Distinct In Vivo Roles of Caspase-8 in β-Cells in Physiological and Diabetes Models

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 9; pp. 2302 - 2311
• Main Authors: Liadis, Nicole, Salmena, Leonardo, Kwan, Edwin, Tajmir, Panteha, Schroer, Stephanie A, Radziszewska, Anna, Li, Xie, Sheu, Laura, Eweida, Mohamed, Xu, Shilong, Gaisano, Herbert Y, Hakem, Razqallah, Woo, Minna
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.09.2007
• Subjects: Animals; Blood Glucose - metabolism; Caspase 8 - genetics; Caspase 8 - metabolism; Cell Death; Cell Separation; Diabetes Mellitus, Experimental - enzymology; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 1 - enzymology; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - pathology; Insulin-Secreting Cells - enzymology; Insulin-Secreting Cells - pathology; Mice; Mice, Inbred C57BL; Reference Values; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-1771

Distinct In Vivo Roles of Caspase-8 in β-Cells in Physiological and Diabetes Models Nicole Liadis 1 , Leonardo Salmena 1 2 , Edwin Kwan 3 , Panteha Tajmir 1 , Stephanie A. Schroer 1 , Anna Radziszewska 1 , Xie Li 3 , Laura Sheu 3 , Mohamed Eweida 1 , Shilong Xu 1 , Herbert Y. Gaisano 3 , Razqallah Hakem 1 2 and Minna Woo 1 4 1 Department of Medical Biophysics, Ontario Cancer Institute, and the University of Toronto, Toronto, Ontario, Canada 2 Advanced Medical Discovery Institute, University of Toronto, Toronto, Ontario, Canada 3 Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada 4 Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada Address correspondence and reprint requests to Minna Woo, Ontario Cancer Institute, Room 8-205, 610 University Ave., 8-113, Toronto, Ontario, Canada M5G 2M9. E-mail: mwoo{at}uhnres.utoronto.ca Abstract Inadequate pancreatic β-cell mass resulting from excessive β-cell apoptosis is a key defect in type 1 and type 2 diabetes. Caspases are the major molecules involved in apoptosis; however, in vivo roles of specific caspases in diabetes are unclear. The purpose of this study is to examine the role of Caspase (Casp)8 in β-cells in vivo. Using the Cre-loxP system, mice lacking Casp8 in β-cells ( RIPcre + Casp8 fl/fl mice) were generated to address the role of Casp8 in β-cells in physiological and diabetes models. We show that islets isolated from RIPcre + Casp8 fl/fl mice were protected from Fas ligand (FasL)–and ceramide-induced cell death. Furthermore, RIPcre + Casp8 fl/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 β-cell mass under physiological conditions. With aging, RIPcre + Casp8 fl/fl mice gradually develop hyperglycemia and a concomitant decline in β-cell mass. Their islets display decreased expression of molecules involved in insulin/IGF-I signaling and show decreased pancreatic duodenal homeobox-1 and cAMP response element binding protein expression. At the level of individual islets, we observed increased insulin secretory capacity associated with increased expression of exocytotic proteins. Our results show distinct context-specific roles of Casp8 in physiological and disease states; Casp8 is essential for β-cell apoptosis in type 1 and type 2 diabetes models and in regulating β-cell mass and insulin secretion under physiological conditions. 7-AAD, 7-amino-actinomycin D Casp, caspase CREB, cAMP response element binding protein FACS, fluorescent-activated cell sorting FasL, Fas ligand GSIS, glucose-stimulated insulin secretion GTT, glucose tolerance test H-E, hematoxylin and eosin HFD, high-fat diet IGF-IR, IGF-I receptor IRS, insulin receptor substrate PDX-1, pancreatic duodenal homeobox-1 pGSK3β, phospho–glycogen synthase kinase 3β STZ, streptozotocin TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 11 June 2007. DOI: 10.2337/db06-1771. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 30, 2007. Received December 20, 2006. DIABETES