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

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 () and Shi-Min Zhao ()
Additional contact information
Qian Zhou: Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University
Wan-Wan Sun: Fudan University Shanghai Cancer Center, Fudan University
Jia-Cong Chen: Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University
Hui-Lu Zhang: Fudan University Shanghai Cancer Center, Fudan University
Jie Liu: Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University
Yan Lin: Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University
Peng-Cheng Lin: Qinghai University for Nationalities
Bai-Xing Wu: Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
Yan-Peng An: Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University
Lin Huang: Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University
Wen-Xing Sun: School of Public Health, Nantong University
Xin-Wen Zhou: Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University
Yi-Ming Li: Fudan University Shanghai Cancer Center, Fudan University
Yi-Yuan Yuan: Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University
Jian-Yuan Zhao: Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University
Wei Xu: Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University
Shi-Min Zhao: Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32000-0

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