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Human IAPP is a driver of painful diabetic peripheral neuropathy

Mohammed M. H. Asiri, View ORCID ProfileSabine Versteeg, Elisabeth M. Brakkee, J. Henk Coert, C. Erik Hack, Jo W. M. Höppener, View ORCID ProfileNiels Eijkelkamp
doi: https://doi.org/10.1101/2021.12.03.471098
Mohammed M. H. Asiri
1Center for Translational Immunology, trecht University, 3584 EA Utrecht, The Netherlands
4National Centre for Genomic Technology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology, P.O. Box 6086, 11461 Riyadh, Saudi Arabia
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Sabine Versteeg
1Center for Translational Immunology, trecht University, 3584 EA Utrecht, The Netherlands
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  • ORCID record for Sabine Versteeg
Elisabeth M. Brakkee
3Department of Plastic and Reconstructive Surgery, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands
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J. Henk Coert
3Department of Plastic and Reconstructive Surgery, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands
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C. Erik Hack
1Center for Translational Immunology, trecht University, 3584 EA Utrecht, The Netherlands
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Jo W. M. Höppener
1Center for Translational Immunology, trecht University, 3584 EA Utrecht, The Netherlands
2Center for Molecular Medicine, trecht University, 3584 EA Utrecht, The Netherlands
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Niels Eijkelkamp
1Center for Translational Immunology, trecht University, 3584 EA Utrecht, The Netherlands
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  • ORCID record for Niels Eijkelkamp
  • For correspondence: N.Eijkelkamp@umcutrecht.nl
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Abstract

Peripheral neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM), of which the pathogenesis is not fully understood. We investigated whether human islet amyloid polypeptide (hIAPP), which forms pathogenic aggregates that damage islet β-cells in T2DM, is involved in T2DM-associated peripheral neuropathy. In vitro, hIAPP incubation with sensory neurons reduced neurite outgrowth. Transgenic hIAPP Ob/Ob mice, an established animal model for T2DM, as well as hIAPP mice, which have elevated plasma hIAPP levels but no hyperglycaemia. Both transgenic mice developed peripheral neuropathy as evidenced by pain-associated behavior and reduced intra-epidermal nerve fibers (IENF), suggesting hIAPP is a mediator of diabetic neuropathy. Intraplantar and intravenous hIAPP injection in WT mice induced long-lasting mechanical hypersensitivity and reduced IENF, whereas non-aggregating murine IAPP or mutated hIAPP (Pramlintide) did not have these effects, and were not toxic for cultured sensory neurons. In T2DM patients, significantly more hIAPP oligomers were found in the skin compared to non-T2DM controls. Thus, we provide evidence that hIAPP is toxic to sensory neurons, and mediates peripheral neuropathy in mice. The presence of hIAPP aggregates in skin of humans with T2DM supports the notion that human IAPP is a potential driver of T2DM neuropathy in man.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 04, 2021.
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Human IAPP is a driver of painful diabetic peripheral neuropathy
Mohammed M. H. Asiri, Sabine Versteeg, Elisabeth M. Brakkee, J. Henk Coert, C. Erik Hack, Jo W. M. Höppener, Niels Eijkelkamp
bioRxiv 2021.12.03.471098; doi: https://doi.org/10.1101/2021.12.03.471098
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Human IAPP is a driver of painful diabetic peripheral neuropathy
Mohammed M. H. Asiri, Sabine Versteeg, Elisabeth M. Brakkee, J. Henk Coert, C. Erik Hack, Jo W. M. Höppener, Niels Eijkelkamp
bioRxiv 2021.12.03.471098; doi: https://doi.org/10.1101/2021.12.03.471098

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