Phenylalanine impairs insulin signaling and inhibits glucose uptake through modification of IRβ

• DOI: 10.1038/s41467-022-32000-0
• Publication Date: 2022-07-25T13:03:29Z
• 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
• Keywords: 0301 basic medicine; Science; Phenylalanine; Q; Article; 3. Good health; Mice; 03 medical and health sciences; Glucose; Diabetes Mellitus, Type 2; Sirtuin 1; Animals; Humans; Insulin; Insulin Resistance

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.