IRS1 and metabolic syndrome: In RA patients with severe and active disease even in the presence of anti-TNF-α therapy, high-grade inflammation was correlated negatively and independently with circulating adiponectin concentration [40], an important anti-inflammatory adipokine related to insulin resistance and metabolic syndrome [41]. In vitro studies have shown that TNF-α induced serine phosphorylation of insulin receptor substrate-1 (IRS-1) and inhibited insulin receptor tyrosine kinase, causing a change of the insulin signaling [40].