Moghei M, Tavajohi-Fini P, Beatty B, Adegoke OA. Ketoisocaproic acid, a metabolite of leucine, suppresses insulin-stimulated glucose transport in skeletal muscle cells in a BCAT2-dependent manner. Am J Physiol Cell Physiol. 2016 Sep 1;311(3):C518-27.
From the authors: "Dietary protein and amino acids have many important functions in the body, including regulation of body weight, stimulation of muscle protein synthesis and muscle mass. In spite of these positive effects, elevated blood levels of amino acids and their metabolites have been associated with obesity, insulin resistance (especially in muscle), and type 2 diabetes. However, current evidence about the direct effect of amino acids on insulin action in muscle and link to type 2 diabetes is inconclusive. In this regard, one of the amino acids that have received significant attention is leucine. In this study, we showed that the inhibitory effect of leucine on insulin-induced glucose transport in rat skeletal muscle cells was weakened in the presence of other amino acids. We demonstrated, for the first time, that α-ketoisocaproic acid (KIC), a main metabolite of leucine, suppressed insulin-stimulated glucose transport and activated pathways that suppress insulin signaling. Significantly, we also showed that the effects of KIC were dependent on its conversion back to leucine because when we removed the enzyme needed for this conversion, KIC had no effect on glucose transport. Because other studies suggest that the body’s ability to use KIC is diminished in obesity and T2DM, mechanisms that prevent KIC accumulation may have therapeutic potential for the management of insulin resistance and its sequelae."