Effects of Sulfonylureas on Peroxisome Proliferator Activated Receptor. Activity and on Glucose Uptake by Thiazolidinediones

Background: Sulfonylurea primarily stimulates insulin secretion by binding to its receptor on the pancreatic beta-cells. Recent studies have suggested that sulfonylureas induce insulin sensitivity through peroxisome proliferator-activated receptor. (PPAR gamma), one of the nuclear receptors. In this study, we investigated the effects of sulfonylurea on PPAR gamma transcriptional activity and on the glucose uptake via PPAR gamma Methods: Transcription reporter assays using Cos7 cells were performed to determine if specific sulfonylureas stimulate PPAR. transactivation. Glimepiride, gliquidone, and glipizide (1 to 500 mu M) were used as treatment, and rosiglitazone at 1 and 10 mu M was used as a control. The effects of sulfonylurea and rosiglitazone treatments on the transcriptional activity of endogenous PPAR gamma were observed. In addition, 3T3-L1 adipocytes were treated with rosiglitazone (10 mu M), glimepiride (100 mu M) or both to verify the effect of glimepiride on rosiglitazone-induced glucose uptake. Results: Sulfonylureas, including glimepiride, gliquidone and glipizide, increased PPAR. transcriptional activity, gliquidone being the most potent PPAR gamma agonist. However, no additive effects were observed in the presence of rosiglitazone. When rosiglitazone was co-treated with glimepiride, PPAR gamma transcriptional activity and glucose uptake were reduced compared to those after treatment with rosiglitazone alone. This competitive effect of glimepiride was observed only at high concentrations that are not achieved with clinical doses. Conclusion: Sulfonylureas like glimepiride, gliquidone and glipizide increased the transcriptional activity of PPAR gamma Also, glimepiride was able to reduce the effect of rosiglitazone on PPAR. agonistic activity and glucose uptake. However, the competitive effect does not seem to occur at clinically feasible concentrations.