PFKFB3 DEPLETION ACTIVATES β-CELL REPLICATION BY CELL COMPETITIVE CULLING OF COMPROMISED β-CELLS UNDER STRESS
Highly conserved hypoxia-inducible factor 1 alpha (HIF1) and its target 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) play a critical role in the survival of damaged {beta}-cells in type 2 diabetes (T2D) while rendering {beta}-cells non-responsive to glucose stimulation by mitochondrial suppression. HIF1-PFKFB3 is activated in 30-50% of all {beta}-cells in diabetic islets, leaving an open question of whether targeting this pathway may adjust {beta}-cell mass and function to the specific metabolic demands during diabetogenic stress. Our previous studies of {beta}-cells under amyloidogenic stress by human islet amyloid polypeptide (hIAPP) revealed that PFKFB3 is a metabolic execution arm of the HIF1 pathway with potent implications on Ca2+ homeostasis, metabolome, and mitochondrial form and function. To discriminate the role of PFKFB3 from HIF1 in vivo, we generated mice with conditional {beta}-cell specific disruption of the Pfkfb3 gene on a hIAPP+/- background and a high-fat diet (HFD) [PFKFB3{beta}KO + diabetogenic stress (DS)]. PFKFB3 disruption in {beta}-cells under diabetogenic stress led to selective purging of hIAPP-damaged {beta}-cells and the disappearance of bihormonal insulin- and glucagon-positive cells, thus compromised {beta}-cells. At the same time, PFKFB3 disruption led to a three-fold increase in {beta}-cell replication resembling control levels as measured with minichromosome maintenance 2 protein (MCM2). PFKFB3 disruption depleted bihormonal cells while increased {beta}-cell replication that was reflected in the increased {beta}-/-cell ratio and maintained {beta}-cell mass. Analysis of metabolic performance indicated comparable glucose intolerance and reduced plasma insulin levels in PFKFB3{beta}KO DS relative to PFKFB3WT DS mice. In the PFKFB3{beta}KO DS group, plasma glucagon levels were reduced compared to PFKFB3WT DS mice and were in line with increased insulin sensitivity. Glucose intolerance in PFKFB3{beta}KO DS mice could be explained by the compensatory expression of HIF1 after disruption of PFKFB3. Our data strongly suggest that the replication and functional recovery of {beta}-cells under diabetogenic stress depend on selective purification of HIF1 and PFKFB3-positive {beta}-cells. Thus, HIF1-PFKFB3-dependent activation of cell competition and purging of compromised {beta}-cells may yield functional competent {beta}-cell mass in diabetes.