Modulation of Insulin Action by Testosterone in Men

睾酮对男性胰岛素作用的调节

• 批准号: 7146740
• 负责人: FRANCES J HAYES
• 金额: $ 32.52万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146740
• 关键词: androgen receptor; blood chemistry; body composition; calorimetry; clinical research; endocrine pharmacology; estradiol; gene expression profiling; glucose clamp technique; gonadotropin releasing factor; hormone inhibitor; hormone therapy; human subject; insulin sensitivity /resistance; lipid metabolism; longitudinal human study; magnetic resonance imaging; male; metabolic syndrome; muscle function; oxidative phosphorylation; patient oriented research; photon absorptiometry; radiotracer; striated muscles; testosterone

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.

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着关键作用，这种疾病现在达到流行病的比例，预计到2010年会影响全球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健康影响。尽管流行病学研究始终显示出男性胰岛素抵抗与睾丸激素水平之间的反比关系，但缺乏有关因果关系的数据。此外，尚不清楚T是否会通过通过雄激素受体介导的直接效应或通过芳香化介导的雌二醇介导的直接效应来调节胰岛素作用（E2）。因此，该提案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。具体目标（SA）＃1将检查性类固醇对正常男性胰岛素敏感性的急性（24小时）和短期（4周）的影响（协议1）。促性腺激素释放激素的拮抗剂将用于诱导性能症。胰岛素敏感性的变化将通过高胰岛素 - 糖血糖夹评估。通过分析人体组成的变化以及脂肪代谢（脂解和脂质氧化速率）和骨骼肌（肌肉纤维类型，细胞内细胞内脂质脂质含量和基因表达概要）的详细研究，将探索胰岛素敏感性变化的机制。方案2将检查3个月治疗对代谢综合征所有成分的影响（SA＃2），使用SA＃1概述的方法在胰岛素敏感性变化的基础机制以及E2在介导T对T对胰岛素敏感性的影响（SA＃3）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研究和成像研究结合起来，为确定是否以及如何调节男性的胰岛素敏感性提供了机会。目前，据估计，60岁以上的男性中有20％的T水平较低。因此，如果显示低的T水平在胰岛素抵抗的发病机理中起作用，则T可能代表了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。