28-OR: GLP1R R131Q is a Gs-Biased Gain-of-Function Variant Associated with Preservation of β-Cell Function

by sugaradmin



Introduction and Objective:GLP1R R131Q (rs3765467) has been reported as a type 2 diabetes protective variant in genome-wide association studies and glucagon-like peptide-1 receptor (GLP1R) activation has been shown to have various β cell protective effects. We hypothesized that the variant induces a gain-of-function change enhancing the β cell protective effects mediated by GLP1R activation.Methods: We performed real-time luminescence assays in GLP1R expressing human embryonic kidney 293 (HEK293) cells to measure cAMP and protein-protein interaction (PPI). We analyzed 6,312 participants without T2D at baseline from Ansan Ansung cohort, who underwent biennial 75 g 2 h oral glucose tolerance tests for 18 years. Trajectory of disposition index (DI), a marker for β cell function, was assessed using linear mixed model.Results:GLP1R R131Q expressing HEK293 cells had similar surface expression compared to wild-type but showed larger total cAMP production, measured by area under the curve, upon exendin-4 (Ex4) stimulation (1.6 fold in Emax, P < 0.001). The slopes indicated a faster cAMP production rate by the variant, and PPI assays demonstrated increased mini-Gs coupling and reduced β-arrestin-2 recruitment. Stimulation with GLP-1 and semaglutide similarly showed larger total cAMP production. In the Ansan Ansung cohort, while baseline DI levels were similar, individuals homozygous for the GLP1R R131Q variant (N=242) had a slower decline in DI, with 1.18-fold higher DI at the end of follow-up compared to non-carriers (N=4012) and heterozygous carriers (N=2058) in the recessive model (P=0.039). This significant difference was not observed in additive or dominant analyses.Conclusion: Functional characterization of GLP1R R131Q demonstrated a gain-of-function of the receptor with Gs protein-biased signaling. This functional change could have mediated enhanced β cell protective effect related with GLP1R, leading to a slower decline in DI observed in homozygous carriers.

Disclosure

H. Lee: None. H. Choi: None. S. Kwak: None. J. Kim: None. K. Park: None.



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