Reactive oxygen species enhance insulin sensitivity.
Chronic reactive oxygen species (ROS) production by mitochondria may contribute to the development of insulin resistance, a primary feature of type 2 diabetes. In recent years it has become apparent that ROS generation in response to physiological stimuli such as insulin may also facilitate signaling by reversibly oxidizing and inhibiting protein tyrosine phosphatases (PTPs). Here we report that mice lacking one of the key enzymes involved in the elimination of physiological ROS, glutathione peroxidase 1 (Gpx1), were protected from high-fat-diet-induced insulin resistance. The increased insulin sensitivity in Gpx1(-/-) mice was attributed to insulin-induced phosphatidylinositol-3-kinase/Akt signaling and glucose uptake in muscle and could be reversed by the antioxidant N-acetylcysteine. Increased insulin signaling correlated with enhanced oxidation of the PTP family member PTEN, which terminates signals generated by phosphatidylinositol-3-kinase. These studies provide causal evidence for the enhancement of insulin signaling by ROS in vivo.
Loh
Kim
K
Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
Deng
Haiyang
H
Fukushima
Atsushi
A
Cai
Xiaochu
X
Boivin
Benoit
B
Galic
Sandra
S
Bruce
Clinton
C
Shields
Benjamin J
BJ
Skiba
Beata
B
Ooms
Lisa M
LM
Stepto
Nigel
N
Wu
Ben
B
Mitchell
Christina A
CA
Tonks
Nicholas K
NK
Watt
Matthew J
MJ
Febbraio
Mark A
MA
Crack
Peter J
PJ
Andrikopoulos
Sofianos
S
Tiganis
Tony
T
D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002478:Cells, Cultured; D004734:Energy Metabolism; D005260:Female; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009765:Obesity / Q000378:metabolism; D010084:Oxidation-Reduction; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000094765:Glutathione Peroxidase GPX1
D000975:Antioxidants; D007328:Insulin; D017382:Reactive Oxygen Species; D005979:Glutathione Peroxidase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D000111:Acetylcysteine; D000094765:Glutathione Peroxidase GPX1