Pos1072 insulin inhibits activity of cd4+ t cells in rheumatoid arthritis

Background Rheumatoid arthritis (RA) and diabetes mellitus (DM) have common genetic risk factors, while molecular mechanisms behind this commonality have not been studied. Objectives To study non-metabolic effects of insulin in CD4+ T cells of RA patients. Methods Incidental DM was studied in a consecutive cohort of 330 (256 female, 74 male) RA patients and 1011 (798 female, 213 male) gout patients matched to RA by age and gender (1 to 3) retrieved from the Health Care Register of Western Sweden during 10 years of follow-up. Insulin was measured at baseline and analyzed in relation to clinical and serological disease parameters. Transcriptomics by RNAseq was done on CD4 + T cells of 57 RA patients. Differentially expressed genes (DEG, nominal p<0.05) in patients with hyperinsulinemia (n=11, median 344 pmol/L) were identified using DESEq2 (R studio, Bioconductor) and analyzed for enrichment of biological processes and transcription factor (TF) families using GSEA (Broad Institute). To study direct effect of insulin on CD4 + T cell function, in vitro culture experiments were performed. Analysis of CD4 + Tcell phenotype for senescence, exhaustion and apoptosis was done by flow cytometry, transcriptomics and cytokine measurement. Results In total, 102 new cases of DM were registered, significantly less often in RA patients compared to gout patients (p=3.2e-4, OR=0.34 [0.18-0.64]). The new DM were more prevalent in men (p=0.012) with no difference between RA and gout patients (9.8 vs 7.5%, OR=1.34 [0.46-3.52] p=0.55). In females, RA patients developed significantly fewer cases of DM than gout patients (2.1 vs 9.4%, OR=0.21 [0.07; 0.47], p=3.2e-5). In RA patients, the insulin levels correlated positively to inflammation measured by serum levels of IL6, VEGF and IL8 followed by IFNγ total, 102 new cases of DM were registered, significantly less often in RA patients compared to gout patients (p=3.2e-4, OR=0.34 [0.18-0.64]). The new DM were more prevalent in men (p=0.012) with no difference between RA and gout patients (9.ol/L). Transcription profile of CD4 + T cells revealed 688 (131 upregulated, 557 downregulated) protein-coding DEG in patients with hyperinsulinemia. The down-regulated DEG showed enrichment for T cell activation (GO:0042110, FDR 2.6e-26) and inflammatory response (GO:0006954, FDR 2.9e-21). Analysis for TF families showed that the down-regulated DEG were controlled by TFs HMGB1, NFAT and NFκB (all FDR更多