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As aggregation of human islet amyloid polypeptide (hIAPP) is toxic to beta cells, we sought to determine whether activation of the fibrinolytic system can also reduce islet amyloid deposition and its cytotoxic effects, which are both observed in type 2 diabetes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The expression of <jats:italic>Plat<\/jats:italic> (encoding tPA) and plasmin activity were measured in isolated islets from amyloid-prone hIAPP transgenic mice or non-transgenic control islets expressing non-amyloidogenic mouse islet amyloid polypeptide cultured in the absence or presence of the amyloid inhibitor Congo Red. <jats:italic>Plat<\/jats:italic> expression was also determined in hIAPP-treated primary islet endothelial cells, bone marrow-derived macrophages (BMDM) and INS-1 cells, in order to determine the islet cell type(s) producing tPA in response to hIAPP aggregation. Cell-free thioflavin-T assays and MS were used to respectively monitor hIAPP aggregation kinetics and investigate plasmin cleavage of hIAPP. Cell viability was assessed in INS-1 beta cells treated with hIAPP with or without plasmin. Finally, to confirm the findings in human samples, <jats:italic>PLAT<\/jats:italic> expression was measured in freshly isolated islets from donors with and without type 2 diabetes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In isolated islets from transgenic mice, islet <jats:italic>Plat<\/jats:italic> expression and plasmin activity increased significantly with the process of amyloid deposition (<jats:italic>p<\/jats:italic>\u22640.01, <jats:italic>n<\/jats:italic>=5); these effects were not observed in islets from non-transgenic mice and were blocked by Congo Red (<jats:italic>p<\/jats:italic>\u22640.01, <jats:italic>n<\/jats:italic>=4). In response to hIAPP exposure, <jats:italic>Plat<\/jats:italic> expression increased in BMDM and INS-1 cells vs vehicle-treated cells (<jats:italic>p<\/jats:italic>\u22640.05, <jats:italic>n<\/jats:italic>=4), but not in islet endothelial cells. Plasmin reduced hIAPP fibril formation in a dose-dependent manner in a cell-free system, and restored hIAPP-induced loss of cell viability in INS-1 beta cells (<jats:italic>p<\/jats:italic>\u22640.01, <jats:italic>n<\/jats:italic>=5). Plasmin cleaved monomeric hIAPP, inducing a rapid decrease in the abundance of full-length hIAPP and the appearance of hIAPP 1\u201311 and 12\u201337 fragments. hIAPP 12\u201337, which contains the critical amyloidogenic region, was not toxic to INS-1 cells. Finally, <jats:italic>PLAT<\/jats:italic> expression was significantly increased by 2.4-fold in islets from donors with type 2 diabetes (<jats:italic>n<\/jats:italic>=4) vs islets from donors without type 2 diabetes (<jats:italic>n<\/jats:italic>=7) (<jats:italic>p<\/jats:italic>\u22640.05).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions\/interpretation<\/jats:title>\n                <jats:p>The fibrinolytic system is upregulated in islets with hIAPP aggregation. Plasmin rapidly degrades hIAPP, limiting its aggregation into amyloid and thus protecting beta cells from hIAPP-induced toxicity. Thus, increasing islet plasmin activity might be a strategy to limit beta cell loss in type 2 diabetes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1007\/s00125-024-06161-0","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T02:02:06Z","timestamp":1725847326000},"page":"1897-1911","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The islet tissue plasminogen activator\/plasmin system is upregulated with human islet amyloid polypeptide aggregation and protects beta cells from aggregation-induced toxicity"],"prefix":"10.1007","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1823-3817","authenticated-orcid":false,"given":"Nathalie","family":"Esser","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5767-1599","authenticated-orcid":false,"given":"Meghan F.","family":"Hogan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6241-9304","authenticated-orcid":false,"given":"Andrew T.","family":"Templin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4475-3093","authenticated-orcid":false,"given":"Rehana","family":"Akter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brendy S.","family":"Fountaine","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4080-2545","authenticated-orcid":false,"given":"Joseph J.","family":"Castillo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7968-7375","authenticated-orcid":false,"given":"Assam","family":"El-Osta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9809-4193","authenticated-orcid":false,"given":"Lakshan","family":"Manathunga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Zhyvoloup","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3248-7493","authenticated-orcid":false,"given":"Daniel P.","family":"Raleigh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4831-7034","authenticated-orcid":false,"given":"Sakeneh","family":"Zraika","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9690-4087","authenticated-orcid":false,"given":"Rebecca L.","family":"Hull","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7307-9002","authenticated-orcid":false,"given":"Steven E.","family":"Kahn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,9,9]]},"reference":[{"issue":"2","key":"6161_CR1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1517\/03009734000000014","volume":"77","author":"P Westermark","year":"1972","unstructured":"Westermark P (1972) Quantitative studies on amyloid in the islets of Langerhans. 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Aplin, B. Barrow, S. Mongovin, D. Hackney and C. Schmidt (Seattle Institute for Biomedical and Clinical Research, Seattle, WA, USA) for excellent technical support, and J. Edgar (University of Washington, Seattle, WA, USA) for expert assistance with MS analysis. Some of the data from this study were presented at the ADA\u2019s 78th, 79th and 80th Scientific Sessions in 2018, 2019 and 2020, and at the EASD\u2019s 58th Annual Meeting in 2022.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The data that support the findings of this study are available from the corresponding author on reasonable request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This work was supported by grants from the National Institutes of Health (P30 DK017047, T32 DK007247, T32 HL007028 and R01 GM078114), Wellcome Trust (107927\/Z\/15\/Z), the US Department of Veterans Affairs (I01 BX001060 to SEK, I01 BX004063 to RLH and IK2 BX004659 to ATT), an American Diabetes Association Postdoctoral Fellowship (1-18-PDF-174 to MFH), the University of Washington (Dick and Julia McAbee Endowed Postdoctoral Fellowship to MFH and NE), the Seattle Institute for Biomedical and Clinical Research and a seed grant from the office of the Vice President for Research at Stony Brook University. NE is an F.R.S-FNRS Post doctorate Clinical Master Specialist and acknowledges support from the Soci\u00e9t\u00e9 Francophone du Diab\u00e8te, the Belgian American Educational Foundation and the Baillet-Latour Found, the Belgian Diabetes Association, the Horlait-Dapsens Foundation, the Leon Fredericq Foundation, and the Fondation du Rotary Club de Li\u00e8ge. AE-O is a National Health and Medical Research Council (NHMRC) Senior Research Fellow (1154650) and acknowledges JDRF support (1-INO-2022-1123-A-N).","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":"NE conceived and designed the study, performed experiments, analysed and interpreted data, and wrote the manuscript. MFH performed experiments, analysed and interpreted data, and revised the manuscript. BSF, LM and AZ performed experiments, analysed data and revised the manuscript. ATT, RA, JJC, AE-O, DPR, SZ and RLH interpreted data and revised the manuscript. SEK conceived and designed the study, interpreted data, and revised the manuscript. All authors approved the final version to be published. SEK is responsible for the integrity of the work as a whole.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}