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

项目摘要 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%的女性在一生中会患有OSA。OSA与一个 胰岛素抵抗和2型糖尿病的患病率增加，重度OSA，非酒精性 脂肪肝（NAFLD）也是如此。胰岛素抵抗与糖尿病的关系 和OSA是不完全理解的。我们之前已经证明，实验诱导睡眠 在健康志愿者中，限制胰岛素摄入导致全身胰岛素敏感性降低， 脂肪分解和脂肪生成，伴随着应激激素水平的增加。其他人的研究 表明，在缺氧条件下研究的动物模型中， 受到干扰导致肝脂肪变性和炎症。综合起来，这些观察结果构成了 根据我们的总体假设，患有OSA和缺氧（H-OSA）的患者具有更大程度的 与无缺氧（NH-OSA）相比，肝脏和脂肪组织中胰岛素抵抗， 导致前一组患糖尿病的风险增加。 在目标1中，我们将测试假设，虽然患有OSA的个体已被证明具有胰岛素 在多个靶组织（脂肪、肌肉、肝脏、β细胞）中的抵抗，这些异常将显著 与无缺氧的患者相比，伴有缺氧的OSA（H-OSA）患者的 （NH-OSA）。我们将比较30例H-OSA和30例NH-OSA患者的组织特异性胰岛素敏感性 匹配性别、种族、年龄、BMI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-正常血糖钳夹和内源性胰岛素的稳定同位素示踪剂研究来测量 葡萄糖产生、脂肪生成、从头脂肪生成（DNL）和脂解。β细胞功能和胰岛素 在口服葡萄糖耐量试验期间，从胰岛素和C-肽浓度评估动力学。肝 通过磁共振测量脂肪，通过双能X射线吸收测定法测量总瘦体重和脂肪质量。 在目标2中，我们将检验持续气道正压通气（CPAP）治疗将 改善所有靶组织中的胰岛素敏感性，并且这些改善在具有以下特征的组织中更大： 基线缺氧。在CPAP治疗稳定并维持6周后， 目标1中研究的个体将接受重复的睡眠研究和代谢评估， 如上文第1段所述。我们推测，在NH-OSA中，胰岛素抵抗主要是由增加的 由于睡眠不完整而导致的应激激素水平升高，这主要表现在肝外组织中 （肌肉和脂肪），而在H-OSA中，存在肝脏DNL的额外刺激，导致肝脏脂肪 积累和肝胰岛素抵抗。 .

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. .