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1 S.U.N.Y. Downstate Medical Center, Brooklyn, NY, USA
2 Departments of Internal Medicine and Physiology, University of Missouri, Columbia, MO, USA; Harry S. Truman Memorial Veterans Medical Center, Columbia, MO, USA
3 Bowman Gray School of Medicine at Wake Forrest University, Winston-Salem, NC, USA
* To whom correspondence should be addressed. E-mail: Sowersj{at}health.missouri.edu.
To evaluate the role of renin-angiotensin system (RAS) mediated oxidative stress in insulin-resistance (IR) we compared the effects of the angiotensin receptor blocker (ARB) valsartan and a superoxide dismutase (SOD) mimetic, tempol on whole body glucose tolerance and soleus muscle insulin stimulated glucose uptake in transgenic hypertensive TG(mREN2)27 (Ren2) rats. Ren2 rats and Sprague-Dawley (SD) controls were given valsartan (30 mg/kg) or tempol (1 mmol/l) in their drinking water for 21 days. IR was measured by intraperitoneal glucose tolerance testing (1g/kg i.p. glucose). IR index (AUCglucose X AUCinsulin), was significantly higher in the Ren2 animals, compared to SD controls (30.5±7.0 x 106 arbitrary units in Ren2 vs. 10.2±2.4 x 106 in SD, p<0.01). Both valsartan and tempol treatment normalized Ren2 IR index. Compared to SD controls (100%), there was a significant increase in superoxide anion production (measured by lucigenin-enhanced chemiluminescence), in soleus muscles of Ren2 rats (133±15%). However, superoxide production was reduced in both valsartan and tempol treated (85±22%, and 59±12%, respectively) Ren2 rats. Insulin (INS) mediated 2- deoxyglucose uptake (2-DG; % of SD basal levels) was substantially lower in Ren2 rat soleus muscle compared to SD (Ren2+INS=110±3% vs. SD+INS=206±12%, p<0.05). However, Ren2 rats treated with valsartan or tempol exhibited a significant increase in insulin-mediated 2-DG uptake compared to untreated transgenic animals. Improvements in skeletal muscle insulin-dependent glucose uptake and whole body IR in rats over-expressing Ang II by ARB or SOD mimetic indicates that oxidative stress plays an important role in Ang II mediated insulin resistance.
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