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

周期性昼夜节律紊乱

• 批准号: 8598130
• 负责人: Charles A Czeisler
• 金额: $ 57.81万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598130
• 关键词: Accounting; Acute; Adipose tissue; Adrenal Glands; Affect; Age; Aging; American; Animals; Attenuated; B-Lymphocytes; Beta Cell; Cells; Cholesterol; Chronic; Circadian Dysregulation; Circadian Rhythms; Cities; Coupled; Development; Diabetes Mellitus; Elderly; Environment; Epidemiology; Exhibits; Exposure to; Financial compensation; Functional disorder; Genes; Glucose; Health; Hepatocyte; Hour; Human; Hydrocortisone; Hypothalamic structure; Individual; Instruction; Insulin; Insulin Resistance; Jet Lag Syndrome; Lead; Leptin; Light; Link; Lipids; Mammals; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Molecular; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Organ; Organism; Pacemakers; Pancreas; Participant; Periodicity; Peripheral; Phase; Photoperiod; Prevalence; Protocols documentation; Quality of life; Recording of previous events; Recurrence; Regulation; Relative (related person); Research; Research Design; Rest; Risk; Schedule; Sleep; Stimulus; Structure; System; Testing; Time; Tissues; Travel; Triglycerides; Variant; Work; age related; design; energy balance; experience; fasting blood glucose level; feeding schedule; genome wide association study; glucose metabolism; glucose tolerance; impaired glucose tolerance; insulin secretion; insulin sensitivity; nutrition; obesity risk; response; shift work; social; therapy development; young adult

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.

项目总结(见说明)： 器官、组织和细胞的昼夜节律随着年龄的增长而失去幅度和相位稳定性，这些昼夜节律被光和营养循环影响到24小时。人类表现出葡萄糖耐量的内源性昼夜节律，并对夜间血糖水平较高的食物做出反应。GWAs涉及昼夜节律基因与T2D的风险，以及调节葡萄糖代谢的昼夜节律分子钟(CMC)的一些关键组件。我们发现，尽管胰岛素升高，但年轻人的急性昼夜节律失调会导致餐后血糖升高，而反复发生的昼夜节律紊乱(RCD)合并睡眠限制 会导致餐后血糖升高和胰岛素降低，即使在 一个合适的昼夜节律阶段。这可能解释了为什么上夜班的人患上与代谢老化相关的疾病的风险更高：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300万人在夜间工作，因此开发有针对性的治疗方法对于了解与RCD相关的代谢风险至关重要，即使在睡眠损失降至最低的情况下也是如此。 项目1将评估RCD对老年人葡萄糖代谢的影响。虽然慢性睡眠不足和急性昼夜节律失调导致胰岛素抵抗，但我们假设RCD扰乱了中枢和外周CMCs之间的协调，从而深刻地损害了胰腺P细胞的反应性，并诱导了胰岛素抵抗。通过比较年龄较大的参与者在强制去同步化(T=28h)方案下一个月和24小时内的反应，我们将检验以下假设：1)尽管胰岛素水平升高，但急性昼夜节律失调会导致血糖水平升高； RCD的3周病史(同时最大限度地减少睡眠损失)将导致血糖水平升高并伴随胰岛素水平降低，即使在正常的昼夜节律阶段也是如此；3)3周的RCD病史(同时将睡眠损失降至最低)将改变昼夜皮质醇节律的波形和幅度；4)重新实施24小时明暗/进餐时间表1周将重新影响昼夜节律，使皮质醇节律以及血糖和胰岛素对标准化膳食的反应正常化。 该项目将有助于了解昼夜节律紊乱带来的独特新陈代谢风险，为旨在开发旨在降低肥胖、代谢综合征和糖尿病风险的疗法的研究奠定基础，并提高美国老年人的健康和生活质量，他们的昼夜节律被年龄相关的变化、不规则的时间表和/或夜班工作打乱。