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

Apiradee Sriwijitkamol, Christine Christ-Roberts, Rachele Berria, Phyllis Eagan, Thongchai Pratipanawatr, Ralph A. DeFronzo, Lawrence J. Mandarino, Nicolas Musi

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

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 (Rd) 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 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.

Original languageEnglish (US)
Pages (from-to)760-767
Number of pages8
JournalDiabetes
Volume55
Issue number3
DOIs
StatePublished - Mar 2006

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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