Impact of Shiftwork on Metabolic Flexibility and Skeletal Muscle Clocks

项目总结 轮班工作现在被认为是2型糖尿病(T2D)的危险因素；然而，这些因素背后的机制 人们对两者之间的联系知之甚少。解决这一知识鸿沟需要将新陈代谢的各个领域 和时间生物学。T2D病理生理学的特点是代谢灵活性受损和昼夜节律 而骨骼肌昼夜节律时钟可能处于这些特征的交叉点。代谢灵活性 是有效地在燃料来源之间切换的能力，主要由骨骼肌维持，而 代谢不灵活与胰岛素抵抗(IR)有关。同样，骨骼肌时钟的紊乱会导致 临床前模型中的胰岛素抵抗，并与人类糖耐量受损有关。 短期夜班的实验模拟诱导了糖尿病前期的表型，表明昼夜节律 系统在葡萄糖代谢中起着重要作用。在这里，我们将检验这样一个假设，即现实世界中的夜班工作 削弱新陈代谢的灵活性，这将与骨骼肌钟被打乱有关。我们会 进行严格控制的住院研究，以评估和比较全身代谢的灵活性 创新的24小时代谢室方案，以及白班中骨骼肌时钟基因的昼夜变化 对阵上夜班的工人。NIH K01指导科学家职业发展奖旨在丰富 应聘者的研究和培训经验，导致独立的跨学科研究利基 解决公众对轮班工人的T2D风险的健康担忧。应聘者将学习经典概念 从高级导师那里获得代谢灵活性和时间生物学，并获得强化培训和实践 在尖端方法学方面的经验：全室代谢室、人类骨骼肌细胞培养、 和临床昼夜节律协议。调查小组在解决轮班工作之间的联系方面具有独特的地位， 新陈代谢不灵活和骨骼肌时钟。AdventHealth翻译研究所(赞助商 机构)拥有一个临床研究单位，准备收集生物样品，4最先进的新陈代谢 室内服和潮湿的实验室空间，专门用于人类骨骼肌细胞培养工作。这个项目是一个 与AdventHealth的护理、全人和学术研究小组合作，后者将 通过直接联系到约1,500名上夜班的当地护士来支持招聘。这些研究将 通过识别特定于轮班工作的代谢缺陷，可能会改变这种模式 针对胰岛素抵抗和代谢脂肪酸氧化受损成分的干预措施 24小时昼夜循环的灵活性。在资助期结束时，候选人将会很好 有能力获得R级资金。运动/体力活动干预极有可能缓解或 预防轮班相关的代谢功能障碍将是未来方向的主要重点。我们完全期待 这项提议将在调查小组之间启动一系列富有成效的合作，这将 最终以大量的工作来解决倒班带来的慢性代谢性疾病负担。

PROJECT SUMMARY Shiftwork is now recognized as a risk factor for type 2 diabetes (T2D); yet the mechanisms underlying these associations are poorly understood. Addressing this knowledge gap requires converging the fields of metabolism and chronobiology. T2D pathophysiology is characterized by both impaired metabolic flexibility and circadian disruption, and skeletal muscle circadian clocks may be at the intersection of these features. Metabolic flexibility is the capacity to efficiently switch between fuel sources and is largely maintained by skeletal muscle, whereas metabolic inflexibility is implicated in insulin resistance (IR). Similarly, skeletal muscle clock disruption causes insulin resistance in pre-clinical models and is associated with impaired glucose tolerance in humans. Experimental simulations of short-term nightshift induce a prediabetic phenotype, indicating that the circadian system plays a role in glucose metabolism. Herein, we will test the hypothesis that real-world nightshift work impairs metabolic flexibility, and that this will be associated with disrupted skeletal muscle clocks. We will conduct rigorously controlled in-patient studies to assess and compare whole-body metabolic flexibility using innovative 24h metabolic chamber protocols, as well as diurnal shifts in skeletal muscle clock genes in dayshift vs. nightshift workers. This NIH K01 Mentored Scientist Career Development Award was designed to enrich the candidate’s research and training experiences, leading to an independent transdisciplinary research niche that addresses the public health concerns of T2D risk in shift workers. The candidate will learn classic concepts in metabolic flexibility and chronobiology from senior-level mentors and gain intensive training and hands-on experience in cutting-edge methodologies: whole-room metabolic chambers, human skeletal muscle cell culture, and clinical circadian protocols. The investigative team is uniquely positioned to address links between shiftwork, metabolic inflexibility, and skeletal muscle clocks. AdventHealth’s Translational Research Institute (sponsoring institution) houses a clinical research unit prepared for biospecimen collections, 4 state-of-the-art metabolic chamber suits, and wet lab space dedicated to human skeletal muscle cell culture work. This project is a collaborative effort with AdventHealth’s Nursing, Whole-Person, and Academic Research Group, who will support recruitment through directly reaching ~1,500 local nurses working nightshift. These studies will potentially shift the paradigm by identifying a metabolic defect specific to shiftwork that could be modified by interventions targeting both insulin resistance and impaired fatty acid oxidation components of metabolic flexibility across the 24h day-night cycle. At the conclusion of the funding period, the candidate will be well equipped to pursue R-level funding. It is highly likely that exercise/physical activity interventions to mitigate or prevent shiftwork-associated metabolic dysfunction will be a major focus in future directions. We fully expect that this proposal will initiate a long line of productive collaborations among the investigative team, which will eventually culminate in a significant body of work addressing the chronic metabolic disease burden of shiftwork.