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Diabetes 55:760-767, 2006
DOI: 10.2337/diabetes.55.03.06.db05-0677
© 2006 by the American Diabetes Association
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Pathophysiology

Reduced Skeletal Muscle Inhibitor of {kappa}Bß Content Is Associated With Insulin Resistance in Subjects With Type 2 Diabetes

Reversal by Exercise Training

Apiradee Sriwijitkamol1,2, Christine Christ-Roberts1, Rachele Berria1, Phyllis Eagan1,2, Thongchai Pratipanawatr1, Ralph A. DeFronzo1,2, Lawrence J. Mandarino1, and Nicolas Musi1,2

1 Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas
2 Texas Diabetes Institute, San Antonio, Texas

Address correspondence and reprint requests to Nicolas Musi, MD, 701 S. Zarzamora, MS 10-5, San Antonio, TX 78207. E-mail: nicolas.musi{at}uhs-sa.com

Abbreviations: AMPK, AMP-activated protein kinase; FFA, free fatty acid; GCRC, General Clinical Research Center; I{kappa}B, inhibitor of {kappa}B; IKK, I{kappa}B kinase; IL, interleukin; NF{kappa}B, nuclear factor {kappa}B; TNF{alpha}, tumor necrosis factor {alpha}

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}Bß protein abundance, an indicator of increased activation of the I{kappa}B/NF{kappa}B pathway. I{kappa}Bß abundance directly correlated with insulin-mediated glucose disposal (Rd) 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}Bß protein. In subjects with type 2 diabetes, training increased I{kappa}B{alpha} and I{kappa}Bß 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.


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Copyright © 2006 by the American Diabetes Association.