Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells
Open accessAbstract
Aims/hypothesis Glucagon-like peptide-1 is a potent glucoincretin hormone and a potentially important drug in the treatment of Type II (non-insulin-dependent) diabetes mellitus. We have investigated whether it acts as a growth factor in beta (INS-1)-cells and have studied the signalling pathways and transcription factors implicated in this process.Methods Cell proliferation was assessed by tritiated thymidine incorporation measurements. We have examined the action of glucagon-like peptide-1 on the enzymatic activity of phosphatidylinositol 3-kinase. The DNA binding activity of transcription factors was investigated by electrophoretic mobility shift assay. Measurements of mRNA were done using the northern technique.Results Glucagon-like peptide-1 caused an increase in tritiated thymidine incorporation in beta (INS-1)-cells and phosphatidylinositol 3-kinase activity in a dose-dependent manner non-additively with glucose. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 blocked the effects of glucagon-like peptide-1 on DNA synthesis. Transcription factor pancreatic and duodenal homebox gene 1 (PDX-1) DNA binding activity was increased by glucagon-like peptide-1 at 3 or 11 mmol/l glucose and the phosphatidylinositol 3-kinase inhibitor LY294002 suppressed the action of glucagon-like peptide-1 on PDX-1 DNA binding activity. Glucagon-like peptide-1 and glucose alone did not change activating protein-1 DNA binding activity. They synergised, however, to increase the activity of activating protein-1. Glucagon-like peptide-1 also increased the expression of PDX-1, glucose transporter 2, glucokinase and insulin mRNAs. Finally, glucagon-like peptide-1 increased the incorporation of tritiated thymidine in isolated rat islets.Conclusion/interpretation The results suggest that glucagon-like peptide-1 may act as a growth factor for the beta cell by a phosphatidylinositol 3-kinase mediated event. Glucagon-like peptide-1 could also regulate the expression of the insulin gene and genes encoding enzymes implicated in glucose transport and metabolism through the phosphatidylinositol 3-kinase/PDX-1 transduction signalling pathway.
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GLP-1 and GIP exert pancreatic effects including GLP-1-stimulated insulin gene expression, incretin-induced β-cell neogenesis, proliferation, survival, and prevention of β-cell apoptosis.
“both hormones exert pancreatic effects, such as GLP-1-stimulated insulin gene expression,77, 187 incretin-induced β-cell neogenesis, proliferation188, 189, 190, 191 and survival,192 the prevention of β-cell apoptosis in general193, 194 and in response to glucolipotoxicity.195”
From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [187]
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- Authors
- Buteau, J., Roduit, R., Susini, S., & Prentki, M.
- Affiliations
- Centre Hospitalier de l’Université de Montréal (CA)
- University of Geneva (CH)
- Venue
- Diabetologia
- Published
- 1999-06-21
- Volume
- 42
- Issue
- 7
- Pages
- 856-864
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2090007082
- Cited by
- 413
- References
- 41
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 6 · 2023: 5 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 6 · 2018: 4 · 2017: 11 · 2016: 11 · 2015: 9 · 2014: 18 · 2013: 14 · 2012: 25
- FWCI
- 22.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- Canadian Diabetes Association
- Cancer Research Society
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Medical Research Council Canada
- Medical Research Council
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- glucagon-like peptide-1, beta-cell proliferation, INS-1 cells, phosphatidylinositol 3-kinase, PDX1, transcription factor-DNA binding, AP-1, GLUT2, glucokinase, insulin gene expression, pancreatic islets, type 2 diabetes, incretin-based therapy, wortmannin, LY294002
- MeSH terms
- Wortmannin, Phosphoinositide-3 Kinase Inhibitors, Androstadienes, Animals, Chromones, DNA, DNA-Binding Proteins, Duodenum, Enzyme Activation, Enzyme Inhibitors, Genes, Homeobox, Glucagon, Glucose, Humans, Insulin, Islets of Langerhans, Morpholines, Nifedipine, Pancreas, Peptide Fragments, Potassium Chloride, Protein Precursors, RNA, Messenger, Transcription Factors, Tumor Cells, Cultured, Signal Transduction, Rats, Wistar, Transcription Factor AP-1, Phosphatidylinositol 3-Kinases, Rats, Glucagon-Like Peptide 1
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