{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:53:01Z","timestamp":1792803181123,"version":"4.5.0"},"reference-count":33,"publisher":"American Diabetes Association","issue":"11","license":[{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK123292"],"award-info":[{"award-number":["R01 DK123292"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK131059"],"award-info":[{"award-number":["R01 DK131059"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["U01 DK135001"],"award-info":[{"award-number":["U01 DK135001"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01 AI042288"],"award-info":[{"award-number":["P01 AI042288"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Breakthrough-T1D","award":["3-PDF-2025-1675-A-N"],"award-info":[{"award-number":["3-PDF-2025-1675-A-N"]}]},{"name":"Breakthrough-T1D","award":["Grant#3-SRA-2023-1417-S-B"],"award-info":[{"award-number":["Grant#3-SRA-2023-1417-S-B"]}]},{"name":"The Leona M. & Harry B. Helmsley Charitable Trust","id":[{"id":"https:\/\/ror.org\/011x6n313","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,11,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>In type 1 diabetes (T1D), insulin (INS) deficiency results from immune-mediated destruction of \u03b2-cells. The majority of functional \u03b2-cell mass is typically lost within months to years of disease diagnosis, but the timing and nature of this loss, particularly in early disease stages, remain unclear. We developed a whole-slide scanned image analysis pipeline for semiautomated quantitation of endocrine area, islet frequency, interislet distance, and endocrine object size distribution in 145 human pancreata from 60 donors without diabetes, 19 donors with single autoantibody positivity, 10 with multiple autoantibody positivity (mAAb+), 16 with recent-onset T1D (duration 0\u20131 year), 23 with medium-duration T1D (1\u20137 years), and 17 with long-duration T1D (\u22657 years). We observed age-related differences in endocrine composition and islet frequency in pancreata from donors without diabetes. Age-corrected data revealed decreased islet frequency and greater interislet distance in the T1D pancreas. INS+ single cells (\u226410 \u03bcm), cell clusters (&amp;gt;10 to &amp;lt;35 \u03bcm), and small- and medium-sized islets (35\u2013100 and 100\u2013200 \u03bcm, respectively) were significantly lost at T1D onset, whereas large INS+ islets (&amp;gt;200 \u03bcm) were preserved. Moreover, changes in endocrine composition also occurred in pancreata from mAAb+ donors, including a significant decrease in the INS+ islet fraction. These data suggest preferential loss of INS+ small endocrine objects early in T1D development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>Understanding the timing and nature of \u03b2-cell loss is essential for developing effective strategies to interrupt type 1 diabetes progression. Which types of islets, in terms of size and cellular composition, are lost first during disease development? Insulin-positive single cells and cell clusters are lost before large islets during disease development. Insulin-positive single cells and cell clusters might be more susceptible to destruction in type 1 diabetes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-0326","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T14:59:33Z","timestamp":1753369173000},"page":"2008-2015","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":21,"title":["Loss of Insulin-Positive Cell Clusters Precedes the Decrease in Islet Frequency and \u03b2-Cell Area in Type 1 Diabetes"],"prefix":"10.2337","volume":"74","author":[{"given":"Denise M.","family":"Drotar","sequence":"first","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute 1 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni J.A.","family":"Vazquez Ramos","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute 1 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MacKenzie D.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute 1 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surya T.","family":"David","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute 1 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlyn","family":"Luce","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute 1 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute 1 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda L.","family":"Posgai","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute 1 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhonda","family":"Bacher","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Florida 2 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Campbell-Thompson","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute 1 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Kusmartseva","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute 1 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maigan A.","family":"Brusko","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute 1 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute 1 , Gainesville, FL"},{"name":"Department of Pediatrics, College of Medicine, University of Florida Diabetes Institute 3 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3522-8932","authenticated-orcid":false,"given":"Clive H.","family":"Wasserfall","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute 1 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"key":"2026061115075510500_B1","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1369\/0022155415570969","article-title":"Human islet morphology revisited: human and rodent islets are not so different after all","volume":"63","author":"Bonner-Weir","year":"2015","journal-title":"J Histochem 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Diagnosis and classification of diabetes: standards of care in diabetes\u20142025","volume":"48","author":"American Diabetes Association Professional Practice Committee","year":"2024","journal-title":"Diabetes Care"},{"key":"2026061115075510500_B20","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci Rep"},{"key":"2026061115075510500_B21","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.2337\/db15-1615","article-title":"Differential insulitic profiles determine the extent of \u03b2-cell destruction and the age at onset of type 1 diabetes","volume":"65","author":"Leete","year":"2016","journal-title":"Diabetes"},{"key":"2026061115075510500_B22","doi-asserted-by":"crossref","first-page":"719","DOI":"10.2337\/db15-0779","article-title":"Insulitis and \u03b2-cell mass in the natural history of type 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