{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:20:00Z","timestamp":1791811200659,"version":"4.3.4"},"reference-count":35,"publisher":"American Society for Clinical Investigation","issue":"1","license":[{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research","award":["16K09752,20K08887,19H03710,19K07506"],"award-info":[{"award-number":["16K09752,20K08887,19H03710,19K07506"]}]},{"DOI":"10.13039\/501100008644","name":"Japan Diabetes Society","doi-asserted-by":"crossref","award":["Junior Scientist Development Grant"],"award-info":[{"award-number":["Junior Scientist Development Grant"]}],"id":[{"id":"10.13039\/501100008644","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Japan Foundation Applied Enzymology","award":["Grant for Front Runner of Future Diabetes Research"],"award-info":[{"award-number":["Grant for Front Runner of Future Diabetes Research"]}]},{"DOI":"10.13039\/100016573","name":"Japan Association for Diabetes Education and Care","doi-asserted-by":"crossref","award":["Grants for young researchers"],"award-info":[{"award-number":["Grants for young researchers"]}],"id":[{"id":"10.13039\/100016573","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100013236","name":"MSD Life Science Foundation, Public Interest Incorporated Foundation","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100013236","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,11]]},"abstract":"<jats:p>Dedifferentiation has been implicated in \u03b2 cell dysfunction and loss in rodent diabetes. However, the pathophysiological significance in humans remains unclear. To elucidate this, we analyzed surgically resected pancreatic tissues of 26 Japanese subjects with diabetes and 11 nondiabetic subjects, who had been overweight during adulthood but had no family history of diabetes. The diabetic subjects were subclassified into 3 disease stage categories, early, advanced, and intermediate. Despite no numerical changes in endocrine cells immunoreactive for chromogranin A (ChgA), diabetic islets showed profound \u03b2 cell loss, with an increase in \u03b1 cells without an increase in insulin and glucagon double-positive cells. The proportion of dedifferentiated cells that retain ChgA immunoreactivity without 4 major islet hormones was strikingly increased in diabetic islets and rose substantially during disease progression. The increased dedifferentiated cell ratio was inversely correlated with declining C-peptide index. Moreover, a subset of islet cells converted into exocrine-like cells during disease progression. These results indicate that islet remodeling with dedifferentiation is the underlying cause of \u03b2 cell failure during the course of diabetes progression in humans.<\/jats:p>","DOI":"10.1172\/jci.insight.143791","type":"journal-article","created":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T14:01:27Z","timestamp":1610287287000},"source":"Crossref","is-referenced-by-count":61,"title":["Islet cell dedifferentiation is a pathologic mechanism of long-standing progression of type 2 diabetes"],"prefix":"10.1172","volume":"6","author":[{"given":"Kikuko","family":"Amo-Shiinoki","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Department of Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan."},{"name":"Department of Diabetes Research, Yamaguchi University School of Medicine, Ube, Yamaguchi, 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, Department of Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0192-7791","authenticated-orcid":true,"given":"Yoshinobu","family":"Hoshii","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Pathology, Yamaguchi University Hospital, Ube, Yamaguchi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3588-8751","authenticated-orcid":true,"given":"Hiroto","family":"Matsui","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risa","family":"Harano","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Department of Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takato","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryotaro","family":"Bouchi","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan."},{"name":"Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tokiyo","family":"Takagi","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Department of Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Hatanaka","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Department of Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komei","family":"Takeda","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Department of Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4405-3193","authenticated-orcid":true,"given":"Shigeru","family":"Okuya","sequence":"additional","affiliation":[{"name":"Health Administration Center, Yamaguchi University Organization for University Education, Yamaguchi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8068-1277","authenticated-orcid":true,"given":"Wataru","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, International University of Health and Welfare School of Medicine, Chiba, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5301-3847","authenticated-orcid":true,"given":"Atsushi","family":"Kudo","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7718-3453","authenticated-orcid":true,"given":"Shinji","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Tanabe","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Akashi","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0834-2836","authenticated-orcid":true,"given":"Yoshihiro","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan."},{"name":"Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan."},{"name":"Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan."},{"name":"AMED-CREST, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Nagano","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukio","family":"Tanizawa","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Department of Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2021,1,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.12031"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60614-4"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)07019-6"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)07037-8"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1210\/er.2007-0023"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI29103"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.1.102"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-2018"},{"issue":"suppl 4","key":"B9","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.1463-1326.2008.00969.x","article-title":"Pancreatic beta-cell mass in European subjects with type 2 diabetes","volume":"10","author":"Rahier","year":"2008","journal-title":"Diabetes Obes Metab"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-009-1321-z"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1172\/JCI83657"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.07.029"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.03.010"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-2860"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-013-3098-3"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.2337\/db14-1752"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-00968"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2337\/dc16-0619"},{"issue":"suppl 1","key":"B19","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/dom.12727","article-title":"Pancreatic \u03b2-cell identity in diabetes","volume":"18","author":"Remedi","year":"2016","journal-title":"Diabetes Obes Metab"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-0705"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.2337\/db13-1013"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.2337\/db18-0856"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1172\/JCI65390"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-3832"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.08.010"},{"key":"B26","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms12631","article-title":"Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic \u03b2 cells in diabetic mice","volume":"7","author":"Kim-Muller","year":"2016","journal-title":"Nat Commun"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2007.08.014"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-1374"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-48-6-999"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.2337\/db16-1213"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2010.04.009"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60762-X"},{"issue":"4","key":"B33","doi-asserted-by":"crossref","DOI":"10.1210\/clinem\/dgz224","article-title":"Paraneoplastic \u03b2 cell dedifferentiation in nondiabetic patients with pancreatic cancer","volume":"105","author":"Wang","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/j.2040-1124.2010.00074.x"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2006.03.030"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/143791\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:49:13Z","timestamp":1779151753000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/143791"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,11]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1,11]]},"published-print":{"date-parts":[[2021,1,11]]}},"alternative-id":["10.1172\/jci.insight.143791"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.143791","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,11]]},"article-number":"e143791"}}