Hyperinsulinemia counteracts inflammation by suppressing IFNg and inducing senescence in CD4+ T cells of patients with rheumatoid arthritis

Background. Clinical evidence connects hyperinsulinemia with obesity, and development of type 2 diabetes (T2D). However, its role in autoimmune conditions was questioned. We investigated consequences of hyperinsulinemia for development of T2D and CD4+T cell function in rheumatoid arthritis (RA). Methods. Incident T2D was prospectively studied in two independent RA cohorts and in gout patients matched to RA by age and gender, for 10 years. Effect of hyperinsulinemia and JAK-STAT signaling inhibition (JAKi) in CD4+T cells was studied by integrating transcriptional sequencing with direct effect of insulin, and JAKi on cell proliferation, DNA enrichment, and cytokine production. Results. T2D was 3.2-2.5 times less prevalent in RA compared to gout, particularly in females. Hyperinsulinemia predicted the development of T2D, regardless of metabolic parameters and insulin resistance. Additionally, hyperinsulinemia correlated with the senescence-associated high serum levels of IL6, IL8, and VEGF. Hyperinsulinemia, along with ex-vivo exposure of CD4+ cells to insulin, inhibited cell cycle progression and induced DNA enrichment through the suppression of the PI3K-Src kinases and cell cycle promoting genes. It also reduced IFNg production. JAKi-treated CD4+ cells regained insulin sensitivity, which activated glucose metabolism and facilitated senescence. This insulin-dependent mechanism promoted the accumulation of naive CD4+ cells in JAKi-treated patients. Conclusions. This study shows that insulin has important immunosuppressive ability controlling the adaptive immunity by suppressing IFNg production and inducing senescence in the effector CD4+ T cells. Inhibition of JAK-STAT signaling enhances insulin sensitivity and rejuvenates CD4+ cell population in RA patients.