Sleep apnea, Type 2 diabetes, and CVD: a cluster related to insulin resistance

描述（由申请人提供）：超重/肥胖个体胰岛素抵抗的风险增加，更容易发生心血管疾病（CVD）， 2型糖尿病（2DM）和阻塞性睡眠呼吸暂停（OSA）。CVD和2DM常见于OSA患者，因此认为CVD和2DM继发于OSA。然而，有证据表明胰岛素抵抗可导致OSA的发展，类似于2DM和CVD的发病机制。我们对上述关系提出一种新的解释；胰岛素抵抗不仅有助于OSA的病因，而且是解释OSA、2DM和CVD形成临床集群的共同特征。我们还假设，胰岛素抵抗（IR） OSA患者使用吡格列酮（PIO）治疗可提高胰岛素敏感性，与临床改善和心脏代谢风险降低相关。这项提议有三个主要目标。1)比较超重OSA患者与体重匹配对照组胰岛素作用、胰岛素分泌及多种心脏代谢危险因素的特异性测量；预测阻塞性睡眠呼吸暂停患者的胰岛素抵抗性更强，心脏代谢风险更大。2)对伴有OSA的IR患者给予PIO或安慰剂，我们预测plo治疗的患者胰岛素敏感性将增强，与OSA的临床改善相关，胰岛素分泌恢复正常；降低心脏代谢风险。3)同样的实验方法将用于评估对plo治疗和安慰剂治疗的OSA患者增加持续气道正压通气（CPAP）的临床和/或代谢益处；预测单独CPAP不会产生与PIO相同的总体效益，但会增强PIO的效益。第二个目标是评估APJ受体的内源性配体apelin活性的变化作为过度肥胖和胰岛素抵抗之间的重要机制联系的假设。Apelin及其受体位于脂肪组织中，似乎参与维持正常的胰岛素敏感性。我们将通过比较OSA患者与对照组的血浆apelin水平，以及IR OSA患者两种干预后的血浆apelin水平，来验证apelin在过度肥胖与胰岛素抵抗之间的关系中起着重要作用的假设。在两种干预前后，还将对患有OSA的IR患者进行脂肪组织活检，以评估组织水平上apelin调节糖脂代谢的变化。相关性：阻塞性睡眠呼吸暂停（OSA）在肥胖人群中更为常见，并与2型糖尿病和心血管疾病（CVD）的风险增加有关。这项研究提出的假设是，对胰岛素作用的抵抗是OSA、2型糖尿病和心血管疾病聚集的原因。如果这一观点能够得到证实，它将极大地改变目前对阻塞性睡眠呼吸暂停的病因和治疗的认识。（摘要结束）

DESCRIPTION (provided by applicant): Overweight/obese Individuals are at increased risk of being insulin resistant, and more likely to develop cardiovascular disease (CVD), type 2 diabetes (2DM), and obstructive sleep apnea (OSA). CVD and 2DM occur commonly in patients with OSA, leading to the view that CVD and 2DM are secondary to OSA. However, there is evidence that insulin resistance can lead to the development of OSA, similar to the pathogenesis of 2DM and CVD. We propose a new explanation for the relationships outlined above; insulin resistance not only contributes to the etiology of OSA, but is the common feature explaining why OSA, 2DM, and CVD form a clinical cluster. We also postulate that treatment with pioglitazone (PIO) in insulin resistant (IR) patients with OSA will enhance insulin sensitivity, associated with clinical improvement and decreases in cardio-metabolic risk. This proposal has three primary goals. 1) A comparison of specific measurements of insulin action, insulin secretion, and multiple cardio-metabolic risk factors in overweight patients with OSA with a weight-matched control group; predicting that subjects with OSA will be more insulin resistant, and at greater cardio-metabolic risk. 2) PIO, or placebo, will be given to IR patients with OSA, and we predict that insulin sensitivity will be enhanced in PlO-treated patients, associated with clinical improvement in OSA, a return towards normal of insulin secretion; and a decrease in cardio-metabolic risk. 3) The same experimental approaches will be used to evaluate the clinical and/or metabolic benefits of adding continuous positive airway pressure (CPAP) to PlO-treated and placebo-treated patients with OSA.; predicting that CPAP alone will not have the same overall benefits of PIO, but will enhance those of PIO. A secondary goal is to evaluate the hypothesis that changes in the activity of apelin, the endogenous ligand for the APJ receptor, serves as an important mechanistic link between excess adiposity and insulin resistance. Apelin, and its receptor, are located in adipose tissue, and appear to be involved in maintenance of normal insulin sensitivity. We will test the hypothesis that apelin contributes significantly to the relationship between excess adiposity and insulin resistance by comparing plasma apelin levels in patients with OSA vs. the control group, as well as after the two interventions in IR patients with OSA. Adipose tissue biopsies will also be obtained in IR with OSA before and after each of the two interventions to evaluate changes in apelin modulation of glucose and lipid metabolism at the tissue level. RELEVANCE: Obstructive sleep apnea (OSA) is more common in obese individuals, and is associated with increased risk of type 2 diabetes and cardiovascular disease (CVD).The hypothesis underlying this research proposal is that resistance to insulin action accounts for the clustering of OSA, type 2 diabetes and CVD. If this view can be validated it will dramatically change current understanding of the cause and the treatment of OSA. (End of Abstract)