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：睡眠中的脂肪分解和睡眠呼吸暂停对心脏代谢的影响 阻塞性睡眠呼吸暂停(OSA)是一种常见的疾病，会损害睡眠中的呼吸。阻塞性睡眠呼吸暂停综合征是一个危险因素 对于2型糖尿病和心血管疾病，这是全球死亡和残疾的主要原因。 此外，OSA可导致胰岛素抵抗、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性心血管疾病。目前，通过这种机制 OSA导致心脏代谢功能障碍的原因尚不清楚。这种知识的缺乏使我们不可能 确定哪些无症状的患者需要治疗，或为那些无法治疗的患者开发保护性疗法 耐受持续气道正压(CPAP)治疗。我们认为，这种知识差距是 由于缺乏对夜间睡眠的关注而引起的，因为几乎所有的阻塞性睡眠呼吸暂停综合征代谢研究都集中在 早晨的结果而不是夜间的结果。我们实验室通过以下方式发现了OSA的动态代谢变化 经常在不间断的睡眠中抽血。我们使用CPAP撤退来检查孤立的 OSA对代谢的影响，比较相同的患者接受CPAP和不接受CPAP的代谢。CPAP 与CPAP相比，停药后动态增加夜间FFA、血糖、血压和心率。 底物升高从睡眠开始时立即开始，并在睡眠期间持续。过度刺激 脂肪组织脂肪分解，可引起“脂毒性”，导致胰岛素抵抗、高脂血症、血管 功能障碍和炎症。因此，我们的首要假设是OSA会导致过多的SNS 刺激睡眠中的脂肪分解，这可以通过β肾上腺素能受体阻滞剂来预防。在这项提案中，我们 使用CPAP戒断、β-肾上腺素能阻断和稳定同位素技术来揭示机制和 睡眠中阻塞性睡眠呼吸暂停综合征引起的代谢功能障碍的后果。首先，我们检查决定因素 夜间FFA升高，包括OSA严重程度、SNS活动和患者人体测量特征。 其次，我们研究了β受体阻滞剂和稳定同位素对夜间游离脂肪酸升高的作用机制。 技巧。第三，我们检查夜间FFA升高对下游心脏代谢的影响。如果 成功后，我们将确定哪些OSA患者存在心脏代谢功能障碍的风险，并为 用于临床试验，以保护数百万无法或不愿接受治疗的患者的代谢健康 使用CPAP。