PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction

 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经济和公共卫生负担。肥胖者心血管风险增加与代谢失调直接相关，其主要特征包括 能量平衡和胰岛素抵抗。由于高体重增加累犯率，减肥努力降低肥胖患者心脏代谢风险的有效性有限。因此，直接针对肥胖症代谢适应性的干预措施是一个重要的研究领域。实验模型和我们在人类中的初步数据的证据表明，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合成和氧化能力。磷酸二酯酶5型（PDE 5）抑制剂如他达拉非可防止cGMP降解。这些药物具有良好的耐受性并改善葡萄糖代谢，但尚未作为肥胖相关的心脏代谢功能障碍的靶点进行全面测试。我们提出了一项随机、安慰剂对照研究，以检查PDE 5抑制对肥胖糖尿病前期个体的心脏代谢影响。受试者将接受他达拉非20 mg/天或安慰剂治疗12周。 目的1将使用代谢室检查慢性PDE 5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PDE 5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，生活质量和性功能。次要目的将检查PDE 5抑制对cGMP敏感性和糖尿病风险循环介质的影响。这项拟议的研究将是在心血管疾病高风险人群中首次对PDE 5抑制进行大型综合评价。我们选择的终点提供了高度相关的临床结局和cGMP作用的心脏代谢效应的机制见解。不依赖于体重减轻而改善代谢适应性的治疗将代表在降低肥胖患者心血管风险方面的重要进展。

 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.