Nitrate Supplementation and Exercise Tolerance in Patients With Type 2 Diabetes

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.

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