biostudies-literatureAlbariqi MMKing Abdulaziz City for Science and Technology (KACST), Saudi Arabiae156993https://www.ebi.ac.uk/biostudies/studies/S-EPMC10104883biostudies-literatureUnknown133(8)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-tyThe Journal of clinical investigationHuman IAPP is a contributor to painful diabetic peripheral neuropathy.PMC1010488369082/1438/MCoert JHPrado JVersteeg SElenbaas BOEijkelkamp NAlbariqi MMHack CEHoppener JWBrakkee EMfalseHuman IAPP is a contributor to painful diabetic peripheral neuropathy.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-ty2023-01-01T00:00:00Z2023 Apr2025-04-04T22:59:56.401Z2025-04-04T22:59:56.401ZS-EPMC101048833691717710.1172/JCI156993