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型糖尿病是一种在美国影响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。在人类中，雄激素和胰岛素抵抗之间的关系是复杂的，有明确的证据表明存在性别二型性。在女性中，胰岛素抵抗与高雄激素血症有关，而在男性中，流行病学研究一直表明睾酮和胰岛素之间存在相反的关系。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准确地定义男性胰岛素抵抗和睾丸素之间反向关系的因果决定因素。 具体目标1将确定2型糖尿病患者下丘脑-垂体-性腺轴的异常是否可以通过注射胰岛素增敏剂来纠正。具体目标2将利用两个实验人体模型确定睾酮增加和胰岛素抵抗之间的剂量-反应关系：a)正常男性在用GnRH拮抗剂诱导性腺功能减退后，在生理性睾酮替代后再次；以及b)先天性特发性性腺激素低促性腺功能减退患者在雄激素替代前后。具体目标3将研究补充睾丸素对2型糖尿病男性患者胰岛素抵抗和血糖控制的影响。 这项建议中概述的选择性和顺序的性类固醇和胰岛素水平的操作将使人们能够准确地确定男性睾酮和胰岛素抵抗之间的关系，并明确定义它们的因果决定因素。鉴于肥胖和2型糖尿病等与胰岛素抵抗状态相关的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，并有可能促进这些极其常见的代谢疾病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.