title: Combination of omeprazole with GLP-1 agonist therapy improves insulin sensitivity and antioxidant activity in liver in type 1 diabetic mice.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No.8A, Moraiya, Ahmedabad 382210, India. amitjoharapurkar@zyduscadila.com.
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
authors.forename: Amit
authors.initials: A
authors.lastname: Joharapurkar
authors.forename: Nirav
authors.initials: N
authors.lastname: Dhanesha
authors.forename: Samadhan
authors.initials: S
authors.lastname: Kshirsagar
authors.forename: Jaysukh
authors.initials: J
authors.lastname: Detroja
authors.forename: Kartikkumar
authors.initials: K
authors.lastname: Patel
authors.forename: Tejal
authors.initials: T
authors.lastname: Gandhi
authors.forename: Kirti
authors.initials: K
authors.lastname: Patel
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bahekar
authors.forename: Mukul
authors.initials: M
authors.lastname: Jain
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D004359:Drug Therapy, Combination; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000819:agonists*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009853:Omeprazole / Q000494:pharmacology* / Q000627:therapeutic use; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D054328:Proton Pump Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D014688:Venoms / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D051267:NF-E2-Related Factor 2; D010455:Peptides; D054328:Proton Pump Inhibitors; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D009853:Omeprazole