Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2.

Autor:	Wortham M; Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA., Ramms B; Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA., Zeng C; Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA., Benthuysen JR; Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA., Sai S; Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Pollow DP; Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA., Liu F; Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA., Schlichting M; Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA., Harrington AR; Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA., Liu B; Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA., Prakash TP; Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, CA, USA., Pirie EC; Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, CA, USA., Zhu H; Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA., Baghdasarian S; Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Auwerx J; Laboratory of Integrated Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland., Shirihai OS; Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Sander M; Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 28. Date of Electronic Publication: 2024 Feb 28.
DOI:	10.1101/2024.02.24.581864
Abstrakt:	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. Competing Interests: DECLARATION OF INTERESTS: The authors have declared that no conflict of interest exists.
Databáze:	MEDLINE
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