PUBLICATION
Beta-cell excitability and excitability-driven diabetes in adult Zebrafish islets
- Authors
- Emfinger, C.H., Lőrincz, R., Wang, Y., York, N.W., Singareddy, S.S., Ikle, J.M., Tryon, R.C., McClenaghan, C., Shyr, Z.A., Huang, Y., Reissaus, C.A., Meyer, D., Piston, D.W., Hyrc, K., Remedi, M.S., Nichols, C.G.
- ID
- ZDB-PUB-190605-11
- Date
- 2019
- Source
- Physiological Reports 7: e14101 (Journal)
- Registered Authors
- Meyer, Dirk, Nichols, Colin G., Tryon, Robert
- Keywords
- KATP, Calcium channels, insulin secretion, metabolism, pancreas, zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Calcium/metabolism*
- Diabetes Mellitus, Experimental/metabolism*
- Diabetes Mellitus, Experimental/pathology
- Glucose/pharmacology
- Insulin-Secreting Cells/drug effects
- Insulin-Secreting Cells/metabolism
- Insulin-Secreting Cells/pathology*
- Membrane Potentials
- Potassium Channels, Inwardly Rectifying/metabolism*
- Sweetening Agents/pharmacology
- Zebrafish
- PubMed
- 31161721 Full text @ Physiol. Rep.
Citation
Emfinger, C.H., Lőrincz, R., Wang, Y., York, N.W., Singareddy, S.S., Ikle, J.M., Tryon, R.C., McClenaghan, C., Shyr, Z.A., Huang, Y., Reissaus, C.A., Meyer, D., Piston, D.W., Hyrc, K., Remedi, M.S., Nichols, C.G. (2019) Beta-cell excitability and excitability-driven diabetes in adult Zebrafish islets. Physiological Reports. 7:e14101.
Abstract
Islet β-cell membrane excitability is a well-established regulator of mammalian insulin secretion, and defects in β-cell excitability are linked to multiple forms of diabetes. Evolutionary conservation of islet excitability in lower organisms is largely unexplored. Here we show that adult zebrafish islet calcium levels rise in response to elevated extracellular [glucose], with similar concentration-response relationship to mammalian β-cells. However, zebrafish islet calcium transients are nor well coupled, with a shallower glucose-dependence of cytoplasmic calcium concentration. We have also generated transgenic zebrafish that conditionally express gain-of-function mutations in ATP-sensitive K+ channels (KATP -GOF) in β-cells. Following induction, these fish become profoundly diabetic, paralleling features of mammalian diabetes resulting from equivalent mutations. KATP -GOF fish become severely hyperglycemic, with slowed growth, and their islets lose glucose-induced calcium responses. These results indicate that, although lacking tight cell-cell coupling of intracellular Ca2+ , adult zebrafish islets recapitulate similar excitability-driven β-cell glucose responsiveness to those in mammals, and exhibit profound susceptibility to diabetes as a result of inexcitability. While illustrating evolutionary conservation of islet excitability in lower vertebrates, these results also provide important validation of zebrafish as a suitable animal model in which to identify modulators of islet excitability and diabetes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping