Nitrate Supplementation and Exercise Tolerance in Patients With Type 2 Diabetes

Darren P Casey54 enrolled

Overview

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).

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

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Enrollment

Conditions

Type 2 Diabetes

Interventions

Super BeetsDIETARY_SUPPLEMENT

Nitrate rich beetroot powder (10g/day) for 8 weeks

Super Beets PlaceboOTHER

Nitrate deficient beetroot powder (10g/day) for 8 weeks

Eligibility

Sex: ALLMin age: 40 YearsMax age: 77 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

University of Iowa

Iowa City, Iowa, United States

Outcomes

Primary Outcomes

Maximal Exercise Capacity (VO2max)

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.

Time frame: 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.

Time frame: Pre and post 8 weeks of dietary nitrate supplementation

Change in Skeletal Muscle Mitochondrial Function

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°.

Time frame: Pre and post 8 weeks of dietary nitrate supplementation

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.