Ozone exposure triggers insulin resistance through muscle c-Jun N-terminal kinase activation

Diabetes. 2015 Mar;64(3):1011-24. doi: 10.2337/db13-1181. Epub 2014 Oct 2.


A growing body of evidence suggests that exposure to traffic-related air pollution is a risk factor for type 2 diabetes. Ozone, a major photochemical pollutant in urban areas, is negatively associated with fasting glucose and insulin levels, but most aspects of this association remain to be elucidated. Using an environmentally realistic concentration (0.8 parts per million), we demonstrated that exposure of rats to ozone induced whole-body insulin resistance and oxidative stress, with associated endoplasmic reticulum (ER) stress, c-Jun N-terminal kinase (JNK) activation, and disruption of insulin signaling in skeletal muscle. Bronchoalveolar lavage fluids from ozone-treated rats reproduced this effect in C2C12 myotubes, suggesting that toxic lung mediators were responsible for the phenotype. Pretreatment with the chemical chaperone 4-phenylbutyric acid, the JNK inhibitor SP600125, or the antioxidant N-acetylcysteine alleviated insulin resistance, demonstrating that ozone sequentially triggered oxidative stress, ER stress, and JNK activation to impair insulin signaling in muscle. This study is the first to report that ozone plays a causative role in the development of insulin resistance, suggesting that it could boost the development of diabetes. We therefore provide a potential mechanism linking pollutant exposure and the increased incidence of metabolic diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Anthracenes / pharmacology
  • Bronchoalveolar Lavage Fluid / chemistry
  • Cell Line
  • Enzyme Activation / drug effects
  • Insulin Resistance / physiology*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Mice
  • Ozone / toxicity*
  • Phenylbutyrates / pharmacology
  • Rats


  • Anthracenes
  • Phenylbutyrates
  • pyrazolanthrone
  • Ozone
  • 4-phenylbutyric acid
  • JNK Mitogen-Activated Protein Kinases
  • Acetylcysteine