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

Abstract

IntroductionPrevalence 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 Ser312 phosphorylation (p-Ser312) 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.MethodsProspective 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-Ser312 IRS-1 and p-AKT. RA patients treated with abatacept (CTLA4.Ig) were used as a control group for insulin signaling studies.ResultsAt 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-Ser312 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-Ser312 IRS-1 and p-AKT levels was variable.ConclusionsAnti-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.

Insulin resistance pathogenesis in metabolic obesity

“…Использование анти-TNF-a антител привело к неутешительным результатам, так как нейтрализация TNF-a не нормализовала чувствительность к инсулину [65]. С другой стороны, у пациентов с тяжёлыми воспалительными заболеваниями, такими как ревматоидный артрит и болезнь Бехтерева, анти-TNF-a терапия оказалась успешной, так как вызывала снижение ИР и остальных компонентов МС [66][67][68]. В настоящее время исследуется потенциальный эффект блокады IL-1b на чувствительность к инсулину.…”

Effects of TNF-α Inhibitors on Abdominal Adiposity in Patients with Inflammatory Rheumatic Diseases

“…Second, a higher prevalence of MetS has been reported in patients with AS and RA 6,7 . Clinical studies have shown an improvement in MetS during anti-TNF treatment, suggesting a favorable cardiometabolic effect of these agents 7 .…”

“…Clinical studies have shown an improvement in MetS during anti-TNF treatment, suggesting a favorable cardiometabolic effect of these agents 7 . But a number of studies have described changes in lipid profile under anti-TNF treatment, with an increase in both total and low-density lipoprotein cholesterol 8 .…”

Systemic therapy of psoriasis in diabetic patients

“…Ustekinumab is not associated with weight gain in patients with chronic plaque psoriasis [49]. The effects of TNF-α inhibitors therapy on insulin sensitivity are controversial [50,51]. The effects of anti-TNFs on glycaemic parameters and insulin resistance in patients with psoriasis have been addressed mostly in small studies by means of the HOMA and the Quantitative Insulin Sensitivity Check Index (QUICKI], two widely used non-invasive surrogate markers of insulin resistance and sensitivity, respectively.…”