Protective effect of oleanolic acid against beta cell dysfunction and mitochondrial apoptosis: crucial role of ERK-NRF2 signaling pathway.

Pancreatic beta cell dysfunction is a hallmark of diabetes. Our previous results have shown that oleanolic acid (OA) has anti-diabetic potential. However, there is little literature reporting the effect of OA on beta cell dysfunction. The present study was designed to investigate the protective effect of OA against lipotoxicity and the underlying mechanisms. Lepr (db/db) diabetic mice were subjected to fasting blood glucose measurement, intraperitoneal glucose tolerance test after the administration of OA for two weeks. Histopathological observation was conducted by HE staining and transmission electron microscopy assay. Pancreatic islets were isolated from db/db diabetic mice and C57BL/6J mice. Palmitic acid (PA) was used to induce lipotoxicity in vitro. Apoptosis was evaluated in pancreatic islets in diabetic mice and in isolated pancreatic islets and beta-TC3 cells by TUNEL assay. Cellular ATP content, mitochondrial function and redox balance were examined. Phosphorylation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) and the activation of nuclear erythroid factor 2 p45-related factor 2 (Nrf2) signaling were evaluated by western blotting. In db/db mice, OA significantly protects beta cell function against lipotoxicity, evidenced by inhibition of apoptosis and improvement of glucose tolerance. In cells, OA administration may protect against PA-induced apoptosis and decrease of GSIS, in which process the activation of Nrf2 is essential. Once Nrf2 is activated, OA could induce GCLc expression, promote the production of GSH, and thus inhibit JNK phosphorylation and solid the antioxidant defense of mitochondria, leading to the inhibition of mitochondrial apoptosis. ERK signaling pathway is responsible for OA-induced activation of Nrf2 and the protective effect of OA. Overall, our study enhances the understanding of the protective effect of OA on beta cell and provides clues for further studies on the underlying mechanisms.