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1 Clinical Sciences Research Institute, University of Warwick, University of Warwick, Coventry, West Midlands, United Kingdom
2 university of wales, heart research institute, cardiff, Wales, United Kingdom
* To whom correspondence should be addressed. E-mail: sudhesh.kumar{at}warwick.ac.uk.
Type-2 diabetes (T2DM) is associated with chronic low-grade inflammation. Adipose tissue (AT) may represent an important site of inflammation. 3T3-L1 studies have demonstrated that lipopolysaccharide (LPS) activates toll like receptors (TLRs) to cause inflammation. For this study we (1) examined activation of TLRs and adipocytokines by LPS in human abdominal subcutaneous (AbdSc) adipocytes; (2) examined blockade of nuclear factor-kappa B (NF
B) in human AbdSc adipocytes (3) examined the innate immune pathway in AbdSc AT from lean, obese and T2DM subjects; and (4) examined the association of circulating LPS in T2DM subjects.
LPS increased TLR-2 protein expression two-fold (p<0.05). Treatment of AbdSc adipocytes with LPS caused a significant increase in TNF-
and IL-6 secretion (IL-6, Control: 2.7±0.5ng/mL vs. LPS: 4.8±0.3ng/mL; p<0.001; TNF-, Control: 1.0±0.83pg/mL vs. LPS: 32.8±6.23pg/mL; p<0.001). NFB inhibitor reduced IL-6 in AbdSc adipocytes (Control: 2.7±0.5ng/mL vs. NFB inhibitor: 2.1±0.4 ng/mL; p<0.001). AbdSc AT protein expression for TLRs, MyD88, TRAF6, NFB was increased in T2DM's (p<0.05). Circulating LPS was 76% higher in T2DM subjects compared with matched controls. LPS correlated with insulin in controls (r=0.678, p<0.0001). Rosiglitazone significantly reduced both fasting serum insulin levels (reduced by 51%, p=0.0395) and serum LPS (reduced by 35%, p=0.0139) in a sub-group of previously untreated T2DM patients. In summary, our results suggest that T2DM is associated with increased endotoxemia, with adipose tissue able to initiate an innate immune response. Thus, increased adiposity may increase pro-inflammatory cytokines and therefore contribute to the pathogenic risk of T2DM.
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