The peripheral metabolism of glucose involves movement across the cell membrane of tissues followed by intracellular processing via oxidative and non-oxidative pathways. Peripheral insulin resistance is a well documented abnormality in obesity and Type II diabetes mellitus (NIDDM) and is due primarily to a post-receptor (post-binding) once it enters the cells and if abnormalities in intracellular metabolism might play a role in the insulin resistance of these disorders. Due to insulin resistance, at any given level of serum insulin and glucose, lower rates of glucose disposal result in reduced rates of glucose flux through intracellular pathways compared to non-diabetic nonobese individuals. Because of this, accurate comparisons of intermediary metabolism or delineation of any intrinsic intracellular metabolic defects independent of the decreased glucose disposal rates are difficult to make. In these studies, we plan to evaluate the effects of obesity and NIDDM on in vivo and in vitro intracellular glucose metabolism to determine whether intrinsic defects of intracellular glucose metabolism exist in NIDDM and/or obesity or whether these defects are merely secondary to the decreased rate of glucose entry into the cell. We propose to accomplish this by using levels of hyperinsulinemia and hyperglycemia designed to attain similar rates of in vivo glucose disposal in comparably matched groups of non-obese, obese and NIDDM subjects. To conduct these studies the insulin-glucose clamp technique will be employed to measure glucose uptake rates in conjunction with simultaneous computerized open circuit indirect calorimetry to quantitate oxidative and non-oxidative glucose metabolism (NOGM). To determine whether corresponding changes are occurring in the primary peripheral target organ, samples or quadriceps femoris muscle will be obtained by needle biopsy during these studies for determination of glycolytic pathway metabolites and the rate limiting enzyme for glycogen synthesis, glycogen synthase. It is anticipated that these studies will delineate the importance of insulin, glucose and overall glucose disposal on the metabolic fate of glucose and indicate whether an intrinsic defect(s) in the intermediary metabolic handling of glucose exists in obesity and NIDDM.
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