{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T23:39:20Z","timestamp":1789774760650,"version":"4.0.1"},"reference-count":47,"publisher":"American Diabetes Association","issue":"10","license":[{"start":{"date-parts":[[2017,9,20]],"date-time":"2017-09-20T00:00:00Z","timestamp":1505865600000},"content-version":"vor","delay-in-days":48,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK111460"],"award-info":[{"award-number":["R01DK111460"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK112836"],"award-info":[{"award-number":["R01DK112836"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,10,1]]},"abstract":"<jats:p>Many patients with chronic pancreatitis develop diabetes (chronic pancreatitis\u2013related diabetes [CPRD]) through an undetermined mechanism. Here we used long-term partial pancreatic duct ligation (PDL) as a model to study CPRD. We found that long-term PDL induced significant \u03b2-cell dedifferentiation, followed by a time-dependent decrease in functional \u03b2-cell mass\u2014all specifically in the ligated tail portion of the pancreas (PDL-tail). High levels of transforming growth factor \u03b21 (TGF\u03b21) were detected in the PDL-tail and were mainly produced by M2 macrophages at the early stage and by activated myofibroblasts at the later stage. Loss of \u03b2-cell mass was then found to result from TGF\u03b21-triggered epithelial-mesenchymal transition (EMT) by \u03b2-cells, rather than resulting directly from \u03b2-cell apoptosis. Mechanistically, TGF\u03b21-treated \u03b2-cells activated expression of the EMT regulator gene Snail in a SMAD3\/Stat3-dependent manner. Moreover, forced expression of forkhead box protein O1 (FoxO1), an antagonist for activated Stat3, specifically in \u03b2-cells ameliorated \u03b2-cell EMT and \u03b2-cell loss and prevented the onset of diabetes in mice undergoing PDL. Together, our data suggest that chronic pancreatitis may trigger TGF\u03b21-mediated \u03b2-cell EMT to lead to CPRD, which could substantially be prevented by sustained expression of FoxO1 in \u03b2-cells.<\/jats:p>","DOI":"10.2337\/db17-0537","type":"journal-article","created":{"date-parts":[[2017,8,4]],"date-time":"2017-08-04T00:25:20Z","timestamp":1501806320000},"page":"2646-2658","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":36,"title":["SMAD3\/Stat3 Signaling Mediates \u03b2-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis\u2013Related Diabetes"],"prefix":"10.2337","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0890-9203","authenticated-orcid":false,"given":"Xiangwei","family":"Xiao","sequence":"first","affiliation":[{"name":"Division of Pediatric Surgery, Department of Surgery, Children\u2019s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane","family":"Fischbach","sequence":"additional","affiliation":[{"name":"Division of Pediatric Surgery, Department of Surgery, Children\u2019s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Pediatric Surgery, Department of Surgery, Children\u2019s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA"},{"name":"Division of Immunogenetics, Department of Pediatrics, Children\u2019s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congde","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Pediatric Surgery, Department of Surgery, Children\u2019s Hospital of Pittsburgh, University of 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