HORMONAL CONTROL OF GLUCONEOGENESIS IN DIABETES MELLITUS

糖尿病中糖异生的激素控制

• 批准号: 3081014
• 负责人: JOHN A TAYEK
• 金额: $ 9.29万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3081014
• 关键词: Krebs' cycle; analytical chemistry; blood chemistry; blood glucose; carbon; diabetes mellitus; gas chromatography; glucagon; gluconeogenesis; hormone regulation /control mechanism; human subject; mass spectrometry; phosphoenolpyruvate carboxylase; pyruvate carboxylase; pyruvate dehydrogenase; pyruvate kinase; radionuclides; somatotropin; stable isotope

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.

这项研究的重点是使用一种新的令人兴奋的方法 稳定同位异体分析用于确定激素机制 控制糖异生。为了更好地理解规则， 糖异生，将有必要量化和验证 生糖前体通过三羧酸(TCA)的运动 周而复始。糖异生的量化研究一直是 受阻于无法确定1)三氯乙烷循环通量的速率 (柠檬酸合成酶)和2)发生在 丙酮酸羧化酶、脱氢酶和激活酶的步骤。因为乳酸盐是 被认为是整个糖异生的主要贡献者，这 研究提案将管理U-13C乳酸盐和其他相关 并进行稳定的同位素分析以定量 测定三氯乙酸稀释参数的糖异生作用 周而复始。这是我们的假设，糖尿病患者有缺陷的 丙酮酸脱氢酶和丙酮酸羧基酶的继发性升高 和禁食糖异生。这可能是主要缺陷或 由于荷尔蒙调节改变而产生的次要影响。为了 评价肝丙酮酸脱氢酶的激素调节作用 羧基酶，我们将进行垂体-胰腺正血糖钳夹 在正常志愿者中评价激素对TCA循环影响的研究 新陈代谢。类似的研究将在糖尿病患者中进行，以 测试我们的整体假设并确定丙酮酸的缺陷 脱氢酶活性是导致血糖异常的原因 新陈代谢已知发生在糖尿病患者身上。