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

Diabetologia. 2006 Sep;49(9):2185-91. doi: 10.1007/s00125-006-0332-2. Epub 2006 Jul 11.


Aims/hypothesis: 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.

Subjects, materials and 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/interpretation: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • C-Reactive Protein / metabolism
  • Cell Adhesion
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 2 / blood
  • Diabetic Retinopathy / blood
  • Diabetic Retinopathy / enzymology*
  • Diabetic Retinopathy / pathology
  • Female
  • Glycosylation
  • Humans
  • Immunoprecipitation
  • Male
  • Middle Aged
  • N-Acetylglucosaminyltransferases / metabolism*
  • Neutrophils / cytology
  • Neutrophils / metabolism
  • Phosphorylation
  • Tumor Necrosis Factor-alpha / blood*


  • Tumor Necrosis Factor-alpha
  • C-Reactive Protein
  • N-Acetylglucosaminyltransferases