IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v6y2015i1d10.1038_ncomms8078.html
   My bibliography  Save this article

Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo

Author

Listed:
  • Paul M. Titchenell

    (Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania)

  • Qingwei Chu

    (Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania)

  • Bobby R. Monks

    (Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania)

  • Morris J. Birnbaum

    (Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania
    Present address: CVMED, Pfizer Inc., Cambridge, MA.)

Abstract

Insulin signalling and nutrient levels coordinate the metabolic response to feeding in the liver. Insulin signals in hepatocytes to activate Akt, which inhibits Foxo1 suppressing hepatic glucose production (HGP) and allowing the transition to the postprandial state. Here we provide genetic evidence that insulin regulates HGP by both direct and indirect hepatic mechanisms. Liver-specific ablation of the IR (L-Insulin Receptor KO) induces glucose intolerance, insulin resistance and prevents the appropriate transcriptional response to feeding. Liver-specific deletion of Foxo1 (L-IRFoxo1DKO) rescues glucose tolerance and allows for normal suppression of HGP and gluconeogenic gene expression in response to insulin, despite lack of autonomous liver insulin signalling. These data indicate that in the absence of Foxo1, insulin signals via an intermediary extrahepatic tissue to regulate liver glucose production. Importantly, a hepatic mechanism distinct from the IR–Akt–Foxo1 axis exists to regulate glucose production.

Suggested Citation

  • Paul M. Titchenell & Qingwei Chu & Bobby R. Monks & Morris J. Birnbaum, 2015. "Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8078
    DOI: 10.1038/ncomms8078
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms8078
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms8078?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
    ---><---

    Citations

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


    Cited by:

    1. Marko Groeger & Koji Matsuo & Emad Heidary Arash & Ashley Pereira & Dounia Guillou & Cindy Pino & Kayque A. Telles-Silva & Jacquelyn J. Maher & Edward C. Hsiao & Holger Willenbring, 2023. "Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages," Nature Communications, Nature, vol. 14(1), pages 1-14, 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:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8078. 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.