Nitrate Supplementation and Exercise Tolerance in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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Nitrate Supplementation and Exercise Tolerance in Patients With Type 2 Diabetes

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Dietary Supplement: Super Beets
* Other: Super Beets Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 77 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Beetroot crystals (nitrate)<br>Participants will receive a nitrate rich beetroot powder (10g/day) for 8 weeks. | Dietary Supplement: Super Beets<br>* Nitrate rich beetroot powder (10g/day) for 8 weeks<br>* Other names: Beetroot crystals;|
| Placebo Comparator: Placebo (beetroot powder, no nitrate)<br>Participants will receive a beetroot powder placebo (no nitrate) for 8 weeks. | Other: Super Beets Placebo<br>* Nitrate deficient beetroot powder (10g/day) for 8 weeks<br>* Other names: Beetroot crystals no nitrate;|

What is the study measuring?
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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 |