The Fas pathway is involved in pancreatic beta cell secretory function.
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.
Schumann
Desiree M
DM
Clinic of Endocrinology and Diabetes, and Department of Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Maedler
Kathrin
K
Franklin
Isobel
I
Konrad
Daniel
D
Størling
Joachim
J
Böni-Schnetzler
Marianne
M
Gjinovci
Asllan
A
Kurrer
Michael O
MO
Gauthier
Benoit R
BR
Bosco
Domenico
D
Andres
Axel
A
Berney
Thierry
T
Greter
Melanie
M
Becher
Burkhard
B
Chervonsky
Alexander V
AV
Halban
Philippe A
PA
Mandrup-Poulsen
Thomas
T
Wollheim
Claes B
CB
Donath
Marc Y
MY
D000818:Animals; D001786:Blood Glucose; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D018398:Homeodomain Proteins; D007328:Insulin; D016328:NF-kappa B; D012333:RNA, Messenger; D015534:Trans-Activators; D019014:fas Receptor; C084010:pancreatic and duodenal homeobox 1 protein