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.
