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Transcription Factor FoxO1 Mediates Glucagon-Like Peptide-1 Effects on Pancreatic ß-Cell Mass

From the Naomi Berrie Diabetes Center, Department of Medicine, Columbia University Medical Center, New York

Address correspondence and reprint requests to Domenico Accili, Berrie Research Pavilion, 1150 St. Nicholas Ave., Room 238, New York, NY 10032. E-mail: da230{at}columbia.edu

Abbreviations: ß-Gal, ß-galactosidase; BrdU, bromodeoxyuridine; BTC, betacellulin; EGFR, epidermal growth factor receptor; ERK, extracellular signal–related kinase; FKHR, forkhead transcription factor Foxo1; GLP-1, glucagon-like peptide-1; Pdx1, pancreatic and duodenal homeobox gene-1; PI, phosphatidylinositol

The glucoincretin hormone glucagon-like peptide-1 (GLP-1) increases pancreatic ß-cell proliferation and survival through sequential activation of the epidermal growth factor receptor (EGFR), phosphatidylinositol-3 kinase (PI 3-kinase), and Akt. We investigated the role of transcription factor FoxO1 in the proliferative and antiapoptotic actions of GLP-1 in ß-cells. GLP-1 inhibited FoxO1 through phosphorylation-dependent nuclear exclusion in pancreatic ß (INS832/13) cells. The effect of GLP-1 was suppressed by inhibitors of EGFR (AG1478) and PI 3-kinase (LY294002). In contrast, LY294002 but not AG1478 suppressed insulin-induced FoxO1 phosphorylation. Expression of constitutively nuclear FoxO1 in ß-cells prevented the proliferative and antiapoptotic actions of GLP-1 in cultured ß-cells and the increase in pancreatic ß-cell mass in response to Exendin4 in transgenic mice. Gene expression and chromatin immunoprecipitation assays demonstrated that GLP-1 increases pancreatic and duodenal homeobox gene-1 and Foxa2 expression and inhibits FoxO1 binding to both promoters. We propose that FoxO1 mediates the pleiotropic effects of the glucoincretin hormone on cell proliferation and survival.

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