Mechanisms of Prediabetic States in Obstructive Sleep Apnea

阻塞性睡眠呼吸暂停的糖尿病前期状态机制

基本信息

  • 批准号:
    10439458
  • 负责人:
  • 金额:
    $ 77.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-07-15 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Substantial clinical and experimental evidence indicates that obstructive sleep apnea (OSA) is associated with impaired glucose metabolism. Our laboratory has demonstrated that treatment of OSA by all-night continuous positive airway pressure (CPAP) improves insulin sensitivity and glucose tolerance in prediabetes. To date, the mechanisms by which OSA impairs glucose metabolism remain unclear. It is widely recognized that OSA patients have increased sympathetic activity, which is a potent stimulator of adipose tissue lipolysis leading to increased release of free fatty acids (FFA) into the systemic circulation. FFAs are a major source of energy for the skeletal muscle, which is the tissue that accounts for the majority of insulin-stimulated glucose uptake. Extensive research has demonstrated that ectopic lipid accumulation in the skeletal muscle is one of the key determinants of insulin resistance. We therefore hypothesized is that increased adipose tissue lipolysis (i.e. excess FFA delivery) induced by OSA impairs metabolism in the skeletal muscle, leading to insulin resistance and glucose intolerance. We hypothesize that these impairments occur in part through mitochondrial dysfunction, as mitochondria are important in glucose and fatty acid oxidation, and are highly abundant in the skeletal muscle. Specifically, we will determine whether OSA leads to insulin resistance and glucose intolerance through impairments of cellular metabolism resulting in incomplete substrate utilization and ectopic lipid accumulation in the skeletal muscle (Aim 1) and determine to what extent the metabolic impairments in OSA are explained by increased adipose tissue lipolysis and excess FFA release (Aim 2). To address these aims, we propose to study OSA patients with prediabetes under three in-laboratory conditions in a randomized cross-over design: untreated condition (OSA), treated condition (CPAP), untreated but pharmacologically suppressed lipolysis condition (FFA-suppressed). We will perform whole body and cellular assessments under each study condition. Glucose metabolism will be assessed during both fasting and postprandial states using stable isotope tracers. In muscle tissue, we will assess mitochondrial oxygen consumption, reactive oxygen species, glucose and fat oxidation, fatty acid transport to mitochondria, ectopic accumulation of lipid metabolites, and insulin signaling. The proposed work will be the first to assess cellular bioenergetics (i.e. mitochondrial function) in OSA patients and seeks to determine whether cellular metabolic impairments in the skeletal muscle contribute to insulin resistance and glucose intolerance in OSA, and whether these impairments are occurring in the presence of excess FFA delivery (i.e. by overwhelming mitochondrial capacity) and/or are primary (occurring without excess FFA presence). The mechanistic insights that are expected to be gained from the proposed work will help identify novel targets for risk prediction and/or treatment of metabolic impairments in OSA beyond CPAP.
项目摘要/摘要 大量的临床和实验证据表明,阻塞性睡眠呼吸暂停(OSA)与 葡萄糖代谢受损。我们实验室已经证明,通宵连续治疗阻塞性睡眠呼吸暂停综合征 气道正压(CPAP)可改善糖尿病前期患者的胰岛素敏感性和糖耐量。到目前为止, 阻塞性睡眠呼吸暂停综合征损害糖代谢的机制尚不清楚。人们普遍认为,OSA 患者交感神经活性增加,这是脂肪组织脂肪分解的有力刺激因素,导致 增加游离脂肪酸(FFA)进入体循环的释放。脂肪酸是人体的主要能量来源 骨骼肌,它是胰岛素刺激的葡萄糖摄取的主要组织。 广泛的研究表明,骨骼肌中异位脂质堆积是关键之一。 胰岛素抵抗的决定因素。因此,我们假设脂肪组织脂解作用增加(即 OSA诱导的过量FFA传递)损害骨骼肌的代谢,导致胰岛素抵抗 和葡萄糖不耐受。我们假设这些损伤部分通过线粒体发生。 功能障碍,因为线粒体在葡萄糖和脂肪酸氧化中是重要的,并且在 骨骼肌。具体来说,我们将确定OSA是否会导致胰岛素抵抗和血糖 通过细胞代谢障碍导致底物利用不完全和异位的不耐受 骨骼肌脂类蓄积(目标1),并确定代谢损伤的程度 OSA的解释是脂肪组织脂解增加和FFA释放过多(目标2)。要解决这些问题 目的:我们建议在三种实验室条件下随机研究患有糖尿病前期的阻塞性睡眠呼吸暂停综合征患者。 交叉设计:未治疗状态(OSA),已治疗状态(CPAP),未治疗但有药理作用 抑制脂解状态(FFA抑制)。我们将在以下条件下进行全身和细胞评估 每种学习条件。在空腹和餐后状态下都将使用以下方法评估葡萄糖代谢 稳定的同位素示踪剂。在肌肉组织中,我们将评估线粒体耗氧量、活性氧 种类,葡萄糖和脂肪的氧化,脂肪酸向线粒体的运输,异位积累的脂肪 代谢物和胰岛素信号。拟议的工作将是第一次评估细胞生物能量学(即 线粒体功能),并试图确定阻塞性睡眠呼吸暂停患者的细胞代谢损伤是否 骨骼肌导致阻塞性睡眠呼吸暂停患者的胰岛素抵抗和糖耐量异常,以及这些因素是否 FFA传递过多(即线粒体容量过大)时会发生损伤 和/或是主要的(在没有过量FFA存在的情况下发生)。机械性的洞察力预计将是 从拟议工作中获得的成果将有助于确定风险预测和/或代谢治疗的新目标 CPAP以外的阻塞性睡眠呼吸暂停综合征的损害。

