The Parasite-Derived Peptide, FhHDM-1, Selectively Modulates miRNA Expression in ß-Cells to Prevent Apoptotic Pathways Induced by Proinflammatory Cytokines.

We have previously identified a parasite-derived peptide, FhHDM-1, that prevented the progression of diabetes in nonobese diabetic (NOD) mice. Disease prevention was mediated by the activation of the PI3K/Akt pathway to promote ß-cell survival and metabolism without inducing proliferation. To determine the molecular mechanisms driving the antidiabetogenic effects of FhHDM-1, miRNA:mRNA interactions and in silico predictions of the gene networks were characterised in ß-cells, which were exposed to the proinflammatory cytokines that mediate ß-cell destruction in Type 1 diabetes (T1D), in the presence and absence of FhHDM-1. The predicted gene targets of miRNAs differentially regulated by FhHDM-1 mapped to the biological pathways that regulate ß-cell biology. Six miRNAs were identified as important nodes in the regulation of PI3K/Akt signaling. Additionally, IGF-2 was identified as a miRNA gene target that mediated the beneficial effects of FhHDM-1 on ß-cells. The findings provide a putative mechanism by which FhHDM-1 positively impacts ß-cells to permanently prevent diabetes. As ß-cell death/dysfunction underlies diabetes development, FhHDM-1 opens new therapeutic avenues.

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.

Targeting the PI3K/Akt signaling pathway in pancreatic ß-cells to enhance their survival and function: An emerging therapeutic strategy for type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of the insulin-producing ß-cells within the pancreas. Islet transplantation represents one cure; however, during islet preparation and post transplantation significant amounts of ß-cell death occur. Therefore, prevention and cure of T1D is dependent upon the preservation of ß-cell function and the prevention of ß-cell death. Phosphoinositide 3-kinase (PI3K)/Akt signaling represents a promising therapeutic target for T1D due to its pronounced effects on cellular survival, proliferation, and metabolism. A growing amount of evidence indicates that PI3K/Akt signaling is a critical determinant of ß-cell mass and function. Modulation of the PI3K/Akt pathway, directly (via the use of highly specific protein and peptide-based biologics, excretory/secretory products of parasitic worms, and complex constituents of plant extracts) or indirectly (through microRNA interactions) can regulate the ß-cell processes to ultimately determine the fate of ß-cell mass. An important consideration is the identification of the specific PI3K/Akt pathway modulators that enhance ß-cell function and prevent ß-cell death without inducing excessive ß-cell proliferation, which may carry carcinogenic side effects. Among potential PI3K/Akt pathway agonists, we have identified a novel parasite-derived protein, termed FhHDM-1 (Fasciola hepatica helminth defense molecule 1), which efficiently stimulates the PI3K/Akt pathway in ß-cells to enhance function and prevent death without concomitantly inducing proliferation unlike several other identified stimulators of PI3K/Akt signaling . As such, FhHDM-1 will inform the design of biologics aimed at targeting the PI3K/Akt pathway to prevent/ameliorate not only T1D but also T2D, which is now widely recognized as an inflammatory disease characterized by ß-cell dysfunction and death. This review will explore the modulation of the PI3K/Akt signaling pathway as a novel strategy to enhance ß-cell function and survival.

The parasite-derived peptide FhHDM-1 activates the PI3K/Akt pathway to prevent cytokine-induced apoptosis of ß-cells.

Type 1 diabetes (T1D) is an autoimmune disease characterised by the destruction of the insulin-producing beta (ß)-cells within the pancreatic islets. We have previously identified a novel parasite-derived molecule, termed Fasciola hepatica helminth defence molecule 1 (FhHDM-1), that prevents T1D development in non-obese diabetic (NOD) mice. In this study, proteomic analyses of pancreas tissue from NOD mice suggested that FhHDM-1 activated the PI3K/Akt signalling pathway, which is associated with ß-cell metabolism, survival and proliferation. Consistent with this finding, FhHDM-1 preserved ß-cell mass in NOD mice. Examination of the biodistribution of FhHDM-1 after intraperitoneal administration in NOD mice revealed that the parasite peptide localised to the pancreas, suggesting that it exerted a direct effect on the survival/function of ß-cells. This was confirmed in vitro, as the interaction of FhHDM-1 with the NOD-derived ß-cell line, NIT-1, resulted in increased levels of phosphorylated Akt, increased NADH and NADPH and reduced activity of the NAD-dependent DNA nick sensor, poly(ADP-ribose) polymerase (PARP-1). As a consequence, ß-cell survival was enhanced and apoptosis was prevented in the presence of the pro-inflammatory cytokines that destroy ß-cells during T1D pathogenesis. Similarly, FhHDM-1 protected primary human islets from cytokine-induced apoptosis. Importantly, while FhHDM-1 promoted ß-cell survival, it did not induce proliferation. Collectively, these data indicate that FhHDM-1 has significant therapeutic applications to promote ß-cell survival, which is required for T1D and T2D prevention and islet transplantation. KEY MESSAGES: FhHDM-1 preserves ß-cell mass in NOD mice and prevents the development of T1D. FhHDM-1 enhances phosphorylation of Akt in mouse ß-cell lines. FhHDM-1 increases levels of NADH/NADPH in mouse ß-cell lines in vitro. FhHDM-1 prevents cytokine-induced cell death of mouse ß-cell lines and primary human ß-cells in vitro via activation of the PI3K/Akt pathway.