Oxidative stress induces insulin resistance by activating the nuclear factor-?B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase

Abstract

Aims/hypothesis. Oxidative stress is associated with diabetes, hypertension and atherosclerosis. Insulin resistance is implicated in the development of these disorders. We tested the hypothesis that oxidative stress induces insulin resistance in rats, and endeavoured to identify mechanisms linking the two. Methods. Buthionine sulfoximine (BSO), an inhibitor of glutathione synthase, was administered to SpragueDawley rats and 3T3-L1 adipocytes. Glucose metabolism and insulin signalling both in vivo and in 3T3-L1 adipocytes were examined. In 3T3-L1 adipocytes, the effects of overexpression of a dominant negative mutant of inhibitory κB (IκB), one role of which is to block oxidative-stress-induced nuclear factor (NF)-κB activation, were investigated. Results. In rats given BSO for 2 weeks, the plasma lipid hydroperoxide level doubled, indicating increased oxidative stress. A hyperinsulinaemic-euglycaemic clamp study and a glucose transport assay using isolated muscle and adipocytes revealed insulin resistance in BSO-treated rats. BSO treatment also impaired insulin-induced glucose uptake and GLUT4 translocation in 3T3-L1 adipocytes. In BSO-treated rat muscle, adipose tissue and 3T3-L1 adipocytes, insulin-induced IRS-1 phosphorylation in the low-density microsome (LDM) fraction was specifically decreased, while that in whole cell lysates was not altered, and subsequent translocation of phosphatidylinositol (PI) 3-kinase from the cytosol and the LDM fraction was disrupted. BSO-induced impairments of insulin action and insulin signalling were reversed by overexpressing the dominant negative mutant of IκB, thereby suppressing NF-κB activation. Conclusions/interpretation. Oxidative stress induces insulin resistance by impairing IRS-1 phosphorylation and PI 3-kinase activation in the LDM fraction, and NF-κB activation is likely to be involved in this process.

From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy

“…Some studies reported that such protein movements are redox-sensitive. In skeletal muscle of rats, insulin-stimulated subcellular redistribution of tyrosine-phosphorylated IRS-1 and p85 were altered by oxidative stress induced by an inhibitor of glutathione synthesis [164]. Similar results were obtained in adipose tissue and 3T3-L1 adipocytes [164,165].…”

“…In skeletal muscle of rats, insulin-stimulated subcellular redistribution of tyrosine-phosphorylated IRS-1 and p85 were altered by oxidative stress induced by an inhibitor of glutathione synthesis [164]. Similar results were obtained in adipose tissue and 3T3-L1 adipocytes [164,165]. Additional evidences revealed that, in L6 myotubes, oxidative stress prevents insulin-induced actin reorganization [166].…”

Resistin-like Molecule β Activates MAPKs, Suppresses Insulin Signaling in Hepatocytes, and Induces Diabetes, Hyperlipidemia, and Fatty Liver in Transgenic Mice on a High Fat Diet

“…PI 3-kinase activities in the immunoprecipitants were assayed as previously described (23). For the Akt kinase assay, an Akt kinase assay kit (Cell signaling) was used according to the manufacturer's instructions.…”

The hOGG1 Ser326Cys gene polymorphism is associated with decreased insulin sensitivity in subjects with normal glucose tolerance

“…In a variety of tissues, elevated glucose and free fatty acid levels result in the generation of ROS and, consequently, increased oxidative stress (Maddux et al 2001;Tretter and Adam-Vizi 2000). ROS directly damage cells by activating a variety of stress-sensitive intracellular signaling pathways such as NF-jB, p38 MAPK, JNK/SAPK, PKC, and others (Ogihara et al 2004;Tretter and Adam-Vizi 2000). It has also been demonstrated that oxidative stress may result in IR via a similar intracellular signaling pathway (Bruce et al 2003;Ceriello et al 2004;Evans et al 2003;Rudich et al 1998;Talior et al 2003).…”