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

Jinsook Son (), Wen Du, Mark Esposito, Kaavian Shariati, Hongxu Ding, Yibin Kang and Domenico Accili
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Jinsook Son: Vagelos College of Physicians and Surgeons, Columbia University
Wen Du: Vagelos College of Physicians and Surgeons, Columbia University
Mark Esposito: Kayothera Inc
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

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36315-4

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