Reversing vascular dysfunction in type 1 diabetes

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 DESCRIPTION (provided by applicant): Large and small cerebral, coronary and peripheral arterial disease is the major cause of morbidity/mortality in type 1 diabetes (DM1). This begins early as indicated by evidence for arterial dysfunction in DM1 adolescents. Multicenter trials testing efficacy of vascular interventions to improve CVD outcomes in DM1 are lacking. Our general hypothesis is that DM1 impairs vascular function at multiple levels of the arterial vasculature and arterial vessels are resistant to insulin-induced vascular relaxation. We further hypothesize that mineralocorticoid receptor (MCR) blockade and/or enhanced fitness will improve DM1 arterial dysfunction. We will use non-invasive methods to assess arterial stiffness, (i.e. Pulse Wave Velocity and Augmentation Index) in conduit vessels, We will measure Flow-Mediated Dilation and Post-Ischemic Flow Velocity to assess endothelial function in conduit and resistance vessels and contrast-enhanced ultrasound to assess microvascular function. In Aim 1 we will measure pan-arterial vascular function in 18-50 y.o. DM1 and healthy age/gender matched controls in both the basal and insulin-stimulated state. Aim 1 will define whether the entire arterial tree is adversely affected by DM1 and whether vascular insulin sensitivity is impaired. It may also indicate which specific tests provide greatest discrimination between DM1 and controls. Duration of DM1, glycemic control, lipid profile, hypertension and evidence of inflammation will be co-variates in this analysis, In Aim 2 we will test whether basal or insulin-responsive pan-arterial function in 18-50 y.o. DM1 responds to a 12 week lifestyle (fitness training) or pharmacologic (eplerenone) intervention or combined fitness plus eplerenone. Fitness and eplerenone have beneficial vascular effects in other populations. If these hypotheses prove correct, they will indicate: A) whether in the basal or insulin treated state ther is pan-arterial vascular dysfunction or is it restricted to one or another vascular level; B) whethr insulin's vascular action (or resistance) contributes to the linkage between DM 1 and CVD; C) a compelling rationale for further emphasizing diet/exercise interventions or early pharmacologic interventions to avoid CVD. In addition, the approach used here may suggest that early assessment pan-arterial function can afford a platform to improve selection of drug candidates for later hard endpoint clinical trials in DM1.