Dissociation between skeletal muscle inhibitor-kappaB kinase/nuclear factor-kappaB pathway activity and insulin sensitivity in nondiabetic twins.
BACKGROUND
Several studies suggest a link between increased activity of the inflammatory inhibitor-kappaB kinase/nuclear factor-kappaB (IKK/NF-kappaB) pathway in skeletal muscle and insulin resistance.


OBJECTIVE
We aimed to study the regulation of skeletal muscle IKK/NF-kappaB pathway activity as well as the association with glucose metabolism and skeletal muscle insulin signaling.


METHODS
The study population included a metabolically well-characterized cohort of young and elderly predominantly nondiabetic twins (n = 181). Inhibitor-kappaBbeta (IkappaBbeta) protein levels are negatively associated with IKK/NF-kappaB pathway activity and were used to evaluate pathway activity with p65 levels included as loading control. This indirect measure for IKK/NF-kappaB pathway activity was validated by a p65 binding assay.


RESULTS
Evaluating the effects of heritability, age, sex, obesity, aerobic capacity, and several hormonal factors (eg insulin and TNF-alpha), only sex and age were significant predictors of IkappaBbeta to p65 ratio (28% decreased ratio in the elderly, P < 0.01, and 49% increased in males P < 0.01). IkappaBbeta to p65 ratio was unrelated to peripheral insulin sensitivity (P = 0.51) and in accordance with this also unrelated to proximal insulin signaling (P = 0.81). Although no association was seen with plasma glucose after oral glucose challenge, there was a tendency for lower IkappaBbeta to p65 ratio (adjusted for age and sex) in subjects with impaired as opposed to normal glucose tolerance (P = 0.055).


CONCLUSIONS
Altogether the subtle elevated IKK/NF-kappaB pathway activity seen in glucose-intolerant subjects suggests that IKK/NF-kappaB pathway activation may be secondary to impaired glucose tolerance and that skeletal muscle IKK/NF-kappaB pathway activity is unlikely to play any major role in the control of skeletal muscle insulin action in nondiabetic subjects.
Friedrichsen
Martin
M
Steno Diabetes Center, DK-2820 Gentofte, Denmark. mfrc@steno.dk
Ribel-Madsen
Rasmus
R
Wojtaszewski
Jørgen
J
Grunnet
Louise
L
Richter
Erik A
EA
Billestrup
Nils
N
Ploug
Thorkil
T
Vaag
Allan
A
Poulsen
Pernille
P
D000328:Adult; D003920:Diabetes Mellitus / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism* / Q000502:physiology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D009765:Obesity / Q000378:metabolism; D010809:Physical Fitness / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014427:Twins / Q000378:metabolism*
D007328:Insulin; D016328:NF-kappa B; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D005947:Glucose