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

Abstract

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.

• Authors: Mingyu Li, Lisette A Maddison, Patrick Page-McCaw, Wenbiao Chen
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 306 Issue 7 Pg. E799-807 (Apr 01 2014) ISSN: 1522-1555 [Electronic] United States
• PMID: 24473439 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channels, L-Type
• KATP Channels
• Kir6.2 channel
• Potassium Channels, Inwardly Rectifying
• Glucokinase

Topics

• Animals
• Animals, Genetically Modified
• Calcium Channels, L-Type (physiology)
• Cell Count
• Cell Differentiation
• Disease Models, Animal
• Embryo, Nonmammalian
• Glucokinase (genetics)
• Insulin-Secreting Cells (cytology, physiology)
• KATP Channels (physiology)
• Larva
• Membrane Potentials (physiology)
• Overnutrition (metabolism, physiopathology)
• Potassium Channels, Inwardly Rectifying (genetics)
• Zebrafish