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 2

Sirt2 inactivation enhances β cell proliferation in hyperglycemic conditions in vivo.

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Sirt2 inactivation enhances β cell proliferation in hyperglycemic condi...
(A) β Cell–selective Sirt2-KO mice (hereafter referred to as Sirt2Δβ) were generated by tamoxifen injection of 12- to 15-week-old Sirt2fl/fl Pdx1CreER mice. Tamoxifen-treated Sirt2+/+ Pdx1CreER and Sirt2fl/+ Pdx1CreER mice were used as controls. (B) Blood glucose levels measured for 52 weeks after tamoxifen treatment (n = 5–9 mice/group). (C) Blood glucose levels at the indicated time points following an intraperitoneal glucose injection, 52 weeks after tamoxifen treatment (n = 5–9 mice/group). (D) Quantification of β cell proliferation as a percentage of insulin+ and BrdU+ cells relative to total insulin+ cells, 4–6 weeks following tamoxifen treatment (n = 11–12 mice/group). (E) Hyperglycemia was induced in control and Sirt2Δβ mice by intraperitoneal injection of STZ (200 mg/kg body weight). After 3 weeks, (F) blood glucose levels (n = 6 mice/group), (G) β cell proliferation (n = 5 mice/group, and (H) relative β cell area (n = 4–5 mice/group) were measured. (I) Hyperglycemia was induced in control and Sirt2Δβ mice by administering S961 via transplanted minipumps (20 nmol/week). After 1 week, (J) blood glucose levels (n = 10–13 mice/group), (K) β cell proliferation (n = 10–13 mice/group), and (L) β cell area (n = 4 mice/group) were measured. Data are shown as the mean ± SEM. Statistical differences were calculated using a 2-way ANOVA with Tukey’s post hoc analysis (B and C) or an unpaired, 2-tailed Student’s t test (D, F–H, and J–L). *P < 0.05, **P < 0.01, and ***P < 0.001. q2d, every 2 days; Ctrl, control.