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

Selective and controlled expansion of endogenous b-cells has been pursued as a potential therapy for diabetes. Ideally, such therapies would preserve feedback control of b-cell proliferation to avoid excessive b-cell expansion and an increased risk of hypoglycemia. Here, we identified a regulator of b-cell proliferation whose inactivation results in controlled b-cell expansion: the protein deacetylase Sirtuin 2 (SIRT2). Sirt2 deletion in b-cells of mice increased b-cell proliferation during hyperglycemia with little effect in homeostatic conditions, indicating preservation of feedback control of b-cell mass. SIRT2 restrains proliferation of human islet b-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, Sirt2 inactivation has context-dependent effects on b-cells, with Sirt2 controlling how b-cells interpret hyperglycemia as a stress. Finally, we provide proof-of-principle that systemic administration of a GLP1-coupled Sirt2-targeting antisense oligonucleotide achieves b-cell selective Sirt2 inactivation and stimulates b-cell proliferation under hyperglycemic conditions. Overall, these studies identify a therapeutic strategy for increasing b-cell mass in diabetes without circumventing feedback control of b-cell proliferation.