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

项目摘要/摘要 动脉疾病是代谢综合征(METS)发病/死亡的主要原因。这种情况发生得很早，因为 动脉功能障碍证明了这一点，而动脉功能障碍反过来又会升高血压和血糖。卫生组织 建议以强度为基础的方式进行锻炼，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型糖尿病和心血管疾病的风险。然而， 与二甲双胍联合使用对血管功能产生附加作用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HIGH之后钝化适应。 强度运动训练(HiEx)通过降低线粒体衍生的氧化应激信号。我们进一步 假设低强度运动(LOEX)训练与二甲双胍联合使用将促进相加效应 与LOEX或HiEx二甲双胍相比，对血管功能的影响，并维持/改善非运动体能 活动模式。在这项双盲试验中，30-60岁的肥胖METS患者将被随机分为：1)LOEX安慰剂； 2)LOEX二甲双胍，3)HiEx安慰剂；或4)HiEx二甲双胍，疗程16周。我们将评估以下措施 动脉僵硬(脉搏波速度和增大指数)和一氧化氮介导的动脉功能 管道(血流介导的扩张)、阻力(缺血后血流速度)和微血管(增强对比 超声)血管，在正常血糖钳夹干预前和干预后(目标1)。我们还将 评估24小时血压，并测定骨骼肌代谢、胰岛素抵抗和血糖 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，我们还将 研究二甲双胍对运动依从性、非运动性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 健康体力活动推荐联合用药时。如果这些假设是正确的，他们 将表明1)二甲双胍是否以及如何与预防心血管疾病的体力活动相结合；2) 提供运动强度是否通过多层次血管功能降低心血管疾病风险的第一个指示 对比代谢胰岛素的作用，3)为甲硫氨酸代谢综合征患者提供合理的早期治疗。因此，确定 运动相互作用的最佳药物将阐明如何发展个性化运动/二甲双胍 纠正血管和改善减缓/防止进展的代谢性胰岛素抵抗的处方 对未来糖尿病和心血管疾病的发病率和死亡率的影响。

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.