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

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  • 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
    Shanghai Key Laboratory of Metabolic Remodeling, and Children’s Hospital of Fudan University
    Fudan University Shanghai Cancer Center, 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
    Shanghai Key Laboratory of Metabolic Remodeling, and Children’s Hospital of 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
    Fudan University Shanghai Cancer Center, 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
    Shanghai Key Laboratory of Metabolic Remodeling, and Children’s Hospital of 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
    Shanghai Key Laboratory of Metabolic Remodeling, and Children’s Hospital of 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
    Shanghai Key Laboratory of Metabolic Remodeling, and Children’s Hospital of 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
    Shanghai Key Laboratory of Metabolic Remodeling, and Children’s Hospital of Fudan University
    Fudan University Shanghai Cancer Center, 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
    Shanghai Key Laboratory of Metabolic Remodeling, and Children’s Hospital of Fudan University
    Qinghai University for Nationalities)

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.

Suggested Citation

  • 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-Yua, 2022. "Phenylalanine impairs insulin signaling and inhibits glucose uptake through modification of IRβ," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32000-0
    DOI: 10.1038/s41467-022-32000-0
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    References listed on IDEAS

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    1. My-Nuong Vo & Markus Terrey & Jeong Woong Lee & Bappaditya Roy & James J. Moresco & Litao Sun & Hongjun Fu & Qi Liu & Thomas G. Weber & John R. Yates & Kurt Fredrick & Paul Schimmel & Susan L. Ackerma, 2018. "ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase," Nature, Nature, vol. 557(7706), pages 510-515, May.
    2. E. Dale Abel & Odile Peroni & Jason K. Kim & Young-Bum Kim & Olivier Boss & Ed Hadro & Timo Minnemann & Gerald I. Shulman & Barbara B. Kahn, 2001. "Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver," Nature, Nature, vol. 409(6821), pages 729-733, February.
    3. My-Nuong Vo & Markus Terrey & Jeong Woong Lee & Bappaditya Roy & James J. Moresco & Litao Sun & Hongjun Fu & Qi Liu & Thomas G. Weber & John R. Yates & Kurt Fredrick & Paul Schimmel & Susan L. Ackerma, 2018. "Publisher Correction: ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase," Nature, Nature, vol. 560(7720), pages 35-35, August.
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