Insulin Signaling in Arthritis

Abstract

Inflammatory arthritis is burdened by an increased risk of metabolic disorders. Cytokines and other mediators in inflammatory diseases lead to insulin resistance, diabetes and hyperlipidemia. Accumulating evidence in the field of immunometabolism suggests that the cause-effect relationship between arthritis and metabolic abnormalities might be bidirectional. Indeed, the immune response can be modulated by various factors such as environmental agents, bacterial products and hormones. Insulin is produced by pancreatic cells and regulates glucose, fat metabolism and cell growth. The action of insulin is mediated through the insulin receptor (IR), localized on the cellular membrane of hepatocytes, myocytes and adipocytes but also on the surface of T cells, macrophages, and dendritic cells. In murine models, the absence of IR in T-cells coincided with reduced cytokine production, proliferation, and migration. In macrophages, defective insulin signaling resulted in enhanced glycolysis affecting the responses to pathogens. In this review, we focalize on the bidirectional cause-effect relationship between impaired insulin signaling and arthritis analyzing how insulin signaling may be involved in the aberrant immune response implicated in arthritis and how inflammatory mediators affect insulin signaling. Finally, the effect of glucose-lowering agents on arthritis was summarized.

Mitochondrial Dysfunction and Oxidative Stress in Rheumatoid Arthritis

“…Thus, tofacitinib, an oral Janus kinase inhibitor for the treatment of RA, decreases in RA synoviocytes [ 100 ] and CD8+ T cells [ 114 ] the mRNA expression of different glycolysis rate-limiting enzymes such as the mentioned HK2, PFKFB or other molecules involved in aerobic glycolysis, as GLUT1, also higher in RA synoviocytes, which in turn results in the attenuation of inflammatory response and hyperplasia state. In the same line, glucose-lowering agents such as metformin or thiazolidinediones (TZDs) have shown potential anti-inflammatory activities and protective effects on RA [ 123 , 124 , 125 ]. Interestingly, blockade of glycolysis alleviates inflammatory phenotype in RA macrophages and RA fibroblasts, even when metabolic regulation of both cell types is distinct [ 126 ].…”

Rheumatoid Arthritis Treatment Options and Type 2 Diabetes: Unravelling the Association

“…The latter are expressed on multiple target cells including hepatocytes, adipocytes, synoviocytes and muscle cells [ 27 ]. Intriguingly, these receptors may also be found on the surface membrane of immune cells [ 27 , 28 ]. In fact, these cells need glucose to produce energy, and through its receptors, insulin exerts its hypoglycaemic function and behaves as a growth-like factor as well as a cytokine regulator [ 29 , 30 ].…”

“…In this context, it has been shown that hyperglycaemia has negative effects on the immune cells leading to the production of advanced glycation end products and reactive oxygen species, which in turn may stimulate the generation of various pro-inflammatory mediators [ 33 ]. Thus, insulin may have a role in reducing the “glucose toxicity” and cell stress, exerting an anti-inflammatory effect [ 28 ]. Other evidence performed in healthy nondiabetic subjects explored the effects of insulin on polymorphonuclear leukocytes functions [ 34 ].…”

Glucose as a Potential Key to Fuel Inflammation in Rheumatoid Arthritis

“…The IRs are expressed ubiquitously on the cell surface of adipose tissue, muscle, and many other cells including the synovial cells and T lymphocytes under regulation by the inflammatory cytokines [ 34 , 35 , 36 ]. The insulin signaling via IRs is thought to play an important role in RA, both metabolically and immunologically [ 7 , 37 , 38 ]. For example, the insulin signaling via IRs regulates the development of regulatory T cells (Treg); in addition, hyperinsulinemia, which is an insulin resistance hallmark, may lead to Treg function suppression [ 34 , 35 ].…”