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

Authors

Hyunsuk Lee, Hannah E Christie, Ji Seon Lee, Woo-Il Kwon, Min Kyong Moon, Sung Hee Choi, Dae Ho Lee, Seunggeun Lee, Hyunbeom Lee, Minjung Kho, Federica Boscolo, Chiara Dalla Man, Nam H Cho, Jaewon Choi, Jeongeun Lee, Jongseok Park, Yeeun Jo, Sangwon Lee, Adrian Vella, Soo Heon Kwak, Jong-Il Kim, Kyong Soo Park

Published in

Diabetes care. Aug 06, 2026. Epub Aug 06, 2026.

Abstract

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).
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.
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.
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.

PMID:
42561183
Bibliographic data and abstract were imported from PubMed on 07 Aug 2026.

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