24: Human Islet Amyloid Polypeptide Aggregation Drives Diabetic Peripheral Neuropathy

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Neuroimmunology, Omics (Proteomics/Metabolomics/Transcriptomics/Genomics), Assessment and Measurement of Pain/Nociception

Background and Aims: Diabetic peripheral neuropathy (DPN) affects approximately 50% of patients with type 2 diabetes mellitus (Albariqi et al., 2020). Since strict glycemic control is often insufficient to alleviate symptoms, other drivers likely contribute to the disease. The aggregation of human islet amyloid polypeptide (hIAPP) is a known mediator of pancreatic β-cell damage. However, its impact on the peripheral nervous system remains poorly understood. Recent work implicates hIAPP aggregation in painful DPN (Albariqi et al., 2023). We investigated the molecular mechanisms by which toxic hIAPP aggregates promote neurotoxicity and painful DPN.

Methods: The neurotoxic effects of hIAPP were evaluated in neuronal cell lines and characterized in multiple mouse models. We compared normoglycemic hIAPP-transgenic mice and hyperglycemic hIAPP ob/ob mice to wild-type controls, and validated findings using a mouse model in which aggregating and non-aggregating IAPP was injected into the hind paw of mice. Mechanical hypersensitivity (von Frey) and intraepidermal nerve fiber (IENF) density were assessed as measures of neuropathy. Molecular mechanisms were investigated using bulk RNA sequencing of lumbar DRGs.

Results: In vitro, hIAPP but not non-aggregating mIAPP induced mitochondrial dysfunction, oxidative stress, increased caspase-3/7 activity, and reduced neurite outgrowth. In vivo, normoglycemic hIAPP-transgenic mice and hIAPP-injected wild-type mice developed mechanical allodynia and IENF loss. DRG transcriptomics in hIAPP mice identified 19 differentially expressed genes associated with neuronal injury and pain sensitization. In ob/ob mice, hIAPP induced neuropathy-associated symptoms at lower concentrations, suggesting hyperglycemia and dyslipidemia enhance hIAPP neurotoxicity. Moreover, in hIAPP ob/ob mice, transcriptomics revealed activation of pro-inflammatory AGE-RAGE signaling. Finally, intraplantar hIAPP injection revealed sex-specific Neurobeachin downregulation in male mice, a protein orchestrating synaptic receptor trafficking.

Conclusions: hIAPP aggregation is neurotoxic and contributes to painful DPN independent of hyperglycemia by triggering oxidative stress, nerve fiber loss, and pain hypersensitivity. Transcriptomic profiling reveals distinct degenerative and inflammatory transcriptional pathways. These findings identify hIAPP aggregation as a putative driver of painful diabetic neuropathy.

References: Albariqi, M. M., Versteeg, S., Brakkee, E. M., Coert, J. H., Elenbaas, B. O., Prado, J., Hack, C. E., Höppener, J. W., & Eijkelkamp, N. (2023). Human IAPP is a contributor to painful diabetic peripheral neuropathy. The Journal of Clinical Investigation, 133(8), e156993. https://doi.org/10.1172/JCI156993

Albariqi, M. M. H., Engelsman, S., Eijkelkamp, N., & Höppener, J. W. M. (2020). Amyloid proteins and peripheral neuropathy. Cells, 9(6), 1553. https://doi.org/10.3390/cells9061553

Presenting Author: Chilam Chan
Submitting Author: Chilam Chan

Senior Author: Prof. Niels Eijkelkamp

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Tim R. Mocking: PhD - Center for Translational Immunology, University Medical Center Utrecht.
• Mohammed M.H. Albariqi: PhD - Center for Translational Immunology, University Medical Center Utrecht.
• Sabine Versteeg - Center for Translational Immunology, University Medical Center Utrecht.
• J. Henk Coert: PhD - Department of Plastic and Reconstructive Surgery, University Medical Center Utrecht.
• Judith Prado: PhD - Center for Translational Immunology, University Medical Center Utrecht.
• Jo W.M. Höppener: PhD - Center for Translational Immunology, University Medical Center Utrecht.
• Niels Eijkelkamp: PhD - Center for Translational Immunology, University Medical Center Utrecht.