Selenite Induces Insulin Resistance In HepG2 Cells: The Underlying Mechanisms

Selenium is an essential micronutrient in mammals. Selenium was found to have several insulin-like effects. Recent studies show that low and high selenium intake both increase the incidence of type 2 diabetes. However the underlying mechanism remains poorly understood. Insulin resistance holds an extremely important position in the pathogenesis of type 2 diabetes. Thus, studies of the relationship between selenium and insulin resistance will be beneficial to further understand the connections between selenium and diabetes, and may provide some information for the prevention and treatment of type 2 diabetes.In this paper, HepG2 cells were treated with sodium selenite to explore the effects of sodium selenite on the insulin signaling pathway and the mechanism between them. We focus on the influences of high sodium selenite on glucose metabolism(glycogen synthesis and gluconeogenesis), the insulin signaling pathway, oxidative stress and endoplasmic reticulum stress level in HepG2 cells. The main results are as follows:We use glycogen colorimetric assay kit II, real-time quantitative PCR, western blotting, spectrophotometry and reactive oxygen species assay kit to explore the effects of sodium selenite on the insulin signaling pathway in HepG2 cells. The connections and possible mechanisms between slenite and insulin resistance were carried out. The results showed that high concentrations of sodium selenite decreased glycogen content in HepG2 cells, promoted part of gluconeogenesis gene expression and reduced Akt phosphorylation level. It suggests that high concentrations of sodium selenite decreased insulin sensitivity,causing insulin resistance. Selenite did not change the expression of GRP78, indicating that at cellular level, there may be no clear relationship between selenite and endoplasmic reticulum stress. High selenium increased the content of ROS in HepG2 cells, and NAC reduced high ROS levels caused by high selenite. NAC treatment could reverse decreasedlevel of glycogen and increased gluconeogenesis gene expression caused by sodium selenite, indicating that ROS inhibited insulin signal and lower levels of oxidative stress was beneficial for insulin signal transduction. At the same time, NAC treatment increased Akt phosphorylation level, reduced the level of JNK phosphorylation, elevated level of tyrosine phosphorylation of IRS1, indicating that reduction of ROS could enhance insulin signaling. ROS caused activation of JNK and then reduced tyrosine phosphorylation of IRS1 inhibiting insulin signal transduction, causing insulin resistance, reducing glycogen synthesis and promoting gluconeogenesis.Our experimental results demonstrated that selenite induced ROS production in HepG2 cells, causing oxidative stress, activation of JNK and inhibition the insulin signal transduction, finally causing insulin resistance.