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

• DOI: 10.1111/bph.13921
• Publication Date: 2017-06-19T11:32:48Z
• Authors: Fei‐Fei Chen; Jian‐Ta Wang; Li‐Xia Zhang; Shu‐Fang Xing; Yun‐Xia Wang; Kai Wang; Shu‐Li Deng; Ji‐Quan Zhang; Lei Tang; Hao‐Shu Wu
• Keywords: Blood Glucose; Male; 0301 basic medicine; Enteroendocrine Cells; Body Weight; Alanine Transaminase; Lipid Metabolism; Cyclic AMP-Dependent Protein Kinases; 3. Good health; Cell Line; Diabetes Mellitus, Experimental; Mice; 03 medical and health sciences; Liver; Glucagon-Like Peptide 1; Cyclic AMP; Animals; Humans; Hypoglycemic Agents; Aspartate Aminotransferases; Obesity; Oleanolic Acid; Pancreas

Background and PurposeGlucagon‐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 ApproachThe 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 ResultsDKS26 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 ImplicationsDKS26 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.