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Impact of mitochondrial ROS production in the pathogenesis of insulin resistance

Takeshi Nishikawa1, Daisuke Kukidome, Kazuhiro Sonoda

  • 1Department 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

Diabetes Research and Clinical Practice
|May 8, 2007
PubMed

Insights

Tumor necrosis factor-alpha (TNF-alpha) activates c-jun NH(2)-terminal kinases (JNK) via mitochondrial reactive oxygen species (ROS) and apoptosis signal-regulating kinase 1 (ASK1). This pathway contributes to insulin resistance and may play a role in type 2 diabetes development.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Metabolic Diseases

Background:

  • Tumor necrosis factor-alpha (TNF-alpha) impairs insulin action by activating c-jun NH(2)-terminal kinases (JNK).
  • The exact mechanisms of TNF-alpha-induced JNK activation remain unclear.
  • Hyperglycemia is linked to mitochondrial reactive oxygen species (ROS) production, contributing to diabetic vascular complications.

Purpose of the Study:

  • To elucidate the mechanisms by which TNF-alpha activates JNK.
  • To investigate the role of mitochondrial ROS and apoptosis signal-regulating kinase 1 (ASK1) in TNF-alpha-induced insulin resistance.
  • To explore the potential link between mitochondrial ROS and type 2 diabetes pathogenesis.

Main Methods:

  • Investigated TNF-alpha's effects on mitochondrial ROS production and ASK1 activity in relevant cellular models.
  • Assessed the association between TNF-alpha, ROS, ASK1, and JNK activation.
  • Examined the impact on insulin signaling pathways, specifically IRS-1 phosphorylation.

Main Results:

  • TNF-alpha was found to increase mitochondrial ROS production and ASK1 activity.
  • These TNF-alpha-induced changes were associated with JNK activation.
  • The study observed increased Ser(307) phosphorylation of IRS-1 and decreased insulin-stimulated tyrosine phosphorylation of IRS-1, key indicators of insulin resistance.

Conclusions:

  • Mitochondrial ROS production and ASK1 activation are critical mediators of TNF-alpha-induced JNK activation and subsequent insulin resistance.
  • Mitochondrial ROS may be a significant factor in both diabetic vascular complications and the development of type 2 diabetes.
  • This research offers a new framework for understanding and potentially treating type 2 diabetes.

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