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PMID: 12060768 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

FLIP switches Fas-mediated glucose signaling in human pancreatic beta cells from apoptosis to cell replication.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 12 ·2002-06-11 ·Pages 8236-41

Maedler K, Fontana A, Ris F, Sergeev P, Toso C, Oberholzer J, Lehmann R, Bachmann F, Tasinato A, Spinas GA, Halban PA, Donath MY

Abstract

Type 2 diabetes mellitus results from an inadequate adaptation of the functional pancreatic beta cell mass in the face of insulin resistance. Changes in the concentration of glucose play an essential role in the regulation of beta cell turnover. In human islets, elevated glucose concentrations impair beta cell proliferation and induce beta cell apoptosis via up-regulation of the Fas receptor. Recently, it has been shown that the caspase-8 inhibitor FLIP may divert Fas-mediated death signals into those for cell proliferation in lymphatic cells. We observed expression of FLIP in human pancreatic beta cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro exposure of islets from nondiabetic organ donors to high glucose levels decreased FLIP expression and increased the percentage of apoptotic terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL)-positive beta cells; FLIP was no longer detectable in such TUNEL-positive beta cells. Up-regulation of FLIP, by incubation with transforming growth factor beta or by transfection with an expression vector coding for FLIP, protected beta cells from glucose-induced apoptosis, restored beta cell proliferation, and improved beta cell function. The beneficial effects of FLIP overexpression were blocked by an antagonistic anti-Fas antibody, indicating their dependence on Fas receptor activation. The present data provide evidence for expression of FLIP in the human beta cell and suggest a novel approach to prevent and treat diabetes by switching Fas signaling from apoptosis to proliferation.

MeSH Terms
Aged Aged, 80 and over CASP8 and FADD-Like Apoptosis Regulating Protein Carrier Proteins/metabolism Caspase Inhibitors Cell Division/physiology Cells, Cultured Diabetes Mellitus, Type 2/physiopathology Glucose/pharmacology Humans Intracellular Signaling Peptides and Proteins Islets of Langerhans/cytology,drug effects,physiology Liposomes Middle Aged Recombinant Proteins/metabolism Signal Transduction Transfection Transforming Growth Factor beta/pharmacology fas Receptor/physiology
Chemicals
CASP8 and FADD-Like Apoptosis Regulating Protein CFLAR protein, human Carrier Proteins Caspase Inhibitors Intracellular Signaling Peptides and Proteins Liposomes Recombinant Proteins Transforming Growth Factor beta fas Receptor Glucose
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Maedler Kathrin
Divisions of Endocrinology and Diabetes and Clinical Immunology, University Hospital, Zurich CH-8091, Switzerland.
Fontana Adriano
Ris Frédéric
Sergeev Pavel
Toso Christian
Oberholzer José
Lehmann Roger
Bachmann Felix
Tasinato Andrea
Spinas Giatgen A
Halban Philippe A
Donath Marc Y
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.122686299
Published
2002-06-11
Pages
8236-41
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC123051
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.122686299 PMC Full Text View journal details
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