INTERPLAY BETWEEN GONADAL STEROIDS AND INSULIN IN MEN

描述(取自应用程序) 这项提案的总体目标是定义 男性胰岛素抵抗与睾酮水平呈负相关。 在正常男性、瘦削的II型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 糖尿病患者是否可以确定两者之间的相互作用 胰岛素抵抗和睾酮与体重和血糖无关 宽容。鉴于严重的心血管疾病发病率和死亡率 与肥胖和II型糖尿病相关，对 睾酮和胰岛素抵抗之间的相互作用具有重要的公共意义 对健康的影响，并可能促进新的 针对这些极其常见的代谢紊乱的治疗策略。 该提案的具体目标1-3将涉及胰岛素的影响 雄性生殖轴上的抗性，具体地说：i) 明确胰岛素抵抗增加与剂量反应关系 男性的睾丸素分泌；ii)定位引起的缺陷 下丘脑-垂体-性腺(HPG)轴受胰岛素抵抗频繁使用 内源性促性腺激素释放激素和人绒毛膜促性腺激素检测 用促性腺激素释放激素拮抗剂阻断促性腺激素释放激素；以及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将解决以下影响 睾酮在胰岛素抵抗中的作用，并将具体：IV)定义 睾酮升高与胰岛素的量效关系 用葡萄糖钳夹测量胰岛素敏感性后的胰岛素抵抗 用促性腺激素释放激素激动剂诱导性腺功能减退 和药理学睾丸素替代；以及v)检查 睾酮治疗对II型胰岛素抵抗和血糖控制的影响 糖尿病。 性类固醇和胰岛素水平的选择性和序贯操作 本提案中概述的内容将允许对关系进行精确定义 男性睾丸素和胰岛素抵抗之间的关系有待建立 因果决定因素有明确的定义。

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.