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ß-Cell Pdx1 Expression Is Essential for the Glucoregulatory, Proliferative, and Cytoprotective Actions of Glucagon-Like Peptide-1

¹ Department of Medicine, University of Toronto, The Banting and Best Diabetes Centre, The Toronto General Hospital, University of Toronto, Toronto, Canada
² Department of Physiology, University of Toronto, Toronto, Canada
³ Umea Centre for Molecular Medicine, Umea University, Umea, Sweden

Glucagon-like peptide-1 (GLP-1) regulates energy intake, gastrointestinal motility, and nutrient disposal. The relative importance of the islet ß-cell for GLP-1 actions remains unclear. We determined the role of the islet ß-cell and the pancreatic duodenal homeobox-1 (Pdx1) transcription factor for GLP-1 receptor (GLP-1R)-dependent actions through analysis of mice with ß-cell–specific inactivation of the Pdx1 gene (ß-cell^Pdx1–/– mice). The GLP-1R agonist exendin-4 (Ex-4) reduced glycemic excursion following intraperitoneal (i.p.) glucose challenge in control littermates (ß-cell^Pdx1+/+ mice) but not in ß-cell^Pdx1–/– mice. Similarly, Ex-4 failed to increase levels of plasma insulin, pancreatic insulin content, and pancreatic insulin mRNA transcripts in ß-cell^Pdx1–/– mice. Furthermore, Ex-4 significantly increased ß-cell proliferation and reduced ß-cell apoptosis in ß-cell^Pdx1+/+ mice but not in ß-cell^Pdx1–/– mice. Moreover, Ex-4 increased the levels of insulin and amylin mRNA transcripts and augmented glucose-stimulated insulin secretion in islets from ß-cell^Pdx1+/+ mice but not in ß-cell^Pdx1–/– islets. Surprisingly, Ex-4 failed to reduce levels of plasma glucagon in ß-cell^Pdx1–/– mice. These findings demonstrate that Pdx1 expression is essential for integrating GLP-1R–dependent signals regulating -cell glucagon secretion and for the growth, differentiated function, and survival of islet ß-cells.

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