Insulin Resistance in Pulmonary Arterial Hypertension

肺动脉高压的胰岛素抵抗

• 批准号: 8804720
• 负责人: GUSTAVO Adolfo HERESI DAVILA
• 金额: $ 14.94万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8804720
• 关键词: Activities of Daily Living; Age; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Arteries; Blood; Blood Glucose; Blood Vessels; Body Composition; Caring; Cell Proliferation; Cessation of life; Chronic; Clinic; Clinical; Clinical Research; Collaborations; Counseling; Data; Diagnosis; Diet; Dietary Intervention; Disease; Epidemic; Epidemiology; Exercise; Fasting; Future; Gender; Glucose; Glycemic Index; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Goals; Heart; Heart failure; High Density Lipoprotein Cholesterol; Human; Hyperglycemia; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Interleukin-6; Intervention Trial; Journals; Lead; Link; Lipids; Lung; Measurement; Measures; Mediator of activation protein; Mentors; Metabolic; Metabolism; Modeling; Necrosis; OGTT; Obesity; Oral; Outcome; Patients; Peripheral; Phenotype; Plasma; Population; Process; Production; Publications; Pulmonary Hypertension; Pulmonary Vascular Resistance; Randomized; Reporting; Research; Research Personnel; Right Ventricular Function; Role; Severities; Survival Rate; Testing; Training; Vasodilator Agents; Visceral; Work; base; career; cytokine; diabetic; diet and exercise; effective therapy; follow-up; improved; indexing; insulin sensitivity; insulin sensitizing drugs; monocyte; mortality; novel; patient oriented research; patient population; premature; pressure; programs; public health relevance; pulmonary arterial hypertension; sedentary lifestyle; skills; standard of care; success; targeted treatment; tumor

 DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a deadly disease, partially treated with pulmonary vasodilators. Emerging data suggest a potential role for insulin resistance in PAH. Both conditions are linked to chronic low- grade inflammation and monocyte (MNC) activation. However, direct measurements of insulin resistance in PAH patients have not been performed to date. Furthermore, the extent to which exercise and diet may improve PAH through the modulation of insulin sensitivity and inflammation has not been investigated. Our central hypothesis is that insulin resistance is a mediator of the disease process in PAH. We will test this hypothesis by pursuing the following Specific Aims: 1) Quantitate insulin sensitivity and body composition in PAH, and correlate with PAH severity. Indices of insulin sensitivity will be calculated using an oral glucose tolerance test (OGTT), and body composition will be measured by means of dual energy x-ray absorptiometry. These data will be correlated with PAH severity and mortality during a 2-3-year follow up. 2) Measure the inflammatory response of PAH-MNCs to hyperglycemia. Our working hypothesis is that insulin resistance elicits an enhanced inflammatory response in PAH. We will test this hypothesis by measuring the release of interleukin 6 and tumor necrosis-alpha by peripheral MNCs, both in the fasting state and after an oral glucose load. Aims 1 and 2 will include age-, gender-, and BMI-matched healthy controls. 3) Determine the extent to which improvements in insulin resistance via diet and exercise impact PAH. The working hypothesis is that improvement in insulin sensitivity might lead to improvements in PAH parameters through blunting of the inflammatory response. We will assess the impact of a 12-week exercise and low glycemic index Mediterranean type diet program compared to standard of care on insulin resistance, PAH indices of severity (echo estimated pulmonary pressure and right ventricular function) and monocyte- derived inflammatory cytokines, and in a "proof-of-concept" randomized study. The candidate has a strong clinical background in PAH, a track record of successful research endeavors with publications in major pulmonary journals, and a clear commitment and passion for patient-oriented research. The proposal's feasibility and success are predicated upon the large PAH population followed at the Cleveland Clinic; the one on one mentoring by Dr. Dweik, a PAH expert, and Dr. Kirwan, an insulin resistance expert; the collaboration with Dr. Barkoukis, an expert in diet interventions; and the CTSA Clinical Research Unit where the metabolic testing, diet counseling and exercise training will take place. The career plan includes didactic courses and guidance from a Mentoring Committee. The ultimate goal is to expand the applicant's research skills to allow a future career as an independent investigator able to conduct research that will directly benefit PAH patients.

 描述（由申请人提供）：肺动脉高压（PAH）是一种致命的疾病，部分可以用肺血管扩张剂治疗。新数据表明胰岛素抵抗在 PAH 中具有潜在作用。这两种情况都与慢性低度炎症和单核细胞 (MNC) 激活有关。然而，迄今为止尚未对 PAH 患者的胰岛素抵抗进行直接测量。此外，运动和饮食在多大程度上可以通过调节胰岛素敏感性和炎症来改善 PAH。我们的中心假设是胰岛素抵抗是 PAH 疾病过程的介质。我们将通过追求以下具体目标来检验这一假设：1) 定量 PAH 中的胰岛素敏感性和身体成分，并与 PAH 严重程度相关联。胰岛素敏感性指数将使用口服葡萄糖耐量试验（OGTT）计算，身体成分将通过双能X射线吸收测定法测量。这些数据将在 2-3 年随访期间与 PAH 严重程度和死亡率相关。 2）测量PAH-MNCs对高血糖的炎症反应。我们的工作假设是胰岛素抵抗会引起 PAH 炎症反应增强。我们将通过测量外周 MNC 在禁食状态和口服葡萄糖负荷后释放的白细胞介素 6 和肿瘤坏死-α 来检验这一假设。目标 1 和 2 将包括年龄、性别和 BMI 匹配的健康对照。 3) 确定通过饮食和运动改善胰岛素抵抗对 PAH 的影响程度。目前的假设是，胰岛素敏感性的改善可能会通过减弱炎症反应来改善 PAH 参数。我们将评估为期 12 周的运动和低血糖指数地中海式饮食计划与标准护理相比对胰岛素抵抗、PAH 严重程度指数（回波估计肺动脉压力和右心室功能）和单核细胞衍生的炎症细胞因子的影响，以及在“概念验证”随机研究中的影响。该候选人在肺动脉高压方面拥有深厚的临床背景、在主要肺部期刊上发表文章的成功研究记录以及对以患者为导向的研究的明确承诺和热情。该提案的可行性和成功取决于克利夫兰诊所对大量 PAH 人群的跟踪； PAH 专家 Dweik 博士和胰岛素抵抗专家 Kirwan 博士进行一对一指导；与饮食干预专家 Barkoukis 博士的合作； CTSA 临床研究中心将进行代谢测试、饮食咨询和运动训练。职业规划包括教学课程和指导委员会的指导。最终目标是扩展申请人的研究技能，使未来的职业生涯成为一名独立研究者，能够进行直接造福 PAH 患者的研究。