Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

Chien Wen Chen*, Bo Jhih Guan, Mohammed R. Alzahrani, Zhaofeng Gao, Long Gao, Syrena Bracey, Jing Wu, Cheikh A. Mbow, Raul Jobava, Leena Haataja, Ajay H. Zalavadia, Ashleigh E. Schaffer, Hugo Lee, Thomas LaFramboise, Ilya Bederman, Peter Arvan, Clayton E. Mathews, Ivan C. Gerling, Klaus H. Kaestner, Boaz TiroshFeyza Engin*, Maria Hatzoglou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Pancreatic β-cells are prone to endoplasmic reticulum (ER) stress due to their role in insulin secretion. They require sustainable and efficient adaptive stress responses to cope with this stress. Whether episodes of chronic stress directly compromise β-cell identity is unknown. We show here under reversible, chronic stress conditions β-cells undergo transcriptional and translational reprogramming associated with impaired expression of regulators of β-cell function and identity. Upon recovery from stress, β-cells regain their identity and function, indicating a high degree of adaptive plasticity. Remarkably, while β-cells show resilience to episodic ER stress, when episodes exceed a threshold, β-cell identity is gradually lost. Single cell RNA-sequencing analysis of islets from type 1 diabetes patients indicates severe deregulation of the chronic stress-adaptation program and reveals novel biomarkers of diabetes progression. Our results suggest β-cell adaptive exhaustion contributes to diabetes pathogenesis.

Original languageAmerican English
Article number4621
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - 8 Aug 2022

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© 2022, The Author(s).

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