The Transcription Factor is Required for Pancreatic β Cell Identity, Glucose-regulated ATP Synthesis, and Ca Dynamics in Adult Mice

Heterozygous mutations in the human paired box gene lead to impaired glucose tolerance. Although embryonic deletion of the gene in mice leads to loss of most pancreatic islet cell types, the functional consequences of loss in adults are poorly defined. Here we developed a mouse line in which was selectively inactivated in β cells by crossing animals with floxed alleles to mice expressing the inducible Pdx1CreERT transgene. deficiency, achieved by tamoxifen injection, caused progressive hyperglycemia. Although 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. RNA sequencing and quantitative real-time PCR analyses revealed that, although the expression of key β cell genes, including , , , , and , was reduced after deletion, that of several genes that are usually selectively repressed ("disallowed") in β cells, including , was increased. Assessed in intact islets, glucose-induced ATP:ADP increases were significantly reduced ( < 0.05) in βKO control β cells, and the former displayed attenuated increases in cytosolic Ca Unexpectedly, glucose-induced increases in intercellular connectivity were enhanced after deletion, consistent with increases in the expression of the glucose sensor glucokinase, but decreases in that of two transcription factors usually expressed in fully differentiated β-cells, and , were observed in islet "hub" cells. These results indicate that is required for the functional identity of adult β cells. Furthermore, deficiencies in β cell glucose sensing are likely to contribute to defective insulin secretion in human carriers of mutations.