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

TY - JOUR

T1 - A temporal switch in the insulin-signalling pathway that regulates hepatic IGF-binding protein-1 gene expression

AU - Finlay, David

AU - Ruiz-Alcaraz, Antonio J.

AU - Lipina, Christopher

AU - Perrier, Stephane

AU - Sutherland, Calum

PY - 2006/10

Y1 - 2006/10

N2 - 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.

AB - 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.

U2 - 10.1677/jme.1.02084

DO - 10.1677/jme.1.02084

M3 - Article

C2 - 17032741

SN - 0952-5041

VL - 37

SP - 227

EP - 237

JO - Journal of Molecular Endocrinology

JF - Journal of Molecular Endocrinology

IS - 2

ER -