ANTIDIABETIC DRUG INTERVENTION

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African Americans (AA) have higher prevalence of type 2 diabetes and its associated complications when compared to whites. The reason for the racial discrepancy in the two American populations remains uncertain. Although obesity is more common in the AA, recent evidence indicates that this can not explain the racial disparity in the two groups. Several recent metabolic studies including those from our lab have demonstrated that nondiabetic blacks have greater insulin resistance and hyperinsulinemia. Because hyperinsulinemia has been associated with hypertension and cardiovascular diseases, which are also more common in the AA, we have postulated that AA could have accelerated disease. Secondly, it is possible that AA are more constitutively susceptible to adverse effects of diabetes and the associated hypertension, when compared to whites. Therefore, intervention and prevention approaches for type 2 diabetes are urgently needed. Thus, the aims of the present proposal are to: 1) reduce the insulin resistance and hyperinsulinemia, 2) improve glucose-dependent glucose disposal, 3) maintain or preserve beta cell insulin secretion and 4) determine the effect of reduction of hyperinsulinemia on lipids and lipoproteins and blood pressure in the AA at greater risk for type 2 diabetes. The study population will consist of Group 1 (n=40) healthy control subjects and Group 2 (n= 160) AA who are either first-degree relatives of patients with type 2 diabetes, patients with impaired glucose tolerance test, former gestational diabetic patients, and former diabetic patients in remission. Serial anthropometric, blood pressure and metabolic studies will be performed at yearly intervals for 5 years. The metabolic studies will include standard glucose tolerance test (OGTT), insulin sensitivity (S1) and glucose- dependent glucose disposal (S-G) by the minimal model method by Bergman et al. and basal hepatic glucose production (HGP). The AA subjects in Group 2 will be randomized to receive a) diet + placebo, b) diet + metformin, c) diet + troglitazone and d) diet + glipizide. The 3 antidiabetic medications will be administered in very low doses at breakfast daily. The endpoint of the study is to determine which therapeutic approach will be most efficacious, well tolerated and accepted with respect to preventing deterioration in the glucose control with subsequent development of IGT and diabetes in the AA population at greater risk for type 2 diabetes. The significance of the present study is to: 1) provide the first placebo- controlled, randomized pharmacologic study to delay and/or prevent type 2 diabetes and to determine which metabolic parameter is critically important in preventing or delaying the onset of the disease in the AA population at greater risk for type 2 diabetes.