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

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 ALD...

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Bibliographic Details
Published in:Nature communications Vol. 14; no. 1; pp. 558 - 14
Main Authors: Son, Jinsook, Du, Wen, Esposito, Mark, Shariati, Kaavian, Ding, Hongxu, Kang, Yibin, Accili, Domenico
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 02.02.2023
Nature Publishing Group
Nature Portfolio
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Ablation
Aldehyde dehydrogenase
Aldehyde Dehydrogenase 1 Family
Aldehyde Oxidoreductases - metabolism
Aldehydes
Animals
Beta cells
Blood glucose
Cell differentiation
Cell Line, Tumor
Diabetes
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Experimental - drug therapy
Diabetes Mellitus, Experimental - genetics
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - genetics
Humanities and Social Sciences
Insulin
Insulin secretion
Insulin-Secreting Cells - metabolism
Mice
multidisciplinary
Pharmacology
Science
Science (multidisciplinary)
Tracing
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. β-cell dedifferentiation is a key feature of type 2 diabetes. Here, the authors show evidence of re-differentiation of de-differentiated β-cells and identify ALDH1A3 as a key player in this process, proposing inhibition of ALDH1A3 as a treatment method for β-cell dysfunction in diabetes.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-36315-4