Abstract: This study was designed to investigate the effect and mechanism of atorvastatin on blood glucose of mild diabetic rats.Mild diabetic rats were induced by ip injection of streptozotocin (35 mg/kg),and treated with 20 mg/kg or 100 mg/kg atorvastatin for 2 weeks.Oral glucose tolerance test (OGTT) was carried out and insulin level was measured;liver microsome CYP3A1/2 and CYP2C9 activity was determined;and QT-PCR analysis was used to quantify CYP3A1/2 mRNA expression.The effect of atorvastatin on glucose consumption,CYP3A activity and reactive oxygen species (ROS) of HepG2 cell was investigated,and its effect on INS-1 cell insulin secretion and ROS formation was determined.The result showed that low dose atorvastatin (20 mg/kg)deteriorated OGTT of mild diabetic rats;however,the effect of high dose atorvastatin (100 mg/kg) was less potent.Low dose atorvastatin treatment led to an increased CYP3A and CYP2C activity.QT-PCR result also confirmed an induction of CYP3A1/2 mRNA expression by low dose atorvastatin.Atorvastatin treatment of HepG2 cells demonstrated a two-phase effect of atorvastatin on CYP3A activity.Along with decreased glucose consumption,atorvastatin increased ROS concentration in HepG2 cells.They were reversed by CYP3A inhibitor,erythromycin.Erythromycin also increased atorvastatin-impaired insulin secretion of INS-1 cells,which was accompanied by a decreased ROS formation.These results indicated that the adverse effect of atorvastatin on OGTT of mild diabetic rats could be a result of overproduction of ROS through an induction of CYP450.