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 (NO 3 - ) and nitrite (NO 2 - ) (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 NO 3 - (100%; p < 0.001) and lower plasma NO 2 - 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). NO 3 - /NO 2 - supplementation increased VO 2 max (5.3%; p < 0.01). Further, circulating NO 2 - , but not NO 3 - , positively correlated with VO 2 max after supplementation (R 2 = 0.40; p < 0.05). Within the NO 3 - /NO 2 - 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 NO 3 - /NO 2 - group (1.21 ± 0.51 mL/(kg*min) vs. 0.31 ± 0.10 mL/(kg*min); p = 0.09). NO 3 - /NO 2 - 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.