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Division of Cell and Molecular Biology (F.Y., I.G.F., T.J.), Toronto General Research Institute, University Health Network; Departments of Medicine (I.G.F., P.L.B., T.J.), Physiology (G.E.L., I.G.F., P.L.B., T.J.), and Laboratory Medicine and Pathobiology (J.S., T.J.); and Banting and Best Diabetes Centre (I.G.F., T.J.), Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1L7
Address all correspondence and requests for reprints to: Tianru Jin, Room 10-354, 10th Floor, Toronto Medical Discovery Tower, MaRS Centre, University Health Network, 101 College Street, Toronto, Ontario, Canada M5G 1L7. E-mail: tianru.jin{at}utoronto.ca.
The proglucagon gene (glu) encodes the incretin hormone glucagon-like peptide-1 (GLP-1), produced in the intestinal endocrine L cells. We found previously that the bipartite transcription factor β-catenin/T cell factor (cat/TCF), the major effector of the canonical Wnt signaling pathway, activates intestinal glu expression and GLP-1 production. We show here that 100 nM insulin stimulated glu expression and enhanced GLP-1 content in the intestinal GLUTag L cell line as well as in primary fetal rat intestinal cell cultures. Increased intestinal glu mRNA expression and GLP-1 content were also observed in vivo in hyperinsulinemic MKR mice. In the GLUTag cells, insulin-induced activation of glu expression occurred through the same TCF site that mediates cat/TCF activation. Phosphatidylinositol 3-kinase inhibition, but not protein kinase B inhibition, attenuated the stimulation by insulin. Furthermore, nuclear β-catenin content in the intestinal L cells was increased by insulin. Finally, insulin enhanced the binding of TCF-4 and β-catenin to the TCF site in the glu promoter G2 enhancer element, as determined by quantitative chromatin immunoprecipitation assay. Collectively, these findings indicate that enhancement of β-catenin nuclear translocation and cat/TCF binding are among the mechanisms underlying cross talk between the insulin and Wnt signaling pathways in intestinal endocrine L cells.
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