Glucagon like peptide 1 (GLP-1) stimulates human insulin promoter activity through multiple cAMP responsive elements (CREs) that lie upstream and downstream of the transcription start site.

Colin William Hay, E. Sinclair, G. Bermano, E. Durward, M. Tadayyon, Kevin Docherty

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted from the enteroendocrine L-cells of the gut and which acts primarily to potentiate the effects of glucose on insulin secretion from pancreatic beta-cells. It also stimulates insulin gene expression, proinsulin biosynthesis and affects the growth and differentiation of the islets of Langerhans. Previous studies on the mechanisms whereby GLP-1. regulates insulin gene transcription have focused on the rat insulin promoter. The aim of this study was to determine whether the human insulin promoter was also responsive to GLP-1, and if so to investigate the possible role of cAMP-responsive elements (CREs) that lie upstream (CRE1 and CRE2) and downstream (CRE3 and CRE4) of the transcription start site. INS-1 pancreatic beta-cells were transfected with promoter constructs containing fragments of the insulin gene promoter placed upstream of the firefly luciferase reporter gene. GLP-1 was found to stimulate the human insulin promoter, albeit to a lesser degree than the rat insulin promoter. Mutagenesis of CRE2, CRE3 and CRE4 blocked the stimulatory effect of GLP-1 while mutagenesis of CRE1 had no effect. Analysis of nuclear protein binding to the four CREs showed that, while they share some proteins, each CRE site is unique. Stimulation of transcription by GLP-1 through CRE2, CRE3 and CRE4 resulted in altered protein binding that was different for each of the CRE sites involved. Collectively, these data show that the four human CREs are not simply multiple copies of the rat CRE site and further emphasise that the human insulin promoter is distinct from the rodent promoter.

Original languageEnglish
Pages (from-to)353-365
Number of pages12
JournalJournal of Endocrinology
Volume186
DOIs
Publication statusPublished - 2005

Keywords

  • GENE PROMOTER
  • PROTEIN-KINASE
  • CELL-LINE
  • I GENE
  • PRIMATE INSULIN
  • EXPRESSION
  • EXENDIN-4
  • HYPOGLYCEMIA
  • ACTIVATION
  • INITIATION

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