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

Jinsook Son1, Wen Du2, Mark Esposito3,4

  • 1Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA. js4730@cumc.columbia.edu.

Nature Communications
|February 2, 2023
PubMed

Insights

Inhibiting Aldehyde dehydrogenase 1 isoform A3 (ALDH1A3) can restore function in pancreatic beta cells. This finding suggests ALDH1A3 inhibition is a promising therapeutic strategy for type 2 diabetes.

Area of Science:

  • Endocrinology
  • Metabolic Diseases
  • Cell Biology

Background:

  • Type 2 diabetes (T2D) is linked to pancreatic beta-cell dedifferentiation.
  • Aldehyde dehydrogenase 1 isoform A3 (ALDH1A3) is a marker of beta-cell dedifferentiation and T2D progression.

Purpose of the Study:

  • To determine if ALDH1A3 activity contributes to beta-cell failure in T2D.
  • To investigate if ALDH1A3-positive beta-cells (A+) can be restored to a functional state.

Main Methods:

  • Lineage tracing to track A+ cells during pair-feeding in diabetic models.
  • Somatic ablation of ALDH1A3 in diabetic beta-cells.
  • Treatment of diabetic mice using a novel selective ALDH1A3 inhibitor.

Main Results:

  • A+ cells can revert to functional, mature beta-cells.
  • ALDH1A3 inhibition (genetic or pharmacological) in diabetic mice reduced blood glucose levels and improved insulin secretion.
  • ALDH1A3 inhibition promoted beta-cell differentiation and regeneration pathways.

Conclusions:

  • ALDH1A3 activity contributes to beta-cell dysfunction in T2D.
  • Inhibiting ALDH1A3 represents a potential therapeutic approach for treating beta-cell dysfunction in diabetes.

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