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

Abstract

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−) and nitrite (NO2−) (250 mg and 20 mg/day) to test potential benefits on VO2max and skeletal muscle oxidative capacity in T2DM. T2DM (N = 36, Age = 59 ± 9 years; BMI = 31.9 ± 5.0 kg/m2) and age- and BMI-matched non-diabetic controls (N = 15, Age = 60 ± 9 years; BMI = 29.5 ± 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− (100%; p < 0.001) and lower plasma NO2− levels (-46.8%; p < 0.0001) than controls. VO2max 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 VO2max (5.3%; p < 0.01). Further, circulating NO2−, but not NO3−, positively correlated with VO2max after supplementation (R2= 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). VO2max 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 VO2max in T2DM individuals and improvements in skeletal muscle oxidative capacity appear to occur in those with more pronounced increases in VO2max.

Lipotoxicity as a therapeutic target in obesity and diabetic cardiomyopathy

“…These findings suggest that metformin may not directly target cardiac steatosis but may achieve the effects through the modulation of gut microbiota populations. In addition to pharmaceutical interventions, the intake of dietary nitrate (NO 3 − ) through beetroot juice has been shown to enhance exercise capacity in patients with HFpEF [239] and increase the maximum rate of oxygen consumption during exercise in patients with diabetes [240]. Rodent studies demonstrated the beneficial effect of dietary nitrate on HFD-induced liver steatosis through the modulation of microbiota [241] and cardiomyopathy [242] in mice.…”

RELATIONSHIP BETWEEN NITRATE SUPPLEMENTATION AND SPORTS PERFORMANCE: an integrative review

“…In relation to Type 2 Diabetes Mellitus, substantial reductions in VO2 maximum make daily activities more demanding, which reinforces the need for additional strategies that can have significant clinical implications, which include nitrate supplementation. 3 Aging contributes to reduction in NO bioavailability, with chronic supplementation of NO precursors having potential effects on vascular function and health, cerebral and muscular oxygenation and physical performance in healthy elderly people. 4 Furthermore, studies present the importance of modulating the oral and intestinal microbiota as influential for the conversion of nitrate to nitrite, affecting nitric oxide signaling and also potentially improving sports performance.…”