苯丙氨酸
胰岛素
内科学
内分泌学
胰岛素受体
2型糖尿病
氨基酸
胰岛素抵抗
化学
信号转导
医学
糖尿病
生物化学
作者
Qian Zhou,Wan-Wan Sun,Jia-Cong Chen,Hui-Lu Zhang,Jie Liu,Yan Lin,Peng-Cheng Lin,Baixing Wu,Yanpeng An,Lin Huang,Wen-Xing Sun,Xin‐Wen Zhou,Yiming Li,Yiyuan Yuan,Jian Zhao,Wei Xu,Shimin Zhao
标识
DOI:10.1038/s41467-022-32000-0
摘要
Abstract 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) develop insulin resistance and T2D symptoms. Mechanistically, FARS phenylalanylate lysine 1057/1079 of IRβ (F-K1057/1079), inactivating IRβ and preventing insulin from promoting glucose uptake by cells. SIRT1 reverse F-K1057/1079 and counteract the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels in white blood cells from T2D patients are positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitizes insulin signaling and relieves 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.
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