Recurrent circadian disruption & pancreatic B-cell responsiveness in older peopl

项目总结（见说明）： 器官、组织和细胞中的昼夜节律被光和营养的周期带入24小时，随着年龄的增长而失去振幅和相位稳定性。人类在葡萄糖耐量方面表现出内源性昼夜节律，并在夜间对具有较高葡萄糖水平的膳食做出反应。GWAS涉及T2 D风险的昼夜节律基因，以及调节葡萄糖代谢的昼夜节律分子钟（CMC）的一些关键成分。我们发现，尽管胰岛素水平升高，但年轻人急性昼夜节律失调导致餐后血糖升高，而周期性昼夜节律紊乱（RCD）与睡眠限制相结合 导致餐后血糖升高和胰岛素降低，即使在 一个适当的昼夜节律阶段。这可以解释为什么夜班工人患上与代谢老化相关的疾病的风险增加：肥胖，代谢综合征和糖尿病。由于昼夜节律失调在美国老年人中很常见，其中有300万人在夜间工作，因此即使在睡眠不足最小化的情况下，开发靶向治疗以了解与RCD相关的代谢风险也至关重要。 项目1将评估RCD对老年人葡萄糖代谢的影响。而慢性睡眠不足和急性昼夜节律失调诱导胰岛素抵抗，我们假设，RCD破坏中央和外周CMC之间的协调，从而深刻地损害胰腺P细胞的反应性和诱导胰岛素抵抗。通过比较老年受试者对强制禁食（T= 28小时）方案的反应，我们将测试以下假设：1）急性昼夜节律失调将诱导葡萄糖水平升高，尽管胰岛素水平升高; 2） 3-刚果民盟一周历史（同时最大限度地减少睡眠损失）将诱导葡萄糖水平升高，伴随胰岛素水平降低，即使在正常昼夜节律时进食; 3）3周RCD病史（同时最大限度地减少睡眠损失）将改变昼夜皮质醇节律的波形和幅度;以及4）重新实施24小时光暗/进餐时间表1周将重新引导昼夜节律，使皮质醇节律以及葡萄糖和胰岛素对标准化进餐的反应正常化。 该项目将有助于了解昼夜节律紊乱的独特代谢风险，为旨在开发针对肥胖，代谢综合征和糖尿病风险的治疗方法的研究奠定基础，并提高老年人的健康和生活质量。

PROJECT SUMMARY (See instructions): Circadian rhythms in organs, tissues and cells, which are entrained to the 24-h day by cycles of light and nutrition, lose amplitude and phase stability with age. Humans exhibit an endogenous circadian rhythm in glucose tolerance and respond to meals with higher glucose levels at night. GWAS implicate circadian genes in the risk of T2D, and some key components of the circadian molecular clock (CMC) that regulate glucose metabolism. We have found that acute circadian misalignment in young adults leads to higher post-prandial glucose despite elevated insulin, whereas recurrent circadian disruption (RCD) combined with sleep restriction leads to higher post-prandial glucose and decreased insulin, even when the meal is consumed at an appropriate circadian phase. This may explain why night workers are at increased risk of conditions associated with metabolic aging: obesity, metabolic syndrome and diabetes. Since circadian dysregulation is common in older Americans, 3 million of whom work at night, it is critical for development of targeted therapies to understand the metabolic risks associated with RCD, even when sleep loss is minimized. Project 1 will evaluate the impact of RCD on glucose metabolism in older adults. Whereas chronic sleep loss and acute circadian misalignment induce insulin resistance, we hypothesize that RCD disrupts coordination among central and peripheral CMCs, thereby profoundly impairing pancreatic P-cell responsiveness and inducing insulin resistance. By comparing responses of older participants on a forced desynchrony (T=28h) protocol for a month with those on a 24-h day, we will test the hypotheses that in response to a standard test meal: 1) acute circadian misalignment will induce increase glucose levels, despite increased insulin levels; 2) 3-week history of RCD (while minimizing sleep loss) will induce increased glucose levels accompanied by reduced insulin levels, even when the meal is consumed at a normal circadian phase; 3) 3-week history of RCD (while minimizing sleep loss) will alter the waveform and amplitude of the circadian Cortisol rhythm; and that 4) re-imposing a 24-h light-dark/meal schedule for 1 week will re-entrain circadian rhythms, normalizing the Cortisol rhythm and the glucose and insulin responses to a standardized meal. This Project will contribute to understanding the distinct metabolic risks from circadian disruption, laying the groundwork for research designed to develop therapies targeted to reduce the risk of obesity, metabolic syndrome and diabetes, and enhance the health and quality of life of older Americans whose circadian rhythms are disrupted by age-related changes, irregular schedules, and/or night shift work.