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Endocrinology Vol. 142, No. 5 1820-1827
Copyright © 2001 by The Endocrine Society

ARTICLES

Glucagon-Like Peptide-1 Causes Pancreatic Duodenal Homeobox-1 Protein Translocation from the Cytoplasm to the Nucleus of Pancreatic ß-Cells by a Cyclic Adenosine Monophosphate/Protein Kinase A-Dependent Mechanism

Xiaolin Wang, Jie Zhou, Máire E. Doyle and Josephine M. Egan

Diabetes Section, Gerontology Research Center, National Institute on Aging, NIH, Baltimore, Maryland 21224

Address all correspondence and requests for reprints to: Josephine M. Egan, M.D., Diabetes Section, #23, NIA/NIH, 5600 Nathan Shock Drive, Baltimore, Maryland 21224. E-mail: eganj{at}vax.grc.nia.nih.gov

Glucagon-like peptide-1 (GLP-1) enhances insulin secretion and synthesis. It also regulates the insulin, glucokinase, and GLUT2 genes. It mediates increases in glucose-stimulated insulin secretion by activating adenylyl cyclase and elevating free cytosolic calcium levels in the ß-cell. In addition, GLP-1 has been shown, both in vitro and in vivo, to be involved in regulation of the transcription factor, pancreatic duodenal homeobox-1 protein (PDX-1), by increasing its total protein levels, its translocation to the nucleus and its binding and resultant increase in activity of the insulin gene promoter in ß-cells of the pancreas. Here we have investigated the role of protein kinase A (PKA) in these processes in RIN 1046–38 cells. Three separate inhibitors of PKA, and a cAMP antagonist, inhibited the effects of GLP-1 on PDX-1. Furthermore, forskolin, (which stimulates adenylyl cyclase 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. These effects were also prevented by PKA inhibitors. Glucose-mediated increases in nuclear translocation of PDX-1 were not prevented by PKA inhibitors. Our results suggest that regulation of PDX-1 by GLP-1 occurs through activation 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 ß-cells.




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