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Discriminating between pancreatic cancer\u2010associated new\u2010onset diabetes (PCAND) and new\u2010onset type 2 diabetes mellitus (T2DM) holds promise for enabling an earlier diagnosis of pancreatic cancer. Nevertheless, the absence of effective biomarkers for distinguishing PCAND from the more prevalent new\u2010onset T2DM persists, primarily because of the elusive pathogenesis of PCAND. In this study, the intricate intercellular communication is comprehensively elucidated through single\u2010cell RNA sequencing. The findings identified Midkine (MDK) as a potential mediator of the interaction between tumor and beta cells. MDK, which originated from pancreatic ductal adenocarcinoma cells, exerted deleterious effects on paraneoplastic beta cells by binding to the SDC4 receptor on the beta cell surface and subsequently downregulating the Ras signaling pathway, thereby impairing insulin production and secretion. Notably, the plasma levels of MDK are higher in patients with PCAND than in those with T2DM. In conclusion, MDK has emerged as a pivotal driver of PCAND pathogenesis and may function as a blood\u2010based biomarker for discriminating between PCAND and T2DM in populations with new\u2010onset diabetes, thereby facilitating the advancement of early detection strategies for pancreatic cancer.<\/jats:p>","DOI":"10.1002\/advs.202409987","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T10:53:59Z","timestamp":1753440839000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Unraveling the Role of MDK\u2010SDC4 Interaction in Pancreatic Cancer\u2010Associated New\u2010Onset Diabetes by Single\u2010Cell Transcriptomic Analysis"],"prefix":"10.1002","volume":"12","author":[{"given":"Zengyu","family":"Feng","sequence":"first","affiliation":[{"name":"Department of General Surgery Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310009 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