Administration of Troglitazone, but Not Pioglitazone, Reduces Insulin Resistance Caused by Short-Term Dexamethasone (DXM) Treatment by Accelerating the Metabolism of DXM

Thiazolidine derivatives are newly developed insulin sensitizer agents that act to lower plasma glucose and reduce hyperinsulinemia (1), and they are being used to treat patients with type 2 diabetes accompanying insulin resistance. However, the precise molecular mechanism by which thiazolidines counteract general insulin resistance has yet to be clarified. Glucocorticoid induces gluconeogenesis and insulin resistance, resulting in the development of diabetes (2), but the precise molecular mechanisms remain to be elucidated. Recent studies showed that troglitazone, which was the first clinically applied drug of thiazolidine derivatives, improved dexamethasone (DXM)-induced insulin resistance in rats in a glucose clamp study (3) and that it had a good effect on patients with glucocorticoid-induced diabetes (4). In the present study, we examined the effects of troglitazone and pioglitazone, another insulin sensitizer, on insulin resistance induced by short-term DXM treatment, and compared their effects with those of metformin. Furthermore, troglitazone has been reported to reduce the plasma concentration of the oral contraceptives ethinylestradiol and norethindrone, which are metabolized by the liver enzyme CYP3A4 (5). Troglitazone is also believed to be an inducer of CYP3A4 like rifampicin and phenytoin, and it has been speculated that troglitazone may reduce the effects of glucocorticoid, which is metabolized by CYP3A4, by enhancing the activity of CYP3A4. In this study, we investigated the effects of troglitazone and pioglitazone on …