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

Nat Commun. 2022-07; 
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
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摘要

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 h... More

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