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

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

Abbreviations: 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; pGSK3ß, phospho–glycogen synthase kinase 3ß; STZ, streptozotocin; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling

Inadequate pancreatic ß-cell mass resulting from excessive ß-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 ß-cells in vivo. Using the Cre-loxP system, mice lacking Casp8 in ß-cells (RIPcre⁺Casp8^fl/fl mice) were generated to address the role of Casp8 in ß-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 ß-cell mass under physiological conditions. With aging, RIPcre⁺Casp8^fl/fl mice gradually develop hyperglycemia and a concomitant decline in ß-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 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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