Lipolysis during sleep and cardiometabolic consequences of sleep apnea

点击翻译按钮获取中文摘要

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.