项目成果

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Esra Tasali其他文献

Esra Tasali的其他文献

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{{ truncateString('Esra Tasali', 18)}}的其他基金

Sleep Extension: A Novel Intervention for Weight Loss in Young Adults
延长睡眠:年轻人减肥的新干预措施
  • 批准号:
    10753226
  • 财政年份:
    2023
  • 资助金额:
    $ 77.16万
  • 项目类别:
Technology-Supported Treatment of Sleep Apnea in Prediabetes
糖尿病前期睡眠呼吸暂停的技术支持治疗
  • 批准号:
    9762470
  • 财政年份:
    2019
  • 资助金额:
    $ 77.16万
  • 项目类别:
Mechanisms of Prediabetic States in Obstructive Sleep Apnea
阻塞性睡眠呼吸暂停的糖尿病前期状态机制
  • 批准号:
    10222768
  • 财政年份:
    2019
  • 资助金额:
    $ 77.16万
  • 项目类别:
Technology-Supported Treatment of Sleep Apnea in Prediabetes
糖尿病前期睡眠呼吸暂停的技术支持治疗
  • 批准号:
    10226277
  • 财政年份:
    2019
  • 资助金额:
    $ 77.16万
  • 项目类别:
Mechanisms of Prediabetic States in Obstructive Sleep Apnea
阻塞性睡眠呼吸暂停的糖尿病前期状态机制
  • 批准号:
    9973169
  • 财政年份:
    2019
  • 资助金额:
    $ 77.16万
  • 项目类别:
Technology-Supported Treatment of Sleep Apnea in Prediabetes
糖尿病前期睡眠呼吸暂停的技术支持治疗
  • 批准号:
    10677837
  • 财政年份:
    2019
  • 资助金额:
    $ 77.16万
  • 项目类别:
Technology-Supported Treatment of Sleep Apnea in Prediabetes
糖尿病前期睡眠呼吸暂停的技术支持治疗
  • 批准号:
    10459449
  • 财政年份:
    2019
  • 资助金额:
    $ 77.16万
  • 项目类别:
Technology-Supported Treatment of Sleep Apnea in Prediabetes
糖尿病前期睡眠呼吸暂停的技术支持治疗
  • 批准号:
    9980894
  • 财政年份:
    2019
  • 资助金额:
    $ 77.16万
  • 项目类别:
Technology-Supported Treatment of Sleep Apnea in Prediabetes
糖尿病前期睡眠呼吸暂停的技术支持治疗
  • 批准号:
    10886362
  • 财政年份:
    2019
  • 资助金额:
    $ 77.16万
  • 项目类别:
Mechanisms of Prediabetic States in Obstructive Sleep Apnea
阻塞性睡眠呼吸暂停的糖尿病前期状态机制
  • 批准号:
    10674545
  • 财政年份:
    2019
  • 资助金额:
    $ 77.16万
  • 项目类别:

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