O-GlcNAc and aging: C. elegans as a genetic model to test O-GlcNAc roles in type II diabetic insulin resistance

in type II diabetic insulin resistance [2, 4, 12, 13]. O-GlcNAc levels are responsive to increased nutrient flux through the hexosamine biosynthetic pathway. Hyperglycemia in type II diabetes thus drives abnormal elevation of O-GlcNAc [1]. Mice over-expressing OGT (the enzyme which catalyzes addition of O-GlcNAc to proteins) display insulin resistant type II diabetic phenotypes [9]. However, OGT appears to be fundamentally essential for mammalian cellular life [10], limiting the potential to test models of O-GlcNAc involvement in insulin resistance/signaling by OGT knockout studies in mammals. C. elegans has a conserved insulin-like signaling pathway which regulates phenotypes including life span, dauer larvae formation, stress responses, and macronutrient storage. Additionally, there is a high level of conservation between C. elegans and mammalian OGT and OGA (enzyme that removes O-GlcNAc) [3, 8]. In contrast to mammalian systems, C. elegans with OGT and OGA null mutant alleles are viable and fertile [5, 3]. Thus, C. elegans is potentially amenable to genetic testing of interactions between O-GlcNAc cycling and insulin signaling/phenotypes. In C. elegans, attenuation of insulin-like signaling induces a so-called dauer larval stage. An insulin receptor-like mutant allele (daf-2) with reduced signaling induces dauer formation, and this was enhanced by an OGA null mutant which elevated O-GlcNAc [3], and inhibited by an OGT null mutant which reduced O-GlcNAc levels [5]. Those results suggested that O-GlcNAc negatively regulates insulin-like signaling in the context of dauer formation. This is reminiscent of the model in which increased hexosamine flux and elevated O-GlcNAc are Commentary linked to type II diabetic insulin resistance (reduced insulin signaling) in mammals. Similar regulation of entry into the dauer state induced by a synthetic pheromone called daumone was observed in C. elegans with OGT and OGA inactivating mutant alleles [6]. Additionally, C. elegans OGA mutants display macro-nutrient storage phenotypes that parallel those of mammalian diabetic states [3]. In this issue, Rahman et al. [11] extend genetic studies of OGT and OGA inactivation in C. elegans to provide important information about specificity of O-GlcNAc regulation of insulin-like phenotypes and the steps in insulin-like signaling that are regulated by O-GlcNAc. Attenuation of insulin-like signaling extends lifespan in C. elegans. Rahman et al. find that OGA inactivating mutants increase life span, while OGT inactivating mutants decrease life span. Similar observations were previously reported [7] and will be discussed in more detail below. The genetic studies of O-GlcNAc cycling linked to longevity indicate elevation of O-GlcNAc inhibits, …