Metabolic Reprogramming in Insomnia as a Function of Objective Sleep Duration

项目摘要 失眠是最常见的症状之一，与严重的痛苦和 损伤失眠症的评估依赖于患者的自我报告，而患者的自我报告往往受到以下因素的影响： 疾病严重程度以外的其他因素，使准确的诊断和治疗复杂化。此外， 失眠的存在可能基于睡眠持续时间短或不短。生物识别 失眠的“签名”，可以促进评估和亚型将显着改善症状 管理代谢生物标志物具有满足这一需求的重要前景。失眠症患者 与睡眠好的人相比，表现出代谢性过度觉醒。实验室中的急性睡眠中断 影响代谢组，但这些发现在多大程度上外推到慢性睡眠障碍， 睡眠不足是未知的。我们自己的数据显示有一个明显的代谢特征 失眠患者从良好的睡眠。因此，本研究的目的是调查 慢性失眠和睡眠不足对新陈代谢的影响为了验证这一假设，我们将进行- 四组之一的100名受试者的睡眠和代谢的深度表型（每组n=25）：1） 体动记录仪显示失眠和客观睡眠时间短（<6小时）的患者; 2）失眠患者， 客观短睡眠（>6小时）; 3）习惯性短睡眠者（<6小时），无失眠证据;以及4） 睡得好。家庭过夜多导睡眠描记和活动描记将用于排除共病睡眠 呼吸紊乱并确认失眠的存在。所有受试者将参加为期4天的住院治疗 人类表型科学中心的实验方案。食物摄入将以每小时等热量零食的形式提供， 控制饮食引起的代谢变化。前两天将用于使受试者适应 环境和饮食。在第3天早上，他们将有一个留置导管放置血液 每两小时采样一次，持续48小时，每晚进行过夜多导睡眠描记。在此期间，照明 水平将保持恒定昏暗（<250勒克斯）以最小化光暴露对昼夜节律的影响。 将使用NMR和质谱法对血清样本进行代谢组学分析。血液 样品还将用于褪黑激素和皮质醇测定，作为昼夜节律性的标准标志物。的 一个全球性的假设是，慢性失眠，睡眠不足，以及它们的组合， 与不同的全身代谢失调有关。

Project Summary Insomnia is among the most commonly experienced symptoms and is associated with significant distress and impairment. The assessment of insomnia is reliant on patient self-report, which is often influenced by a number of factors other than illness severity, complicating accurate diagnosis and treatment. Further, subtypes of insomnia may exist based on the presence or absence of short sleep duration. Identification of a biological ‘signature’ of insomnia that could facilitate assessment and subtyping would dramatically improve symptom management. Metabolic biomarkers have significant promise for meeting this need. Individuals with insomnia demonstrate metabolic hyperarousal compared to good sleepers. Acute disruption of sleep in the laboratory impacts the metabolome but the extent to which these findings extrapolate to chronic sleep disturbance or insufficient sleep is unknown. Our own data indicate there is a clear metabolic signature that differentiates patients with insomnia from good sleepers. The objective of this study is therefore to investigate the effects of chronic insomnia and insufficient sleep on metabolic profiles. In order to test this hypothesis we will conduct in- depth phenotyping of sleep and metabolism in 100 subjects who are in one of four groups (n=25 per group): 1) patients with insomnia and objective short sleep (<6 hours) on actigraphy; 2) patients with insomnia without objective short sleep (>6 hours); 3) habitual short sleepers (<6 hours) without evidence of insomnia; and 4) good sleepers. Home overnight polysomnography and actigraphy will be used to rule out comorbid sleep disordered breathing and confirm the presence of insomnia. All subjects will participate in a four-day inpatient protocol in the Center for Human Phenomic Science. Food intake will be provided in hourly isocaloric snacks to control for meal-induced shifts in metabolism. The first two days will be used to acclimate subjects to the environment and meals. On the morning of day 3 they will have an indwelling catheter placed for blood sampling every two hours for 48 hours with overnight polysomnography each night. During this time lighting levels will be kept constantly dim (<250 lux) to minimize the effects of light exposure on circadian rhythms. Metabolomics analysis of serum samples will be carried out using NMR and mass spectroscopy. Blood samples will also be used for melatonin and cortisol assays as standard markers of circadian rhythmicity. The global hypothesis that motivates this proposal is that chronic insomnia, insufficient sleep, and their combination are associated with distinct profiles of systemic metabolic dysregulation.