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Recently, it was demonstrated that pancreatic new-born glucagon-producing cells can regenerate and convert into insulin-producing β-like cells through the ectopic expression of a single gene,  Pax4 . Here, combining conditional loss-of-function and lineage tracing approaches, we show that the selective inhibition of the  Arx  gene in α-cells is sufficient to promote the conversion of adult α-cells into β-like cells at any age. Interestingly, this conversion induces the continuous mobilization of duct-lining precursor cells to adopt an endocrine cell fate, the glucagon +  cells thereby generated being subsequently converted into β-like cells upon  Arx  inhibition. Of interest, through the generation and analysis of  Arx  and  Pax4  conditional double-mutants, we provide evidence that  Pax4  is dispensable for these regeneration processes, indicating that Arx represents the main trigger of α-cell-mediated β-like cell neogenesis. Importantly, the loss of  Arx  in α-cells is sufficient to regenerate a functional β-cell mass and thereby reverse diabetes following toxin-induced β-cell depletion. Our data therefore suggest that strategies aiming at inhibiting the expression of  Arx , or its molecular targets/co-factors, may pave new avenues for the treatment of diabetes.

The Inactivation of Arx in Pancreatic α-Cells Triggers Their Neogenesis and Conversion into Functional β-Like Cells