Dietary Nitrate and Exercise to Augment Exercise Training Benefits in Subjects With DM+PAD

• Change in Functional Ability [ Time Frame: Baseline and 16 Weeks ] [ Designated as safety issue: No ]
  Six-Minute Walk test. This test simple and practical assessment of functional capacity. The test measures the distance that a patient can walk on a flat, hard surface in a period of 6 minutes. The test is self-paced and assesses the submaximal level of functional capacity. The subjects choose their own intensity and are allowed to stop and rest if necessary during the test.
• Change In Vascular Function [ Time Frame: Baseline and 16 weeks ] [ Designated as safety issue: No ]
  Ankle-brachial Index (ABI), Brachial artery flow-mediated dilation (BAFMD), calf blood flow (plethysmography), and arterial stiffness (pulse wave velocity and pulse wave reflection).
• Change in Angiogenesis [ Time Frame: Baseline and 16 weeks ] [ Designated as safety issue: No ]
  Gastrocnemius muscle biopsy will be performed to measure markers of angiogenesis including; capillaries per unit area and per muscle fiber, endothelial cells with surrounding pericytes, relative fraction of type I, IIa, IIb, and IId/x fibers. If differences exist we will look for changes in cell proliferation (PCNA) and apoptosis (TUNEL); (b) oxidative capacity including; mitochondria volume with citrate synthase activity. (c) mitochondrial volume and density; (d) mitochondrial oxygen efficiency (respiratory control ratio, the ratio of ATP phosphorylation rate per oxygen consumption rate (P/O ratio), and maximal rate of ATP production). These are measurements for potential mediation analyses and gaining insight into the relative effect sizes will inform mechanistic aims in a larger trial.

The hypothesis of this proposal is that in subjects with Type II diabetes mellitus (T2D) and peripheral arterial disease (PAD) with intermittent claudication (IC), regular consumption of a high nitrate supplement which raises plasma nitrite, in conjunction with 12 weeks of supervised exercise training at the limb ischemic threshold (SET) will produce a greater clinical benefit (increases in claudication onset time [COT] and peak walking time [PWT] relative to a group with the same exercise training but supplemented with placebo .This study is essentially exploratory in nature and designed to provide us with information to adequately develop power and execute a larger study. We have previously seen benefits from nitrate supplementation on function in PAD.

• Drug: Beetroot Juice (Beet-It Stamina Shot) and Exercise Training
  The beverage is high in inorganic nitrate and bottled and supplied by James White Drinks. This supplement will be used in conjunction with supervised exercise training.
  Other Name: James White Drinks
• Other: Placebo Comparator Beverage (Beet-It Stamina Shot) & Exercise Training
  The beverage is identical in look and taste to Beet-It Stamina Shot but with active ingredient removed. It is also bottled and supplied by James White Drinks. This placebo supplement will be used in conjunction with supervised exercise training.
  Other Name: James White Drinks

• Experimental: BR Juice (Beet-It Stamina Shot) & Supervised Exercise Training
  Subjects consume 70 ml of Beetroot Juice (Beet-It Stamina Shot) to assess acute effects of beverage supplementation at the start (between Testing Visits 1 & 2) and at the end of the trial (between Visits 3 & 4). It also allows for comparisons of the combination of beetroot juice and chronic training effects (between Visits 2 & 3) to when the subject has not consumed the beverage (Visits 1 & 4). All subjects will consume Beet-It Stamina Shot 3 hours prior to all beverage tolerance visits, Testing Visits 2 & 3 and for all supervised exercise training visits during the 12 week intervention.
  Intervention: Drug: Beetroot Juice (Beet-It Stamina Shot) and Exercise Training
• Placebo Comparator: BR Juice Placebo and Exercise Training
  Subjects consume 70 ml of Beetroot Juice (Beet-It Stamina Shot; Placebo) to assess acute effects of beverage supplementation at the start (between Testing Visits 1 & 2) and at the end of the trial (between Visits 3 & 4). It also allows for comparisons of the combination of placebo beverage and chronic training effects (between Visits 2 & 3) to when the subject has not consumed the beverage (Visits 1 & 4). All subjects will consume Beet-It Stamina Shot (Placebo) 3 hours prior to all beverage tolerance visits, Testing Visits 2 & 3 and for all supervised exercise training visits during the 12 week intervention.
  Intervention: Other: Placebo Comparator Beverage (Beet-It Stamina Shot) & Exercise Training

Inclusion Criteria:

• Peripheral Arterial Disease (ABI of less than 0.9)
• Diagnosed Type II Diabetes
• Intermittent Claudication for 3 or more months

Exclusion Criteria:

• Individuals with known alcohol or drug abuse problems
• Individuals who have suffered a heart attack or stroke, or have changes on a resting ECG, in the last 3 months
• Those classified as American Heart Association Class D
• Gangrene, impending limb loss or osteomyelitis
• Lower extremity vascular surgery, angioplasty or lumbar sympathectomy within 3 months of enrollment
• Severe peripheral neuropathy
• Any condition other than PAD that limits walking
• Chest pain during treadmill exercise which appears before the onset of claudication, or >3mm ST depression during exercise
• Subjects taking nitrates or nitroglycerin products
• Must not be taking protein pump inhibitor medications