{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T07:57:16Z","timestamp":1785571036373,"version":"3.56.0"},"reference-count":39,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["#32470636"],"award-info":[{"award-number":["#32470636"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["#ZR2024MH031"],"award-info":[{"award-number":["#ZR2024MH031"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Diabetes Invest"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Objectives<\/jats:title>\n                    <jats:p>Clinical research indicates an association between hyperuricemia (HU) and diabetes; however, the precise impact of soluble serum urate on glucose metabolism is still unclear. Using a novel spontaneous HU mouse model, this study seeks to characterize glucose metabolism and elucidate the associated molecular mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We employed targeted disruption of the\n                      <jats:italic>Uricase<\/jats:italic>\n                      (\n                      <jats:italic>Uox<\/jats:italic>\n                      ) gene and established an original mouse model exhibiting a robust spontaneous HU phenotype. To seek the candidate gene(s) in the proapoptosis process in pancreatic \u03b2 cells, we analyzed the microarray data of the isolated islets from\n                      <jats:italic>Uox<\/jats:italic>\n                      knockout (KO) mice and wild\u2010type counterparts. Apoptosis levels and expression of associated proteins in MIN6 cells transfected with candidate siRNA were quantified by flow cytometry and Western blotting, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Male\n                      <jats:italic>Uox<\/jats:italic>\n                      \u2010KO mice exhibited glucose intolerance without concomitant insulin resistance. TUNEL staining showed an elevated apoptosis level in pancreatic tissues of male\n                      <jats:italic>Uox<\/jats:italic>\n                      \u2010KO mice. Microarray analysis identified neuregulin\u20104 (\n                      <jats:italic>Nrg4<\/jats:italic>\n                      ) as a potential mediator of hyperuricemia (HU)\u2010induced \u03b2\u2010cell apoptosis.\n                      <jats:italic>In vitro<\/jats:italic>\n                      studies using the mouse \u03b2\u2010cell line MIN6 demonstrated that urate upregulates Nrg4 expression and triggers apoptosis, with Nrg4 being essential for urate\u2010induced cell death. Mechanistically, urate promotes pancreatic \u03b2\u2010cell apoptosis by elevating Nrg4, which subsequently amplifies urate\u2010induced mitogen\u2010activated protein kinase (MAPK) activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings collectively establish that HU disrupts glucose homeostasis and induces pancreatic \u03b2\u2010cell apoptosis via Nrg4 upregulation and subsequent amplification of the MAPK signaling cascade.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jdi.70348","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T13:05:49Z","timestamp":1780664749000},"page":"1257-1267","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuregulin 4\u2010dependent\n                    <scp>MAPK<\/scp>\n                    amplification mediates urate\u2010induced \u03b2\u2010cell dysfunction"],"prefix":"10.1111","volume":"17","author":[{"given":"Yunyang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism The Affiliated Hospital of Qingdao University  Qingdao China"},{"name":"Shandong Provincial Clinical Research Center for Immune Diseases and Gout and Qingdao Key Laboratory of Gout The Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism Yantai Yeda Hospital  Yantai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Medical Research Center The Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1277-4364","authenticated-orcid":false,"given":"Shuhui","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The Affiliated Hospital of Qingdao University  Qingdao China"},{"name":"Shandong Provincial Clinical Research Center for Immune Diseases and Gout and Qingdao Key Laboratory of Gout The Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1085-7640","authenticated-orcid":false,"given":"Yiru","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The Affiliated Hospital of Qingdao University  Qingdao China"},{"name":"Shandong Provincial Clinical Research Center for Immune Diseases and Gout and Qingdao Key Laboratory of Gout The Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The Affiliated Hospital of Qingdao University  Qingdao China"},{"name":"Shandong Provincial Clinical Research Center for Immune Diseases and Gout and Qingdao Key Laboratory of Gout The Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The Affiliated Hospital of Qingdao University  Qingdao China"},{"name":"Shandong Provincial Clinical Research Center for Immune Diseases and Gout and Qingdao Key Laboratory of Gout The Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2886-8285","authenticated-orcid":false,"given":"Jie","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The Affiliated Hospital of Qingdao University  Qingdao China"},{"name":"Shandong Provincial Clinical Research Center for Immune Diseases and Gout and Qingdao Key Laboratory of Gout The Affiliated Hospital of Qingdao University  Qingdao China"},{"name":"Medical Research Center The Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00569-9"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41256-020-00178-9"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-024-01295-3"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38918"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2016.06.041"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.2337\/db14-0742"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2013.1064"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-2595"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12013-015-0597-5"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2017.04.031"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.931087"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.653819"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/15257770.2013.865742"},{"key":"e_1_2_8_15_1","article-title":"Lepr(db) mouse model of type 2 diabetes: Pancreatic islet isolation and live\u2010cell 2\u2010photon imaging of intact islets","volume":"99","author":"Do OH","year":"2015","journal-title":"J Vis Exp"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-39824-2_3"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2500"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072682"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2013.97"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2016.06.011"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0067759"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/7523960"},{"key":"e_1_2_8_23_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0179482","article-title":"The association between serum uric acid and the incidence of prediabetes and type 2 diabetes mellitus: The Rotterdam study","volume":"12","author":"Schaft N","year":"2017","journal-title":"PLoS One"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.2337\/db19-0704"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2016.04.007"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.2870"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-017-1324-3"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.crstbi.2020.06.001"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2022.170748"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1202631"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4827(02)00102-7"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.42"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2368"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0078284"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2013.04.027"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-016-0158-6"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005050572"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00600.2006"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000072820.07472.3B"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1791"}],"container-title":["Journal of Diabetes Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jdi.70348","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jdi.70348","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jdi.70348","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T06:58:23Z","timestamp":1785567503000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jdi.70348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,5]]},"references-count":39,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1111\/jdi.70348"],"URL":"https:\/\/doi.org\/10.1111\/jdi.70348","archive":["Portico"],"relation":{},"ISSN":["2040-1116","2040-1124"],"issn-type":[{"value":"2040-1116","type":"print"},{"value":"2040-1124","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,5]]},"assertion":[{"value":"2025-11-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}