Local activation of the I kappa K-NF-kappa B pathway in muscle does not cause insulin resistance

Polkinghorne, E and Lau, Q and Cooney, J and Kraegen, E W and Cleasby, M E (2008) Local activation of the I kappa K-NF-kappa B pathway in muscle does not cause insulin resistance. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 294 (2). E316-E325.

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Insulin resistance of skeletal muscle is a major defect in obesity and type 2 diabetes. Insulin resistance has been associated with a chronic subclinical inflammatory state in epidemiological studies and specifically with activation of the inhibitor kappa B kinase (I kappa BK)-nuclear factor-kappa B (NF-kappa B) pathway. However, it is unclear whether this pathway plays a role in mediating insulin resistance in muscle in vivo. We separately overexpressed the p65 subunit of NF-kappa B and I kappa BK beta in single muscles of rats using in vivo electrotransfer and compared the effects after 1 wk vs. paired contralateral control muscles. A 64% increase in p65 protein ( P < 0.001) was sufficient to cause muscle fiber atrophy but had no effect on glucose disposal or glycogen storage in muscle under hyperinsulinemic-euglycemic clamp conditions. Similarly, a 650% increase in I kappa BK beta expression (P < 0.001) caused a significant reduction in I kappa B protein but also had no effect on clamp glucose disposal after lipid infusion. In fact, I kappa BK beta overexpression in particular caused increases in activating tyrosine phosphorylation of insulin receptor substrate- 1 (24%; P = 0.02) and serine phosphorylation of Akt (23%; P < 0.001), implying a moderate increase in flux through the insulin signaling cascade. Interestingly, p65 overexpression resulted in a negative feedback reduction of 36% in Toll-like receptor (TLR)-2 (P = 0.03) but not TLR-4 mRNA. In conclusion, activation of the I kappa BK beta-NF-kappa B pathway in muscle does not seem to be an important local mediator of insulin resistance.