The Fas pathway is involved in pancreatic beta cell secretory function

Schumann, D. M.; Maedler, Kathrin; Franklin, Isobel; Konrad, Daniel; Storling, Joachim; Boni-Schnetzler, Marianne; Gjinovci, Asllan; Kurrer, M. O.; Gauthier, B. R.; Bosco, Domenico; Andres, Axel; Berney, Thierry; Greter, Melanie; Becher, Burkhard; Chervonsky, A. V.; Halban, Philippe A.; Mandrup-Poulsen, Thomas; Wollheim, Claes; Donath, M. Y.

doi:10.1073/pnas.0611487104

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Title		The Fas pathway is involved in pancreatic beta cell secretory function
Authors		Schumann, D. M. Maedler, Kathrin Franklin, Isobel Konrad, Daniel Storling, Joachim Boni-Schnetzler, Marianne Gjinovci, Asllan Kurrer, M. O. Gauthier, B. R. Bosco, Domenico Andres, Axel Berney, Thierry Greter, Melanie Becher, Burkhard Chervonsky, A. V. Halban, Philippe A. Mandrup-Poulsen, Thomas Wollheim, Claes Donath, M. Y. show all authors [1 - 19]
Published in		Proceedings of the National Academy of Sciences of the United States of America. 2007, vol. 104, no. 8, p. 2861-2866
Abstract		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.
Keywords		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
Identifiers		DOI: 10.1073/pnas.0611487104 PMID: 17299038
Full text		Article - Limited access to UNIGE Other version: http://ukpmc.ac.uk/picrender.cgi?artid=1056639&blobtype=pdf
Structures		Faculté de médecine / Section de médecine clinique / Département de médecine
Research group		La transplantation d'îlots de Langerhans (623)
Citation (ISO format)		SCHUMANN, D. M. et al. The Fas pathway is involved in pancreatic beta cell secretory function. In: Proceedings of the National Academy of Sciences of the United States of America, 2007, vol. 104, n° 8, p. 2861-2866. doi: 10.1073/pnas.0611487104 https://archive-ouverte.unige.ch/unige:9025