| Exendin-4 protects pancreatic beta cells from human islet amyloid polypeptide-induced cell damage: potential involvement of AKT and mitochondria biogenesis. | |
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MedLine Citation:
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PMID: 20649634 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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AIM: Glucagon-like peptide-1 (GLP-1) stimulates beta-cell proliferation and enhances beta-cell survival, whereas oligomerization of human islet amyloid polypeptide (hIAPP) may induce beta-cell apoptosis and reduce beta-cell mass. Type 2 diabetes is associated with increased expression of IAPP. As GLP-1-based therapy is currently developed as a novel antidiabetic therapy, we examined the potential protective action of the GLP-1 receptor agonist exendin-4 on hIAPP-induced beta-cell apoptosis. METHODS: The study was performed in clonal insulinoma (INS-1E) cells. Both method of transcriptional and translational and sulphorhodamine B (SRB) assays were used to evaluate cell viability and cell mass. Western blot analysis was applied to detect protein expression. Transfection of constitutively active protein kinase B (PKB/AKT) was performed to examine the role of AKT. Mitochondrial biogenesis was quantified by mitogreen staining and RT-PCR. RESULTS: First, we confirmed that hIAPP induced cell apoptosis and growth inhibition in INS-1E cells. These effects were partially protected by exendin-4 in association with partial recovery of the hIAPP-mediated AKT inhibition. Furthermore, AKT constitutive activation attenuated hIAPP-induced apoptosis, whereas PI3K/AKT inhibition abrogated exendin-4-mediated effects. These findings suggest that the antiapoptotic and proliferative effects of exendin-4 in hIAPP-treated INS-1E cells were partially mediated through AKT pathway. Moreover, hIAPP induced FOXO1 but inhibited pdx-1 nucleus translocation. These effects were restored by exendin-4. Finally, mitogreen staining and RT-PCR revealed enhanced mitochondrial biogenesis by exendin-4 treatment. CONCLUSIONS: Collectively, these results suggest that GLP-1 receptor agonist protects beta cells from hIAPP-induced cell death partially through the activation of AKT pathway and improved mitochondrial function. |
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Authors:
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R Fan; X Li; X Gu; J C N Chan; G Xu |
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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: Diabetes, obesity & metabolism Volume: 12 ISSN: 1463-1326 ISO Abbreviation: Diabetes Obes Metab Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-07-23 Completed Date: 2011-03-16 Revised Date: 2013-03-19 |
Medline Journal Info:
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Nlm Unique ID: 100883645 Medline TA: Diabetes Obes Metab Country: England |
Other Details:
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Languages: eng Pagination: 815-24 Citation Subset: IM |
Affiliation:
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Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, China. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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physiology Cytoprotection Diabetes Mellitus, Type 2 / drug therapy*, physiopathology Glucagon-Like Peptide 1 / agonists, pharmacology* Humans Hypoglycemic Agents / pharmacology* Insulin-Secreting Cells / drug effects*, physiology Islet Amyloid Polypeptide / antagonists & inhibitors*, physiology Mitochondria / drug effects*, physiology Peptides / pharmacology* Receptors, Glucagon Signal Transduction / physiology Venoms / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Hypoglycemic Agents; 0/Islet Amyloid Polypeptide; 0/Peptides; 0/Receptors, Glucagon; 0/Venoms; 0/glucagon-like peptide-1 receptor; 141732-76-5/exenatide; 89750-14-1/Glucagon-Like Peptide 1 |
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