Investigating the impact of the parasite derived peptide FhHDM-1 on β-cell survival and function
- Publication Type:
- Thesis
- Issue Date:
- 2023
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Type 1 diabetes (T1D) is an autoimmune disease characterized by the irreversible immune-mediated destruction of the insulin producing β-cells within the pancreatic islets. Fasciola hepatica helminth defence molecule-1 (FhHDM-1), was previously identified as a parasite-derived peptide that permanently prevented T1D development in non-obese diabetic (NOD) mice. Disease prevention was associated with increased insulin content and decreased insulitis within the islet, however the exact protective mechanisms have yet to be elucidated. Therefore, the aim of this project was to determine whether this beneficial effect of FhHDM-1 was mediated by alterations to the survival and/or function of pancreatic β-cells. Initial analysis revealed that FhHDM-1 localised to the pancreas in vivo and directly interacted with β-cells in vitro to promote survival/function and prevent apoptosis in the presence of pro-inflammatory cytokines, without inducing proliferation. These positive effects were associated with the activation of PI3K/Akt signaling. Investigation of the underlying transcriptome and proteome changes induced by FhHDM-1 that led to activation of PI3K/Akt signaling identified insulin growth factor 1 receptor (IGF1R) as the probable initiating factor. However, despite an increase in expression and protein abundance of this receptor in FhHDM-1 treated β-cells, no direct interaction between FhHDM-1 and IGF1R occurred. Instead, FhHDM-1 treatment enhanced the secretion of IGF-2, in turn increasing the total abundance and phosphorylation of IGF1R at the tyrosine residue 1316. This phosphorylation site is associated with the recruitment of PI3K to IGF1R, and subsequent activation of the PI3K/Akt signaling cascade, in turn leading to enhanced β-cell survival and function. Since IGF-2 is not stored in the intracellular vesicles of β-cells, the data indicated that FhHDM-1 was activating the transcription of IGF-2 to mediate its positive downstream effects. This was confirmed by analysis of the miRNA-gene regulation within FhHDM-1 treated β-cells, which identified several miRNAs that correlated with IGF-2/PI3K/Akt modulation (such as upregulation of miR-483-3p and miR-124-3p, and downregulation of miR-466i-5p, miR-7689-3p, miR-30d-5p, miR-3470a, miR-677-5p, and miR-7033-5p). The collective outcomes of this research demonstrate that FhHDM-1 would be efficacious across multiple pathogeneses in which preservation of functional β-cell mass is required such as in individuals who are at-risk of T1D, in individuals that have undergone seroconversion, in recently diagnosed T1D patients with residual β-cell mass, in patients undergoing islet transplantation, and putatively in T2D, in which inflammation compromises β-cell function. Accordingly, FhHDM-1 represents a potential cure for a compilation of diseases that are the fastest growing and most chronic conditions worldwide.
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