Associations between insulin resistance and TNF-alpha in plasma, skeletal muscle and adipose tissue in humans with and without type 2 diabetes.
OBJECTIVE
Clear evidence exists that TNF-alpha inhibits insulin signalling and thereby glucose uptake in myocytes and adipocytes. However, conflicting results exist with regard to the role of TNF-alpha in type 2 diabetes.


METHODS
We obtained blood and biopsy samples from skeletal muscle and subcutaneous adipose tissue in patients with type 2 diabetes (n = 96) and healthy controls matched for age, sex and BMI (n = 103).


RESULTS
Patients with type 2 diabetes had higher plasma levels of fasting insulin (p < 0.0001) and glucose (p < 0.0001) compared with controls, but there was no difference between groups with regard to fat mass. Plasma levels of TNF-alpha (p = 0.0009) and soluble TNF receptor 2 (sTNFR2; p = 0.002) were elevated in diabetic patients. Insulin sensitivity was correlated with quartiles of plasma TNF-alpha after adjustment for age, sex, obesity, WHR, neutrophils, IL-6 and maximum O(2) uptake (VO2/kg) in the diabetes group (p < 0.05). The TNF mRNA content of adipose or muscle tissue did not differ between the groups, whereas muscle TNF-alpha protein content, evaluated by western blotting, was higher in type 2 diabetic patients. Immunohistochemistry revealed more TNF-alpha protein in type 2 than in type 1 muscle fibres.


CONCLUSIONS
After adjustment for multiple confounders, plasma TNF-alpha is associated with insulin resistance. This supports the idea that TNF-alpha plays a significant role in the pathogenesis of chronic insulin resistance in humans. However, findings on the TNF-alpha protein levels in plasma and skeletal muscle indicate that measurement of TNF mRNA content in adipose or muscle tissue provides no information with regard to the degree of insulin resistance.
Plomgaard
P
P
Centre of Inflammation and Metabolism, Department of Infectious Diseases, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. plomgaard@dadlnet.dk
Nielsen
A R
AR
Fischer
C P
CP
Mortensen
O H
OH
Broholm
C
C
Penkowa
M
M
Krogh-Madsen
R
R
Erikstrup
C
C
Lindegaard
B
B
Petersen
A M W
AM
Taudorf
S
S
Pedersen
B K
BK
D000273:Adipose Tissue / Q000378:metabolism*; D001823:Body Composition / Q000502:physiology; D002097:C-Reactive Protein / Q000032:analysis; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D015850:Interleukin-6 / Q000097:blood; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood* / Q000235:genetics / Q000378:metabolism*
D015850:Interleukin-6; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein