Diabetes occurs when insulin producing pancreatic β-cells are impacted: type 1 diabetes due to destruction of β-cells, and type 2 diabetes due to a decrease in their number and/or potency. Consequently, therapy that aims to replace β-cells is a promising long term alternative to the currently prevalent insulin injections. However, the difficulty in finding viable sources to generate functional β-cells remains a crucial bottleneck. Herrera and colleagues recently discovered that under conditions of near-total depletion of β-cells in mice, only α-cells within pancreatic islets spontaneously convert into β-cells1. Encouragingly, there is in fact an overabundance of α-cells in the pancreas of diabetes patients. However, today we lack the knowledge to initiate and maintain α-to-β-cell conversion and are thus unable to exploit the availability of abundant α-cells to orchestrate this process reproducibly in humans.

Exciting preliminary results from our laboratory and others reveal that a subset of pancreatic α-cells in T1D juvenile donors lose α-cell gene expression and acquire the expression of several key β-cell genes including Insulin. These data suggest that α-to-β-cell conversion may have occurred in these T1D donors. Further, we identified genes that likely control α-cell fate by recapitulating our T1D findings in mice that were engineered to delete specific genes (Dnmt1 and Arx) in their α-cells. The work proposed here aims to extend our findings in multiple T1D donor samples with long or short disease durations. To our knowledge, the question of whether α-to-β-cell conversion occurs in T2D has not been previously studied.

We therefore request pancreas samples from T2D donors to analyze them for evidence towards α-to-β-cell conversion. We will use state-of-the-art technologies to enable us to isolate α-cells undergoing conversion and probe them for changes in their genetic and epigenetic landscape. These studies are expected to a) Elucidate the similarities and differences between the fates of pancreatic α-cells in early and late stage T1D, and between T1D and T2D, and b) Identify new molecules and pathways that can be targeted for developing drugs to enhance the generation of functional β-cells.