Role of inflammatory mediators in the suppression of insulin receptor phosphorylation in circulating mononuclear cells of obese subjects.
OBJECTIVE
Obesity is associated with insulin resistance and inflammation. The circulating human mononuclear cell (MNC) has been shown to respond to low-dose insulin infusion. We have now investigated whether in obesity: (1) phosphorylated insulin receptor beta subunit (p-INSR-beta) is reduced in the MNC; (2) pro-inflammatory mediators including inhibitor of kappa light polypeptide gene enhancer in B cells-kinase beta (IKBKB), suppressor of cytokine signalling-3 (SOCS) and protein kinase C-beta 2 (PRKCB2) are increased and related to p-INSR-beta; and (3) the reduction in MNC p-INSR-beta is related to the reduction in insulin sensitivity.


METHODS
MNCs were prepared from fasting blood samples of 16 normal weight and 16 obese female subjects.


RESULTS
Our data show that p-INSR-beta is reduced significantly in MNCs from obese subjects compared with that of normal controls. MNCs from obese subjects have higher IKBKB expression, increased nuclear factor kappa B (NFkappaB) binding and higher mRNA expression of TNFAIP1 and IL6 genes. NFkappaB binding, TNFAIP1 mRNA and plasma C-reactive protein are inversely related to p-INSR-beta. PRKCB2 mRNA and protein expression were significantly higher in the obese subjects and were related significantly to pro-inflammatory mediators but not to p-INSR-beta. SOCS3 mRNA expression was markedly elevated and positively related to pro-inflammatory mediators including IKBKB and PRKCB2 on the one hand and inversely related to p-INSR-beta on the other.


CONCLUSIONS
We conclude that in obesity the MNC is characterised by reduced p-INSR-beta and increased inflammatory mediators including IKBKB, PRKCB2 and SOCS3. The increase in SOCS3 but not IKBKB or PRKCB2 is related inversely to p-INSR-beta and might mediate the inhibition of p-INSR-beta. These data elucidate the relationship between inflammation and insulin resistance using the MNC as a model.
Ghanim
H
H
Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Buffalo, NY, USA.
Aljada
A
A
Daoud
N
N
Deopurkar
R
R
Chaudhuri
A
A
Dandona
P
P
D000328:Adult; D001794:Blood Pressure; D002784:Cholesterol / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000503:physiopathology*; D007328:Insulin / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D008875:Middle Aged; D009765:Obesity / Q000097:blood* / Q000503:physiopathology; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000097:blood*; D012016:Reference Values; D014280:Triglycerides / Q000097:blood
D005230:Fatty Acids, Nonesterified; D007328:Insulin; D014280:Triglycerides; D002784:Cholesterol; D011972:Receptor, Insulin