Glycogen synthesis is the major fate of a glucose load in healthy humans and abnormalities in glycogen synthesis is the major factor responsible for insulin resistance in type Il diabetes mellitus. The overall goal of this proposal is the application of NMR spectroscopic techniques in conjunction with GC-MS and radioisotopic techniques to investigate the regulation of liver and muscle glycogen metabolism in healthy humans and their respective roles in the pathogenesis of insulin resistance and glucose intolerance in diabetic humans. During the tenure of this grant we will examine: (l) The relative contributions of net hepatic glycogenolysis and gluconeogenesis to glucose production in healthy humans during the first 6-10 hours of a fast, (2) The respective roles of hepatic and muscle glycogen synthesis as well as suppression of hepatic glucose production following a mixed meal in causing postprandial hyperglycemia in non insulin dependent diabetes mellitus, (3) Whether liver glycogen synthesis is altered in type l diabetic subjects throughout the course of a 24 hour period in which 3 mixed meals are ingested, (4) Under conditions of a hyperglycemic-hyperinsulinemic clamp, the impact of type l and type II diabetes on net rates and pathways (direct and indirect) of hepatic glycogen synthesis as well as the role of glucagon on the regulation of these fluxes, (5) Whether defects in glucose transport/phosphorylation are primary or secondary in the pathogenesis of type Il diabetes mellitus and if they are reversible with an intensive 12 week aerobic exercise program and (6) The effects of an intensive bout of exercise on glucose transport/phosphorylation and glycogen synthase activity during the rapid insulin-independent phase of glycogen repletion as well as the slower insulin-dependent phase in insulin resistant offspring of NIDDM patients. The results from these studies should: (l) provide new insights into the regulation of liver and muscle glycogen metabolism in healthy humans during fed and fasted states, (2) quantify the relative roles of liver and muscle in causing postprandial hyperglycemia in NIDDM, (3) identify alterations in hepatic glycogen synthesis that occur in type l diabetes mellitus which might be an important predisposing factor in the development of severe hypoglycemia, (4) assist with the search for candidate gene(s) for NIDDM by determining whether glucose transport/phosphorylation is a primary defect in its pathogenesis and (5) elucidate the mechanism by which acute and chronic exercise training reverses insulin resistance which has important therapeutic implications for treatment of patients with NIDDM.