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

描述(由申请人提供)：超重/肥胖的人胰岛素抵抗的风险增加，更有可能发展为心血管疾病(CVD)、2型糖尿病(2 DM)和阻塞性睡眠呼吸暂停(OSA)。心脑血管疾病和2 DM在OSA患者中常见，因此认为CVD和2 DM是继发于OSA的。然而，有证据表明，胰岛素抵抗可导致OSA的发展，类似于2 DM和CVD的发病机制。我们对上述关系提出了新的解释：胰岛素抵抗不仅是OSA的病因，而且是解释OSA、2 DM和CVD形成临床簇的共同特征。我们还假设，在胰岛素抵抗(IR)合并OSA的患者中，使用吡格列酮(PIO)治疗将提高胰岛素敏感性，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)对超重OSA患者和体重匹配的对照组的胰岛素作用、胰岛素分泌和多种心脏代谢风险因素的具体测量进行比较；预测OSA患者的胰岛素抵抗程度更高，心脏代谢风险更大。2)患有OSA的IR患者将接受PIO或安慰剂治疗，我们预测接受PLO治疗的患者的胰岛素敏感性将得到增强，这与OSA的临床改善、胰岛素分泌恢复正常以及心脏代谢风险的降低有关。3)同样的实验方法将被用来评估对接受PLO治疗和安慰剂治疗的OSA患者增加持续正压(CPAP)的临床和/或代谢益处。预测CPAP本身将不具有PIO的整体益处，但将增强PIO的益处。第二个目标是评估APJ受体的内源性配体apelin的活性变化是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，似乎与维持正常的胰岛素敏感性有关。我们将通过比较OSA患者和对照组的血浆APELIN水平，以及两种干预措施后IR OSA患者的血浆APELIN水平，来检验APELIN在过度肥胖和胰岛素抵抗之间的关系中起重要作用的假设。在两种干预措施的前后，也将在IR和OSA中获得脂肪组织活检，以在组织水平上评估apelin对糖脂代谢调节的变化。相关性：阻塞性睡眠呼吸暂停(OSA)在肥胖者中更为常见，并与2型糖尿病和心血管疾病(CVD)的风险增加有关。支持这项研究建议的假设是，胰岛素抵抗是OSA、2型糖尿病和CVD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综合征的病因和治疗的理解。(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)