The transcription factor Pax6 is required for pancreatic β cell identity, glucose-regulated ATP synthesis and Ca2+ dynamics in adult mice.

Heterozygous mutations in the human paired box gene PAX6 lead to impaired glucose tolerance. Although embryonic deletion of the Pax6 gene in mice leads to the loss of most pancreatic islet cell types, the functional consequences of Pax6 loss in adults are poorly defined. Here, we developed a mouse line in which Pax6 was selectively inactivated in β cells by crossing animals with floxed Pax6 alleles to mice expressing the inducible Pdx1CreERT transgene. Pax6 deficiency, achieved by tamoxifen injection, caused progressive hyperglycemia. While β-cell mass was preserved 8 days post injection, total insulin content and insulin:chromogranin A immunoreactivity were reduced by ~60%, and glucose-stimulated insulin secretion was eliminated. RNAseq and qRT-PCR analyses revealed that whereas the expression of key β cell genes including Ins2, Slc30a8, MafA, Slc2a2, G6pc2 and Glp1r was reduced after Pax6 deletion, that of several genes which are usually selectively repressed ("disallowed") in β-cells, including Slc16a1, was increased. Assessed in intact islets, glucose-induced ATP:ADP increases were significantly reduced (p