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

β-Cell Pdx1 Expression Is Essential for the Glucoregulatory, Proliferative, and Cytoprotective Actions of Glucagon-Like Peptide-1 Yazhou Li 1 , Xiemin Cao 1 , Li-Xin Li 2 , Patricia L. Brubaker 1 2 , Helena Edlund 3 and Daniel J. Drucker 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 Address correspondence and reprint requests to Dr. Daniel J. Drucker, Toronto General Hospital, BantingBest Diabetes Centre, 200 Elizabeth St., MBRW 4R402-2, Toronto, Canada M5G 2C4. E-mail: d.drucker{at}utoronto.ca Abstract Glucagon-like peptide-1 (GLP-1) regulates energy intake, gastrointestinal motility, and nutrient disposal. The relative importance of the islet β-cell for GLP-1 actions remains unclear. We determined the role of the islet β-cell and the pancreatic duodenal homeobox-1 (Pdx1) transcription factor for GLP-1 receptor (GLP-1R)-dependent actions through analysis of mice with β-cell–specific inactivation of the Pdx1 gene (β-cell Pdx1−/− mice). The GLP-1R agonist exendin-4 (Ex-4) reduced glycemic excursion following intraperitoneal (i.p.) glucose challenge in control littermates (β-cell Pdx1+/+ mice) but not in β-cell Pdx1−/− mice. Similarly, Ex-4 failed to increase levels of plasma insulin, pancreatic insulin content, and pancreatic insulin mRNA transcripts in β-cell Pdx1−/− mice. Furthermore, Ex-4 significantly increased β-cell proliferation and reduced β-cell apoptosis in β-cell Pdx1+/+ mice but not in β-cell Pdx1−/− mice. Moreover, Ex-4 increased the levels of insulin and amylin mRNA transcripts and augmented glucose-stimulated insulin secretion in islets from β-cell Pdx1+/+ mice but not in β-cell Pdx1−/− islets. Surprisingly, Ex-4 failed to reduce levels of plasma glucagon in β-cell Pdx1−/− mice. These findings demonstrate that Pdx1 expression is essential for integrating GLP-1R–dependent signals regulating α-cell glucagon secretion and for the growth, differentiated function, and survival of islet β-cells. Footnotes H.E. is cofounder of and shareholder in Betagenon, Sweden. D.J.D. is a consultant to Amylin and Eli Lilly and is on Amylin’s science advisory board. Ex-4, exendin-4; GLP-1, glucagon-like peptide-1; GLP-1R, GLP-1 receptor; IBMX, 3-isobutyl-1-methylxanthine; IPGTT, intraperitoneal glucose tolerance test; KR