HORMONAL CONTROL OF GLUCONEOGENESIS IN DIABETES MELLITUS

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The focus of this research is to use a new and exciting methodology of stable isotopomer analysis to determine the hormonal mechanisms controlling gluconeogenesis. In order to understand the regulation of gluconeogenesis, it will be necessary to quantitate and verify the movement of gluconeogenic precursors through the tricarboxylic (TCA) cycle. Research in the quantification of gluconeogenesis has been hampered by the inability to determine 1) the rate of TCA cycle flux (citrate synthase) and 2) the dilution of tracer that occurs at the pyruvate carboxylase, dehydrogenase and kinase steps. Since lactate is believed to be the major contributor to overall gluconeogenesis, this research proposal will administer U-13C lactate and other related isotopes and perform stable isotopomer analysis to quantitate gluconeogenesis by determining the dilutional parameters of the TCA cycle. It is our hypothesis that diabetic patients have a defect in pyruvate dehydrogenase and a secondary increase in pyruvate carboxylase and fasting gluconeogenesis. This may be a primary defect or a secondary effect due to altered hormonal regulation. In order to evaluate the hormonal regulation of hepatic pyruvate dehydrogenase and carboxylase, we will perform pituitary pancreatic euglycemic clamp studies in normal volunteers to evaluate hormonal effects on TCA cycle metabolism. Similar studies will be performed in diabetic patients to test our overall hypothesis and determine if a defect in pyruvate dehydrogenase activity is responsible for the abnormal glucose metabolism known to occur in diabetic patients.