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Dissociation between Skeletal Muscle Inhibitor-{kappa}B Kinase/Nuclear Factor-{kappa}B Pathway Activity and Insulin Sensitivity in Nondiabetic Twins.

Friedrichsen, Martin; Ribel-Madsen, Rasmus; Wojtaszewski, Jørgen; Grunnet, Louise; Richter, Erik A; Billestrup, Nils; Ploug, Thorkil; Vaag, Allan LU and Poulsen, Pernille (2010) In Journal of Clinical Endocrinology and Metabolism 95(1). p.414-421
Abstract
Context: 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... (More)
Context: 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Clinical Endocrinology and Metabolism
volume
95
issue
1
pages
414 - 421
publisher
The Endocrine Society
external identifiers
  • wos:000273391300059
  • pmid:19875481
  • scopus:75149167395
ISSN
1945-7197
DOI
10.1210/jc.2009-1147
language
English
LU publication?
yes
id
7fd9ac83-e63e-44f4-8296-45cf506939e8 (old id 1499862)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19875481?dopt=Abstract
date added to LUP
2009-11-03 09:35:49
date last changed
2018-05-29 10:54:40
@article{7fd9ac83-e63e-44f4-8296-45cf506939e8,
  abstract     = {Context: 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 &lt; 0.01, and 49% increased in males P &lt; 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.},
  author       = {Friedrichsen, Martin and Ribel-Madsen, Rasmus and Wojtaszewski, Jørgen and Grunnet, Louise and Richter, Erik A and Billestrup, Nils and Ploug, Thorkil and Vaag, Allan and Poulsen, Pernille},
  issn         = {1945-7197},
  language     = {eng},
  number       = {1},
  pages        = {414--421},
  publisher    = {The Endocrine Society},
  series       = {Journal of Clinical Endocrinology and Metabolism},
  title        = {Dissociation between Skeletal Muscle Inhibitor-{kappa}B Kinase/Nuclear Factor-{kappa}B Pathway Activity and Insulin Sensitivity in Nondiabetic Twins.},
  url          = {http://dx.doi.org/10.1210/jc.2009-1147},
  volume       = {95},
  year         = {2010},
}