JNK activity in subcutaneous adipose tissue but not NFκB activity in peripheral blood mononuclear cells is an independent determinant of insulin resistance in healthy individuals.

Abstract

Objective: Chronic low-grade activation of the immune system (CLAIS) predicts type 2 diabetes (T2D) via a decrease in insulin sensitivity. Our study investigated potential relationships between the nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, two pathways proposed as the link between CLAIS and insulin resistance.

Research Design and Methods: Adiposity (DEXA), waist-to-hip ratio (WHR), and insulin sensitivity (M, hyperinsulinaemic-euglycaemic clamp) were measured in 22 healthy non-diabetic volunteers (age 29±11y, body fat 28±11%). NFκB activity (DNA binding assay) and JNK1/2 activity (phosphorylated JNK) were assessed in biopsies from the vastus lateralis muscle and subcutaneous adipose tissue and in peripheral blood mononuclear cell (PBMC) lysates.

Results: NFκB activity in PBMC and muscle was positively associated with WHR after adjustment for age, sex, % body fat (both p<0.05). NFκB activity in PBMC was inversely associated with M after adjustment for age, sex and %body fat, WHR (p=0.02) and explained 16% of the variance of M. There were no significant relationships between NFκB activity and M in muscle or adipose tissue (both p=ns). Adipose derived JNK1/2 activity was not associated with obesity (all p>0.1), although it was inversely related to M (r=−0.54, p<0.05) and explained 29% of its variance. When both NFκB and JNK1/2 were statistically examined, only JNK1/2 activity in adipose tissue was a significant determinant of insulin resistance (p=0.02).

Conclusions: JNK1/2 activity in adipose tissue but not NFκB activity in PBMC is an independent determinant of insulin resistance in healthy individuals.