Mechanisms of Prediabetic States in Obstructive Sleep Apnea

项目概要/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 糖代谢受损我们的实验室已经证明，通过通宵连续治疗OSA 气道正压通气（CPAP）改善糖尿病前期的胰岛素敏感性和葡萄糖耐量。到目前为止， OSA损害葡萄糖代谢的机制仍不清楚。人们普遍认为，OSA 患者的交感神经活动增加，交感神经活动是脂肪组织脂解的有效刺激物， 增加游离脂肪酸（FFA）释放到体循环中。FFAs是一种主要的能源， 骨骼肌是占胰岛素刺激的葡萄糖摄取的大部分的组织。 广泛的研究表明，骨骼肌中异位脂质积聚是骨骼肌损伤的关键之一。 胰岛素抵抗的决定因素。因此，我们假设增加的脂肪组织脂解（即， 过量FFA递送）损害骨骼肌中的代谢，导致胰岛素抵抗 和葡萄糖耐受不良我们假设这些损伤部分是通过线粒体 功能障碍，因为线粒体在葡萄糖和脂肪酸氧化中很重要，并且在葡萄糖和脂肪酸中高度丰富。 骨骼肌。具体来说，我们将确定OSA是否会导致胰岛素抵抗和葡萄糖 通过细胞代谢受损导致底物利用不完全和异位 骨骼肌中的脂质积累（目标1），并确定在多大程度上代谢障碍， OSA的原因是脂肪组织脂解增加和FFA释放过量（目的2）。解决这些 目的，我们建议在三种实验室条件下随机研究OSA伴糖尿病前期患者。 交叉设计：未治疗条件（OSA）、治疗条件（CPAP）、未治疗但未给药 抑制脂解条件（FFA抑制）。我们将进行全身和细胞评估， 每个研究条件。将使用以下方法评估空腹和餐后状态下的葡萄糖代谢 稳定同位素示踪剂在肌肉组织中，我们将评估线粒体氧消耗，活性氧 种，葡萄糖和脂肪氧化，脂肪酸转运到线粒体，脂质异位积累 代谢物和胰岛素信号传导。拟议的工作将是第一个评估细胞生物能量学（即， 线粒体功能），并试图确定是否在OSA患者的细胞代谢障碍， 骨骼肌对OSA患者胰岛素抵抗和葡萄糖耐受不良有影响， 在存在过量FFA递送的情况下发生损伤（即通过压倒性的线粒体能力） 和/或为原发性（在没有过量FFA存在的情况下发生）。机械论的见解， 从拟议的工作中获得的信息将有助于确定风险预测和/或代谢性疾病治疗的新靶点。 在CPAP之外的OSA中的损伤。

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.