Glucagon-like peptide-1 (GLP-1) stimulates insulin secre-tion from pancreatic ?-cells in a glucose-dependent man-ner. However, factors other than glucose that regulate the β-cell response to GLP-1 remain poorly understood. In this study, we examined the possible involvement of insulin and receptor tyrosine kinase signaling in regulation of the GLP-1 responsiveness of beta-cells. Pretreatment of beta-cells with HNMPA, an insulin receptor inhibitor, and AG1478, an epidermal growth factor receptor inhibitor, further increased the cAMP level and Erk phosphorylation in the presence of exendin-4 (exe-4), a GLP-1 agonist. When beta-cells were exposed to a high concentration of glucose (25 mM), which stimulates insulin secretion, exe-4-induced cAMP formation declined gradually as exposure time was increased. This decreased cAMP formation was not observed in the presence of HNMPA. HNMPA was able to further increase the exe-4-induced insulin secretion when beta-cells were exposed to high glucose for 18 h. Treatment of beta-cells with insulin significantly decreased exe-4-induced cAMP formation in a dose-dependent manner. Lowering the phospho-Akt level by HNMPA or LY294002, a PI3K in-hibitor, further augmented exe-4-induced cAMP forma-tion and Erk phosphorylation. These results suggest that insulin contributes to fine-tuning of the beta-cell response to GLP-1.

Keywords: beta-cells, cAMP, Erk, GLP-1, insulin, RTK