Exercise Dose and Metformin for Vascular Health in Adults with Metabolic Syndrome

项目概要/摘要 动脉疾病是代谢综合征（MetS）发病/死亡的主要原因。这种情况发生早， 动脉功能障碍会导致血压和血糖升高。卫生组织 建议以强度为基础的方式进行运动，以促进心血管适应和预防疾病。 二甲双胍是一种常见的抗糖尿病药物，可降低未来2型糖尿病和CVD风险。然而，在这方面， 与二甲双胍联合对血管功能产生累加效应的最佳运动剂量尚不清楚。 基于我们的初步工作，我们的总体假设是二甲双胍在高血糖后会减弱适应性， 高强度运动训练（HiEx）通过降低线粒体衍生的氧化应激信号传导。我们进一步 假设低强度运动（LoEx）训练联合二甲双胍将促进累加效应 与LoEx或HiEx+二甲双胍相比，对血管功能的影响，并维持/改善非运动体力 活动模式。在这项双盲试验中，肥胖的30- 60岁MetS患者将随机接受：1）LoEx+安慰剂; 2)LoEx+二甲双胍，3）HiEx+安慰剂;或4）HiEx+二甲双胍16周。我们将评估 动脉僵硬度（脉搏波速度和增强指数）和一氧化氮介导的动脉功能， 导管（血流介导的扩张）、阻力（缺血后血流速度）和微血管（对比增强） 超声）血管，在干预前和干预后（AIM 1）的正葡萄糖钳夹之前和期间。我们还将 评估24小时血压并确定骨骼肌代谢胰岛素抵抗和葡萄糖 耐受性（AIM 2），以解决与医疗保健相关的临床和实验问题。此外，我们将 检查二甲双胍对运动依从性、非运动体力活动和生活质量的影响， 16周的干预以及8周的“自由生活”期间（探索性目标3），以改善公众 健康的身体活动的建议，当共同处方药。如果这些假设是正确的， 将指出1）二甲双胍是否以及如何与体力活动联合用于CVD预防，2） 提供运动强度是否经由多水平脉管系统功能降低CVD风险的第一指示 vs.代谢胰岛素作用; 3）为代谢综合征患者提供合理的早期治疗。因此， 最佳药物与运动相互作用将阐明如何开发个体化运动/二甲双胍 纠正血管和改善代谢性胰岛素抵抗的处方， 未来糖尿病和CV发病率和死亡率。

PROJECT SUMMARY/ABSTRACT Arterial disease is the leading cause of morbidity/mortality in Metabolic syndrome (MetS). This occurs early as evidenced by arterial dysfunction that, in turn, raises blood pressure and glucose. Health organizations recommend exercise in an intensity based manner to promote cardiovascular adaptation and prevent disease. Metformin is a common anti-diabetes medication that reduces future type 2 diabetes and CVD risk. However, the optimal exercise dose to be combined with metformin for additive effects on vascular function is unknown. Based on our preliminary work, our overall hypothesis is that metformin blunts adaptation following high intensity exercise training (HiEx) by lowering mitochondrial derived oxidative stress signaling. We further hypothesize that low intensity exercise (LoEx) training combined with metformin will promote additive effects on vascular function compared to LoEx or HiEx+metformin, and maintain/improve non-exercise physical activity patterns. In this double-blind trial, obese 30-60y MetS patients will be randomized to: 1) LoEx+placebo; 2) LoEx+metformin, 3) HiEx+placebo; or 4) HiEx+metformin for 16 weeks. We will evaluate measures of arterial stiffness (pulse wave velocity and augmentation index), and nitric oxide-mediated arterial function in conduit (flow mediated dilation), resistance (post-ischemic flow velocity) and microvascular (contrast enhanced ultrasound) vessels, before and during a euglycemic clamp pre and post intervention (AIM 1). We will also assess 24 hr blood pressure as well as determine skeletal muscle metabolic insulin resistance and glucose tolerance (AIM 2) to address clinical and experimental questions related to health care. Further, we will examine the effect of metformin on exercise adherence, non-exercise physical activity and quality of life during the 16 week intervention as well as during an 8 week “free-living” period (Exploratory AIM 3) to improve public health physical activity recommendations when co-prescribed medication. If these hypothesis are correct, they will indicate 1) whether and how metformin should be combined with physical activity for CVD prevention, 2) provide the first indication of whether exercise intensity reduces CVD risk via multi-level vasculature function vs. metabolic insulin action, 3) provide a rational early treatment for people with MetS. Thus, identification of the optimal drug to exercise interaction will illuminate how to develop individualized exercise/metformin prescriptions to correct vascular and ameliorate metabolic insulin resistance that attenuate/prevent progression to future diabetes and the CV morbidity and mortality.