Mentored Patient-Oriented Research Career Development Aw

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PROPOSAL (Adapted from the applicant's abstract): The goal of the proposed research is to define the roles played by resistance to insulin-mediated glucose disposal (insulin resistance) and circulating insulin concentrations as factors affecting: 1) the ability of obese individuals to lose weight; and 2) risk for CHD in both non-diabetic individuals and patients with Type 2 diabetes. These issues are important, as the prevalence of obesity in the U.S. has reached epidemic proportions, and is contributing to an increase in Type 2 diabetes and CHD. While obesity, insulin resistance, and diabetes are highly associated, it is not clear whether insulin resistance and compensatory hyperinsulinemia play important roles in the tendency to gain weight and/or inability to lose weight. The role of hyperinsulinemia in CHD is also unclear. In this regard, the specific aims of the proposed research are as follows: 1) to compare insulin resistant versus insulin sensitive nondiabetic, overweight individuals with respect to their ability to lose weight on a low calorie diet. CHD risk factors before and after weight loss will also be assessed to determine the degree to which insulin resistance is associated with increased CHD risk in non-diabetic overweight individuals, as well as the impact that differences in insulin resistance have on the metabolic benefits of weight loss. 2) To determine if weight loss and its associated metabolic benefits vary as a function of the relative amounts of dietary fat and carbohydrate in hypocaloric diets. Because high carbohydrate diets increase insulin secretion, the relationship between dietary composition and change in circulating insulin concentrations will be analyzed with respect to both weight loss and CHD risk factors. 3) To quantify and compare the improvement in glycemic control and CHD risk factors associated with weight loss in obese Type 2 diabetics, while being treated with: a) an insulin secretagogue (sulfonylurea); or b) an insulin sensitizer (thiazolidenedione). Manipulation of plasma insulin concentrations with these medications will provide a mechanism by which to evaluate the impact of circulating insulin concentrations on the described outcome measurements.