Type II diabetes mellitus (T2DM) is a major health concern, affecting over 20 million Americans. MGEA5 has been identified as a susceptibility locus for the disease in the Mexican-American population (Lehman et al. 2005). The gene encoded by the MGEA5 locus is OGA-1, a glucosaminidase that removes the post-translational O-GlcNAc (O-linked N-acetyl glucosamine) modification from serine and threonine residues on over 500 proteins in the cell. The action of OGA-1 counteracts the action of OGT-1, the O-GlcNAc transferase. UDP-GlcNAc pools are regulated in part by glucose levels and thus these proteins may act as cellular nutrient sensors. In addition to the human genetic link to T2DM, transgenic mice that overexpress OGT in muscle develop insulin resistance (McClain et al. 2002), as do cells in culture treated with an inhibitor of OGA (Vosseller et al. 2002). Unlike post-translational phosphate modifications on serines and threonines, which are regulated by hundreds of phosphatases and kinases, there is only a single OGA enzyme and a single OGT enzyme in animals, so it is not surprising that both these genes are essential in mammals. However, although both proteins are highly conserved in the nematode C. elegans (63% and 88% identity), knockouts of
oga-1 and
ogt-1 are viable, making it a good model system to study the mechanism of O-GlcNAc modification and its effect on insulin resistance and nutrient signaling. Previous work in our laboratory (Forsythe et al. 2006) demonstrated that in a
daf-2 (
e1370) mutant background, the absence of OGT-1 results in fewer dauers, indicating that these worms are insulin hypersensitive. The absence of OGA-1 in this background leads to more dauers, modeling insulin resistance. We are currently investigating how OGT-1 and OGA-1 interact with the insulin pathway. The
oga-1 and
ogt-1 mutants are viable and have no obvious phenotypes, so we are also currently testing phenotypes that could be used in a screen. One potential assay would exploit the role of glucose in this pathway.
ogt-1 (
ok430) mutants are sensitive to glucose (DC Love and JA Hanover, unpublished results); these worms have shorter lifespans and smaller brood sizes compared to wild type when challenged with glucose. We have recently obtained a new allele,
ogt-1 (
ok1474) and find that this glucose sensitivity phenotype is not allele-specific and that brood size decreases as glucose concentration increases.