Oxidative stress through the activation of renin-angiotensin system in skeletal muscle causes insulin resistance in mice with heart failure

      Background: Insulin resistance has been known to occur as a consequence of heart failure (HF). However, its mechanisms remain unknown. Oxidative stress through the activation of renin-angiotensin system in skeletal muscle (SKM) may impair insulin signaling and cause insulin resistance in HF. Methods: Myocardial infarction (MI) and sham (n = 14) operation were performed in C57BL/6 J mice. MI mice were divided into following 3 groups; no treatment (n = 25), treatment with apocynin (25 mg/kg/day, n = 14), an inhibitor of NAD(P)H oxidase activation, and telmisartan (0.3 mg/kg/day, n = 14). After 4 weeks, intraperitorial insulin tolerance tests were performed. SKM samples after insulin infusion were obtained for insulin signaling measurements. Results: MI mice showed left ventricular (LV) remodeling and failure. Fasting plasma glucose was comparable, but insulin levels were increased in MI compared to sham. Percent decrease of plasma glucose after insulin load was smaller in MI. Insulin-stimulated Akt phosphoryration and transition of glucose transporter 4 to plasma membrane were decreased in SKM from MI. Thiobarbituric acid-reactive substances and NAD(P)H oxidase activity in SKM were increased in MI. Treatment of MI mice with apocynin or telmisartan ameliorated insulin resistance and improved the impaired insulin signaling without affecting LV function and structure. Conclusions: Insulin resistance in HF was associated with the impairment of insulin signaling, which was caused by oxidative stress through the activation of renin-angiotensin system in SKM.
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