Abstract
Type 1 diabetes (T1D) is a progressive autoimmune condition that culminates in loss of insulin-producing beta cells. Pancreatic histopathology provides essential insights into disease initiation/progression yet an integrated perspective onto in situ pathogenic processes is lacking. Here, we combined multiplexed immunostaining, high-magnification whole-slide imaging, digital pathology, and semi-automated image analyses to interrogate pancreatic tail and head sections across T1D stages, including at-risk and at-onset cases. Deconvolution of architectural features, endocrine cell composition, immune cell burden, and spatial relations of ~25,000 islets effectively contextualizes previously established and additional pancreatic hallmarks in health and T1D. Our results reveal a spatially homogenous and islet size-contingent architectural organization of the endocrine pancreas, a notable coordination of organ-wide pathogenic processes, and multiple histopathological correlates that foreshadow distinctive T1D histopathology already at the preclinical stage. Altogether, we propose a revised natural history of T1D with implications for further histopathological investigations and considerations of pathogenetic modalities.
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Data availability
The supplemental information provided for this study includes detailed pancreas specimen information and donor metadata (Supplementary Data 1); properties of individual donor tissue sections and all ~25,000 islets captured therein and stratified according to pancreas region, donor group and UMAP sub/cluster affiliation (Supplementary Data 2); details for antibodies and MICSSS staining conditions (Table S1); and source data for all main and supplemental figures (source data file). Raw whole-slide brightfield images of pancreatic tissue sections captured at 40× will be provided by the lead contact upon request. All other data are available in the article and its Supplementary files or from the corresponding author upon request. Source data are provided with this paper.
Code availability
Code used for image analysis using QuPath and MATLAB is accessible on GitHub: https://github.com/saramcardle/MICSSSPancreas or as a DOI on Zenodo: https://doi.org/10.5281/zenodo.17655136104.
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Acknowledgements
We thank Dr. R. Brody (ISMMS Biorepository and Pathology CoRE) for provision of additional pancreatic tissue sections used for MICSSS optimization, Dr. O. Madsen (Novo Nordisk) for the gift of ProINS antibody, Dr. P. Bankhead (University of Edinburgh) for advice about QuPath customization, Dr. E. Bagiella (ISMMS Center for Biostatistics) for assistance with statistical analyses, Dr. B. Rosenberg (ISMMS Department of Microbiology) for advice about UMAP clustering, J. Gregory (ISMMS) for design of the model figure panel, and Dr. S. Richardson for detailed feedback on the manuscript. This research was supported by JDRF Fellowship 3-PDF-2018-575-A-N and a supplement (V.v.d.H.); Chan Zuckerberg Initiative grant DAF2019-198153 (S.M.); NIH grants CA224319, DK124165, CA234212, and CA196521 (S.G.); and NIH grants R01AI134971, R01DK130425, R21ES027916 and P30DK020541 (D.H.). To provide context for the multiplicity of observations reported here, we repeatedly cite consensus opinions summarized in authoritative reviews; we apologize to the authors whose pertinent primary contributions are not explicitly mentioned here. Most importantly, we thank the families of the organ donors for the gift of tissues.
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Conceptualization: V.v.d.H. and D.H.; investigation: V.v.d.H.; formal analysis: V.v.d.H., S.M., Z.M., K.C., and D.H.; software: S.M. and M.N.; writing - original draft: D.H.; writing - review and editing: all authors; visualization: V.v.d.H., S.M., and D.H.; resources: S.G., Z.M., A.L.P., I.K., and M.A.A.; funding acquisition: V.v.d.H. and D.H.; supervision: D.H.
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K.C. reports other research funding from Cour Pharmaceuticals, IM Therapeutics, GentiBio Inc., and InduPro not related to this study; S.G. reports other research funding from Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, Regeneron, and Takeda not related to this study; S.G. is a named co-inventor on an issued patent for MICSSS, a multiplex immunohistochemistry technology to characterize tumors and treatment responses that is filed through ISMMS and currently remains unlicensed; all other authors declare no competing interests.
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van der Heide, V., McArdle, S., Nelson, M.S. et al. Integrated histopathology of the human pancreas throughout stages of type 1 diabetes progression. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68610-1
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DOI: https://doi.org/10.1038/s41467-026-68610-1
