The Regulatory Effect And Mechanism Of Ebselen On TNF-? Induced Hepatic Insulin Resistance In HepG2 Cells

Type 2 diabetes is a multifaceted disease, marked by decreased glucose peripheral uptake, increased hepatic glucose production, and decreased insulin secretion and reduced insulin sensitivity. Insulin resistance is the main characteristic of type 2 diabetes, and it results from impairment of one or more steps in insulin signal transduction pathway.Oxidative stress has been implicated in the pathogenesis of insulin resistance. It has been suggested that increased reactive oxygen species(ROS) levels are an important trigger for insulin resistance. TNF-? is the main inflammatory factor leading to insulin resistance, it can reduce the insulin signal transduction, or induce oxidative stress-activated downstream stress sensitive signal pathway. Recently, studies have found that Ebselen is an organoselenium compound having potent antioxidant capacity. It is also a novel anti-inflammatory agent having glutathione peroxidase-like activity. Also, Ebselen reduces glucose levels in Zucker diabetic fatty rats. However, a link between Ebselen and the development of insulin resistance and diabetes remains poorly understood.In this paper, HepG2 cells were treated with TNF-? to establish insulin resistant cell model and the effects and mechanisms of Ebselen on TNF-? induced insulin resistance were investigated. We focus on the influences of Ebselen on glycogen content,gluconeogenesis and signaling pathways in HepG2 cells. The main results are as follows:MTT, reactive oxygen species assay, real-time quantitative PCR, western blotting,glycogen colorimetric assay and spectrophotometry were used to explore the effects of Ebselen on TNF-? induced insulin resistance. The experimental results showed that under the condition of TNF-? induced insulin resistance, exposure of HepG2 cells to Ebselen can obviously increase glycogen content and decrease gluconeogenesis gene expression. It suggested that Ebselen can reverse the disorder of glucose metabolism and ameliorate hepatic insulin resistance. At the same time, Ebselen inhibited excessive ROS generation,reduced phosphorylation of JNK, IKK?, p38 MAPK and also decreased serine phosphorylation of IRS-1 and raised its tyrosine phosphorylation, upregulated IRS-1expression, accompanied by increased phosphorylation of Akt, GSK-3? and FOXO1. It indicated that Ebselen ameliorated hepatic insulin resistance through inhibition a variety of stress-sensitive intracellular signaling pathways, such as IKK?, p38 MAPK and JNK.