The effect of GLP-1 receptor antagonists and agonists on islet function in non-diabetic subjects with the GLP1R polymorphism at rs3765467

Background and aims: Glucagon-Like Peptide-1 (GLP-1) interacts with its β-cell transmembrane receptor (GLP1R) to produce insu- lin secretion in a glucose-dependent manner. Previously the non- synonymous SNP (nsSNP) R131Q (rs3765467) in the GLP1R locus has been associated with an increased insulin secretory response to infused GLP-1. Population based studies demonstrate an association with decreased fasting glucose and decreased risk of type 2 diabetes. Although recent work has suggested that this nsSNP does not alter receptor-ligand binding affinity or cAMP production in response to GLP-1 binding, the recruitment of β-arrestin is decreased. These find- ings are increasingly relevant given the observation that intra-islet GLP-1 production supports α-cell and β-cell function in health and in diabetes. We aimed to assess the effect of rs3765467 on islet function in response to GLP1R blockade with exendin 9-39 or GLP1R agonism with liraglutide. Materials and methods: We studied 20 healthy individuals (age=45±5 years, BMI=27±1 kg/m2, fasting glucose 5.1 ± 0.1 mmol/L) on three occasions in random order. Half of the subjects were heterozygous or homozygous for the minor allele (CT/TT) at rs3765467 while the remainder were homozygous for the major allele (CC). Subject groups were matched for age, BMI, sex and fasting glu- cose. On each occasion after an overnight fast, subjects were studied using a hyperglycemic clamp. A variable infusion maintained periph- eral glucose concentrations at 160 mg/dl for 180 minutes. On one occasion, saline was infused from -120 min to the end of the study (180 min - Saline Day); on another Exendin 9-39 was infused from -120 to 180 min @ 300pmol/kg/min (Exendin Day); on the other day liraglutide 0.6mg was administered by subcutaneous injection at -120 min (Liraglutide Day). Results: Liraglutide lowered fasting glucose significantly in both groups. GLP1R blockade with exendin 9-39 raised fasting glucose (Fig. 1, Panel A: One-way ANOVA (* P < 0.05) and a Tukey’s post- hoc test (ο P < 0.05) was used to determine within-group differences) and decreased fasting insulin secretion in subjects with 1 or 2 copies of the minor allele (CT/TT) at rs3765467. Exendin 9-39 did not alter fasting glucose in those with the CC genotype (Fig. 1, Panel B). No between group differences were observed during the hyperglycemic clamp in response to either exendin 9-39 or liraglutide. Conclusion: The T allele at rs3765467 increases responsiveness of GLP1R to its endogenous ligand. These effects are relevant to the fasting state and less apparent when the islet is stimulated by hyper- glycemia or liraglutide.