Effects of angiotensin II receptor blockade on glucose metabolism via AMP-activated protein kinase in insulin-resistant hypertensive rats

AMP-activated protein kinase (AMPK) mediates metabolic responses of muscle to exercise and is involved in improvement of insulin resistance by endurance exercise. Recent studies have suggested that the renin-angiotensin system (RAS) might negatively modulate insulin-mediated actions, but there has been little investigation of the correlation between RAS and AMPK. To determine the correlations between insulin resistance, the RAS, and AMPK, we performed glucose clamp studies using both insulin and 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) to investigate the effects of various hypotonics on insulin and AMPK sensitivities. Six-week-old male Sprague-Dawley rats were divided into two groups: those fed a standard chow (SD) and those fed a fructose-rich chow (fructose-fed rats [FFRs]) for 6 weeks. FFRs were treated either with a vehicle or with valsartan or hydralazine for the last 2 weeks. We also performed Western blotting for AMPK, phospho-AMPK, and stimulating glucose transporter (GLUT)-4 proteins in each group. The glucose infusion rate for insulin (GIRI) was significantly lower in FFRs (10.5 ± 1.8 mg/kg/min) than in SD (15.5 ± 0.4 mg/kg/min), and GIRI was improved by valsartan (13.0 ± 1.0 mg/kg/min) but not by hydralazine (8.3 ± 1.6 mg/kg/min). The glucose infusion rate for AICAR (GIRA) in FFRs (11.1 ± 2.2 mg/kg/min) was significantly lower than that in SD (15.5 ± 2.8 mg/kg/min), and GIRA was improved by valsartan (17.5 ± 3.1 mg/kg/min) but not by hydralazine in FFRs (11.8 ± 1.5 mg/kg/min). Serum triglyceride level was significantly higher in FFRs; however, no difference was observed in serum triglyceride level after AICAR infusion among the groups. The amounts of AMPKα protein and the amounts of phospho-AMPK protein in the soleus muscle in basal conditions were not different among SD, FFRs, and FFRs treated with valsartan. There was no difference in the levels of phosphorylation of AMPK in the soleus muscle by AICAR among these three groups. No difference was observed in acetyl-CoA carboxylase (ACC) protein or phospho-ACC in both the basal condition and after AICAR infusion between SD and FFRs. Treatment with valsartan significantly increased GLUT-4 content of the soleus muscle compared with that in FFRs. These results suggest that the RAS has a significant role in the AMPK system and that impairment of response to AICAR in FFRs could be downstream of AMPK or ACC phosphorylation.