How do parasitic worms prevent diabetes? An exploration of their influence on macrophage and ß-cell crosstalk.

Diabetes is the fastest growing chronic disease globally, with prevalence increasing at a faster rate than heart disease and cancer. While the disease presents clinically as chronic hyperglycaemia, two distinct subtypes have been recognised. Type 1 diabetes (T1D) is characterised as an autoimmune disease in which the insulin-producing pancreatic ß-cells are destroyed, and type 2 diabetes (T2D) arises due to metabolic insufficiency, in which inadequate amounts of insulin are produced, and/or the actions of insulin are diminished. It is now apparent that pro-inflammatory responses cause a loss of functional ß-cell mass, and this is the common underlying mechanism of both T1D and T2D. Macrophages are the central immune cells in the pathogenesis of both diseases and play a major role in the initiation and perpetuation of the proinflammatory responses that compromise ß-cell function. Furthermore, it is the crosstalk between macrophages and ß-cells that orchestrates the inflammatory response and ensuing ß-cell dysfunction/destruction. Conversely, this crosstalk can induce immune tolerance and preservation of ß-cell mass and function. Thus, specifically targeting the intercellular communication between macrophages and ß-cells offers a unique strategy to prevent/halt the islet inflammatory events underpinning T1D and T2D. Due to their potent ability to regulate mammalian immune responses, parasitic worms (helminths), and their excretory/secretory products, have been examined for their potential as therapeutic agents for both T1D and T2D. This research has yielded positive results in disease prevention, both clinically and in animal models. However, the focus of research has been on the modulation of immune cells and their effectors. This approach has ignored the direct effects of helminths and their products on ß-cells, and the modulation of signal exchange between macrophages and ß-cells. This review explores how the alterations to macrophages induced by helminths, and their products, influence the crosstalk with ß-cells to promote their function and survival. In addition, the evidence that parasite-derived products interact directly with endocrine cells to influence their communication with macrophages to prevent ß-cell death and enhance function is discussed. This new paradigm of two-way metabolic conversations between endocrine cells and macrophages opens new avenues for the treatment of immune-mediated metabolic disease.