{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T18:52:02Z","timestamp":1793299922030,"version":"4.5.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Type 1 diabetes (T1D) is characterized by the immune-mediated destruction of insulin-producing \u03b2-cells in pancreatic islets. The peri-islet extracellular matrix (ECM) is a complex protein barrier that is lost in T1D, in part due to infiltrating immune cells. The contribution of stressed \u03b2-cells to ECM degradation during T1D remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To bridge this gap, we used 12\u201315-week-old NOD mice and pancreas sections from healthy, \u22652 autoantibody positive (Aab+), and recent onset T1D donors. We focused on MMP-3 due to its role in degrading type IV collagen (COL IV) in the peri-islet ECM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Treatment with proinflammatory cytokines or hyperglycemia increased MMP-3 gene expression and protein levels in mouse and human islets. In NOD pancreas sections, increased MMP-3 expression in \u03b2-cells correlates with loss of COL IV during insulitis and hyperglycemia; however, this was independent of insulitis score. We observed similar increases in MMP-3 and loss of COL IV in islets and exocrine tissue from Aab+ and recent onset T1D donors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These results suggest that stressed \u03b2-cells degrade the ECM during preclinical T1D, further weakening the peri-islet ECM barrier and facilitating islet infiltration and death. Inhibiting expression of MMP-3 may represent a novel treatment to prevent islet death in T1D.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2025.1675043","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T04:19:47Z","timestamp":1760069987000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Stressed \u03b2-cells contribute to loss of peri-islet extracellular matrix in type 1 diabetes"],"prefix":"10.3389","volume":"16","author":[{"given":"Chelsea G.","family":"Johansen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenedee","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikki L.","family":"Farnsworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3727\/096368909788237195","article-title":"Extracellular matrix in pancreatic islets: relevance to scaffold design and transplantation","volume":"18","author":"Stendahl","year":"2009","journal-title":"Cell Transplant"},{"key":"B2","doi-asserted-by":"publisher","first-page":"413","DOI":"10.3390\/cells9020413","article-title":"Shaping pancreatic \u03b2-cell differentiation and functioning: the influence of mechanotransduction","volume":"9","author":"Alessandra","year":"2020","journal-title":"Cells"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2337\/db12-0432","article-title":"The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human","volume":"62","author":"Korpos","year":"2013","journal-title":"Diabetes"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-008-1085-x","article-title":"Molecular composition of the peri-islet basement membrane in NOD mice: a barrier against destructive insulitis","volume":"51","author":"Irving-Rodgers","year":"2008","journal-title":"Diabetologia"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1172\/JCI46177","article-title":"Heparan sulfate and heparanase play key roles in mouse \u03b2 cell survival and autoimmune diabetes","volume":"122","author":"Ziolkowski","year":"2012","journal-title":"J Clin Invest"},{"key":"B6","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1007\/s11892-014-0552-7","article-title":"Extracellular matrix components in the pathogenesis of type 1 diabetes","volume":"14","author":"Bogdani","year":"2014","journal-title":"Curr Diabetes Rep"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s00776-006-1012-2","article-title":"Current concepts of extracellular matrix","volume":"11","author":"Tanzer","year":"2006","journal-title":"J Orthopaedic Science"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/science.1176009","article-title":"The extracellular matrix: not just pretty fibrils","volume":"326","author":"Hynes","year":"2009","journal-title":"Science"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2008.08.001","article-title":"Hydrogel Encapsulation environments functionalized with extracellular matrix interactions increase islet insulin secretion","volume":"27","author":"Weber","year":"2008","journal-title":"Matrix Biol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.8.2034","article-title":"Extracellular matrix protects pancreatic b-cells against apoptosis","volume":"53","author":"Hammar","year":"2004","journal-title":"Diabetes"},{"key":"B11","article-title":"Chapter 22 - Co-encapsulation of ECM proteins to enhance pancreatic islet cell function","volume-title":"Giuseppe O, lorenzo P, camillo R, robert JS, rainer WGG, editors. Transplantation, bioengineering, and regeneration of the endocrine pancreas","author":"Amanda","year":"2020"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1172\/JCI142242","article-title":"Type 1 diabetes mellitus: much progress, many opportunities","volume":"131","author":"Powers","year":"2021","journal-title":"J Clin Invest"},{"key":"B13","doi-asserted-by":"publisher","first-page":"17016","DOI":"10.1038\/nrdp.2017.16","article-title":"Type 1 diabetes