Selective angiotensin II receptor antagonism enhances whole-body insulin sensitivity and muscle glucose transport in hypertensive TG(mREN2)27 rats

Essential hypertension is frequently associated with insulin resistance of skeletal muscle glucose transport, and angiotensin II(ANGII) can contribute to the pathogenesis of both conditions. The male heterozygous TG(mREN2)27 rat (TGR) harbors the mouse transgene for renin, exhibits local tissue elevations in ANGII and is an excellent model of both hypertension and insulin resistance associated with defective insulin signaling. The present study was designed to assess the specific role of ANGII in the insulin resistance of the male heterozygous TGR. TGRs were treated with either vehicle or the ANGII (AT(1)-specific) receptor antagonist, irbesartan (50 mg/kg body weight), for 21 consecutive days. Compared with vehicle-treated TGRs, whole-body insulin sensitivity was increased 35% (P < .05) in the irbesartan-treated group, and insulin-mediated glucose transport was increased (P < .05) in both type IIb epitrochlearis (80%) and type I soleus (59%) muscles after irbesartan treatment. Moreover, glycogen synthase activation due to insulin was increased 58% (P < .05) in the soleus of the irbesartan-treated TGRs. However, no significant improvements were observed for functionality of insulin-signaling elements (tyrosine phosphorylation of insulin receptor and insulin receptor substrate 1 [IRS1], IRS1 associated with the p85 regulatory subunit of phosphatidylinositol 3'-kinase, and Ser473 of Akt) in muscle of irbesartan-treated animals, except for a 25% increase (P < .05) in IRS1 tyrosine phosphorylation in soleus. Collectively, these data indicate that the improvements in whole-body and skeletal muscle insulin action after long-term antagonism of ANGII action in TGRs occur independently of modulation of the functionality of these insulin-signaling elements. (c) 2005 Elsevier Inc. All rights reserved.