Using Caenorhabditis elegans to elucidate the role of O-GlcNAc in insulin signal transduction

O-GlcNAc is a regulatory carbohydrate post-translational modification found on serine and threonine residues on cytosolic and nuclear proteins in multicellular organisms. Global elevation of O-GlcNAc levels on intracellular proteins induces insulin resistance, the hallmark of type II diabetes, in mammalian systems. In C. elegans, attenuation of the insulin-like signal transduction pathway increases lifespan of the nematode. We demonstrate that the O-GlcNAc cycling enzymes, OGT that adds O-GlcNAc and OGA, which removes it, modulate lifespan in C. elegans. The median lifespan of the oga deletion strain increases ~25% while the median life span of the ogt deletion strain decreases ~25%. Furthermore, we demonstrate that the O-GlcNAc effect on nematode median lifespan is due to attenuation of insulin-like signal transduction above PDK1 in the pathway. These results highlight the conserved feature of the O-GlcNAc modification in attenuating insulin signaling and more finely define the point in the pathway in which elevated O-GlcNAc modification is inducing insulin resistance.