Document Detail


Exendin-4 protects pancreatic beta cells from human islet amyloid polypeptide-induced cell damage: potential involvement of AKT and mitochondria biogenesis.
MedLine Citation:
PMID:  20649634     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
R Fan; X Li; X Gu; J C N Chan; G Xu
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Diabetes, obesity & metabolism     Volume:  12     ISSN:  1463-1326     ISO Abbreviation:  Diabetes Obes Metab     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-07-23     Completed Date:  2011-03-16     Revised Date:  2013-03-19    
Medline Journal Info:
Nlm Unique ID:  100883645     Medline TA:  Diabetes Obes Metab     Country:  England    
Other Details:
Languages:  eng     Pagination:  815-24     Citation Subset:  IM    
Affiliation:
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:
Apoptosis / 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:
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

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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