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Local activation of the IK-NF-B pathway in muscle does not cause insulin resistance

¹Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney; ²School of Medical Sciences, Faculty of Medicine, and ³St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia

Submitted 17 August 2007 ; accepted in final form 19 November 2007

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 B kinase (IBK)-nuclear factor-B (NF-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-B and IBKβ 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 IBKβ expression (P < 0.001) caused a significant reduction in IB protein but also had no effect on clamp glucose disposal after lipid infusion. In fact, IBKβ 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 IBKβ-NF-B pathway in muscle does not seem to be an important local mediator of insulin resistance.

inhibitor kinase-nuclear factor-B pathway; skeletal muscle; Toll-like receptors; in vivo electrotransfer

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