mellitus","volume":"3","author":"Katsarou","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.suppl_2.S25","article-title":"Natural history of type 1 diabetes","volume":"54","author":"Achenbach","year":"2005","journal-title":"Diabetes"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3109\/14756366.2016.1161620","article-title":"Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs","volume":"31","author":"Jab\u0142o\u0144ska-Trypu\u0107","year":"2016","journal-title":"J Enzyme Inhib Med Chem"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1096\/fba.2021-00092","article-title":"New insights into the role of matrix metalloproteinase 3 (MMP3) in bone","volume":"4","author":"Jehan","year":"2022","journal-title":"FASEB BioAdvances"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-014-2056-9","article-title":"IL-6 upregulates a disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS-2) in human osteosarcoma cells mediated by JNK pathway","volume":"393","author":"Alper","year":"2014","journal-title":"Mol Cell Biochem"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/cells9051076","article-title":"Structure and function of human matrix metalloproteinases","volume":"9","author":"Laronha","year":"2020","journal-title":"Cells"},{"key":"B19","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.coi.2018.09.006","article-title":"Extracellular matrix and the maintenance and loss of peripheral immune tolerance in autoimmune insulitis","volume":"55","author":"Medina","year":"2018","journal-title":"Curr Opin Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.67.2.149","article-title":"Extracellular matrix moieties, cytokines, and enzymes: dynamic effects on immune cell behavior and inflammation","volume":"67","author":"Vaday","year":"2000","journal-title":"J Leukoc Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4889(93)90054-S","article-title":"Production and regulation of gelatinase B by human T-cells","volume":"1176","author":"Montgomery","year":"1993","journal-title":"Mol Cell Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.65.2.137","article-title":"The cell biology of leukocyte-mediated proteolysis","volume":"65","author":"Owen","year":"1999","journal-title":"J Leukoc Biol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4889(93)90037-P","article-title":"Induction of metalloproteinase activity in human T-lymphocytes","volume":"1177","author":"Zhou","year":"1993","journal-title":"Mol Cell Res"},{"key":"B24","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/s41536-021-00129-z","article-title":"Coordinated interactions between endothelial cells and macrophages in the islet microenvironment promote b cell regeneration","volume":"6","author":"Saunders","year":"2021","journal-title":"NPJ Regenerative Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2013.02.007","article-title":"Unexpected new roles for heparanase in Type 1 diabetes and immune gene regulation","volume":"32","author":"Parish","year":"2013","journal-title":"Matrix Biol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/cti2.1122","article-title":"Cytokines in type 1 diabetes: mechanisms of action and immunotherapeutic targets","volume":"9","author":"Lu","year":"2020","journal-title":"Clin Trans Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1111\/j.1749-6632.2012.06826.x","article-title":"The role of reactive oxygen species and proinflammatory cytokines in type 1 diabetes pathogenesis","volume":"1281","author":"Padgett","year":"2013","journal-title":"Ann New York Acad Sci"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a005058","article-title":"Extracellular matrix degradation and remodeling in development and disease","volume":"3","author":"Lu","year":"2011","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphys.2021.663978","article-title":"Matrix metalloproteinase 3: A promoting and destabilizing factor in the pathogenesis of disease and cell differentiation","volume":"12","author":"Wan","year":"2021","journal-title":"Front Physiol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1039\/D2RA07005G","article-title":"Matrix metalloproteinase profiling and their roles in disease","volume":"13","author":"Chang","year":"2023","journal-title":"RSC Advances"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.679506","article-title":"Low level pro-inflammatory cytokines decrease connexin36 gap junction coupling in mouse and human islets through nitric oxide-mediated protein kinase C\u03b4","volume":"291","author":"Farnsworth","year":"2016","journal-title":"J Biol Chem"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115989","article-title":"Prolonged exposure of human pancreatic islets to high glucose concentrations in vitro impairs the beta-cell function","volume":"90","author":"Eizirik","year":"1992","journal-title":"J Clin Invest"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1580205","article-title":"Long-term in vitro exposure to high glucose increases proinsulin-like-molecules release by isolated human islets","volume":"158","author":"Bertuzzi","year":"1998","journal-title":"J Endocrinol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.2337\/db20-0847","article-title":"The impact of pro-inflammatory cytokines on alternative splicing patterns in human