Fig. 1.

The inflammatory pathogenic mechanisms associated with glucose derangement may be exacerbated by rheumatoid arthritis (RA). Interleukin (IL)-1β, IL-6, and TNF may contribute to the development of glucose derangement and type 2 diabetes (T2D). β-cell has a high density of IL-1β receptors; based on the overexpression of IL-1β, as observed in RA, β-cells may become more susceptible to the negative effects of this cytokine but also of other inflammatory mediators, such as IL-6 and TNF. In turn, these other molecules may also attract macrophages and other immune cells, which infiltrate the pancreatic islets. The consequent inflammatory infiltration is characterised largely by macrophages. These alterations may first lead to β-cell dysfunction and consequently to their apoptosis, with the result of a progressive glucose derangement and the consequent occurrence of T2D. Furthermore, β cells and other insulin-sensitive tissues, stressed by the high glucose levels, may produce elevated amounts of IL-1β via the hyper-expression of nucleotide-binding domain and leucine-rich repeat containing family pyrin 3 (NLRP3) inflammasome in perpetuating this pathogenic vicious circle. Tumour necrosis factor (TNF) may be of some relevance in the development of both insulin resistance (IR) and of T2D since it is produced in the adipose tissue. This cytokine may reduce the expression of glucose transporter type 4 (GLUT4), an insulin-regulated glucose transporter mainly located in adipocytes, skeletal and cardiac muscles, thereby reducing glucose uptake. Moreover, serine phosphorylation of insulin receptor substrate-1 (IRS-1) induced by TNF may inhibit the insulin receptor and may antagonise its signal. Interleukin-6 is produced by both adipocytes and macrophages within adipose tissues, skeletal muscle, and liver, and it is hyper-activated in RA. Furthermore, hyperinsulinemia may lead to an increase in IL-6 blood levels, thus leading an additional vicious cycle involving a pro-inflammatory molecule and glucose abnormalities