ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/079/SRR22302379/SRR22302379_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/081/SRR22302381/SRR22302381_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/080/SRR22302380/SRR22302380_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/083/SRR22302383/SRR22302383_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/082/SRR22302382/SRR22302382_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/085/SRR22302385/SRR22302385_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/079/SRR22302379/SRR22302379_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/080/SRR22302380/SRR22302380_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/082/SRR22302382/SRR22302382_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/084/SRR22302384/SRR22302384_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/083/SRR22302383/SRR22302383_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/081/SRR22302381/SRR22302381_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/085/SRR22302385/SRR22302385_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR223/084/SRR22302384/SRR22302384_1.fastq.gzprimaryOK200GenomicsColumbia Universityhttps://www.ebi.ac.uk/ena/browser/view/PRJNA901979Mus musculusxref:PubMed:36732513Type 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. Overall design: Sorted beta cells from db/db, db/+ or Aldh1a3 KO_db/db miceENAfalseGenetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failureGenetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure2025-09-242023-01-20PRJNA901979GSE2180471009036732513