GSK-3β mediates dexamethasone-induced pancreatic β cell apoptosis

• Published in: Life sciences (1973) 2016-01, Vol.144, p.1-7
• Main Authors: Guo, Bin, Zhang, Wenjian, Xu, Shiqing, Lou, Jinning, Wang, Shuxia, Men, Xiuli
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Cell Line; Cell Proliferation - drug effects; Dexamethasone; Dexamethasone - pharmacology; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Glucocorticoids - pharmacology; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - physiology; Glycogen Synthase Kinase 3 beta; GSK-3β; Insulin-Secreting Cells - drug effects; Lithium Chloride - pharmacology; NADPH Oxidase 4; NADPH Oxidases - biosynthesis; NADPH Oxidases - genetics; Oxidative Stress - drug effects; Phosphorylation; Rats; Reactive Oxygen Species - metabolism; ROS
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2015.11.017

Glucocorticoids, such as dexamethasone, are widely used anti-inflammatory drugs. Their use is frequently associated with the development of steroid- associated diabetes. Pancreatic β-cell dysfunction has been suggested to be one of the main causes of steroid-associated diabetes. However, the mechanism is not fully understood. Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase and plays an important role in energy metabolism, cell growth and apoptosis. Therefore, the contribution of GSK-3β in dexamethasone-induced pancreatic β-cell apoptosis was determined in the present study. The effect of dexamethasone treatment on rat pancreatic β-cell line (INS-1) apoptosis (determined by TUNEL and Flow Cytometry), generation of reactive oxidative stress (ROS), and the phosphorylation status of GSK-3β was determined. The inhibitory effect of GSK-3β inhibitor-lithium chloride (LiCl) on dexamethasone-induced β-cell apoptosis was also evaluated. Dexamethasone (0.1μM) treatment induced INS-1 apoptosis, which was associated with increased GSK-3β activation and increased NOX4-derived ROS generation. Pretreatment of INS-1 with LiCl inhibited dexamethasone induced ROS generation and INS-1 apoptosis. This study provides a new mechanism of Dex induced pancreatic β cell apoptosis and may serve as a new therapeutic option for treating GC induced diabetes.