Nitrate Supplementation and Exercise Tolerance in Patients With Type 2 Diabetes

Not Applicable

Completed

Conditions: Type 2 Diabetes

Interventions: Other: Super Beets Placebo
Dietary Supplement: Super Beets

Registration Number: NCT02804932

Lead Sponsor: Darren P Casey

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 54

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo (beetroot powder, no nitrate)	Super Beets Placebo	Participants will receive a beetroot powder placebo (no nitrate) for 8 weeks.
Beetroot crystals (nitrate)	Super Beets	Participants will receive a nitrate rich beetroot powder (10g/day) for 8 weeks.

Primary Outcome Measures

Name	Time	Method
Change in Skeletal Muscle Mitochondrial Function	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°.
Maximal Exercise Capacity (VO2max)	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.
Change in Skeletal Muscle Perfusion During Exercise	Pre and post 8 weeks of dietary nitrate supplementation	Forearm blood flow will be determined using Doppler ultrasound during rhythmic forearm exercise.