PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction

PDE5 抑制治疗肥胖相关的心脏代谢功能障碍

基本信息

批准号：
9113813
负责人：
Evan L Brittain
金额：
$ 77.78万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113813
关键词：
Acids Address Adult Adverse effects Aerobic Area Beta Cell Biochemical Biogenesis Biological Markers Blinded Body Composition Body Weight decreased Branched-Chain Amino Acids Cardiopulmonary Cardiovascular Diseases Cardiovascular system Cell physiology Chronic Clinical Clinical Trials Cyclic GMP Data Diabetes Mellitus Dual-Energy X-Ray Absorptiometry Effectiveness Energy Metabolism Enzyme Inhibition Evaluation Exercise Exercise stress test Exhibits Experimental Models Fasting Fatty acid glycerol esters Functional disorder Health Homeostasis Human Individual Insulin Insulin Resistance Intervention Investigation Knowledge Measurement Measures Mediator of activation protein Metabolic Metabolism Mitochondria Mus Natriuretic Peptides Nitric Oxide Obesity Organ Outcome Oxygen Consumption Participant Pathway interactions Pharmaceutical Preparations Physiological Pilot Projects Placebos Plasma Population Production Public Health Quality of life Quality-of-Life Assessment Randomized Research Design Research Personnel Resistance Rest Risk SF-36 Sampling Second Messenger Systems Signal Pathway Signal Transduction Skeletal Muscle Techniques Testing Transgenic Animals Weight Weight Gain animal data cardiometabolic risk cardiovascular risk factor circulating biomarkers clinically relevant diabetes risk effective therapy fitness glucose metabolism guanylate heart disease risk high risk human data improved indexing inhibitor/antagonist insight insulin secretion insulin sensitivity intravenous glucose tolerance test lean body mass metabolic rate metabolomics novel phosphoric diester hydrolase prevent public health relevance randomized placebo controlled trial recidivism response second messenger tadalafil trait treatment group

项目摘要

DESCRIPTION (provided by applicant): The metabolic and cardiovascular sequelae of obesity constitute a major financial and public health burden. Increased cardiovascular risk in obesity is directly related to metabolic dysregulation, key features of which include abnormalities in energy homeostasis and insulin resistance. The effectiveness of weight loss efforts to reduce cardiometabolic risk in obesity is limited due to high weight gain recidivism. Therefore, interventions that directly target metabolic fitness in obesity represent an important area of investigation. Evidence in experimental models and our preliminary data in humans suggest that the cyclic guanylate monophosphate pathway (cGMP) is a critical mediator of insulin resistance and energy homeostasis. Increased cGMP signaling raises resting energy expenditure and provides resistance to obesity and diabetes. Cyclic GMP also stimulates mitochondrial biogenesis and oxidative capacity in skeletal muscle. Phosphodiesterase type 5 (PDE5) inhibitors such as tadalafil prevent the degradation of cGMP. These medications are well-tolerated and improve glucose metabolism, but have not been comprehensively tested as a target for obesity-related cardiometabolic dysfunction in humans. We propose a randomized, placebo-controlled study to examine the cardiometabolic effects of PDE5 inhibition in obese prediabetic individuals. Participants will receive tadalafil 20 mg per day or placebo for 12 weeks. Aim 1 will examine the effect of chronic PDE5 inhibition on resting and exercise energy expenditure using a metabolic chamber. In Aim 2, we will test the effect of PDE5 inhibition on insulin sensitivity and secretion. We will also assess body composition, quality of life, and sexua function. A Secondary Aim will examine the effect of PDE5 inhibition on cGMP sensitivity and circulating mediators of diabetes risk. The proposed study will be the first large comprehensive evaluation of PDE5 inhibition in a population at high risk of cardiovascular disease. Our endpoints were selected to provide highly relevant clinical outcomes and mechanistic insight into the cardiometabolic effects of cGMP action. Therapy that improves metabolic fitness independent of weight loss would represent an important advance in the effort to reduce cardiovascular risk in obesity.

描述（由申请人提供）：肥胖的代谢和心血管后遗症构成了主要的财务和公共健康负担。肥胖导致的心血管风险增加与代谢失调直接相关，其主要特征包括异常。由于体重增加频繁，减肥努力降低肥胖症心脏代谢风险的效果有限，因此，直接针对肥胖症代谢健康的干预措施是实验研究的一个重要领域。模型和我们在人体中的初步数据表明，环鸟苷酸单磷酸途径 (cGMP) 是胰岛素抵抗和能量稳态的关键介质，cGMP 信号传导的增加会增加静息能量消耗，并提供对肥胖和糖尿病的抵抗力。环 GMP 还刺激骨骼肌中的线粒体生物发生和氧化能力，例如他达拉非，这些药物具有良好的耐受性并可改善葡萄糖代谢，但尚未作为目标进行全面测试。我们提出了一项随机、安慰剂对照研究来检查 PDE5 抑制对肥胖者心脏代谢的影响。糖尿病前期患者将每天服用他达拉非 20 毫克或服用安慰剂，持续 12 周。目标 1 将使用代谢室检查长期 PDE5 抑制对静息和运动能量消耗的影响。在目标 2 中，我们将测试 PDE5 抑制对胰岛素敏感性和分泌的影响。我们还将评估身体成分、生活质量、次要目标是研究 PDE5 抑制对 cGMP 敏感性和糖尿病风险循环介质的影响。选择终点是为了提供与 cGMP 作用的心脏代谢影响高度相关的临床结果和机制见解。独立于体重减轻而改善代谢健康的治疗将代表着降低肥胖症心血管风险的重要进展。