INTERPLAY BETWEEN GONADAL STEROIDS AND INSULIN IN MEN

描述（由申请人提供）： 胰岛素抵抗在2型糖尿病的发病机制中起着关键作用，2型糖尿病是一种影响美国1600万人的疾病。因此，阐明调节胰岛素作用的因素具有重要的公共卫生意义。雄激素和胰岛素抵抗之间的关系在人类是复杂的，有明确的证据表明性别二型性。在女性中，胰岛素抵抗与高雄激素血症相关，而男性的流行病学研究一致表明睾酮和胰岛素之间呈反比关系。目前关于因果关系的数据相互矛盾。因此，这项建议的总体目标是精确定义男性胰岛素抵抗和睾酮之间的负相关关系的因果决定因素。 具体目标1将确定2型糖尿病男性患者的下丘脑-垂体-性腺轴异常是否可以通过胰岛素增敏剂的给药得到纠正。具体目标2将使用两种实验性人类模型定义睾酮增加与胰岛素抵抗之间的剂量-反应关系：a）用GnRH拮抗剂诱导性腺功能减退症后和生理性睾酮替代后的正常男性;和B）雄激素替代前后的先天性特发性低促性腺激素性性腺功能减退症男性。具体目标3将研究睾酮补充对2型糖尿病男性胰岛素抵抗和血糖控制的影响。 如本提案所述，选择性和顺序操纵性类固醇和胰岛素水平将允许精确定义男性睾酮和胰岛素抵抗之间的关系，并明确定义其因果决定因素。鉴于与胰岛素抵抗状态（如肥胖和2型糖尿病）相关的显著心血管发病率和死亡率，更清楚地了解睾酮和胰岛素抵抗之间的相互作用具有重要的临床意义，并可能促进这些极其常见的代谢紊乱的新治疗策略的开发。

DESCRIPTION (provided by applicant): Insulin resistance plays a key role in the pathogenesis of type 2 diabetes, a disorder that affects 16 million people in the United States. Thus, elucidation of the factors that modulate insulin action has important public health implications. The relationship between androgens and insulin resistance in the human is complex with clear evidence of sexual dimorphism. In the female, insulin resistance is associated with hyperandrogenenism, while epidemiologic studies in the male consistently demonstrate an inverse relationship between testosterone and insulin. Current data on causality are conflicting. Therefore, the overall goat of this proposal is to define precisely the causal determinants of the inverse relationship between insulin resistance and testosterone in men. Specific aim 1 will determine if the abnormalities demonstrated in the hypothalamic-pituitary-gonadal axis of men with type 2 diabetes can be corrected by administration of an insulin sensitizing agent. Specific aim 2 will define the dose-response relationship between increasing testosterone and insulin resistance using two experimental human models: a) normal men after induction of hypogonadism with a GnRH antagonist and again after physiologic testosterone replacement; and b) men with congenital idiopathic hypogonadotropic hypogonadism before and after androgen replacement. Specific aim 3 will examine the impact of testosterone supplementation on insulin resistance and gtycemic control in men with type 2 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 causal determinants unequivocally defined. Given the significant cardiovascular morbidity and mortality associated with insulin resistant states such as obesity and type 2 diabetes, a clearer understanding of the interplay between testosterone and insulin resistance has important clinical significance and may potentially facilitate the development of new therapeutic strategies for these extremely common metabolic disorders.