Zinc-dependent effects of small molecules on the insulin-sensitive transcription factor FOXO1a and gluconeogenic genes

Amy R Cameron, Siji Anil, Emma Sutherland, Jean Harthill, Graham Rena (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    17 Citations (Scopus)

    Abstract

    Metal-binding compounds have recently been reported to have anti-hyperglycaemic properties in vivo. In the current study, we have investigated the ability of these compounds and related structures to induce insulin-like signal transduction to downstream effectors such as the transcription factor FOXO1a and the key gluconeogenic regulatory enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). Our results indicate that ß-thujaplicin, diethyldithiocarbamate (DEDTC) and its clinically-used dimer disulfiram, induce insulin-like dose-dependent effects on signalling to FOXO1a in a manner that is strictly dependent on the presence of zinc ions, as other ions including aluminium, cobalt, copper, lithium and manganese cannot substitute. The most potent compound tested on gluconeogenesis is disulfiram, which in the presence of 10 µM zinc, inhibited both PEPCK and G6Pase with an IC50 of 4 µM. Our results demonstrate that metal-binding compounds with diverse structures can induce zinc-dependent insulin-like effects on signal transduction and gene expression.
    Original languageEnglish
    Pages (from-to)195-203
    Number of pages9
    JournalMetallomics: Integrated Biometal Science
    Volume2
    Issue number3
    DOIs
    Publication statusPublished - 2010

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