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

• Published in: Nutrients 2022-10, Vol.14 (21), p.4479
• Main Authors: Turner, Kristen D, Kronemberger, Ana, Bae, Dam, Bock, Joshua M, Hughes, William E, Ueda, Kenichi, Feider, Andrew J, Hanada, Satoshi, de Sousa, Luis G O, Harris, Matthew P, Anderson, Ethan J, Bodine, Sue C, Zimmerman, M Bridget, Casey, Darren P, Lira, Vitor A
• Format: Article
• Language: English
• Subjects: Age; Aged; Analysis; Beta vulgaris; Bioavailability; Biopsy; Blood pressure; Carbohydrates; Carbohydrates - pharmacology; Cardiorespiratory Fitness; Cardiovascular disease; Clinical trials; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes therapy; Dietary Supplements; Double-Blind Method; Ethical aspects; Exercise; Fatty Acids - metabolism; Heart rate; Humans; Intervention; Metabolism; Microscopy; Middle Aged; Mitochondria; Mortality; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Nitrates; Nitric oxide; Nitric Oxide - metabolism; Nitrites; Nitrogen dioxide; Nitrogen Dioxide - metabolism; Nitrogen Dioxide - pharmacology; Nitrogen Oxides - metabolism; nutraceutical; Oxidative Stress; Oxygen consumption; Physical fitness; Pilot Projects; Placebos; Prognosis; Skeletal muscle; Subgroups; Type 2 diabetes
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu14214479

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.