2. Academic Validation
  3. Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure

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

  • Nat Commun. 2023 Feb 2;14(1):558. doi: 10.1038/s41467-023-36315-4.
Jinsook Son 1,  Wen Du 2,  Mark Esposito 3 4,  Kaavian Shariati 2,  Hongxu Ding 5,  Yibin Kang 4,  Domenico Accili 2
Affiliations

Affiliations

  • 1 Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA. js4730@cumc.columbia.edu.
  • 2 Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
  • 3 Kayothera Inc, Seattle, WA, USA.
  • 4 Department of Molecular Biology, Princeton University, 08544, Princeton, NJ, USA.
  • 5 Department of Pharmacy Practice & Science, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA.
PMID: 36732513 DOI: 10.1038/s41467-023-36315-4
Abstract

Type 2 diabetes (T2D) is associated with β-cell dedifferentiation. Aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) is a marker of β-cell dedifferentiation and correlates with T2D progression. However, it is unknown whether ALDH1A3 activity contributes to β-cell failure, and whether the decrease of ALDH1A3-positive β-cells (A+) following pair-feeding of diabetic Animals 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. Characterization of β-cells following ALDH1A3 inhibition shows reactivation of differentiation as well as regeneration pathways. We conclude that ALDH1A3 inhibition offers a therapeutic strategy against β-cell dysfunction in diabetes.

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