Oleanolic acid derivative DKS26 exerts antidiabetic and hepatoprotective effects in diabetic mice and promotes glucagon‐like peptide‐1 secretion and expression in intestinal cells

• Published in: British journal of pharmacology Vol. 174; no. 17; pp. 2912 - 2928
• Main Authors: Chen, Fei‐Fei, Wang, Jian‐Ta, Zhang, Li‐Xia, Xing, Shu‐Fang, Wang, Yun‐Xia, Wang, Kai, Deng, Shu‐Li, Zhang, Ji‐Quan, Tang, Lei, Wu, Hao‐Shu
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.09.2017; John Wiley and Sons Inc
• Subjects: Alanine; Alanine transaminase; Alanine Transaminase - blood; Animal models; Animals; Antidiabetics; Aspartate aminotransferase; Aspartate Aminotransferases - blood; Blood Glucose - analysis; Body Weight - drug effects; Cell Line; Cyclic AMP; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Cytokines; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Enteroendocrine Cells - drug effects; Enteroendocrine Cells - metabolism; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - metabolism; Glucose; Glucose tolerance; Homeostasis; Humans; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Inflammation; Insulin; Intestine; Lipid Metabolism - drug effects; Lipids; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice; Morphology; Obesity - blood; Obesity - drug therapy; Obesity - metabolism; Oleanolic acid; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - pharmacology; Oleanolic Acid - therapeutic use; Pancreas; Pancreas - drug effects; Pancreas - pathology; Plasma levels; Protective Agents - pharmacology; Protective Agents - therapeutic use; Protein kinase A; Research Paper; Research Papers; Rodents; Secretion; Signal transduction; Streptozocin; Studies
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13921

Background and Purpose Glucagon‐like peptide‐1 (GLP‐1) is an important target for diabetes therapy based on its key role in maintaining glucose and lipid homeostasis. This study was designed to investigate antidiabetic and hepatoprotective effects of a novel oleanolic acid derivative DKS26 in diabetic mice and elucidate its underlying GLP‐1 related antidiabetic mechanisms in vitro and in vivo. Experimental Approach The therapeutic effects of DKS26 were investigated in streptozotocin (STZ)‐induced and db/db diabetic mouse models. Levels of plasma glucose, glycosylated serum protein (GSP), lipid profiles, insulin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), oral glucose tolerance (OGT), pancreatic islets and hepatic histopathological morphology, liver lipid levels and expression of pro‐inflammatory cytokines were assessed. Intestinal NCI‐H716 cells and diabetic models were used to further validate its potential GLP‐1‐related antidiabetic mechanisms. Key Results DKS26 treatment (100 mg·kg−1·day−1 ) decreased plasma levels of glucose, GSP, ALT and AST; ameliorated OGT and plasma lipid profiles; augmented plasma insulin levels; alleviated islets and hepatic pathological morphology; and reduced liver lipid accumulation, inflammation and necrosis in vivo. Furthermore, DKS26 enhanced GLP‐1 release and expression, accompanied by elevated levels of cAMP and phosphorylated PKA in vitro and in vivo. Conclusion and Implications DKS26 exerted hypoglycaemic, hypolipidaemic and islets protective effects, which were associated with an enhanced release and expression of GLP‐1 mediated by the activation of the cAMP/PKA signalling pathway, and alleviated hepatic damage by reducing liver lipid levels and inflammation. These findings firmly identified DKS26 as a new viable therapeutic option for diabetes control.