The protein deacetylase SIRT2 exerts metabolic control over adaptive β cell proliferation
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
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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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 4

Sirt2 inactivation affects the transcriptional response of β cells to hyperglycemia.

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Sirt2 inactivation affects the transcriptional response of β cells to h...
(A) Schematic of the scRNA-Seq experiment. Tamoxifen-treated Sirt2+/+ Pdx1CreER and Sirt2fl/+ Pdx1CreER mice were used as controls. (B) Uniform manifold approximation and projection (UMAP) plot of clustered β cells colored by subset. (C) Abundance of each β cell subset as a proportion of total β cells for the indicated treatments and genotypes (n = 2 technical replicates of islets pooled from 2–3 mice per group). (D) Enriched gene ontologies and pathways for mRNAs more highly expressed in each subset relative to all other β cells (FDR < 0.05). val., value. (E) Network of GOs and pathways for mRNAs more highly expressed in β-5 cells compared with β-1 cells (FDR < 0.05). (F) GSEA of the indicated β cell stress response gene sets for genes ranked by FDR for pairwise comparisons between the indicated subsets of β cells. The FDR was determined by Wilcoxon rank-sum test for subset-specific genes (D) and pairwise comparisons of β cell subsets (E and F). NES, normalized enrichment score; norm, normal; trsln, translation.