Effects of Combined Inorganic Nitrate and Nitrite Supplementation on Cardiorespiratory Fitness and Skeletal Muscle Oxidative Capacity in Type 2 Diabetes: A Pilot Randomized Controlled Trial

Nitric oxide (NO) stimulates mitochondrial biogenesis in skeletal muscle. However, NO metabolism is disrupted in individuals with type 2 diabetes mellitus (T2DM) potentially contributing to their decreased cardiorespiratory fitness (i.e., VO2max) and skeletal muscle oxidative capacity. We used a randomized, double-blind, placebo-controlled, 8-week trial with beetroot juice containing nitrate (NO3&minus:) and nitrite (NO2&minus:) (250 mg and 20 mg/day) to test potential benefits on VO2max and skeletal muscle oxidative capacity in T2DM. T2DM (N = 36, Age = 59 &plusmn: 9 years: BMI = 31.9 &plusmn: 5.0 kg/m2) and age- and BMI-matched non-diabetic controls (N = 15, Age = 60 &plusmn: 9 years: BMI = 29.5 &plusmn: 4.6 kg/m2) were studied. Mitochondrial respiratory capacity was assessed in muscle biopsies from a subgroup of T2DM and controls (N = 19 and N = 10, respectively). At baseline, T2DM had higher plasma NO3&minus: (100%: p &lt: 0.001) and lower plasma NO2&minus: levels (&minus:46.8%: p &lt: 0.0001) than controls. VO2max was lower in T2DM (&minus:26.4%: p &lt: 0.001), as was maximal carbohydrate- and fatty acid-supported oxygen consumption in permeabilized muscle fibers (&minus:26.1% and &minus:25.5%, respectively: p &lt: 0.05). NO3&minus:/NO2&minus: supplementation increased VO2max (5.3%: p &lt: 0.01). Further, circulating NO2&minus:, but not NO3&minus:, positively correlated with VO2max after supplementation (R2= 0.40: p &lt: 0.05). Within the NO3&minus:/NO2&minus: group, 42% of subjects presented improvements in both carbohydrate- and fatty acid-supported oxygen consumption in skeletal muscle (vs. 0% in placebo: p &lt: 0.05). VO2max improvements in these individuals tended to be larger than in the rest of the NO3&minus:/NO2&minus: group (1.21 &plusmn: 0.51 mL/(kg*min) vs. 0.31 &plusmn: 0.10 mL/(kg*min): p = 0.09). NO3&minus:/NO2&minus: supplementation increases VO2max in T2DM individuals and improvements in skeletal muscle oxidative capacity appear to occur in those with more pronounced increases in VO2max.