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Deletion of Fas in the pancreatic beta-cells leads to enhanced insulin secretion

Choi, D; Radziszewska, A; Schroer, SA; Liadis, N; Liu, YF; Zhang, Y; Lam, PPL; ... Woo, M; + view all (2009) Deletion of Fas in the pancreatic beta-cells leads to enhanced insulin secretion. AM J PHYSIOL-ENDOC M , 297 (6) E1304 - E1312. 10.1152/ajpendo.00217.2009.

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Abstract

Choi D, Radziszewska A, Schroer SA, Liadis N, Liu Y, Zhang Y, Lam PP, Sheu L, Hao Z, Gaisano HY, Woo M. Deletion of Fas in the pancreatic beta-cells leads to enhanced insulin secretion. Am J Physiol Endocrinol Metab 297: E1304-E1312, 2009. First published September 15, 2009; doi:10.1152/ajpendo.00217.2009.-Fas/Fas ligand belongs to the tumor necrosis factor superfamily of receptors/ligands and is best known for its role in apoptosis. However, recent evidence supports its role in other cellular responses, including proliferation and survival. Although Fas has been implicated as an essential mediator of beta-cell death in the pathogenesis of type 1 diabetes, the essential role of Fas specifically in pancreatic beta-cells has been found to be controversial. Moreover, the role of Fas on beta-cell homeostasis and function is not clear. The objective of this study is to determine the role of Fas specifically in beta-cells under both physiological and diabetes models. Mice with Fas deletion specifically in the beta-cells were generated using the Cre-loxP system. Cre-mediated Fas deletion was under the control of the rat insulin promoter. Absence of Fas in beta-cells leads to complete protection against FasL-induced cell death. However, Fas is not essential in determining beta-cell mass or susceptibility to streptozotocin-or HFD-induced diabetes. Importantly, Fas deletion in beta-cells leads to increased p65 expression, enhanced glucose tolerance, and glucose-stimulated insulin secretion, with increased exocytosis as manifested by increased changes in membrane capacitance and increased expression of Syntaxin1A, VAMP2, and munc18a. Together, our study shows that Fas in the beta-cells indeed plays an essential role in the canonical death receptor-mediated apoptosis but is not essential in regulating beta-cell mass or diabetes development. However, beta-cell Fas is critical in the regulation of glucose homeostasis through regulation of the exocytosis machinery.

Type: Article
Title: Deletion of Fas in the pancreatic beta-cells leads to enhanced insulin secretion
DOI: 10.1152/ajpendo.00217.2009
Keywords: diabetes, apoptosis, exocytosis, islets, DIABETES-MELLITUS, DEATH, APOPTOSIS, LIGAND, CD95, ISLETS, ROLES, MICE, DESTRUCTION, MECHANISMS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/65910
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