T2DM is characterized by progressive impairment of insulin secretion and insulin resistance. Introductionĭiabetes mellitus is the most common chronic disease, which is predicted to affect approximately 592 million adults worldwide by 2030 among these, type 2 diabetes mellitus (T2DM) accounts for ~90% of diabetes mellitus cases. These results demonstrate that CHS protected βTC3 cells against PA-induced oxidative stress and cell dysfunction through Nrf2 by the IRS-2/Akt/GSK-3 β-mediated pathway. In addition, inhibition of PI3K/Akt or GSK-3 β with specific inhibitors dramatically abrogated the protective effects of CHS, revealing that the IRS-2/Akt/GSK-3 β signaling axis was involved in the protective effects of CHS. The phosphorylation of IRS-2, PI3K, Akt, and GSK-3 β was markedly increased by CHS which were inhibited by PA. The antioxidative and benefit effects of CHS were inhibited by siNrf2. CHS treatment significantly increased the expression of Nrf2 in the cytoplasm and nuclear protein. As the results showed, CHS treatment inhibited apoptosis, promoted insulin release, and reduced oxidative stress. Furthermore, siRNA-targeted Nrf2, PI3K/Akt inhibitor (LY294002), or GSK-3 β inhibitor (LiCl) was used to investigate the crosstalk relationships between proteins. Protein expression levels were measured by Western blotting. Pancreatic functions, ROS, and antioxidant protein measurements were performed to evaluate the effects of CHS on cell injuries. High-fat (HF) diet and a low dose of streptozotocin- (STZ-) induced type 2 diabetes mellitus (T2DM) model in vivo and βTC3 cells subjected to 0.5 mM palmitate (PA) to imitate the lipotoxic model in vitro were performed. This study was designed to investigate the effects of CHS against lipotoxicity-induced β-cell injuries and its possible mechanism involved. Chikusetsu saponin IVa (CHS) showed antioxidant and antidiabetic properties in our previous studies however, its protective effects against lipotoxicity-induced β-cell oxidative stress and dysfunction are not clear. Chronic hyperlipidemia leads to pancreatic β-cell apoptosis and dysfunction through inducing oxidative stress.
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