Chemical genetic approach for screening insulin sensitizer

Abstract

Insulin signaling pathway is an evolutionary conserved mechanism. In organisms ranging from yeast to mouse, mutations in insulin or insulin-like receptors extend life span but also cause glycogen or fat accumulation and dwarfism. To develop insulin sensitizer, a simple diabetic model is adapted. DAF-2 is the only member of the insulin receptor family in whole C.elegans genome and if there is a mutation, worms are arrested on dauer larval stage instead of growing to adulthood. A chemical genetics approach is adopted to identify a novel potential drug for diabetes. If a molecule activates the down stream protein of insulin signaling pathway, the molecule can make daf-2 mutant worms overcome dauer and also, would be a insulin sensitizer. Three compounds that rescued dauer arrest were primarily screened out of a collection of 1120 compounds of a TGBz library and also, those compounds have the activity of increasing glucose uptake in 3T3 adiphocytes. Further studies show that the molecular target of the compounds is GAPDH, Glyceraldehyde 3-phospate dehydrogenase, and they act as a insulin sensitizer by inhibiting GAPDH activity.