Pilot Study of Beta Adrenergic Blockade to Prevent Metabolic Consequences of Sleep Apnea

β 肾上腺素能阻滞剂预防睡眠呼吸暂停代谢后果的初步研究

基本信息

  • 批准号:
    9372432
  • 负责人:
  • 金额:
    $ 8.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-01 至 2019-07-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Obstructive sleep apnea (OSA) is a common disorder that impairs stable breathing during sleep. OSA is a risk factor for type 2 diabetes, a leading cause of worldwide disability and cardiovascular disease. 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 salvage the metabolic health of those unable to tolerate continuous positive airway pressure (CPAP) therapy. Intermittent hypoxia (IH) has been used to simulate a OSA in mice. Chronic IH has been shown to cause dyslipidemia, vascular stiffness, and glucose intolerance. Moreover, acute IH increased plasma free fatty acids (FFA) and hyperglycemia in a dose- dependent manner, and these effects were abolished by pharmacologic or surgical interruption of the sympathetic nervous system. Recently, it has also been shown that OSA increases nocturnal FFA and glucose levels and causes insulin resistance during sleep. These findings demonstrate that OSA is a potent episodic cause of adipose tissue lipolysis and inhibited glucose clearance, with potentially devastating cumulative long-term impacts. The goal of this project is to understand: (Aim 1) in which OSA patients do FFA and glucose elevations occur, and (Aim 2) by what mechanism? Answers to these questions will identify susceptible patients with OSA, and identify treatment targets for these individuals. It is hypothesized that severity of OSA (as measured by AHI or by increased median heart rate during sleep) correlates with substrate elevations. Additionally, independent and/or interactive effects of gender and AHI on metabolism will be assessed. In a mouse model of IH, beta adrenergic blockade with propranolol prevented metabolic dysfunction. Thus, the second aim of this project is to test the efficacy of propranolol versus placebo in human OSA for preventing nocturnal substrate elevations. This proposal will discover mechanisms by which OSA contributes to metabolic dysfunction, identify patients susceptible to this pathophysiology, and introduce the novel use of beta blockade for therapy.
项目概要 阻塞性睡眠呼吸暂停 (OSA) 是一种常见疾病,会损害睡眠期间的稳定呼吸。 OSA 是一个 2 型糖尿病的危险因素,是全球残疾和心血管疾病的主要原因。 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,或挽救那些无法治疗的患者的代谢健康 耐受持续气道正压通气 (CPAP) 治疗。间歇性缺氧(IH)已被用于 模拟小鼠的 OSA。慢性 IH 已被证明会导致血脂异常、血管僵硬和血糖升高 不宽容。此外,急性 IH 在一定剂量下会增加血浆游离脂肪酸 (FFA) 和高血糖。 依赖的方式,并且这些作用可以通过药物或手术中断来消除 交感神经系统。最近,也有研究表明 OSA 会增加夜间 FFA 和 血糖水平升高并导致睡眠期间的胰岛素抵抗。这些发现表明 OSA 是一种有效的 脂肪组织脂肪分解和葡萄糖清除受抑制的偶发原因,具有潜在的破坏性 累积的长期影响。 该项目的目标是了解:(目标 1)OSA 患者在进行 FFA 治疗时会出现血糖升高, 以及(目标 2)通过什么机制?这些问题的答案将识别 OSA 易感患者, 并确定这些人的治疗目标。据推测,OSA 的严重程度(通过测量 AHI 或睡眠期间增加的中位心率)与底物升高相关。此外, 将评估性别和 AHI 对新陈代谢的独立和/或交互影响。在小鼠模型中 IH 中,用普萘洛尔阻断 β 肾上腺素能可预防代谢功能障碍。于是,第二个目标 该项目旨在测试普萘洛尔与安慰剂在人类 OSA 中预防夜间睡眠障碍的功效 基材标高。该提案将发现 OSA 促进代谢的机制 功能障碍,识别易受这种病理生理学影响的患者,并介绍 β 的新用途 封锁治疗。

项目成果

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Jonathan C. Jun其他文献

Jonathan C. Jun的其他文献

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{{ truncateString('Jonathan C. Jun', 18)}}的其他基金

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:
    9445159
  • 财政年份:
    2018
  • 资助金额:
    $ 8.18万
  • 项目类别:
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
  • 财政年份:
    2018
  • 资助金额:
    $ 8.18万
  • 项目类别:
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:
    10599368
  • 财政年份:
    2018
  • 资助金额:
    $ 8.18万
  • 项目类别:
Mechanisms and Consequences of Intermittent Hypoxia-Induced Lipolysis
间歇性缺氧诱导脂肪分解的机制和后果
  • 批准号:
    8299819
  • 财政年份:
    2012
  • 资助金额:
    $ 8.18万
  • 项目类别:
Mechanisms and Consequences of Intermittent Hypoxia-Induced Lipolysis
间歇性缺氧诱导脂肪分解的机制和后果
  • 批准号:
    8487439
  • 财政年份:
    2012
  • 资助金额:
    $ 8.18万
  • 项目类别:
Mechanisms and Consequences of Intermittent Hypoxia-Induced Lipolysis
间歇性缺氧诱导脂肪分解的机制和后果
  • 批准号:
    8669812
  • 财政年份:
    2012
  • 资助金额:
    $ 8.18万
  • 项目类别:

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