Combination of omeprazole with GLP-1 agonist Therapy improves insulin sensitivity and antioxidant activity in liver in type 1 diabetic mice

Background: combination with suitable pharmacological agents can improve the antiobesity and antidiabetic actions of glucagon like peptide-1 (glp-1) based therapies. glp-1 agonist exendin-4 may have insulin-independent effects on amelioration of insulin resistance and hepatic steatosis by virtue of its action on hepatic glp-1 receptors,and these effects can be improved by combination with proton pump inhibitors. however,it was not assessed whether omeprazole can improve the peripheral actions of exendin-4 in the state of insulin deficiency. methods: we investigated the effects of combination of omeprazole with glp-1 agonist exendin-4 in multiple low-dose streptozotocin( stz)-induced diabetes in c57bl/ksj mice,a model of type 1 diabetes. male diabetic mice were treated with exendin-4 and/or omeprazole for a period of 4 weeks. results: omeprazole treatment had no significant effect on lowering the blood glucose levels of diabetic mice,when compared to control,although it improved the antihyperglycemic actions of exendin-4. similarly,serum triglycerides and total cholesterols levels were significantly lower in the combination treated mice compared to either exendin-4 and omeprazole alone. in addition,the combination treatment significantly ameliorated lipid peroxidation and hepatic triglycerides in diabetic mice compared to either exendin-4 and omeprazole alone. the improvement in hepatic insulin sensitivity,as indicated by insulin tolerance test (itt) and pyruvate tolerance test (ipptt),was correlated with the expression of nuclear factor erythroid-related factor 2 (nrf2) and insulin receptor substrate-1 (irs-1) and the combination treatment significantly improved the insulin sensitivity in comparison to vehicle control. conclusion:we conclude that combination with omeprazole improves the insulin sensitizing actions of glp-1 therapy and these effects are partially mediated through the decrease in hepatic steatosis and improvement in antioxidant status in the liver.