We are using model organism genetics to identify new genes in the Insulin Receptor (InR) signaling pathway. Such genes might encode targets for the development of novel therapeutics for the treatment of Type 2 Diabetes. Both C. elegans and Drosophila have homologs of the human insulin receptor, and genetic analyses in these organisms have demonstrated that the regulation of downstream signaling components also is conserved. We have taken several genetic approaches to identify new components of the InR signaling pathway, using InR mutants in C. elegans and Drosophila as entry points. In C. elegans , we performed large-scale RNAi of selected gene classes, including kinases, phosphatases, and proteases, and screened for suppressors of the dauer constitutive phenotype of
daf-2 (InR) mutants. To facilitate detection of weak modifiers of
daf-2 signaling, we screened for suppression in
daf-2 backgrounds that display more moderate mutant phenotypes than the canonical
e1370 allele used in the majority of previous screens. In parallel, a reverse genetics screen was done in Drosophila , using transposon insertion lines to look for modifiers of InR mutant phenotypes. Strikingly, subunits of the metabolic sensor AMP kinase were identified as one of the modifiers of InR signaling in both screens. AMP kinase is a key modulator of metabolic flux in mammalian cells, regulating pathways involved in fatty acid and carbohydrate metabolism. Furthermore, AMP kinase activity stimulates glucose transport in an insulin-independent manner. The identification of AMP kinase as a modifier of insulin signaling in C. elegans and Drosophila indicates that this interaction is conserved, and will allow genetic dissection of the mechanism of this interaction.