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Am J Physiol Endocrinol Metab 288: E353-E359, 2005. First published October 19, 2004; doi:10.1152/ajpendo.00402.2004
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Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression

Mihaela C. Blendea,3 David Jacobs,3 Craig S. Stump,1,2 Samy I. McFarlane,3 Cristina Ogrin,3 Gul Bahtyiar,3 Samir Stas,3 Pawan Kumar,3 Quan Sha,3 Carlos M. Ferrario,4 and James R. Sowers1,2

1Departments of Internal Medicine and Physiology, University of Missouri; 2Harry S. Truman Memorial Veterans Medical Center, Columbia, Missouri; 3State University of New York Downstate Medical Center, Brooklyn, New York; and 4Bowman Gray School of Medicine at Wake Forest University, Winston-Salem, North Carolina

Submitted 27 August 2004 ; accepted in final form 13 October 2004

To evaluate the role of renin-angiotensin system (RAS)-mediated oxidative stress in insulin resistance (IR), we compared the effects of the angiotensin II (ANG II) 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(mREN-2)27 (Ren-2) rats. Ren-2 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 glucose tolerance testing (1 g/kg glucose ip). IR index (AUCglucose x AUCinsulin) was significantly higher in the Ren-2 animals compared with SD controls (30.5 ± 7.0 x 106 arbitrary units in Ren-2 vs. 10.2 ± 2.4 x 106 in SD, P < 0.01). Both valsartan and tempol treatment normalized Ren-2 IR index. Compared with SD controls (100%), there was a significant increase in superoxide anion production (measured by lucigenin-enhanced chemiluminescence) in soleus muscles of Ren-2 rats (133 ± 15%). However, superoxide production was reduced in both valsartan- and tempol-treated (85 ± 22% and 59 ± 12%, respectively) Ren-2 rats. Insulin (INS)-mediated 2-deoxyglucose (2-DG) uptake (%SD basal levels) was substantially lower in Ren-2 rat soleus muscle compared with SD (Ren-2 + INS = 110 ± 3% vs. SD + INS = 206 ± 12%, P < 0.05). However, Ren-2 rats treated with valsartan or tempol exhibited a significant increase in insulin-mediated 2-DG uptake compared with untreated transgenic animals. Improvements in skeletal muscle insulin-dependent glucose uptake and whole body IR in rats overexpressing ANG II by ARB or SOD mimetic indicate that oxidative stress plays an important role in ANG II-mediated insulin resistance.

insulin resistance; superoxide; valsartan


Address for reprint requests and other correspondence: C. S. Stump, Harry S. Truman Memorial Veterans Medical Center, Columbia, MO 65201 (E-mail: stumpc{at}health.missouri.edu)




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