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.

Public Health Relevance

/RELEVANCE Arterial vascular disease (including large to small peripheral vessels) is the major cause of morbidity and mortality in Metabolic Syndrome (MetS). We propose the first examination of pharmacology interaction with exercise training dose on improving baseline and insulin dependent vascular stiffness and function in middle- aged MetS patients. The proposed studies will define the role of pharmacology on optimal physical activity behavior to reverse clinical vascular and metabolic abnormalities as well as be the first effort to improve public health recommendations of physical activity when people are prescribed medication.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
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Mcdonald, Cheryl
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University of Virginia
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Malin, Steven K (2018) Dosing Exercise: Is More Really Better for Obesity-Related Outcomes? Obesity (Silver Spring) 26:1672
Gilbertson, Nicole M; Paisley, Andrew S; Kranz, Sibylle et al. (2017) Bariatric Surgery Resistance: Using Preoperative Lifestyle Medicine and/or Pharmacology for Metabolic Responsiveness. Obes Surg 27:3281-3291