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Diabetes Care, Aug 06 2026, dc260662 | https://doi.org/10.2337/dc26-0662 The Gain-of-Function GLP1R R131Q Variant Preserves β-Cell Function and Enhances Response to GLP-1 Receptor Agonists

Hyunsuk Lee ^{1 2}, Hannah E Christie ³, Ji Seon Lee ⁴, Woo-Il Kwon ⁵, Min Kyong Moon ⁶, Sung Hee Choi ⁷, Dae Ho Lee ⁸, Seunggeun Lee ^{1 9}, Hyunbeom Lee ¹⁰, Minjung Kho ⁹, Federica Boscolo ¹¹, Chiara Dalla Man ¹¹, Nam H Cho ¹², Jaewon Choi ^{2 13}, Jeongeun Lee ², Jongseok Park ^{2 13}, Yeeun Jo ^{2 13}, Sangwon Lee ^{2 13}, Adrian Vella ³, Soo Heon Kwak ^2*, Jong-Il Kim ^{1 13*}, Kyong Soo Park ^4*

¹Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea.
²Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
³Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, MN.
⁴Department of Internal Medicine, Konkuk University Medical Center, Seoul, Republic of Korea.
⁵Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁶Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁷Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea.
⁸Division of Endocrinology and Metabolism, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea.
⁹Graduate School of Data Science, Seoul National University, Seoul, Republic of Korea.
¹⁰Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul, Republic of Korea.
¹¹Department of Information Engineering, University of Padova, Padova, Italy.
¹²Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Republic of Korea.
¹³Department of Biomedical Sciences, Seoul National University College of Medicine, Republic of Korea.

^*S.H.K., J.-I.K., and K.S.P. jointly directed this work and contributed equally as corresponding authors.

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.

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