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

  1. Nicole Liadis1,
  2. Leonardo Salmena12,
  3. Edwin Kwan3,
  4. Panteha Tajmir1,
  5. Stephanie A. Schroer1,
  6. Anna Radziszewska1,
  7. Xie Li3,
  8. Laura Sheu3,
  9. Mohamed Eweida1,
  10. Shilong Xu1,
  11. Herbert Y. Gaisano3,
  12. Razqallah Hakem12 and
  13. Minna Woo14
  1. 1Department of Medical Biophysics, Ontario Cancer Institute, and the University of Toronto, Toronto, Ontario, Canada
  2. 2Advanced Medical Discovery Institute, University of Toronto, Toronto, Ontario, Canada
  3. 3Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada
  4. 4Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
  1. 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+Casp8fl/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+Casp8fl/fl mice were 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 β-cell mass under physiological conditions. With aging, RIPcre+Casp8fl/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.

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.
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  1. Diabetes vol. 56 no. 9 2302-2311
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