Recent evidence suggests that beta cell dedifferentiation is a key early mechanism that underlies the pathogenesis of type 2 diabetes (T2D) [1]. This includes the loss of transcriptional regulators of beta cell function as well as other critical components of beta cell function. The study further suggests that beta cell dedifferentiation and acquisition of progenitor markers precedes beta cell death in T2D. Whether the same sequence of events and loss of factors occurs during progression of type 1 diabetes (T1D) is currently unknown. Interestingly, the analysis of pancreata from T1D individuals suggests that T1D patients retain insulin-producing cells even years after the onset of disease [2]. However, preliminary, still unpublished evidence suggests that these remaining beta cells have impaired health and have lost expression of some critical beta cells genes (Mark Aktinson, ADA meeting, June 2012). This observation raises the question of how function and mass of these remaining beta cells could be improved. We hypothesize that similar factors as lost in T2D are also lost in T1D and result in impaired function of remaining beta cells.

The overall goal of this proposal is to identify pathways that can prevent and/or reverse beta cell dedifferentiation in type 1 diabetes. The strategy is to define upstream pathways that maintain the expression of critical beta cell differentiation factors. It is predicted that sustained expression of these differentiation factors will restore beta cell function and mass in type 1 diabetes.