Overnutrition induces β-cell differentiation through prolonged activation of β-cells in zebrafish larvae.

Li M, Maddison LA, Page-McCaw P, Chen W
Am J Physiol Endocrinol Metab. 2014 306 (7): E799-807

PMID: 24473439 · PMCID: PMC3962607 · DOI:10.1152/ajpendo.00686.2013

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 differentiation (neogenesis) as part of a compensatory response. However, it is not well understood how a persistent increase in insulin demand is detected. We have previously demonstrated that a persistent increase in 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 this 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 an ATP-sensitive potassium (K ATP) channel agonist and an L-type Ca(2+) channel blocker, suppressed overnutrition-induced β-cell differentiation. Genetic experiments specifically targeting β-cells confirm existing β-cells as the overnutrition sensor. First, inducible expression of a constitutively active K ATP channel in β-cells suppressed the overnutrition effect. Second, inducible expression of a dominant-negative K ATP mutant induced β-cell differentiation independent of nutrients. Third, sensitizing β-cell metabolism by transgenic expression of a hyperactive glucokinase 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.

MeSH Terms (15)

Animals Animals, Genetically Modified Calcium Channels, L-Type Cell Count Cell Differentiation Disease Models, Animal Embryo, Nonmammalian Glucokinase Insulin-Secreting Cells KATP Channels Larva Membrane Potentials Overnutrition Potassium Channels, Inwardly Rectifying Zebrafish

Connections (2)

This publication is referenced by other Labnodes entities: