D1 | Abstract 16

Annual NUTRIM Symposium 18 November 2020


Lowering branched-chain amino acid levels in patients with type 2 diabetes using sodium-phenylbutyrate

F. Vanweert1, E. Tapia1, T. de Weijer1,2, J. Hoeks1, V.B. Schrauwen-Hinderling1,2, P. Schrauwen1, M.K.C. Hesselink1 and E. Phielix1

Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
2Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
E-mail: f.vanweert@maastrichtuniversity.nl
Branched-chain amino acid (BCAA) levels are elevated in patients with type 2 diabetes (T2DM) and associate with insulin resistance. An impaired BCAA catabolism may possibly lead to increased BCAA levels and affect metabolic health. Sodium-phenylbutyrate (NaPB), a drug known to boost BCAA oxidation, may therefore lower BCAA levels and improve metabolic health in T2DM. This was investigated in the present study.

Sixteen men and women (3f/13m) with T2DM underwent a 2-week NaPB (4.8 mg/kg/day) treatment in a randomized, placebo-controlled, double-blind cross-over design with a wash-out of 6-8 weeks. The primary outcome was whole-body insulin sensitivity, measured with 2-step hyperinsulinemic-euglycemic clamps expressed as insulin-stimulated glucose disposal rate minus baseline (ΔRd). Secondary outcomes were ex-vivo mitochondrial oxidative capacity measured with high-resolution respirometry expressed as O2-flux and metabolic flexibility using indirect calorimetry expressed as the insulin-stimulated respiratory exchange ratio minus baseline ( ΔRER).

End-of-treatment fasting BCAA levels significantly decreased after NaPB vs. placebo (479 ± 12 vs. 501 ± 16 µmol/l, p=0.05) and tended to decrease for glucose levels (7.8 ± 0.4 vs. 8.2 ± 0.5 mmol/L, p=0.06). Furthermore, whole-body insulin sensitivity was 27% higher (ΔRd: 13.2 ± 1.84 vs. 9.7 ± 1.8 µmol/kg/min, p=0.02) and ex-vivo mitochondrial oxidative capacity on glycolytic substrate was 10% higher after NaPB compared to placebo (O2-flux: 74.0 ± 4.1 vs. 67.1 ± 4.3 pmol/(s*mg), p=0.05). In addition, metabolic flexibility tended to be higher after NaPB treatment compared to placebo ( ΔRER: 0.09 ± 0.01 vs. 0.08 ± 0.01, p=0.09).

NaPB-reduced BCAA plasma levels in patients with T2DM seem to improve glucose metabolism. This data strengthens future research to investigate the metabolic effects of long-term NaPB administration in T2DM.

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