The Fas pathway is involved in pancreatic beta cell secretory function.

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

SN - 0027-8424

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

IS - 8

ER -