Glucagon-like peptide 1 inhibits the sirtuin deacetylase SirT1 to stimulate pancreatic β-cell mass expansion.
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.


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.
Department of Medicine, Université Laval and Centre de Recherchede l’Institut Universitaire de Cardiologie et de Pneumologie de Quebec(CRIUCPQ), Quebec City, Quebec, Canada.
Pierre-Olivier
PO
Bastien-Dionne
Luca
L
Valenti
Ning
N
Kon
Wei
W
Gu
Jean
J
Buteau
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D000077270:Exenatide; D051858:Forkhead Transcription Factors / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D056564:Sirtuin 1 / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology
D051858:Forkhead Transcription Factors; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D054409:Nicotinamide Phosphoribosyltransferase; D056564:Sirtuin 1