ZFIN ID: ZDB-PUB-140402-15
Overnutrition induces β-cell differentiation through prolonged activation of β-cells in zebrafish larvae.
Li, M., Maddison, L.A., Page-McCaw, P., and Chen, W.
Insulin from islet β cells maintains glucose homeostasis by stimulating peripheral tissues to remove glucose from circulation. Persistent elevation of insulin demand increases β-cell number through self-replication or neogenesis (differentiation) as part of a compensatory response. However, it is not well understood how a persistent increase of insulin demand is detected. We have previously demonstrated that a persistent increase of insulin demand by overnutrition induces compensatory β-cell differentiation in zebrafish. Here, we use a series of pharmacological and genetic analyses to show that prolonged stimulation of existing β cells is necessary and sufficient for the compensatory response. In the absence of feeding, tonic, but not intermittent, pharmacological activation of β-cell secretion was sufficient to induce β-cell differentiation. Conversely, drugs that block β-cell secretion, including a KATP channel agonist and an L-type Ca2+ channel blocker, suppressed the overnutrition response. Genetic experiments specifically targeting β cells confirm existing β cells as the overnutrition sensor. First, inducible expression of a constitutively active KATP channel in β cells suppressed the overnutrition effect. Second, inducible expression of a dominant-negative KATP mutant induced β-cell differentiation independent of nutrients. Third, sensitizing β-cell metabolism by transgenic expression of a hyperactive GCK potentiated differentiation. Finally, ablation of the existing β cells abolished the differentiation response. Taken together, these data establish that overnutrition induces β-cell differentiation in larval zebrafish through prolonged activation of β cells. These findings demonstrate an essential role for existing β cells in sensing overnutrition and compensating for their own insufficiency by recruiting additional β cells.