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| Item Type: | Preprint |
|---|---|
| Title: | Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2 |
| Creators Name: | Wortham, M., Ramms, B., Zeng, C., Benthuysen, J.R., Sai, S., Pollow, D.P., Liu, F., Schlichting, M., Harrington, A.R., Liu, B., Prakash, T.P., Pirie, E.C., Zhu, H., Baghdasarian, S., Auwerx, J., Shirihai, O.S. and Sander, M. |
| Abstract: | Selective and controlled expansion of endogenous β-cells has been pursued as a potential therapy for diabetes. Ideally, such therapies would preserve feedback control of β-cell proliferation to avoid excessive β-cell expansion and an increased risk of hypoglycemia. Here, we identified a regulator of β-cell proliferation whose inactivation results in controlled β-cell expansion: the protein deacetylase Sirtuin 2 (SIRT2). Sirt2 deletion in β-cells of mice increased β-cell proliferation during hyperglycemia with little effect in homeostatic conditions, indicating preservation of feedback control of β-cell mass. SIRT2 restrains proliferation of human islet β-cells cultured in glucose concentrations above the glycemic set point, demonstrating conserved SIRT2 function. Analysis of acetylated proteins in islets treated with a SIRT2 inhibitor revealed that SIRT2 deacetylates enzymes involved in oxidative phosphorylation, dampening the adaptive increase in oxygen consumption during hyperglycemia. At the transcriptomic level, Sirt2 inactivation has context-dependent effects on β-cells, with Sirt2 controlling how β-cells interpret hyperglycemia as a stress. Finally, we provide proof-of-principle that systemic administration of a GLP1-coupled Sirt2-targeting antisense oligonucleotide achieves β-cell selective Sirt2 inactivation and stimulates β-cell proliferation under hyperglycemic conditions. Overall, these studies identify a therapeutic strategy for increasing β-cell mass in diabetes without circumventing feedback control of β-cell proliferation. |
| Keywords: | B-Cell Proliferation, B-Cell Adaptation, Diabetes, Hyperglycemia, Oxidative Phosphorylation, Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2024.02.24.581864 |
| Date: | 28 February 2024 |
| Official Publication: | https://doi.org/10.1101/2024.02.24.581864 |
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