{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T16:32:59Z","timestamp":1792773179382,"version":"4.5.0"},"reference-count":37,"publisher":"American Diabetes Association","issue":"11","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"name":"SNU-SNUH Physician Scientist Training Program","award":["800-20240636"],"award-info":[{"award-number":["800-20240636"]}]},{"DOI":"10.13039\/501100003569","name":"Ministry of Food and Drug Safety","doi-asserted-by":"publisher","award":["23212MFDS202"],"award-info":[{"award-number":["23212MFDS202"]}],"id":[{"id":"10.13039\/501100003569","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK126206, DK78646, DK116231, DK126206 and DK126206"],"award-info":[{"award-number":["DK126206, DK78646, DK116231, DK126206 and DK126206"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["RS-2023-00262002"],"award-info":[{"award-number":["RS-2023-00262002"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["MD-PhD\/Medical Scientist Training Program"],"award-info":[{"award-number":["MD-PhD\/Medical Scientist Training Program"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["RS-2026-25516569"],"award-info":[{"award-number":["RS-2026-25516569"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2020R1A6A1A03047972"],"award-info":[{"award-number":["2020R1A6A1A03047972"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,11,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>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, \u03b2-cell function, and response to glucagon-like peptide 1 receptor agonists (GLP-1RAs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>Trajectory of \u03b2-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\u00a0vitro assays were conducted to characterize GLP1R R131Q effects on receptor signaling and islet function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>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\u2009\u00d7\u200910\u22124). Hyperglycemic clamp and human islet experiments demonstrated allele-dependent enhancement of GLP-1RA\u2013stimulated insulin secretion (P = 0.050 and P = 0.037, respectively). In vitro, GLP1R R131Q increased GLP-1RA\u2013stimulated cAMP production with directional observations consistent with pathway bias.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>GLP1R R131Q is a gain-of-function variant associated with preservation of \u03b2-cell function and enhanced glycemic response to GLP-1RA treatment, supporting further investigation as a candidate pharmacogenetic marker for precision diabetes care.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc26-0662","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T20:01:26Z","timestamp":1786046486000},"page":"1982-1990","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":1,"title":["The Gain-of-Function\n                    <i>GLP1R<\/i>\n                    R131Q Variant Preserves \u03b2-Cell Function and Enhances Response to GLP-1 Receptor Agonists"],"prefix":"10.2337","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9751-5868","authenticated-orcid":false,"given":"Hyunsuk","family":"Lee","sequence":"first","affiliation":[{"name":"Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine 1 , Seoul, Republic of Korea"},{"name":"Department of Internal Medicine, Seoul National University Hospital 2 , Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0606-6778","authenticated-orcid":false,"given":"Hannah E.","family":"Christie","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine 3 , Rochester, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Seon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Konkuk University Medical Center 4 , Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo-Il","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine 5 , Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5460-2846","authenticated-orcid":false,"given":"Min Kyong","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul Metropolitan Government\u2013Seoul National University Boramae Medical Center, Seoul National University College of Medicine 6 , Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0740-8116","authenticated-orcid":false,"given":"Sung Hee","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine 7 , Seongnam, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8832-3052","authenticated-orcid":false,"given":"Dae Ho","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Gachon University Gil Medical Center 8 , Gachon University College of Medicine, Incheon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seunggeun","family":"Lee","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine 1 , Seoul, Republic of Korea"},{"name":"Graduate School of Data Science, Seoul National University 9 , Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunbeom","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology 10 , Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjung","family":"Kho","sequence":"additional","affiliation":[{"name":"Graduate School of Data Science, Seoul National University 9 , Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0545-7288","authenticated-orcid":false,"given":"Federica","family":"Boscolo","sequence":"additional","affiliation":[{"name":"Department of Information Engineering, University of Padova 11 , Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4908-0596","authenticated-orcid":false,"given":"Chiara","family":"Dalla Man","sequence":"additional","affiliation":[{"name":"Department of Information Engineering, University of Padova 11 , Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4551-7591","authenticated-orcid":false,"given":"Nam H.","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, Ajou University School of Medicine 12 , Suwon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3735-625X","authenticated-orcid":false,"given":"Jaewon","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Hospital 2 , Seoul, Republic of Korea"},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine 13 , Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongeun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Hospital 2 , Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jongseok","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Hospital 2 , Seoul, Republic of Korea"},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine 13 , Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeeun","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Hospital 2 , Seoul, Republic of Korea"},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine 13 , Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangwon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Hospital 2 , Seoul, Republic of Korea"},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine 13 , Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6493-7837","authenticated-orcid":false,"given":"Adrian","family":"Vella","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine 3 , Rochester, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1230-0919","authenticated-orcid":false,"given":"Soo Heon","family":"Kwak","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Hospital 2 , Seoul, Republic of 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