Amelioration of glucose tolerance by hepatic inhibition of nuclear factor κB in db/db mice

Abstract

Aims/hypothesis: Recent studies have identified the involvement of inhibitor IκB kinase (IKK) in the pathogenesis of insulin resistance. To investigate the mechanism involved, we examined the role of nuclear factor κB (NF-κB), the distal target of IKK, in hepatic glucose metabolism. Methods: To inhibit NF-κB activity, db/db mice were infected with adenovirus expressing the IκBα super-repressor. Results: The IκBα super-repressor adenovirus infection caused a moderate reduction of NF-κB activity in liver. The treatment was associated with improved glucose tolerance, reduction in the serum insulin level, and increased hepatic triacylglycerol and glycogen contents, but had no effect on insulin-stimulated phosphorylation of Akt. On the other hand, quantification of mRNA in the liver revealed marked reduction of expression of gluconeogenic genes, such as those encoding phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, concurrent with reduced expression of gene encoding peroxisome proliferator-activated receptor gamma coactivator-1α (PPARGC1A, also known as PGC-1α). Furthermore, the production of super-repressor IκBα suppressed the increase in blood glucose level after pyruvate injection. Conclusions/interpretation: Our results indicate that moderate inhibition of NF-κB improved glucose tolerance through decreased gluconeogenesis associated with reduced PGC-1α gene expression in db/db mice, and suggest that inhibition of NF-κB activity in liver is a potentially suitable strategy for the normalisation of blood glucose concentration in type 2 diabetes. © 2006 Springer-Verlag.