Dexamethasone Inhibits PDX-1 In Pancreatic β-Cell Partially Through Foxo1 Transcription Factor

Glucocorticoids are widely used in clinical therapy and steroiddiabetes is one of the side effects of glucocorticoid treatment. Themolecular mechanisms involved in the process of steroid diabetes are notfully understood. The Foxo proteins, key transcriptional effectors ofinsulin and IGF signaling pathways could play an important role inβ-celldysfunction. In this study, we investigated the role of syntheticglucocorticoid, dexamethasone in the expression and activity of Foxofamily member Foxol inβ-cells. The results showed that dexamethasoneinduced Foxol expression in pancreaticβ(RINm5F) cells and this effectwas glucocorticoid receptor (GR)-dependent. Additionally,dexamethasone decreased the phosphorylation of Foxol and thephosphorylation of AKT, upstream of Foxol, and stimulant ofPI-3kinase/Akt signaling pathway reverted this effect. However, GRcompetitive antagonist couldn't block this effect and played a same roleas dexamethasone. The decrease of PDX-1, an important target gene ofFoxol in [3-cells, is involved inβ-cell dysfunction. Luciferase reporterstudies proofed that dexamethasone could increase Foxol transcriptional activity. Through RNA interference, we indicated that dexamethasonereduces PDX-1 expression partially by the increase of active Foxol.Besides, our research indicated that dexamethasone could induce PDX-1nuclear export by the increase of nuclear Foxo 1.In conclusion, the present study suggest that dexamethasone reducesPDX-1 expression partially by the increase of active Foxol and couldinduce PDX-1 nuclear export by the increase of nuclear Foxol. Thisnovel viewpoint will replenish the molecular mechanism of steroiddiabetes andβ-cell dysfunction induced by dexamethasone.