Testosterone effects on insulin sensitivity & inflammation in T2DM and obesity

描述（由申请人提供）：低促性腺激素性性腺功能减退症（HH）发生在大约三分之一的肥胖和2型糖尿病男性中。考虑到有2400万糖尿病患者和1亿肥胖患者，其中一半是男性，肥胖和2型糖尿病可能构成人群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型糖尿病男性中的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、性功能受损和抑郁情绪相关; 2）HH男性中睾酮替代治疗24周可改善这些参数。我们提出的研究将是第一个前瞻性的随机试验，以全面评估HH对肥胖和2型糖尿病受试者的胰岛素敏感性，身体组成，炎症和氧化指数的影响，以及6个月的T替代对这些参数的影响。该研究将有2组（肥胖和2型糖尿病组），每组120名受试者，每组将有60名HH男性和60名睾酮浓度正常的男性（性腺正常男性）。将通过高胰岛素-正常血糖钳夹评估胰岛素敏感性。将通过DEXA测量皮下脂肪量和瘦体重，并通过MRI测量腹腔内（内脏）脂肪量。所有受试者将接受高胰岛素-正常血糖钳夹、MRI、DEXA，并在基线时提供血液和尿液样本（用于测量炎症和氧化应激）。然后，HH男性患者将随机接受睾酮或安慰剂凝胶治疗，共24周。这些男性将接受高胰岛素-正常血糖钳夹，并在4周和24周时提供血液和尿液样本用于炎症和氧化应激。将在24周时再次对HH男性进行MRI和DEXA检查。本研究的主要终点是定义基线时性腺功能减退和性腺功能正常患者之间在高胰岛素-正常血糖钳夹期间的全身葡萄糖摄取差异，以及睾酮治疗24周后HH受试者的葡萄糖摄取增加。每组30例受试者（睾酮和安慰剂凝胶各30例）将提供足够的把握度（0.8），以检测全身葡萄糖摄取的10%显著差异。因此，每组将有60名男性HH。对于基线比较，每组还需要60名睾酮浓度正常的男性。因此，每组将有120名男性，研究中共有240名受试者。公共卫生相关性：睾酮治疗后胰岛素抵抗的降低对2型糖尿病患者的葡萄糖稳态和肥胖男性2型糖尿病的预防具有重要意义。睾酮治疗的炎症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.