Background/Purpose:  Rheumatoid arthritis (RA) patients are at higher risk for insulin resistance (IR). The association between RA and IR, and its role on the different characteristics of the disease, such as duration and activity have not been well defined. In addition, there is a gap of knowledge regarding the link between systemic/local inflammation and insulin sensitivity and lipid metabolism in RA patients. Objective: To explore the effects of the systemic and local inflammation on the insulin sensitivity and lipid metabolism in RA patients and collagen induced arthritis (CIA) mouse model.

Methods:  Human study: 120 RA patients and 40 healthy donors were included. IR was quantified using the homeostatic model assessment of IR (HOMA-IR) and was compared between RA patients and demographically matched non-RA controls. Mouse model: To investigate the mechanisms underlying the link between inflammation and insulin sensitivity and lipid metabolism in RA, a CIA mouse model was used. A total number of 20 mice were used; five mice were used as non diseased control group, and 15 were used in CIA modelling. Scoring for CIA was performed after injection of chicken collagen type II and arthritis index (AI) was calculated. Leukocytes, skeletal muscle and adipose tissue were collected for gene and protein profiling. mRNA expression of genes involved in lipid and glucose metabolism, insulin signalling and inflammation were evaluated (CD36, CPT1a, MCAD, PGC1b, PPARa, PPARg2, ACC, DGAT2, FADS1, FADS2, LPL, PLIN2, AOX, FAS, GLUT4, IRS1, IRS2, TNFa, MCP-1 and F4/80). Phosphorylation and expression of AKT and JNK as markers of insulin sensitivity and inflammation were analysed. Protein expression of IL-1b was also evaluated.

Results: Percentages of obesity, hypertension, atherogenic risk, metabolic syndrome and insulin resistance were significantly increased in the RA group. Although mean time of evolution was 8 years, no association between insulin resistance and the duration of the disease was found. Levels of HOMA-IR significantly correlated with number of swollen joints, DAS28 and C-reactive protein levels, suggesting that systemic and local inflammation might lead to the development of insulin resistance. In mice, the induction of arthritis promoted an alteration of the expression of genes involved in inflammation as well as lipid metabolism and insulin signalling in skeletal muscle, adipose tissue and leukocytes of diseased CIA mice vs. controls. Levels of phosphorylation of AKT and JNK and protein expression of IL1b were significantly increased in those tissues of the CIA mice group.

Conclusion: 1) Insulin resistance was closely associated with an increase in disease activity and systemic and local inflammation in RA patients. 2) Induction of arthritis in mice promoted an increase in inflammation markers in skeletal muscle, adipose tissue and leukocytes, and a reduction of genes involved in lipid uptake and storage, generating an insulin resistance state in those tissues. In sum, our results suggest that chronic inflammation associated with RA might directly impact relevant metabolic tissues, altering glucose and lipid homeostasis. Funded by CP15/00158 and PI2013/0191.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effect-of-systemic-and-local-inflammation-on-the-insulin-resistance-and-glucoselipid-metabolism-in-rheumatoid-arthritis-humans-and-cia-mouse-model/