Lipidomics Biomarkers Link Sleep Restriction to Adiposity Phenotype, Diabetes, and Cardiovascular Risk

脂质组学生物标志物将睡眠限制与肥胖表型、糖尿​​病和心血管风险联系起来

• 批准号: 10212442
• 负责人: BRUCE S KRISTAL
• 金额: $ 85.07万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212442
• 关键词: Address; Adult; Age; Aging; Awareness; Bioinformatics; Biological; Biological Markers; Biology; Body fat; Chronic; Clinical; Clinical Trials; Coronary; Counseling; Data; Development; Diabetes Mellitus; Disease; Dual-Energy X-Ray Absorptiometry; Early Intervention; Epidemiology; Ethnic Origin; Ethnic group; Face; Fatty acid glycerol esters; Future; Goals; Health; Heterogeneity; Hospitals; Human; Individual; Insulin Resistance; Laboratories; Link; Lipids; Liver; Magnetic Resonance Imaging; Mathematics; Measures; Metabolic; Metabolic syndrome; Myocardial; Nested Case-Control Study; Obesity; Patient Self-Report; Pattern; Penetrance; Pericardial body location; Pharmacologic Substance; Phenotype; Population; Population Heterogeneity; Published Comment; Research; Research Design; Risk; Risk Factors; Safety; Sampling; Schedule; Science; Series; Sleep; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Testing; United States National Institutes of Health; Visceral; Visceral fat; Woman; biomarker development; biomarker identification; biomarker panel; cardiovascular risk factor; case control; circadian; cohort; diabetes risk; diabetic; disorder risk; ethnic diversity; experience; extracellular; improved; interdisciplinary approach; lipidomics; mortality risk; multi-ethnic; personalized medicine; prospective; sex; sleep abnormalities; sleep pattern; subcutaneous; tool

Chronic sleep restriction and altered sleep patterns have emerged as a common and serious health and safety issue, and there is growing evidence that disrupted sleep directly underlies and/or contributes to metabolic abnormalities and diseases, including diabetes. Despite the obvious need, however, there are as yet no objective means of assessing chronic sleep status and limited understanding of intermediate phenotypes, especially in diverse populations. Not surprisingly, the first goal of the 2011 NIH Sleep Disorders Research Plan is to identify: "...metabolic... biomarkers of sleep deficiency ... that will facilitate personalized treatments, and clarify the risk associated with untreated sleep and circadian disorders and disturbances." It is biologically plausible that the metabolic consequences of restricted/altered sleep are, at least at some level, reflected in shifts within an individual's circulating lipids and overall adiposity status -- i.e., the clinical hallmarks that associate with, precede, and predict, metabolic syndrome and overt diabetes. Conversely, healthy, physically active adults display a fat distribution with a relatively low level of visceral and liver adiposity – regardless of their overall adiposity. The heterogeneity in level and types of obesity that exists among the five ethnic groups in the Multiethnic Cohort (MEC) offers a unique research setting to better understand the ill effects of abnormalities in sleep duration and patterns, how these changes relate to diabetes risk, and how this relationship is modified by age and ethnicity. More specifically, we propose a general viewpoint -- and set of hypotheses, in which: (i) Sleep restriction and/or altered sleep patterns directly induce altered circulating lipids short-term and altered adiposity phenotypes (e.g., shifts in the ratios between visceral, liver, and subcutaneous fat) long-term; (ii) the core risk of insufficient sleep or altered sleep patterns is ethnic and sex- independent, but its penetrance on diabetes risk is influenced by the underlying risk within the different ethnic groups; (iii) the consequences of sleep problems continue and increase risk of mortality in diabetics specifically and, more generally, in the MEC. This proposal leverages data on ~1850 older individuals (age~65-70) DEXA/MRI-assessed for body fat/distribution (e.g., visceral fat, liver fat, subcutaneous fat, etc) and the availability of 2400 nested (in MEC), ethnically- and age-diverse (age~50 to 80) case-control pairs for future diabetes, as well as existing clinical and sleep study data in Brigham and Women's Hospital. Identification of biomarker panels for insufficient or abnormal sleep will impact multiple aspects of science and health: (i) contribute to clinical recognition and treatment (e.g., counseling, pharmaceuticals) of sleep issues; (ii) create epidemiologic tools to relate limited sleep with disease risk and aid development of other disease biomarkers, and; (iii) contribute to research on sleep biology and its implications for human health. Completion will further NIH goals of focusing on health and early interventions rather than late stage disease. The study is well within our lab's capacity to complete in 4 years.

慢性睡眠限制和睡眠方式改变已成为一种常见和严重的健康 和安全问题，并且越来越多的证据表明睡眠干扰直接基础和/或有助于 代谢异常和疾病，包括糖尿病。尽管有明显的需求，但仍有 然而，没有评估慢性睡眠状况和对中级的理解有限的客观手段 表型，尤其是在潜水员种群中。毫不奇怪，2011年NIH睡眠障碍的第一个目标 研究计划将确定：“ ...代谢...睡眠不足的生物标志物...这将有助于个性化 治疗，并阐明与未经治疗的睡眠以及昼夜节律和灾难有关的风险。 在生物学上，至少在某种程度上，限制/改变睡眠的代谢后果是 反映在个人循环脂质和整体肥胖状态的转移中 - 即临床标志 与代谢综合征和明显的糖尿病相关联和预测。相反，健康， 体育活跃的成年人表现出脂肪分布，具有相对低的内脏和肝肥胖水平 - 不管他们的整体肥胖。五个水平和肥胖水平和类型的异质性 多民族队列（MEC）的种族群体提供了独特的研究环境，以更好地了解病情 睡眠持续时间和模式异常的影响，这些变化如何与糖尿病风险有关 关系通过年龄和种族修改。更具体地说，我们提出了一个一般的观点 - 并集 假设，其中：（i）睡眠限制和/或改变的睡眠模式直接引起循环改变 脂质短期和肥胖表型改变（例如，内脏，肝脏和 皮下脂肪）长期； （ii）睡眠不足或睡眠方式不足的核心风险是种族和性别 - 独立，但其对糖尿病风险的外观受到不同种族中潜在风险的影响 群体； （iii）睡眠问题的后果继续并增加糖尿病患者死亡的风险 特别是在MEC中，更普遍地。该提案利用〜1850个老年人的数据 （〜65-70岁）DEXA/MRI评估人体脂肪/分布（例如，内脏脂肪，肝脂肪，皮下脂肪等） 以及2400个嵌套（MEC）的可用性 未来的糖尿病，以及杨百翰和妇女医院的现有临床和睡眠研究数据。 识别生物标志物面板是否不足或异常睡眠会影响科学的多个方面 健康：（i）有助于临床识别和治疗（例如，咨询，药物）的睡眠问题； （ii）创建流行病学工具，以将有限的睡眠与疾病风险联系起来并有助于其他疾病的发展 生物标志物，以及； （iii）有助于研究睡眠生物学及其对人类健康的影响。完成 NIH将进一步关注健康和早期干预措施，而不是晚期疾病。这项研究是 符合我们实验室在4年内完成的能力。