A novel target for the insulin signaling pathway in glucose-mediated growth regulation.

In Caenorhabditis elegans, 40 insulin-like peptides (ILPs) interact with DAF-2, the sole insulin/IGF receptor, to regulate lifespan and stress responses via the FOXO transcription factor DAF-16. By examining worms deficient in the ILP member INS-7 under glucose-present and glucose-absent conditions, we uncovered a previously unrecognized DAF-2-AKT/SGK signaling output that drives reversible growth arrest specifically under glucose-present conditions, while allowing normal development in the absence of glucose, in a manner independent of DAF-16. Through genetic screening, we identified lon-1, transcriptionally downregulated by TGF-β/BMP signaling, as a potential suppressor of this arrest. The lon-1;ins-7 double mutants fully regained normal growth under glucose conditions, suggesting that LON-1 may act as a downstream effector linking insulin/IGF activity to growth regulation. We propose a model in which INS-7 antagonizes DAF-2 signaling in a glucose-dependent manner, thereby influencing LON-1-mediated developmental processes. These findings point to a DAF-16-independent branch of insulin signaling and raise the possibility of crosstalk with TGF-β/BMP pathways, offering new perspectives on hormonal regulation of nutrient-driven growth.