{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:04:00Z","timestamp":1788458640620,"version":"build-2803163510"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000361","name":"Diabetes UK","doi-asserted-by":"publisher","award":["EPSRC\/EP\/V048716\/1"],"award-info":[{"award-number":["EPSRC\/EP\/V048716\/1"]}],"id":[{"id":"10.13039\/501100000361","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000361","name":"Diabetes UK","doi-asserted-by":"publisher","award":["RD Lawrence Fellowship\/22\/0006378"],"award-info":[{"award-number":["RD Lawrence Fellowship\/22\/0006378"]}],"id":[{"id":"10.13039\/501100000361","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Aims\/hypothesis<\/jats:title>\n            <jats:p>The organisation and cellular architecture of islets of Langerhans are critical to the physiological regulation of hormone secretion but it is debated whether human islets adhere to the characteristic mantle\u2013core (M-C) structure seen in rodents. It is also unclear whether inherent architectural changes contribute to islet dysfunction in type 1 diabetes, aside from the loss of beta cells. Therefore, we have exploited advances in immunostaining, spatial biology and machine learning to undertake a detailed, systematic analysis of adult human islet architecture in health and type 1 diabetes, by a quantitative analysis of a dataset of &gt;250,000 endocrine cells in &gt;3500 islets from ten individuals.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Formalin-fixed paraffin-embedded pancreatic sections (4 \u03bcm) from organ donors without diabetes and living donors with recent-onset type 1 diabetes were stained for all five islet hormones and imaged prior to analysis, which employed a novel automated pipeline using QuPath software, capable of running on a standard laptop. Whole-slide image analysis involved segmentation classifiers, cell detection and phenotyping algorithms to identify islets, specific cell types and their locations as\u00a0(<jats:italic>x,y<\/jats:italic>)-coordinates\u00a0in regions of interest. Each endocrine cell was categorised into binary variables for cell type (i.e. beta or non-beta) and position (mantle or core). A \u03c7<jats:sup>2<\/jats:sup> test for independence of these properties was performed and the OR was considered to estimate the effect size of the potential association between position and cell type. A quantification of the M-C structure at islet level was performed by computing the probability, <jats:italic>r<\/jats:italic>, that the observed number of non-beta cells in the mantle is due to a random arrangement. The distribution of the <jats:italic>r<\/jats:italic> values for the islets in the study was contrasted against the <jats:italic>r<\/jats:italic> values of a digital population of equivalent randomly arranged islets, termed digital siblings. Both distributions of <jats:italic>r<\/jats:italic> values were compared using the earth mover\u2019s distance (EMD), a mathematical tool employed to describe differences in distribution patterns. The EMD was also used to contrast the distribution of islet size and beta cell fraction between type 1 diabetes and control islets.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The \u03c7<jats:sup>2<\/jats:sup> test supports the existence of a significant (<jats:italic>p<\/jats:italic>&lt;0.001) relationship between cell position and type. The effect size was measured via the OR &lt;0.8, showing that non-beta cells are more likely to be found at the mantle (and vice versa). At the islet level, the EMD between the distributions of <jats:italic>r<\/jats:italic> values of the observed islets and the digital siblings was emd-1d=0.10951 (0&lt;emd-1d&lt;1). The transport plan showed a substantial group of islets with a small <jats:italic>r<\/jats:italic> value, thus supporting the M-C hypothesis. The bidimensional distribution (beta cell fraction vs size) of islets showed a distance emd-2d=0.285 (0&lt;emd-2d&lt;2) between the control and type 1 diabetes islets. The suffixes \u2018-1d\u2019 and \u2018-2d\u2019 are used to distinguish the comparison between the distribution of one and two variables.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\/interpretation<\/jats:title>\n            <jats:p>Using a novel analysis pipeline, statistical evidence supports the existence of an M-C structure in human adult islets, irrespective of type 1 diabetes status. The methods presented in the current study offer potential applications in spatial biology, islet immunopathology, transplantation and organoid research, and developmental research.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s00125-025-06376-9","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T18:11:49Z","timestamp":1740593509000},"page":"1031-1043","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Beyond the loss of beta cells: a quantitative analysis of islet architecture in adults with and without type 1 diabetes"],"prefix":"10.1007","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1086-4625","authenticated-orcid":false,"given":"Nicol\u00e1s","family":"Verschueren van Rees","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7330-4951","authenticated-orcid":false,"given":"Peter","family":"Ashwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3329-1559","authenticated-orcid":false,"given":"Conor","family":"McMullan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1057-7095","authenticated-orcid":false,"given":"Lars","family":"Krogvold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6952-9899","authenticated-orcid":false,"given":"Knut","family":"Dahl-J\u00f8rgensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1537-8113","authenticated-orcid":false,"given":"Noel G.","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4013-0040","authenticated-orcid":false,"given":"Pia","family":"Leete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8109-2765","authenticated-orcid":false,"given":"Kyle C. 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We are also humbled by their faith in our commitment to unravel the disease pathogenesis and its contributing factors. We are additionally grateful to the funders\u2019 commitment to supporting multidisciplinary endeavours, such as this, to grow our research and discovery potential.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Data and code are available on request and can be obtained from the corresponding author.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This research was performed with the generous support of Diabetes UK, including via an RD Lawrence Fellowship, awarded to PL (grant no. 22\/0006378) and the support of EPSRC via grant EP\/T017856\/1 (gratefully received by NVvR, PA and KCAW). In addition, this study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The authors also gratefully acknowledge that this research would not have been possible without the enormous generosity of the organ and tissue donors, and their families, in collaboration with the Network for Pancreatic Organ donors with Diabetes (nPOD; RRID:SCR_014641), a collaborative type 1 diabetes research project supported by Breakthrough T1D (formerly known as JDRF [nPOD: 5-SRA-2018-557-Q-R]) and The Leona M. & Harry B. Helmsley Charitable Trust (grant no. 2018PG-T1D053, G-2108-04793), and the DiViD project, which was funded by the South-Eastern Norway Regional Health Authority (grant to KD-J) and the Novo Nordisk Foundation (grant to KD-J) and through the PEVNET Study Group funded by the European Union\u2019s Seventh Framework Programme under grant agreement (FP7\/2007-2013). The content and views expressed are the responsibility of the authors and do not necessarily reflect the official view of nPOD. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at . The DiViD project was funded by the South-Eastern Norway Regional Health Authority (grant to KD-J), the Novo Nordisk Foundation (grant to KD-J) and through the PEVNET Study Group funded by the European Union\u2019s Seventh Framework Programme (FP7\/2007-2013) under grant agreement.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"NVvR, PA, NGM, KCAW and PL conceived and contributed to the design of the work, the analysis and interpretation of the data, and the drafting and reviewing of the article. CM designed and performed all wet lab histology staining, whole-slide scanning and image processing. All authors contributed to the interpretation of the results, and critically reviewed and approved the final version of the manuscript. KCAW and PL are joint guarantors of this work as a whole.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}