The Gain-of-Function GLP1R R131Q Variant Preserves β Cell Function and Enhances Response to GLP-1 Receptor Agonists

<jats:p>&lt;p dir="ltr"&gt;Objective: Genetic variation in the glucagon-like peptide-1 receptor (GLP1R) has been implicated in type 2 diabetes (T2D) risk and treatment response. We investigated whether GLP1R R131Q, which was previously reported as a T2D-protective variant in genome-wide association studies, alters receptor signaling, β cell function and response to glucagon-like peptide-1 receptor agonists (GLP-1RAs).&lt;/p&gt;&lt;p dir="ltr"&gt;Research Design and Methods: Trajectory of β cell function was evaluated in a 20-year community-based prospective cohort in Korea (n=6,373), where participants underwent biennial 2-h 75-g oral glucose tolerance tests, and disposition index was used as surrogate marker. Pharmacogenetic response to GLP-1RAs was assessed in a hospital-based T2D cohort in Korea (n=177). Hyperglycemic clamp studies (n=17), human islet experiments (n=21) and in vitro assays were conducted to characterize GLP1R R131Q effects on receptor signaling and islet function.&lt;/p&gt;&lt;p dir="ltr"&gt;Results: GLP1R R131Q was associated with slower decline in disposition index in individuals without T2D, with reductions from baseline of 30% in homozygous carriers, 35% in heterozygotes and 37% in wild-type individuals. In people with T2D, each allele conferred an additional 0.53% or 5.8 mmol/mol reduction in HbA1c after 6 months of GLP-1RA treatment (P=5.8×10⁻⁴). Hyperglycemic clamp and human islet experiments demonstrated allele-dependent enhancement of GLP-1RA-stimulated insulin secretion (P=0.050 and P=0.037, respectively). In vitro, GLP1R R131Q increased GLP-1RA–stimulated cAMP production with directional observations consistent with pathway bias.&lt;/p&gt;&lt;p dir="ltr"&gt;Conclusions: GLP1R R131Q is a gain-of-function variant associated with preservation of β cell function and enhanced glycemic response to GLP-1RA treatment, supporting further investigation as a candidate pharmacogenetic marker for precision diabetes care.&lt;/p&gt;&lt;p&gt;&lt;br&gt;&lt;/p&gt;</jats:p>