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., VO(2)max) and skeletal muscle oxidative capacity. We used a randomized, double-blind, placebo-controlled, 8-week trial with beetroot juice containing nitrate (NO3-) and nitrite (NO2-) (250 mg and 20 mg/day) to test potential benefits on VO(2)max and skeletal muscle oxidative capacity in T2DM. T2DM (N = 36, Age = 59 +/- 9 years; BMI = 31.9 +/- 5.0 kg/m(2)) and age- and BMI-matched non-diabetic controls (N = 15, Age = 60 +/- 9 years; BMI = 29.5 +/- 4.6 kg/m(2)) 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- (100%; p < 0.001) and lower plasma NO2- levels (-46.8%; p < 0.0001) than controls. VO(2)max was lower in T2DM (-26.4%; p < 0.001), as was maximal carbohydrate- and fatty acid-supported oxygen consumption in permeabilized muscle fibers (-26.1% and -25.5%, respectively; p < 0.05). NO3-/NO2- supplementation increased VO(2)max (5.3%; p < 0.01). Further, circulating NO2-, but not NO3-, positively correlated with VO(2)max after supplementation (R-2= 0.40; p < 0.05). Within the NO3-/NO2- group, 42% of subjects presented improvements in both carbohydrate- and fatty acid-supported oxygen consumption in skeletal muscle (vs. 0% in placebo; p < 0.05). VO(2)max improvements in these individuals tended to be larger than in the rest of the NO3-/NO2- group (1.21 +/- 0.51 mL/(kg*min) vs. 0.31 +/- 0.10 mL/(kg*min); p = 0.09). NO3-/NO2- supplementation increases VO(2)max in T2DM individuals and improvements in skeletal muscle oxidative capacity appear to occur in those with more pronounced increases in VO(2)max.