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

Abstract

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 <i>GLP1R</i> 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, <i>GLP1R</i> 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 <i>GLP1R</i> 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, <i>GLP1R</i> rs3765467 and rs10305492 might also impair GLP-1 interaction with GLP1R, therefore attenuating the therapeutic effect of RYGB.