Unraveling the Role of MDK‐SDC4 Interaction in Pancreatic Cancer‐Associated New‐Onset Diabetes by Single‐Cell Transcriptomic Analysis

Abstract Elevated blood glucose levels may serve as an early indicator of underlying pancreatic cancer. Discriminating between pancreatic cancer‐associated new‐onset diabetes (PCAND) and new‐onset 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‐onset T2DM persists, primarily because of the elusive pathogenesis of PCAND. In this study, the intricate intercellular communication is comprehensively elucidated through single‐cell 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‐based biomarker for discriminating between PCAND and T2DM in populations with new‐onset diabetes, thereby facilitating the advancement of early detection strategies for pancreatic cancer.