Mineralocorticoid receptor blockade to improve pan-arterial vascular function in Type 1 Diabetes

University Of Virginia, Charlottesville VA

Investigators

Abstract

? DESCRIPTION (provided by applicant): Large and small cerebral, coronary, and peripheral arterial disease is the leading cause of morbidity and mortality in Type-1 diabetes (T1DM). This begins earlier as indicated by the evidence for arterial dysfunction in adolescents. Trials to mitigate, reverse, or improve arterial dysfunction in T1DM are lacking. There is evidence that mineralocorticoid receptor (MR) activation contributes to diabetic vascular injury, though the mechanisms are uncertain. My central hypothesis is that MR blockade will improve both baseline and insulin-responsive pan- arterial vascular dysfunction in patients with T1DM (Aim 1). A secondary hypothesis is that select circulating CVD markers, including those of inflammation, will correlate with the degree of arterial dysfunction at baseline and may serve as clinically useful markers of the effect of MR blockade (Aim 2). I will use non-invasive methods to assess arterial stiffness, (i.e. Pulse Wave Velocity and Augmentation Index) in conduit vessels; and will measure Flow-Mediated Dilation and Post-ischemic Flow Velocity to assess endothelial function in conduit vessels and resistance arterioles, respectively. In addition I will use contras- enhanced ultrasound to assess microvascular function in the skeletal muscle and myocardium. In Aim 1 I test whether basal or insulin-responsive pan-arterial function in 18-50 y.o. persons with uncomplicated T1DM responds to a 24-week pharmacologic intervention using the MR blocker, spironolactone. MR blockade had beneficial vascular effects in non-T1DM populations. Using the above non-invasive methods for vascular profiling, I will assess vascular function at 3 levels of the arterial tree. Forty T1DM subjects will be enrolled and randomized to spironolactone or placebo. Young adults are targeted since stiffness, which contributes to CVD pathogenesis, begins early, long before the development of clinical atherosclerotic disease. In Aim 2 I test whether baseline and insulin-responsive arterial function in T1DM correlate with circulating CVD markers, and whether changes in such markers will correlate with changes in pan-arterial vascular function with MR blockade. This work will increase our understanding of the contribution of MR activation to premature arterial dysfunction in T1DM. In addition, it may potentially identify a soluble biomarker(s) that can independently predict this impairment and has the potential to be an early screening test of vascular health in this population. If my hypothesis is supported by this study, it may provide a rationale for a larger trial targeting clincal endpoints. This will be a critical step toward our ultimate goal of improving CVD outcomes in T1DM.