Combination of omeprazole with GLP-1 agonist therapy improves insulin sensitivity and antioxidant activity in liver in type 1 diabetic mice |
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Authors: | Vishal Patel Amit Joharapurkar Nirav Dhanesha Samadhan Kshirsagar Jaysukh Detroja Kartikkumar Patel Tejal Gandhi Kirti Patel Rajesh Bahekar Mukul Jain |
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Affiliation: | 1. Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No.8A, Moraiya, Ahmedabad 382210, India;2. Anand Pharmacy College, Anand 388001, India;3. Department of Medicinal Chemistry, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad 382210, India |
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Abstract: | BackgroundCombination 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.MethodsWe 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.ResultsOmeprazole 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.ConclusionWe 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. |
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Keywords: | GLP-1 exendin-4 omeprazole type 1 diabetes insulin sensitivity Nrf-2 IRS-1 |
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