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ResearchIn-Press PreviewEndocrinologyMetabolism Open Access | 10.1172/JCI187020

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

Matthew Wortham,1 Bastian Ramms,1 Chun Zeng,1 Jacqueline R. Benthuysen,1 Somesh Sai,2 Dennis P. Pollow,1 Fenfen Liu,1 Michael Schlichting,1 Austin R. Harrington,1 Bradley Liu,1 Thazha P. Prakash,3 Elaine C. Pirie,3 Han Zhu,1 Siyouneh Baghdasarian,4 Sean T. Lee,5 Victor A. Ruthig,6 Kristen L. Wells,5 Johan Auwerx,7 Orian S. Shirihai,4 and Maike Sander1

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Wortham, M. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Ramms, B. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Zeng, C. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Benthuysen, J. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Sai, S. in: PubMed | Google Scholar |

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Pollow, D. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Liu, F. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Schlichting, M. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Harrington, A. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Liu, B. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Prakash, T. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Pirie, E. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Zhu, H. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Baghdasarian, S. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Lee, S. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Ruthig, V. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Wells, K. in: PubMed | Google Scholar |

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Auwerx, J. in: PubMed | Google Scholar

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Shirihai, O. in: PubMed | Google Scholar |

1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America

2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany

3Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, United States of America

4Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

5Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Developmental Biology Microscopy Consortium, Section of Developmental Biolo, University of Colorado Anschutz Medical Campus, Aurora, United States of America

7Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Find articles by Sander, M. in: PubMed | Google Scholar |

Published July 31, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI187020.
Copyright © 2025, Wortham et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 31, 2025 - Version history
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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 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, 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 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 that these findings translate to human β-cells from individuals with and without diabetes.

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  • Version 1 (July 31, 2025): In-Press Preview
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