Combination of APD668, a G protein-coupled receptor 119 agonist with linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in a murine model of non-alcoholic steatohepatitis with diabetes

• Published in: Medical molecular morphology Vol. 52; no. 1; pp. 36 - 43
• Main Authors: Bahirat, Umakant Ashok, Talwar, Rashmi, Shenoy, Rekha Raghuveer, Nemmani, Kumar V. S., Goel, Rajan Naresh
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.03.2019; Springer Nature B.V
• Subjects: Anatomy; Animal models; Diabetes; Diabetes mellitus; Dipeptidyl-peptidase IV; Fatty liver; Fibrosis; High fat diet; Medicine; Medicine & Public Health; Molecular Medicine; Neonates; Original Paper; Oxidative stress; Pathology; Rodents; Steatosis; Streptozocin; Tumor necrosis factor-α; DPPIV inhibitor; Inflammation; GLP-1; NASH; GPR119 agonist; Fibrosis
• ISSN: 1860-1480; 1860-1499
• DOI: 10.1007/s00795-018-0200-4

Non-alcoholic steatohepatitis (NASH) is characterized by the presence of hepatic steatosis, oxidative stress, inflammation, and hepatocyte injury with or without fibrosis. In this study, we explored the effect of APD668, a GPR119 agonist alone or in combination with linagliptin, a DPPIV inhibitor, on the progression of steatohepatitis in a murine model of NASH with diabetes. A novel NASH model with diabetes was generated by administration of streptozotocin injection to neonatal C57BL/6 mice (2–3 days old) combined with a high-fat diet feeding from the age of 4 weeks. The plasma biochemical parameters, oxidative stress, inflammation and histopathological changes were assessed. APD668 alone showed reduction in plasma glucose (− 39%, P  < 0.05) and triglyceride level (− 26%) whereas a combined treatment of APD668 with linagliptin resulted in a more pronounced reduction in plasma glucose (− 52%, P  < 0.001) and triglyceride (− 50%, P  < 0.05) in NASH mice. In addition, co-administration of APD668 with linagliptin demonstrated a significant decrease in hepatic triglyceride, NAS score, hepatic TBARS and hepatic TNF-α in NASH mice with diabetes. These findings suggest that GPR119 receptor agonists in combination with DPPIV inhibitors may represent a promising therapeutic strategy for the treatment of NASH.