Modulation of Insulin Action by Testosterone in Men

描述（申请人提供）：胰岛素抵抗在2型糖尿病的发病机制中发挥着关键作用，这种疾病现已达到流行病的程度，预计到2010年将影响全球2.2亿人。因此，阐明改变胰岛素敏感性的因素具有重要的公共卫生意义。虽然流行病学研究一致表明男性胰岛素抵抗和睾酮（T）水平之间存在负相关关系，但缺乏因果关系的数据。此外，目前还不清楚T是否可能通过雄激素受体介导的直接作用或雌二醇（E2）芳构化介导的间接作用来调节胰岛素的作用。因此，这项建议的总体目标是确定性腺性类固醇在调节男性胰岛素作用中的作用。特定目标（SA）#1将检查性类固醇的急性（24小时）和短期（4周）抑制对正常男性胰岛素敏感性的影响（方案1）。将使用促性腺激素释放激素拮抗剂诱导性腺功能减退。将通过高胰岛素-正常血糖钳夹法评估胰岛素敏感性的变化。胰岛素敏感性变化的潜在机制将通过分析身体成分的变化，以及脂肪代谢（脂解和脂质氧化速率）和骨骼肌（肌纤维类型，肌细胞内脂质含量和基因表达谱）的详细研究来探索。方案2将检查3个月T治疗对代谢综合征所有组分的影响（SA #2），使用SA #1概述的方法研究胰岛素敏感性变化的潜在机制，以及E2在介导T对胰岛素敏感性影响中的作用（SA #3）。本研究通过将精心设计的生理实验与最先进的遗传学和成像研究相结合，提供了确定T是否以及如何调节男性胰岛素敏感性的机会。据估计，目前60岁以上的男性中有20%的T水平较低。因此，如果低T水平被证明在胰岛素抵抗的发病机制中起作用，那么T很可能代表预防和治疗男性代谢综合征和2型糖尿病的重要治疗方式。

DESCRIPTION (provided by applicant): Insulin resistance plays a key role in the pathogenesis of type 2 diabetes, a disease now reaching epidemic proportions and anticipated to affect 220 million people worldwide by 2010. Thus, elucidating the factors that alter insulin sensitivity has important public health implications. While epidemiologic studies consistently demonstrate an inverse relationship between insulin resistance and testosterone (T) levels in men, data on causality are lacking. In addition, it is unclear whether T might modulate insulin action by a direct effect mediated through the androgen receptor or an indirect effect mediated by aromatization to estradiol (E2). Thus, the overall goal of this proposal is to define the role of gonadal sex steroids in modulating insulin action in men. Specific Aim (SA) #1 will examine the impact of acute (24 hours) and short-term (4 weeks) suppression of sex steroids on insulin sensitivity in normal men (Protocol 1). A gonadotropin-releasing hormone antagonist will be used to induce hypogonadism. Changes in insulin sensitivity will be assessed by a hyperinsulinemic-euglycemic clamp. The mechanisms underlying changes in insulin sensitivity will be explored by analyzing changes in body composition, and detailed studies of fat metabolism (rates of lipolysis & lipid oxidation) and skeletal muscle (muscle fiber type, intramyocellular lipid content, & gene expression profiles). Protocol 2 will examine the impact of 3 months of T therapy on all components of the metabolic syndrome (SA #2), the mechanism underlying any changes in insulin sensitivity using the methods outlined for SA #1, and the role of E2 in mediating the effect of T on insulin sensitivity (SA# 3). The present study, by combining carefully designed physiologic experiments with state of the art genetic and imaging studies, affords the opportunity to determine, if and how, T modulates insulin sensitivity in men. It is currently estimated that 20% of men over 60 years of age have low T levels. Therefore, if low T levels are shown to play a role in the pathogenesis of insulin resistance, T may well represent an important therapeutic modality for both preventing and treating the metabolic syndrome and type 2 diabetes in men.