Authors: Qian Zhou, Wan-Wan Sun, Jia-Cong Chen, Hui-Lu Zhang, Jie Liu, Yan Lin, Peng-Cheng Lin, Bai-Xing Wu, Yan-Peng An, Lin Huang, Wen-Xing Sun, Xin-Wen Zhou, Yi-Ming Li, Yi-Yuan Yuan, Jian-Yuan Zhao, Wei Xu, Shi-Min Zhao
Published: 2022-07-25
DOI: 10.1038/s41467-022-32000-0
Source: Full article
AbstractWhether 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.