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

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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.

Key messages

  • FhHDM-1 preserves β-cell mass in NOD mice and prevents the development of T1D.

  • FhHDM-1 enhances phosphorylation of Akt in mouse β-cell lines.

  • FhHDM-1 increases levels of NADH/NADPH in mouse β-cell lines in vitro.

  • FhHDM-1 prevents cytokine-induced cell death of mouse β-cell lines and primary human β-cells in vitro via activation of the PI3K/Akt pathway.

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This manuscript has data included as electronic supplementary material.

Abbreviations

PI3K/Akt:

Phosphoinositide 3-kinase/protein kinase B

SGK1:

Serum/glucocorticoid-regulated kinase 1

THBS1:

Thrombospondin 1

IGF1R:

Insulin-like growth factor 1 receptor

FBP1:

Fructose bisphosphatase 1

AKR1B7:

Aldo-keto reductase family 1, member B7

NOD:

Non-obese diabetic

VC:

Vehicle control

PARP:

Poly-ADP-ribose polymerase

IP:

Intraperitoneal

PBS:

Phosphate-buffered saline

LC–MS/MS:

Liquid chromatography-tandem mass spectrometry

FBS:

Foetal bovine serum

GO:

Gene ontology

CM:

Pro-inflammatory cytokine mix

HRP:

Horseradish peroxidase

ECL:

Enhanced chemiluminescence

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labelling

PI:

Propidium iodide

GLP:

Glucagon-like peptide-1

GIP:

Glucose-dependent insulinotropic polypeptide

FOXO:

Forkhead box O

CRAMP:

Cathelicidin-related antimicrobial peptide

EGFR:

Epidermal growth factor receptor

ROI:

Reactive oxygen intermediates

NADH:

Nicotinamide adenine dinucleotide reduced form

NADPH:

Nicotinamide adenine dinucleotide phosphate reduced form

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Acknowledgements

We thank the UTS Microbial Imaging Facility and director Dr L. Cole for providing technical training for the Zeiss slide scanner and A. Zebib and E. van Dijk for assisting in the sectioning of mouse pancreata. We would also like to acknowledge the guidance provided by Alison Ricafrente and Dr Alen Faiz for the EdgeR analysis of the transcriptome data. Commentary and feedback on the final manuscript from Prof. John Dalton and Prof. Bruce Milthorpe were gratefully received.

Funding

This work was funded by a National Health and Medical Research Council project grant (APP1087341), a JDRF Beta Cell Regeneration Innovative grant (1-INO-2019-785-S-B) and a Royal Society research grant (RG2012R2).

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Authors and Affiliations

  1. School of Life Sciences, Faculty of Science, the University of Technology Sydney, Ultimo, Australia

    Inah Camaya, Tsz Y. Mok, Maria Lund, Joyce To, Jerran Santos, Bronwyn O’Brien & Sheila Donnelly

  2. Centre for Healthy Brain Ageing, University of New South Wales, Sydney, Randwick, Australia

    Nady Braidy

  3. School of Biological Sciences, Queen’s University, Belfast, Northern Ireland, UK

    Mark W. Robinson

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  1. Inah Camaya
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Contributions

I.C. and T.Y.M. performed the experiments; I.C., M.L., J.T., N.B., M.W.R., J.S. and S.D. performed data analysis; I.C., S.D. and B.O.B. designed the study and all authors contributed to the discussion and manuscript preparation.

Corresponding author

Correspondence to Sheila Donnelly.

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All animal work was conducted in accordance with the approved guidelines of the University of Technology Sydney Animal Care and Ethics Committee (protocols ETH17-1226 and ETH19-4082).

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The authors declare no competing interests.

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Camaya, I., Mok, T.Y., Lund, M. et al. The parasite-derived peptide FhHDM-1 activates the PI3K/Akt pathway to prevent cytokine-induced apoptosis of β-cells. J Mol Med 99, 1605–1621 (2021). https://doi.org/10.1007/s00109-021-02122-x

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