Metabolic reprogramming drives pancreatic β cell neogenesis from α cells [ATAC-seq 2]

One potential strategy is to convert non-β cells in the islet, such as α cells, into insulin-producing cells. Although several compounds have been identified to induce β cell-like features in α cells, none have yet been successfully translated into clinical applications.

In this study, we identify PRC2 inhibitors as potent inducers of β cell-enriched gene expression in α cells, acting through modulation of the AR-ETV1 complex. AR inhibition suppresses glycogen synthesis and enhances the pentose phosphate pathway (PPP). Direct metabolic reprogramming with methyl esterified 6-phosphogluconate (ME-6-PG), an intermediate metabolite of the PPP, induces β cell-like features in α cells, stimulate β cell regeneration and ameliorates diabetes.