Reduced Skeletal Muscle Inhibitor of κBβ Content Is Associated With Insulin Resistance in Subjects With Type 2 Diabetes

• 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: American Diabetes Association 01.03.2006
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.55.03.06.db05-0677

Reduced Skeletal Muscle Inhibitor of κBβ Content Is Associated With Insulin Resistance in Subjects With Type 2 Diabetes Reversal by Exercise Training Apiradee Sriwijitkamol 1 2 , Christine Christ-Roberts 1 , Rachele Berria 1 , Phyllis Eagan 1 2 , Thongchai Pratipanawatr 1 , Ralph A. DeFronzo 1 2 , Lawrence J. Mandarino 1 and Nicolas Musi 1 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 Abstract 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 ( R d ) during a hyperinsulinemic (40 mU · m −2 · min −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 IκBα 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. AMPK, AMP-activated protein kinase FFA, free fatty acid GCRC, General Clinical Research Center IκB, inhibitor of κB IKK, IκB kinase IL, interleukin NFκB, nuclear factor κB TNFα, tumor necrosis factor α Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted November 18, 2005. Received May 26, 2005. DIABETES