Impact of mitochondrial ROS production in the pathogenesis of insulin resistance.
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.
Nishikawa
Takeshi
T
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
Kukidome
Daisuke
D
Sonoda
Kazuhiro
K
Fujisawa
Kazuo
K
Matsuhisa
Takako
T
Motoshima
Hiroyuki
H
Matsumura
Takeshi
T
Araki
Eiichi
E
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
D007328:Insulin; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D005947:Glucose