Thiazolidinediones are a novel class of antidiabetic drugs that reduce insulin resistance through interaction with nuclear peroxisome proliferator-activated receptor (PPAR)gamma. One of these agents, troglitazone, was also proposed to protect beta cells against FFA-induced toxicity, but this effect has not yet been directly demonstrated. We recently reported in vitro conditions under which free fatty acids (FFA) cause beta cell death by necrosis or apoptosis. The present study investigates whether troglitazone (10 microM) interferes with this FFA-induced toxicity. Addition of this compound did not protect against oleate- or palmitate-induced toxicity. On the contrary, it increased palmitate-induced necrosis during the first two days of culture, and elevated (increase by 10-20%, P<0.05) both oleate- and palmitate-induced apoptosis after 8 days. These results do not support the view that troglitazone exerts a direct protective effect on beta cells that are exposed to cytotoxic FFA concentrations. They instead indicate that the agent may sensitize pancreatic beta cells to FFA-induced damage, raising the possibility that its use facilitates the deleterious effect of increased FFA levels on the pancreatic beta cell mass.