SMAD3/Stat3 Signaling Mediates -Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis-Related Diabetes

Many patients with chronic pancreatitis develop diabetes (chronic pancreatitis-related diabetes [CPRD]) through an undetermined mechanism. Here we used long-term partial pancreatic duct ligation (PDL) as a model to study CPRD. We found that long-term PDL induced significant beta-cell dedifferentiation, followed by a time-dependent decrease in functional beta-cell massall specifically in the ligated tail portion of the pancreas (PDL-tail). High levels of transforming growth factor 1 (TGF1) were detected in the PDL-tail and were mainly produced by M2 macrophages at the early stage and by activated myofibroblasts at the later stage. Loss of beta-cell mass was then found to result from TGF1-triggered epithelial-mesenchymal transition (EMT) by beta-cells, rather than resulting directly from beta-cell apoptosis. Mechanistically, TGF1-treated beta-cells activated expression of the EMT regulator gene Snail in a SMAD3/Stat3-dependentmanner. Moreover, forced expression of forkhead box protein O1 (FoxO1), an antagonist for activated Stat3, specifically in beta-cells ameliorated beta-cell EMT and beta-cell loss and prevented the onset of diabetes in mice undergoing PDL. Together, our data suggest that chronic pancreatitis may trigger TGF1-mediated beta-cell EMT to lead to CPRD, which could substantially be prevented by sustained expression of FoxO1 in beta-cells.