Glycogen synthesis is quantitatively one of the most important fates of a glucose load and defects in glycogen synthesis have been demonstrated to be quantitatively the most important factor contributing to glucose intolerance in the Non Insulin Dependent Diabetes Mellitus. This project continues studies on the hormonal and substrate regulation of hepatic glycogen synthesis in vivo using both nuclear magnetic resonance spectroscopy (NMR) and gas chromatography-mass spectrometry (GC-MS) techniques. The specific questions that will be addressed are: (l) Whether or not there is functional heterogeneity in regards to glucose and glycogen metabolism in periportal versus perivenous hepatocytes in vivo using the dual digitonin pulse technique. (2) To validate 13C NMR measurements of hepatic glycogen concentration in vivo as well to validate acetaminophen as a noninvasive probe to assess fluxes of the direct and indirect pathways of hepatic glycogen synthesis in vivo. Both will be done by direct biochemical comparison with 13C NMR tissue measurements. (3) To develop a method to assess pyruvate kinase flux relative to pyruvate carboxylase flux in vivo and then to apply this technique to examine the regulation of this substrate cycle acutely by glucagon, epinephrine and chronically by triiodothyronine. (4) To assess the roles of glucose and insulin in regulating hepatic glycogen turnover in vivo as well as address the question of whether or not the last glycogen molecule synthesized is the first molecule degraded and (5) To assess net intrahepatic flux of substrate through the direct and indirect pathways of hepatic glycogen synthesis as well as flux through pyruvate dehydrogenase, pyruvate carboxylase and fumarase by performing computer modeling of the 13C labeling patterns in intrahepatic metabolites obtained from hepatically catheterized conscious dogs to examine: i) The effect of hepatic denervation on these pathways and ii) The effect of hypercortisolemia on these pathways. Overall, these studies will validate novel noninvasive methods for studying liver glycogen metabolism in humans and provide new insights into the regulation of liver glycogen synthesis, glycogen turnover and mechanisms by which hepatic glycogen is degraded. Such data are important for understanding the pathogenesis of glucose intolerance in Non Insulin Dependent Mellitus.
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