Reduced skeletal muscle inhibitor of kappaB beta 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 kappaB (IkappaB)/nuclear factor kappaB (NFkappaB) inflammatory pathway is a mechanism underlying skeletal muscle insulin resistance. However, it is not known whether IkappaB/NFkappaB signaling in muscle from subjects with type 2 diabetes is abnormal. We studied IkappaB/NFkappaB 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 IkappaB beta protein abundance, an indicator of increased activation of the IkappaB/NFkappaB pathway. IkappaB beta abundance directly correlated with insulin-mediated glucose disposal (Rd) during a hyperinsulinemic (40 mU x m(-2) x min(-1))-euglycemic clamp (r = 0.63, P = 0.01), indicating that increased IkappaB/NFkappaB 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 IkappaB alpha and IkappaB beta protein. In subjects with type 2 diabetes, training increased IkappaB alpha and IkappaB beta 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 IkappaB protein abundance in muscle, suggesting excessive activity of the IkappaB/NFkappaB pathway. Moreover, this abnormality is reversed by exercise training.
Sriwijitkamol
Apiradee
A
Diabetes Division, University of Texas Health Science Center at San Antonio, USA.
Christ-Roberts
Christine
C
Berria
Rachele
R
Eagan
Phyllis
P
Pratipanawatr
Thongchai
T
DeFronzo
Ralph A
RA
Mandarino
Lawrence J
LJ
Musi
Nicolas
N
D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D015444:Exercise; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000032:analysis*; D007333:Insulin Resistance; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry*; D016328:NF-kappa B / Q000502:physiology; D010766:Phosphorylation; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; C496560:IKBKB protein, human