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 的最初授予期来看，我们有非常令人兴奋的证据表明肝脏胰岛素抵抗 是与 PCOS 易感性变异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) 被定位到 fibrillin-3 基因的内含子 55，作为 本 SCOR 的项目 2。携带 A8 变异的男性一级亲属有证据表明存在异常 胰岛素分泌表明与 A8 变体相关的代谢表型具有性别特异性。 NU SCOR 的中心假设是基因变异导致高雄激素血症 调节类固醇生成通过关键时期的编程行为导致 PCOS 代谢表型 发展以及成人持续的行动。我们将计划三个具体目标： 1. 测试 假设 PCOS 女性的 A8 基因型的肝葡萄糖稳态有所不同。吸收后 肝葡萄糖稳态，包括糖异生率和糖原不裂解率，将通过以下方法进行评估 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. 检验假设 雄激素直接或通过拮抗雌激素作用改变患有以下疾病的女性的肝葡萄糖稳态 PCOS 且这种作用因 A8 基因型而异。用非类固醇阻断雄激素作用的影响 受体拮抗剂氟他胺单独使用或在透皮雌二醇替代疗法期间使用 调查了。终点将包括肝脏和外周胰岛素作用以及肝脏的任何变化 目标 1. 3 中确定的葡萄糖稳态。检验代谢表型相关的假设 A8 在患有 PCOS 的女性家庭中具有性别特异性。 A8基因型对肝功能的影响 将在患有 PCOS 的妇女的兄弟中检查外周胰岛素作用和胰岛素分泌 在年龄、体重和种族方面与对照组男性相当。由于高雄激素血症似乎是最终的 女性生殖表型的共同途径，阐明其与 代谢缺陷将有助于了解 PCOS 的多种原因以及重要的风险 2 型糖尿病的影响因素。