PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in Veterans with type 2 diabetes (T2D). Lifestyle modifications, including increased physical activity, are recommended as first-line therapy for the management of T2D. Unfortunately, the efficacy of these lifestyle interventions for preventing CVD morbidity and mortality in patients with T2D is not well-established. Available evidence from our group and others indicates that vascular adaptations to exercise training are impaired in subjects with T2D. We propose that diminished vascular adaptations explain why increased physical activity does not lead to a robust reduction in CVD morbidity and mortality in T2D. However, the mechanisms responsible for this deficit in vascular adaptations to exercise in T2D remain unknown. This is a major limitation for identifying new adjuvant therapeutics to maximize the cardiovascular benefits of exercise in the diabetic population. Exercise exerts direct effects on the vasculature via repetitive exposure to hemodynamic stimuli or shear stress. The increased blood flow and luminal shear stress attendant to each bout of exercise are primary mechanisms contributing to vascular adaptations. Shear stress is detected by mechanosensitive endothelial luminal structures, such as the glycocalyx, that convert mechanical forces into biochemical signals via mechanotransduction. As such, we propose that an intact endothelial glycocalyx is required for the mechanotransduction of increased shear stress and the subsequent chronic vascular adaptations associated with exercise to occur. Notably, glycocalyx degradation is a classic feature of T2D. Accordingly, our overarching hypothesis is that endothelial glycocalyx degradation is a key factor precluding shear stress mechanotransduction and consequent exercise-induced vascular adaptations in T2D. The corollary to this hypothesis is that restoration of the endothelial glycocalyx by dietary supplementation of glycocalyx precursors (DSGP) will improve vascular adaptations to exercise in T2D. Specifically, in Aim 1 (Proof of Concept Clinical Trial Phase), we will document that DSGP enhances endothelial glycocalyx integrity in patients with T2D. Although we provide preliminary evidence that DSGP can increase glycocalyx thickness and endothelial function in a mouse model of T2D, this will be the first study to demonstrate these effects in T2D subjects. The effects of DSGP for eight weeks will be studied using a double-blinded randomized placebo control trial. Subsequently, in Aim 2 (Expended Clinical Trial Phase), we will demonstrate the permissive role of the endothelial glycocalyx in exercise-induced vascular adaptations in patients with T2D. Having shown that restoration of the endothelial glycocalyx via DSGP is feasible in T2D subjects, we will now investigate whether such supplementation will potentiate exercise training-induced improvements in endothelial function. This will be accomplished in a ...