Dissociation between Skeletal Muscle Inhibitor-κB Kinase/Nuclear Factor-κB Pathway Activity and Insulin Sensitivity in Nondiabetic Twins

Abstract

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 IκBβ to p65 ratio (28% decreased ratio in the elderly, P < 0.01, and 49% increased in males P < 0.01). IκBβ 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 IκBβ 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-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.