Beta cell exhaustion and glucotoxicity in Diabetes

Project summary Diabetes is characterized by progressive loss or dysfunction of pancreatic insulin- producing β-cells. Previous efforts demonstrated loss of β-cell identity, rather than cell death, as a primary contributor in loss of functional β-cell mass in diabetes progression. Strikingly, this process is reversible, challenging the notion of permanent β-cell damage in diabetes. However, underlying mechanisms remain elusive, and we have poor understanding of the window for intervention to preserve or restore functional β-cell mass. The long-term goals of this project are to understand temporal progression and underlying mechanisms of loss of pancreatic β-cell identity in diabetes. In this proposal we seek to understand β-cell adaptation to metabolic changes and conditions, determine the temporal progression and underlying mechanisms of loss of β-cell mass and identity in diabetes in vivo, and ways to prevent or restore functional β-cell mass. Proposed studies will utilize novel inducible mouse models of monogenic neonatal diabetes and of polygenic type 2 diabetes to understand β-cell adaptation to changes in metabolism, determine the temporal progression and underlying mechanisms of loss of functional β- cell mass and identity in different forms of diabetes, the role of autophagy in this process, and mechanisms to mitigate glucotoxicity-induced β-cell failure. Successful completion of the proposed aims will provide new molecular and mechanistic insights into the adaptive potential of β-cells and will shed light on mechanisms to preserve β-cell mass and identity.