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Prevalence of insulin resistance and the metabolic syndrome has been reported to be high in rheumatoid arthritis (RA) patients. Tumor necrosis factor (TNF), a pro-inflammatory cytokine with a major pathogenetic role in RA, may promote insulin resistance by inducing Ser 312  phosphorylation (p-Ser 312 ) of insulin receptor substrate (IRS)-1 and downregulating phosphorylated (p-)AKT. We examined whether anti-TNF therapy improves insulin resistance in RA patients and assessed changes in the insulin signaling cascade.    Methods  Prospective study of RA patients receiving anti-TNF agents (infliximab,  n  = 49, adalimumab,  n  = 11, or etanercept,  n  = 1) due to high disease activity score in 28 joints (DAS28 > 5.1). A complete biochemical profile was obtained at weeks 0 and 12 of treatment. Insulin resistance, insulin sensitivity and pancreatic beta cell function were measured by the Homeostasis Model Assessment (HOMA-IR), the Quantitative Insulin Sensitivity Check Index (QUICKI) and the HOMA-B respectively. Protein extracts from peripheral blood mononuclear cells were assayed by western blot for p-Ser 312  IRS-1 and p-AKT. RA patients treated with abatacept (CTLA4.Ig) were used as a control group for insulin signaling studies.    Results  At study entry, RA patients with high insulin resistance (HOMA-IR above median) had significantly higher mean DAS28 ( P  = 0.011), serum triglycerides ( P  = 0.015), and systolic blood pressure levels ( P  = 0.024) than patients with low insulin resistance. After 12 weeks of anti-TNF therapy, patients with high insulin resistance demonstrated significant reduction in HOMA-IR ( P  < 0.001), HOMA-B ( P  = 0.001), serum triglycerides ( P  = 0.039), and increase in QUICKI ( P  < 0.001) and serum HDL-C ( P  = 0.022). Western blot analysis in seven active RA patients with high insulin resistance showed reduction in p-Ser 312  IRS-1 ( P  = 0.043) and increase in p-AKT ( P  = 0.001) over the study period. In contrast, the effect of CTLA4.Ig on p-Ser 312  IRS-1 and p-AKT levels was variable.    Conclusions  Anti-TNF therapy improved insulin sensitivity and reversed defects in the insulin signaling cascade in RA patients with active disease and high insulin resistance. The impact of these biochemical changes in modifying cardiovascular disease burden in active RA patients remains to be seen.

arthritis research and therapy

Anti-tumor necrosis factor therapy improves insulin resistance, beta cell function and insulin signaling in active rheumatoid arthritis patients with high insulin resistance