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Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression

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 (AUC_glucose x AUC_insulin) 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

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