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 5

β Cell–targeted Sirt2 ASO enhances β cell proliferation under hyperglycemic conditions in vivo.

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β Cell–targeted Sirt2 ASO enhances β cell proliferation under hyperglyce...
(A) Schematic of systemic GLP1-Sirt2-ASO treatment. (B and C) Quantitative PCR (qPCR) analysis of Sirt2 mRNA levels in the indicated tissues (B) and Glp1r mRNA levels in islets (C). (D) Schematic of GLP1-Sirt2 ASO treatment followed by implantation of S961 pumps. (E) qPCR analysis of Sirt2 mRNA level in islets from S961-treated mice. (F and G) Blood glucose levels (F) (n = 7–9 mice/group) and β cell proliferation (G) (n = 6–8 mice/group) for the indicated groups of S961-treated mice. (H) Schematic of GLP1-Sirt2-ASO treatment in STZ-treated mice. (I and J) Blood glucose levels (I) (n = 4–9 mice/group) and β cell proliferation (J) (n = 3–4 mice/group) for the indicated groups of STZ-treated mice. Data are shown as the mean ± SEM. Statistical differences were calculated using a 2-way ANOVA followed by Fisher’s LSD test (B and E), unpaired, 2-tailed Student’s t test (C), or 1-way ANOVA followed by Tukey’s post hoc test (F, G, I, and J). *P < 0.05, **P < 0.01, and ***P < 0.001. rel., relative.