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

• Published in: Diabetes (New York, N.Y.) Vol. 55; no. 3; pp. 760 - 767
• Main Authors: SRIWIJITKAMOL, Apiradee, CHRIST-ROBERTS, Christine, BERRIA, Rachele, EAGAN, Phyllis, PRATIPANAWATR, Thongchai, DEFRONZO, Ralph A, MANDARINO, Lawrence J, MUSI, Nicolas
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.2006
• Subjects: Biological and medical sciences; Diabetes; Diabetes research; Diabetes. Impaired glucose tolerance; Drug therapy; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Genetic aspects; Insulin; Medical sciences; Risk factors; Striated muscle. Tendons; Type 2 diabetes; Vertebrates: osteoarticular system, musculoskeletal system; Endocrinopathy; Type 2 diabetes; Physical exercise; Human; Metabolic diseases; Insulin resistance; Striated muscle
• ISSN: 0012-1797
• DOI: 10.2337/diabetes.55.03.06.db05-0677

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 κB (IκB)/nuclear factor κB (NFκB) inflammatory pathway is a mechanism underlying skeletal muscle insulin resistance. However, it is not known whether IκB/NFκB signaling in muscle from subjects with type 2 diabetes is abnormal. We studied IκB/NFκB 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 IκBβ protein abundance, an indicator of increased activation of the IκB/NFκB pathway. IκBβ abundance directly correlated with insulin-mediated glucose disposal (Rd) during a hyperinsulinemic (40 mU x [m.sup.-2] x [min.sup.-1])-euglycemic clamp (r = 0.63, P = 0.01), indicating that increased IκB/NFκB 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 IκBα and IκBβ protein. In subjects with type 2 diabetes, training increased IκBβ and IκBβ protein to levels comparable with that of control subjects, and these increments were accompanied by a 40% decrease in tumor necrosis factor α muscle content and a 37% increase in insulin-stimulated glucose disposal. In summary, subjects with type 2 diabetes have reduced IκB protein abundance in muscle, suggesting excessive activity of the IκB/NFκB pathway. Moreover, this abnormality is reversed by exercise training.