Repurposing sodium phenylbutyrate as a novel therapeutic agent to manage type 2 diabetes via alterations in circulating branched chain amino acids

Elevations in circulating Branched Chain Amino Acids (BCAA) are well-established as a biomarker of obesity and act as a strong independent prognostic factor for insulin resistance and the development of Type 2 Diabetes Mellitus (T2DM). Over the last decade, BCAA catabolism has been considered to have a crucial role in the development of insulin resistance in people with obesity and T2DM. Moreover, pre-clinical work has highlighted that dietary restriction of BCAA in a diabetic rat model, improves insulin sensitivity while we and others have shown that defects in BCAA catabolism in the liver and other peripheral insulin-sensitive tissues have been shown to contribute to the pathophysiology of aberrant BCAA metabolism in states of obesity and insulin resistance. Here we propose to take a novel approach by re-purposing an already licensed and approved drug, sodium phenylbutyrate (NaPb), to reduce circulating BCAA levels as a strategy to treat T2DM. NaPb is currently used to treat rare genetic disorders of ammonia metabolism (i.e. Urea-Cycle disorder) and hyperammonaemia due to liver disease using catabolism of BCAA to sequester circulating ammonia, thereby reducing BCAA as a by-product of ammonia removal. A previous experimental study using NaPb was limited to 2 weeks which is insufficient for longer term markers of glucose and muscle metabolism as well as metabolomic outcomes. In line with duration of previous experimental studies using Very-Low-Calorie Diet in T2DM and phase-1 studies to investigate the efficacy of glucose lowering therapies, we therefore aim to undertake one of the first studies in humans charting the effects of short-term (6-weeks) administration of NaPb in the form of Pheburane vs placebo on BCAA, glucose and muscle metabolism. The latter is highly relevant given ongoing concerns regarding the effects of loss of lean muscle mass with glucose lowering strategies that incorporate weight loss. This will be a randomised double-blinded, cross-over design study. Patients will be eligible for the trial if they were 18-75years, BMI of 20-45 kg/m², relatively well-controlled T2DM (HbA1C < 86mmol/mol (10%)) and treated with oral glucose-lowering medication. Thirty-six participants will be randomly assigned to receive either Pheburane 4.8g/m²/day and placebo for 6 weeks via controlled randomization, in a cross-over study design. The formulation and dose of Pheburane has been shown in our pilot study as well as published study from our collaborators to be well tolerated, safe and associated with a significant reduction in BCAA levels by 8% (in people with T2DM) and by ~20% in people with pre-diabetes, predominantly via reductions in valine levels. Using state-of-the-art metabolic and molecular techniques which includes: hyperinsulinaemic-euglycaemic clamp (HIEC) to measure peripheral insulin resistance as the primary outcome; hepatic insulin resistance using HIEC, pancreatic beta cell function measured by hyperglycaemic clamp, the impact of NaPB on insulin and anabolic signalling pathways in muscle using immunoblotting studies, body composition (DXA), muscle architecture (ultrasound), muscle structure and function, mitochondrial function and metabolomics signatures from plasma and muscle; this study will determine mechanisms underlying the potential role of NaPb in regulating glucose and muscle metabolism in T2DM. Evidence derived from this study will form a basis for future experimental and subsequent randomised clinical study to harness the metabolic benefits of reducing circulating BCAA as an important therapeutic strategy as well as novel biochemical and molecular targets to treat the underlying pathogenic mechanism contributing to the development of T2DM and/or obesity.