Author(s): BenMahmud BM, Chan WH, Abdulahad RM, Datti A, Orlacchio A,
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Abstract 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.
This article was published in Diabetologia
and referenced in Journal of Clinical & Cellular Immunology