Iron overload induces islet β cell ferroptosis by activating ASK1/P-P38/CHOP signaling pathway

Abstract

Background Recent studies have shown that the accumulation of free iron and lipid peroxides will trigger a new form of cell death—ferroptosis. This form of cell death is associated with a variety of diseases, including type 2 diabetes. We hypothesize that iron overload may play a role in driving glucose metabolism abnormalities by inducing endoplasmic reticulum stress that mediates ferroptosis in islet β cells. In this study, we tested this conjecture from in vivo and in vitro experiments. Methods We established a mouse iron overload model by intraperitoneal injection of iron dextrose (50 mg/kg) and an iron overload cell model by treating MIN6 cells with ferric ammonium citrate (640 μmol/L, 48 h) in vitro. The iron deposition in pancreatic tissue was observed by Prussian blue staining, and the pathological changes in pancreatic tissues by HE staining and the protein expression level by pancreatic immunohistochemistry. In the cellular experiments, we detected the cell viability by CCK8 and observed the cellular ultrastructure by transmission electron microscopy. We also used MDA and ROS kits to detect the level of oxidative stress and lipid peroxidation in cells. Western blotting was performed to detect the expression levels of target proteins. Results Iron overload induces MIN6 cell dysfunction, leading to increased fasting blood glucose, impaired glucose tolerance, and significantly decreased insulin sensitivity in mice. This process may be related to the ferroptosis of islet β cells and the activation of ASK1/P-P38/CHOP signaling pathway.

Keywords

• Iron overload
• Ferroptosis
• Type 2 diabetes
• Deferasirox
• Pancreatic β-cell function
• Lipid peroxidation