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These cells are part of islets or appear as extra-islet insulin-positive cells scattered in the exocrine parenchyma. The latter are poorly described, and the presence of scattered endocrine cells expressing other islet hormones than insulin has not been explored. This study aimed to compare the extra-islet insulin- or glucagon-positive cells concerning their frequency, transcription-factor expression, and mitotic activity in subjects with and without T1D. Multispectral imaging was used to examine extra-islet cells by staining for insulin, glucagon, ARX, PDX1, and Ki67. This was done in well-preserved pancreatic tissue obtained from heart-beating organ donors with or without T1D. In three T1D donors, lobes with insulin-containing islets (ICI) were found. Within these, a higher frequency of extra-islet insulin-positive cells was observed compared to lobes with insulin-deficient islets (IDI). Increased frequency of glucagon-positive extra-islet cells was observed in donors with T1D (median 53 cells\/mm<jats:sup>2<\/jats:sup>) when compared with non-diabetic donors (11 cells\/mm<jats:sup>2<\/jats:sup>, <jats:italic>p<\/jats:italic>\u2009=\u20090.004). Proliferating endocrine cells were present in donors with, and without T1D, as demonstrated by Ki67-positive staining (0\u20133% of the cells expressing insulin or glucagon). The reduced frequency of extra-islet insulin-positive cells in lobes with IDI in donors with T1D suggests that the pathological mechanism causing beta cell demise in T1D affects entire lobes. The presence of an increased frequency of glucagon-positive extra-islet cells supports the notion of a preserved capacity to regenerate the endocrine pancreas in donors with T1D.<\/jats:p>","DOI":"10.1007\/s00428-024-03842-4","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T04:01:36Z","timestamp":1719374496000},"page":"687-695","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Loss of insulin-expressing extra-islet cells in type 1 diabetes is accompanied with increased number of glucagon-expressing extra-islet cells"],"prefix":"10.1007","volume":"486","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2888-486X","authenticated-orcid":false,"given":"Louise","family":"Granlund","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7916-2237","authenticated-orcid":false,"given":"Marcus","family":"Lundberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,26]]},"reference":[{"issue":"8","key":"3842_CR1","doi-asserted-by":"publisher","first-page":"2647","DOI":"10.1210\/jc.2016-3806","volume":"102","author":"CJ Lam","year":"2017","unstructured":"Lam CJ, Jacobson DR, Rankin MM, Cox AR, Kushner JA (2017) \u03b2 cells persist in T1D pancreata without evidence of ongoing \u03b2-cell turnover or neogenesis. 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All tissue included in the study was procured, stored, and analyzed as approved by the Regional Ethics Committee in Uppsala (Dnr 2015\/444).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}