Adverse metabolic impact of sleep loss in older adults: insulin resistance

睡眠不足与不利的代谢变化和增加慢性疾病的风险有关，包括肥胖、2型糖尿病和早期死亡。随着年龄的增长，大多数美国人内脏脂肪增加，更容易患糖尿病。与“正常衰老”相关的慢性睡眠不足可能是导致“代谢衰老”的因素之一。中青年1-2周的睡眠不足会导致新陈代谢的生理变化，包括胰岛素敏感性降低和激素变化，这些变化会增加长期肥胖和糖尿病的可能性。我们目前的数据表明，代谢功能障碍发生在慢性睡眠不足和周期性昼夜节律紊乱的情况下，持续3周的年轻人和老年人。然而，缺觉实验延长了光周期，对昼夜节律性产生了潜在的混淆效应，而昼夜节律中断本身已被证明会导致不利的代谢变化。因此，睡眠不足对老年人葡萄糖代谢的影响（伴有最小的昼夜节律紊乱）尚不清楚。在项目2中，我们将在一个最小昼夜节律中断的方案中检查3周睡眠不足的代谢反应，以检验老年人总体和脂肪组织胰岛素敏感性会逐渐下降的假设。我们将确定变化的程度（对标准化膳食的血糖反应，通过正糖高胰岛素钳的胰岛素敏感性），变化的机制（通过脂肪组织活检，交感神经激活和糖皮质激素激活）和变化的动态（区分几天的影响和3周的慢性影响）。此外，我们假设老年人在1周的睡眠恢复后代谢功能会恢复。该项目将有助于了解睡眠不足损害老年人代谢的机制，有助于未来降低糖尿病风险的研究，改善现有治疗方法，并提高睡眠不足的美国老年人的健康和生活质量。

Insufficient sleep has been linked to adverse metabolic changes and increased risk of chronic disease including obesity, type 2 diabetes mellitus and early mortality. With age, most Americans increase visceral adiposity and become more likely to develop diabetes. Chronic insufficient sleep associated with 'normal aging' may be one of the factors involved in contributing to "metabolic aging'. Physiological changes in metabolism due to sleep loss for 1-2 weeks in young and middle-aged adults include reduced insulin sensitivity and hormonal changes that would increase the likelihood of obesity and diabetes in the long term. Our current data demonstrate that metabolic dysfunction occurs in young and older adults exposed to the combination of chronic sleep loss and recurrent circadian disruption for 3 weeks. Yet sleep loss experiments lengthen photoperiod, introducing a potential confounding effect on circadian rhythmicity, and circadian disruption itself has been shown to lead to adverse metabolic changes. Thus, the effects of sleep loss (with minimal circadian disruption) on glucose metabolism in older adults are not known. In Project 2, we will examine the metabolic responses to 3 weeks of sleep loss in a protocol with minimal circadian disruption to test the hypothesis that older adults will exhibit progressive decrements in total body and adipose tissue insulin sensitivity. We will determine the extent of the changes (glycemic responses to standardized meals, insulin sensitivity via euglycemic hyperinsulinemic clamps), the mechanisms of changes (via adipose tissue biopsy, sympathetic activation, and glucocorticoid activation) and the dynamics of changes (distinguishing effects over a few days and chronic effects over 3 weeks). Moreover, we hypothesize older adults will exhibit recovery of metabolic function with 1 week of sleep recovery. This Project will contribute to understanding the mechanisms by which sleep loss impairs metabolism in older adults, contributing to future research to reduce the risk of diabetes, improve existing therapies, and enhance the health and quality of life of older Americans whose sleep is insufficient.