SIRT2 puts the brakes on human β cell proliferation: therapeutic opportunities and next challenges.

Abstract

The numbers of insulin-producing β cells in the pancreas are reduced in people with type 1 or type 2 diabetes, prompting efforts to replace these missing or lost β cells through transplant or regenerative medicine approaches. In this issue of the JCI, Wortham et al. describe a function for the deacetylase enzyme sirtuin 2 (SIRT2) in a novel pathway that acts as a brake on β cell proliferation. They show that inhibiting SIRT2 through pharmacologic or genetic approaches can induce human and mouse β cells to reenter a proliferative cell cycle. A surprising observation that remains unexplained is that the main targets of SIRT2 are mitochondrial oxidative phosphorylation (OxPhos) enzymes. It also remains unknown if and how these unanticipated acetylated OxPhos targets lead to cell-cycle entry. SIRT2 inhibitors will be a welcome addition to the growing repertoire of human β cell-regenerative drugs.