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Diabetes 51:691-698, 2002
© 2002 by the American Diabetes Association, Inc.

NFAT Regulates Insulin Gene Promoter Activity in Response to Synergistic Pathways Induced by Glucose and Glucagon-Like Peptide-1

Michael C. Lawrence, Harshika S. Bhatt, and Richard A. Easom

From the Department of Molecular Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Texas

Currently there is intense interest to define the mechanism of action of glucagon-like peptide-1 (GLP-1) in regulating ß-cell function, including insulin gene transcription. In this study, GLP-1 (100 nmol/l), in the presence of glucose (11 mmol/l), induced a ~71-fold increase in insulin gene promoter activity in INS-1 pancreatic ß-cells, an effect that was an order of magnitude larger than with either stimulant alone. The response to GLP-1 was mimicked by forskolin and largely inhibited by the protein kinase A (PKA) inhibitors, H89 and myristoylated PKI(14–22) amide, indicating partial mediation via a cAMP/PKA pathway. Significantly, the actions of both GLP-1 and forskolin were abolished by the selective Ca2+/calmodulin-dependent phosphatase 2B (calcineurin) inhibitor, FK506, as well as by the chelation of intracellular Ca2+ by BAPTA (bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate). Glucose and GLP-1 also synergistically activated NFAT (nuclear factor of activated T-cells)-mediated transcription from a minimal promoter construct containing tandem NFAT consensus sequences. Furthermore, two-point base pair mutations in any of the three identified NFAT sites within the rat insulin I promoter resulted in a significant reduction in the combined effect of glucose and GLP-1. These data suggest that the synergistic action of glucose and GLP-1 to promote insulin gene transcription is mediated through NFAT via PKA- and calcineurin-dependent pathways in pancreatic ß-cells.


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