文章基本信息

标题：FLIP switches Fas-mediated glucose signaling in human pancreatic β cells from apoptosis to cell replication
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作者：Kathrin Maedler ; Adriano Fontana ; Frédéric Ris 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2002
卷号：99
期号：12
页码：8236-8241
DOI：10.1073/pnas.122686299
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.