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

Endocrinology. 1998 Nov;139(11):4448-54. doi: 10.1210/endo.139.11.6295.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Northern
  • Cell Line
  • Cyclic AMP / metabolism*
  • Glucagon / biosynthesis
  • Glucagon / metabolism
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptide-1 Receptor
  • Glucose / metabolism*
  • Islets of Langerhans / metabolism*
  • Ligands
  • Mice
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology*
  • Proglucagon
  • Protein Precursors / biosynthesis
  • Protein Precursors / metabolism
  • RNA / biosynthesis
  • RNA / isolation & purification
  • Receptors, Glucagon / agonists*


  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Ligands
  • Peptide Fragments
  • Protein Precursors
  • Receptors, Glucagon
  • exendin (9-39)
  • Proglucagon
  • RNA
  • Glucagon-Like Peptide 1
  • Glucagon
  • Cyclic AMP
  • Glucose