Abstract This revised application proposes 2 small, single-center, mechanistic clinical trials. Our overarching hypothesis is that acute hyperglycemia and/or glucose variability (GV) negatively impact microvascular perfusion in cardiac (CM) and skeletal muscle (SM) and this could in part account for the strongly negative impact of acute hyperglycemia on clinical outcomes in acute coronary syndromes. While chronic hyperglycemia provokes functional and anatomic diabetic microvascular disease, and acute hyperglycemia can raise plasma endothelial cell (EC) stress “biomarkers” concentrations, the functional microvascular consequences, if any, of acute hyperglycemia and GV are unknown. Microvascular perfusion is a critical determinant of nutrient and oxygen delivery to SM and CM and is adversely affected by insulin resistance. Using our considerable experience with contrast enhanced ultrasound (CEU) measurement of microvascular perfusion in complex metabolic studies we will test in AIM 1 the effect of acute hyperglycemia on basal and insulin-mediated microvascular perfusion in CM and SM of healthy humans. In AIM 2 we will quantify microvascular perfusion at baseline, in response to insulin and in response to meal ingestion in patients with T2DM. We will further test in T2DM whether decreasing GV and post-prandial hyperglycemic excursions with an SGLT-2 inhibitor (vs placebo) for 12 weeks enhances CM microvascular perfusion, either at baseline, or in response to acute hyperinsulinemia or to meal ingestion. Aim 3 will identify whether the behavior of the microvasculature seen in Aims 1 and 2, is matched by the responses of large arteries to either hyperglycemic, hyperinsulinemic or meal stimuli or drug treatment, measured by flow-mediated dilation (FMD), pulse wave velocity (PWV), augmentation index (AI), or post-ischemic flow velocity (PIFV). Completion of these studies will provide unprecedented mechanistic information on the effects of hyperglycemia, GV, T2DM and T2DM treatment on CM and SM microvascular function.