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

2002; National Academy of Sciences; Volume: 99; Issue: 12 Linguagem: Inglês

10.1073/pnas.122686299

1091-6490

Kathrin Maedler, A. Fontana, Frédéric Ris, П. В. Сергеев, Christian Toso, José Oberholzer, Roger Lehmann, Felix Bachmann, Andrea Tasinato, Giatgen A. Spinas, Philippe A. Halban, Marc Y. Donath,

Plant responses to water stress

Type 2 diabetes mellitus results from an inadequate adaptation of the functional pancreatic β cell mass in the face of insulin resistance. Changes in the concentration of glucose play an essential role in the regulation of β cell turnover. In human islets, elevated glucose concentrations impair β cell proliferation and induce β 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 β 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 β cells; FLIP was no longer detectable in such TUNEL-positive β cells. Up-regulation of FLIP, by incubation with transforming growth factor β or by transfection with an expression vector coding for FLIP, protected β cells from glucose-induced apoptosis, restored β cell proliferation, and improved β 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 β cell and suggest a novel approach to prevent and treat diabetes by switching Fas signaling from apoptosis to proliferation.