Lipolysis during sleep and cardiometabolic consequences of sleep apnea

睡眠期间的脂肪分解和睡眠呼吸暂停的心脏代谢后果

• 批准号: 10352213
• 负责人: Jonathan C. Jun
• 金额: $ 76.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352213
• 关键词: Adipose tissue; Adrenergic Agents; Adult; Affect; Animal Model; Atherosclerosis; Attention; Blood Pressure; Blood Vessels; Blood specimen; Breathing; Cardiovascular Diseases; Cessation of life; Chronic; Clinical Trials; Continuous Positive Airway Pressure; Cross-Over Studies; Diabetes Mellitus; Disease; Double-Blind Method; Dyslipidemias; Equilibrium; Functional disorder; Glucose; Glucose Intolerance; Health; Heart Rate; Heart failure; Hyperglycemia; Hyperlipidemia; Hypertension; Hypoxia; Impairment; Inflammation; Insulin Resistance; Knowledge; Laboratories; Lead; Link; Lipids; Lipolysis; Metabolic; Metabolic dysfunction; Metabolic syndrome; Metabolism; Modeling; Mus; Muscle Tonus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Obstructive Sleep Apnea; Outcome; Patient Noncompliance; Patients; Pharmaceutical Preparations; Pharmacology; Placebos; Plasma; Propranolol; Respiration Disorders; Risk Factors; Role; Sampling; Severities; Sleep; Sleep Apnea Syndromes; Stable Isotope Labeling; Statistical Data Interpretation; Stress; Sympathetic Nervous System; Techniques; Testing; Tracer; Triglycerides; Vascular Diseases; Withdrawal; airway muscle; base; blood glucose regulation; body position; cardiometabolic risk; cardiometabolism; diabetes pathogenesis; diabetes risk; disability; fatty acid oxidation; glucose tolerance; metabolic abnormality assessment; novel; patient stratification; prevent; risk stratification; sleep onset; stable isotope; supplemental oxygen

PROJECT SUMMARY: Lipolysis during Sleep and Cardiometabolic Consequences of Sleep Apnea Obstructive sleep apnea (OSA) is a common disorder that impairs breathing during sleep. OSA is a risk factor for type 2 diabetes and cardiovascular disease, leading causes of worldwide death and disability. Furthermore, OSA can induce insulin resistance, vascular dysfunction, and inflammation – insults that ultimately lead to diabetes and atherosclerotic cardiovascular disease. Currently, the mechanism by which OSA causes cardiometabolic dysfunction is not known. This lack of knowledge makes it impossible to determine which asymptomatic patients require treatment, or to develop protective therapies for those unable to tolerate continuous positive airway pressure (CPAP) therapy. We contend that this knowledge gap is caused by lack of attention to the nocturnal sleep period, as nearly all OSA metabolic studies have focused on morning rather than nocturnal outcomes. Our laboratory discovered dynamic metabolic changes in OSA by frequently sampling blood during uninterrupted sleep. We used CPAP withdrawal to examine the isolated metabolic impact of OSA, comparing the same patients on CPAP to their metabolism off CPAP. CPAP withdrawal dynamically increased nocturnal FFA, glucose, blood pressure, and heart rate compared to CPAP. Substrate elevations began immediately with sleep onset and persisted during sleep. Excessive stimulation of adipose tissue lipolysis, can cause “lipotoxicity” resulting in insulin resistance, hyperlipidemia, vascular dysfunction, and inflammation. Therefore, our overarching hypothesis is that OSA causes excessive SNS stimulation of lipolysis during sleep which can be prevented by beta adrenergic blockade. In this proposal, we use CPAP withdrawal, beta adrenergic blockade, and stable isotope techniques to unravel mechanisms and consequences of OSA-induced metabolic dysfunction during sleep. First, we examine determinants of nocturnal FFA elevation, including metrics of OSA severity, SNS activity, and patient anthropometric features. Second, we examine mechanisms of nocturnal FFA elevation with beta blockade and stable isotope techniques. Third, we examine downstream cardiometabolic consequences of nocturnal FFA elevation. If successful, we will identify which OSA patients are at risk for cardiometabolic dysfunction, and pave the way for clinical trials of beta blockade to protect the metabolic health of millions of patients unable or unwilling to use CPAP.

项目摘要：睡眠期间的脂解和睡眠呼吸暂停的心脏代谢结构 阻塞性睡眠呼吸暂停（OSA）是一种常见的疾病，会损害睡眠期间的鲜活。 对于2型糖尿病和心血管疾病，全球死亡和残疾的主要原因。 此外，OSA可以放纵耐药性，血管功能障碍和炎症 - 侮辱 最终导致糖尿病和动脉粥样硬化心血管疾病。 OSA导致心脏代谢功能障碍尚不清楚。 确定哪些无症状患者需要治疗或为无法为无法的人开发保护剂疗法 为了耐受持续的气道压力（CPAP）治疗。 由于缺乏夜间睡眠时期的治疗，因此所有OSA代谢研究都集中在 早晨而不是夜间成果。 CPAP提取期间经常采样血液以检查孤立的 CPAP。 与CPAP相比，戒断动态增加了夜间FFA，葡萄糖，血压和心率。 底物高度立即开始睡眠，在睡眠期间持续 脂肪组织脂解会导致“脂毒性”，导致胰岛素抵抗，高脂血症，Vascalar 功能障碍和炎症。 在此提案中，可以预防β肾上腺素能阻止的睡眠期间的脂肪分解。 使用CPAP提取，β肾上腺素能阻断和稳定的同位素技术来解开机制和 OSA诱导的代谢功能障碍的后果首先检查的决定因素 夜间FFA高程，包括OSA严重程度的指标，SNS活动和患者人体测量值。 其次，我们检查了具有β封锁和稳定同位素的夜间FFA高程的机制 技术。 成功，我们将确定哪些OSA患者患有心脏代谢功能障碍的风险，并铺平道路 对于Beta封锁的临床试验，以保护数百万无法或不愿接受的患者的代谢健康。 使用CPAP。