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| Item Type: | Preprint |
|---|---|
| Title: | Workload-induced changes to cell state contribute to β-cell failure in diabetes |
| Creators: |
Sai, Somesh  ORCID: https://orcid.org/0000-0001-6865-341X, Liu, Fenfen, Harrington, Austin R., Zhu, Han, Omar, Ibrahim, Zeng, Chun, Mallick, Medhavi, Sui, Yinghui, Sander, Maike ORCID: https://orcid.org/0000-0001-5308-7785 and Wortham, Matthew ORCID: https://orcid.org/0009-0003-1302-4167
|
| Abstract: | Insufficient insulin secretion relative to insulin demand is a key feature of type 2 diabetes (T2D). While the defects of insulin-producing β-cells in T2D are well defined, little is known about how β-cells progress from the functionally normal state to the decompensated state during the natural history of this disease. Here, we provide evidence that workload-induced β-cell overstimulation precipitates β-cell failure in T2D. We employ scRNA-seq to define workload-induced changes to β-cell transcriptional states, identifying a novel compensating state that is distinct from the stressed state of decompensated β-cells. We demonstrate a key role for the chromatin-modifying enzyme Lysine-specific demethylase 1 (Lsd1) in restraining workload-induced β-cell state transitions, indicating epigenomic control of β-cell state. Experimental manipulations that promote the compensating state accelerate β-cell failure in mouse models of diabetes. Altogether, these findings show that the compensatory response of the β-cell to increased workload becomes maladaptive over time and contributes to the pathogenesis of T2D. |
| Keywords: | Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2026.05.13.725004 |
| Date: | 18 May 2026 |
| Official Publication: | https://doi.org/10.64898/2026.05.13.725004 |
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