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HIF1α and PFKFB3 play a critical role in the survival of damaged β-cells in type–2 diabetes while rendering β-cells non-responsive to glucose stimulation. To discriminate the role of PFKFB3 from HIF1α in vivo, we generated mice with conditional β-cell specific disruption of the  Pfkfb3  gene on a human islet pancreatic polypeptide (hIAPP +/− ) background and a high-fat diet (HFD) [PFKFB3 βKO  + diabetogenic stress (DS)]. PFKFB3 disruption in β-cells under DS led to selective purging of hIAPP-damaged β-cells and the disappearance of insulin- and glucagon positive bihormonal cells. PFKFB3 disruption induced a three-fold increase in β-cell replication as evidenced by minichromosome maintenance 2 protein (MCM2) expression. Unlike high-, lower DS or switch to restricted chow diet abolished HIF1α levels and reversed glucose intolerance of PFKFB3 βKO  DS mice. Our data suggest that replication and functional recovery of β-cells under DS depend on β-cell competitive and selective purification of HIF1α and PFKFB3-positive β-cells.

β-cell-specific deletion of PFKFB3 restores cell fitness competition and physiological replication under diabetogenic stress