Overnutrition induces β-cell differentiation through prolonged activation of β-cells in zebrafish larvae.
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.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee.
Mingyu
M
Li
Lisette A
LA
Maddison
Patrick
P
Page-McCaw
Wenbiao
W
Chen
D000818:Animals; D030801:Animals, Genetically Modified; D020746:Calcium Channels, L-Type / Q000502:physiology; D002452:Cell Count; D002454:Cell Differentiation; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian; D005941:Glucokinase / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D054086:KATP Channels / Q000502:physiology; D007814:Larva; D008564:Membrane Potentials / Q000502:physiology; D044343:Overnutrition / Q000378:metabolism / Q000503:physiopathology*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D015027:Zebrafish; D000099161:Kcnj11 Channel
D020746:Calcium Channels, L-Type; D005941:Glucokinase; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel
diabetes; nutrient sensing; zebrafish