beta-Cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1.
Glucagon-like peptide-1 (GLP-1) regulates energy intake, gastrointestinal motility, and nutrient disposal. The relative importance of the islet beta-cell for GLP-1 actions remains unclear. We determined the role of the islet beta-cell and the pancreatic duodenal homeobox-1 (Pdx1) transcription factor for GLP-1 receptor (GLP-1R)-dependent actions through analysis of mice with beta-cell-specific inactivation of the Pdx1 gene (beta-cell(Pdx1-/-) mice). The GLP-1R agonist exendin-4 (Ex-4) reduced glycemic excursion following intraperitoneal (i.p.) glucose challenge in control littermates (beta-cell(Pdx1+/+) mice) but not in beta-cell(Pdx1-/-) mice. Similarly, Ex-4 failed to increase levels of plasma insulin, pancreatic insulin content, and pancreatic insulin mRNA transcripts in beta-cell(Pdx1-/-) mice. Furthermore, Ex-4 significantly increased beta-cell proliferation and reduced beta-cell apoptosis in beta-cell(Pdx1+/+) mice but not in beta-cell(Pdx1-/-) mice. Moreover, Ex-4 increased the levels of insulin and amylin mRNA transcripts and augmented glucose-stimulated insulin secretion in islets from beta-cell(Pdx1+/+) mice but not in beta-cell(Pdx1-/-) islets. Surprisingly, Ex-4 failed to reduce levels of plasma glucagon in beta-cell(Pdx1-/-) mice. These findings demonstrate that Pdx1 expression is essential for integrating GLP-1R-dependent signals regulating alpha-cell glucagon secretion and for the growth, differentiated function, and survival of islet beta-cells.
Li
Yazhou
Y
Department of Medicine, University of Toronto, Banting and Best Diabetes Centre, Toronto General Hospital, 200 Elizabeth St., MBRW 4R402-2, Toronto, Canada M5G 2C4.
Cao
Xiemin
X
Li
Li-Xin
LX
Brubaker
Patricia L
PL
Edlund
Helena
H
Drucker
Daniel J
DJ
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077270:Exenatide; D005260:Female; D005934:Glucagon / Q000502:physiology*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins / Q000235:genetics*; D006706:Homeostasis; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010446:Peptide Fragments / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D011498:Protein Precursors / Q000502:physiology*; D018027:Receptors, Glucagon / Q000502:physiology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics*; D014688:Venoms / Q000494:pharmacology
D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D018398:Homeodomain Proteins; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D018027:Receptors, Glucagon; D015534:Trans-Activators; D014688:Venoms; C084010:pancreatic and duodenal homeobox 1 protein; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide