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1 Department of Physiology, University of Toronto, Toronto, ON, Canada; Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada
2 Department of Physiology, University of Toronto, Toronto, ON, Canada
3 Department of Medicine, Mount Sinai Hospital, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada; Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada
* To whom correspondence should be addressed. E-mail: fantus{at}mshri.on.ca.
Exposure to high concentrations of glucose and insulin results in insulin resistance of metabolic target tissues, a characteristic feature of type 2 diabetes. High glucose has also been associated with oxidative stress, and increased levels of ROS (reactive oxygen species) have been proposed to cause insulin resistance. To determine whether oxidative stress contributes to insulin resistance induced by hyperglycemia in vivo, non-diabetic rats were infused with glucose for 6 h to maintain a circulating glucose concentration of 15 mM with and without coinfusion of the antioxidant, N-acetylcysteine (NAC), followed by a 2 h hyperinsulinemic-euglycemic clamp. High glucose (HG) induced a significant decrease in insulin-stimulated glucose uptake (tracer determined Rd) (Control 41.2± 1.7 mg.kg-1.min-1, HG 32.4 ± -1.9 mg.kg-1.min-1,p < 0.05) which was prevented by NAC(HG + NAC 45.9 ± 3.5 mg.kg-1.min-1). Similar results were obtained with the antioxidant, taurine. Neither NAC nor taurine alone altered Rd. HG caused a significant (5-fold) increase in soleus muscle protein carbonyl content, a marker of oxidative stress which was blocked by NAC, as well as elevated levels of malondialdehyde and 4-hydroxynonenal, markers of lipid peroxidation, which were reduced by taurine. In contrast to findings after long term hyperglycemia, there was no membrane translocation of novel isoforms of protein kinase C in skeletal muscle after 6 h. These data support the concept that oxidative stress contributes to the pathogenesis of hyperglycemia-induced insulin resistance.
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