title: The role of O-linked protein glycosylation in beta-cell dysfunction.
abstract: Although only recently described, the pathway of O-linked protein glycosylation is already being implicated in diseases as diverse as cancer and Alzheimer's. Unlike the better known N-linked pathway, O-linked protein glycosylation is a dynamic and regulated event, much like tyrosine phosphorylation. During the process of O-glycosylation, the enzyme O-GlcNAc transferase (OGT) uses the substrate UDP-N-acetylglucosamine (UDP-GlcNAc) to attach a single O-linked N-acetylglucosamine (O-GlcNAc) to nuclear and cytosolic proteins on serine or threonine residues. Conversely, the enzyme O-GlcNAc-selective N-acetyl-beta-D-glucosaminidase (O-GlcNAcase) removes the O-GlcNAc, returning the protein to its baseline state until the cycle repeats itself. Although proving to be of interest in many different tissues, this pathway is especially important in pancreatic beta-cells. The beta-cell is unique in containing much more OGT than any other cell type. This enables beta-cells to respond to physiological increases in the glucose concentration by converting glucose to the OGT substrate UDP-GlcNAc, thereby dynamically coupling intracellular O-linked protein glycosylation to the extracellular glucose concentration. As a result, the beta-cell also appears to be especially susceptible to disruption of the O-glycosylation pathway. The diabetogenic agent streptozotocin (STZ), a UDP-GlcNAc analogue, causes beta-cell toxicity by irreversibly inhibiting O-GlcNAcase, while the diabetogenic agent alloxan (ALX), also a UDP-GlcNAc analog irreversibly inhibits OGT. This review will summarize what is currently known about beta-cell O-glycosylation and expand upon historical observations of chemically-induced beta-cell toxicity in animals to develop a model suggesting how beta-cell O-glycosylation is also involved in the development and progression of type 2 diabetes in humans.
authors.affiliation: Department of Diagnostic and Experimental Medicine, Eli Lilly and Company, Indianapolis, IN 46285, USA. konrad_robert@lilly.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Konrad
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Kudlow
mesh_terms: D000496:Alloxan / Q000633:toxicity; D000818:Animals; D003920:Diabetes Mellitus / Q000209:etiology / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D013311:Streptozocin / Q000633:toxicity
chemical_list: D006023:Glycoproteins; D013311:Streptozocin; D000496:Alloxan