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 5

Aggregation of human IAPP is required to induce neuropathic pain.

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Aggregation of human IAPP is required to induce neuropathic pain. (A and...
(A and B) Fluorescence (indicates amount of amyloid fibrils) of thioflavin T (A) and transmission electron microscopy imaging (scale bars: 0.2 nm) (B) after 24 hours of incubation of hIAPP, mIAPP, or pramlintide. (C) Sensory neurons were treated with 100 nM hIAPP, mIAPP, pramlintide, or saline for 24 hours. The average neurite length per neuron was assessed and expressed as the percentage length per neuron of vehicle-treated neurons (n = 8; n represents a DRG culture of 1 mouse). (D) Mitochondrial ROS level in cultured DRG neurons incubated with hIAPP or pramlintide (10, 100, and 1,000 nM). Measurements are per cell from 3 different cultures, n = 551–654 neurons per group. (E and F) Course of mechanical sensitivity (n = 5) (E) and IENF density (n = 7) on day 6 (F) after intraplantar injection of 1,000 fg hIAPP, mIAPP, and pramlintide in male and female WT mice. (G) Density of IENFs in skin of T2DM subjects (n = 6) and non-T2DM controls (n = 9). (H) Representative images of G stained for the pan-neuronal marker PGP9.5 and collagen IV (lines indicate the border between dermis and epidermis; white arrows represent the IENF; scale bar: 20 μm). (I) IAPP-positive oligomers in skin of T2DM subjects (n = 6) and non-T2DM controls (n = 9). (J) Representative images of I stained for collagen IV (C IV), IAPP, and oligomers (I11). IAPP- and oligomer-positive spots are indicated by arrowheads. Lines indicate the border between dermis and epidermis. (C and D) One-way ANOVA with Dunnett’s test; *P < 0.05, **P < 0.01, ***P < 0.001. (E and F) Two-way ANOVA with Tukey’s test; *P < 0.05 vs. vehicle; ##P < 0.01 vs. pramlintide. (G and I) Unpaired t test; *P < 0.05, **P < 0.01. Data are expressed as mean ± SEM.