| β cell apoptosis is essential for homeostatic maintenance of β cell mass and this cellular process is inappropriately exaggerated in type 1 and type 2 diabetes. Caspases are the major molecules involved in apoptosis, and more recently their additional roles in other cellular processes have been described. Understanding the functions of caspases in β cells is relevant for elucidating molecular mechanisms involved in β cell homeostasis and in the pathogenesis of type 1 and type 2 diabetes. In this thesis, gene targeted mouse models were used to study in vivo molecular functions of specific caspases in physiological and disease contexts. In chapter 1, the specific role of Caspase-3 (Casp3) in a type 1 diabetes mouse model was evaluated. It was found that Casp3-mediated β cell apoptosis is a requisite step for T cell priming, a key initiating event in type 1 diabetes. In chapter 2, the specific in vivo and in vitro roles of Caspase-8 (Casp8) in β cells were examined, under physiological and pathological conditions. It was found that Casp8 is essential for β cell apoptosis in type 1 and type 2 diabetes models. In addition, a novel unexpected role of Casp8 in the maintenance of β cell mass and insulin secretion was found under homeostatic conditions. The studies in this thesis define novel context-specific functions of Casp3 and Casp8 in β cells. Together, the results presented in this thesis suggest that therapeutically targeting caspases in β cells may be relevant for prevention and treatment of diabetes and for islet transplantation. |
