title: GLP-1 protects β-cells against apoptosis by enhancing the activity of an IGF-2/IGF1-receptor autocrine loop.
abstract: GLP-1 protects β-cells against apoptosis by still incompletely understood mechanisms. In a recent study, we searched for novel anti-apoptotic pathways by performing comparative transcriptomic analysis of islets from Gipr-/-;Glp-1r-/- mice, which show increased susceptibility to cytokine-induced apoptosis. We observed a strong reduction in IGF-1R expression in the knockout islets suggesting a link between the gluco-incretin and IGF-1R signaling pathways. Using MIN6 and primary islet cells, we demonstrated that GLP-1 strongly stimulates IGF-1R expression and that activation of the IGF-1R/Akt signaling pathway required active secretion of IGF-2 by the β-cells. We showed that inactivation of the IGF-1 receptor gene in β-cells or preventing its up-regulation by GLP-1, as well as suppressing IGF-2 expression or action, blocked the protective effect of GLP-1 against cytokine-induced apoptosis. Thus, an IGF-2/IGF-1 receptor autocrine loop operates in β-cells and GLP-1 increases its activity by enhancing IGF-1R expression and by stimulating IGF-2 secretion. This mechanism is required for GLP-1 to protect β-cells against apoptosis.
authors.affiliation: Department of Physiology and Center for Integrative Genomics, University of Lausanne, Génopode Building, CH-1015 Lausanne, Switzerland.
authors.forename: Marion
authors.initials: M
authors.lastname: Cornu
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D019898:Autocrine Communication / Q000235:genetics / Q000502:physiology*; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D007335:Insulin-Like Growth Factor II / Q000378:metabolism* / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D007335:Insulin-Like Growth Factor II; D052216:Glucagon-Like Peptide 1; C041086:gastric inhibitory polypeptide receptor; D017526:Receptor, IGF Type 1