Hormonal Mechanisms of Sleep Restriction

描述（由申请人提供）：睡眠限制，睡眠不足或中断导致的睡眠减少，影响了美国三分之一的成年人。它由睡眠期缩短、环境干扰或阻塞性睡眠呼吸暂停、运动障碍或其他病理引起的睡眠中断引起。睡眠不足会引起压力，并导致胰岛素抵抗，导致2型糖尿病的发展。2型糖尿病影响2600万美国人，估计每年花费1740亿美元。尽管参与应激反应的激素，主要是皮质醇（F）和睾酮（T），似乎起着主要作用，但睡眠限制导致胰岛素抵抗的潜在机制仍不清楚。在胰岛素抵抗上升的潜在机制被揭示之前，无法开发靶向治疗。该建议旨在确定增加的F和减少的T是胰岛素抵抗发展的基础。我们还将揭示导致下丘脑-肾上腺（HPA）轴激活和下丘脑-睾丸（HPT）失活的过程，当F增加和T减少时，这些过程必须存在。通过干预来改变这两种激素的释放或作用是非常可行的，并将提供一种方法来改变这个国家2型糖尿病发病率的惊人增长，但这些激素的作用必须首先概述。我们将进行2项随机安慰剂对照研究，将40名和20名年轻（22- 45岁）男性的睡眠限制为4小时/夜，持续4晚。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与在两者都固定的条件下睡眠限制对胰岛素抵抗的影响，来证明增加F和减少T对于睡眠限制诱导胰岛素抵抗是必不可少的。我们还将在另外20名年轻男性中确定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），通过检查次最大剂量地塞米松对垂体ACTH的改变进行评估;（B）增加肾上腺产生F，对标准低剂量i. v.促肾上腺皮质激素试验作出反应;和（c）F抑制垂体ACTH负反馈，通过量化释放的ACTH分泌适应酮康唑阻断类固醇生成来评估。然后，我们将通过以下方式检查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），通过检查垂体LH对次最大剂量加尼瑞克的反应进行测试;（B）抑制Leydig细胞对rhLH的T产生;（c）通过T增加垂体LH的负反馈，通过定量LH分泌对酮康唑剥夺T进行测试。其目的是了解睡眠缩短或睡眠紊乱如何导致代谢疾病，并揭示基础激素机制。这些研究有可能对理解导致2型糖尿病的机制产生重大影响，2型糖尿病与睡眠呼吸障碍和其他缩短睡眠时间的疾病密切相关，并造成过高的国家卫生成本。

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.