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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 ß-Cell Glucose Competence¹

Institute of Pharmacology and Toxicology, University of Lausanne (V.S., W.D., E.S., B.T.), CH-1005 Lausanne, Switzerland; the Department of Molecular Pharmacology, Albert Einstein College of Medicine (S.E.), Bronx, New York 10461; and the Endocrine Division, The Toronto Hospital (L.S., D.D.), Toronto, Ontario, Canada M5G 2C4

Address all correspondence and requests for reprints to: Dr. Bernard Thorens, Institute of Pharmacology and Toxicology, 27 rue du Bugnon, CH-1005 Lausanne, Switzerland. E-mail: bernard.thorens{at}ipharm.unil.ch

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 ßTC-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 ß-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 ßTC-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, ßTC-Tet cells; it was also seen with nontransformed mouse ß-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 ßTC-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 ß-cells.

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