[Mechanisms of thiazolidinedione derivatives for hypoglycemic and insulin sensitizing effects]

Abstract

Ciglitazone was the first insulin sensitizer with a thiazolidinedione structure to reduce insulin resistance and hyperglycemia and many thiazolidinedione derivatives (TZDs) have since been reported as insulin sensitizers. Pioglitazone is reported to lower blood glucose through reductions in both hepatic and peripheral insulin resistance. Regarding the molecular mechanism, pioglitazone was first reported to increase the tyrosine kinase activity of the insulin receptor and then TZDs were reported to increase the insulin signal transduction. TNF-alpha causes insulin resistance through inhibition of the insulin signal transduction and TZDs have been shown to reduce insulin resistance by the suppression of the TNF-alpha gene expression. In addition, TZDs are specific agonists of PPAR gamma and the hypoglycemic effect of TZDs has been shown to involve PPAR gamma among the PPARs. Based on these observations, the molecular mechanisms of TZDs are discussed.