ORIGINAL ARTICLE Effects of Sitagliptin on Nonalcoholic Fatty Liver Disease in Diet-Induced Obese Rats Selvihan Beysel Akaslan, MD, 1 Ceyla Konca Degertekin, MD, 2 Guldal Yilmaz, MD, 3 Nuri Cakir, MD, 2 Metin Arslan, MD, 2 and Fusun Balos Toruner, MD 2 Abstract Background: Studies investigating the effects of dipeptidyl peptidase-4 inhibitors on hepatic steatosis are lacking. We aimed to determine the effects of sitagliptin on nonalcoholic fatty liver disease (NAFLD) in rats with diet- induced obesity. Methods: A total of 24 adult female Sprague-Dawley rats, which were 24 weeks old and weighed 199–240 grams, were used. The rats were randomly separated into two groups. The control group (n = 6) was fed with standard rat diet; the remaining rats (n = 18) were fed with a high-fat diet (HFD) to induce NAFLD. After 12 weeks, rats that were fed with a HFD were randomly separated into two groups: (1) HFD-only group (n = 8) was fed with a HFD for an additional 4 weeks, (2) HFD-sitagliptin group (n = 10) received sitagliptin (3 mg/kg) for 4 weeks in addition to HFD. At the end of the study (16 th week), blood samples were drawn from all rats to determine serum glucose, triglyceride, cholesterol, alanine aminotransferase (ALT), and plasma insulin levels. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR) index. Histopathologic evaluation of liver samples was undertaken. Results: The HFD-sitagliptin group had significantly lower serum glucose (140.8 – 18.8 vs. 224.7 – 20.6 mg/dL, P < 0.001), plasma insulin (15.8 – 4.4 vs. 28.0 – 5.9 mIU/L, P < 0.001), HOMA-IR index (4.9 – 1.8 vs. 15.9 – 2.3, P < 0.001), serum triglycerides (199.0 – 108.7 vs. 468.0 – 370.7 mg/dL, P < 0.001), and cholesterol (82.0 – 26.7 vs. 90.5 – 7.0, P < 0.001) values compared to the HFD-only group. Hepatic steatosis was significantly less (mean score, 1 vs. 2; P < 0.001) in the HFD-sitagliptin group compared to the HFD-only group, whereas there was no difference in hepatic inflammation (P = 0.057), liver weight (P = 0.068), and ALT levels (P = 0.232). Conclusion: Sitagliptin may improve hepatic steatosis by increasing insulin sensitivity and improving lipid profiles in rats. Introduction N onalcoholic fatty liver disease (NAFLD) is the most common liver disease with an estimated preva- lence of 20%–30% in Western countries. 1 NAFLD displays a histological spectrum of disease ranging from simple hepatic steatosis to lobular necroinflammation with or without cen- trilobular fibrosis, which is called nonalcoholic steatohepa- titis (NASH). 2 It has been shown that NAFLD is strongly associated and often coexists with the features of metabolic syndrome as central obesity, type 2 diabetes mellitus (T2DM), hypertension, and hyperlipidemia. 3 Insulin resis- tance is the primary pathogenic factor in both NAFLD and metabolic syndrome. 3 Due to the absence of treatment mo- dalities with proven efficacy, therapy is directed to the cor- rection of risk factors of insulin resistance and decrease in delivery of fatty acids to the liver. 2,4 Hence, agents that im- prove insulin action and regulate fatty acid trafficking may serve as new treatment strategies for the resolution of NAFLD. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that are released from the intestine following oral ingestion of nutrients. 5 They promote insulin secretion from pancreatic b-cells. GLP-1 regulates postprandial glucose disposal by inhibiting glucose-dependent glucagon secretion from a-cells 1 Department of Internal Medicine, 2 Department of Endocrinology and Metabolism, and 3 Department of Pathology, Gazi University Faculty of Medicine, Ankara, Turkey. METABOLIC SYNDROME AND RELATED DISORDERS Volume X, Number X, 2013 Ó Mary Ann Liebert, Inc. Pp. 1–8 DOI: 10.1089/met.2012.0128 1