The protein deacetylase SIRT2 exerts metabolic control over adaptive β cell proliferation
Matthew Wortham, … , Orian S. Shirihai, Maike Sander
Matthew Wortham, … , Orian S. Shirihai, Maike Sander
Published July 31, 2025
Citation Information: J Clin Invest. 2025;135(19):e187020. https://doi.org/10.1172/JCI187020.
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Research Article Endocrinology Metabolism

The protein deacetylase SIRT2 exerts metabolic control over adaptive β cell proliferation

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. Here, we identified a regulator of β cell proliferation whose inactivation resulted 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 under homeostatic conditions, indicating preservation of feedback control of β cell mass. SIRT2 restrains proliferation of human islet β cells, 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 glucagon-like peptide 1–coupled (GLP1-coupled), Sirt2-targeting antisense oligonucleotide achieves β cell Sirt2 inactivation and stimulates β cell proliferation during hyperglycemia. Overall, these studies identify a therapeutic strategy for increasing β cell mass in diabetes without circumventing feedback control of β cell proliferation. Future work should test the extent to which these findings translate to human β cells from individuals with or without diabetes.

Authors

Matthew Wortham, Bastian Ramms, Chun Zeng, Jacqueline R. Benthuysen, Somesh Sai, Dennis P. Pollow, Fenfen Liu, Michael Schlichting, Austin R. Harrington, Bradley Liu, Thazha P. Prakash, Elaine C. Pirie, Han Zhu, Siyouneh Baghdasarian, Sean T. Lee, Victor A. Ruthig, Kristen L. Wells, Johan Auwerx, Orian S. Shirihai, Maike Sander

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Figure 1

SIRT2 inhibition stimulates β cell proliferation in a glucose-dependent manner in cultured mouse and human islets.

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SIRT2 inhibition stimulates β cell proliferation in a glucose-dependent ...
(A) Immunofluorescence staining for the indicated proteins in mouse pancreata and human islet sections. Enlarged images for the indicated areas, including DNA overlay, are shown below each channel. Scale bars: 50 µm (top) and 10 µm (enlarged images at bottom). Sections were counterstained for DNA using DAPI. Images are representative of 4 mouse pancreata and 2 human islet donors. (B) Quantification of β cell proliferation as a percentage of insulin-expressing cells positive for EdU in isolated mouse (blue, n = 3–7 islet preparations/group) and human (red, n = 10–25 islet preparations/group) islets after DMSO or AGK2 treatment during culture with the indicated glucose concentrations. (C) Quantification of non–β islet cell proliferation as a percentage of insulin–EdU+ cells in isolated mouse (blue, n = 4 islet preparations/group) and human (red, n = 6 islet preparations/group) islets after DMSO or AGK2 treatment. (D) Quantification of β cell proliferation as a percentage of insulin-expressing cells positive for EdU in isolated mouse (blue, n = 3 islet preparations/group) and human (red, n = 9–10 islet preparations/group) islets after treatment with DMSO, AGK2, NMN (an NAD+ precursor), or combinations thereof at 16.8 mM glucose. Data are shown as the mean ± SEM. Statistical differences were calculated using a multiple paired, 2-tailed Student’s t test (B) or a paired, 2-tailed Student’s t test (C) to determine statistical differences between 2 groups. A 1-way ANOVA with Tukey post hoc analysis was performed to analyze statistical differences between 3 or more groups (D). *P < 0.05, **P < 0.01, and ***P < 0.001. Glc, glucose; Ins, insulin.