Role of Microvascular insulin resistance and cardiorespiratory fitness in diabetes

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Project Summary The goal of this two-site proposal is to determine whether and by what means insulin resistance, in the form of impaired insulin regulation of microvascular perfusion, leads to decreased functional exercise capacity (FEC) in type 2 diabetes (T2D). Data from our two research teams suggest that the cardiac and skeletal muscle microvascular dysfunction present in people with T2D contributes to limitations in cardiac and skeletal muscle oxygenation and function associated with impaired function exercise capacity (a major predictor of CV and all- cause mortality). Insulin action is a potent predictor of the FEC impairment in T2D. The exact relationship between insulin action, cardiac and muscle dysfunction, cardiac and skeletal muscle perfusion and decreased FEC in T2D remains unclear. Here we propose to address this gap in knowledge by defining the roles of impaired insulin-mediated cardiac and skeletal muscle perfusion and exercise performance in people with T2D. Hypothesis: Decreased insulin-mediated muscle perfusion found in T2D contributes to the development of cardiac and skeletal muscle dysfunction and subsequent impairment in exercise capacity. We further hypothesize that exercise training attenuates insulin resistance and restores insulin-mediated perfusion to the skeletal and cardiac muscle, leading to improved exercise performance. Specific Aim 1: To test the hypothesis that impairment in insulin-mediated cardiac perfusion limits exercise performance through its effect on cardiac function in people with T2D. We will examine the relationship between insulin- mediated cardiac perfusion, other measures of cardiac function, and VO2 peak at rest and with exercise in subjects with and without T2D. Given that there is a sex disparity in diabetes outcomes and exercise impairment with a lack of mechanistic insights on sex differences, we will analyze all parameters for differences by sex on an exploratory basis in the three aims. Specific Aim 2: To test the hypothesis that impaired insulin-mediated skeletal muscle perfusion limits exercise performance through its effect on oxidative capacity in people with T2D. We will examine the relationship between insulin-mediated skeletal muscle perfusion; muscle oxygenation, skeletal muscle mitochondrial function and in vivo skeletal muscle oxidative flux; and VO2 peak in subjects with and without T2D. Specific Aim 3: To test the hypothesis that the improvement in FEC subsequent to exercise training operates via action on cardiac and muscle function in T2D. These experiments will test whether the improvements in VO2peak observed with exercise training correlate with improvements in insulin-mediated perfusion, cardiac and skeletal muscle function and the impact of T2D on these changes. Understanding the role of microvascular disease in the diabetes-mediated exercise impairment may offer novel targets for intervention to improve exercise capacity, functional status and longevity in people with diabetes. Together, our two groups will employ complementary theoretical backgrounds and research methods in a synergistic approach to address the innovative hypothesis posed to improve health in T2D.