| First Author | Xiao X | Year | 2017 |
| Journal | Diabetes | Volume | 66 |
| Issue | 10 | Pages | 2646-2658 |
| PubMed ID | 28775125 | Mgi Jnum | J:248308 |
| Mgi Id | MGI:5919735 | Doi | 10.2337/db17-0537 |
| Citation | Xiao X, et al. (2017) SMAD3/Stat3 Signaling Mediates beta-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis-Related Diabetes. Diabetes 66(10):2646-2658 |
| abstractText | 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 mass-all specifically in the ligated tail portion of the pancreas (PDL-tail). High levels of transforming growth factor beta1 (TGFbeta1) 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 TGFbeta1-triggered epithelial-mesenchymal transition (EMT) by beta-cells, rather than resulting directly from beta-cell apoptosis. Mechanistically, TGFbeta1-treated beta-cells activated expression of the EMT regulator gene Snail in a SMAD3/Stat3-dependent manner. 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 TGFbeta1-mediated beta-cell EMT to lead to CPRD, which could substantially be prevented by sustained expression of FoxO1 in beta-cells. |
