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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-16020

Schumann, D M; Maedler, K; Franklin, I; Konrad, D; Størling, J; Böni-Schnetzler, M; Gjinovci, A; Kurrer, M O; Gauthier, B R; Bosco, D; Andres, A; Berney, T; Greter, M; Becher, B; Chervonsky, A V; Halban, P A; Mandrup-Poulsen, T; Wollheim, C B; Donath, M Y (2007). The Fas pathway is involved in pancreatic beta cell secretory function. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 104(8):2861-2866.

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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.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Endocrinology and Diabetology
04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:February 2007
Deposited On:22 Mar 2009 11:52
Last Modified:28 Nov 2013 01:21
Publisher:National Academy of Sciences
ISSN:0027-8424
Additional Information:Copyright: National Academy of Sciences USA
Publisher DOI:10.1073/pnas.0611487104
PubMed ID:17299038
Citations:Web of Science®. Times Cited: 34
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