cAMP is required for normal glucose-induced insulin release by pancreatic β-cells. In a previous study, we showed that cAMP production in β-cells depends on the expression of receptors for glucagon, glucagon-like peptide 1(7-36) amide [GLP-1(7-36) amide], and glucose- dependent insulinotropic polypeptide. Although the latter two peptides are thought to amplify mealinduced insulin release (incretin effect), the role of glucagon in the regulation of insulin release remains elusive. In the present study, we analyzed the interaction of glucagon with its own receptor and with the glucagon-like peptide 1 (GLP-1) receptor using purified rat β-cells. Glucagon binding was partially displaced by 1 μmol/1 des-His1-[Glu9]glucagon-amide, a glucagon receptor antagonist, and by 1 μmol/1 GLP-1. Conversely, GLP-1 binding was competitively inhibited by high glucagon concentrations (Ki = 0.3 μmol/1). Glucagoninduced cAMP production in β-cells was inhibited both by 1 μmol/1 des-His1-[Glu9]glucagon-amide and exendin-(9-39)-amide, a specific GLP-1 receptor antagonist, whereas GLP-1-induced cAMP formation was suppressed only by exendin-(9-39)-amide. Finally, addition of 1 βmol/1 exendin-(9-39)-amide to 20 mmol/1 glucosestimulated β-cells did not antagonize the potentiating effect of 1 nmol/1 glucagon, although it prevented 45% of glucagon potentiation when the peptide was administered at 10 nmol/1. Our data suggest that glucagon recognition via two distinct receptors allows pancreatic β-cells to detect this peptide both when diluted in the systemic circulation and when concentrated as local signal in the islet interstitium.

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