Impact of mitochondrial ROS production in the pathogenesis of insulin resistance

Abstract

Tumor necrosis factor-alpha (TNF-α) inhibits insulin action, in part, by activating c-jun NH 2-terminal kinases (JNK). However, the precise mechanisms by which TNF-α activates JNK are unknown. Recently, we confirmed that hyperglycemia increased mitochondrial reactive oxygen species (ROS) production, and which can associate with the pathogenesis of diabetic vascular complications. In addition, apoptosis signal-regulating kinase 1 (ASK1) was reported to activate the JNK and p38 signaling pathways and is required for TNF-α-induced apoptosis. Here we demonstrate that TNF-α increases mitochondrial ROS production and ASK1 activity, and that these TNF-α-induced phenomena associate with JNK activation, increase in Ser 307 phosphorylation of IRS-1 and decrease in insulin-stimulated tyrosine phosphorylation of IRS-1, all of which are believed to be the molecular basis of TNF-α-induced insulin resistance. We claim that mitochondrial ROS production may be a key factor not only in diabetic vascular complications, but also in the development of type 2 diabetes. This integrating paradigm could provide a new conceptual framework for further research and therapies for the treatment of type 2 diabetes.