Mechanisms underlying adverse health consequences of shift work

描述(申请人提供)：流行病学研究表明，倒班工作与糖尿病、肥胖症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，这种联系可能是由于禁食/进食和睡眠/觉醒周期相对于内源性昼夜节律系统的周期不一致所致。也就是说，在“生物之夜”期间的活动和食物摄入，或在“生物之日”的睡眠不足，可能会导致代谢、自主神经和内分泌的变化，这些变化是糖尿病、肥胖症和心血管疾病的先兆。例如，我们最近发现，睡眠/清醒与禁食/进食周期之间的急性实验错位--轮班工作的典型特征--可能导致血浆瘦素显著降低，血糖升高，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-迷走神经平衡的程度。在这些新发现的基础上，并克服先前工作中的一些限制，我们的目标是确定在现实模拟轮班工作的一周内的渐进性生理变化，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记物。此外，由于轮班工作的影响在临床上与实际的轮班工人最相关，我们将确定潜在的适应不良生理影响是否也在长期轮班工人中观察到，或者这一人群已经适应。我们将使用14个昼夜的实验室方案，包括受试者内的随机交叉设计，包括模拟夜班和日班时间表，使用健康的日班和日班工人的预定行为和光暴露的正式电池。主要因变量来自循环脂肪细胞激素(瘦素、脂联素、抵抗素、Ghrelin)、胰岛素抵抗(混合餐反应和静脉葡萄糖耐量试验)、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-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许多日夜轮班工作中进行监测，比较日班和夜班之间的时间表，并比较非轮班工人和长期轮班工人之间的变化。在令人信服的流行病学研究和最近的急性生理学研究之后，拟议的紧张生理学研究利用现实的轮班工作制度，现在需要确定特定的潜在代谢、内分泌、炎症、自主神经和心血管机制，这些机制解释了长期轮班工作对健康的不利影响。我们预计，这项工作将为开发有针对性和定时的疗法奠定基础，以抵消轮班工作带来的公共卫生负担。公共卫生相关性：倒班工作与糖尿病、肥胖症和心血管疾病的风险增加有关。这项研究将确定模拟夜班工作是否会增加倒班工人和非倒班工人的代谢、激素、神经、心脏和血管风险因素。这项研究将为倒班工人患糖尿病、肥胖症和心血管疾病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.