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. .

项目总结 阻塞性睡眠呼吸暂停(OSA)是一种常见的疾病，与严重的不良健康后果有关。 据估计，25%的男性和10%的女性会在一生中患上阻塞性睡眠呼吸暂停综合症。OSA与一个 胰岛素抵抗和2型糖尿病的患病率增加，严重程度的阻塞性睡眠呼吸暂停，非酒精性 还有脂肪肝(NAFLD)。胰岛素抵抗之间关系的机制 和阻塞性睡眠呼吸暂停综合征还没有完全被理解。我们之前已经证明了实验诱导的睡眠 健康志愿者禁食导致全身胰岛素敏感度降低， 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 提示，在低氧条件下研究的动物模型中，肝脏碳水化合物和脂肪动态平衡 会导致肝脏脂肪变性和炎症。综上所述，这些观察结果构成了 我们的总体假设的基础是OSA和低氧(H-OSA)患者有更大程度的 肝脏和脂肪组织中的胰岛素抵抗与没有缺氧的(NH-OSA)相比 导致前者患糖尿病的风险增加。 在目标1中，我们将检验这一假设，尽管OSA患者已被证明有胰岛素 在多个靶组织(脂肪、肌肉、肝脏、β细胞)中耐药，这些异常将显著 阻塞性睡眠呼吸暂停伴低氧(H-OSA)患者与无低氧患者相比 (NH-OSA)。我们将比较30例H-OSA患者和30例NH-OSA患者的组织特异性胰岛素敏感性 在性别、种族、年龄、体重指数和呼吸暂停低通气指数方面匹配。肝脏和肝外胰岛素敏感性 将用高胰岛素-正常血糖钳夹和稳定同位素示踪研究内源性 葡萄糖生成、糖异生、从头脂肪生成(DNL)和脂解作用。胰岛β细胞功能与胰岛素 动力学将根据口服葡萄糖耐量试验中胰岛素和C-肽的浓度进行评估。肝 用核磁共振测量脂肪，用双能X射线吸收法测量总瘦肉量和脂肪量。 在目标2中，我们将检验这样的假设，即持续正压(CPAP)治疗将 改善所有靶组织的胰岛素敏感性，这些改善在那些有 基线时缺氧。在CPAP治疗和维持六周稳定后，每个 在目标1中被研究的人将接受与那些相同的重复睡眠研究和代谢评估 我们推测，在NH-OSA中，胰岛素抵抗的主要触发因素是 睡眠片断引起的压力荷尔蒙水平，这主要表现在肝外组织中 (肌肉和脂肪)，而在H-OSA中，肝脏DNL有额外的刺激，导致肝脏脂肪 蓄积和肝脏胰岛素抵抗。 。