It is well known that
reactive oxygen species (ROS) plays a role in the pathogenesis of
insulin resistance which is the hallmark of
type 2 diabetes. However, it is still needed to clarify the mechanism underlying
insulin resistance.
Glucose oxidase (GOD) is an oxi-
reductase catalyzing the conversion of
glucose to glucolactone, which is further converted to
glucuronic acid and H(2)O(2). The present study was designed to establish a rat model of
insulin resistance using GOD and to investigate possible mechanisms. The results showed that three days administration of GOD could significantly increase fasting
blood glucose, resulting in impaired
glucose and
insulin tolerance. Moreover, GOD disrupted
insulin signaling both in rats and in hepatocytes, as evidenced by decreased phosphorylation of
insulin-stimulated Akt, GSK3 and FOXO1α. Furthermore, GOD administration decreased the expression of PPARγ, alterated the phosphorylation of MAPKs, including p38, ERK and JNK, increased the expression of
GRP78 and reduced the expression of PGC-1α and decreased the activities of
ATPase and respiratory complexes, all of which have been reported to contribute to
insulin resistance. Redox balance was evaluated by detecting the expression of
antioxidant defenses and ROS generation. After the treatment with GOD, nuclear factorerythroid 2 p45-related factor 2 (Nrf2)-regulated
antioxidant enzymes were damaged and ROS production increased significantly.
N-acetyl-L-cysteine (NAC), a potent
antioxidant, could notably inhibit these effects of GOD. Although further studies are needed to investigate the clear mechanism, these data also support the conclusion that, if not the most early event, ROS generation is the most important event that plays a central role in the pathogenesis of
insulin resistance. Overall, our study established an
insulin resistant animal model induced by GOD, elucidated the importance of ROS in pathogenesis of
insulin resistance and provided the clue for further studies on the underlying mechanisms.