IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31563-2.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31563-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-31563-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.

      More about this item

      Statistics

      Access and download statistics

      Corrections

      All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31563-2. See general information about how to correct material in RePEc.

      If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

      If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

      If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

      For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

      Please note that corrections may take a couple of weeks to filter through the various RePEc services.

      IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.