Skeletal muscle is an insulin sensitive tissue comprising about 35% of body weight. Its glucose metabolism is affected by insulin resistance in noninsulin-dependent diabetes mellitus (NIDDM). Whether this insulin resistance primarily involves glucose oxidation or glucose storage is not known. The goals of this project are to define the role of plasma insulin, glucose and free fatty acids (FFA) in the regulation of skeletal muscle glucose uptake, glucose oxidation, glycolysis and storage in normal man and to determine the effects of insulin resistance on these pathways in NIDDM. To accomplish this, the technique of steady-state arteriovenous substrate balance across the leg will be used to measure muscle glucose uptake, release of glycolytic products, glucose oxidation (muscle indirect calorimetry) and storage as glycogen during infusions of insulin and glucose nd manipulations of plasma FFA levels. Muscle samples will be obtained by needle biopsy to assess insulin activation of pyruvate dehydrogenase (PDH) and glycogen synthase (GS), which catalyze key steps for glucose oxidation and storage. In normal man, the specific aims are to determine 1) the effect of physiologic hyperinsulinemia on specific pathways of muscle glucose metabolism, and to determine whether insulin activation of muscle PDHC and GS regulates these pathways, 2) whether the effects of hyperglycemia differ from those of physiologic hyperinsulinemia by comparing pathways of muscle glucose metabolism and enzyme activation at identical rates of muscle glucose uptake achieved with various combinations of hyperglycemia and hyperinsulinemia, and 3) to determine if insulin stimulation of muscle glucose oxidation is mediated by decreased FFA availability. In NIDDM, the specific aims are to determine 1) the effects of insulin resistance on the pathways of muscle glucose metabolism, 2) whether the rate of activation of these pathways is decreased, 3) whether decreased insulin activation of muscle PDHC and GS or decreased suppression of fat oxidation is responsible for muscle resistance and 4) whether hyperglycemia in NIDDM compensates for decreased muscle glucose metabolism.
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