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Published online May 16, 2008
Diabetes 57:2083-2091, 2008
DOI: 10.2337/db08-0144
© 2008 by the American Diabetes Association
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Impact of Oxidative Stress and Peroxisome Proliferator–Activated Receptor {gamma} Coactivator-1{alpha} in Hepatic Insulin Resistance

Naoki Kumashiro1, Yoshifumi Tamura1, Toyoyoshi Uchida1, Takeshi Ogihara1, Yoshio Fujitani1,2, Takahisa Hirose1,2, Hideki Mochizuki3, Ryuzo Kawamori1,2, and Hirotaka Watada1

1 Department of Medicine, Metabolism, and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan
2 Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo, Japan
3 Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan

Corresponding author: Hirotaka Watada, hwatada{at}med.juntendo.ac.jp

OBJECTIVE—Recent studies identified accumulation of reactive oxygen species (ROS) as a common pathway causing insulin resistance. However, whether and how the reduction of ROS levels improves insulin resistance remains to be elucidated. The present study was designed to define this mechanism.

RESEARCH DESIGN AND METHODS—We investigated the effect of overexpression of superoxide dismutase (SOD)1 in liver of obese diabetic model (db/db) mice by adenoviral injection.

RESULTS—db/db mice had high ROS levels in liver. Overexpression of SOD1 in liver of db/db mice reduced hepatic ROS and blood glucose level. These changes were accompanied by improvement in insulin resistance and reduction of hepatic gene expression of phosphoenol-pyruvate carboxykinase and peroxisome proliferator–activated receptor {gamma} coactivator-1{alpha} (PGC-1{alpha}), which is the main regulator of gluconeogenic genes. The inhibition of hepatic insulin resistance was accompanied by attenuation of phosphorylation of cAMP-responsive element-binding protein (CREB), which is a main regulator of PGC-1{alpha} expression, and attenuation of Jun NH2-terminal kinase (JNK) phosphorylation. Simultaneously, overexpression of SOD1 in db/db mice enhanced the inactivation of forkhead box class O1, another regulator of PGC-1{alpha} expression, without the changes of insulin-induced Akt phosphorylation in liver. In hepatocyte cell lines, ROS induced phosphorylation of JNK and CREB, and the latter, together with PGC-1{alpha} expression, was inhibited by a JNK inhibitor.

CONCLUSIONS—Our results indicate that the reduction of ROS is a potential therapeutic target of liver insulin resistance, at least partly by the reduced expression of PGC-1{alpha}.


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