Olmesartan Ameliorates Insulin Sensitivity by Modulating Tumor Necrosis Factor-α and Cyclic AMP in Skeletal Muscle

We have reported that tumor necrosis factor (TNF)-α in skeletal muscle is one of the determinants of insulin resistance and that the renin-angiotensin system may be related to the regulation of TNF-α in skeletal muscle. Recent studies have suggested the involvement of cyclic adenosine monophosphate (cAMP) in the regulation of TNF-α in vascular smooth muscle cells or monocytes. The aim of this study was to determine the relationship between cAMP and TNF-α in skeletal muscle in connection with the renin-angiotensin system. Six-week-old male Sprague-Dawley rats were fed either normal rat chow or fructose-rich chow for 6 weeks. For the last 2 weeks of a 6-week period, the rats were treated with a vehicle or with an angiotensin II type 1 receptor antagonist (olmesartan medoxomil, 0.1 mg/kg/day). TNF-α levels in the soleus muscle were significantly higher and cAMP levels in the soleus muscle were significantly lower in fructose-fed rats than in control rats. Olmesartan increased cAMP and reduced TNF-α simultaneously in fructose-fed rats. There was a significant negative correlation between levels of cAMP and TNF-α. Moreover, a cAMP analogue reduced TNF-α levels in the soleus muscle. These results indicate that the increase in TNF-αvia suppression of cAMP may affect the induction of insulin resistance. In addition, the facts that olmesartan increased cAMP and decreased TNF-α suggest that a part of the TNF-α regulation by angiotensin II might consist of modulation of cAMP through Gi protein activation in skeletal muscle.