Exercise dose and metformin for vascular health in adults with metabolic syndrome

运动剂量和二甲双胍对代谢综合征成人血管健康的影响

• 批准号: 9239977
• 负责人: Steven K Malin
• 金额: $ 73.97万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239977
• 关键词: Accelerometer; Address; Adherence; Adult; Aerobic Exercise; Affect; Attenuated; Behavior; Blood Glucose; Blood Pressure; Blood Vessels; Carbohydrates; Cardiovascular system; Cause of Death; Clinical; Closure by clamp; Diabetes Mellitus; Disease; Dose; Double-Blind Method; Double-blind trial; Drug Interactions; Early treatment; Etiology; Euglycemic Clamping; Exercise; Exercise Therapy; Fasting; Functional disorder; Future; Glucose; Glycosylated hemoglobin A; Goals; Health; Healthcare; Hyperglycemia; Hypertension; Indirect Calorimetry; Inflammation; Insulin; Insulin Resistance; Intervention; Knowledge; Measures; Mediating; Metabolic; Metabolic syndrome; Metformin; Microcirculation; Mitochondria; Morbidity - disease rate; Muscle Cells; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Outcome; Oxidative Stress; Patients; Pattern; Perception; Peripheral; Pharmaceutical Preparations; Pharmacology; Physical activity; Physiologic pulse; Placebos; Pre-Post Tests; Public Health; Quality of life; Randomized; Recommendation; Resistance; Role; Signal Transduction; Skeletal Muscle; Testing; Therapeutic; Training; Trees; Ultrasonography; Vascular Diseases; Work; arterial stiffness; arteriole; base; cardiovascular health; contrast enhanced; disorder prevention; disorder risk; endothelial dysfunction; exercise adherence; exercise intensity; exercise training; glucose disposal; glucose tolerance; glycemic control; health organization; improved; indexing; insight; insulin sensitivity; middle age; mortality; oxidation; post intervention; prevent; sedentary lifestyle; treatment effect; trend; trial design

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.

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。 动脉功能障碍证明了这一点，进而导致血压和血糖升高。 建议以基于强度的方式进行锻炼，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，可降低未来患 2 型糖尿病和 CVD 的风险。 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。 根据我们的初步工作，我们的总体假设是二甲双胍会减弱高强度后的适应 我们进一步通过降低线粒体衍生的氧化应激信号来进行强度运动训练（HiEx）。 研究发现低强度运动（LoEx）训练与二甲双胍相结合将促进相加效应 与 LoEx 或 HiEx+二甲双胍相比，可改善血管功能，并维持/改善非运动体能 在这项双盲试验中，肥胖的 30-60 岁 MetS 患者将被随机分配至：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。 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（缺血后流速）和微血管（对比增强 超声）血管，在干预前后进行正常血糖钳夹之前和期间（AIM 1）。 评估 24 小时血压并确定骨骼肌代谢、胰岛素抵抗和血糖 耐受性（AIM 2）来解决与医疗保健相关的临床和实验问题。 检查二甲双胍对运动坚持、非运动身体活动和生活质量的影响 为期 16 周的干预以及为期 8 周的“自由生活”期（探索性 AIM 3），以改善公众 联合处方药物时的健康体力活动建议 如果这些假设正确，则它们是有效的。 将表明 1) 二甲双胍是否以及如何与身体活动相结合以预防 CVD，2) 首次表明运动强度是否通过多层次脉管系统功能降低 CVD 风险 与代谢性胰岛素作用相比，3) 为 MetS 患者提供合理的早期治疗。 最佳药物与运动相互作用将阐明如何制定个体化运动/二甲双胍 纠正血管和改善代谢性胰岛素抵抗以减轻/预防进展的处方 未来的糖尿病以及心血管发病率和死亡率。