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

December 17, 2019 updated by: Eugene Barrett, University of Virginia

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

32

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Virginia
      • Charlottesville, Virginia, United States, 22906
        • University of Virginia

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 50 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: FACTORIAL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Exercise alone
24 weeks of exercise treatment
Other: Exercise
24 weeks of exercise treatment
EXPERIMENTAL: spironolactone alone
24 weeks of Spironolactone treatment
Drug: Spironolactone
24 weeks of spironolactone
EXPERIMENTAL: Exercise + Spironolactone
24 weeks of exercise + Spironolactone treatment
Other: Exercise
24 weeks of exercise treatment
Drug: Spironolactone
24 weeks of spironolactone

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Augmentation Index-Change from baseline
Time Frame: 24 weeks
measured at baseline and 24 weeks
24 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Flow Mediated Dilation-Change from baseline
Time Frame: 24 weeks
measured at baseline and 24 weeks
24 weeks
Pulse Wave Velocity-Change from baseline
Time Frame: 24 weeks
measured at baseline and 24 weeks
24 weeks
Post Ischemic Flow Velocity-Change from baseline
Time Frame: 24 weeks
measured at baseline and 24 weeks
24 weeks
Insulin Sensitivity-Change from baseline
Time Frame: 24 weeks
measured by euglycemic insulin clamp at baseline and 24 weeks
24 weeks
Microvascular Blood Volume-Change from baseline
Time Frame: 24 weeks
measured at baseline and 24 weeks
24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Virginia

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

  • Principal Investigator: Eugene Barrett, MD, PhD, University of Virginia, Dept of Endocrinology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2015

Primary Completion (ACTUAL)

May 22, 2019

Study Completion (ACTUAL)

May 22, 2019

Study Registration Dates

First Submitted

May 23, 2017

First Submitted That Met QC Criteria

May 30, 2017

First Posted (ACTUAL)

June 2, 2017

Study Record Updates

Last Update Posted (ACTUAL)

December 18, 2019

Last Update Submitted That Met QC Criteria

December 17, 2019

Last Verified

December 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 18237
  • 5R01DK101944-03 (NIH)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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