| First Author | Son J | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 558 |
| PubMed ID | 36732513 | Mgi Jnum | J:336250 |
| Mgi Id | MGI:7431871 | Doi | 10.1038/s41467-023-36315-4 |
| Citation | Son J, et al. (2023) Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of beta-cell failure. Nat Commun 14(1):558 |
| abstractText | Type 2 diabetes (T2D) is associated with beta-cell dedifferentiation. Aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) is a marker of beta-cell dedifferentiation and correlates with T2D progression. However, it is unknown whether ALDH1A3 activity contributes to beta-cell failure, and whether the decrease of ALDH1A3-positive beta-cells (A+) following pair-feeding of diabetic animals is due to beta-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 beta-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 beta-cells. Genetic or pharmacological inhibition of ALDH1A3 in diabetic mice lowers glycemia and increases insulin secretion. Characterization of beta-cells following ALDH1A3 inhibition shows reactivation of differentiation as well as regeneration pathways. We conclude that ALDH1A3 inhibition offers a therapeutic strategy against beta-cell dysfunction in diabetes. |
