Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3-L1 adipocytes.

Abstract

Prolonged exposure of 3T3-L1 adipocytes to micromolar concentrations of H2O2 results in an impaired response to the acute metabolic effects of insulin. In this study, we further characterized the mechanisms by which oxidative stress impairs insulin stimulation of glucose transport activity. Although insulin induced a 2.5-fold increase in plasma membrane GLUT4 content and a 50% reduction in its abundance in the low-density microsomal (LDM) fraction in control cells, oxidation completely prevented these responses. The net effect of insulin on 2-deoxyglucose uptake activity was reduced in oxidized cells and could be attributed to GLUT1 translocation. Insulin stimulation of insulin receptor substrate (IRS) 1 tyrosine phosphorylation and the association of IRS-1 with phosphatidylinositol (PI) 3-kinase were not impaired by oxidative stress. However, a 1.9-fold increase in the LDM content of the p85 subunit of PI 3-kinase after insulin stimulation was observed in control, but not in oxidized, cells. Moreover, although insulin induced an increase in IRS-1-associated PI 3-kinase activity in the LDM in control cells, this effect was prevented by oxidation. These findings suggest that prolonged low-grade oxidative stress impairs insulin-stimulated GLUT4 translocation, potentially by interfering with compartment-specific activation of PI 3-kinase.

Evaluation of salivary oxidative parameters in overweight and obese young adults

“…Oxidative stress occurring in obesity contributes to the oxidation of proteins in the plasma; these proteins may then undergo functional changes, in particular, loss of metabolic, enzymatic, and immunological properties (8). Protein thiol groups are the most susceptible to oxidation.…”

“…Obesity is associated with an increase in oxidative stress, defined as an increased load of free radicals comprised of ROS and RNS generated during cellular metabolism (8). These free radicals are chemically reactive molecules that may damage cellular proteins, membranes, and DNA.…”

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

“…Genetic (Moller et al 1996) and environmental (Paolisso et al 1999) factors may play a role. A recent line of evidence has indicated that increased generation of oxidative stress may also be a common pathogenetic factor mediating the appearance of IR (Bruce et al 2003;Ceriello et al 2004;Evans et al 2003;Rudich et al 1998;Talior et al 2003). 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).…”

“…Several studies have demonstrated that oxidative stress may impair insulin action (Bruce et al 2003;Ceriello et al 2004;Evans et al 2003;Rudich et al 1998;Talior et al 2003). In particular, elevated free radical levels were found to impair insulin-induced glucose transporter-4 translocation in adipocytes, resulting in a degree of IR (Rudich et al 1998). However, the identity of the genes involved has not been fully elucidated.…”

“…The contribution of genetic (Moller et al 1996) and environmental (Paolisso et al 1999) factors to the development of IR has been widely recognized. Several studies have demonstrated that oxidative stress may impair insulin action (Bruce et al 2003;Ceriello et al 2004;Evans et al 2003;Rudich et al 1998;Talior et al 2003). In particular, elevated free radical levels were found to impair insulin-induced glucose transporter-4 translocation in adipocytes, resulting in a degree of IR (Rudich et al 1998).…”