Association of GLP1R Polymorphisms With the Incretin Response

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-naive 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.