Document Detail


The Fas pathway is involved in pancreatic beta cell secretory function.
MedLine Citation:
PMID:  17299038     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Pancreatic beta cell mass and function increase in conditions of enhanced insulin demand such as obesity. Failure to adapt leads to diabetes. The molecular mechanisms controlling this adaptive process are unclear. Fas is a death receptor involved in beta cell apoptosis or proliferation, depending on the activity of the caspase-8 inhibitor FLIP. Here we show that the Fas pathway also regulates beta cell secretory function. We observed impaired glucose tolerance in Fas-deficient mice due to a delayed and decreased insulin secretory pattern. Expression of PDX-1, a beta cell-specific transcription factor regulating insulin gene expression and mitochondrial metabolism, was decreased in Fas-deficient beta cells. As a consequence, insulin and ATP production were severely reduced and only partly compensated for by increased beta cell mass. Up-regulation of FLIP enhanced NF-kappaB activity via NF-kappaB-inducing kinase and RelB. This led to increased PDX-1 and insulin production independent of changes in cell turnover. The results support a previously undescribed role for the Fas pathway in regulating insulin production and release.
Authors:
Desiree M Schumann; Kathrin Maedler; Isobel Franklin; Daniel Konrad; Joachim Størling; Marianne Böni-Schnetzler; Asllan Gjinovci; Michael O Kurrer; Benoit R Gauthier; Domenico Bosco; Axel Andres; Thierry Berney; Melanie Greter; Burkhard Becher; Alexander V Chervonsky; Philippe A Halban; Thomas Mandrup-Poulsen; Claes B Wollheim; Marc Y Donath
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-02-13
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  104     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-03-15     Completed Date:  2007-04-12     Revised Date:  2011-06-01    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2861-6     Citation Subset:  IM    
Affiliation:
Clinic of Endocrinology and Diabetes, and Department of Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD95 / deficiency,  genetics,  metabolism*
Blood Glucose
CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
Fas Ligand Protein / genetics,  metabolism
Gene Expression Regulation
Homeodomain Proteins / genetics,  metabolism
Insulin / genetics,  metabolism
Insulin-Secreting Cells / cytology,  metabolism,  secretion*
Male
Mice
Mice, Inbred C57BL
Mitochondria / metabolism
NF-kappa B / metabolism
RNA, Messenger / genetics,  metabolism
Trans-Activators / genetics,  metabolism
Chemical
Reg. No./Substance:
0/Antigens, CD95; 0/Blood Glucose; 0/CASP8 and FADD-Like Apoptosis Regulating Protein; 0/Fas Ligand Protein; 0/Fas protein, mouse; 0/Homeodomain Proteins; 0/NF-kappa B; 0/RNA, Messenger; 0/Trans-Activators; 0/pancreatic and duodenal homeobox 1 protein; 11061-68-0/Insulin
Comments/Corrections

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


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