UC Davis

Key PointsBranched-chain amino acids (BCAAs) have beneficial nutrient signalling effects but paradoxically are associated with obesity, insulin resistance and type 2 diabetes mellitus (T2DM)BCAAs might be a marker of, rather than, a cause of insulin resistance, as insulin resistance increases the rate of appearance of BCAAs and is linked to reduced expression of mitochondrial BCAA catabolic enzymesAlternatively, two mechanisms have emerged indicating that a causative link exists between increased plasma concentrations of BCAAs and T2DM or insulin resistanceIn the first mechanism, persistent activation of the mammalian target of rapamycin complex 1 signalling pathway uncouples the insulin receptor from the insulin signalling mediator, IRS-1, which leads to insulin resistanceIn the second mechanism, abnormal BCAA metabolism in obesity results in accumulation of toxic BCAA metabolites that in turn trigger the mitochondrial dysfunction and stress signalling associated with insulin resistance and T2DMFactors that alter expression of genes involved in the BCAA metabolic pathway (or post-translational modification of the encoded proteins) are associated with obesity and T2DM; three genes in the pathway are candidate genes for obesity and/or T2DM