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Diabetes Publish Ahead of Print published online ahead of print June 11, 2007
DOI: 10.2337/db06-1771
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Original Research

Distinct in vivo roles of Caspase-8 in ß cells in physiological and diabetes models

Nicole Liadis, MSc1, Leonardo Salmena, PhD1,,2, Edwin Kwan, MSc3, Panteha Tajmir, MSc1, Stephanie A. Schroer1, Anna Radziszewska, BSc1, Xie Li, PhD3, Laura Sheu, BSc3, Mohamed Eweida, PhD1, Shilong Xu, BSc1, Herbert Y. Gaisano, MD3, Razqallah Hakem, PhD1,,2, and Minna Woo, MD, PhD1,,4

1Department of Medical Biophysics, Ontario Cancer Institute, and University of Toronto, ON M5G 2M9,
2The Advanced Medical Discovery Institute (AMDI), University of Toronto, Toronto, ON M5G 2C1,
3Departments of Medicine and Physiology, University of Toronto, Toronto ON, M5S 1A8,
4Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto ON, M5G 2C1

Correspondence: mwoo{at}uhnres.utoronto.ca

Objective:The purpose of this study is to examine the role of Caspase-8 (Casp8) in ß cells in vivo.

Research Design and Methods:Using the Cre-loxP system, mice lacking Casp8 in ß cells (RIPcre+Casp8fl/fl mice) were generated to address the role of Casp8 in ß cells in physiological and diabetes models.

Results:We show that islets isolated from RIPcre+Casp8fl/fl mice are protected from Fas ligand (FasL) and ceramide-induced cell death. Furthermore, RIPcre+Casp8fl/fl mice were protected from in vivo models of type 1 and type 2 diabetes. In addition to being the central mediator of apoptosis in diabetes models, we show that Casp8 is critical for maintenance of ß cell mass under physiological conditions. With aging, RIPcre+Casp8fl/fl mice gradually develop hyperglycemia and a concomitant decline in ß cell mass. Their islets display decreased expression of molecules involved in insulin/insulin-like growth factor (IGF)-1 signaling and show decreased PDX-1 and CREB expression. At the level of individual islets, we observed increased insulin secretory capacity associated with increased expression of exocytotic proteins.

Conclusions:Our results show distinct context-specific roles of Casp8 in physiologic and disease states; being essential for ß cell apoptosis in type 1 and type 2 diabetes models and in regulating ß cell mass and insulin secretion under physiological conditions.


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