Effects of losartan in combination with or without exercise on insulin resistance in Otsuka Long-Evans Tokushima Fatty rats

Hypertension often complicates type 2 diabetes mellitus, and angiotensin co nverting enzyme inhibitor treatment has been shown to improve insulin resis tance in such cases. However, the effect of angiotensin II type-1 (AT(1)) r eceptor antagonists on insulin resistance is still controversial. To gain f urther information on this effect, we examined the effect of losartan on in sulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus. Losartan administration alone lowered systoli c blood pressure, but did not improve oral glucose tolerance test or insuli n resistance in OLETF rats. However, the administration of losartan with ex ercise significantly improved both systolic blood pressure and insulin resi stance relative to control OLETF rats. On the other hand, losartan treatmen t, regardless of exercise, increased glucose uptake in excised soleus muscl e and fat cells. To explore the beneficial effect of losartan on skeletal m uscle glucose uptake, we examined intracellular signaling of soleus muscle. Although Akt activity and glucose transporter type 4 (GLUT4) expressions w ere not affected by losartan with or without exercise, extracellular signal -regulated kinase (ERK1/2) and p38 mitogen-activated protein (MAP) kinase a ctivities were increased by both interventions. These results indicate that angiotensin AT, receptor antagonist improved local insulin resistance, but not systemic insulin resistance. These findings may explain the controvers y over the effect of angiotensin AT(1) receptor antagonists on insulin resi stance in clinical use. The enhancing effect of angiotensin AT(1) receptor antagonist on skeletal muscle glucose uptake may be attributable to MAT kin ase activation or other mechanisms rather than phosphatidylinositol 3-kinas e activation. (C) 2001 Elsevier Science B.V. All rights reserved.