Moghei Mahshid, Tavajohi-Fini Pegah, Beatty Brendan, Adegoke Olasunkanmi A J
School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Ontario, Canada
Am J Physiol Cell Physiol. 2016 Sep 1;311(3):C518-27. doi: 10.1152/ajpcell.00062.2016. Epub 2016 Aug 3.
Although leucine has many positive effects on metabolism in multiple tissues, elevated levels of this amino acid and the other branched-chain amino acids (BCAAs) and their metabolites are implicated in obesity and insulin resistance. While some controversies exist about the direct effect of leucine on insulin action in skeletal muscle, little is known about the direct effect of BCAA metabolites. Here, we first showed that the inhibitory effect of leucine on insulin-stimulated glucose transport in L6 myotubes was dampened when other amino acids were present, due in part to a 140% stimulation of basal glucose transport (P < 0.05). Importantly, we also showed that α-ketoisocaproic acid (KIC), an obligatory metabolite of leucine, stimulated mTORC1 signaling but suppressed insulin-stimulated glucose transport (-34%, P < 0.05) in an mTORC1-dependent manner. The effect of KIC on insulin-stimulated glucose transport was abrogated in cells depleted of branched-chain aminotransferase 2 (BCAT2), the enzyme that catalyzes the reversible transamination of KIC to leucine. We conclude that although KIC can modulate muscle glucose metabolism, this effect is likely a result of its transamination back to leucine. Therefore, limiting the availability of leucine, rather than those of its metabolites, to skeletal muscle may be more critical in the management of insulin resistance and its sequelae.
尽管亮氨酸对多个组织的代谢有许多积极影响，但这种氨基酸以及其他支链氨基酸（BCAAs）及其代谢产物水平升高与肥胖和胰岛素抵抗有关。虽然关于亮氨酸对骨骼肌胰岛素作用的直接影响存在一些争议，但对于BCAA代谢产物的直接影响知之甚少。在这里，我们首先表明，当存在其他氨基酸时，亮氨酸对L6肌管中胰岛素刺激的葡萄糖转运的抑制作用会减弱，部分原因是基础葡萄糖转运受到140%的刺激（P<0.05）。重要的是，我们还表明，亮氨酸的一种必需代谢产物α-酮异己酸（KIC）以mTORC1依赖性方式刺激mTORC1信号传导，但抑制胰岛素刺激的葡萄糖转运（-34%，P<0.05）。在缺乏支链氨基转移酶2（BCAT2）的细胞中，KIC对胰岛素刺激的葡萄糖转运的影响被消除，BCAT2是催化KIC可逆转氨生成亮氨酸的酶。我们得出结论，虽然KIC可以调节肌肉葡萄糖代谢，但这种影响可能是其转氨回亮氨酸的结果。因此，限制亮氨酸而非其代谢产物向骨骼肌的供应，在胰岛素抵抗及其后遗症的管理中可能更为关键。
