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Exploring mechanistic links between extracellular BCAA & muscle insulin resistance: an in vitro approach
American Journal of Physiology-Cell Physiology ( IF 5.0 ) Pub Date : 2020-10-07 , DOI: 10.1152/ajpcell.00377.2020
Hannah Crossland 1 , Kenneth Smith 1 , Iskandar Idris 1 , Bethan E Phillips 1 , Philip J Atherton 1 , Daniel J Wilkinson 1
Affiliation  

Branched-chain amino acids (BCAAs) are essential for critical metabolic processes, however recent studies have associated elevated plasma BCAA levels with increased risk of insulin resistance. Using skeletal muscle cells, we aimed to determine whether continued exposure of high extracellular BCAA would result in impaired insulin signalling, and whether the compound sodium phenylbutyrate (PB), which induces BCAA metabolism, would lower extracellular BCAA, thereby alleviating their potentially inhibitory effects on insulin-mediated signalling. Prolonged exposure of elevated BCAA to cells resulted in impaired IRS-1/AKT signalling and insulin-stimulated glycogen synthesis. PB significantly reduced media BCAA and branched-chain keto acid (BCKA) concentrations, and increased phosphorylation of AKT (+20±2%; P<0.05 vs. Ctl) and AS160 (+24±2%; P<0.05 vs. Ctl), however insulin-stimulated glycogen synthesis was further reduced upon PB treatment. Continued exposure of high BCAA resulted in impaired intracellular insulin signalling and glycogen synthesis, and while forcing BCAA catabolism using PB resulted in increases in proteins important for regulating glucose uptake, PB did not prevent the impairments in glycogen synthesis with BCAA exposure.

中文翻译:

探索细胞外 BCAA 与肌肉胰岛素抵抗之间的机制联系:一种体外方法

支链氨基酸 (BCAA) 对关键代谢过程至关重要,但最近的研究表明血浆 BCAA 水平升高与胰岛素抵抗风险增加有关。使用骨骼肌细胞,我们旨在确定持续暴露于高细胞外 BCAA 是否会导致胰岛素信号传导受损,以及诱导 BCAA 代谢的化合物苯基丁酸钠 (PB) 是否会降低细胞外 BCAA,从而减轻其对胰岛素介导的信号传导。升高的 BCAA 长时间暴露于细胞会导致 IRS-1/AKT 信号传导和胰岛素刺激的糖原合成受损。PB 显着降低培养基 BCAA 和支链酮酸 (BCKA) 浓度,并增加 AKT (+20±2%; P<0.05 vs. Ctl) 和 AS160 (+24±2%; P<0. 05 vs. Ctl),然而胰岛素刺激的糖原合成在 PB 治疗后进一步降低。持续暴露于高 BCAA 会导致细胞内胰岛素信号传导和糖原合成受损,而使用 PB 强制 BCAA 分解代谢会导致对调节葡萄糖摄取很重要的蛋白质增加,但 PB 并不能防止 BCAA 暴露对糖原合成的损害。
更新日期:2020-10-08
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