Glucagon-expressing cells can be converted into insulin-expressing cells upon <i>Arx</i> inactivation.

(A–C) By means of X-Gal staining, α-cell lineage tracing on 2.5 month-old Glu-ArxKO::Rosa pancreata showed β-galactosidase activity in a number of cells located within the islet core where insulin+ cells are normally located (B–C), while β-galactosidase was expectedly and solely detected in the islet mantle of Glu-Cre::Rosa controls (A). (D–L) Immunohistochemical analyses revealed that most β-gal+ cells were in fact insulin+ (D–F), indicating a conversion of glucagon+ cells into insulin+ cells. Such a shift in identity was also observed in 1mDox+ IndGlu-ArxKO animals (G–I), suggesting that adult/mature α-cells can also acquire a β-like cell phenotype. Interestingly, β-gal labeling was found in insulin+ (G–I) and glucagon+ (J–L) cells, but not in somatostatin+ cells (J–L), demonstrating that these did not pass through a phase of glucagon expression. For the purpose of clarity, islets are outlined with dashed black lines in A–C or with white lines in J–L. In J–L, arrowheads provide examples of β-gal+ glucagon+ cells. (Each photograph is representative of at least three independent animals).