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D2D3 transgenic mice also exhibited insulin-dependent diabetes mellitus evidenced by decreased levels of insulin and C-peptide, impaired glucose-stimulated insulin secretion, decreased pancreatic \u03b2 cell mass, and high fasting blood glucose. Injection of anti-uPAR antibody restored \u03b2 cell mass and function in D2D3 transgenic mice. At the cellular level, the D2D3 protein impaired \u03b2 cell proliferation and inhibited the bioenergetics of \u03b2 cells, leading to dysregulated cytoskeletal dynamics and subsequent impairment in the maturation and trafficking of insulin granules. D2D3 protein was predominantly detected in the sera of patients with nephropathy and insulin-dependent diabetes mellitus. These sera inhibited glucose-stimulated insulin release from human islets in a D2D3-dependent manner. Our study showed that D2D3 injures the kidney and pancreas and suggests that targeting this protein could provide a therapy for kidney diseases and insulin-dependent diabetes mellitus.<\/jats:p>","DOI":"10.1126\/scitranslmed.abq6492","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T13:59:09Z","timestamp":1695218349000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":7,"title":["The D2D3 form of uPAR acts as an immunotoxin and may cause diabetes and kidney disease"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1794-1328","authenticated-orcid":true,"given":"Ke","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Medicine, Rush University Medical Center, Chicago, IL 60612, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5483-7450","authenticated-orcid":true,"given":"Kamalika","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8876-8871","authenticated-orcid":true,"given":"Changli","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Medicine, Rush University Medical Center, Chicago, IL 60612, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0180-349X","authenticated-orcid":true,"given":"Salim S.","family":"Hayek","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Collins","sequence":"additional","affiliation":[{"name":"Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1257-0583","authenticated-orcid":true,"given":"Changkyu","family":"Gu","sequence":"additional","affiliation":[{"name":"Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4336-8089","authenticated-orcid":true,"given":"Kristin","family":"Corapi","sequence":"additional","affiliation":[{"name":"Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1871-6985","authenticated-orcid":true,"given":"Mehmet M.","family":"Altintas","sequence":"additional","affiliation":[{"name":"Department of Medicine, Rush University Medical Center, Chicago, IL 60612, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Virginia, Charlottesville, VA 22903, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4004-326X","authenticated-orcid":true,"given":"Sushrut S.","family":"Waikar","sequence":"additional","affiliation":[{"name":"Section of Nephrology, Boston University Chobanian &amp; 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