Selenite exacerbates hepatic insulin resistance in mouse model of type 2 diabetes through oxidative stress-mediated JNK pathway

• Published in: Toxicology and applied pharmacology 2015-12, Vol.289 (3), p.409-418
• Main Authors: Zhou, Jun, Xu, Gang, Bai, Zhaoshuai, Li, Kaicheng, Yan, Junyan, Li, Fen, Ma, Shuai, Xu, Huibi, Huang, Kaixun
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ALBUMINS; Animals; BLOOD; c-Jun N-terminal kinase; CHEMILUMINESCENCE; DIABETES MELLITUS; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diet, High-Fat - adverse effects; Fasting - blood; Fasting - metabolism; Gene Expression - drug effects; GLUCOSE; Glucose Intolerance - genetics; Glucose Intolerance - metabolism; GLUTATHIONE; GLYCOLYSIS; INSULIN; Insulin - blood; Insulin resistance; Insulin Resistance - genetics; Insulin Resistance - physiology; LIVER; Liver - drug effects; Liver - metabolism; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; MICE; Mice, Inbred C57BL; OXIDATION; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; PEROXIDASES; PHOSPHATASES; PHOSPHOTRANSFERASES; POLYMERASES; Pyruvate Kinase - genetics; Pyruvate Kinase - metabolism; Pyruvic Acid - metabolism; RECEPTORS; Selenious Acid - pharmacology; SELENITES; Selenium; Selenoprotein; Signal Transduction - drug effects; Signal Transduction - genetics; STREPTOZOCIN; Streptozocin - pharmacology
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2015.10.019

Recent evidence suggests a potential pro-diabetic effect of selenite treatment in type 2 diabetics; however, the underlying mechanisms remain elusive. Here we investigated the effects and the underlying mechanisms of selenite treatment in a nongenetic mouse model of type 2 diabetes. High-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice were orally gavaged with selenite at 0.5 or 2.0mg/kgbody weight/day or vehicle for 4weeks. High-dose selenite treatment significantly elevated fasting plasma insulin levels and insulin resistance index, in parallel with impaired glucose tolerance, insulin tolerance and pyruvate tolerance. High-dose selenite treatment also attenuated hepatic IRS1/Akt/FoxO1 signaling and pyruvate kinase gene expressions, but elevated the gene expressions of phosphoenolpyruvate carboxyl kinase (PEPCK), glucose 6-phosphatase (G6Pase), peroxisomal proliferator-activated receptor-γ coactivator 1α (PGC-1α) and selenoprotein P (SelP) in the liver. Furthermore, high-dose selenite treatment caused significant increases in MDA contents, protein carbonyl contents, and a decrease in GSH/GSSG ratio in the liver, concurrent with enhanced ASK1/MKK4/JNK signaling. Taken together, these findings suggest that high-dose selenite treatment exacerbates hepatic insulin resistance in mouse model of type 2 diabetes, at least in part through oxidative stress-mediated JNK pathway, providing new mechanistic insights into the pro-diabetic effect of selenite in type 2 diabetes. •Selenite exacerbates hepatic insulin resistance in HFD/STZ-induced diabetic mice.•Selenite elevates hepatic gluconeogenesis and reduces glycolysis in diabetic mice.•Selenite exacerbates hepatic oxidative stress and triggers JNK signaling pathway.•Selenite elevates hepatic selenoprotein P expression in diabetic mice.