Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-23673-0
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Funding
- European Research Council under the Horizon 2020 Research and Innovation Programme [772365]
- Swedish Research Council
- Novo Nordisk Foundation
- Ragnar Soderberg's Foundation
- Strategic Research Programme in Diabetes
- Stem Cells & Regenerative Medicine at the Karolinska Institutet
- NordForsk (NorPreSS) [83539]
- Karolinska Institutet
- European Research Council (ERC) [772365] Funding Source: European Research Council (ERC)
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Research in zebrafish and neonatal pig islets revealed that overexpression of folate receptor 1 (folr1) and treatment with folinic acid can promote beta-cell differentiation, originating from ductal cells. Comparative metabolomic analysis suggested that changes in pyrimidine, carnitine, and serine pathways may contribute to beta-cell regeneration.
Diabetes can be caused by an insufficiency in beta-cell mass. Here, we performed a genetic screen in a zebrafish model of beta-cell loss to identify pathways promoting beta-cell regeneration. We found that both folate receptor 1 (folr1) overexpression and treatment with folinic acid, stimulated beta-cell differentiation in zebrafish. Treatment with folinic acid also stimulated beta-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 beta-cell differentiation originated from ductal cells. Mechanistically, comparative metabolomic analysis of zebrafish with/without beta-cell ablation and with/without folinic acid treatment indicated beta-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 beta-cells. Regeneration of insulin-producing beta-cells may become a future alternative treatment of diabetes. Here the authors report a genetic screen in a zebrafish model that mimics the loss of beta-cells in diabetes, and identified that the folate receptor Folr1 or folinic acid treatment can stimulate beta-cell regeneration.
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