Hormonal Mechanisms of Sleep Restriction

睡眠限制的荷尔蒙机制

基本信息

批准号：
9059175
负责人：
Peter Yiwen Liu
金额：
$ 40.91万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-10 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9059175
关键词：
Address Adrenal Glands Adult Affect American Amino Acids Anabolism Blood Pressure Carbohydrates Catabolism Circadian Rhythms Cognition Complement 3 Corticotropin Corticotropin-Releasing Hormone Cosyntropin Country Cross-Over Studies Data Development Dexamethasone Diabetes Mellitus Diet Disease Dose Drug Targeting Equilibrium Estradiol Family Fatty Acids Fatty acid glycerol esters Feedback Female Future Glucocorticoids Goals Gonadotropin Hormone Releasing Hormone Gonadotropin-Releasing Hormone Receptor Health Health Care Costs High Prevalence Hormonal Hormonal Change Hormones Hydrocortisone Hypothalamic structure Impaired cognition Incidence Infusion procedures Insulin Resistance Intervention Ketoconazole Lead Link Luteinizing Hormone Measures Mediator of activation protein Mental disorders Metabolic Metabolic syndrome Middle Insomnia Mineralocorticoid Receptor Modeling Moods Movement Disorders Muscular Atrophy Non-Insulin-Dependent Diabetes Mellitus Obesity Obstructive Sleep Apnea Occupational Osteoporosis Pathology Pattern Physiological Pituitary Gland Pituitary-Adrenal System Placebo Control Play Post-Traumatic Stress Disorders Prediabetes syndrome Predisposition Process Production Pulse Pressure Randomized Regulation Restless Legs Syndrome Role Signal Transduction Sleep Sleep Apnea Syndromes Sleep Disorders Steroid biosynthesis Stress Testing Testis Testosterone Time Virulence Factors biological adaptation to stress bone cognitive function cost deprivation diabetic ganirelix leydig interstitial cell male men prevent psychologic public health relevance randomized placebo controlled trial response sarcopenia social stressor targeted treatment young man

项目摘要

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.

描述（由申请人提供）：睡眠限制，即由于睡眠不足或睡眠中断而导致的睡眠减少，影响着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导致的睡眠中断引起的。睡眠限制会引发压力，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，估计每年造成 1740 亿美元的损失。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，但睡眠限制导致胰岛素抵抗的机制仍不清楚。在胰岛素抵抗上升的机制被揭示之前，无法开发靶向疗法。该提案旨在确定增加的 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垂体肾上腺 (HPA) 轴激活和下丘脑垂体睾丸 (HPT) 失活的过程，这些过程在 F 增加和 T 减少时必须存在。改变这两种激素的释放或作用的干预措施是非常可行的，并将提供一种方法来改变该国2型糖尿病发病率的急剧上升，但首先必须概述这些激素的作用。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）男性分组，将睡眠时间限制在每晚 4 小时，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两者固定的条件下睡眠限制对胰岛素抵抗的影响，证明增加 F 和减少 T 对于睡眠限制诱导胰岛素抵抗至关重要。我们还将确定另外 20 名年轻男性的睡眠限制是否会通过以下方式增加 F： (a) 增加下丘脑促肾上腺皮质激素释放激素 (CRH)，通过检查垂体 ACTH 对次最大剂量地塞米松的变化进行评估； (b) 肾上腺产生的 F 增加，以响应标准低剂量静脉注射。促收缩素测试； (c) F 对垂体 ACTH 的负反馈减弱，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，我们将检查睡眠限制是否会通过以下方式降低这 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) 间质细胞响应 rhLH 产生 T 细胞减弱； (c) 通过 T 增强垂体 LH 的负反馈，通过用酮康唑量化 LH 分泌到 T 剥夺来测试。目标是了解睡眠时间缩短或睡眠紊乱如何导致代谢疾病，并揭示其基础荷尔蒙机制。这些研究有可能对理解 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，并造成高昂的国民健康成本。