Glucagon-Like Peptide 1 Inhibits the Sirtuin Deacetylase SirT1 to Stimulate Pancreatic β-Cell Mass Expansion

Abstract

OBJECTIVE The glucoincretin hormone glucagon-like peptide 1 (GLP-1) enhances glucose-stimulated insulin secretion and stimulates pancreatic β-cell mass expansion. We have previously shown that the forkhead transcription factor FoxO1 is a prominent transcriptional effector of GLP-1 signaling in the β-cell. FoxO1 activity is subject to a complex regulation by Akt-dependent phosphorylation and SirT1-mediated deacetylation. In this study, we aimed at investigating the potential role of SirT1 in GLP-1 action. RESEARCH DESIGN AND METHODS FoxO1 acetylation levels and binding to SirT1 were studied by Western immunoblot analysis in INS832/13 cells. SirT1 activity was evaluated using an in vitro deacetylation assay and correlated with the NAD+-to-NADH ratio. The implication of SirT1 in GLP-1–induced proliferation was investigated by BrdU incorporation assay. Furthermore, we determined β-cell replication and mass in wild-type and transgenic mice with SirT1 gain of function after daily administration of exendin-4 for 1 week. RESULTS Our data show that GLP-1 increases FoxO1 acetylation, decreases the binding of SirT1 to FoxO1, and stunts SirT1 activity in β-INS832/13 cells. GLP-1 decreases both the NAD+-to-NADH ratio and SirT1 expression in INS cells and isolated islets, thereby providing possible mechanisms by which GLP-1 could modulate SirT1 activity. Finally, the action of GLP-1 on β-cell mass expansion is abolished in both transgenic mice and cultured β-cells with increased dosage of SirT1. CONCLUSIONS Our study shows for the first time that the glucoincretin hormone GLP-1 modulates SirT1 activity and FoxO1 acetylation in β-cells. We also identify SirT1 as a negative regulator of β-cell proliferation.