Cardiometabolic Risk of Shift Work: Sleep Loss vs. Circadian Disruption

描述(申请人提供)：近20%的美国工作人口从事倒班工作。众所周知，倒班工作与患心血管疾病和糖尿病的风险增加有关，但这种心脏代谢风险增加的机制尚不清楚。轮班工作通常与睡眠不足和昼夜节律失调有关。虽然睡眠减少最近被认为是肥胖、糖尿病和高血压的一个新的危险因素，但内源性节律的内在同步性的临床意义是一个基本的、尚未回答的昼夜生物学问题。我们小组最近完成了一项实验室研究，表明短期暴露在睡眠不足和昼夜节律失调的环境中与心脏代谢变化有关，而当睡眠保持一致和延长时，这种变化不会逆转。相比之下，暴露在睡眠不足而没有昼夜节律失调的情况下观察到的变化在延长睡眠后得到完全纠正。这些实验室发现首次提供了证据，支持昼夜节律紊乱的不利健康后果与睡眠不足无关。本申请的总体目标是检验这样一种假设，即长期暴露于昼夜节律失调和睡眠不足的倒班工人比白天工作的人有更高的心脏代谢风险，并且昼夜节律失调和睡眠不足都是心脏代谢风险增加的原因。我们将测量心脏代谢风险的标记物，这些标记物会迅速而深刻地受到睡眠时间和/或质量减少的影响，并详细评估由中央昼夜节律起搏器控制的节律与外周组织时钟基因表达节律之间的相位关系。我们建议研究两组工作人员(即日间工作人员、轮班工作人员)，他们受雇于芝加哥大学医学中心，并且他们的工作时间表至少保持了一年。在对暴露于昼夜节律失调和正常睡眠时间的长期动态监测之后，受试者将接受反复详细的实验室评估：1.昼夜节律的内部去同步，包括白细胞中昼夜节律的基因表达节律；2.心脏代谢风险的标记物：通过静脉葡萄糖耐量试验(IvGTT)、高敏感性C反应蛋白(HsCRP)、24小时心率变异性评估的葡萄糖耐量和胰岛素抵抗；3.白细胞中的端粒长度和端粒酶活性，这是生物衰老的标记物，已与心脏代谢风险因素有关，并受生活方式的影响。这项工作有望证明昼夜节律失调对数百万参与倒班工作的人的临床意义，并提出新的策略来提高对倒班工作的耐受性。 公共卫生相关性：近20%的美国工作人口从事倒班工作，这种情况与患心血管疾病和糖尿病的风险增加有关。该项目的总体目标是确定昼夜节律失调与睡眠不足在倒班工作增加的心脏代谢风险中各自所起的作用。

DESCRIPTION (provided by applicant): Nearly 20% of the US working population is engaged in shift work. It is well recognized that shift work is associated with an increased risk of developing cardiovascular disease and diabetes but the mechanisms underlying this elevated cardiometabolic risk remain unclear. Shift work is generally associated with sleep loss and circadian misalignment. While sleep curtailment has been recently identified as a putative novel risk factor for obesity, diabetes and hypertension, the clinical significance of the internal synchrony of endogenous rhythms is a fundamental and as yet unanswered question of circadian biology. Our group has recently completed a laboratory study showing that short-term exposure to sleep loss with circadian misalignment is associated with cardiometabolic alterations that are not reversed when sleep is aligned and extended. By comparison, alterations observed following exposure to sleep loss without circadian misalignment are fully corrected after sleep extension. These laboratory findings provided for the first time evidence in support of adverse health consequences of circadian disruption independent of sleep loss. The overall goal of the present application is to test the hypothesis that shift workers, who are chronically exposed to circadian misalignment and sleep loss, have a higher cardiometabolic risk than day workers, and that both circadian misalignment and sleep loss contribute to the elevated cardiometabolic risk. We will measure markers of cardiometabolic risk that are rapidly and profoundly affected by reduced sleep duration and/or quality and perform a detailed assessment of the phase relationships between rhythms controlled by the central circadian pacemaker and rhythms of clock gene expression in peripheral tissue. We propose to study two groups of workers (i.e. day workers, shift workers) who are employed at the University of Chicago Medical Center and who have maintained their work schedules for at least one year. Following extended ambulatory monitoring of exposure to circadian misalignment and usual sleep duration, the subjects will undergo repeated detailed laboratory assessments of 1. internal desynchrony of circadian rhythms, including rhythms of circadian gene expression in leukocytes; 2. markers of cardiometabolic risk: glucose tolerance and insulin resistance assessed by intravenous glucose tolerance testing (ivGTT), high sensitivity C-reactive protein (hsCRP), 24-h profile of heart rate variability; 3. telomere length and telomerase activity in leukocytes, which are markers of biological aging that have been linked to cardiometabolic risk factors and are influenced by lifestyle. This work is expected to demonstrate the clinical significance of circadian misalignment for the millions of individuals involved in shift work and to suggest novel strategies to improve tolerance to shift work. Public Health Relevance: Nearly 20% of the US working population is engaged in shift work, a condition associated with an increased risk of developing cardiovascular disease and diabetes. The overall goal of this project is to define the respective roles of circadian misalignment versus sleep loss in the elevated cardiometabolic risk of shift work.