Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure

Type 2 diabetes (T2D) is associated with defective insulin secretion, reduced β-cell mass, and β-cell dedifferentiation. Aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) serves as a marker of β-cell dedifferentiation and correlates with T2D progression. ALDH1A3-positive β-cells (A+) demonstrate impaired insulin secretion, and their numbers decrease when diabetic mice are rendered euglycemic by pair-feeding. It is unknown whether ALDH1A3 activity contributes to β-cell failure, and whether the decrease of A+ cells under pair-feeding is due to β-cell restoration. To tackle these questions, we (i) investigated the fate of A+ cells during pair-feeding by lineage-tracing, (ii) somatically ablated ALDH1A3 in diabetic β-cells, and (iii) used a novel selective ALDH1A3 inhibitor to treat diabetes. Lineage tracing and functional characterization show that A+ cells can be reconverted to functional, mature β-cells. Genetic or pharmacological inhibition of ALDH1A3 in diabetic mice lowers glycemia and increases insulin secretion. Molecular interrogation of β-cells following ALDH1A3 inhibition show a reactivation of differentiation as well as regeneration pathways through the REG gene family. We conclude that ALDH1A3 inhibition offers a therapeutic strategy for β-cell dysfunction in diabetes. Sorted beta cells from db/db, db/+ or Aldh1a3 KO_db/db mice