title: Exendin-(9-39) is an inverse agonist of the murine glucagon-like peptide-1 receptor: implications for basal intracellular cyclic adenosine 3',5'-monophosphate levels and beta-cell glucose competence.
abstract: The effect of exendin-(9-39), a described antagonist of the glucagon-like peptide-1 (GLP-1) receptor, was evaluated on the formation of cAMP- and glucose-stimulated insulin secretion (GSIS) by the conditionally immortalized murine betaTC-Tet cells. These cells have a basal intracellular cAMP level that can be increased by GLP-1 with an EC50 of approximately 1 nM and can be decreased dose dependently by exendin-(9-39). This latter effect was receptor dependent, as a beta-cell line not expressing the GLP-1 receptor was not affected by exendin-(9-39). It was also not due to the endogenous production of GLP-1, because this effect was observed in the absence of detectable preproglucagon messenger RNA levels and radioimmunoassayable GLP-1. Importantly, GSIS was shown to be sensitive to this basal level of cAMP, as perifusion of betaTC-Tet cells in the presence of exendin-(9-39) strongly reduced insulin secretion. This reduction of GSIS, however, was observed only with growth-arrested, not proliferating, betaTC-Tet cells; it was also seen with nontransformed mouse beta-cells perifused in similar conditions. These data therefore demonstrated that 1) exendin-(9-39) is an inverse agonist of the murine GLP-1 receptor; 2) the decreased basal cAMP levels induced by this peptide inhibit the secretory response of betaTC-Tet cells and mouse pancreatic islets to glucose; 3) as this effect was observed only with growth-arrested cells, this indicates that the mechanism by which cAMP leads to potentiation of insulin secretion is different in proliferating and growth-arrested cells; and 4) the presence of the GLP-1 receptor, even in the absence of bound peptide, is important for maintaining elevated intracellular cAMP levels and, therefore, the glucose competence of the beta-cells.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Lausanne, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Serre
authors.forename: W
authors.initials: W
authors.lastname: Dolci
authors.forename: E
authors.initials: E
authors.lastname: Schaerer
authors.forename: L
authors.initials: L
authors.lastname: Scrocchi
authors.forename: D
authors.initials: D
authors.lastname: Drucker
authors.forename: S
authors.initials: S
authors.lastname: Efrat
authors.forename: B
authors.initials: B
authors.lastname: Thorens
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D005934:Glucagon / Q000096:biosynthesis / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D052336:Proglucagon; D011498:Protein Precursors / Q000096:biosynthesis / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D018027:Receptors, Glucagon / Q000819:agonists*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D008024:Ligands; D010446:Peptide Fragments; D011498:Protein Precursors; D018027:Receptors, Glucagon; C083773:exendin (9-39); D052336:Proglucagon; D012313:RNA; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D005947:Glucose