A surviving beta cell subpopulation enriched in patients with T1D
- 1Yale University
Abstract
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of pancreatic beta cells. While most beta cells are lost, a subset of beta cells persists years and even decades after disease onset. Studying these surviving cells is challenging, and thus how they escape immune killing remains poorly understood. Here, we applied a gene regulatory network inference-based clustering approach on existing islet scRNAseq data from cadaveric donors with T1D, autoantibody positive donors at risk for T1D, and non-diabetic donors to analyze beta cells from patients with established T1D. This approach identified a novel beta cell subtype enriched in T1D donors defined by the activity of several transcription factors which have well-characterized roles in beta cell survival, most notably IRF1. We found increased expression of immunomodulatory genes (e.g. SOCS1/3, HLA-E) as well as decreased expression of autoantigens and secretory genes, suggesting loss of cellular identity. We identified inflammatory cytokines as a driver of this phenotype by reanalyzing public data from primary human beta cells stimulated with inflammatory cytokines in vitro. We find a similar transcriptional program active in a subset of alpha cells, consistent with cell-extrinsic inflammatory cytokine signaling in vivo. We additionally use immunofluorescence to validate these findings. Overall, this study defines the features of surviving beta cells in patients with T1D, revealing several genes and pathways active in these cells as potential targets for T1D prevention and reversal.
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BibTeX
@misc{spurrell2026surviving,
title = {{A surviving beta cell subpopulation enriched in patients with T1D}},
author = {M. Spurrell and Z. Tobiasova and J. S. Pober and J. Tsang and K. C. Herold},
howpublished = {bioRxiv},
year = {2026},
month = may,
doi = {10.64898/2026.05.15.725449},
url = {https://www.biorxiv.org/content/10.64898/2026.05.15.725449v3},
note = {CC BY},
}
RIS
TY - UNPB
TI - A surviving beta cell subpopulation enriched in patients with T1D
AU - M. Spurrell
AU - Z. Tobiasova
AU - J. S. Pober
AU - J. Tsang
AU - K. C. Herold
PY - 2026
DA - 2026/05/15
PB - bioRxiv
DO - 10.64898/2026.05.15.725449
UR - https://www.biorxiv.org/content/10.64898/2026.05.15.725449v3
AB - Type 1 diabetes (T1D) is characterized by the autoimmune destruction of pancreatic beta cells. While most beta cells are lost, a subset of beta cells persists years and even decades after disease onset. Studying these surviving cells is challenging, and thus how they escape immune killing remains poorly understood. Here, we applied a gene regulatory network inference-based clustering approach on existing islet scRNAseq data from cadaveric donors with T1D, autoantibody positive donors at risk for T1D, and non-diabetic donors to analyze beta cells from patients with established T1D. This approach identified a novel beta cell subtype enriched in T1D donors defined by the activity of several transcription factors which have well-characterized roles in beta cell survival, most notably IRF1. We found increased expression of immunomodulatory genes (e.g. SOCS1/3, HLA-E) as well as decreased expression of autoantigens and secretory genes, suggesting loss of cellular identity. We identified inflammatory cytokines as a driver of this phenotype by reanalyzing public data from primary human beta cells stimulated with inflammatory cytokines in vitro. We find a similar transcriptional program active in a subset of alpha cells, consistent with cell-extrinsic inflammatory cytokine signaling in vivo. We additionally use immunofluorescence to validate these findings. Overall, this study defines the features of surviving beta cells in patients with T1D, revealing several genes and pathways active in these cells as potential targets for T1D prevention and reversal.
ER -