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