In vivo insulin mediated glucose uptake (IMGU) occurs principally in skeletal muscle and is determined by the arteriovenous glucose difference (AVGd) across and the rate of blood flow (F) into muscle, such that IMGU = AVGD X F. Human obesity, Type II and Type I diabetes are associated with decreased rates of IMGU, which have been attributed in large part to binding and post-binding cellular defects in insulin action. These defects would be predicted to decrease cellular and thus tissue glucose uptake i.e., AVGd. However, the contribution of hemodynamic defects in glucose and insulin delivery (F) to in vivo insulin resistance has received little attention. Yet, information regarding this is crucial to our understanding of the pathophysiology of in vivo insulin resistance. The studies outlined in this proposal are designed to test the overall hypothesis that a defect(s) in insulin's normal ability to generate increments in blood flow to skeletal muscle is an important contributor to in vivo insulin resistance. It is postulated that obesity and the diabetic state are associated with hemodynamic defects which contribute significantly to postprandial glucose intolerance and frank hyperglycemia, respectively.
The specific aims of the proposed studies are: (1) to assess the ability of insulin and glucose to generate increases in skeletal blood flow in obese non-diabetic, Type II and Type I diabetic subjects; (2) to determine the ability of blood flow to independently increase skeletal muscle glucose uptake; (3) to characterize the impact of increments in skeletal muscle blood flow on the volume of distribution of glucose and the kinetics of insulin action; (4) to quantitate postprandial hemodynamic changes in Type II diabetic and obese subjects, respectively. To accomplish these goals, cardia output (dye dilution technique), leg blood flow (thermodilution technique), whole body glucose uptake (glucose clamp + isotopic dilution technique) and leg muscle glucose uptake (limb balance technique) will be quantitated under various perturbations of circulating serum insulin and glucose levels to determine the role of peripheral blood flow to glucose uptake and its contribution to in vivo insulin resistance. The results of these studies should result in an enhanced understanding of in vivo insulin resistance and more rational therapeutic approaches.
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