Reduced skeletal muscle inhibitor of kB f content is associated with insulin resistance in subjects with type 2 diabetes: 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 B (IB)/nuclear factor B (NFB) inflammatory pathway is a mechanism underlying skeletal muscle insulin resistance. However, it is not known whether IB/NFB signaling in muscle from subjects with type 2 diabetes is abnormal. We studied IB/NFB 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 IB f protein abundance, an indicator of increased activation of the IB/NFB pathway. IB f abundance directly correlated with insulin-mediated glucose disposal (Rd) during a hyperinsulinemic (40 mU \ub7 m\u962 \ub7 min\u961)-euglycemic clamp (r =3D 0.63, P =3D 0.01), indicating that increased IB/NFB 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 IB and IB f protein. In subjects with type 2 diabetes, training increased IB and IB f protein to levels comparable with that of control subjects, and these increments were accompanied by a 40% decrease in tumor necrosis factor muscle content and a 37% increase in insulin-stimulated glucose disposal. In summary, subjects with type 2 diabetes have reduced IB protein abundance in muscle, suggesting excessive activity of the IB/NFB pathway. Moreover, this abnormality is reversed by exercise training