Reduced skeletal muscle inhibitor of κBβ content is associated with insulin resistance in subjects with type 2 diabetes:: Reversal by exercise training -: Reversal by exercise training

Skeletal muscle insulin resistance plays a key role in the pathogenesis of type 2 diabetes. It recently has been hypothesized that excessive activity of the inhibitor Of kappa B (I kappa B)/nuclear factor kappa B (NF kappa B) inflammatory pathway is a mechanism underlying skeletal muscle insulin resistance. However, it is not known whether I kappa B/NF kappa B signaling in muscle from subjects with type 2 diabetes is abnormal. We studied I kappa B/NF kappa B signaling in vastus lateralis muscle from six subjects with type 2 diabetes and eight matched control subjects. Muscle from type 2 diabetic subjects was characterized by a 60% decrease in I kappa B beta protein. abundance, an indicator of increased activation of the I kappa B/NF kappa B pathway. I kappa B beta abundance directly correlated with insulin-mediated glucose disposal (R-d) during a hyperinsulinemic (40 mU . m(-2) . min(-1))-euglycemic clamp (r = 0.63, P = 0.01), indicating that increased I kappa B/NF kappa B pathway activity is associated with muscle insulin resistance. We also investigated whether reversal of this abnormality could be a mechanism by which training improves insulin sensitivity. In control subjects, 8 weeks of aerobic exercise training caused a 50% increase in both I kappa B alpha and I kappa B beta protein. In subjects with type 2 diabetes, training increased I kappa B alpha and I kappa B beta protein to levels comparable with that of control subjects, and these increments were accompanied by a 40% decrease in tumor necrosis factor alpha muscle content and a 37% increase in insulin-stimulated glucose disposal. In summary, subjects with type 2 diabetes have reduced I kappa B protein abundance in muscle, suggesting excessive activity of the I kappa B/NF kappa B pathway. Moreover, this abnormality is reversed by exercise training.