{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T18:40:15Z","timestamp":1789584015562,"version":"build-2803163510"},"reference-count":50,"publisher":"American Society for Clinical Investigation","issue":"1","license":[{"start":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T00:00:00Z","timestamp":1767312000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01-DK073716,DK132103,DK133183"],"award-info":[{"award-number":["R01-DK073716,DK132103,DK133183"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R56-DK138005"],"award-info":[{"award-number":["R56-DK138005"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,2]]},"abstract":"<jats:p>The c-Jun N-terminal kinases (JNKs) regulate diverse physiological processes. Whereas JNK1 and JNK2 are broadly expressed and associated with insulin resistance, inflammation, and stress responses, JNK3 is largely restricted to central nervous system neurons and pancreatic \u03b2 cells, and its physiological role in \u03b2 cells remains poorly defined. To investigate its function, we generated mice lacking JNK3 specifically in \u03b2 cells (\u03b2JNK3-KO). These mice displayed glucose intolerance and defective insulin secretion, particularly after oral glucose challenge, indicating impaired incretin responses. Consistently, Exendin-4\u2013stimulated (Ex4-stimulated) insulin secretion was blunted in \u03b2JNK3-KO islets, accompanied by reduced GLP-1R expression. Similar findings were observed in human islets treated with a selective JNK3 inhibitor (iJNK3). Downstream of GLP-1R, Ex4-induced CREB phosphorylation was diminished in \u03b2JNK3-KO islets, indicating impaired canonical signaling. Moreover, activation of the GLP-1R\/CREB\/IRS2 pathway, a key regulator of \u03b2 cell survival, was reduced in \u03b2JNK3-KO islets and iJNK3-treated human islets. As a consequence, the protective effects of Ex4 were lost in cytokine-treated \u03b2JNK3-KO and human islets, and Ex4-mediated protection was partially attenuated in \u03b2JNK3-KO mice exposed to multiple low-dose streptozotocin. These findings identify JNK3 as a regulator of \u03b2 cell function and survival and suggest that targeting this pathway may enhance incretin-based therapies.<\/jats:p>","DOI":"10.1172\/jci185707","type":"journal-article","created":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T19:01:04Z","timestamp":1767294064000},"source":"Crossref","is-referenced-by-count":2,"title":["JNK3 regulates \u03b2 cell responses to incretins in human islets and mouse models"],"prefix":"10.1172","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1789-4234","authenticated-orcid":true,"given":"Ruy A.","family":"Louzada","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marel","family":"Gonzalez Medina","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Pita-Grisanti","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Bouviere","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda F.","family":"Neves","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9316-712X","authenticated-orcid":true,"given":"Joana","family":"Alma\u00e7a","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myoung Sook","family":"Han","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0130-1652","authenticated-orcid":true,"given":"Roger J.","family":"Davis","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6915-4361","authenticated-orcid":true,"given":"Gil","family":"Leibowitz","sequence":"additional","affiliation":[{"name":"Diabetes Unit and Endocrine Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1712-8233","authenticated-orcid":true,"given":"Manuel","family":"Blandino-Rosano","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9997-3301","authenticated-orcid":true,"given":"Ernesto","family":"Bernal-Mizrachi","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and"},{"name":"Veterans Affairs Medical Center, Miami, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,1,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.2337\/dc15-0144"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.11.2815"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006072"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-009-1431-7"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.49.9.1468"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-008-1169-7"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.50.1.77"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4892(03)00068-7"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M208359200"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1104649"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.2337\/db12-1097"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2005.03.020"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2209810120"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1172\/JCI18581"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1097103"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035997"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-020-03499-7"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.04.003"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.08.020"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.2337\/db23-0130"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2023.101769"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-014-3468-5"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S0303-7207(98)00028-8"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms16014"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abf1948"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M809430200"},{"issue":"17","key":"B27","doi-asserted-by":"crossref","DOI":"10.1128\/MCB.00200-19","article-title":"CREB promotes beta cell gene expression by targeting its coactivators to tissue-specific enhancers","volume":"39","author":"Van de Velde","year":"2019","journal-title":"Mol Cell Biol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1021\/jacsau.2c00130"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.00043-14"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/S1382-6689(00)00064-8"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/36116"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.03.001"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2019.109555"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.28719"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/dom.15083"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23158679"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/srep21025"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5496.1574"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03941-2"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1819230116"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.08.007"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209423200"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.09.004"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.2.365"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/1312705"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/814854"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.10031"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00076.2022"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-018-4772-2"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.13.4929-4942.2002"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/185707\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T17:05:49Z","timestamp":1779210349000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/185707"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,2]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1,2]]},"published-print":{"date-parts":[[2026,1,2]]}},"alternative-id":["10.1172\/JCI185707"],"URL":"https:\/\/doi.org\/10.1172\/jci185707","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,2]]},"article-number":"e185707"}}