Cardiovascular Mechanisms of Exercise Intolerance in Diabetes and the Role of Sex

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Statement of Problem: Type 2 Diabetes (T2D) affects 24% of Veterans and it is associated with impaired cardiovascular exercise capacity (CVEC) which is important because of a strong relationship between CVEC and excess mortality. The goal of this proposal is to understand the contribution of preclinical cardiac, vascular dysfunction and skeletal muscle perfusion abnormalities to impaired CVEC in men and women with T2D and, further, to test the adaptive response to intervention using exercise training to reveal modifiable targets for therapy to improve cardiometabolic health. Overall Hypothesis: Impaired CVEC in T2D is the result of preclinical cardiac, vascular dysfunction and skeletal muscle perfusion abnormalities. Exercise training will improve CVEC and will reveal specific reversible therapeutic aspects of this pathology. Specific Aims: SA#1: To test the hypothesis that the integration of cardiac function, macrovascular function, and microvascular function is impaired in T2D and correlates with CVEC impairment. Rationale: CVEC is dependent upon a coordinated delivery of substrate (E.g. O2) from the pulmonary circula- tion to the working tissue (e.g. muscle). We postulate that poor integration of CV function and net blood flow and/or flow distribution to working muscle results in diminished CVEC. Measurements to examine CV effects of diabetes to date have focused on cardiac, vascular and skeletal muscle tissues separately but not simulta- neously. Experiments: Conventional endpoints (peak O2 consumption (VO2peak), resting echocardiography and insulin clamp) and advanced imaging modalities (4D flow CV magnetic resonance imaging (MRI), 2D PC- MRI and muscle 1H magnetic resonance spectroscopy (1H MRS) will be employed to construct a systemic model of pathological changes in CVEC in men and women with and without T2D at rest and during exercise. Outcomes: The proposed studies will employ a comprehensive view of integrated CV systemic function in health and T2D using MR-based imaging in men and women with and without T2D. SA#2: To test the hypothesis that exercise training will elicit specific adaptive responses in the integrated CV system, muscle perfusion and metabolism with differences by T2D status. Rationale: Exercise training impacts cardiac, macrovascular and microvascular function and metabolism through improving the integrated CV system. New pilot data demonstrate that abnormal muscle oxidative function in vivo in T2D is acutely normalized with supplemental O2 (consistent with an O2 supply limitation) and unchanged in obese nondiabetic control subjects. Perfusion heterogeneity has been reported in rodent models and human subjects with T2D. New modeling algorithms, developed in our lab, indicate that perfusion heterogeneity can explain impaired O2 extraction in DM models. With our novel systematic approach, we will be able to discern which aspects of the systemic response to exercise improve with training. Experiments: All participants will undergo 3 months of standardized exercise training established to improve fitness in people with and without diabetes, followed by repeated measurement of endpoints described in Aim 1. Outcomes: Identification of differences in the effects of exercise training on the integrated CV system and metabolism in men and women with and without T2D will reveal specific adaptive responses to exercise. We will also determine the impact of exercise training on skeletal muscle perfusion and O2 extraction. Impact on Veterans: CVEC impairment in T2D is a preclinical marker of poor integration of CV function that is understudied, clinically important and present in 24% of Veterans. Understanding the discrete contributions of cardiac and vascular dysfunction and skeletal muscle perfusion to CVEC impairments and the response to exercise training will identify targets for therapy. Perfusion heterogeneity is a novel factor defining CVEC impairments that is potentially targetable with behavioral or pharmaceutical intervention.