The Role of Receptor Interacting Protein Kinases in Diabetogenic Beta-Cell Loss and Hyperglycemia

Abstract

Diabetes is characterized by pancreatic -cell loss, insulin insufficiency, and hyperglycemia. Although major efforts have been made to manage diabetes using pharmacological agents that lower blood glucose levels, less effort has been focused on therapies to prevent the two major forms of diabetes, type 1 (T1D) and type 2 diabetes (T2D). Hence, there is a critical need to understand the mechanisms that underlie -cell demise in these diseases, and to develop therapies targeting such mechanisms. Recent studies in non-islet cell types identified receptor interacting protein kinase 1 and 3 (RIPK1 and RIPK3) as mediators of inflammation and programmed cell death. RIPKs are being considered as potential therapeutic target in human diseases including renal, hepatic and neurodegenerative diseases. However, the role of RIPKs in -cell loss in diabetes remains unknown. My thesis work evaluated the roles of RIPK1 and RIPK3 in mediating -cell cytotoxicity and islet inflammation in diabetes pathogenesis. Through the studies, I examined the role of RIPK1 and RIPK3 in -cell loss in response to known inducers of diabetogenic -cell stress, including proinflammatory cytokines, endoplasmic reticulum (ER) stress and islet amyloid deposition. My work revealed roles of RIPK1 and RIPK3 in mediating both caspase-dependent and caspase-independent cell death, kinase activation and transcriptional responses in vitro. Furthermore, I found that RIPK1 and RIPK3 play important roles in regulating glucose homeostasis in mouse models in vivo. The studies revealed a novel role of RIPKs in the pathogenesis of diabetes and suggests that RIPKs might be a potential target to treat or prevent the disease.