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Cited by 152Diabetes and associated disordersPancreatic function and diabetesEndoplasmic Reticulum Stress and Disease

Beta Cell Dedifferentiation Induced by IRE1α Deletion Prevents Type 1 Diabetes

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Lee, Hugo, Lee, Yong-Syu, Harenda, Quincy, Pietrzak, Stefan, Oktay, Hülya Zeynep, Schreiber, Sierra, Liao, Yian, Sonthalia, Shreyash +5 more·2020·Cell Metabolism
DOI 10.1016/j.cmet.2020.03.002PMC PMC7346095
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Abstract

Immune-mediated destruction of insulin-producing β cells causes type 1 diabetes (T1D). However, how β cells participate in their own destruction during the disease process is poorly understood. Here, we report that modulating the unfolded protein response (UPR) in β cells of non-obese diabetic (NOD) mice by deleting the UPR sensor IRE1α prior to insulitis induced a transient dedifferentiation of β cells, resulting in substantially reduced islet immune cell infiltration and β cell apoptosis. Single-cell and whole-islet transcriptomics analyses of immature β cells revealed remarkably diminished expression of β cell autoantigens and MHC class I components, and upregulation of immune inhibitory markers. IRE1α-deficient mice exhibited significantly fewer cytotoxic CD8+ T cells in their pancreata, and adoptive transfer of their total T cells did not induce diabetes in Rag1-/- mice. Our results indicate that inducing β cell dedifferentiation, prior to insulitis, allows these cells to escape immune-mediated destruction and may be used as a novel preventive strategy for T1D in high-risk individuals.

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  • Over 40% of genes associated with type 1 diabetes are expressed in the islet or beta cell.

    “More recently, there has been increased focus on whether many of these variants may influence beta cell interactions with the immune system, with over 40% of genes associated with type 1 diabetes being expressed in the islet or beta cell.”

    From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [59]

    The Introduction says genetic predisposition is associated with type 1 diabetes, and the Results report gene-expression changes in islets from IRE1α-deficient mice. Neither passage gives the proportion of type 1 diabetes-associated genes expressed in islets or beta cells; searches for that proportion and for “40%” found no supporting passage in our copy. (LLM, conf=0.73)

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Cited by

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Authors
Lee, H., Lee, Y.-S., Harenda, Q., Pietrzak, S., Oktay, H. Z., Schreiber, S., Liao, Y., Sonthalia, S., Ciecko, A. E., Chen, Y.-G., Keles, S., Sridharan, R., & Engin, F.
Affiliations
  • University of Wisconsin–Madison (US)
  • Wisconsin Institutes for Discovery (US)
  • Medical College of Wisconsin (US)
Corresponding author
Engin, Feyza
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2020-04
Volume
31
Issue
4
Pages
822-836.e5
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2020.03.002
PMC
PMC7346095
OpenAlex
W3013062548
Cited by
152
References
3
Citations by year
2026: 17 · 2025: 23 · 2024: 32 · 2023: 15 · 2022: 22 · 2021: 32 · 2020: 11
FWCI
11.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (DK107541, DK118786, T32 GM007215, T32 NHGRI 5T32HG002760, DK121747, R01GM113033)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
type 1 diabetes, beta-cell dedifferentiation, IRE1α, unfolded protein response, insulitis, beta-cell apoptosis, beta cell autoantigens, MHC class I, CD8+ T cells, diabetes prevention, NOD mice, adoptive T cell therapy
MeSH terms
Animals, Diabetes Mellitus, Type 1, Endoribonucleases, Hyperglycemia, Mice, Inbred NOD, Protein Serine-Threonine Kinases, Gene Deletion, Mice, Knockout, CD8-Positive T-Lymphocytes, Insulin-Secreting Cells, Mice, Cell Dedifferentiation, Unfolded Protein Response

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