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Acute oxidative stress can reverse insulin resistance by inactivation of cytoplasmic JNK

Alina Berdichevsky1, Leonard Guarente, Avirup Bose

  • 1Novartis Institute for Biomedical Research, Cardiovascular and Metabolism Disease Area, Cambridge, Massachusetts 02139, USA.

The Journal of Biological Chemistry
|May 1, 2010
PubMed

Insights

Acute oxidative stress improves insulin sensitivity by altering JNK signaling pathway localization, contrasting with chronic stress effects. This finding is crucial for understanding diabetes and cardiovascular disease mechanisms.

Area of Science:

  • Cellular biology
  • Metabolic signaling
  • Molecular mechanisms of disease

Background:

  • Chronic oxidative stress impairs insulin sensitivity, contributing to diabetes and cardiovascular disease.
  • JNK signaling pathway activation, via insulin receptor substrate 1 phosphorylation, mediates stress-induced insulin resistance.
  • Exercise, despite inducing acute oxidative stress, enhances insulin sensitivity in Type 2 diabetes patients.

Purpose of the Study:

  • To investigate the mechanisms behind contrasting effects of acute versus chronic oxidative stress on insulin sensitivity.
  • To elucidate the role of JNK signaling and MKP7 in insulin resistance.

Main Methods:

  • Utilized a cellular model of insulin-resistant muscle.
  • Induced chronic and acute oxidative stress to study insulin and JNK signaling.
  • Analyzed the subcellular distribution of JNK and MKP7.

Main Results:

  • Chronic oxidative stress increased cytoplasmic phosphorylated JNK.
  • Acute oxidative stress caused MKP7 to move from the nucleus to the cytoplasm, reducing cytoplasmic phospho-JNK and increasing nuclear phospho-JNK.
  • Acute oxidative stress, dependent on MKP7, restored insulin sensitivity and glucose uptake.

Conclusions:

  • Contrasting effects of acute and chronic stress on insulin sensitivity are linked to subcellular distribution of MKP7 and activated JNK.
  • MKP7's role in regulating JNK localization is key to improving insulin sensitivity under acute stress conditions.

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