Abstract-Effects of oral administration of the angiotensin II receptor antagonist (selective AT 1 -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; PϽ0.05) 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 (rϭϪ0.732; PϽ0.05), as assessed during an oral glucose tolerance test. After chronic administration of irbesartan (21 days at 50 mg · kg), 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 (rϭϪ0.677; PϽ0.05) and soleus (rϭϪ0.892; PϽ0.05) muscle. In summary, angiotensin II receptor (AT 1 -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 Ⅲ glucose Ⅲ muscle, skeletal Ⅲ transport, glucose Ⅲ rats, Zucker Ⅲ receptors, angiotensin I ndividuals with essential hypertension frequently display a clustering of additional atherogenic risk factors, including insulin resistance of skeletal-muscle glucose uptake, hyperinsulinemia, dyslipidemia, and central adiposity, in a condition described as "insulin resistance syndrome." 1 Angiotensin (Ang) II is a potent vasoconstrictor and can contribute to the pathogenesis of hypertension. 2 Reductions in formation of Ang II, as results from treatment with ACE inhibitors or inhibition of the cellular actions of Ang II by the use of specific Ang II (AT 1 -subtype) antagonists, are effective interventions for lowering blood pressure. [3][4][5] Although both animal model studies 6 -12 and clinical investigations 6,[13][14][15][16][17][18] have demonstrated that ACE inhibitor treatment can ameliorate peripheral insulin resistance, the role of a specific reduction in Ang II action on whole-body and skeletal-muscle ins...