Chemical screen identifies FDA-approved drugs and target pathways that induce precocious pancreatic endocrine differentiation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-11, Vol.108 (48), p.19264-19269
• Main Authors: Rovira, Meritxell, Huang, Wei, Yusuff, Shamila, Shim, Joong Sup, Ferrante, Anthony A, Liu, Jun O, Parsons, Michael J
• Format: Article
• Language: English
• Subjects: Acetanilides - pharmacology; Animals; Animals, Genetically Modified; autoimmunity; Biological Sciences; Biosynthesis; Caffeic Acids - pharmacology; Cell Differentiation - drug effects; Cell Line, Tumor; Cell lines; Cell Proliferation; Cells; Cellular differentiation; Danio rerio; Diabetes; Dimethyl Sulfoxide; DNA Primers - genetics; Dose-Response Relationship, Drug; Drug Discovery - methods; drugs; Endocrine cells; Epirizole - pharmacology; Exocrine cells; FDA approval; fish; Fluorescent Antibody Technique; Green Fluorescent Proteins; guanosine triphosphate; Guanosine Triphosphate - biosynthesis; HMGB1 Protein - metabolism; Insulin; insulin-dependent diabetes mellitus; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; islets of Langerhans; Larva - drug effects; Larvae; Larval development; mechanism of action; Microscopy, Confocal; Mycophenolic Acid - pharmacology; p-Aminoazobenzene - analogs & derivatives; p-Aminoazobenzene - pharmacology; Pancreas; Pharmaceutical Preparations - metabolism; Progenitor cells; Real-Time Polymerase Chain Reaction; retinoic acid; Sulfanilic Acids - pharmacology; swimming; Tretinoin - metabolism; Type 1 diabetes mellitus; Zebrafish
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1113081108

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.