Glucagon-like peptide-1 causes pancreatic duodenal homeobox-1 protein translocation from the cytoplasm to the nucleus of pancreatic B-cells by a cyclic adenosine monophosphate/protein kinase A-dependent mechanism

Glucagon-like peptide-1 (GLP-1) enhances insulin secretion and synthesis. I t also regulates the insulin, glucokinase, and GLUT2 genes. It mediates inc reases in glucose-stimulated insulin secretion by activating adenylyl cycla se and elevating free cytosolic calcium levels in the beta -cell. In additi on, GLP-1 has been shown, both in vitro and in vivo, to be involved in regu lation of the transcription factor, pancreatic duodenal homeobox-l protein (PDX-1), by increasing its total protein levels, its translocation to the n ucleus and its binding and resultant increase in activity of the insulin ge ne promoter in beta -cells of the pancreas. Here we have investigated the r ole of protein kinase A (PKA) in these processes in RIN 1046-38 cells. Thre e separate inhibitors of PKA, and a cAMP antagonist, inhibited the effects of GLP-1 on PDX-1. Furthermore, forskolin, (which stimulates adenylyl cycla se and insulin secretion), and 8-Bromo-cAMP, (an analog of cAMP which also stimulates insulin secretion), mimicked the effects of GLP-1 on PDX-1. Thes e effects were also prevented by PKA inhibitors. Glucose-mediated increases in nuclear translocation of PDX-1 were not prevented by PKA inhibitors. Ou r results suggest that regulation of PDX-1 by GLP-1 occurs through activati on of adenylyl cyclase and the resultant increase in intracellular cAMP, in turn, activates PKA, which ultimately leads to increases in PDX-1 protein levels and translocation of the protein to the nuclei of beta -cells.