| Cultured pancreatic ductal cells undergo cell cycle re-distribution and beta-cell-like differentiation in response to glucagon-like peptide-1. | |
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MedLine Citation:
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PMID: 12459036 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The intestinal hormone glucagon-like peptide-1 (GLP-1) has been shown to promote an increase in pancreatic beta-cell mass via proliferation of islet cells and differentiation of non-insulin-secreting cells. In this study, we have characterized some of the events that lead to the differentiation of pancreatic ductal cells in response to treatment with human GLP-1. Rat pancreatic ductal (ARIP) cells were cultured in the presence of GLP-1 and analyzed for cell counting, cell cycle distribution, expression of cyclin-dependent-kinase (Cdk) inhibitors, transcription of beta-cell-specific genes, loss of ductal-like phenotype and acquisition of beta-cell-like gene expression profile. Exposure of ARIP cells to 10 nM GLP-1 induced a significant reduction in the cell replication rate and a significant decrease in the percentage of cells in S phase of the cell cycle. This was associated with an increase in the number of cells in G0-G1 phase and a reduction of cells in G2-M phase. Western blot analysis for the Cdk inhibitors, kinase inhibitor protein 1 (p27(Kip1)) and Cdk-interacting protein 1 (p21(Cip1)), demonstrated a significant increase in p27(Kip1) and p21(Cip1) levels within the first 24 h from the beginning of GLP-1 treatment. As cells slowed down their proliferation rate, GLP-1 also induced a time-dependent expression of various beta-cell-specific mRNAs. The glucose transporter GLUT-2 was the first of those factors to be expressed (24 h treatment), followed by insulin (44 h) and finally by the enzyme glucokinase (56 h). In addition, immunocytochemistry analysis showed that GLP-1 induced a time-dependent down-regulation of the ductal marker cytokeratin-20 (CK-20) and a time-dependent induction of insulin expression. Finally, GLP-1 promoted a glucose-dependent secretion of insulin, as demonstrated by HPLC and RIA analyses of the cell culture medium. The present study has demonstrated that GLP-1 induces a cell cycle re-distribution with a decrease in cell proliferation rate prior to promoting the differentiation of cells towards an endocrine-like phenotype. |
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Authors:
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A Bulotta; H Hui; E Anastasi; C Bertolotto; L G Boros; U Di Mario; R Perfetti |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of molecular endocrinology Volume: 29 ISSN: 0952-5041 ISO Abbreviation: J. Mol. Endocrinol. Publication Date: 2002 Dec |
Date Detail:
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Created Date: 2002-12-02 Completed Date: 2003-10-15 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8902617 Medline TA: J Mol Endocrinol Country: England |
Other Details:
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Languages: eng Pagination: 347-60 Citation Subset: IM |
Affiliation:
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Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Cycle / drug effects* Cell Cycle Proteins / metabolism Cell Differentiation / drug effects* Cells, Cultured Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinase Inhibitor p27 Cyclins / metabolism Flow Cytometry Gene Expression Regulation / drug effects Glucagon / pharmacology* Glucagon-Like Peptide 1 Glucokinase / metabolism Glucose / pharmacology Glucose Transporter Type 2 Humans Immunohistochemistry Insulin / analysis, secretion Monosaccharide Transport Proteins / metabolism Pancreatic Ducts / cytology*, drug effects* Peptide Fragments / pharmacology* Protein Precursors / pharmacology* Rats Tumor Suppressor Proteins / metabolism |
| Chemical | |
Reg. No./Substance:
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0/CDKN1A protein, human; 0/Cdkn1a protein, rat; 0/Cdkn1b protein, rat; 0/Cell Cycle Proteins; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Glucose Transporter Type 2; 0/Monosaccharide Transport Proteins; 0/Peptide Fragments; 0/Protein Precursors; 0/Tumor Suppressor Proteins; 11061-68-0/Insulin; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 50-99-7/Glucose; 89750-14-1/Glucagon-Like Peptide 1; 9007-92-5/Glucagon; EC 2.7.1.2/Glucokinase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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