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Am J Physiol Endocrinol Metab (November 20, 2007). doi:10.1152/ajpendo.00537.2007
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Submitted on August 17, 2007
Accepted on November 19, 2007

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

Emma Polkinghorne1, Quintin Lau1, Gregory James Cooney1, Edward W Kraegen1, and Mark Edward Cleasby1*

1 Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

* To whom correspondence should be addressed. E-mail: mcleasby{at}rvc.ac.uk.

Insulin resistance of skeletal muscle is a major defect in obesity and type 2 diabetes. Insulin resistance has been associated with a chronic sub-clinical 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 over-expressed the p65 sub-unit of NF{kappa}B and I{kappa}BK{beta} in single muscles of rats using in vivo electrotransfer and compared the effects after one week versus paired contralateral control muscles. A 64% increase in p65 protein (p<0.001) was sufficient to cause muscle fibre atrophy but had no effect on glucose disposal or glycogen storage in muscle under hyperinsulinaemic-euglycaemic clamp conditions. Similarly a 650% increase in I{kappa}BK{beta} expression (p<0.001) caused a significant reduction in Inhibitor {kappa}-B protein but also had no effect on clamp glucose disposal after lipid infusion. In fact, I{kappa}BK{beta} over-expression 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 signalling cascade. Interestingly, p65 over-expression 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.







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