N-Glycan Profile and Kidney Disease in Type 1 Diabetes

Abstract

Higher HbA in type 1 diabetes is associated with changes in the serum N-glycome that have elsewhere been shown to regulate the epidermal growth factor receptor and transforming growth factor-β pathways that are implicated in DKD. Furthermore, N-glycans are associated with ACR and eGFR slope. These data suggest that the role of altered N-glycans in DKD warrants further investigation.

Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

“…A majority of studies in this area focused on UDP-GlcNAc stimulation of O-glycosylation (O-glycosidic linkage between glycan and an amino acid containing a hydroxyl group [77]) when discussing the possible mechanism of diabetic complications as a consequence of increased flux through HBP [78,79]. In a recent study, we have demonstrated that serum N-glycan alterations are associated with diabetic kidney disease [40], which is further discussed below. Taken together, there is accumulating evidence for the role of HBP in both diabetes onset and diabetes complications.…”

“…However, under conditions of hyperglycaemia the percentage of total glucose utilized through the HBP could be enhanced, leading to increased levels of the major product of the HBP, uridine diphosphate N ‐acetylglucosamine (UDP‐GlcNAc). This was proposed as one of the mechanisms for the observed increase in plasma levels of the highly branched N‐glycan structures in type 1 diabetes patients, type 2 diabetes patients and even healthy people at the increased risk of developing diabetes in the future .…”

“…In a recent study we investigated serum N‐glycosylation changes in adult type 1 diabetes patients with kidney disease and demonstrated that N‐glycan profile of both total serum proteins and of IgG is altered . The most important observation was increase in complex N‐glycans (highly branched, triantennary and tetra‐antennary structures) and decrease in simpler biantennary N‐glycans among total serum proteins that was correlated with higher HbA1c, higher albumin‐to‐creatinine ratio (ACR) and steeper decline in estimated glomerular filtration rate (eGFR); reflecting poorer glycaemic control and renal function . The most complex IgG N‐glycan is a biantennary N‐glycan , however, again, an increase in more complex (more galactosylated and sialylated biantennary structures) and a decrease in simpler (monogalactosylated biantennary glycans) N‐glycans was observed, and correlated with higher HbA1c, higher ACR and greater mean annual decline in eGFR .…”

“…However, under conditions of hyperglycaemia the percentage of total glucose utilized through the HBP could be enhanced, leading to increased levels of the major product of the HBP, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). This was proposed as one of the mechanisms for the observed increase in plasma levels of the highly branched N-glycan structures in type 1 diabetes patients, type 2 diabetes patients and even healthy people at the increased risk of developing diabetes in the future [39,40,58]. Uridine diphosphate N-acetylglucosamine, a nucleotide-activated sugar, serves as a substrate for different glycosyltransferases in the process of eukaryotic protein N-glycosylation, which occurs when a block of 14 sugars is relocated cotranslationally to specific asparagine residues in the endoplasmic reticulum [32].…”

MetaLab 2.0 enables accurate post-translational modifications profiling in metaproteomics

“…The alterations of glycosylation could affect the immune system of mammals 37 . The relationship between abnormal glycosylation and the pathogenesis of diabetes has also been reported 38 . In this dataset, decreases in the abundance of HexNAc modified peptides were detected in NO patients compared to CO subjects (p=0.048 by a two-sample, two-tailed t-test) (Figure 6b).…”