GLP1R Single-Nucleotide Polymorphisms rs3765467 and rs10305492 Affect β Cell Insulin Secretory Capacity and Apoptosis...

Area of Science:

• Endocrinology
• Genetics
• Metabolic Surgery

Background:

• Roux-en-Y gastric bypass (RYGB) improves blood glucose, largely attributed to increased glucagon-like peptide-1 (GLP-1) secretion.
• Single-nucleotide polymorphisms (SNPs) in the GLP-1 Receptor (GLP1R) gene can compromise receptor function, impacting beta cell insulin secretion and RYGB efficacy.

Purpose of the Study:

• To investigate the functional impact of two specific GLP1R SNPs (rs3765467 and rs10305492) on pancreatic beta cell function and apoptosis.
• To determine how these SNPs affect glucose-stimulated insulin secretion and beta cell viability under high glucose conditions.

Main Methods:

• Analysis of GLP1R gene SNPs rs3765467 and rs10305492 in relation to beta cell insulin secretion and cyclic AMP levels.
• Assessment of beta cell apoptosis and viability under high glucose exposure.
• Evaluation of the effects of GLP-1 antagonist Exendin (9-39) and GLP-1 agonist Exendin-4 on SNP-affected beta cells.

Main Results:

• The GLP1R SNPs rs3765467 and rs10305492 significantly reduced insulin secretion and cyclic AMP concentration in beta cells, while promoting apoptosis.
• These SNPs impaired beta cell insulin secretion and viability under high glucose conditions.
• GLP-1 antagonist Exendin (9-39) exacerbated SNP effects, whereas GLP-1 agonist Exendin-4 partially mitigated them.

Conclusions:

• GLP1R SNPs rs3765467 and rs10305492 critically affect beta cell insulin secretory capacity and mass.
• These genetic variations may impair GLP-1 interaction with GLP1R, leading to beta cell dysfunction and apoptosis, thus potentially attenuating the therapeutic benefits of RYGB.