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

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.

• Authors: Desiree M Schumann, Kathrin Maedler, Isobel Franklin, Daniel Konrad, Joachim Størling, Marianne Böni-Schnetzler, Asllan Gjinovci, Michael O Kurrer, Benoit R Gauthier, Domenico Bosco, Axel Andres, Thierry Berney, Melanie Greter, Burkhard Becher, Alexander V Chervonsky, Philippe A Halban, Thomas Mandrup-Poulsen, Claes B Wollheim, Marc Y Donath
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 8 Pg. 2861-6 (Feb 20 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17299038 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Fas Ligand Protein
• Fas protein, mouse
• Homeodomain Proteins
• Insulin
• NF-kappa B
• RNA, Messenger
• Trans-Activators
• fas Receptor
• pancreatic and duodenal homeobox 1 protein

Topics

• Animals
• 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)
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria (metabolism)
• NF-kappa B (metabolism)
• RNA, Messenger (genetics, metabolism)
• Trans-Activators (genetics, metabolism)
• fas Receptor (deficiency, genetics, metabolism)