Min, JieMa, FeiyangSeyran, BerfinPellegrini, MatteoGreeff, O.B.W. (Oppel Bernhardt Wilhelm)Moncada, SalvadorTudzarova, Slavica2022-07-292022-07-292022-03-22Min, J., Ma, F., Seyran, B. et al. β-cell-specific deletion of PFKFB3 restores cell fitness competition and physiological replication under diabetogenic stress. Communications Biology 5, 248 (2022). https://doi.org/10.1038/s42003-022-03209-y.2399-3642 (online)10.1038/s42003-022-03209-yhttps://repository.up.ac.za/handle/2263/86578HIF1α 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.en© The Author(s) 2022. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License.Mechanisms of diseaseType 2 diabetes mellitus (T2DM)Article