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

Author

Listed:
  • Jinsook Son

    (Vagelos College of Physicians and Surgeons, Columbia University)

  • Wen Du

    (Vagelos College of Physicians and Surgeons, Columbia University)

  • Mark Esposito

    (Kayothera Inc
    Princeton University)

  • Kaavian Shariati

    (Vagelos College of Physicians and Surgeons, Columbia University)

  • Hongxu Ding

    (University of Arizona)

  • Yibin Kang

    (Princeton University)

  • Domenico Accili

    (Vagelos College of Physicians and Surgeons, Columbia University)

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.

Suggested Citation

  • Jinsook Son & Wen Du & Mark Esposito & Kaavian Shariati & Hongxu Ding & Yibin Kang & Domenico Accili, 2023. "Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36315-4
    DOI: 10.1038/s41467-023-36315-4
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    1. repec:ucp:bkecon:9780226320625 is not listed on IDEAS
    2. Melissa F. Brereton & Michaela Iberl & Kenju Shimomura & Quan Zhang & Alice E. Adriaenssens & Peter Proks & Ioannis I. Spiliotis & William Dace & Katia K. Mattis & Reshma Ramracheya & Fiona M. Gribble, 2014. "Reversible changes in pancreatic islet structure and function produced by elevated blood glucose," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
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