Testosterone effects on insulin sensitivity & inflammation in T2DM and obesity

描述(由申请人提供)：大约三分之一的肥胖和2型糖尿病男性会发生性腺激素减退症(HH)。考虑到有2400万糖尿病和1亿肥胖者，其中一半是男性，肥胖症和2型糖尿病可能是人口性腺功能减退的主要原因。我们假设：1)与睾酮浓度正常的糖尿病和肥胖男性相比，肥胖和2型糖尿病男性的HH与胰岛素敏感性降低、脂肪组织质量增加、瘦体重减少、炎症和氧化应激增加、性功能受损和情绪低落有关；2)HH男性服用睾丸素24周会导致这些参数的改善。我们提出的研究将是第一个前瞻性随机试验，全面评估HH对肥胖和2型糖尿病受试者的胰岛素敏感性、身体成分、炎症和氧化指数的影响，以及T替代治疗6个月对这些参数的影响。这项研究将有两只手臂(肥胖和2型糖尿病手臂)，每只手臂有120名受试者。每支手臂将有60名患有HH的男性和60名睾酮浓度正常的男性(优降糖男性)。胰岛素敏感性将通过高胰岛素-正常血糖钳夹来评估。皮下脂肪和瘦体重由DEXA测量，腹部(内脏)脂肪由MRI测量。所有受试者都将接受高胰岛素-正常血糖钳夹、MRI、DEXA，并在基线时提供血液和尿样(用于测量炎症和氧化应激)。患有HH的男性随后将被随机接受睾酮或安慰剂凝胶治疗，总共持续24周。这些人将接受高胰岛素-正常血糖夹住，并在4周和24周提供血液和尿样检查炎症和氧化应激。患有HH的男性患者将在24周时再次进行MRI和DEXA检查。这项研究的主要终点是确定性腺功能低下和性腺功能正常的患者在基线状态下在高胰岛素-正常血糖钳夹期间全身葡萄糖摄取量的差异，以及HH受试者在接受睾酮治疗24周后葡萄糖摄取量的增加。每组30名受试者(睾丸激素和安慰剂凝胶各一组)将提供足够的能量(0.8)来检测全身葡萄糖摄取量10%的显著差异。因此，每条膀臂上有60个人，都带着HH。为了进行基线比较，每只手臂也需要60名睾丸素浓度正常的男性。因此，在这项研究中，每条胳膊上将有120名男性，总共有240名研究对象。公共卫生相关性：睾酮治疗后胰岛素抵抗的减少对2型糖尿病患者的血糖稳态和肥胖男性的2型糖尿病的预防都有重要的意义。睾酮治疗后炎症的减少可能与动脉粥样硬化和心血管风险有关。

DESCRIPTION (provided by applicant): Hypogonadotropic hypogonadism (HH) occurs in approximately one-third of obese and type 2 diabetic men. Considering that there are 24 million diabetic and 100 million obese people, of whom half are males, obesity and type 2 diabetes potentially constitute the major cause of hypogonadism in the population. We hypothesize that 1) HH in obese and type 2 diabetic men is associated with decreased insulin sensitivity, increased fat tissue mass, decreased lean body mass, increased inflammatory and oxidative stress, impaired sexual function and depressed mood as compared to diabetic and obese men with normal testosterone concentrations; and that 2) testosterone replacement for 24 weeks in men with HH leads to an improvement in these parameters. Our proposed study would be the first prospective, randomized trial to comprehensively evaluate the effect of HH on insulin sensitivity, body composition, inflammatory and oxidative indices in obese and type 2 diabetic subjects and the effect of six months of T replacement on these parameters. The study will have 2 arms (obese and type 2 diabetic arm) with 120 subjects in each arm. Each arm will have 60 men with HH and 60 men with normal testosterone concentrations (eugonadal men). Insulin sensitivity will be assessed by hyperinsulinemic-euglycemic clamps. Subcutaneous fat mass and lean body mass will be measured by DEXA and intra-abdominal (visceral) fat mass by MRI. All subjects will undergo hyperinsulinemic-euglycemic clamp, MRI, DEXA and give blood and urine samples (for measurement of inflammatory and oxidative stress) at baseline. Men with HH will then be randomized to receive testosterone or placebo gel for a total of 24 weeks. These men will undergo hyperinsulinemic- euglycemic clamps and give blood and urine samples for inflammation and oxidative stress at 4 weeks and 24 weeks. MRI and DEXA examinations will be carried out at 24 weeks again in men with HH. The primary endpoint of the study is to define a difference in whole body glucose uptake during hyperinsulinemic- euglycemic clamps between hypogonadal and eugonadal patients at baseline and an increase in glucose uptake in HH subjects after treatment with testosterone for 24 weeks. 30 subjects per group (testosterone and placebo gel each) will provide adequate power (0.8) to detect a significant difference of 10% in whole body glucose uptake. Therefore there will be 60 men with HH in each arm. For baseline comparisons, 60 men with normal testosterone concentrations will also be needed in each arm. Thus there will be 120 men in each arm and a total of 240 subjects in the study. PUBLIC HEALTH RELEVANCE: The decrease in insulin resistance after treatment with testosterone has important implications for both glucose homeostasis in type 2 diabetic patients and for prevention of type 2 diabetes in obese men. The decrease in inflammation with testosterone treatment may have relevance for atherosclerosis and cardiovascular risk.