GLP1R Single-Nucleotide Polymorphisms rs3765467 and rs10305492 Affect β Cell Insulin Secretory Capacity and Apoptosis Through GLP-1

The increased secretion of glucagon-like peptide-1 (GLP-1) after Roux-en-Y gastric bypass (RYGB) is regarded as the main reason for the improvement of blood glucose. However, the single-nucleotide polymorphisms (SNPs) of GLP-1 Receptor (GLP1R) impair receptor function, subsequently affecting β cell insulin secretion function, ultimately affecting the efficacy of RYGB. In this study, we revealed that two SNPs in GLP1R gene, rs3765467 and rs10305492, could significantly reduce the insulin secreted by β cells and the cyclic AMP concentration, whereas promote β cell apoptosis. Under high glucose exposure, rs3765467 and rs10305492 impaired β cell secretion of insulin and β cell viability in the same way; in other words, GLP1R rs3765467 and rs10305492 exert an effect on pancreatic β cell glucose-stimulated insulin secretion. Moreover, GLP-1 antagonist Exendin (9-39) further enhanced, whereas GLP-1 agonist Exendin-4 partially attenuated the effects of SNPs on the functions and apoptosis of β cells. In conclusion, the rs3765467 and rs10305492 SNPs in GLP1R show to exert a critical effect on regulating insulin secretory capacity of β cells and β cell mass. Through leading to the dysfunction and apoptosis of β cells, GLP1R rs3765467 and rs10305492 might also impair GLP-1 interaction with GLP1R, therefore attenuating the therapeutic effect of RYGB.