Hypertension. 2001;38:884-890
doi: 10.1161/hy1101.092970
doi: 10.1161/hy1101.092970
(Hypertension. 2001;38:884.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Selective Angiotensin II Receptor Antagonism Reduces Insulin Resistance in Obese Zucker Rats
From the Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine (E.J.H., T.R.K., M.K.T.), Tucson; Department of Endocrinology, Eberhard-Karls University (S.J.), Tübingen, Germany; and Bristol-Myers Squibb (M.K.), Munich, Germany.
Correspondence to Erik J. Henriksen, PhD, Department of Physiology, Ina E. Gittings Bldg 93, University of Arizona, Tucson, AZ 85721-0093. E-mail ejhenrik{at}u.arizona.edu
Abstract—— Effects of oral administration of the angiotensin II receptor antagonist (selective AT1-subtype) irbesartan on glucose tolerance and insulin action on skeletal-muscle glucose transport were assessed in the insulin-resistant obese Zucker rat. In the acute study, obese rats received either vehicle (water) or irbesartan 1 hour before the experiment. Although irbesartan had no effect on glucose transport (2-deoxyglucose uptake) in the epitrochlearis muscle, which consists mainly of type IIb fibers, acute angiotensin II receptor antagonism led to a dose-dependent increase in insulin action in the predominantly type I soleus muscle. Irbesartan at 25 and 50 mg/kg induced significant increases (41% and 50%, respectively; P<0.05) in insulin-mediated glucose transport. Moreover, these acute irbesartan-induced improvements in soleus-muscle glucose transport were associated with enhancements in whole-body insulin sensitivity (r=-0.732; P<0.05), as assessed during an oral glucose tolerance test. After chronic administration of irbesartan (21 days at 50 mg · kg-1 · d-1), glucose tolerance was enhanced further, and insulin-mediated glucose transport was significantly elevated in both epitrochlearis (32%) and soleus (73%) muscle. Chronic angiotensin II receptor antagonism was associated with significant increases in glucose transporter-4 (GLUT-4) protein expression in soleus (22%) and plantaris (20%) muscle and myocardium (15%). Chronic irbesartan-induced increases in whole-body insulin sensitivity were associated with increased insulin-mediated glucose transport in both epitrochlearis (r=-0.677; P<0.05) and soleus (r=-0.892; P<0.05) muscle. In summary, angiotensin II receptor (AT1-subtype) antagonism, either acutely or chronically, improves glucose tolerance, at least in part because of an enhancement in skeletal-muscle glucose transport, and the effect of chronic angiotensin II receptor antagonism on type I skeletal-muscle glucose uptake is associated with an increase in GLUT-4 protein expression.
Key Words: irbesartan • glucose • muscle, skeletal • transport, glucose • rats, Zucker • receptors, angiotensin
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