Therapeutic Efficiency of Lowering Branched-Chain Amino Acid Levels in Patients with Type 2 Diabetes Using Sodium-Phenylbutyrate: <i>A Randomized Placebo Controlled Clinical Intervention Study</i>

Abstract

Background: Elevations in plasma branched-chain amino acid (BCAA) levels associate with insulin resistance and type 2 diabetes (T2D). Pre-clinical models have suggested that lowering BCAA levels improve glucose tolerance, but data in humans are lacking. In the present study, we used sodium phenylbutyrate (NaPB), an accelerator of BCAA catabolism, as a tool to lower plasma BCAA levels in patients with T2D, and to evaluate its effect on patients’ metabolic health. Methods: This trial had a randomized, placebo-controlled, double-blind cross-over design and was performed in the Netherlands. Patients were eligible for the trial if they were 40-75years, BMI of 25-38 kg/m², relatively well-controlled T2D (HbA1C<8.5%) and treated with oral glucose-lowering medication. Participants were randomly assigned to receive either the NaPB 4.8g/m²/day or placebo three times a day for two weeks, separated by a washout period of six to eight weeks. The primary outcome was peripheral insulin sensitivity. Secondary outcomes were ex vivo muscle mitochondrial oxidative capacity, whole-body substrate oxidation, ectopic fat accumulation. Fasting blood samples were collected to determine levels of BCAA and their intermediates. The trial is registered with Netherlands Trial Register, NTR 7426. Findings: Between February 2019 and February 2020, sixteen patients were included. NaPB effectively led to a robust improvement in peripheral insulin sensitivity (ΔRd:13.2±1.8 vs. 9.6±1.8 µmol/kg/min, p=0.0155), carbohydrate-driven muscle mitochondrial oxidative capacity (O2-flux:74.0±4.1 vs. 67.1±4.3 pmol/(s*mg), p=0.0417), whole-body insulin-stimulated carbohydrate oxidation (10.9±0.6 vs. 9.6±0.7 µmol/kg/min, p=0.0246), and reduced plasma BCAA (549.2±4.5 vs. 598.4±5.0 µmol/L, p=0.0125) and oxidation-derived metabolites (KIV:13.4±0.1 vs. 15.2±0.1 µmol/L, p=0.0154; 3-HIB:36.94±0.7 vs. 43.5±0.6 µmol/L, p=0.0194:). No adverse events were reported. Interpretation: In patients with T2D, NaPB treatment significantly improved peripheral insulin sensitivity and glucose oxidation. These data establish the proof-of-concept in humans that targeting the BCAA pathway may represent a potential new treatment strategy for patients with T2D. Trial Registration: The trial has been registered with number NTR 7426, direct link to the trial: https://www.trialregister.nl/trial/7227. Funding: Dutch Diabetes Foundation Declaration of Interest: The authors declare no conflicts of interest. Ethical Approval: The study was conducted at the Maastricht University Medical Center (MUMC+), the Netherlands. The protocol was reviewed and approved by the Medical Review Ethics Committee of Maastricht University and Medical Centre.