Hormonal Mechanisms of Sleep Restriction

描述(申请人提供)：睡眠限制，睡眠不足或睡眠中断导致的睡眠减少，影响到美国三分之一的成年人。它是由睡眠时间缩短、环境干扰或阻塞性睡眠呼吸暂停、运动障碍或其他病理造成的睡眠中断引起的。睡眠限制会导致压力，并导致胰岛素抵抗，从而导致2型糖尿病的发生。2型糖尿病影响着2600万美国人，估计每年的成本为1740亿美元。睡眠受限导致胰岛素抵抗的机制尚不清楚，尽管参与应激反应的激素，主要是皮质醇(F)和睾酮(T)似乎发挥了主要作用。在胰岛素抵抗增加的机制被揭开之前，靶向治疗是不可能被开发出来的。这项建议旨在确定F增加和T减少是胰岛素抵抗发生的基础。我们还将揭示导致下丘脑垂体性肾上腺(HPA)轴激活和下丘脑垂体性睾丸(HPT)失活的过程，这些过程必须在F增加和T减少时出现。干预措施改变这两种激素的释放或作用是非常可行的，并将提供一种手段来改变美国日益增长的2型糖尿病发病率，但必须首先概述这些激素的作用。我们将进行两项随机的安慰剂对照研究，将40名和20名年轻(22-45岁)男性的睡眠限制在4个晚上，每晚4小时。我们将通过比较40名男性在F和T可以自由变化的条件下和在F和T都固定的条件下睡眠限制对胰岛素抵抗的影响，证明F增加和T减少是导致胰岛素抵抗的睡眠限制所必需的。我们还将确定，在另外20名年轻男性中，睡眠限制是否通过以下方式增加F：(A)增加下丘脑促肾上腺皮质激素释放激素(CRH)，通过检测垂体ACTH对次最大剂量地塞米松的变化来评估；(B)对标准低剂量静脉注射的反应，增加肾上腺F的产生。(C)通过量化释放的ACTH对酮康唑阻断类固醇生成的分泌适应来评估F对垂体ACTH的抑制负反馈。然后，我们将通过以下方法来检验睡眠限制是否会降低这20名男性的T：(A)降低下丘脑促性腺激素释放激素(GnRH)，通过检测下丘脑促性腺激素释放激素(GnRH)对亚最大剂量的Ganirelx的反应来测试；(B)对rh LH的反应抑制Leydig细胞产生T；以及(C)通过用酮康唑量化黄体生成素分泌来测试T对T剥夺的影响，从而增强T对脑垂体促黄体激素的负反馈。其目的是了解睡眠时间缩短或睡眠紊乱如何导致新陈代谢不良，并揭示其背后的荷尔蒙机制。这些研究有可能对理解2型糖尿病的发病机制产生重大影响，2型糖尿病与睡眠呼吸紊乱和其他缩短睡眠时间的疾病密切相关，并给国家健康带来高昂的成本。

DESCRIPTION (provided by applicant): Sleep restriction, the reduction in sleep resulting from insufficient or interrupted sleep, affects a third of adults in the US. It arises from shortened slep periods, environmental disturbances, or disrupted sleep from obstructive sleep apnea, movement disorders, or other pathology. Sleep restriction induces stress, and causes insulin resistance, resulting in development of type 2 diabetes mellitus. Type 2 diabetes mellitus affects 26 million Americans at an estimated cost of $174 billion/year. The mechanisms underlying development of insulin resistance from sleep restriction remain unknown, although hormones involved in the stress response, principally cortisol (F) and testosterone (T), appear to play a major role. Until the mechanisms underlying rising insulin resistance are unveiled, targeted therapies cannot be developed. This proposal aims to establish that increased F and decreased T underlie development of insulin resistance. We will also uncover the processes that cause hypothalamopituitary adrenal (HPA) axis activation and hypothalamopituitary testicular (HPT) deactivation that must be present when F is increased and T is decreased. Interventions to modify release or action of these two hormones is eminently feasible, and will provide a means to alter the formidable increasing incidence of type 2 diabetes in this country, but the role of those hormones must initially be outlined. We will conduct 2 randomized placebo controlled studies that will restrict sleep to 4h/night for 4 nights in groups of 40 and 20 young (22-45y) men. We will show that increased F and decreased T are essential for sleep restriction to induce insulin resistance by comparing effects of sleep restriction on insulin resistance in 40 men under conditions where F and T can change freely with conditions where both are fixed. We will also determine, in 20 additional young men, if sleep restriction increases F through: (a) increasing hypothalamic corticotropin releasing hormone (CRH), evaluated by examining alterations in pituitary ACTH to a submaximal dose of dexamethasone; (b) heightened adrenal gland production of F, in response to the standard low dose i.v. cosyntropin test; and (c) muted negative feedback of pituitary ACTH by F, evaluated by quantifying unleashed ACTH secretory adaptations to blockade of steroidogenesis by ketoconazole. We will then examine if sleep restriction decreases T in these same 20 men by: (a) decreasing hypothalamic gonadotropin releasing hormone (GnRH), tested by examining the pituitary LH response to a submaximal dose of ganirelix; (b) muted Leydig cell production of T in response to rhLH; and (c) heightened negative feedback of pituitary LH by T, tested by quantifying LH secretion to T deprivation with ketoconazole. The goal is to understand how shortened or disturbed sleep results in metabolic ill-health, and to unveil the underpinning hormonal mechanisms. The studies have the potential to exert a major impact on understanding the mechanisms contributing to type 2 diabetes mellitus, which is closely associated with sleep-disordered breathing and other conditions which shorten sleep time, and imposes an exorbitant national health cost.