Smad3 Deficiency Prevents Beta Cell Regression under Diabetic Condition via Restoring Pax6

Rationale: Transforming Growth Factor-beta (TGF-beta) /Smad3 signalling 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.Methods: The role of Smad3 in beta cell function under type 2 diabetes condition was investigated by genetically deleting Smad3 from db/db mice. Phenotypic changes of pancreatic islets and beta cell function were compared between Smad3 knockout db/db (Smad3KO-db/db) mice and Smad3 wild-type db/db (Smad3WT-db/db) mice, and other littermate controls. Islet-specific RNA-sequencing were performed to identify Smad3-dependent differentially expressed genes associated with type 2 diabetes. In vitro beta cell proliferation assay and insulin secretion assay were carried out to validate the mechanism by which Smad3 regulates beta cell proliferation and function.Results: The results showed that Smad3 deficiency completely protected against diabetic-associated beta cell regression and insulin insufficiency in db/db 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 function in db/db mice in vivo and Min6 cells proliferation in vitro. Network analysis further revealed a novel Pax6/DNA2 axis for protecting Smad3-KO islet against diabetic condition.Conclusions: Taken together, we discovered a pathogenic role of Smad3 in beta cell regression via targeting a protective Pax6/DNA2 axis. Thus, Smad3 may represent as a novel therapeutic target for type 2 diabetes prevention and treatment.