title: Impact of mitochondrial ROS production in the pathogenesis of insulin resistance.
abstract: Tumor necrosis factor-alpha (TNF-alpha) inhibits insulin action, in part, by activating c-jun NH(2)-terminal kinases (JNK). However, the precise mechanisms by which TNF-alpha 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-alpha-induced apoptosis. Here we demonstrate that TNF-alpha increases mitochondrial ROS production and ASK1 activity, and that these TNF-alpha-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-alpha-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.
authors.affiliation: Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. takeshi@kaiju.medic.kumamoto-u.ac.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kukidome
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sonoda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Fujisawa
authors.forename: Takako
authors.initials: T
authors.lastname: Matsuhisa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Motoshima
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsumura
authors.forename: Eiichi
authors.initials: E
authors.lastname: Araki
mesh_terms: D000818:Animals; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology
chemical_list: D007328:Insulin; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D005947:Glucose