Sulfonylurea Agents Exhibit Peroxisome Proliferator-activated Receptor γ Agonistic Activity*

Sulfonylurea (SU) agents, including glimepiride and glibenclamide, are the most widely used oral hypoglycemic drugs, which stimulate insulin secretion primarily by binding to the SU receptor on the plasma membrane of pancreatic β-cells. Thiazolidinediones, such as pioglitazone and rosiglitazone, are other hypoglycemic agents that effectively improve peripheral insulin resistance through activation of peroxisome proliferator-activated receptor γ (PPARγ). In the present study, we found that glimepiride specifically induced the transcriptional activity of PPARγ in luciferase reporter assays. Glimepiride enhanced the recruitment of coactivator DRIP205 and dissociation of corepressors such as nuclear receptor corepressor and silencing mediator for retinoid and thyroid hormone receptors. In addition, glimepride directly bound to PPARγ in a manner competitive to rosiglitazone, which is a proven ligand for PPARγ. Furthermore, in 3T3-L1 adipocytes, glimepiride stimulated the transcriptional activity of the gene promoter containing PPAR-responsive element and altered mRNA levels of PPARγ target genes including aP2, leptin, and adiponectin. Finally, glimepiride induced adipose differentiation in 3T3-F442A cells, which was known to differentiate into adipocytes in a PPARγ-dependent manner. Most effects observed with glimepiride were also seen with glibenclamide. These data strongly suggest that glimepiride and glibenclamide, both of which belong to SU agents, should have PPARγ agonist activity, whose potencies were 16–25% of the maximum level achieved by pioglitazone. Our observation that glimepiride and glibenclamide could act not only on SU receptor but also on PPARγ may give an important clue to the development of novel antidiabetic drugs, which can enhance both insulin secretion from pancreatic β-cells and peripheral insulin sensitivity.