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Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor

Author

Listed:
  • Xuanming Guo

    (Hong Kong Baptist University)

  • Pallavi Asthana

    (Hong Kong Baptist University)

  • Susma Gurung

    (Hong Kong Baptist University)

  • Shuo Zhang

    (The University of Hong Kong)

  • Sheung Kin Ken Wong

    (The University of Hong Kong)

  • Samane Fallah

    (Hong Kong Baptist University)

  • Chi Fung Willis Chow

    (Hong Kong Baptist University
    Max Planck Institute for Molecular Cell and Biology)

  • Sijia Che

    (Hong Kong Baptist University)

  • Lixiang Zhai

    (Hong Kong Baptist University)

  • Zening Wang

    (University of Texas Health Science Center at Houston)

  • Xin Ge

    (University of Texas Health Science Center at Houston)

  • Zhixin Jiang

    (The University of Hong Kong)

  • Jiayan Wu

    (Hong Kong Baptist University)

  • Yijing Zhang

    (Hong Kong Baptist University)

  • Xiaoyu Wu

    (Jinhua Guangfu hospital)

  • Keyang Xu

    (Hong Kong Baptist University)

  • Cheng Yuan Lin

    (Hong Kong Baptist University
    Hong Kong Baptist University)

  • Hiu Yee Kwan

    (Hong Kong Baptist University)

  • Aiping Lyu

    (Hong Kong Baptist University)

  • Zhongjun Zhou

    (The University of Hong Kong)

  • Zhao-Xiang Bian

    (Hong Kong Baptist University
    Hong Kong Baptist University)

  • Hoi Leong Xavier Wong

    (Hong Kong Baptist University)

Abstract

Insulin sensitivity progressively declines with age. Currently, the mechanism underlying age-associated insulin resistance remains unknown. Here, we identify membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) as a central regulator of insulin sensitivity during ageing. Ageing promotes MMP14 activation in insulin-sensitive tissues, which cleaves Insulin Receptor to suppress insulin signaling. MT1-MMP inhibition restores Insulin Receptor expression, improving insulin sensitivity in aged mice. The cleavage of Insulin Receptor by MT1-MMP also contributes to obesity-induced insulin resistance and inhibition of MT1-MMP activities normalizes metabolic dysfunctions in diabetic mouse models. Conversely, overexpression of MT1-MMP in the liver reduces the level of Insulin Receptor, impairing hepatic insulin sensitivity in young mice. The soluble Insulin Receptor and circulating MT1-MMP are positively correlated in plasma from aged human subjects and non-human primates. Our findings provide mechanistic insights into regulation of insulin sensitivity during physiological ageing and highlight MT1-MMP as a promising target for therapeutic avenue against diabetes.

Suggested Citation

  • Xuanming Guo & Pallavi Asthana & Susma Gurung & Shuo Zhang & Sheung Kin Ken Wong & Samane Fallah & Chi Fung Willis Chow & Sijia Che & Lixiang Zhai & Zening Wang & Xin Ge & Zhixin Jiang & Jiayan Wu & Y, 2022. "Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31563-2
    DOI: 10.1038/s41467-022-31563-2
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    References listed on IDEAS

    as
    1. Paul J. Meakin & Anna Mezzapesa & Eva Benabou & Mary E. Haas & Bernadette Bonardo & Michel Grino & Jean-Michel Brunel & Christèle Desbois-Mouthon & Sudha B. Biddinger & Roland Govers & Michael L. J. A, 2018. "The beta secretase BACE1 regulates the expression of insulin receptor in the liver," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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    Cited by:

    1. Xuanming Guo & Jianli Cao & Jian-Piao Cai & Jiayan Wu & Jiangang Huang & Pallavi Asthana & Sheung Kin Ken Wong & Zi-Wei Ye & Susma Gurung & Yijing Zhang & Sheng Wang & Zening Wang & Xin Ge & Hiu Yee K, 2022. "Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Xuanming Guo & Pallavi Asthana & Lixiang Zhai & Ka Wing Cheng & Susma Gurung & Jiangang Huang & Jiayan Wu & Yijing Zhang & Arun Kumar Mahato & Mart Saarma & Mart Ustav & Hiu Yee Kwan & Aiping Lyu & Ku, 2024. "Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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