Effect Of Dibutyl Phthalate On Type 2 Diabetes In Mice And Its Molecular Mechanism

The incidence of diabetes is increasing worldwide and has become one of the major diseases endangering human health.Phthalates are thought to be closely associated with diabetes.Epidemiological studies suggest a positive relationship between phthalate exposure and diabetes.However,little is known about the impact of dibutyl phthalate(DBP)exposure on the development of diabetes.To determine the role of DBP exposure on the development of type 2 diabetes,mice were orally exposed to DBP dosages of 0.5,5,50 mg/kg/day for 7 weeks,combined with a high fat diet and injections of a low dose of streptozotocin(STZ)(40 mg/kg).The results showed that exposure to 50 mg/kg/day DBP alone induced a marked decrease in insulin secretion and glucose intolerance,but had no influence on insulin resistance.However,combined with a high fat diet and STZ treatment,DBP exposure markedly aggravated glucose intolerance,insulin tolerance and insulin resistance and induced lesions in the pancreas and kidney.Investigation of the role of DBP on the insulin signaling pathway,we found that DBP exposure could disrupt the PI3K expression and AKT phosphorylation,and decrease the level of GLUT-2 in the pancreas.Administering demethylasterriquinone-B 1,significantly increased the level of PI3K,AKT phosphorylation and GLUT-2 expression,effectively inhibiting the aggravation of diabetes.Our results suggested that DBP aggravated type 2 diabetes by disrupting the insulin signaling pathway and impairing insulin secretion.In addition,The data showed that exposure to DBP induced an increase in ROS levels,and decreased expression of pancreatic antioxidant factor SOD,which was accompanied by a decrease in insulin secretion and an increase in fasting blood glucose levels and insulin resistance.DBP exposure induced a decrease in the expression of liver glucose transporter-2(GLUT2),while pancreatic islet cell apoptosis partly explained the decrease in insulin secretion and the increase in insulin resistance.Administration of Vitamin E to block oxidative stress,alleviated these symptoms and disorders,suggesting that the oxidative damage caused by DBP exposure might be responsible for these diabetic lesions.Our results suggest that DBP promotes the development of type 2 diabetes through oxidative damage,and that the DBP exposure-induced disruption of glucose transportation and of pancreatic islet cell apoptosis might be responsible for this diabetic disorder.In addition,the increase in LDL-C,HDL-C,and TC,the decrease in FFA level suggested that DBP could affect the lipid metabolism.In conclusion,the results of this study show that DBP can promote the development of T2DM by interfering with insulin signal,resulting in oxidative damage and lipid metabolism abnormality.