HORMONAL CONTROL OF GLUCONEOGENESIS IN DIABETES MELLITUS

这项研究的重点是使用一种新的和令人兴奋的方法， 稳定的同位素分析，以确定激素机制 控制着植物的发育。 为了了解规则， 因此，有必要定量和验证 通过三羧酸（TCA） 周期 在定量的研究中， 由于无法确定1）TCA循环通量的速率， （柠檬酸合酶）和2）在柠檬酸合成酶处发生的示踪剂的稀释。 丙酮酸羧化酶、脱氢酶和激酶步骤。 由于乳酸是 被认为是整体生物发生的主要贡献者， 研究提案将管理U-13 C乳酸盐和其他相关的 同位素并进行稳定同位素分析以定量 通过确定TCA的稀释参数来确定再生 周期 我们的假设是糖尿病患者有缺陷， 丙酮酸脱氢酶和丙酮酸羧化酶的继发性增加 和快速的再生。 这可能是一个主要的缺陷或 由于荷尔蒙调节改变而产生的继发性影响。 为了 评估肝脏丙酮酸脱氢酶的激素调节， 羧化酶，我们将进行垂体胰腺正葡萄糖钳夹 在正常志愿者中进行的研究，以评价激素对TCA循环的影响 新陈代谢. 将在糖尿病患者中进行类似的研究， 测试我们的假设并确定丙酮酸缺陷 脱氢酶活性是异常葡萄糖的原因 糖尿病患者体内发生的代谢异常。

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.