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

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. © 2013 courtney et al.