Tissue-Specific Insulin Resistance in Obstructive Sleep Apnea: Role of Hypoxia

阻塞性睡眠呼吸暂停中的组织特异性胰岛素抵抗：缺氧的作用

• 批准号: 9750700
• 负责人: ANDREW D KRYSTAL
• 金额: $ 80.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750700
• 关键词: Accidents; Accounting; Adipose tissue; Age; Animal Model; Apnea; Automobiles; Beta Cell; Blood; Breathing; C-Peptide; Carbohydrates; Cardiovascular Diseases; Cell physiology; Continuous Positive Airway Pressure; Development; Diabetes Mellitus; Dual-Energy X-Ray Absorptiometry; Ethnic Origin; Event; Extrahepatic; Fatty Liver; Fatty acid glycerol esters; Gluconeogenesis; Glucose Clamp; Health; Hepatic; High Prevalence; Homeostasis; Hormones; Hour; Hypoxia; Image; Incidence; Individual; Inflammation; Insulin; Insulin Resistance; Kinetics; Lead; Lipids; Lipolysis; Liver; Magnetic Resonance; Magnetic Resonance Spectroscopy; Maintenance; Measures; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nose; OGTT; Obesity; Obstructive Sleep Apnea; Outcome; Oxygen; Patients; Population; Prevalence; Productivity; Public Health; Research; Risk; Role; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Stress; Study models; Sympathetic Nervous System; Technology; Testing; Thinness; Tissues; Tracer; Woman; experience; glucose production; healthy volunteer; improved; indexing; insulin sensitivity; lipid biosynthesis; men; mortality; multidisciplinary; non-alcoholic fatty liver disease; oxidation; polypeptide C; pressure; sex; sleep quality; stable isotope

PROJECT SUMMARY Obstructive sleep apnea (OSA) is a common condition associated with significant adverse health outcomes. An estimated 25% of men and 10% of women will have OSA during their lifetime. OSA is associated with an increased prevalence of insulin resistance and type 2 diabetes and, with severe degrees of OSA, non-alcoholic fatty liver disease (NAFLD) as well. The mechanisms accounting for the association between insulin resistance and OSA are not fully understood. We have previously demonstrated that experimentally-induced sleep restriction in healthy volunteers led to a reduction in whole-body insulin sensitivity and increased rates of lipolysis and gluconeogenesis, accompanied by an increase in stress hormone levels. Studies by others suggest that, in animal models studied under hypoxic conditions, hepatic carbohydrate and lipid homeostasis are perturbed leading to hepatic steatosis and inflammation. Taken together, these observations form the basis of our overarching hypothesis that patients with OSA and hypoxia (H-OSA) have greater degrees of insulin resistance in both liver and adipose tissue when compared to those without hypoxia (NH-OSA) thus leading to increased risk for the development of diabetes in the former group. In Aim 1 we will test the hypothesis that, although individuals with OSA have been shown to have insulin resistance in multiple target tissues (adipose, muscle, liver, beta cell), these abnormalities will be significantly greater in patients with OSA that is accompanied by hypoxia (H-OSA), in comparison to those without hypoxia (NH-OSA). We will compare tissue-specific insulin sensitivity in 30 subjects with H-OSA and 30 with NH-OSA matched for sex, ethnicity, age, BMI, and apnea-hypopnea index. Hepatic and extra-hepatic insulin sensitivity will be measured using hyperinsulinemic-euglycemic clamps and stable isotope tracer studies of endogenous glucose production, gluconeogenesis, de novo lipogenesis (DNL), and lipolysis. Beta cell function and insulin kinetics will be assessed from insulin and C-peptide concentrations during an oral glucose tolerance test. Liver fat will be measured by magnetic resonance and total lean and fat mass by dual-energy X-ray absorptiometry. In Aim 2 we will test the hypothesis that treatment with continuous positive airway pressure (CPAP) will improve insulin sensitivity in all of the target tissues and that these improvements will be greater in those with hypoxia at baseline. After stabilization on CPAP therapy and maintenance for six weeks, each of the individuals studied in Aim 1 will undergo a repeat sleep study and metabolic assessments identical to those described above in Aim 1. We speculate that in NH-OSA insulin resistance is primarily triggered by increased levels of stress hormones due to fragmented sleep and this is manifested largely in extra-hepatic tissues (muscle and adipose), whereas in H-OSA there is additional stimulation of hepatic DNL, leading to liver fat accumulation and hepatic insulin resistance. .

项目概要 阻塞性睡眠呼吸暂停 (OSA) 是一种与严重不良健康后果相关的常见病症。 据估计，25% 的男性和 10% 的女性一生中都会患有 OSA。 OSA 与 胰岛素抵抗和 2 型糖尿病的患病率增加，并且患有严重的 OSA、非酒精性睡眠障碍 脂肪肝病（NAFLD）也是如此。胰岛素抵抗之间关联的机制 和 OSA 尚未完全理解。我们之前已经证明，实验诱导的睡眠 对健康志愿者的限制导致全身胰岛素敏感性降低和胰岛素抵抗率增加 脂肪分解和糖异生，伴随着应激激素水平的增加。其他人的研究 表明，在低氧条件下研究的动物模型中，肝脏碳水化合物和脂质稳态 受到干扰导致肝脏脂肪变性和炎症。综合起来，这些观察结果形成了 我们总体假设的基础是，患有 OSA 和缺氧 (H-OSA) 的患者有更大程度的 与没有缺氧的组织（NH-OSA）相比，肝脏和脂肪组织中存在胰岛素抵抗 导致前一组患糖尿病的风险增加。 在目标 1 中，我们将检验以下假设：尽管已证明患有 OSA 的个体具有胰岛素 多个靶组织（脂肪、肌肉、肝脏、β细胞）的抵抗力，这些异常将显着 与没有缺氧的患者相比，伴有缺氧的 OSA (H-OSA) 患者的比例更高 （NH-OSA）。我们将比较 30 名 H-OSA 受试者和 30 名 NH-OSA 受试者的组织特异性胰岛素敏感性 匹配性别、种族、年龄、体重指数和呼吸暂停低通气指数。肝脏和肝外胰岛素敏感性 将使用高胰岛素-正常血糖钳和内源性稳定同位素示踪剂研究来测量 葡萄糖产生、糖异生、从头脂肪生成（DNL）和脂肪分解。 β细胞功能和胰岛素 动力学将在口服葡萄糖耐量试验期间根据胰岛素和 C 肽浓度进行评估。肝 脂肪将通过磁共振测量，总瘦肉量和脂肪量通过双能 X 射线吸收测定法测量。 在目标 2 中，我们将检验以下假设：持续气道正压通气 (CPAP) 治疗将 改善所有目标组织的胰岛素敏感性，并且这些改善在患有以下疾病的组织中会更大 基线缺氧。经过 CPAP 治疗和维持稳定六周后，每个患者 目标 1 中研究的个体将接受与那些相同的重复睡眠研究和代谢评估 上文目标 1 中所述。我们推测，在 NH-OSA 中，胰岛素抵抗主要是由胰岛素抵抗增加引发的。 睡眠碎片导致应激激素水平升高，这主要表现在肝外组织中 （肌肉和脂肪），而在 H-OSA 中，肝脏 DNL 受到额外刺激，导致肝脏脂肪增加 积累和肝脏胰岛素抵抗。 。