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

Long-lived PFKFB3 expressing β-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” β-cells, we analyzed the overlap between human β-cells with bona-fide “loser signature” across diabetes pathologies utilizing the HPAP scRNA-seq and spatial transcriptomics of PFKFB3 positive β-cells from nPOD T2D pancreata. The overlapping transcriptional profile of “loser” β-cells was represented by downregulated ribosomal biogenesis- and genes encoding for mitochondrial respiration. PFKFB3 positive “loser” β-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” β-cells in T2D. Inhibition of PFKFB3 resulted in the clearance of dysfunctional “loser” β-cells leading to restored glucose tolerance in mouse model of T2D.