Abstract
Pancreatic β-cells are an essential source of insulin and their destruction because of autoimmunity causes type I diabetes. We conducted a chemical screen to identify compounds that would induce the differentiation of insulin-producing β-cells in vivo. To do this screen, we brought together the use of transgenic zebrafish as a model of β-cell differentiation, a unique multiwell plate that allows easy visualization of lateral views of swimming larval fish and a library of clinical drugs. We identified six hits that can induce precocious differentiation of secondary islets in larval zebrafish. Three of these six hits were known drugs with a considerable background of published data on mechanism of action. Using pharmacological approaches, we have identified and characterized two unique pathways in β-cell differentiation in the zebrafish, including down-regulation of GTP production and retinoic acid biosynthesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetanilides / pharmacology
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Animals
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Animals, Genetically Modified
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Caffeic Acids / pharmacology
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Cell Differentiation / drug effects*
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Cell Line, Tumor
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Cell Proliferation
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DNA Primers / genetics
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Dimethyl Sulfoxide
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Dose-Response Relationship, Drug
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Drug Discovery / methods*
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Epirizole / pharmacology
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Fluorescent Antibody Technique
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Green Fluorescent Proteins
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Guanosine Triphosphate / biosynthesis
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HMGB1 Protein / metabolism
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Insulin-Secreting Cells / cytology*
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Insulin-Secreting Cells / drug effects*
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Larva / drug effects
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Microscopy, Confocal
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Mycophenolic Acid / pharmacology
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Pharmaceutical Preparations / metabolism*
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Real-Time Polymerase Chain Reaction
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Sulfanilic Acids / pharmacology
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Tretinoin / metabolism
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Zebrafish
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p-Aminoazobenzene / analogs & derivatives
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p-Aminoazobenzene / pharmacology
Substances
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Acetanilides
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Caffeic Acids
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DNA Primers
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HMGB1 Protein
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N-(4-(3-(3,4-dihydroxyphenyl)acryloyl)phenyl)-2-(thiophen-2-yl)acetamide
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Pharmaceutical Preparations
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Sulfanilic Acids
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Green Fluorescent Proteins
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C.I. Solvent Yellow 56
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Epirizole
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Tretinoin
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p-Aminoazobenzene
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Guanosine Triphosphate
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Mycophenolic Acid
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Dimethyl Sulfoxide