Tudzarova, S. | bioRxiv Science

bioRxiv2024

Dysfunctional β-cell longevity in diabetes relies on high energy conservation and positive epistasis

Long-lived PFKFB3 expressing {beta}-cells are dysfunctional cells because of prevailing glycolysis that compromises metabolic coupling of insulin secretion. Their accumulation in type-2 diabetes (T2D) appears to be related to the loss of apoptotic competency of cell fitness competition (CFC) that maintains tissue function by favoring constant selection of healthy "winner" cells. To investigate how PFKFB3 can disguise the competitive traits of dysfunctional "loser" {beta}-cells, we analyzed the overlap between human {beta}-cells with bona-fide "loser signature" across diabetes pathologies utilizing the HPAP scRNA-seq and spatial transcriptomics of PFKFB3 positive {beta}-cells from nPOD T2D pancreata. The overlapping transcriptional profile of "loser" {beta}-cells was represented by downregulated ribosomal biogenesis- and genes encoding for mitochondrial respiration. PFKFB3 positive "loser" {beta}-cells had reduced expression of HLA Class I and II genes. Gene-gene interaction analysis revealed that PFKFB3 rs1983890 can interact with anti-apoptotic gene MAIP1 implicating positive epistasis as a mechanism for prolonged survival of "loser" {beta}-cells in T2D. Inhibition of PFKFB3 resulted in the clearance of dysfunctional "loser" {beta}-cells leading to restored glucose tolerance in mouse model of T2D.

cell biology↗

bioRxiv2021

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.

cell biology↗