Dissociation between skeletal muscle inhibitor-{kappa}B kinase/nuclear factor-{kappa}B pathway activity and insulin sensitivity in nondiabetic twins

TY - JOUR

T1 - Dissociation between skeletal muscle inhibitor-{kappa}B kinase/nuclear factor-{kappa}B pathway activity and insulin sensitivity in nondiabetic twins

AU - Friedrichsen, Martin

AU - Ribel-Madsen, Rasmus

AU - Wojtaszewski, Jørgen

AU - Grunnet, Louise

AU - Richter, Erik

AU - Billestrup, Nils

AU - Ploug, Thorkil

AU - Vaag, Allan

AU - Poulsen, Pernille

N1 - CURIS 2010 5200 002

PY - 2010/1

Y1 - 2010/1

N2 - Context: Several studies suggest a link between increased activity of the inflammatory inhibitor-κB kinase/nuclear factor-κB (IKK/NF-κB) pathway in skeletal muscle and insulin resistance. Objective: We aimed to study the regulation of skeletal muscle IKK/NF-κB 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-κBβ (IκBβ) protein levels are negatively associated with IKK/NF-κB pathway activity and were used to evaluate pathway activity with p65 levels included as loading control. This indirect measure for IKK/NF-κB 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-α), only sex and age were significant predictors of IκBβto p65 ratio (28% decreased ratio in the elderly, P < 0.01, and 49% increased in males P < 0.01). IκBβto 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 IκBβto 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-κB pathway activity seen in glucose-intolerant subjects suggests that IKK/NF-κB pathway activation may be secondary to impaired glucose tolerance and that skeletal muscle IKK/NF-κB pathway activity is unlikely to play any major role in the control of skeletal muscle insulin action in nondiabetic subjects.

AB - Context: Several studies suggest a link between increased activity of the inflammatory inhibitor-κB kinase/nuclear factor-κB (IKK/NF-κB) pathway in skeletal muscle and insulin resistance. Objective: We aimed to study the regulation of skeletal muscle IKK/NF-κB 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-κBβ (IκBβ) protein levels are negatively associated with IKK/NF-κB pathway activity and were used to evaluate pathway activity with p65 levels included as loading control. This indirect measure for IKK/NF-κB 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-α), only sex and age were significant predictors of IκBβto p65 ratio (28% decreased ratio in the elderly, P < 0.01, and 49% increased in males P < 0.01). IκBβto 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 IκBβto 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-κB pathway activity seen in glucose-intolerant subjects suggests that IKK/NF-κB pathway activation may be secondary to impaired glucose tolerance and that skeletal muscle IKK/NF-κB pathway activity is unlikely to play any major role in the control of skeletal muscle insulin action in nondiabetic subjects.

U2 - 10.1210/jc.2009-1147

DO - 10.1210/jc.2009-1147

M3 - Journal article

C2 - 19875481

SN - 0021-972X

VL - 95

SP - 414

EP - 421

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 1

ER -