c-Jun NH2-terminal kinase activity in subcutaneous adipose tissue but not nuclear factor-kappaB activity in peripheral blood mononuclear cells is an independent determinant of insulin resistance in healthy individuals.
OBJECTIVE
Chronic low-grade activation of the immune system (CLAIS) predicts type 2 diabetes via a decrease in insulin sensitivity. Our study investigated potential relationships between nuclear factor-kappaB (NF-kappaB) and c-Jun NH(2)-terminal kinase (JNK) pathways-two pathways proposed as the link between CLAIS and insulin resistance.


METHODS
Adiposity (dual-energy X-ray absorptiometry), waist-to-hip ratio (WHR), and insulin sensitivity (M, hyperinsulinemic-euglycemic clamp) were measured in 22 healthy nondiabetic volunteers (aged 29 +/- 11 years, body fat 28 +/- 11%). NF-kappaB activity (DNA-binding assay) and JNK1/2 activity (phosphorylated JNK) were assessed in biopsies of the vastus lateralis muscle and subcutaneous adipose tissue and in peripheral blood mononuclear cell (PBMC) lysates.


RESULTS
NF-kappaB activities in PBMCs and muscle were positively associated with WHR after adjustment for age, sex, and percent body fat (both P < 0.05). NF-kappaB activity in PBMCs was inversely associated with M after adjustment for age, sex, percent body fat, and WHR (P = 0.02) and explained 16% of the variance of M. There were no significant relationships between NF-kappaB activity and M in muscle or adipose tissue (both 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 NF-kappaB and JNK1/2 were examined statistically, 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 NF-kappaB activity in PBMCs is an independent determinant of insulin resistance in healthy individuals.
Sourris
Karly C
KC
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Lyons
Jasmine G
JG
de Courten
Maximilian P J
MP
Dougherty
Sonia L
SL
Henstridge
Darren C
DC
Cooper
Mark E
ME
Hage
Michelle
M
Dart
Anthony
A
Kingwell
Bronwyn A
BA
Forbes
Josephine M
JM
de Courten
Barbora
B
D000293:Adolescent; D000328:Adult; D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002467:Cell Nucleus; D017931:DNA Primers; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050151:Subcutaneous Fat / Q000378:metabolism*; D049629:Waist-Hip Ratio; D055815:Young Adult; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D017931:DNA Primers; D016328:NF-kappa B; D048056:Mitogen-Activated Protein Kinase 9; D019892:eIF-2 Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8