Abstract:
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 highfat diet (HFD) [PFKFB3βKO + 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 PFKFB3βKO 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.
