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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Vydáno v:	Nature communications Ročník 14; číslo 1; s. 558 - 14
Hlavní autoři:	Son, Jinsook, Du, Wen, Esposito, Mark, Shariati, Kaavian, Ding, Hongxu, Kang, Yibin, Accili, Domenico
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 02.02.2023 Nature Publishing Group Nature Portfolio
Témata:	13/106 13/31 13/51 14/19 38 38/91 42 45 631/136/142 631/136/2435 631/443/319/1642/137/773 631/80/304 64 64/60 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
On-line přístup:	Získat plný text
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-023-36315-4