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：
10222768
负责人：
Esra Tasali
金额：
$ 77.16万
依托单位：
UNIVERSITY OF CHICAGO
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

来源：
https://reporter.nih.gov/project-details/10222768
关键词：
Address Adipose tissue Affect Animal Model Animals Bioenergetics Biopsy Blood Circulation Ceramides Clinical Clinical Research Continuous Positive Airway Pressure Crossover Design Disease Energy-Generating Resources Extrahepatic Fasting Fatty Acids Fatty acid glycerol esters Glucose Glucose Intolerance Glycerol Hepatic Hypoxia Impairment Indirect Calorimetry Insulin Insulin Resistance Isotopes Laboratories Lipids Lipolysis Measurement Metabolic Metabolic Pathway Metabolism Mitochondria Muscle NADH Nonesterified Fatty Acids Norepinephrine Obstructive Sleep Apnea Oxidation-Reduction Oxygen Consumption Palmitates Pathway interactions Patients Pharmacology Plasma Prediabetes syndrome Proto-Oncogene Proteins c-akt Pyruvate Randomized Reactive Oxygen Species Research Resolution Respiration Skeletal Muscle Supervision Testing Tissues Tracer Weight Work acylcarnitine experimental study fatty acid oxidation fatty acid transport glucose disposal glucose metabolism glucose production glucose tolerance glucose uptake human model human study improved insight insulin sensitivity insulin signaling lipidomics mitochondrial dysfunction novel oxidation prevent risk prediction stable isotope tool

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.

项目概要/摘要大量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。我们的实验室已经证明，通过整夜连续治疗 OSA 气道正压通气（CPAP）可改善糖尿病前期的胰岛素敏感性和葡萄糖耐量。迄今为止， 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，这是脂肪组织脂解的有效刺激剂，导致增加游离脂肪酸（FFA）释放到体循环中。 FFA 是能源的主要来源骨骼肌，是负责胰岛素刺激的葡萄糖摄取的大部分组织。大量研究表明，骨骼肌中的异位脂质积累是关键因素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（即增加）。 OSA 引起的过量 FFA 输送会损害骨骼肌的新陈代谢，导致胰岛素抵抗和葡萄糖不耐受。我们假设这些损伤部分是通过线粒体发生的功能障碍，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受损而导致的不耐受，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）。为了解决这些为了实现这一目标，我们建议在三种实验室条件下随机研究患有前驱糖尿病的 OSA 患者交叉设计：未治疗状态 (OSA)、已治疗状态 (CPAP)、未治疗但已药理治疗脂肪分解受到抑制（FFA 抑制）。我们将在以下条件下进行全身和细胞评估每个学习条件。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，我们将评估线粒体耗氧量、活性氧物种、葡萄糖和脂肪氧化、脂肪酸转运至线粒体、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 OSA 患者的细胞代谢损伤是否存在骨骼肌导致 OSA 的胰岛素抵抗和葡萄糖不耐受，以及这些是否与在过量 FFA 输送的情况下会发生损伤（即线粒体容量压倒性的）和/或是原发性的（在没有过量 FFA 存在的情况下发生）。预期的机制见解从拟议的工作中获得的成果将有助于确定代谢性疾病风险预测和/或治疗的新目标 CPAP 之外的 OSA 损伤。