.