Paraneoplastic Beta Cell Dedifferentiation In Nondiabetic Patients With Pancreatic Cancer

Context: Beta-cell dedifferentiation was recently proposed as a mechanism of beta-cell dysfunction, but whether it can be a trigger of beta-cell failure preceding hyperglycemia in humans is uncertain. Pancreatic cancer can cause new-onset diabetes, yet the underlying mechanism is unknown.Objective: To investigate whether beta-cell dedifferentiation is present in nondiabetic pancreatic ductal adenocarcinoma (PDAC) patients, we examined pancreatic islets from 15 nondiabetic patients with benign tumors (control) and 15 nondiabetic PDAC patients.Design: We calculated the number of hormone-negative endocrine cells and evaluated important markers of beta-cell dedifferentiation and function in the paraneoplastic islets. We assessed tumor-related inflammatory changes under the pancreatic cancer microenvironment and their influence on beta-cell identity.Results: We found nearly 10% of nonhormone expressing endocrine cells in nondiabetic PDAC subjects. The PDAC islets were dysfunctional, evidenced by low expression of Glucose transporter 2 (GLUT2) and Urocortin3 (UCN3), and concomitant upregulation of Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3) expression and proinsulin accumul ation. Pancreatic cancer caused paraneoplastic inflammation with enhanced tissue fibrosis, monocytes/macrophages infiltration, and elevated inflammatory cytokines. Moreover, we detected beta-cell dedifferentiation and defects in GSIS in islets exposed to PANC-1 (a cell line established from a pancreatic carcinoma of ductal origin from a 56-year-old Caucasian male)-conditioned medium. In a larger cohort, we showed high prevalence of new-onset diabetes in PDAC subjects, and fasting blood glucose (FBG) was found to be an additional useful parameter for early diagnosis of PDAC.Conclusions: Our data provide a rationale for beta-cell dedifferentiation in the pathogenesis of pancreatic cancer-associated diabetes. We propose that beta-cell dedifferentiation can be a trigger for beta-cell failure in humans, before hyperglycemia occurs.