{"doi":"10.1101/2024.02.24.581864","title":"Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":487998,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":511325,"name":"Bastian Ramms","orcid":"0000-0001-7238-8663","position":1,"is_corresponding":false},{"id":23915,"name":"Chun Zeng","orcid":"0000-0001-9034-7873","position":2,"is_corresponding":false},{"id":658529,"name":"Jacqueline R. Benthuysen","orcid":"0000-0003-3050-6160","position":3,"is_corresponding":false},{"id":985692,"name":"Somesh Sai","orcid":"0000-0001-6865-341X","position":4,"is_corresponding":false},{"id":343330,"name":"Dennis P. Pollow","orcid":null,"position":5,"is_corresponding":false},{"id":1058968,"name":"Fenfen Liu","orcid":null,"position":6,"is_corresponding":false},{"id":624621,"name":"Michael Schlichting","orcid":null,"position":7,"is_corresponding":false},{"id":324886,"name":"Austin R. Harrington","orcid":null,"position":8,"is_corresponding":false},{"id":1332822,"name":"Bradley Liu","orcid":null,"position":9,"is_corresponding":false},{"id":901539,"name":"Thazha P. Prakash","orcid":"0000-0002-7466-3312","position":10,"is_corresponding":false},{"id":1120684,"name":"Elaine Pirie","orcid":"0000-0002-1992-9106","position":11,"is_corresponding":false},{"id":809930,"name":"Han Zhu","orcid":"0000-0003-1896-7140","position":12,"is_corresponding":false},{"id":698838,"name":"Siyouneh Baghdasarian","orcid":null,"position":13,"is_corresponding":false},{"id":261803,"name":"Johan Auwerx","orcid":"0000-0002-5065-5393","position":14,"is_corresponding":false},{"id":242295,"name":"Orian S. Shirihai","orcid":"0000-0001-8466-3431","position":15,"is_corresponding":false},{"id":7364,"name":"Maike Sander","orcid":"0000-0001-5308-7785","position":16,"is_corresponding":false},{"id":324887,"name":"Matthew Wortham","orcid":null,"position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:08:15.008850Z","pmid":"38464227","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}