Abstract
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.
Highlights
IntroductionWe performed a genetic screen in a zebrafish model of β-cell loss to identify pathways promoting β-cell regeneration
Diabetes can be caused by an insufficiency in β-cell mass
Folic acid is an important vitamin of the one-carbon metabolism pathway that provides carbon units for numerous cellular processes[29,30], which are conserved from zebrafish to humans[31,32]
Summary
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 stimulated β-cell differentiation in cultures of neonatal pig islets, showing that the effect could be translated to a mammalian system. Treatment with folinic acid (known as 5-formyl-THF or leucovorin) increased β-cell differentiation in both zebrafish and cultures of neonatal pig islets, suggesting that folic acid and onecarbon metabolism can potentiate β-cell differentiation across species. Given how tolerable folic acid is, our results encourage further exploration of its translational potential in preventing or managing diabetes
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