TY - JOUR
T1 - Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure
AU - Son, Jinsook
AU - Du, Wen
AU - Esposito, Mark
AU - Shariati, Kaavian
AU - Ding, Hongxu
AU - Kang, Yibin
AU - Accili, Domenico
N1 - Funding Information:
We thank Ana Flete-Castro and Thomas Kolar (Columbia University) for outstanding technical support. We are grateful to members of the Accili laboratory for insightful discussions of the data. We thank Drs Li Qiang and Lexiang Yu for providing rosiglitazone. FACS experiments were performed in the DRC Flow Cytometry Core (S10OD020056). Human pancreatic islets and/or other resources were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) (RRID:SCR_014387) at City of Hope, NIH Grant # 2UC4DK098085. Funding sources include National Institute of Health grants DK64819 and DK63608 (D.A.); National Institute of Health Kirschstein-NRSA postdoctoral fellowship F32DK117574 (J.S.).
Funding Information:
We thank Ana Flete-Castro and Thomas Kolar (Columbia University) for outstanding technical support. We are grateful to members of the Accili laboratory for insightful discussions of the data. We thank Drs Li Qiang and Lexiang Yu for providing rosiglitazone. FACS experiments were performed in the DRC Flow Cytometry Core (S10OD020056). Human pancreatic islets and/or other resources were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) (RRID:SCR_014387) at City of Hope, NIH Grant # 2UC4DK098085. Funding sources include National Institute of Health grants DK64819 and DK63608 (D.A.); National Institute of Health Kirschstein-NRSA postdoctoral fellowship F32DK117574 (J.S.).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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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U2 - 10.1038/s41467-023-36315-4
DO - 10.1038/s41467-023-36315-4
M3 - Article
C2 - 36732513
AN - SCOPUS:85147312287
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 558
ER -