title: Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression.
abstract: 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 10(6) arbitrary units in Ren-2 vs. 10.2 +/- 2.4 x 10(6) 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.
authors.affiliation: Department of Internal Medicine, University of Missouri, Columbia, MO 65201, USA.
authors.forename: Mihaela C
authors.initials: MC
authors.lastname: Blendea
authors.forename: David
authors.initials: D
authors.lastname: Jacobs
authors.forename: Craig S
authors.initials: CS
authors.lastname: Stump
authors.forename: Samy I
authors.initials: SI
authors.lastname: McFarlane
authors.forename: Cristina
authors.initials: C
authors.lastname: Ogrin
authors.forename: Gul
authors.initials: G
authors.lastname: Bahtyiar
authors.forename: Samir
authors.initials: S
authors.lastname: Stas
authors.forename: Pawan
authors.initials: P
authors.lastname: Kumar
authors.forename: Quan
authors.initials: Q
authors.lastname: Sha
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000284:Administration, Oral; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D003497:Cyclic N-Oxides / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005947:Glucose; D006973:Hypertension / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D013113:Spin Labels; D013777:Tetrazoles / Q000008:administration & dosage*; D014633:Valine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D003497:Cyclic N-Oxides; D007328:Insulin; D044140:Receptor, Angiotensin, Type 1; D013113:Spin Labels; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; D014633:Valine; D005947:Glucose; C001803:tempol