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/肥胖个体出现胰岛素抵抗的风险增加，并且更有可能患心血管疾病 (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 的发生，类似于 2DM 和 CVD 的发病机制。我们对上述关系提出了一个新的解释；胰岛素抵抗不仅是 OSA 的病因，也是解释 OSA、2DM 和 CVD 形成临床集群的共同特征。我们还假设，用吡格列酮 (PIO) 治疗患有 OSA 的胰岛素抵抗 (IR) 患者将增强胰岛素敏感性，与临床改善和心脏代谢风险降低相关。该提案具有三个主要目标。 1) 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危险因素的具体测量结果的比较；预测患有 OSA 的受试者将更容易产生胰岛素抵抗，并且面临更大的心脏代谢风险。 2)将PIO或安慰剂给予伴有OSA的IR患者，我们预测P10治疗的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相关；以及心脏代谢风险的降低。 3)相同的实验方法将用于评估向P10治疗和安慰剂治疗的OSA患者添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 不会获得与 PIO 相同的总体益处，但会增强 PIO 的益处。第二个目标是评估这样的假设：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。 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 水平以及对 OSA IR 患者进行两次干预后的血浆 apelin 水平来检验 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。在两次干预之前和之后，还将在 IR 和 OSA 中获得脂肪组织活检，以评估组织水平上 apelin 对葡萄糖和脂质代谢的调节变化。相关性：阻塞性睡眠呼吸暂停 (OSA) 在肥胖个体中更为常见，并且与 2 型糖尿病和心血管疾病 (CVD) 风险增加相关。本研究提案的假设是，对胰岛素作用的抵抗导致了 OSA 的聚集、2型糖尿病和CVD。如果这一观点得到验证，将极大地改变目前对 OSA 病因和治疗的理解。 （摘要完）