title: Distinct in vivo roles of caspase-8 in beta-cells in physiological and diabetes models.
abstract: Inadequate pancreatic beta-cell mass resulting from excessive beta-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 beta-cells in vivo. Using the Cre-loxP system, mice lacking Casp8 in beta-cells (RIPcre(+)Casp8(fl/fl) mice) were generated to address the role of Casp8 in beta-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 beta-cell mass under physiological conditions. With aging, RIPcre(+)Casp8(fl/fl) mice gradually develop hyperglycemia and a concomitant decline in beta-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 beta-cell apoptosis in type 1 and type 2 diabetes models and in regulating beta-cell mass and insulin secretion under physiological conditions.
authors.affiliation: Department of Medical Biophysics, Ontario Cancer Institute, and the University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Liadis
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salmena
authors.forename: Edwin
authors.initials: E
authors.lastname: Kwan
authors.forename: Panteha
authors.initials: P
authors.lastname: Tajmir
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schroer
authors.forename: Anna
authors.initials: A
authors.lastname: Radziszewska
authors.forename: Xie
authors.initials: X
authors.lastname: Li
authors.forename: Laura
authors.initials: L
authors.lastname: Sheu
authors.forename: Mohamed
authors.initials: M
authors.lastname: Eweida
authors.forename: Shilong
authors.initials: S
authors.lastname: Xu
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism*; D016923:Cell Death; D002469:Cell Separation; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D053181:Caspase 8