Human IAPP is a contributor to painful diabetic peripheral neuropathy
Mohammed M.H. Albariqi, … , Jo W.M. Höppener, Niels Eijkelkamp
Mohammed M.H. Albariqi, … , Jo W.M. Höppener, Niels Eijkelkamp
Published March 14, 2023
Citation Information: J Clin Invest. 2023;133(8):e156993. https://doi.org/10.1172/JCI156993.
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Research Article Immunology Neuroscience

Human IAPP is a contributor to painful diabetic peripheral neuropathy

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 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.

Authors

Mohammed M.H. Albariqi, Sabine Versteeg, Elisabeth M. Brakkee, J. Henk Coert, Barend O.W. Elenbaas, Judith Prado, C. Erik Hack, Jo W.M. Höppener, Niels Eijkelkamp

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Figure 4

Human IAPP reduces mechanical thresholds independent of its receptors and anle145c prevents this action in WT mice.

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Human IAPP reduces mechanical thresholds independent of its receptors an...
(A) Schematic diagram showing the timeline and administration routes for B. (B) Mechanical sensitivity after antagonist (250 μg/kg, CGRP8–37) injection (n = 13) or saline injection (n = 13) prior to intraplantar injection of hIAPP (1,000 fg, n = 8) or CGRP injection (5 μg, n = 5) in one paw and saline (n = 13) in the other paw. Both male and female mice were used. (C) Fluorescence of thioflavin T after 24 hours. Fluorescence intensity is determined by the concentration of amyloid fibrils. (D and E) Course of mechanical sensitivity (n = 8) (D) and plantar IENFs at 7 days (n = 8) (E) after intraplantar injection of hIAPP (1,000 fg/5 μL) with and without anle145c (1 nM), or vehicle. Treatments were prepared and incubated for 24 hours at room temperature before injection into male and female WT mice (n = 8). (B, D, and E) Two-way ANOVA with Tukey’s test; *P < 0.05, **P < 0.01, ***P < 0.001 vs. vehicle. (C) One-way ANOVA with Dunnett’s test; ***P < 0.001 vs. vehicle. Data are expressed as mean ± SEM.