ZFIN ID: ZDB-PUB-190605-11
Beta-cell excitability and excitability-driven diabetes in adult Zebrafish islets
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.
Date: 2019
Source: Physiological Reports   7: e14101 (Journal)
Registered Authors: Meyer, Dirk
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.
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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.
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