Human IAPP is a contributor to painful diabetic peripheral neuropathy
Albariqi, Mohammed Mh; Versteeg, Sabine; Brakkee, Elisabeth M; Coert, J Henk; Elenbaas, Barend Ow; Prado, Judith; Hack, C Erik; Höppener, Jo Wm; Eijkelkamp, Niels
(2023) Journal of Clinical Investigation, volume 133, issue 8
(Article)
Abstract
Peripheral neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). We investigated whether human islet amyloid polypeptide (hIAPP), which forms pathogenic aggregates that damage pancreatic islet β cells in T2DM, is involved in T2DM-associated peripheral neuropathy. In vitro, hIAPP incubation with sensory neurons reduced neurite outgrowth and increased
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levels of mitochondrial reactive oxygen species. hIAPP-transgenic mice, which have elevated plasma hIAPP levels without hyperglycemia, developed peripheral neuropathy as evidenced by pain-associated behavior and reduced intraepidermal nerve fiber (IENF) density. Similarly, hIAPP Ob/Ob mice, which have hyperglycemia in combination with elevated plasma hIAPP levels, had signs of neuropathy, although more aggravated. In wild-type mice, intraplantar and intravenous hIAPP injections induced long-lasting allodynia and decreased IENF density. Non-aggregating murine IAPP, mutated hIAPP (pramlintide), or hIAPP with pharmacologically inhibited aggregation did not induce these effects. T2DM patients had reduced IENF density and more hIAPP oligomers in the skin compared with non-T2DM controls. Thus, we provide evidence that hIAPP aggregation is neurotoxic and mediates peripheral neuropathy in mice. The increased abundance of hIAPP aggregates in the skin of T2DM patients supports the notion that hIAPP is a potential contributor to T2DM neuropathy in humans.
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Keywords: Amyloid, Animals, Diabetes Mellitus, Type 2/pathology, Diabetic Neuropathies/genetics, Humans, Hyperglycemia/pathology, Islet Amyloid Polypeptide/genetics, Islets of Langerhans/pathology, Mice, Mice, Transgenic, Pain/pathology, General Medicine, Journal Article
ISSN: 0021-9738
Publisher: The American Society for Clinical Investigation
Note: Funding Information: This work was financially supported by King Abdulaziz City for Science and Technology, Saudi Arabia. We thank Rakez Kayed (University of Texas Medical Branch, Department of Neurology, Galveston, Texas, USA) for providing the I11 antibody, Lucie Khemtemourian (Institut Polytechnique Bordeaux, Université de Bordeaux, Bordeaux, France) for performing the transmission electron microscopy imaging, and Christian Giesinger, Sergey Ryazanov, and Andrei Leonov (Department of NMR Based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany) for providing the anle145c. Publisher Copyright: © 2023, Albariqi et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
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