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

Inah Camaya, Tsz Mok, Maria Lund, Joyce To, Nady Braidy, Mark W. Robinson, Jerran Santos, Bronwyn O'Brien, Sheila Donnelly*

*Corresponding author for this work

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Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterised by the destruction of the insulin-producing beta (β)-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 β-cell metabolism, survival and proliferation. Consistent with this finding, FhHDM-1 preserved β-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 β-cells. This was confirmed in vitro, as the interaction of FhHDM-1 with the NOD-derived β-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, β-cell survival was enhanced and apoptosis was prevented in the presence of the pro-inflammatory cytokines that destroy β-cells during T1D pathogenesis. Similarly, FhHDM-1 protected primary human islets from cytokine-induced apoptosis. Importantly, while FhHDM-1 promoted β-cell survival, it did not induce proliferation. Collectively, these data indicate that FhHDM-1 has significant therapeutic applications to promote β-cell survival, which is required for T1D and T2D prevention and islet transplantation.
Original languageEnglish
Article number236
JournalJournal of Molecular Medicine
Early online date10 Aug 2021
DOIs
Publication statusEarly online date - 10 Aug 2021

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