INTERPLAY BETWEEN GONADAL STEROIDS AND INSULIN IN MEN

描述（取自应用程序） 这一建议的总体目标是确定造成这一现象的因果决定因素， 男性胰岛素抵抗与睾酮水平呈负相关。 在正常男性、II型精瘦一级亲属中进行研究 糖尿病患者、糖耐量正常的肥胖男性和 II型糖尿病将允许确定是否之间的相互作用 胰岛素抵抗和睾酮与体重和血糖无关 宽容鉴于心血管疾病的发病率和死亡率 与肥胖和II型糖尿病相关，更清楚地了解 睾丸激素和胰岛素抵抗之间相互作用已经引起了重要的公众 健康影响，并可能促进新的 这些极其常见的代谢紊乱的治疗策略。 本提案的具体目标1-3将讨论胰岛素的影响 男性生殖轴上的阻力，具体而言：i） 定义胰岛素抵抗增加与 男性睾酮分泌; ii）定位在 下丘脑-垂体-性腺（HPG）轴通过胰岛素抵抗使用频繁 血液采样研究以及内源性后GnRH和hCG检测 用GnRH拮抗剂阻断促性腺激素;和iii）检查对 噻唑烷二酮降低男性胰岛素抵抗的HPG轴 患有II型糖尿病具体目标4和5将解决以下问题的影响： 睾酮对胰岛素抵抗的影响，并将特别：iv）定义 增加睾酮和胰岛素之间的剂量-反应关系 通过用葡萄糖钳夹测量胰岛素敏感性， 用GnRH激动剂诱导性腺功能减退， 和药理学睾酮替代;和v）检查 睾酮治疗对II型糖尿病胰岛素抵抗和血糖控制作用 糖尿病 性类固醇和胰岛素水平的选择性和顺序操作， 本提案中概述的内容将允许对关系进行精确定义， 睾酮和胰岛素抵抗之间的关系， 因果决定因素明确定义。

DESCRIPTION (taken from the application) The overall goal of this proposal is to define the causal determinants of the inverse relationship between insulin resistance and testosterone in men. Conducting studies in normal men, lean first degree relatives of type II diabetic patients, obese men with normal glucose tolerance, and men with type II diabetes will permit determination of whether the interaction between insulin resistance and testosterone is independent of body weight and glucose tolerance. Given the significant cardiovascular morbidity and mortality associated with obesity and type II diabetes, a clearer understanding of the interplay between testosterone and insulin resistance has important public health implications and may potentially facilitate the development of new therapeutic strategies for these extremely common metabolic disorders. Specific Aims 1-3 of this proposal will address the impact of insulin resistance on the reproductive axis in the male and will specifically: i) define the dose response relationship between increasing insulin resistance and testosterone secretion in men; ii) localize the defect induced in the hypothalamic-pituitary-gonadal (HPG) axis by insulin resistance using frequent blood sampling studies as well as GnRH and hCG testing after endogenous gonadotropin blockade with a GnRH antagonist; and iii) examine the impact on the HPG axis of reducing insulin resistance with a thiazolidinedione in men with type II diabetes. Specific Aims 4 and 5 will address the impact of testosterone on insulin resistance and will specifically: iv) define the dose-response relationship between increasing testosterone and insulin resistance by measuring insulin sensitivity with a glucose clamp after induction of hypogonadism with a GnRH agonist and again after both physiologic and pharmacologic testosterone replacement; and v) examine the impact of testosterone treatment on insulin resistance and glycemic control in type II diabetes. The selective and sequential manipulation of sex steroid and insulin levels as outlined in this proposal will permit precise definition of the relationship between testosterone and insulin resistance in men to be established and their causative determinants unequivocally defined.