title: Development of a highly visual, simple, and rapid test for the discovery of novel insulin mimetics in living vertebrates.
abstract: Diabetes mellitus is a global epidemic with major impacts on human health and society. Drug discovery for diabetes can be facilitated by the development of a rapid, vertebrate-based screen for identifying new insulin mimetic compounds. Our study describes the first development of a zebrafish-based system based on direct monitoring of glucose flux and validated for identifying novel anti-diabetic drugs. Our system utilizes a fluorescent-tagged glucose probe in an experimentally convenient 96-well plate format. To validate our new system, we identified compounds that can induce glucose uptake via activity-guided fractionation of the inner shell from the Japanese Chestnut (Castanea crenata). The best performing compound, UP3.2, was identified as fraxidin and validated as a novel insulin mimetic using a mammalian adipocyte system. Additional screening using sets of saponin- and triazine-based compounds was undertaken to further validate this assay, which led to the discovery of triazine PP-II-A03 as a novel insulin mimetic. Moreover, we demonstrate that our zebrafish-based system allows concomitant toxicological analysis of anti-diabetic drug candidates. Thus, we have developed a rapid and inexpensive vertebrate model that can enhance diabetes drug discovery by preselecting hits from chemical library screens, before testing in relatively expensive rodent assays.
authors.affiliation: New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
authors.forename: Jinho
authors.initials: J
authors.lastname: Lee
authors.forename: Da-Woon
authors.initials: DW
authors.lastname: Jung
authors.forename: Woong-Hee
authors.initials: WH
authors.lastname: Kim
authors.forename: Jung-In
authors.initials: JI
authors.lastname: Um
authors.forename: Soon-Ho
authors.initials: SH
authors.lastname: Yim
authors.forename: Won Keun
authors.initials: WK
authors.lastname: Oh
authors.forename: Darren R
authors.initials: DR
authors.lastname: Williams
mesh_terms: D000818:Animals; D001681:Biological Assay / Q000191:economics; D032701:Biomimetics; D003374:Coumarins / Q000737:chemistry*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005947:Glucose / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry; D007328:Insulin / Q000737:chemistry*; D013997:Time Factors; D015027:Zebrafish
chemical_list: D003374:Coumarins; D007004:Hypoglycemic Agents; D007328:Insulin; C401933:fraxiden; D005947:Glucose