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 β-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-α. We examined the functional link between circulating TNF-α and the activity and phosphorylation of core 2 GlcNAc-T in polymorphonuclear leucocytes of patients with type 1 and type 2 diabetes. Plasma levels of TNF-α, 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-α 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-α-induced protein kinase β2 activation, and subsequently raise activity of core 2 GlcNAc-T through increased enzyme phosphorylation. 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.
Clinical validation of a link between TNF-α and the glycosylation enzyme Core 2 GlcNAc-T and the relationship of this link to diabetic retinopathy
DATTI, Alessandro;ORLACCHIO, Aldo;
2006
Abstract
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 β-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-α. We examined the functional link between circulating TNF-α and the activity and phosphorylation of core 2 GlcNAc-T in polymorphonuclear leucocytes of patients with type 1 and type 2 diabetes. Plasma levels of TNF-α, 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-α 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-α-induced protein kinase β2 activation, and subsequently raise activity of core 2 GlcNAc-T through increased enzyme phosphorylation. 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.