Stress, hypercortisolism, and metabolic risk factors

描述(由申请人提供)： 虽然慢性心理压力(如抑郁)和生理压力(如睡眠呼吸紊乱)都与2型糖尿病和心血管疾病的风险有关，但其机制尚不清楚。由这些应激源引起的神经内分泌变化，特别是下丘脑-垂体-肾上腺(HPA)轴的激活，可能提供一个统一的解释。我们假设，在大规模流行病学队列和干预研究中，唾液皮质醇是评估HPA轴活动的可行方法，HPA轴活动增加是2型糖尿病和心血管疾病的正相关危险因素，这是慢性心理和生理应激导致这些结果的机制。为了验证这些假设，我们提出了一项研究，具体目的如下：1)从我们的初步数据中证实，早上8点唾液皮质醇是HPA轴活动的一个可接受的指标，因此它可以替代24小时尿游离皮质醇(UFC)来评估糖皮质激素暴露。2.)确定HPA轴活动与心理压力、代谢风险因素和睡眠呼吸紊乱的测量之间的横截面关联，作为生理压力的测量。3.)确定适度运动对HPA轴活动的影响，并确定运动对血压、心脏和外周血管功能、身体健康、身体成分、血脂和血糖控制的有益影响是否通过6个月后皮质醇水平和/或皮质醇变异性的变化来调节。为了实现这些目标，我们将利用霍普金斯大学现有的研究基础设施，包括住院GCRC(已经支持一项关于非裔美国女性心理压力、HPA轴活动和代谢风险因素的试点研究)，我们还将把唾液皮质醇分析纳入NIH资助的3项霍普金斯大学正在进行的研究：一项基于人群的颈动脉粥样硬化研究，一项关于睡眠呼吸紊乱的研究，以及一项运动干预研究。

DESCRIPTION (provided by applicant): Although chronic psychological stress (e.g. depression) and physiological stress (e.g. sleep disordered breathing) are associated with the risk of both type 2 diabetes and cardiovascular disease, the mechanism remains unclear. Neuroendocrine changes induced by these stressors, specifically activation of the hypothalamic-pituitary-adrenal (HPA) axis, might provide a unifying explanation. We hypothesize that salivary cortisol represents a feasible approach for assessment of HPA axis activity in large-scale epidemiological cohort and intervention studies, that increased activity of the HPA axis is positively associated risk factors for type 2 diabetes and cardiovascular disease, and that this is the mechanism by which chronic psychological and physiological stressors lead to these outcomes. To test these hypotheses, we propose a study with the following specific aims: 1.) Confirm findings from our preliminary data that 8 am salivary cortisol is an acceptable measure of HPA axis activity such that it can be substituted for 24-hour urine free cortisol (UFC) in assessing glucocorticoid exposure. 2.) Determine the cross-sectional association of HPA axis activity to measures of psychological stress, metabolic risk factors, and sleep disordered breathing, as a measure of physiological stress. 3.) Determine the effect of moderate exercise on HPA axis activity and to determine whether the beneficial effects of exercise on blood pressure, cardiac and peripheral vascular function, physical fitness, body composition, lipids, and glycemic control are mediated by changes in cortisol levels and/or cortisol variability after 6 months. To accomplish these aims, we will exploit existing research infrastructure at Hopkins including the Inpatient GCRC (which is already supporting a pilot study of psychological stress, HPA axis activity, and metabolic risk factors in African-American women) and we will also incorporate salivary cortisol assays into 3 on-going NIH-funded Hopkins studies: a population-based study of carotid atherosclerosis, a study of sleep disordered breathing, and an exercise intervention study.