The Fas pathway is involved in pancreatic beta cell secretory function.
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The Fas pathway is involved in pancreatic beta cell secretory function. / Schumann, Desiree M; Maedler, Kathrin; Franklin, Isobel; Konrad, Daniel; Størling, Joachim; Böni-Schnetzler, Marianne; Gjinovci, Asllan; Kurrer, Michael O; Gauthier, Benoit R; Bosco, Domenico; Andres, Axel; Berney, Thierry; Greter, Melanie; Becher, Burkhard; Chervonsky, Alexander V; Halban, Philippe A; Mandrup-Poulsen, Thomas; Wollheim, Claes B; Donath, Marc Y.
I: Proceedings of the National Academy of Science of the United States of America, Bind 104, Nr. 8, 2007, s. 2861-6.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - The Fas pathway is involved in pancreatic beta cell secretory function.
AU - Schumann, Desiree M
AU - Maedler, Kathrin
AU - Franklin, Isobel
AU - Konrad, Daniel
AU - Størling, Joachim
AU - Böni-Schnetzler, Marianne
AU - Gjinovci, Asllan
AU - Kurrer, Michael O
AU - Gauthier, Benoit R
AU - Bosco, Domenico
AU - Andres, Axel
AU - Berney, Thierry
AU - Greter, Melanie
AU - Becher, Burkhard
AU - Chervonsky, Alexander V
AU - Halban, Philippe A
AU - Mandrup-Poulsen, Thomas
AU - Wollheim, Claes B
AU - Donath, Marc Y
N1 - Keywords: Animals; Antigens, CD95; Blood Glucose; CASP8 and FADD-Like Apoptosis Regulating Protein; Fas Ligand Protein; Gene Expression Regulation; Homeodomain Proteins; Insulin; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mitochondria; NF-kappa B; RNA, Messenger; Trans-Activators
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
U2 - 10.1073/pnas.0611487104
DO - 10.1073/pnas.0611487104
M3 - Journal article
C2 - 17299038
VL - 104
SP - 2861
EP - 2866
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 8
ER -
ID: 8465619