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Angiotensin II-induced skeletal muscle insulin resistance mediated by NF-B activation via NADPH oxidase

¹Department of Internal Medicine, University of Missouri-Columbia; ²Harry S. Truman Memorial Veterans Affairs Medical Center, Columbia, Missouri; ³Wake Forest University School of Medicine, Winston-Salem, North Carolina; ⁴Diabetes Research Program, Department of Medicine, University of Arizona; and ⁵Southern Arizona Veterans Affairs Health Care System, Tucson, Arizona

Submitted 16 July 2007 ; accepted in final form 7 December 2007

Reduced insulin sensitivity is a key factor in the pathogenesis of type 2 diabetes and hypertension. Skeletal muscle insulin resistance is particularly important for its major role in insulin-mediated glucose disposal. Angiotensin II (ANG II) is integral in regulating blood pressure and plays a role in the pathogenesis of hypertension. In addition, we have documented that ANG II-induced skeletal muscle insulin resistance is associated with generation of reactive oxygen species (ROS). However, the linkage between ROS and insulin resistance in skeletal muscle remains unclear. To explore potential mechanisms, we employed the transgenic TG(mRen2)27 (Ren-2) hypertensive rat, which harbors the mouse renin transgene and exhibits elevated tissue ANG II levels, and skeletal muscle cell culture. Compared with Sprague-Dawley normtensive control rats, Ren-2 skeletal muscle exhibited significantly increased oxidative stress, NF-B activation, and TNF- expression, which were attenuated by in vivo treatment with an angiotensin type 1 receptor blocker (valsartan) or SOD/catalase mimetic (tempol). Moreover, ANG II treatment of L6 myotubes induced NF-B activation and TNF- production and decreased insulin-stimulated Akt activation and GLUT-4 glucose transporter translocation to plasma membranes. These effects were markedly diminished by treatment of myotubes with valsartan, the antioxidant N-acetylcysteine, NADPH oxidase-inhibiting peptide (gp91 ds-tat), or NF-B inhibitor (MG-132). Similarly, NF-B p65 small interfering RNA reduced NF-B p65 subunit expression and nuclear translocation and TNF- production but improved insulin-stimulated phosphorylation (Ser⁴⁷³) of Akt and translocation of GLUT-4. These findings suggest that NF-B plays an important role in ANG II/ROS-induced skeletal muscle insulin resistance.

nuclear factor-B; reduced nicotinamide adenine dinucleotide phosphate; renin-angiotensin system; reactive oxygen species; TG(mRen2)27 rat; tumor necrosis factor-; angiotensin receptor blocker

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