Mechanisms underlying adverse health consequences of shift work

描述（由申请人提供）：流行病学研究表明，轮班工作与糖尿病、肥胖和心血管疾病的风险增加有关。最近的动物研究和急性人类研究表明，这种关联可能是由于禁食/进食和睡眠/觉醒周期相对于内源性昼夜节律计时系统的周期之间的不一致。也就是说，在“生物夜晚”期间的活动和食物摄入或在“生物白天”期间的睡眠不足可能导致代谢，自主神经和内分泌变化，从而易患糖尿病，肥胖症和心血管疾病。例如，我们最近发现，睡眠/清醒和禁食/进食周期之间的急性实验性失调（轮班工作的典型特征）可导致血浆瘦素显著降低、血糖升高和平均动脉压升高。我们还发现，在昼夜节律失调期间，睡眠效率降低，在其他急性研究中已显示出显著降低循环瘦素，增加食欲和增加交感神经-迷走神经平衡的程度。在这些新发现的基础上，并克服了先前工作中的一些局限性，我们的目标是确定在现实模拟轮班工作的工作周中的渐进性生理变化，重点关注那些代谢，内分泌，炎症和心血管变量，这些变量是糖尿病，肥胖和心血管疾病易感性的生物标志物。此外，由于轮班工作的影响是最临床相关的实际轮班工人，我们将确定是否也观察到潜在的适应不良的生理影响，在慢性轮班工人或该人群已经适应。我们将使用一项14昼夜的实验室方案，该方案涉及受试者内、随机、交叉设计，包括模拟夜班和白班时间表，在健康的日间工作者和轮班工作者中使用一组正式的计划行为和光暴露。主要因变量来自循环脂肪细胞激素（瘦素、脂联素、Glucin、生长素释放肽）、胰岛素抵抗测量（混合餐反应和静脉内葡萄糖耐量试验）、炎症标志物（CRP、IL-6、TNF-α、MCP-1）、外周血管内皮功能和自主控制（儿茶酚胺、交感神经-迷走神经平衡、压力感受器敏感性和全身血压）。这些变量的变化将在轮班工作的许多昼夜中进行监测，比较白天和夜班时间表，并比较非轮班工人和长期轮班工人。继令人信服的流行病学研究和最近的急性生理学研究，建议强烈的生理学研究，利用现实的轮班工作时间表在几天内，现在需要确定具体的潜在的代谢，内分泌，炎症，自主神经和心血管机制，解释慢性轮班工作的不良健康后果。我们预计，这项工作将为开发有针对性的定时治疗奠定基础，以抵消轮班工作的公共卫生负担。公共卫生相关性：轮班工作与糖尿病、肥胖和心血管疾病的风险增加有关。这项研究将确定模拟夜间工作是否会增加轮班工人和非轮班工人的代谢，激素，神经元，心脏和血管风险因素。这项研究将为轮班工人患糖尿病、肥胖和心血管疾病的风险增加提供一个可能的机制解释。

DESCRIPTION (provided by applicant): Epidemiological studies have shown that shift work is associated with an increased risk for the development of diabetes, obesity, and cardiovascular disease. Recent animal studies and acute human studies suggest that this association may be due to the misalignment between the fasting/feeding and sleep/wake cycles relative to the cycle of the endogenous circadian timing system. That is, activity and food intake during the 'biological night' or sleep loss during the 'biological day' may result in metabolic, autonomic and endocrine changes that pre-dispose to diabetes, obesity, and cardiovascular disease. For instance, we recently found that acute experimental misalignment between the sleep/wake and fasting/feeding cycle-typical of shift work-can lead to significantly decreased plasma leptin, increased plasma glucose and increased mean arterial pressure. We also found reduced sleep efficiency during circadian misalignment to an extent that has been shown to significantly decrease circulating leptin, increase appetite and increase sympatho-vagal balance in other acute studies. Building on these new findings, and overcoming a number of limitations in the prior work, we aim to determine the progressive physiological changes across a work week of realistic simulated shift work focusing on those metabolic, endocrine, inflammatory, and cardiovascular variables that are biomarkers of susceptibility to the development of diabetes, obesity, and cardiovascular disease. Also, since the effect of shift work is most clinically relevant in actual shift workers, we will determine whether the potential maladaptive physiological effects are observed also in chronic shift workers or that this population has adapted. We will use a 14 day/night laboratory protocol involving a within-subject, randomized, cross-over design including a simulated night shift and day shift schedule using a formal battery of scheduled behaviors and light exposures in healthy day workers and shift workers. The principal dependent variables are derived from circulating adipocyte hormones (leptin, adiponectin, resistin, ghrelin), measures of insulin resistance (mixed meal response and intravenous glucose tolerance test), inflammatory markers (CRP, IL-6, TNF-alpha, MCP-1), peripheral vascular endothelial function, and autonomic control (catecholamines, sympatho-vagal balance, baroreceptor sensitivity and systemic blood pressure). Changes in these variables will be monitored across numerous days and nights of shift work, compared between day and night shift schedules, and compared between non-shift workers and chronic shift workers. Following on from the convincing epidemiological studies and recent acute physiology studies, the proposed intense physiological study utilizing realistic shift work-schedules over a number of days are now needed to determine the specific underlying metabolic, endocrine, inflammatory, autonomic and cardiovascular mechanisms that explain the adverse health consequences of chronic shift work. We anticipate that this work will lay the groundwork for the development of targeted and timed therapies to counteract the public health burden of shift work. PUBLIC HEALTH RELEVANCE: Shift work is associated with an increased risk for diabetes, obesity, and cardiovascular disease. This research will determine whether simulated night work increases metabolic, hormonal, neuronal, heart and blood vessel risk factors in shift workers and non-shift workers. This research will provide a possible mechanistic explanation for the increased risk for diabetes, obesity, and cardiovascular disease in shift workers.