Impact of Shiftwork on Metabolic Flexibility and Skeletal Muscle Clocks

项目概要 轮班工作现在被认为是 2 型糖尿病 (T2D) 的危险因素；然而这些背后的机制 人们对协会知之甚少。解决这一知识差距需要融合新陈代谢领域 和时间生物学。 T2D 病理生理学的特点是代谢灵活性和昼夜节律受损 破坏，骨骼肌生物钟可能处于这些特征的交叉点。代谢灵活性 是在燃料来源之间有效切换的能力，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，骨骼肌时钟中断会导致 临床前模型中的胰岛素抵抗与人类葡萄糖耐量受损有关。 短期夜班的实验模拟会诱发糖尿病前期表型，表明昼夜节律 系统在葡萄糖代谢中发挥作用。在这里，我们将检验现实世界夜班工作的假设 损害代谢灵活性，这与骨骼肌时钟紊乱有关。我们会 进行严格控制的住院研究，以评估和比较全身代谢灵活性 创新的 24 小时代谢室方案，以及白班骨骼肌时钟基因的昼夜变化 与夜班工人相比。 NIH K01 导师科学家职业发展奖旨在丰富 候选人的研究和培训经验，导致独立的跨学科研究利基 解决轮班工人 T2D 风险的公共卫生问题。候选人将学习经典概念 高级导师的代谢灵活性和时间生物学，并获得强化培训和实践 尖端方法的经验：全室代谢室、人类骨骼肌细胞培养、 和临床昼夜节律协议。调查团队具有独特的优势，可以解决轮班工作之间的联系， 代谢不灵活和骨骼肌时钟。 AdventHealth 转化研究所（赞助 机构）设有一个为生物样本收集准备的临床研究单位、4 个最先进的代谢中心 室内服和专门用于人类骨骼肌细胞培养工作的湿实验室空间。这个项目是一个 与 AdventHealth 的护理、全人和学术研究小组合作，该小组将 通过直接接触约 1,500 名夜班当地护士来支持招聘。这些研究将 通过识别轮班工作特有的代谢缺陷，可以改变范式，可以通过以下方法进行修改 针对胰岛素抵抗和代谢脂肪酸氧化受损的干预措施 24小时昼夜循环的灵活性。资助期结束时，候选人将表现良好 有能力寻求 R 级资金。锻炼/身体活动干预很可能可以减轻或 预防与轮班工作相关的代谢功能障碍将是未来方向的主要焦点。我们充分期待 该提案将在调查小组之间启动一系列富有成效的合作，这将 最终导致大量工作解决轮班工作带来的慢性代谢疾病负担。

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.