title: Clinical validation of a link between TNF-alpha and the glycosylation enzyme core 2 GlcNAc-T and the relationship of this link to diabetic retinopathy.
abstract: OBJECTIVE
  Increasing evidence suggests that chronic, subclinical inflammation plays an important role in the pathogenesis of diabetic retinopathy. We recently reported that a glycosylating enzyme, core 2 beta-1,6-N-acetylglucosaminyltransferase (core 2 GlcNAc-T), is implicated in increased leucocyte-endothelial cell adhesion in diabetic retinopathy via an upregulation mechanism controlled by TNF-alpha.
  
  
  METHODS
  We examined the functional link between circulating TNF-alpha and the activity and phosphorylation of core 2 GlcNAc-T in polymorphonuclear leucocytes of patients with type 1 and type 2 diabetes.
  
  
  RESULTS
  Plasma levels of TNF-alpha, although similar in patients with type 1 and type 2 diabetes, were significantly higher than in age-matched healthy controls, and correlated well with the severity of retinopathy. Core 2 GlcNAc-T activity followed the same trend and was associated with phosphorylation of the enzyme. Finally, the observation that TNF-alpha levels are also linked to glycaemic values suggests that in patients, as well as in vitro, the glycosylation-mediated cell adhesion process that plays a role in diabetic retinopathy may involve glucose- and TNF-alpha-induced protein kinase beta2 activation, and subsequently raise activity of core 2 GlcNAc-T through increased enzyme phosphorylation.
  
  
  CONCLUSIONS
  Our results reveal a novel rationale towards a specific treatment of diabetic retinopathy, based on the inhibition of core 2 GlcNAc-T activity and/or the blockage of cognate glycans.
authors.affiliation: Cardiovascular Division, 2nd Floor, New Hunt's House, GKT School of Biomedical and Health Sciences, Guy's Campus, King's College London, London, SE1 1UL, UK.
authors.forename: B M
authors.initials: BM
authors.lastname: Ben-Mahmud
authors.forename: W H
authors.initials: WH
authors.lastname: Chan
authors.forename: R M
authors.initials: RM
authors.lastname: Abdulahad
authors.forename: A
authors.initials: A
authors.lastname: Datti
authors.forename: A
authors.initials: A
authors.lastname: Orlacchio
authors.forename: E M
authors.initials: EM
authors.lastname: Kohner
authors.forename: R
authors.initials: R
authors.lastname: Chibber
mesh_terms: D015153:Blotting, Western; D002097:C-Reactive Protein / Q000378:metabolism; D002448:Cell Adhesion; D003922:Diabetes Mellitus, Type 1 / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D003930:Diabetic Retinopathy / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006031:Glycosylation; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008875:Middle Aged; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D017351:N-Acetylglucosaminyltransferases