β-cell-specific deletion of PFKFB3 restores cell fitness competition and physiological replication under diabetogenic stress.
Jie MinFeiyang MaBerfin SeyranMatteo PellegriniOppel GreeffSalvador MoncadaSlavica TudzarovaPublished in: Communications biology (2022)
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.
Keyphrases
- induced apoptosis
- type diabetes
- cell cycle arrest
- high fat diet
- single cell
- endothelial cells
- physical activity
- cell death
- bone marrow
- gene expression
- drug delivery
- cardiovascular disease
- metabolic syndrome
- insulin resistance
- mesenchymal stem cells
- body composition
- skeletal muscle
- weight loss
- binding protein
- big data
- high glucose
- blood glucose