Glycogen synthesis is quantitatively one of the most important fates of a glucose load and defects in nonoxidative glucose metabolism have been demonstrated to be quantitatively the most important in contributing to glucose intolerance in the diabetic patient. In order to gain a better understanding of the regulation of glycogen synthesis, 13C and 1H nuclear magnetic resonance (NMR) spectroscopy will be used in conjunction with 3H/14C tracer and insulin/glucose clamp techniques to address questions pertaining to hormonal and substrate regulation of (a) liver and muscle glycogen synthesis and turnover (b) glucose utilization and (c) fluxes through several rate limiting steps in glycolysis and gluconeogenesis in the normal and diabetic state. NMR spectroscopy has the advantage over existing techniques in that it can determine the 13C enrichment of each carbon of an intracellular metabolite. This data can then be used to calculate in vivo fluxes, under steady state conditions, into different pathways of glycogen synthesis and through rate limiting steps in glycolysis and gluconeogenesis. Furthermore, since this technique is non- invasive it has the potential to be used in similar studies of carbohydrate metabolism in man. 13C NMR spectroscopy will be used in parallel with 3H/14C glucose tracer and insulin/glucose clamp techniques so that hepatic glucose production can also be monitored under different steady-state conditions of glycemia/insulinemia. Since studies will be performed in awake unstressed animals, an integrated picture of whole body glucose homeostasis will be obtained. Besides giving insight to the pathogenesis of the diabetic state new techniques will be developed to study glucose metabolism in vivo which have the potential to do so in man.
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