INSULIN ACTION IN POLYCYSTIC OVARY SYNDROME

胰岛素在多囊卵巢综合症中的作用

• 批准号: 2141412
• 负责人: Andrea E Dunaif
• 金额: $ 20.54万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2141412
• 关键词: alkaline phosphatase; denaturing gradient gel electrophoresis; diabetes mellitus genetics; family genetics; female; glucose metabolism; glucose tolerance test; hormone regulation /control mechanism; human subject; insulin; insulin receptor; insulin sensitivity /resistance; noninsulin dependent diabetes mellitus; obesity; phosphorylation; polycystic ovary syndrome; protein kinase; receptor binding; receptor coupling; women's health

The Overall Specific Aims of this research are to determine the mechanisms and pathogenesis of insulin resistance in the polycystic ovary syndrome (PCO). This research will provide insight into the cause(s) of PCO and of non-insulin dependent diabetes mellitus (NlDDM). PCO, a hyperandrogenic disorder of unknown etiology, is one of the most common endocrine diseases of women of reproductive age. Women with PCO are markedly insulin resistant, independent of obesity. But PCO and obesity have a synergistic deleterious effect on glucose tolerance such that 20% of obese PCO women have impaired glucose tolerance or frank NIDDM. Our preliminary epidemiologic, family, and fibroblast insulin binding studies strongly suggest that there is a genetic component to the insulin resistance of PCO. Further, there is a strikingly increased prevalence of NIDDM in families of women with PCO consistent with a causal and/or genetic association of these disorders. The Specific Aims of this proposal are: 1) To Characterize in Detail the Mechanisms of Insulin Resistance In Vivo in PCO. This will be accomplished by defining the sensitivity and responsiveness to insulin of glucose utilization and hepatic glucose production as well as the feedback inhibition of endogenous insulin secretion by insulin. The effect of gonadal steroids on these parameters will be determined by regression analysis. The sequential multiple insulin dose euglycemic glucose clamp technique will be used to define the in vivo dose-response curve to insulin and the modified frequently sampled intravenous glucose tolerance test will be used to determine C-peptide metabolism. 2) To Determine the Cellular Defects in Insulin Action in PCO. This will be accomplished by investigating in vitro insulin binding and uniformly labeled (14C)- glucose transport in isolated adipocytes. The effect of gonadal steroids on these parameters will also be assessed. 3) To Determine if Decreased Cellular Insulin Binding or Action in PCO is an Acquired or Intrinsic (? Genetic) Defect. This will be accomplished by determining whether there are persistent defects in insulin binding, insulin receptor tyrosine kinase activity, and/or glucose transport in cultured fibroblasts from PCO women.

这项研究的总体具体目标是确定 多囊卵巢患者胰岛素抵抗的机制及发病机制 卵巢综合征(PCO)。这项研究将为我们提供对 多囊卵巢综合征和非胰岛素依赖型糖尿病的病因(S) (NlDDM)。PCO是一种病因不明的高雄激素性疾病， 育龄妇女最常见的内分泌疾病之一 年龄。患有多囊卵巢综合征的女性有明显的胰岛素抵抗，独立 肥胖症。但多囊卵巢综合征和肥胖有协同的有害作用 对糖耐量的影响，20%的肥胖多囊卵巢妇女 糖耐量受损或坦率的NIDDM。我们的预赛 流行病学、家族性和成纤维细胞胰岛素结合研究 强烈地表明胰岛素中有遗传成分 PCO的抵抗力。此外，还有一个显著增加的 符合以下条件的多囊卵巢患者家庭中的NIDDM患病率 这些疾病的因果关系和/或遗传联系。这个 本提案的具体目标是：1)详细描述 多囊卵巢综合征胰岛素抵抗的体内机制。这将是 通过定义对以下各项的敏感性和响应性来实现 胰岛素对葡萄糖的利用和肝脏葡萄糖的产生 以及对内源性胰岛素分泌的反馈抑制。 胰岛素。性腺类固醇对这些参数的影响将 通过回归分析来确定。顺序倍数 胰岛素剂量正糖葡萄糖钳夹技术将用于 确定胰岛素和改良的胰岛素的体内剂量-反应曲线 将使用频繁采样的静脉葡萄糖耐量试验 测定C-肽代谢。2)确定小区 多囊卵巢综合征中胰岛素作用的缺陷。这将通过以下方式实现 体外胰岛素结合和均一标记~(14)C的研究 葡萄糖在分离的脂肪细胞中的转运。性腺激素的作用 对这些参数的类固醇也将进行评估。3)至 确定PCO中细胞胰岛素结合量或作用是否减少 是后天的还是内在的(？遗传)缺陷。这将是 通过确定是否存在永久性缺陷来完成 在胰岛素结合中，胰岛素受体酪氨酸激酶活性， 和/或多囊卵巢患者培养的成纤维细胞的葡萄糖转运。