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.
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.
Ben-Mahmud
B M
BM
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.
Chan
W H
WH
Abdulahad
R M
RM
Datti
A
A
Orlacchio
A
A
Kohner
E M
EM
Chibber
R
R
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*
D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D017351:N-Acetylglucosaminyltransferases