INSULIN ACTION IN THE POLYCYSTIC OVARY SYNDROME

胰岛素在多囊卵巢综合征中的作用

• 批准号: 3240979
• 负责人: Andrea E Dunaif
• 金额: $ 21.09万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 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 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3240979
• 关键词: adipocytes; dosage; female; genetic disorder diagnosis; glucose metabolism; glucose tolerance test; glucose transport; hormone regulation /control mechanism; human subject; insulin; insulin receptor; liver metabolism; noninsulin dependent diabetes mellitus; obesity; pancreatic islet function; polycystic ovary syndrome; protein tyrosine kinase; sex hormones; young adult human (21-34)

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.

本研究的总体具体目标是确定 多囊卵巢胰岛素抵抗的机制及发病机制 卵巢综合征（PCO）。 这项研究将深入了解 PCO 和非胰岛素依赖型糖尿病的原因 （NlDDM）。 PCO 是一种病因不明的高雄激素性疾病， 女性生殖系统最常见的内分泌疾病之一 年龄。 患有 PCO 的女性具有明显的胰岛素抵抗、独立性 肥胖症。 但 PCO 和肥胖具有协同有害作用 对葡萄糖耐量的影响，导致 20% 的肥胖 PCO 女性患有 糖耐量受损或明显的 NIDDM。 我们的初步 流行病学、家庭和成纤维细胞胰岛素结合研究 强烈表明胰岛素存在遗传成分 PCO 的电阻。 此外，还有显着增加 PCO 女性家庭中 NIDDM 的患病率与 这些疾病的因果和/或遗传关联。 这 该提案的具体目标是： 1) 详细描述 PCO 体内胰岛素抵抗的机制。 这将是 通过定义敏感度和响应度来完成 胰岛素对葡萄糖利用和肝葡萄糖生成的影响 以及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。 连续倍数 胰岛素剂量正常血糖葡萄糖钳夹技术将用于 定义胰岛素的体内剂量反应曲线和修改后的曲线 将使用频繁采样的静脉葡萄糖耐量试验 测定C肽代谢。 2) 确定蜂窝 PCO 中胰岛素作用的缺陷。 这将通过以下方式完成 研究体外胰岛素结合并统一标记 (14C)- 分离的脂肪细胞中的葡萄糖转运。 性腺的作用 类固醇对这些参数的影响也将被评估。 3) 至 确定 PCO 中细胞胰岛素结合或作用是否减少 是后天或内在（？遗传）缺陷。 这将是 通过确定是否存在持续性缺陷来完成 胰岛素结合、胰岛素受体酪氨酸激酶活性、 和/或来自 PCO 女性的培养成纤维细胞中的葡萄糖转运。