Thiazolidinediones protect mouse pancreatic β-cells directly from cytokine-induced cytotoxicity through PPARγ-dependent mechanisms.

Since most of the current studies of thiazolidinediones (TZDs) are only focused on improving glycemic control, increasing insulin sensitivity, and regulating inflammatory states in Type 2 Diabetes, it is still controversial whether TZDs have direct, protective effects on pancreatic β-cells in autoimmune diabetes. Here, we show the protective effects of TZDs on mouse pancreatic β-cell line cells (NIT-1) impaired by exposure to inflammatory cytokines (IL-1β and IFN-γ) and explore the potential mechanisms for this. The apoptosis rate and caspase-3 activity were remarkably increased, and insulin secretion response to glucose was impaired severely by exposure to IL-1β/IFN-γ for 48 h compared to control cells, whereas apoptosis rate and caspase-3 activity were significantly decreased in cells with treatment of rosiglitazone (RGZ) or pioglitazone (PIG), and the capacity for insulin secretion response to glucose was recovered. TZDs protect pancreatic β-cells from cytokine-induced cytotoxicity through PPARγ activation. The protective effects of the TZDs on NIT-1 cells disappeared when PPARγ was blocked with PPARγ-siRNA interference or treatment with GW9662, the PPARγ antagonist. Additionally, the enhancement of PPARγ expression by treatment with TZDs inhibited the expression of caspase 3 in IL-1β/IFN-γ-induced NIT-cells. Also, the inhibition of caspase 3 expression by TZDs was blocked by co-treatment with GW9662 or infection with PPARγ-siRNA. Taken together, our data suggest that TZDs might serve to protect pancreatic β-cells directly from cytokine-induced cytotoxicity through a PPARγ-dependent pathway, and caspase-3 may play an important role in the mechanisms involved.