Lipolysis during sleep and cardiometabolic consequences of sleep apnea

项目摘要：睡眠期间的脂肪分解和睡眠呼吸暂停的心脏代谢后果 阻塞性睡眠呼吸暂停 (OSA) 是一种常见疾病，会损害睡眠期间的呼吸。 OSA 是一个危险因素 2 型糖尿病和心血管疾病是全球死亡和残疾的主要原因。 此外，OSA 还可诱发胰岛素抵抗、血管功能障碍和炎症——这些损害 最终导致糖尿病和动脉粥样硬化性心血管疾病。目前，该机制 OSA 导致心脏代谢功能障碍的情况尚不清楚。这种知识的缺乏使得我们无法 确定哪些无症状患者需要治疗，或为那些无法治疗的患者制定保护性疗法 耐受持续气道正压通气 (CPAP) 治疗。我们认为这种知识差距是 由于几乎所有 OSA 代谢研究都集中于夜间睡眠期，因此缺乏对夜间睡眠期的关注所致 早上而不是晚上的结果。我们的实验室通过以下方法发现了 OSA 的动态代谢变化 在不间断的睡眠期间经常采样血液。我们使用 CPAP 停药来检查孤立的 OSA 的代谢影响，将使用 CPAP 的同一患者与不使用 CPAP 的患者的代谢进行比较。持续正压通气 与 CPAP 相比，戒断会动态增加夜间 FFA、血糖、血压和心率。 睡眠开始后，基底升高立即开始，并在睡眠期间持续存在。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、血管性 功能障碍、炎症等。因此，我们的首要假设是 OSA 导致过度 SNS 睡眠期间刺激脂肪分解，可以通过β肾上腺素能阻断来预防。在这个提案中，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 OSA 引起的睡眠期间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的指标。 其次，我们研究了 β 阻断和稳定同位素夜间 FFA 升高的机制 技术。第三，我们检查夜间 FFA 升高的下游心脏代谢后果。如果 如果成功的话，我们将确定哪些 OSA 患者有心脏代谢功能障碍的风险，并为此铺平道路 用于 β 阻断的临床试验，以保护数百万无法或不愿意的患者的代谢健康 使用持续气道正压通气 (CPAP)。

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.