Glucagon-like peptide-1 regulates the beta cell transcription factor, PDX-1, in insulinoma cells.
Glucagon-like peptide-1 (GLP-1) enhances insulin biosynthesis and secretion as well as transcription of the insulin, GLUT2 and glucokinase genes. The latter are also regulated by the PDX-1 homeoprotein. We investigated the possibility that GLP-1 may be having its long-term pleiotropic effects through a hitherto unknown regulation of PDX-1. We found that PDX-1 mRNA level was significantly increased (p<0.01) after 2 hours and insulin mRNA level was subsequently increased (p<0.01) after 3 hours of treatment with GLP-1 (10 nM) in RIN 1046-38 insulinoma cells. Under these experimental conditions, there was also a 1.6-fold increase in the expression of PDX-1 protein in whole cell and nuclear extracts. Overexpression of PDX-1 in these cells confirmed the finding of the wild type cells such that GLP-1 induced a 2-fold increase in whole cell extracts and a 3-fold increase in nuclear extracts of PDX-1 protein levels. The results of electrophoretic mobility shift experiments showed that PDX-1 protein binding to the Al element of the rat insulin II promoter was also increased 2 h post treatment with GLP-1. In summary, we have uncovered a previously unknown aspect to the regulation of PDX-1 in beta cells. This has important implications in the physiology of adult beta cells and the treatment of type 2 diabetes mellitus with GLP-1 or its analogs.
Wang
X
X
Diabetes Section and Laboratory of Biological Chemistry, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Cahill
C M
CM
Piñeyro
M A
MA
Zhou
J
J
Doyle
M E
ME
Egan
J M
JM
D000818:Animals; D005934:Glucagon / Q000494:pharmacology / Q000502:physiology*; D052216:Glucagon-Like Peptide 1; D018398:Homeodomain Proteins; D007340:Insulinoma / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D011498:Protein Precursors / Q000494:pharmacology / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D018398:Homeodomain Proteins; D010446:Peptide Fragments; D011498:Protein Precursors; D012333:RNA, Messenger; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D052216:Glucagon-Like Peptide 1; D005934:Glucagon