Effect and mechanism of atorvastatin on blood glucose of mild diabetic rats

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.