Association of GLP1R Polymorphisms With the Incretin Response

Abstract

Context: Polymorphisms in the gene encoding the glucagon-like peptide-1 receptor (GLP1R) are associated with type 2 diabetes but their effects on incretin levels remain unclear. Objective: We evaluated the physiologic and hormonal effects of GLP1R genotypes before and after interventions that influence glucose physiology. Design: Pharmacogenetic study conducted at 3 academic centers in Boston, Massachusetts. Participants: A total of 868 antidiabetic drug-naïve participants with type 2 diabetes or at risk for developing diabetes. Interventions: We analyzed 5 variants within GLP1R (rs761387, rs10305423, rs10305441, rs742762, and rs10305492) and recorded biochemical data during a 5-mg glipizide challenge and a 75-g oral glucose tolerance test (OGTT) following 4 doses of metformin 500 mg over 2 days. Main Outcomes: We used an additive mixed-effects model to evaluate the association of these variants with glucose, insulin, and incretin levels over multiple timepoints during the OGTT. Results: During the OGTT, the G-risk allele at rs761387 was associated with higher total GLP-1 (2.61 pmol/L; 95% CI, 1.0.72-4.50), active GLP-1 (2.61 pmol/L; 95% CI, 0.04-5.18), and a trend toward higher glucose (3.63; 95% CI, -0.16 to 7.42 mg/dL) per allele but was not associated with insulin. During the glipizide challenge, the G allele was associated with higher insulin levels per allele (2.01 IU/mL; 95% CI, 0.26-3.76). The other variants were not associated with any of the outcomes tested. Conclusions: GLP1R variation is associated with differences in GLP-1 levels following an OGTT load despite no differences in insulin levels, highlighting altered incretin signaling as a potential mechanism by which GLP1R variation affects T2D risk.