Insulin in worms

In a search for the worm equivalent of human insulin, researchers from Massachusetts General Hospital made several findings that may change the way that the scientific community thinks about insulin and its related proteins. As published in Genes & Development, a research team led by Dr. Gary Ruvkun used genomic and genetic approaches to characterize predicted insulin-like genes encoded by the worm genome. They found that the worm has thirty-seven insulin-like genes, many of which encode proteins with novel sequence and structural deviations from previously discovered insulin family members. This surprising discovery has paved the way for the identification of yet undiscovered members of the insulin family in humans.

The small nematode worm, C. elegans, utilizes an insulin signaling pathway to regulate its metabolism, development and longevity. In response to poor growth or reproductive conditions, the worm enters into a state of stress-resistant arrested development, termed dauer arrest. Dauer arrest is mediated by the action of DAF-2, a worm homolog of the human insulin receptor, and several previously identified downstream effectors. Dr. Ruvkun and colleagues set out to identify the missing upstream component of insulin signaling in C. elegans: the insulin-like ligand that binds DAF-2.

Dr. Ruvkun and colleagues used multiple tools to search the essentially complete worm genome for genes encoding members of the insulin family. Of the 37 insulin-like genes, or ins genes, they found in C. elegans, ins-1 proved to be the closest relative of human insulin, as determined by sequence and protein structure similarity. Furthermore, Dr. Ruvkun and colleagues found that ins-1 and human insulin both function in the DAF-2 pathway in worms, and generate identical physiological effects. This work is a potent illustration of the utility of complete genome sequencing.

Through their extensive search of the worm genome Dr. Ruvkun and colleagues have greatly expanded the insulin family in C. elegans. In doing so, these researchers have developed more insightful criteria for the identification of new insulin-like genes, and have broadened our thinking regarding the possible forms that insulin-like molecules may have. Many scientists believe that there are more human insulin genes than we are aware of; this work will enhance the search for these undiscovered insulin-related molecules. Ultimately, the progress that is made in delineating the pathway of insulin signaling in C. elegans moves us closer to the realization of the worm as a model system for insulin signaling and aging in humans.