INTERPLAY BETWEEN GONADAL STEROIDS AND INSULIN IN MEN

男性性腺类固醇和胰岛素之间的相互作用

• 批准号: 6845335
• 负责人: FRANCES J HAYES
• 金额: $ 8.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845335
• 关键词: blood glucose; clinical research; hormone regulation /control mechanism; human subject; hypoglycemic agents; hypogonadism; hypothalamic pituitary axis; insulin sensitivity /resistance; male; noninsulin dependent diabetes mellitus; patient oriented research; pituitary gonadal axis; testosterone

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.

描述（由申请人提供）： 胰岛素抵抗在2型糖尿病的发病机理中起关键作用，这种疾病影响了美国的1600万人。因此，阐明调节胰岛素作用的因素具有重要的公共卫生影响。人类中雄激素和胰岛素抵抗之间的关系是复杂的，有性别二态性的明确证据。在雌性中，胰岛素抵抗与多雄激解术有关，而男性的流行病学研究始终显示出睾丸激素与胰岛素之间的反比关系。有关因果关系的当前数据是矛盾的。因此，该提议的总体山羊是精确定义男性胰岛素抵抗和睾丸激素之间反比关系的因果决定因素。 具体的目标1将确定在2型糖尿病的男性下丘脑 - 垂体 - 基达轴中是否表现出异常，可以通过给药胰岛素敏化剂来纠正。特定的目标2将使用两个实验人类模型来定义增加睾丸激素和胰岛素抵抗之间的剂量反应关系：a）与GNRH拮抗剂诱导性腺功能减退后的正常男性，并在生理睾丸激素替代后再次诱导； b）先天性特发性性低位核性性低负态之前和之后的男性。特定的目标3将检查补充睾丸激素对2型糖尿病男性胰岛素抵抗和肺炎控制的影响。 该提案中概述的性类固醇和胰岛素水平的选择性和顺序操纵将允许确定男性睾丸激素与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（如肥胖症和2型糖尿病）相关的明显心血管发病率和死亡率，对睾丸激素与胰岛素抵抗之间的相互作用具有更清晰的了解具有重要的临床意义，并且有可能促进这些极为常见的代谢性疾病的新治疗策略的发展。