Nitrate Supplementation and Exercise Tolerance in Patients With Type 2 Diabetes

December 7, 2023 updated by: Darren P Casey
The purpose of this study is to use a randomized, double-blind, placebo controlled study design to comprehensively investigate the impact of 8-weeks of dietary nitrate supplementation on skeletal muscle blood flow, mitochondrial function, and exercise capacity in patients with type 2 diabetes (T2D).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Patients with type 2 diabetes (T2D) demonstrate a reduced exercise capacity, a powerful predictor of cardiovascular mortality, which may be due to reductions in skeletal muscle perfusion and mitochondrial dysfunction. Nitric oxide (NO) is a key molecule involved in in the regulation of blood flow to contracting muscles, as well as a critical mediator in mitochondrial respiration. However, there appears to be a decreased enzymatic synthesis of NO and an overall reduction of bioavailable NO in patients with T2D, which likely contributes to the reduced exercise capacity and tolerance. Accumulating evidence suggests that exogenous nitrate supplementation is an effective option for increasing NO bioavailability in vivo. The purpose of the proposal is to use a randomized, double-blind, placebo controlled study design to comprehensively investigate the impact of 8-weeks of dietary nitrate supplementation on skeletal muscle blood flow, mitochondrial function, and exercise capacity in patients with T2D. The central hypothesis is that increasing NO bioavailability via dietary nitrate supplementation in patients with T2D will lead to improved oxygen delivery and utilization during exercise. To address this hypothesis a highly mechanistic and translational experimental strategy will be used to explore whether increased NO bioavailability via dietary nitrate supplementation improves skeletal muscle perfusion during exercise (Aim 1), enhances mitochondrial biogenesis and function (Aim 2), and improves exercise capacity and efficiency (Aim 3). Collectively, these studies will provide important mechanistic insight into the therapeutic potential of dietary nitrate supplementation for improving skeletal muscle blood flow, mitochondrial function and exercise capacity in patients with T2D.

Study Type

Interventional

Enrollment (Actual)

54

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
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • University of Iowa

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

40 years to 77 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

For 50 patients with documented Type 2 diabetes

Inclusion Criteria:

  • Willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures.
  • Age is > or = 40 and < or = 77 years of age
  • Documented Type 2 diabetes

Exclusion Criteria:

  • diagnosis of type 2 diabetes < 3 years prior to enrollment
  • HbA1c <6.0% or >10.0%
  • body mass index > 42 kg/m2
  • incident cardiovascular events in the last year (heart attack, stroke)
  • symptomatic coronary artery disease and/or heart failure
  • uncontrolled hypertension
  • hypotension (resting systolic BP < 90 mmHg)
  • renal impairment with creatinine clearance (eGFR) of <50 ml/min
  • smoking or history of smoking within past one year
  • use of medication which contain nitrates
  • use of anti-coagulant drugs
  • use of anti-platelet drugs
  • participation in research studies in which medications or interventions are given which would potentially alter subject responses in the current study

For 15 age- and weight-matched nondiabetic control subjects

Inclusion Criteria:

  • Willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures.
  • Age is > or = 40 and < or = 77 years of age

Exclusion Criteria:

  • Diagnosis of diabetes (Type 1 or Type 2)
  • body mass index > 42 kg/m2
  • incident cardiovascular events in the last year (heart attack, stroke)
  • symptomatic coronary artery disease and/or heart failure
  • uncontrolled hypertension
  • hypotension (resting systolic BP < 90 mmHg)
  • renal impairment with creatinine clearance (eGFR) of <50 ml/min
  • smoking or history of smoking within past one year
  • use of medication which contain nitrates
  • use of anti-coagulant drugs
  • use of anti-platelet drugs
  • participation in research studies in which medications or interventions are given which would potentially alter subject responses in the current study

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: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Beetroot crystals (nitrate)
Participants will receive a nitrate rich beetroot powder (10g/day) for 8 weeks.
Dietary supplement: Super Beets
Nitrate rich beetroot powder (10g/day) for 8 weeks
Other Names:
  • Beetroot crystals
Placebo Comparator: Placebo (beetroot powder, no nitrate)
Participants will receive a beetroot powder placebo (no nitrate) for 8 weeks.
Other: Super Beets Placebo
Nitrate deficient beetroot powder (10g/day) for 8 weeks
Other Names:
  • Beetroot crystals no nitrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximal Exercise Capacity (VO2max)
Time Frame: Pre and post 8 weeks of dietary nitrate supplementation
A 12-lead ECG, symptom limited cardiopulmonary exercise testing with gas exchange measurements will be performed on a cycle ergometer using a ramp protocol to determine maximal aerobic capacity (VO2max) and exercise efficiency.
Pre and post 8 weeks of dietary nitrate supplementation
Change in Skeletal Muscle Perfusion During Exercise
Time Frame: Pre and post 8 weeks of dietary nitrate supplementation
Forearm blood flow will be determined using Doppler ultrasound during rhythmic forearm exercise.
Pre and post 8 weeks of dietary nitrate supplementation
Change in Skeletal Muscle Mitochondrial Function
Time Frame: Pre and post 8 weeks of dietary nitrate supplementation
Muscle biopsies were obtained from the vastus lateralis using a Bergstrom needle with suction under local anesthesia, which will yield ~200-250mg of tissue. Mitochondrial function was assessed as follows: Fiber bundles were chemically permeabilized with saponin and mitochondrial respiration was analyzed by in situ high-resolution respirometry at 37°.
Pre and post 8 weeks of dietary nitrate supplementation

Collaborators and Investigators

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

Sponsor

Darren P Casey

Collaborators

American Diabetes Association

Investigators

  • Principal Investigator: Darren P Casey, PhD, University of Iowa

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 (Actual)

August 15, 2016

Primary Completion (Actual)

December 20, 2019

Study Completion (Actual)

December 20, 2019

Study Registration Dates

First Submitted

June 14, 2016

First Submitted That Met QC Criteria

June 14, 2016

First Posted (Estimated)

June 17, 2016

Study Record Updates

Last Update Posted (Actual)

May 28, 2024

Last Update Submitted That Met QC Criteria

December 7, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 201511802

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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