Effects of Exercise and GLP-1R Agonism on Muscle Microvascular Perfusion and Insulin Action

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Project Summary/Abstract Patients with metabolic syndrome exhibit metabolic insulin resistance, have increased risks of cardiovascular events and are prone to developing type 2 diabetes mellitus. Substantial evidence has established the value of high levels of physical activity, exercise training, and overall cardiorespiratory fitness in the prevention of cardiovascular diseases. Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to reduce the new onset of diabetes in adult humans with prediabetes and the rate of major adverse cardiovascular events among patients with type 2 diabetes. The mechanisms underpinning the cardiovascular benefits of exercise and GLP-1 receptor agonism remain elusive. In the proposed studies, we will test an overarching hypothesis that exercise and GLP-1 receptor agonism each enhance insulin-mediated microvascular perfusion and muscle angiogenesis, leading to increased muscle delivery and action of insulin in the insulin resistant state. We further hypothesize that the combination of both would be more effective. We will use a translational approach to examine the effects of exercise and GLP-1 receptor agonism on both skeletal muscle and coronary microvasculature in humans with metabolic syndrome and the role of endothelial AMPK and mitochondrial fission in the pathogenesis of microvascular insulin resistance. We will use a state-of-the-art technique, contrast-enhanced ultrasound, in combination with arteriovenous balance, muscle biopsy and insulin clamp to quantify the effects of exercise training and GLP-1 receptor agonism on microvascular and metabolic responses to insulin in humans with insulin resistance/metabolic syndrome and open a new avenue for future mechanistic and/or therapeutic studies. We will further use a variety of rodent models to explore the underlying mechanisms. By understanding the regulation of skeletal and cardiac muscle microvascular function and insulin responses in humans with metabolic syndrome, it may be possible to correct vascular and ameliorate metabolic insulin resistance to prevent diabetes and decrease the associated cardiovascular risks.