TY - JOUR
T1 - A randomized placebo-controlled clinical trial for pharmacological activation of BCAA catabolism in patients with type 2 diabetes
AU - Vanweert, F.
AU - Neinast, M.
AU - Tapia, E.E.
AU - van de Weijer, T.
AU - Hoeks, J.
AU - Schrauwen-Hinderling, V.B.
AU - Blair, M.C.
AU - Bornstein, M.R.
AU - Hesselink, M.K.C.
AU - Schrauwen, P.
AU - Arany, Z.
AU - Phielix, E.
N1 - Funding Information:
E.P. was granted with a senior fellowship from the Dutch Diabetes Foundation (Grant No. 2017.82.010), which supported the present study. E.P. furthermore received a “VENI” Research Grant for innovative research from the Netherlands Organization for Scientific Research (91613132), an EFSD/Lilly grant from the European Foundation for the Study of Diabetes (EFSD). Z.A. is supported by NIH (DK114103). T.W. received a junior fellowship from the Dutch Diabetes Foundation (Grant No. 2015.81.1833). V.S. was supported by an ERC starting grant (Grant no. 759161) ‘MRS in diabetes’. Metabolomics were performed with support from the DRC Regional Metabolomics and Fluxomics Core (NIH 5P30DK019525-45 7239). The funding agencies had no role in study design, data collection and analysis or manuscript writing.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/6/18
Y1 - 2022/6/18
N2 - Elevations in plasma branched-chain amino acid (BCAA) levels associate with insulin resistance and type 2 diabetes (T2D). Pre-clinical models suggest that lowering BCAA levels improve glucose tolerance, but data in humans are lacking. Here, we used sodium phenylbutyrate (NaPB), an accelerator of BCAA catabolism, as tool to lower plasma BCAA levels in patients with T2D, and evaluate its effect on metabolic health. This trial (NetherlandsTrialRegister: NTR7426) had a randomized, placebo-controlled, double-blind cross-over design and was performed in the Maastricht University Medical Center (MUMC+), the Netherlands, between February 2019 and February 2020. Patients were eligible for the trial if they were 40-75years, BMI of 25-38 kg/m(2), relatively well-controlled T2D (HbA1C < 8.5%) and treated with oral glucose-lowering medication. Eighteen participants were randomly assigned to receive either NaPB 4.8 g/m(2)/day and placebo for 2 weeks via controlled randomization and sixteen participants completed the study. The primary outcome was peripheral insulin sensitivity. Secondary outcomes were ex vivo muscle mitochondrial oxidative capacity, substrate oxidation and ectopic fat accumulation. Fasting blood samples were collected to determine levels of BCAA, their catabolic intermediates, insulin, triglycerides, free fatty acids (FFA) and glucose. NaPB led to a robust 27% improvement in peripheral insulin sensitivity compared to placebo (Delta Rd:13.2 +/- 1.8 vs. 9.6 +/- 1.8 mu mol/kg/min, p = 0.02). This was paralleled by an improvement in pyruvate-driven muscle mitochondrial oxidative capacity and whole-body insulin-stimulated carbohydrate oxidation, and a reduction in plasma BCAA and glucose levels. No effects were observed on levels of insulin, triglycerides and FFA, neither did fat accumulation in muscle and liver change. No adverse events were reported. These data establish the proof-of-concept in humans that modulating the BCAA oxidative pathway may represent a potential treatment strategy for patients with T2D.Evidence from preclinical models suggest that lowering levels of branched chain amino acids (BCAA) improves glucose metabolism. Here the authors report that NaPB, an accelerator of BCAA catabolism, improves peripheral insulin sensitivity in patients with type 2 diabetes in a randomized placebo-controlled crossover clinical trial.
AB - Elevations in plasma branched-chain amino acid (BCAA) levels associate with insulin resistance and type 2 diabetes (T2D). Pre-clinical models suggest that lowering BCAA levels improve glucose tolerance, but data in humans are lacking. Here, we used sodium phenylbutyrate (NaPB), an accelerator of BCAA catabolism, as tool to lower plasma BCAA levels in patients with T2D, and evaluate its effect on metabolic health. This trial (NetherlandsTrialRegister: NTR7426) had a randomized, placebo-controlled, double-blind cross-over design and was performed in the Maastricht University Medical Center (MUMC+), the Netherlands, between February 2019 and February 2020. Patients were eligible for the trial if they were 40-75years, BMI of 25-38 kg/m(2), relatively well-controlled T2D (HbA1C < 8.5%) and treated with oral glucose-lowering medication. Eighteen participants were randomly assigned to receive either NaPB 4.8 g/m(2)/day and placebo for 2 weeks via controlled randomization and sixteen participants completed the study. The primary outcome was peripheral insulin sensitivity. Secondary outcomes were ex vivo muscle mitochondrial oxidative capacity, substrate oxidation and ectopic fat accumulation. Fasting blood samples were collected to determine levels of BCAA, their catabolic intermediates, insulin, triglycerides, free fatty acids (FFA) and glucose. NaPB led to a robust 27% improvement in peripheral insulin sensitivity compared to placebo (Delta Rd:13.2 +/- 1.8 vs. 9.6 +/- 1.8 mu mol/kg/min, p = 0.02). This was paralleled by an improvement in pyruvate-driven muscle mitochondrial oxidative capacity and whole-body insulin-stimulated carbohydrate oxidation, and a reduction in plasma BCAA and glucose levels. No effects were observed on levels of insulin, triglycerides and FFA, neither did fat accumulation in muscle and liver change. No adverse events were reported. These data establish the proof-of-concept in humans that modulating the BCAA oxidative pathway may represent a potential treatment strategy for patients with T2D.Evidence from preclinical models suggest that lowering levels of branched chain amino acids (BCAA) improves glucose metabolism. Here the authors report that NaPB, an accelerator of BCAA catabolism, improves peripheral insulin sensitivity in patients with type 2 diabetes in a randomized placebo-controlled crossover clinical trial.
KW - AMINO-ACID CATABOLISM
KW - BRANCHED-CHAIN
KW - INSULIN-RESISTANCE
KW - DEHYDROGENASE KINASE
KW - METABOLISM
KW - OBESITY
KW - EXPRESSION
KW - GLUCONEOGENESIS
KW - TARGET
KW - TISSUE
U2 - 10.1038/s41467-022-31249-9
DO - 10.1038/s41467-022-31249-9
M3 - Article
C2 - 35717342
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3508
ER -