Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

Abstract

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion from pancreatic β-cells in a glucose-dependent manner. 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 β-cells. Pretreatment of β-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 β-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 β-cells were exposed to high glucose for 18 h. Treatment of β-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 inhibitor, further augmented exe-4-induced cAMP formation and Erk phosphorylation. These results suggest that insulin contributes to fine-tuning of the β-cell response to GLP-1.

Insulin receptor signaling and glucagon-like peptide 1 effects on pancreatic beta cells

“…Our present data are somehow in contrast to those of Moon et al [ 27 ] showing that insulin signaling pathway exerts a fine negative tuning on beta cell responsiveness to GLP-1 action. The reasons for such discrepancy are not easy to understand.…”

“…The reasons for such discrepancy are not easy to understand. We can here only speculate that differences in the experimental design for obtaining abnormalities of the insulin signaling pathways, with chemicals whose specificity is far to be demonstrated being utilized in Moon’s study [ 27 ], have played a role.…”

Cyclic AMP sensor EPAC proteins and energy homeostasis

“…However, CNS-specific EPAC2A knockout models are required to test this theory. Additionally, insulin, through its receptor on β-cells of the pancreas is known to enhance GLP-1’s effect on these cells [49], and therefore, the improved insulin sensitivity might have enhanced GLP-1’s action on these cells independently of EPAC2A. Another plausible explanation is that the incretin levels released after an oGTT in mice are usually much lower [46] than those employed in the in vitro and in vivo experiments in this study [44].…”

A Novel Glucagon-Related Peptide (GCRP) and Its Receptor GCRPR Account for Coevolution of Their Family Members in Vertebrates

“…GLP1 and GLP2 are produced in the intestinal L-type endocrine cells in response to food ingestion. GLP1 stimulates insulin secretion from pancreatic β cells in a glucose-dependent manner [6], [7]. GLP2 is a nutrient-responsive growth factor that stimulates specific trophic effects in the small and large intestines [8].…”