islets","volume":"71","author":"Wu","year":"2022","journal-title":"Diabetes"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-024-01012-5","article-title":"AM1241 inhibits chondrocyte inflammation and ECM degradation through the Nrf2\/HO-1 and NF-\u03baB pathways and alleviates osteoarthritis in mice","volume":"31","author":"Zou","year":"2025","journal-title":"Mol Med"},{"key":"B36","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1186\/s13018-025-05719-x","article-title":"MiR-103-3p regulates chondrocyte autophagy, apoptosis, and ECM degradation through the PI3K\/Akt\/mTOR pathway by targeting CPEB3","volume":"20","author":"Li","year":"2025","journal-title":"J Orthopaedic Surg Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2021.10896","article-title":"Vicenin 3 ameliorates ECM degradation by regulating the MAPK pathway in SW1353 chondrocytes","volume":"22","author":"Chen","year":"2021","journal-title":"Exp Ther Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.18502\/ijph.v53i4.15562","article-title":"The role and function of secretory protein matrix metalloproteinase-3 (MMP3) in cervical cancer","volume":"53","author":"Shao","year":"2024","journal-title":"Iran J Public Health"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.bjps.2010.03.051","article-title":"MMP- and TIMP-secretion by human cutaneous keratinocytes and fibroblasts\u2013impact of coculture and hydration","volume":"64","author":"Tandara","year":"2010","journal-title":"J Plast Reconstr Aesthetic Surg"},{"key":"B40","article-title":"Immunohistochemical study of the pancreatic basement membrane in non obese diabetic mice (NOD) with spontaneous autoimmune insulitis","volume":"35","author":"Pavin","year":"2003","journal-title":"Submicrosc Cytol Pathol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"112913","DOI":"10.1016\/j.celrep.2023.112913","article-title":"Pericyte dysfunction and impaired vasomotion are hallmarks of islets during the pathogenesis of type 1 diabetes","volume":"42","author":"Mateus Gon\u00e7alves","year":"2023","journal-title":"Cell Rep"},{"key":"B42","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/S1357-2725(00)00061-3","article-title":"ADAMTS: a novel family of extracellular matrix proteases","volume":"33","author":"Tang","year":"2001","journal-title":"Int J Biochem Cell Biol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"101678","DOI":"10.1016\/j.molmet.2023.101678","article-title":"Sex differences in islet stress responses support female \u03b2 cell resilience","volume":"69","author":"Brownrigg","year":"2023","journal-title":"Mol Metab"},{"key":"B44","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s13287-019-1523-3","article-title":"Pro-inflammatory cytokines induce cell death, inflammatory responses, and endoplasmic reticulum stress in human iPSC-derived beta cells","volume":"11","author":"Demine","year":"2020","journal-title":"Stem Cell Res Ther"},{"key":"B45","doi-asserted-by":"publisher","first-page":"bqac184","DOI":"10.1210\/endocr\/bqac184","article-title":"Inside the \u03b2 Cell: molecular stress response pathways in diabetes pathogenesis","volume":"164","author":"Kulkarni","year":"2023"},{"key":"B46","first-page":"e9516","article-title":"C\/EBP-beta regulates endoplasmic reticulum stress-triggered cell death in mouse and human models","volume-title":"Plos one","author":"Meir","year":"2010"},{"key":"B47","first-page":"661-9","article-title":"Oxidized LDL-exposed human macrophages display increased MMP-9 expression and secretion mediated by endoplasmic reticulum stress","volume-title":"J Cell Biochem","author":"Sanda","year":"2017"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.093799","article-title":"Matrix metalloproteinase-3 is increased and participates in neuronal apoptotic signaling downstream of caspase-12 during endoplasmic reticulum stress","volume":"285","author":"Kim","year":"2010","journal-title":"J Biol Chem"},{"key":"B49","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1002\/dvdy.248","article-title":"The quest for substrates and binding partners: A critical barrier for understanding the role of ADAMTS proteases in musculoskeletal development and disease","volume":"250","author":"Satz-Jacobowitz","year":"2021","journal-title":"Dev Dyn"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1007\/s12013-007-0029-2","article-title":"Roles of cytokines in the pathogenesis and therapy of type 1 diabetes","volume":"48","author":"Rabinovitch","year":"2007","journal-title":"Cell Biochem Biophys"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.02-0874","article-title":"Regulated expression of collagenases MMP-1, -8, and -13 and stromelysins MMP-3, -10, and -11 by human corneal epithelial cells","volume":"44","author":"Li","year":"2003","journal-title":"Investig Ophthalmol Vis Sci"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1675043\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T04:19:49Z","timestamp":1760069989000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1675043\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,10]]},"references-count":51,"alternative-id":["10.3389\/fendo.2025.1675043"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1675043","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.06.25.661601","asserted-by":"object"}]},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,10]]},"article-number":"1675043"}}