Zinc-dependent effects of small molecules on the insulin-sensitive transcription factor FOXO1a and gluconeogenic genes.
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 β-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.
Centre for Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland.
Amy R
AR
Cameron
Siji
S
Anil
Emma
E
Sutherland
Jean
J
Harthill
Graham
G
Rena
D015153:Blotting, Western; D002460:Cell Line; D004221:Disulfiram / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005943:Gluconeogenesis / Q000187:drug effects*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D039821:Monoterpenes / Q000494:pharmacology; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014334:Tropolone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism*
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007328:Insulin; D039821:Monoterpenes; D014334:Tropolone; D004050:Ditiocarb; D017526:Receptor, IGF Type 1; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D015032:Zinc; D004221:Disulfiram; C009479:beta-thujaplicin