Reinforcing one-carbon metabolism via folic acid/Folr1 promotes β-cell differentiation

Nat Commun. 2021 Jun 7;12(1):3362. doi: 10.1038/s41467-021-23673-0.


Diabetes can be caused by an insufficiency in β-cell mass. Here, we performed a genetic screen in a zebrafish model of β-cell loss to identify pathways promoting β-cell regeneration. We found that both folate receptor 1 (folr1) overexpression and treatment with folinic acid, stimulated β-cell differentiation in zebrafish. Treatment with folinic acid also stimulated β-cell differentiation in cultures of neonatal pig islets, showing that the effect could be translated to a mammalian system. In both zebrafish and neonatal pig islets, the increased β-cell differentiation originated from ductal cells. Mechanistically, comparative metabolomic analysis of zebrafish with/without β-cell ablation and with/without folinic acid treatment indicated β-cell regeneration could be attributed to changes in the pyrimidine, carnitine, and serine pathways. Overall, our results suggest evolutionarily conserved and previously unknown roles for folic acid and one-carbon metabolism in the generation of β-cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Animals, Newborn
  • Carbon / metabolism*
  • Carnitine / metabolism
  • Cell Differentiation / drug effects*
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Folate Receptor 1 / genetics
  • Folate Receptor 1 / metabolism*
  • Gene Expression Regulation / drug effects
  • Humans
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Larva / genetics
  • Larva / metabolism
  • Leucovorin / pharmacology*
  • Metabolic Networks and Pathways / drug effects
  • Mice
  • Pyrimidines / metabolism
  • Swine
  • Zebrafish / genetics
  • Zebrafish / metabolism*


  • Folate Receptor 1
  • Pyrimidines
  • Carbon
  • pyrimidine
  • Leucovorin
  • Carnitine