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.
Type 1 diabetes is a condition that results from the loss of insulin-producing β-cells. Despite current therapies, diabetic patients are prone to vascular complications. Using the mouse as a model, we previously found that pancreatic glucagon-expressing cells can be regenerated and converted into β-like cells by the forced expression of a single gene, Pax4. Here, we generated transgenic mice allowing both the permanent labeling of α-cells and the inactivation of Arx solely in this cell subtype. Our results indicate that, upon Arx inactivation, α-cells can be continuously regenerated from duct-lining precursors and converted into β-like cells. Importantly, the additional loss of Pax4 does not impact these processes, suggesting that Arx is the main trigger of α-cell-mediated β-like cell neogenesis. Most interestingly, upon chemical induction of diabetes/β-cell loss, while control animals die or remain severely hyperglycemic, a normalization of the glycemia, a clear regeneration of the β-like cell mass, and an extended lifespan are noted in animals with the conditional inactivation of Arx. 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.