Phenylalanine Impairs Insulin Signaling and Inhibits Glucose Uptake Through Modification of IRβ

Whether amino acids act on cellular insulin signaling remains unclear, given that increased circulating amino acid levels are associated with the onset of type 2 diabetes (T2D). Here, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or phenylalanine-producing aspartame or overexpressing human phenylalanyl-tRNA synthetase (hFARS) developed insulin resistance and T2D symptoms. Mechanistically, FARS phenylalanylated lysine 1057/1079 of IRβ (F-K1057/1079), inactivating IRβ and preventing insulin from promoting glucose uptake by cells. SIRT1 reversed F-K1057/1079 and counteracted the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels in white blood cells from T2D patients wereare positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitizeds insulin signaling and relieveds T2D symptoms in hFARS-transgenic and db/db mice. These findings shed light on the activation of insulin signaling and T2D progression through inhibition of phenylalanylation.

鉴于循环氨基酸水平升高与2型糖尿病（type 2 diabetes, T2D）的发病相关，氨基酸是否作用于细胞胰岛素信号通路仍有待阐明。本研究发现，苯丙氨酸可修饰胰岛素受体β（insulin receptor beta, IRβ），并使胰岛素信号通路与葡萄糖摄取过程失活。喂食富含苯丙氨酸饲料、摄入可产生苯丙氨酸的阿斯巴甜，或过表达人苯丙氨酰-tRNA合成酶（human phenylalanyl-tRNA synthetase, hFARS）的小鼠均出现了胰岛素抵抗与2型糖尿病症状。机制研究显示，hFARS可对IRβ的赖氨酸1057/1079位点进行苯丙氨酰化修饰（F-K1057/1079），使IRβ失活，从而阻断胰岛素促进细胞摄取葡萄糖的过程。沉默信息调节因子1（SIRT1）可逆转F-K1057/1079修饰，并抵消hFARS与苯丙氨酸对胰岛素信号通路的抑制作用。2型糖尿病患者外周血白细胞中的F-K1057/1079修饰水平与SIRT1表达水平，分别与2型糖尿病的发病呈正相关与负相关。使用苯丙氨醇阻断F-K1057/1079修饰，可恢复并增强hFARS转基因小鼠与db/db小鼠的胰岛素信号通路敏感性，并缓解其2型糖尿病症状。上述研究结果揭示了通过抑制苯丙氨酰化修饰调控胰岛素信号通路活化与2型糖尿病进展的机制。