The Impact of Fitness and Mineralocorticoid Receptor Blockade on Vascular Dysfunction in Adults With Type 1 Diabetes (EJB048)

The Impact of Fitness and Mineralocorticoid Receptor Blockade on Vascular Dysfunction in Adults With Type 1 Diabetes

The Impact of Fitness and Mineralocorticoid Receptor Blockade on Vascular Dysfunction in Adults With Type 1 Diabetes

In this protocol, 60 subjects with DM1 will be studied at baseline, after 12 weeks of MCR blockade or 12 weeks of exercise, and again after an additional 12 weeks of MCR blockade, exercise or the combination of both interventions. The investigators will assess function in conduit (pulse wave velocity-PWV, flow-mediated dilation-FMD and augmentation index-AI), resistance (post-ischemic flow velocity-PIFV) and heart and skeletal muscle microvascular (contrast enhanced ultrasound-CEU) vessels before and after 2 hrs of a euglycemic insulin clamp. We hypothesize that compared to healthy controls, both baseline and insulin-responsive vascular function are impaired throughout the arterial vasculature by DM1 and that exercise training and/or mineralocorticoid receptor (MCR) blockade will improve both baseline and insulin-responsive pan-arterial function.

Using non-invasive methods, several small studies have demonstrated conduit artery stiffness and other small studies report impaired brachial artery nitric oxide (NO) release in subjects with type diabetes (DM1). Vascular insulin action (characterized by insulin-induced NO-mediated vasodilation of conduit, resistance or microvascular vessels) has not been studied systematically in DM1. The investigators hypothesize that compared to healthy controls, both baseline and insulin-responsive vascular function are impaired throughout the arterial vasculature by DM1 and that exercise training and/or mineralocorticoid receptor (MCR) blockade will improve both baseline and insulin-responsive pan-arterial function. In this protocol, 60 subjects with DM1 will be studied at baseline, after 12 weeks of MCR blockade or 12 weeks of exercise, and again after an additional 12 weeks of MCR blockade, exercise or the combination of both interventions. Investigators will assess function in conduit (pulse wave velocity-PWV, flow-mediated dilation-FMD and augmentation index-AI), resistance (post-ischemic flow velocity-PIFV) and heart and skeletal muscle microvascular (contrast enhanced ultrasound-CEU) vessels before and after 2 hrs of a euglycemic insulin clamp. This work will: a) identify whether vascular stiffness and indices of NO action are impaired throughout the arterial tree in DM1; b) identify the impact of fitness, MCR blockade or the combination to improve vascular function; and c) introduce a rational paradigm for early, proof-of-concept testing of interventions that may improve vascular health in DM1. While multiple endpoints are measured in the proposed studies, the investigators designate one primary conduit vessel endpoint (augmentation index) and one primary microvascular endpoint (microvascular blood volume by CEU); the studies are powered on these measures. The investigators believe that their laboratories are in a unique position with respect to their demonstrated scientific expertise to deliver this fundamental information. The study proposed here will be the first to assess whether: 1) basal pan-arterial function including myocardial microvascular function is adversely affected by DM1 ; 2) vascular insulin responsiveness in DM1 is impaired as is seen in DM2 3) exercise training or MCR blockade alone or in combination favorably impacts vascular stiffness or NO-induced relaxation in DM1 in the basal state or in response to insulin. This non-invasive vascular profiling provides a functional "biomarker" of pan-arterial health. As such it could be useful for assessing the impact of specific short-term interventions on critical vascular functions in small scale studies (e.g. MCR blockade, statins, GLP-1R agonists) and thereby provide a rationale for selection of candidate therapies for subsequent larger clinical outcome trials. Additionally, non-invasive assessment of pan-arterial function could provide a platform to identify patients for early or more intensive treatment interventions as part of their care plan.

Inclusion Criteria: Age 18-50 years BMI ≤30 No clinically significant lab values other than those consistent with DM1 Subjects will have been on insulin for at least 5 years and HbA1c <9 Exclusion Criteria: Smoking presently or in the past 6 months Medications that affect the vasculature (except ACE or ARB , although they will need to be off these drugs for 2 weeks prior to study). Elevated LDL cholesterol > 160 BP <100/60 or >160/90 Pulse oximetry <90% Pregnant or breastfeeding History of cardiovascular disease, cerebral vascular disease, peripheral vascular disease, liver disease Presence of an intracardiac or intrapulmonary shunt (we will screen for this by auscultation during the physical exam). Known hypersensitivity to perflutren (contained in Definity) Serum Potassium ≥5.0 HbA1c ≥ 9 Retinopathy Ketoacidosis within the past year.

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