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

睡眠呼吸暂停、2 型糖尿病和 CVD：与胰岛素抵抗相关的一组疾病

• 批准号: 8138080
• 负责人: GERALD M. REAVEN
• 金额: $ 62.7万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-16 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138080
• 关键词: Accounting; Address; Adipose tissue; Biopsy; Cardiovascular Diseases; Clinical; Complex; Continuous Positive Airway Pressure; Control Groups; Defect; Development; Etiology; Evaluation; Functional disorder; Glucose; Goals; Hyperinsulinism; Individual; Infusion procedures; Insulin; Insulin Resistance; Intervention; Lead; Ligands; Link; Lipolysis; Maintenance; Measurement; Mediating; Metabolic; Methodology; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obstructive Sleep Apnea; Overweight; Pathogenesis; Patients; Peptides; Pioglitazone; Placebos; Plasma; Play; Polysomnography; Prevalence; Questionnaires; Regulation; Research; Research Proposals; Resistance; Risk; Risk Factors; Role; Secondary to; Sleep Apnea Syndromes; Syndrome; System; Testing; Tissues; Weight; abstracting; cardiovascular disorder risk; glucose disposal; glucose metabolism; glucose uptake; improved; insulin secretion; insulin sensitivity; insulin sensitizing drugs; lipid metabolism; pressure; receptor

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)

描述（由申请人提供）：超重/肥胖个体胰岛素抵抗的风险增加，更可能发生心血管疾病（CVD）、2型糖尿病（2DM）和阻塞性睡眠呼吸暂停（OSA）。CVD和2DM在OSA患者中常见，导致CVD和2DM继发于OSA的观点。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。我们提出了一个新的解释上述关系;胰岛素抵抗不仅有助于OSA的病因，但共同的特点，解释为什么OSA，2 DM和CVD形成一个临床集群。我们还推测，吡格列酮（PIO）治疗胰岛素抵抗（IR）的OSA患者将提高胰岛素敏感性，与临床改善和心脏代谢风险降低。这项建议有三个主要目标。1)比较超重OSA患者与体重匹配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结果;预测OSA受试者将更具有胰岛素抵抗，并具有更大的心脏代谢风险。2)PIO或安慰剂将给予患有OSA的IR患者，我们预测PIO治疗患者的胰岛素敏感性将增强，与OSA的临床改善、胰岛素分泌恢复正常以及心脏代谢风险降低相关。3)同样的实验方法将用于评估对经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。预测单独使用CPAP不会具有PIO相同的总体获益，但会增强PIO的获益。第二个目标是评估以下假设：apelin（APJ受体的内源性配体）活性的变化是过度肥胖和胰岛素抵抗之间的重要机制联系。爱帕琳及其受体位于脂肪组织中，并且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，以及对患有OSA的IR患者进行两次干预后，来检验apelin对过度肥胖和胰岛素抵抗之间的关系有显着贡献的假设。在两种干预的每一种之前和之后，还将在具有OSA的IR中获得脂肪组织活检，以评价在组织水平上葡萄糖和脂质代谢的爱帕琳调节的变化。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）的风险增加相关。本研究提出的假设是，胰岛素抵抗是OSA、2型糖尿病和CVD的聚集性原因。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理解。(End摘要）