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Together, they may account for more cases of diabetes than autoimmune type 1 diabetes. All forms of pancreatogenic (type 3c) diabetes are characterised by impaired insulin secretion but maintenance of significant islet beta cell mass, even in the presence of virtually complete destruction of the exocrine component of the gland. Pancreatic ductal injury and associated fibrosis are common features in chronic pancreatitis, cystic fibrosis and ductal adenocarcinoma. Increased peri-ductal fibrosis is also seen in type 2 and type 1 diabetes. Here, we review the literature regarding a potential common aetiological role of pancreatic fibrosis in the pathogenesis of type 3c, type 2 and type 1 diabetes. A vicious profibrotic signalling cycle involving injured ducts, pancreatic stellate cells and macrophages with increased levels of pancreatic tissue TGF-\u03b2 at the core has increasingly been recognised as an essential driver of pancreatic exocrine fibrosis. We propose a second diabetogenic perpetual cycle comprising paracrine signalling between activated pancreatic stellate cells, macrophages and the islets themselves, leading to potentially reversible beta cell failure. The antifibrotic agents pirfenidone and nintedanib, thought to work primarily through suppression of TGF-\u03b2 function, are used routinely in clinical practice for non-pancreatic indications, with a first trial in pancreatitis underway. Trials evaluating these licensed therapeutics that include primary diabetes-related endpoints and measures aiming to elucidate the underlying mechanisms of action merit consideration in type 3c diabetes and ultimately in type 2 diabetes and in combinatorial regimens in type 1 diabetes.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s00125-026-06678-6","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T09:34:37Z","timestamp":1770716077000},"page":"1118-1132","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The emerging role of pancreatic exocrine fibrosis as a common aetiological driver of islet dysfunction and diabetes: opportunities for novel disease-modifying interventions"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2930-5719","authenticated-orcid":false,"given":"Nicole","family":"Kattner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2814-3877","authenticated-orcid":false,"given":"Ayat","family":"Bashir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2893-3211","authenticated-orcid":false,"given":"James A. 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Pancreatology 25:214\u2013220. https:\/\/doi.org\/10.1016\/j.pan.2025.01.004","journal-title":"Pancreatology"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06678-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-026-06678-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06678-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T16:46:14Z","timestamp":1774111574000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-026-06678-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,10]]},"references-count":154,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["6678"],"URL":"https:\/\/doi.org\/10.1007\/s00125-026-06678-6","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,10]]},"assertion":[{"value":"2 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 December 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"NK and JAMS are currently supported by a Diabetes UK project grant exploring the mechanisms underlying pancreatogenic diabetes. AB is supported by an NIHR PhD Fellowship on impaired glucose tolerance and diabetes in chronic pancreatitis. All members of the Shaw research team benefit from unrestricted charitable funding provided through the Ray Wilson Memorial Fund, for which we are sincerely grateful.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"All authors contributed to conceptualising, drafting and reviewing of this article. All authors approved the final version to be published.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Author contributions"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Relationships and activities"}}]}}