A temporal switch in the insulin-signalling pathway that regulates hepatic IGF-binding protein-1 gene expression

David Finlay, Antonio J. Ruiz-Alcaraz, Christopher Lipina, Stephane Perrier, Calum Sutherland

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    Insulin regulation of hepatic gene transcription is a vital component of glucose homeostasis. Understanding the molecular regulation of this process aids the search for the defect(s) that promotes insulin-resistant states, such as diabetes mellitus. We have previously shown that the insulin regulation of hepatic IGF-binding protein-1 (IGFBP1) expression requires the signalling proteins phosphatidylinositol 3-kinase (PI 3-kinase) and mammalian target of rapamycin (mTOR). In this report, we demonstrate that activation of the mTOR pathway, without activation of its upstream regulator PI 3-kinase, reduces IGFBP1 expression. Therefore, mTOR activation is sufficient to mimic insulin regulation of this gene. However, longer exposure (> 3 h) of cells to insulin reduces the importance of this pathway in insulin regulation of the gene, suggesting a temporal switch in signalling mechanisms linking insulin action to the IGFBP1 gene promoter. In contrast, the activation of PI 3-kinase is required for insulin regulation of IGFBP1 under all conditions tested. Therefore, an mTOR-independent, PI 3-kinase-dependent pathway becomes more important in IGFBP1 regulation after long exposure to insulin. This is a novel concept in insulin regulation of gene expression and demonstrates the importance of temporal analysis of signalling processes.

    Original languageEnglish
    Pages (from-to)227-237
    Number of pages11
    JournalJournal of Molecular Endocrinology
    Issue number2
    Publication statusPublished - Oct 2006

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