Article: article from journal or magazin.
Glucagon-like peptide-1 increases beta-cell glucose competence and proliferation by translational induction of insulin-like growth factor-1 receptor expression.
Journal of Biological Chemistry
Glucagon-like peptide-1 (GLP-1) protects beta-cells against apoptosis, increases their glucose competence, and induces their proliferation. We previously demonstrated that the anti-apoptotic effect was mediated by an increase in insulin-like growth factor-1 receptor (IGF-1R) expression and signaling, which was dependent on autocrine secretion of insulin-like growth factor 2 (IGF-2). Here, we further investigated how GLP-1 induces IGF-1R expression and whether the IGF-2/IGF-1R autocrine loop is also involved in mediating GLP-1-increase in glucose competence and proliferation. We show that GLP-1 up-regulated IGF-1R expression by a protein kinase A-dependent translational control mechanism, whereas isobutylmethylxanthine, which led to higher intracellular accumulation of cAMP than GLP-1, increased both IGF-1R transcription and translation. We then demonstrated, using MIN6 cells and primary islets, that the glucose competence of these cells was dependent on the level of IGF-1R expression and on IGF-2 secretion. We showed that GLP-1-induced primary beta-cell proliferation was suppressed by Igf-1r gene inactivation and by IGF-2 immunoneutralization or knockdown. Together our data show that regulation of beta-cell number and function by GLP-1 depends on the cAMP/protein kinase A mediated-induction of IGF-1R expression and the increased activity of an IGF-2/IGF-1R autocrine loop.
1-Methyl-3-isobutylxanthine/pharmacology, Animals, Apoptosis, Blotting, Western, Cell Proliferation, Cells, Cultured, Cyclic AMP/metabolism, Cyclic AMP-Dependent Protein Kinases/metabolism, Fluorescent Antibody Technique, Glucagon-Like Peptide 1/pharmacology, Glucose/metabolism, Insulin-Like Growth Factor II/genetics, Insulin-Like Growth Factor II/metabolism, Insulin-Secreting Cells/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Biosynthesis, RNA, Messenger/genetics, RNA, Messenger/metabolism, Receptor, IGF Type 1/genetics, Receptor, IGF Type 1/metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transcription, Genetic
Web of science
Last modification date