Mice with disruption of the imprinted Grb10 gene exhibit altered body composition, glucose homeostasis and insulin signalling during post-natal life

FM Smith, LJ Holt, AS Garfield, M Charalambous, F Koumanov, MJ Perry, R Bazzani, SA Sheardown, BD Hegarty, RJ Lyons, GJ Cooney, RJ Daly, A Ward

    Research output: Contribution to journalArticle (Academic Journal)peer-review

    92 Citations (Scopus)

    Abstract

    The Grb10 adapter protein is capable of interacting with a variety of receptor tyrosine kinases, including, notably, the insulin receptor. Biochemical and cell culture experiments have indicated that Grb10 might act as an inhibitor of insulin signaling. We have used mice with a disruption of the Grb10 gene (Grb10Delta2-4 mice) to assess whether Grb10 might influence insulin signaling and glucose homeostasis in vivo. Adult Grb10Delta2-4 mice were found to have improved whole-body glucose tolerance and insulin sensitivity, as well as increased muscle mass and reduced adiposity. Tissue-specific changes in insulin receptor tyrosine phosphorylation were consistent with a model in which Grb10, like the closely related Grb14 adapter protein, prevents specific protein tyrosine phosphatases from accessing phosphorylated tyrosines within the kinase activation loop. Furthermore, insulin-induced IRS-1 tyrosine phosphorylation was enhanced in Grb10Delta2-4 mutant animals, supporting a role for Grb10 in attenuation of signal transmission from the insulin receptor to IRS-1. We have previously shown that Grb10 strongly influences growth of the fetus and placenta. Thus, Grb10 forms a link between fetal growth and glucose-regulated metabolism in postnatal life and is a candidate for involvement in the process of fetal programming of adult metabolic health.
    Translated title of the contributionMice with disruption of the imprinted Grb10 gene exhibit altered body composition, glucose homeostasis and insulin signalling during post-natal life
    Original languageEnglish
    Pages (from-to)5871 - 5886
    Number of pages16
    JournalMolecular and Cellular Biology
    Volume27(16)
    DOIs
    Publication statusPublished - Aug 2007

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