When the going gets tough, the nematode Caenorhabditis elegans enters a developmentally arrested state called the dauer stage. Dauer entry is under the control of the insulin and transforming growth factor-β (TGF-β) signalling pathways. But the endogenous ligand for the worm insulin pathway has not been found. Using a sophisticated genomic analysis, Sarah Pierce, Michael Costa and colleagues have now identified a collection of insulin-like ligands in C. elegans, among which is a strong candidate for a ligand that controls dauer entry. But here's the twist — it's an antagonist of insulin signalling.

A key aspect of this work is that the search for new insulin homologues incorporated information about protein structure that is conserved among insulin molecules. Thirty-seven insulin family members were found by screening the C. elegans genome for these structural features, 25 of which were novel.

Because of its close relationship to human insulin, one of the C. elegans genes, ins-1 , was the focus for genetic analysis. Insulin signalling is required to keep the worms in an active state — switch off signalling and worms enter the dauer state. Surprisingly, overexpression of ins-1 increased dauer entry, which indicates that INS-1 might be an antagonist of the insulin receptor DAF-2. Knocking out ins-1 produced no phenotype, and so there might be other signalling molecules the function of which overlaps with INS-1. One of the other insulins, INS-18, was indeed shown to function as an antagonist of insulin signalling. Even human insulin behaved as an antagonist of insulin signalling in C. elegans.

So, there are now some strong candidates for endogenous insulin signals in C. elegans, but is there an endogenous agonist of insulin signalling? Further analysis of this large group of molecules should tell. And for those interested in the role of insulin signalling in disease, the possibility that the vertebrate insulin family is also much larger than expected, and the demonstration that insulin can function as a signalling antagonist, suggest some attractive lines of inquiry.