Skeletal muscle plays a key role in glucose and energy homeostasis and is involved in metabolizing a substantial proportion of glucose through glucose oxidation as well as through non-oxidative pathways. Skeletal muscle insulin resistance is one of the key driving factors associated with the pathophysiology of type 2 diabetes (T2D) and muscle dysfunction. Further, mitochondrial dysfunction is implicated in the pathogenesis of insulin resistance, insulin secretion and T2D. Enhancement of muscle fatty acid oxidation/glucose uptake along with increased mitochondrial biogenesis using natural supplements is an emerging strategy for preventing and managing metabolic diseases. One such natural supplements is nitrate (NO3). The oral microbiome plays a prominent role in the bioactivation of dietary nitrate (NO3) to nitrite (NO2), which is further reduced to nitric oxide (NO) in the gastrointestinal tract to maintain NO homeostasis and vascular health. NO is an important physiological signaling molecule and is involved in the modulation of skeletal muscle functions including regulation of blood flow (hemodynamic effect), muscle contractility, glucose, calcium homeostasis, mitochondrial respiration and biogenesis.~The use of dietary NO3 supplementation has been explored in the literature for mainly improving blood pressure, endothelial function, insulin response, and vascular effects in healthy/obese subjects. However, the metabolic effects of dietary NO3 for improving skeletal muscle glucose/lipid metabolism, muscle mitochondrial energetics, muscle blood flow, and body fat composition are not well studied in diabetic/pre-diabetic subjects.~In view of the potential health benefits of NO3/NO, this study plans to evaluate the therapeutic efficacy of a natural supplement, beetroot juice (rich in NO3) for improving the skeletal muscle mitochondrial function, muscle energetics, insulin sensitivity/glucose homeostasis, body fat composition and overall metabolism in middle aged (40 - 65 years) healthy and pre-diabetic male subjects. This would be the very first pilot study in the domain of metabolic diseases to evaluate the overall metabolic health of both obese pre-diabetic and non-diabetic male subjects using an advanced and comprehensive multi-model metabolic imaging approach.
Dietary nitrate is found to enhance muscle fatty acid oxidation/glucose uptake and increase mitochondrial biogenesis, which in turn, aid in the prevention and management of metabolic diseases. In recent years, inorganic nitrate supplementation is clinically emerging as a therapeutic strategy for possible treatment and management of metabolic diseases and cardiometabolic disorders. This is mostly explored in healthy/obese subjects, for improving blood pressure, endothelial function, insulin response and vascular effects. However, the metabolic effects of dietary nitrate for improving skeletal muscle glucose/lipid metabolism, muscle mitochondrial metabolism, muscle blood flow and body fat composition are not comprehensively studied in diabetic/pre-diabetic subjects. Hence, this study aims to evaluate the therapeutic efficacy of a natural nitrate supplement (beetroot juice) for improving overall metabolic health in obese pre-diabetic and non-diabetic subjects.