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 po ssibility that GLP-1 may be having its long-term pleiotropic effects throug h a hitherto unknown regulation of PDX-1. We found that PDX-1 mRNA level wa s significantly increased (p<0.01) after 2hours and insulin mRNA level was subsequently increased (p<0.01) after 3 hours of treatment with GLP-1 (10nM ) in RIN 1046-38 insulinoma cells. Under these experimental conditions, the re 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 confirme d the finding of the wild type cells such that GLP-1 induced a 2-fold incre ase in whole cell extracts and a 3-fold increase in nuclear extracts of PDX -1 protein levels. The results of electrophoretic mobility shift experiment s showed that PDX-1 protein binding to the A1 element of the rat insulin II promoter was also increased 2h 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.