The BCKDH kinase inhibitor BT2 promotes BCAA disposal and mitochondrial proton leak in both insulin-sensitive and insulin-resistant C2C12 myotubes.

Elevated circulating branched-chain amino acids (BCAAs) have been correlated with the severity of insulin resistance, leading to recent investigations that stimulate BCAA metabolism for the potential benefit of metabolic diseases. BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), an inhibitor of branched-chain ketoacid dehydrogenase kinase, promotes BCAA metabolism by enhancing BCKDH complex activity. The purpose of this report was to investigate the effects of BT2 on mitochondrial and glycolytic metabolism, insulin sensitivity, and de novo lipogenesis both with and without insulin resistance.

Physiological 4-phenylbutyrate promotes mitochondrial biogenesis and metabolism in C2C12 myotubes.

Type 2 diabetes is characterized by elevated circulating blood metabolites such as glucose, insulin, and branched chain amino acids (BCAA), which often coincide with reduced mitochondrial function. 4-Phenylbutyrate (PBA), an ammonia scavenger, has been shown to activate BCAA metabolism, resolve endoplasmic reticulum (ER) stress, and rescue BCAA-mediated insulin resistance. To determine the effect of PBA on the altered metabolic phenotype featured in type 2 diabetes, the present study investigated the effect of PBA on various metabolic parameters including mitochondrial metabolism and mitochondrial biogenesis.

The Selective LAT1 Inhibitor JPH203 Enhances Mitochondrial Metabolism and Content in Insulin-Sensitive and Insulin-Resistant C2C12 Myotubes.

Population data have shown an association between higher circulating branched-chain amino acids (BCAA) and the severity of insulin resistance in people with diabetes. While several studies have assessed BCAA metabolism as a potential target for regulation, less attention has been paid to the role of L-type amino acid transporter 1 (LAT1), the primary transporter of BCAA in skeletal muscle. The aim of this study was to assess the impact of JPH203 (JPH), a LAT1 inhibitor, on myotube metabolism in both insulin-sensitive and insulin-resistant myotubes.