Elevated Plasma Branched-Chain Amino Acid Levels Correlate With Type 2 Diabetes-Related Metabolic Disturbances

Context: Patients with type 2 diabetes mellitus (T2DM) have elevated plasma branched-chain amino acid (BCAA) levels. The underlying cause, however, is not known. Low mitochondrial oxidation of BCAA levels could contribute to higher plasma BCAA levels.Objective: We aimed to investigate ex vivo muscle mitochondrial oxidative capacity and in vivo BCAA oxidation measured by whole-body leucine oxidation rates in patients with T2DM, first-degree relatives (FDRs), and control participants (CONs) with overweight or obesity.Design and Setting: An observational, community-based study was conducted.Participants: Fifteen patients with T2DM, 13 FDR, and 17 CONs were included (age, 40-70 years; body mass index, 27-35 kg/m(2)).Main Outcome Measures: High-resolution respirometry was used to examine ex vivo mitochondrial oxidative capacity in permeabilized muscle fibers. A subgroup of 5 T2DM patients and 5 CONs underwent hyperinsulinemic-euglycemic clamps combined with 1-C-13 leucine-infusion to determine whole-body leucine oxidation.Results: Total BCAA levels were higher in patients with T2DM compared to CONs, but not in FDRs, and correlated negatively with muscle mitochondrial oxidative capacity (r = -0.44, P < .001). Consistently, whole-body leucine oxidation rate was lower in patients with T2DM vs CON under basal conditions (0.202 +/- 0.049 vs 0.275 +/- 0.043 mu mol kg(-1) min(-1), P < .05) and tended to be lower during high insulin infusion (0.326 +/- 0.024 vs 0.382 +/- 0.013 mu mol kg(-1) min(-1), P = .075).Conclusions: In patients with T2DM, a compromised whole-body leucine oxidation rate supports our hypothesis that higher plasma BCAA levels may originate at least partly from a low mitochondrial oxidative capacity.