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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

基本信息

批准号：
10357082
负责人：
Steven K Malin
金额：
$ 73.23万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357082
关键词：
Accelerometer Address Adherence Adult Aerobic Exercise Affect Attenuated Behavior Blood Glucose Blood Pressure Blood Vessels Body mass index Carbohydrates Cardiovascular system Cause of Death Clinical Closure by clamp Diabetes Mellitus Disease Dose Double-Blind Method Double-blind trial Drug Interactions Drug Prescriptions Early treatment Etiology Exercise Exercise Therapy Fasting Functional disorder Future Glucose Glucose Clamp 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 cardiometabolism 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

项目摘要

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.

项目总结/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小时血压以及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，鉴定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。

项目成果

期刊论文数量（31）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Insulin at the Crossroads of Metabolic, Neurologic, and Vasculature Disease.

胰岛素处于代谢、神经和脉管系统疾病的十字路口。

DOI：
10.1249/jes.0000000000000187
发表时间：
2019
期刊：
Exercise and sport sciences reviews
影响因子：
5.7
作者：
Malin,StevenK
通讯作者：
Malin,StevenK

Dosing Exercise: Is More Really Better for Obesity-Related Outcomes?

DOI：
10.1002/oby.22330
发表时间：
2018-11
期刊：
Obesity (Silver Spring, Md.)
影响因子：
0
作者：
Malin SK
通讯作者：
Malin SK

Timing Is Everything, Right? Meal Impact on Circadian Related Health.

DOI：
10.1210/clinem/dgaa533
发表时间：
2021-01-23
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
0
作者：
Malin SK
通讯作者：
Malin SK

Effect of presurgical aerobic exercise on cardiometabolic health 30 days after bariatric surgery.

DOI：
10.14814/phy2.15039
发表时间：
2021-11
期刊：
Physiological reports
影响因子：
2.5
作者：
Gilbertson NM;Eichner NZM;Gaitán JM;Khurshid M;Rexrode EA;Kranz S;Hallowell PT;Malin SK
通讯作者：
Malin SK

β-Aminoisobutyric Acid Relates to Favorable Glucose Metabolism through Adiponectin in Adults with Obesity Independent of Prediabetes.