Background: Type 2 diabetes is a major health problem affecting millions of people.Controlled eating and regular physical activity are important for the management of type 2 diabetes. Dipeptidyl peptidase-4 enzyme (DPP-4) inhibitor sitagliptin is a potent agent for the treatment of type-2 diabetes. The aim of this study was to examine the effects of sitagliptin on the liver of rats with streptozotocin (STZ)-induced diabetes, in terms of (i) the expression levels of the cannabinoid 1 receptor (CB-1R) and glucagon-like peptide 1 receptor (GLP-1R), (ii) alterations in the number and localization of these peptides, and (iii) changes in histological and oxidative damage.Methods: Thirty-two neonatal (two-day-old) rats, which were divided into four groups, were treated with saline (control), sitagliptin (control; 1.5 mg/kg/day for 15 days starting from day 5 of the experimental period), STZ (diabetes; lOO mg/kg single dose), STZ + sitagliptin (diabetes + sitagliptin). After 20 days, hepatic tissues were obtained from rats.Results: The expressions of GLP-1R and CB-1R mRNA increased approximately 1.89- and 2.94-fold, respectively, in the diabetes + sitagliptin group as compared to the diabetic group. Additionally the number of GLP-1R immunopositive cells decreased and CB-1R immunopositive cells increased in comparison to the diabetic group; however, this was not statistically significant. Glutathione levels increased, but malondialdehyde and protein carbonyl levels decreased in the diabetes + sitagliptin group more than the diabetic group.Conclusion: Our findings indicate that sitagliptin treatment regulates GLP-1R and CB-1R gene expressions, which are associated with appetite regulation in diabetic rat, and may decrease oxidative stress and liver tissue damage. (C) 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.