Role of Circadian Misalignment in Beta-cell Failure in Type 2 Diabetes

描述(申请人提供)：在现代社会，由于睡眠不足和轮班工作等常见情况导致的昼夜节律紊乱正变得越来越普遍，美国近20%的劳动力面临着某种类型的轮班工作。暴露于昼夜节律紊乱的个体患2型糖尿病(T2 DM)和其他代谢性疾病的风险增加。然而，这种联系背后的机制在很大程度上仍不清楚。胰岛β细胞质量和功能的丧失是促使T2 DM患者发生高血糖的重要病理生理事件。因此，当前提案的长期目标是描述暴露于与昼夜节律紊乱相关的条件下的个体中导致β细胞功能和质量丧失的分子机制。为了实现这些目标，特定目标1的研究将检查体内长期暴露于昼夜节律失调对β细胞分子昼夜节律时钟功能的影响。为了评估胰岛的生物钟功能，研究人员将使用生物发光方法，使用由增强型电荷耦合器件(ICCD)相机监控的带有PER-1：荧光素酶基因报告的转基因大鼠模型。在《特定目标2》中概述的研究将调查这样一种假设，即破坏了β细胞生物钟功能会损害细胞对氧化应激的防御反应，从而导致β细胞功能丧失和存活。最后，在第三个具体目标中，研究将解决这样的假设，即昼夜节律激素褪黑激素在调节β细胞功能、生存和对氧化应激的防御反应方面发挥着以前被低估的作用。因此，β细胞褪黑素受体信号的激活有可能减轻T2 DM患者的昼夜节律失调和氧化应激对β细胞的有害影响。总而言之，概述的具体目标将解决与理解昼夜节律系统在调节2型糖尿病患者胰岛β细胞功能和生存中的作用相关的临床相关翻译问题。

DESCRIPTION (provided by applicant): Disruption of circadian rhythms due to common conditions such as sleep loss and shift work are becoming increasingly prevalent in modern societies with nearly 20% of the workforce in the United States exposed to some type of shift work. Individuals exposed to circadian disruption have increased risk for development of Type 2 diabetes (T2DM) and other metabolic diseases. However, the mechanisms underlying this association are still largely unknown. The loss of pancreatic beta-cell mass and function is a critical pathophysiological event precipitating development of hyperglycemia in T2DM. Thus, the long-term objectives of the current proposal are to delineate molecular mechanisms responsible for the loss of beta-cell function and mass in individuals exposed to conditions associated with circadian rhythm disruptions. To achieve these objectives studies in Specific Aim 1 will examine effects of chronic exposure to circadian misalignment in-vivo on the function of the beta-cell molecular circadian clock. To assess islet circadian clock function investigators will employ bioluminescence approach using a transgenic rat model with Per-1: luciferase gene reporter monitored by intensified charge-coupled device (ICCD) camera. Studies outlined in Specific Aim 2 will investigate the hypothesis that disrupted beta-cell circadian clock function compromises cellular defense response to oxidative stress resulting in the loss of beta-cell function and survival. Lastly, in the third Specific Aim, studies will address the hypothesis that circadian hormone melatonin plays a previously underappreciated role in the regulation of beta cell function, survival and defense response to oxidative stress. Thus, the activation of beta- cell melatonin receptor signaling has the potential to attenuate deleterious effects of circadian misalignment and oxidative stress on the beta-cell in T2DM. Taken together outlined specific aims will address a clinically relevant translation question related to understanding the role of the circadian system in regulation of pancreatic beta-cell function and survival in T2DM.