Development of anti-diabetic agents based on investigating the mechanism of the onset of type 2 diabetes due to protein glycosilation

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There are many nonle.ar and cytoplasmic proteins that are modified by a single O-linked N-acetylglucosamine (O-GlcNAc) moiety at serine or threonine residues. We proposed that this O-GlcNAc modification (tanned O-GlcNAcylation) is a regulatory modification, analogous to phosphorylation, that is, capping of the potential phosphorylation sites. O-GlcNAc transferase (OGT) is an enzyme responsible for O-GlcNAcylation of proteins. The hexosmine biosynthesis pathway plays an important part in the induction of insulin resistance. In this pathway, glutamine: fructose-6-phosphate amidotransferase (GFAT) has an integral role in the development of insulin resistance. The OGT enzyme uses cytoplasmic uridine diphospho-N-acetylglucosamine (UDP-GlcNAc), which is synthesized in the hexosamine biosynthetic pathway. Animals with diabetes and hyperglycaemia show greatly increased concentrations of hexosamine metabolites including UDP-GlcNAc. This increase in hexosamine biosynthesis could stimulate OGT activity, including O-GlcNAc modification of proteins that are involved in the glucose transport system or in granule secretion. Therefore, it is likely that the effects of hyperglycaemia result from abnormal O-GlcNAcylation. In this study, the effects of metal complexes such as vanadium, zinc, and manganese on the inhibition of OGT activity and on O-GlcNAcylation were investigated in the streptozotocin (STZ)-induced diabetic mice and 3T3-L1 cell lines. As a result, vanadyl-maltolate related complexes were exhibited to suppress the O-GlcNAcylation of proteins in organs of STZ-mice. In addition, zinc compounds were hind to stimulate the de-GlcNAcylation of proteins in the cultured 3T3-L1 cells, without inhibiting the OGT activity, indicating that zinc compounds may enhance the activity of O-GlcNAcase, an degradating enzyme of O-GlcNAcylated proteins.