Nitrate Supplementation and Exercise Tolerance in Patients With Type 2 Diabetes

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: Recruiting
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Dietary supplement: Super Beets; Other: Super Beets Placebo

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 (Anticipated): 65
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Darren P Casey, PhD; Phone Number: 319-384-1009; Email: darren-casey@uiowa.edu

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 77 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

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

How is the study designed?

Design Details

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

Number of Arms

2

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
Change in exercise capacity	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 peak aerobic capacity (VO2peak) and exercise efficiency.	Pre and post 8 weeks of dietary nitrate supplementation
Change in skeletal muscle perfusion during exercise	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	Muscle biopsies will be obtained from the vastus lateralis using a Bergstrom needle with suction under local anesthesia, which will yield ~200-250mg of tissue. Mitochondrial function will be assessed as follows: Fiber bundles will be chemically permeabilized with saponin and mitochondrial respiration will be analyzed by in situ high-resolution respirometry at 37°.	Pre and post 8 weeks of dietary nitrate supplementation

Collaborators and Investigators

• Sponsor: Darren P Casey
• Collaborators: American Diabetes Association
• Investigators: Principal Investigator: Darren P Casey, PhD, University of Iowa

Publications and helpful links

General Publications

• Bock JM, Hughes WE, Ueda K, Feider AJ, Hanada S, Casey DP. Dietary Inorganic Nitrate/Nitrite Supplementation Reduces Central and Peripheral Blood Pressure in Patients With Type 2 Diabetes Mellitus. Am J Hypertens. 2022 Sep 1;35(9):803-809. doi: 10.1093/ajh/hpac068.

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: June 14, 2016
• First Submitted That Met QC Criteria: June 14, 2016
• First Posted (Estimate): June 17, 2016

Study Record Updates

• Last Update Posted (Actual): December 15, 2021
• Last Update Submitted That Met QC Criteria: December 13, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Sympathomimetics; Adrenergic Uptake Inhibitors; Methamphetamine
• Other Study ID Numbers: 201511802

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No