Androgens, Genotype and Insulin Resistance in PCOS

PCOS 中的雄激素、基因型和胰岛素抵抗

• 批准号: 7706885
• 负责人: Andrea E Dunaif
• 金额: $ 23.49万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7706885
• 关键词: Adult; Age; Alleles; Androgens; Arts; Award; Brothers; Complex; Cytolysis; Defect; Development; Dinucleotide Repeats; End Point; Environmental Risk Factor; Estradiol; Estrogens; Ethnic Origin; Family; Female; First Degree Relative; Flutamide; Genes; Genotype; Glucagon; Gluconeogenesis; Glucose; Hepatic; Hereditary Disease; Hypoglycemia; Insulin; Insulin Resistance; Introns; Maps; Metabolic; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Peripheral; Phenotype; Predisposition; Rate; Relative (related person); Risk Factors; Steroid biosynthesis; Stimulus; Techniques; Testing; Variant; Weight; Woman; blood glucose regulation; critical developmental period; disease phenotype; fibrillin; glucose production; glycogenolysis; insulin secretion; male; men; programs; receptor; reproductive; response; sex; stable isotope

We have extremely exciting evidence from the initial award period of Project 1 that hepatic insulin resistance is the major defect in glucose homeostasis associated with the PCOS susceptibility variant. This variant, allele 8 (A8) of the dinucleotide repeat D19S884, was mapped to intron 55 of the fibrillin-3 gene as part of Project 2 of this SCOR. Male first-degree relatives with the A8 variant have evidence for abnormalities in insulin secretion suggesting that the metabolic phenotypes associated with the A8 variant are sex-specific. The central hypothesis of the NU SCOR is that hyperandrogenemia resulting from variation in a gene(s) regulating steroidogenesis causes the PCOS metabolic phenotype by programming actions at critical periods of development as well as by ongoing actions in the adult. We will plan three Specific Aims: 1. To test the hypothesis that hepatic glucose homeostasis differs by A8 genotype in women with PCOS. Postabsorptive hepatic glucose homeostasis, including rates of gluconeogenesis and glycoge no lysis, will be assessed with state-of-the-art stable isotope techniques. Responses to stimuli that modulate hepatic glucose production, such as glucagon, hypoglycemia and glucose per se, will be examined. 2. To test the hypothesis that androgens alter hepatic glucose homeostasis, directly or by antagonizing estrogen action, in women with PCOS and that this action differs by A8 genotype. The impact of blocking androgen action with the nonsteroidal receptor antagonist, flutamide, alone and during transdermal estradiol replacement, will be investigated. Endpoints will include hepatic and peripheral insulin action as well as any alterations in hepatic glucose homeostasis identified in Aim 1. 3. To test the hypothesis that metabolic phenotypes associated with A8 are sex-specific in the families of women with PCOS. The impact of A8 genotype on hepatic and peripheral insulin action and on insulin secretion will be examined in the brothers of women with PCOS and in age, weight and ethnicity comparable control men. Since hyperandrogenemia appears to be a final common path to the female reproductive phenotype, elucidating the mechanisms for its association with metabolic defects will be relevant to understanding diverse causes of PCOS as well as an important risk factor for type 2 diabetes.

从项目1的初始奖励期开始，我们有极其令人兴奋的证据表明肝胰岛素抵抗 是与PCOS易感变体相关的葡萄糖稳态的主要缺陷。这个变体， 二核苷酸重复D19S884的等位基因8（A8）被映射到Fibrillin-3基因的内含子55作为一部分 该SCOR的项目2。具有A8变体的男性一级亲戚有证据表明异常 胰岛素分泌表明与A8变体相关的代谢表型是性别特异性的。 NU SCOR的中心假设是，基因的变化引起的高雄激素血症 调节类固醇发生会导致PCOS代谢表型通过在关键时期进行编程作用 发展以及成人的持续行动。我们将计划三个具体目标：1。测试 PCOS女性中A8基因型的肝葡萄糖稳态有所不同。释放术 肝葡萄糖稳态，包括糖生成率和没有裂解的甘露糖，将通过 最先进的稳定同位素技术。对调节肝葡萄糖产生的刺激的反应， 将检查胰高血糖素，低血糖和葡萄糖本身。 2。检验以下假设 雄激素改变了肝葡萄糖稳态，直接或通过拮抗雌激素作用。 PCOS和该动作因A8基因型而异。通过非甾体固醇阻断雄激素作用的影响 受体拮抗剂，氟他胺，单独及其在经皮雌二醇替代期间，将是 调查。终点将包括肝和外围胰岛素作用以及肝的任何改变 AIM1。3中鉴定出的葡萄糖稳态。测试与代谢表型相关的假设 在患有PCOS的女性家庭中，A8具有针对性的。 A8基因型对肝和 外围胰岛素作用和胰岛素分泌的作用将在PCOS和PCOS妇女的兄弟中进行检查 年龄，体重和种族可比的对照男人。由于高雄激素血症似乎是最终 女性生殖表型的常见路径，阐明了其与之相关的机制 代谢缺陷将与了解PCOS的多种原因以及重要风险有关 2型糖尿病的因素。