Genomic Basis for the Circadian Regulation of B-cell Function and Glucose Homeostasis

项目摘要 昼夜节律计时系统由大脑中存在的自动调节转录反馈回路编程 以及协调代谢过程与睡眠-觉醒周期的外周组织。流行病学，临床， 遗传学研究表明，昼夜节律紊乱是糖尿病发展的一个新的危险因素。 我们的实验室已经证明，胰腺β细胞时钟的遗传废除导致急性低胰岛素血症， 糖尿病，并且胰岛素分泌在整个睡眠中表现出基础和肠促胰岛素刺激的昼夜节律调节， 唤醒周期剩下的问题是：核心的昼夜节律转录机制如何调节 在24小时时间尺度内对葡萄糖和胰岛素促分泌素的反应？生物钟突变体的证据 胰腺β细胞表明，时钟激活剂的缺失导致葡萄糖刺激的胰岛素分泌受损 和β-细胞增强子转录活性的广泛变化。这些转录的变化包括 与cAMP激动剂调节的途径交叉的途径，包括与肠促胰岛素相关的激素 与进食相关的胰岛素分泌。事实上，用胰高血糖素样肽1/cAMP激动剂刺激的胰岛 表现出明显的时间依赖性转录和胰岛素分泌反应。科学 我目前的建议的前提是，生物钟控制一天中的时间依赖性差异， 通过β细胞节律性调节对营养和膳食相关胰岛素促分泌素的反应 染色质，进而影响整个生命中的葡萄糖稳态。本提案中的研究将提供 对昼夜节律紊乱后糖耐量受损的分子病理生理学的了解 在轮班工作和睡眠紊乱的状态下。

Project Summary The circadian timing system is programmed by an autoregulatory transcription feedback loop present in brain and peripheral tissues that coordinates metabolic processes with the sleep-wake cycle. Epidemiologic, clinical, and genetic studies indicate circadian disruption as an emerging risk factor in the development of diabetes. Our lab has demonstrated that genetic abrogation of the pancreatic β cell clock leads to acute hypoinsulinemic diabetes, and that insulin secretion exhibits basal and incretin-stimulated circadian regulation across the sleep- wake cycle. A remaining question is: How does the core circadian transcription mechanism modulate response to glucose and insulin secretagogues over the 24-hr timescale? Evidence from clock mutant pancreatic β-cells suggests that loss of clock activators produces impaired glucose-stimulated insulin secretion and broad changes in transcriptional activity at β-cell enhancers. These changes in transcription include pathways that intersect with those regulated by cAMP agonists, including the incretin hormones associated with meal-related insulin secretion. Indeed, islets stimulated with a glucagon-like peptide 1/cAMP agonist exhibited pronounced time-of-day dependent transcriptional and insulin secretion responses. The scientific premise of my present proposal is that the circadian clock controls time-of-day-dependent differences in the response to nutrient and meal-associated insulin secretagogues through the rhythmic regulation of β cell chromatin, in turn impacting glucose homeostasis throughout life. The studies in this proposal will provide new insight into the molecular pathophysiology underlying impaired glucose tolerance following circadian disruption in shiftwork and states of sleep perturbation.