Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2

Abstract

ABSTRACTSelective 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).Sirt2deletion 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,Sirt2inactivation has context-dependent effects on β-cells, withSirt2controlling how β-cells interpret hyperglycemia as a stress. Finally, we provide proof-of-principle that systemic administration of a GLP1-coupledSirt2-targeting antisense oligonucleotide achieves β-cell selectiveSirt2inactivation 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.