{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T06:01:59Z","timestamp":1786946519286,"version":"build-2736575974"},"reference-count":44,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"786","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,2,19]]},"abstract":"<jats:p>\n            Insulin-dependent diabetes in patients with Wolfram syndrome (WS; OMIM 222300) has been linked to endoplasmic reticulum (ER) stress caused by\n            <jats:italic>WFS1<\/jats:italic>\n            gene mutations. However, the pathological process of ER stress\u2013associated \u03b2 cell failure remains to be fully elucidated. Our results indicate loss of \u03b2 cell lineage and subsequent dedifferentiation as the mechanisms underlying functional and mass deficits in WS. An immunohistochemical analysis of human pancreatic sections from deceased individuals with WS revealed a near-complete loss of \u03b2 cells and subsequent decrease in \u03b1 cells, suggesting loss of endocrine function.\n            <jats:italic>Wfs1<\/jats:italic>\n            -deficient mice displayed dysfunction, gradual loss, and dedifferentiation of \u03b2 cells, leading to permanent hyperglycemia. Impairment of the \u03b2 cell lineage was observed after weaning, leading to the mixed phenotype of insulin- and glucagon-producing cells in a subset of the lineage-traced \u03b2 cells. Islets of\n            <jats:italic>Wfs1<\/jats:italic>\n            -deficient mice increased the number of dedifferentiated cells that maintained general endocrine features but were no longer reactive with antisera against pancreatic hormones. Mechanistically,\n            <jats:italic>Wfs1<\/jats:italic>\n            -null islets had a lower adenosine triphosphate content and impaired oxidative glycolysis, although mitochondrial oxidative function was maintained. The functional and metabolic alterations of WS \u03b2 cells were recovered by deletion of thioredoxin-interacting protein (Txnip), an ER stress\u2013induced protein up-regulated in\n            <jats:italic>Wfs1<\/jats:italic>\n            deficiency.\n            <jats:italic>Txnip<\/jats:italic>\n            deletion preserved functional \u03b2 cells and prevented diabetes progression in\n            <jats:italic>Wfs1<\/jats:italic>\n            -deficient mice. Together, this study deciphered pathological mechanisms of \u03b2 cell dedifferentiation in \u03b2 cell failure and has implications for Txnip inhibition in WS therapy.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adp2332","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T18:58:27Z","timestamp":1739991507000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":10,"title":["\u03b2 cell dedifferentiation, the underlying mechanism of diabetes in Wolfram syndrome"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6974-8331","authenticated-orcid":true,"given":"Kikuko","family":"Amo-Shiinoki","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan."},{"name":"Department of Diabetes Research, Yamaguchi University School of Medicine, Ube, Yamaguchi 755-8505, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9802-0584","authenticated-orcid":true,"given":"Katsuya","family":"Tanabe","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, International University of Health and Welfare School of Medicine, Narita, Chiba 286-8686, Japan."},{"name":"Department of Anatomy, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Hatanaka","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1392-016X","authenticated-orcid":true,"given":"Manabu","family":"Kondo","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syota","family":"Kagawa","sequence":"additional","affiliation":[{"name":"Department of Natural Products Chemistry, Daiichi University of Pharmacy, Fukuoka, Fukuoka 815-8511, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5833-530X","authenticated-orcid":true,"given":"Meng","family":"Zou","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5547-9491","authenticated-orcid":true,"given":"Shuntaro","family":"Morikawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiko","family":"Sato","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan."},{"name":"Department of Internal Medicine, Matsumoto City Hospital, Matsumoto, Nagano 390-1401, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuhisa","family":"Komatsu","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2920-582X","authenticated-orcid":true,"given":"Hiroki","family":"Mizukami","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6921-1768","authenticated-orcid":true,"given":"Naoki","family":"Nishida","sequence":"additional","affiliation":[{"name":"Department of Legal Medicine, Faculty of Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6661-9402","authenticated-orcid":true,"given":"Shun-Ichiro","family":"Asahara","sequence":"additional","affiliation":[{"name":"Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7633-2827","authenticated-orcid":true,"given":"Hiroshi","family":"Masutani","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, Faculty of Health Care, Tenri University, Tenri, Nara 632-0018, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4742-8245","authenticated-orcid":true,"given":"Yukio","family":"Tanizawa","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)92473-6"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1021875403463"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/2441"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg214"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.5.477"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu499"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaq1380"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M507426200"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27344-y"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh125"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-005-1947-4"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-018-4679-y"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-009-1270-6"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.12.2.135"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-015-0702-6"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39678"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl081"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41374-020-0408-5"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq568"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12631"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36315-4"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.03.005"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-014-3464-9"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.3390\/antiox9080765"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.2337\/db11-0955"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1127"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2008-0646"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3287"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-023-05905-8"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-2240"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.07.029"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.05-4439fje"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.127.11.2317"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-213X-1-4"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.143791"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.4103\/0019-509X.12345"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.16.5624-5630.2001"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.05.004"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1021\/ac990976y"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1021\/ac020064n"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1021\/pr034020m"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-009-0178-y"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adp2332","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T10:29:56Z","timestamp":1744885796000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adp2332"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,19]]},"references-count":44,"journal-issue":{"issue":"786","published-print":{"date-parts":[[2025,2,19]]}},"alternative-id":["10.1126\/scitranslmed.adp2332"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adp2332","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,19]]},"assertion":[{"value":"2024-03-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-06","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadp2332"}}