It is not known, however, whether CRP is merely a marker of accompanying inflammation or whether it contributes causally to insulin learn more resistance. The objective of this study is to investigate the role that CRP may play in the development of insulin resistance. We examined the effect of single-dose intravenous

administration of purified human (h)CRP on insulin sensitivity in Sprague-Dawley rats using the euglycemic, hyperinsulinemic clamp technique. hCRP was associated with impaired insulin suppression of endogenous glucose production with no reduction in peripheral tissue glucose uptake, suggesting that hCRP mediated insulin resistance in the liver but not extrahepatic tissues. We further assessed components of the insulin signaling pathway and mitogen-activated protein kinases (MAPKs) in the liver. Liver tissues derived from hCRP-treated rats showed reduced insulin-stimulated insulin receptor substrate (IRS) tyrosine phosphorylation, IRS/phosphatidylinositol 3-kinase (PI3K) association, and Akt phosphorylation, consistent with hCRP-induced impairment of hepatic insulin signaling. Furthermore, hCRP enhanced phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK as well as IRS-1 Ser612. Finally, we observed in primary cultured rat hepatocytes that U0126 (a selective inhibitor of MAPK/ERK kinase1/2) corrected

U0126 supplier hCRP-induced impairment of insulin signaling. Conclusions: hCRP plays an active role in inducing hepatic insulin resistance in the rat, at least in part by activating ERK1/2, with downstream

impairment in the insulin signaling pathway. (HEPATOLOGY 2011) The appreciation that inflammation is a hallmark of the metabolic syndrome1, 2 has stimulated interest in whether systemic inflammatory Buspirone HCl biomarkers such as C-reactive protein (CRP) contribute to the development of insulin resistance. The acute-phase protein CRP is a member of the pentaxin protein family involved in pattern recognition and innate immunity; it is synthesized primarily by the liver in response to inflammation.3 In addition to being an independent predictor of cardiovascular events,4 CRP is also closely associated with insulin resistance5 and related metabolic disturbances such as fatty liver disease and hyperglycemia.6, 7 It remains unclear, however, whether this association simply reflects the inflammatory milieu or whether it suggests a causative role of CRP in the progression of insulin resistance. In vitro studies have shown that human (h)CRP impairs insulin action and the insulin receptor substrate (IRS)/phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and/or activates proinflammatory pathways in various cell types.8–10 To date, in vivo data concerning the effect of hCRP on insulin action are still lacking.