Smad3 deficiency promotes beta cell proliferation and function in mice restoring Pax6 expression.

Transforming Growth Factor-beta (TGF-β) /Smad3 signaling has been shown to play important roles in fibrotic and inflammatory diseases, but its role in beta cell function and type 2 diabetes is unknown. The role of Smad3 in beta cell function under type 2 diabetes condition was investigated by genetically deleting Smad3 from mice. Phenotypic changes of pancreatic islets and beta cell function were compared between Smad3 knockout (Smad3KO-) mice and Smad3 wild-type (Smad3WT-) mice, and other littermate controls. Islet-specific RNA-sequencing was performed to identify Smad3-dependent differentially expressed genes associated with type 2 diabetes. beta cell proliferation assay and insulin secretion assay were carried out to validate the mechanism by which Smad3 regulates beta cell proliferation and function. The results showed that Smad3 deficiency completely protected against diabetes-associated beta cell loss and dysfunction in mice. By islet-specific RNA-sequencing, we identified 8160 Smad3-dependent differentially expressed genes associated with type 2 diabetes, where Smad3 deficiency markedly prevented the down-regulation of those genes. Mechanistically, Smad3 deficiency preserved the expression of beta cell development mediator Pax6 in islet, thereby enhancing beta cell proliferation and function in mice and in Min6 cells . Taken together, we discovered a pathogenic role of Smad3 in beta cell loss and dysfunction via targeting the protective Pax6. Thus, Smad3 may represent as a novel therapeutic target for type 2 diabetes prevention and treatment.