IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v451y2008i7181d10.1038_nature06668.html
   My bibliography  Save this article

Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance

Author

Listed:
  • Xiaoyong Yang

    (Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA)

  • Pat P. Ongusaha

    (Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA)

  • Philip D. Miles

    (University of California, San Diego, La Jolla, California 92093, USA)

  • Joyce C. Havstad

    (Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA)

  • Fengxue Zhang

    (University of Alabama, Birmingham, Alabama 35294, USA)

  • W. Venus So

    (Roche Group Research Information, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110, USA)

  • Jeffrey E. Kudlow

    (University of Alabama, Birmingham, Alabama 35294, USA)

  • Robert H. Michell

    (School of Biosciences, University of Birmingham)

  • Jerrold M. Olefsky

    (University of California, San Diego, La Jolla, California 92093, USA)

  • Seth J. Field

    (University of California, San Diego, La Jolla, California 92093, USA)

  • Ronald M. Evans

    (Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA)

Abstract

Glucose flux through the hexosamine biosynthetic pathway leads to the post-translational modification of cytoplasmic and nuclear proteins by O-linked β-N-acetylglucosamine (O-GlcNAc). This tandem system serves as a nutrient sensor to couple systemic metabolic status to cellular regulation of signal transduction, transcription, and protein degradation. Here we show that O-GlcNAc transferase (OGT) harbours a previously unrecognized type of phosphoinositide-binding domain. After induction with insulin, phosphatidylinositol 3,4,5-trisphosphate recruits OGT from the nucleus to the plasma membrane, where the enzyme catalyses dynamic modification of the insulin signalling pathway by O-GlcNAc. This results in the alteration in phosphorylation of key signalling molecules and the attenuation of insulin signal transduction. Hepatic overexpression of OGT impairs the expression of insulin-responsive genes and causes insulin resistance and dyslipidaemia. These findings identify a molecular mechanism by which nutritional cues regulate insulin signalling through O-GlcNAc, and underscore the contribution of this modification to the aetiology of insulin resistance and type 2 diabetes.

Suggested Citation

  • Xiaoyong Yang & Pat P. Ongusaha & Philip D. Miles & Joyce C. Havstad & Fengxue Zhang & W. Venus So & Jeffrey E. Kudlow & Robert H. Michell & Jerrold M. Olefsky & Seth J. Field & Ronald M. Evans, 2008. "Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance," Nature, Nature, vol. 451(7181), pages 964-969, February.
    • Handle: RePEc:nat:nature:v:451:y:2008:i:7181:d:10.1038_nature06668
    DOI: 10.1038/nature06668
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature06668
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/nature06668?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
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

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


    Cited by:

    1. Shahzina Kanwal & Yann Fardini & Patrick Pagesy & Thierry N’Tumba-Byn & Cécile Pierre-Eugène & Elodie Masson & Cornelia Hampe & Tarik Issad, 2013. "O-GlcNAcylation-Inducing Treatments Inhibit Estrogen Receptor α Expression and Confer Resistance to 4-OH-Tamoxifen in Human Breast Cancer-Derived MCF-7 Cells," PLOS ONE, Public Library of Science, vol. 8(7), pages 1-1, July.
    2. Donghyun Kang & Jeeyeon Lee & Geunho Yook & Sehan Jeong & Jungkwon Shin & Mi-Sung Kim & Yi-Jun Kim & Hyeryeon Jung & Jinsung Ahn & Tae Woo Kim & Moon Jong Chang & Chong Bum Chang & Seung-Baik Kang & W, 2025. "Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    3. Thulaciga Yoganathan & Mailyn Perez-Liva & Daniel Balvay & Morgane Gall & Alice Lallemand & Anais Certain & Gwennhael Autret & Yasmine Mokrani & François Guillonneau & Johanna Bruce & Vincent Nguyen &, 2023. "Acute stress induces long-term metabolic, functional, and structural remodeling of the heart," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

    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:nature:v:451:y:2008:i:7181:d:10.1038_nature06668. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.