Abstract
Insufficient insulin secretion by pancreatic β cells is central to the pathogenesis of diabetes mellitus. As insulin is synthesized in the endoplasmic reticulum (ER), perturbations in ER homeostasis lead to ER stress and activate the ER stress response. Over the past two decades, considerable data have accumulated on the role of β cell ER stress in diabetes mellitus. Several monogenic forms of diabetes mellitus are caused by excessive ER stress, perturbed ER stress response signalling or impaired ER–Golgi protein trafficking. These pathways are now recognized to contribute to β cell failure in both type 1 and type 2 diabetes mellitus. This Review considers the role of β cell ER stress in common forms of diabetes mellitus and examines whether it is a cause or a consequence of these diseases. The strong genetic evidence for a causal role of ER stress in 15 monogenic forms of diabetes mellitus is summarized, and the effects of ER stress on human β cell differentiation, function and survival are described. Although definitive proof is lacking that ER stress responses can be therapeutically targeted to improve β cell function in diabetes mellitus, existing and novel treatments that aim to restore ER homeostasis are also outlined.
Key points
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The unfolded protein response (UPR) is an essential adaptive mechanism in β cells that is activated by perturbed functioning of the endoplasmic reticulum (ER) and/or Golgi organelles.
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The effects of ER stress on β cell proliferation, differentiation, function, apoptosis and immune cell crosstalk depend on the β cell developmental stage, duration of ER stress and genetic background.
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Of ~70 known monogenic forms of diabetes mellitus, 15 provide indisputable genetic evidence for the critical roles of ER stress, dysregulated UPR and impaired ER–Golgi trafficking in human β cells.
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ER stress occurs during both early and late stages in the pathogenesis of polygenic type 1 and type 2 diabetes mellitus, but causality has yet to be firmly demonstrated.
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ER stress modulators have been shown to protect β cells in preclinical studies, and a few early clinical studies are underway.
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Acknowledgements
The laboratory of M.C. is supported by the European Union Horizon Health project NEMESIS, the European Foundation for the Study of Diabetes — Boehringer Ingelheim European Research Programme on Multi-System Challenges in Diabetes, The Leona M. and Harry B. Helmsley Charitable Trust, the Belgian Fonds National de la Recherche Scientifique (FNRS), Walloon Region strategic axis Fonds de la Recherche Scientifique (FRFS) — Walloon Excellence in Life Sciences and Biotechnology (WELBIO), and Research Foundation Flanders (FWO) & Fund for Scientific Research (FRS)-FNRS Excellence of Science (EOS) project Pandarome. Y.T. and E.V. are FNRS-Fund for Research Training in Industry and Agriculture (FRIA) fellows. M.L. is supported by FNRS and Erasmus Fund for Medical Research fellowships.
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Lytrivi, M., Tong, Y., Virgilio, E. et al. Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells. Nat Rev Endocrinol 21, 546–563 (2025). https://doi.org/10.1038/s41574-025-01129-5
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DOI: https://doi.org/10.1038/s41574-025-01129-5
