The Impact of Fitness and Mineralocorticoid Receptor Blockade on Vascular Dysfunction in Adults With Type 1 Diabetes
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Exercise; Spironolactone
Intervention type(s): Other; Drug
Intervention description(s): 24 weeks of exercise treatment; 24 weeks of spironolactone
Intervention MeSH terms: Spironolactone
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Treatment