N-Glycomic Changes in Serum Proteins in Type 2 Diabetes Mellitus Correlate with Complications and with Metabolic Syndrome Parameters

Abstract

BackgroundGlycosylation, i.e the enzymatic addition of oligosaccharides (or glycans) to proteins and lipids, known as glycosylation, is one of the most common co-/posttranslational modifications of proteins. Many important biological roles of glycoproteins are modulated by N-linked oligosaccharides. As glucose levels can affect the pathways leading to glycosylation of proteins, we investigated whether metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM), pathological conditions characterized by altered glucose levels, are associated with specific modifications in serum N-glycome.MethodsWe enrolled in the study 562 patients with Type 2 Diabetes Mellitus (T2DM) (mean age 65.6±8.2 years) and 599 healthy control subjects (CTRs) (mean age, 58.5±12.4 years). N-glycome was evaluated in serum glycoproteins.ResultsWe found significant changes in N-glycan composition in the sera of T2DM patients. In particular, α(1,6)-linked arm monogalactosylated, core-fucosylated diantennary N-glycans (NG1(6)A2F) were significantly reduced in T2DM compared with CTR subjects. Importantly, they were equally reduced in diabetic patients with and without complications (P<0.001) compared with CTRs. Macro vascular-complications were found to be related with decreased levels of NG1(6)A2F. In addition, NG1(6)A2F and NG1(3)A2F, identifying, respectively, monogalactosylated N-glycans with α(1,6)- and α(1,3)-antennary galactosylation, resulted strongly correlated with most MS parameters. The plasmatic levels of these two glycans were lower in T2DM as compared to healthy controls, and even lower in patients with complications and MS, that is the extreme “unhealthy” phenotype (T2DM+ with MS).ConclusionsImbalance of glycosyltransferases, glycosidases and sugar nucleotide donor levels is able to cause the structural changes evidenced by our findings. Serum N-glycan profiles are thus sensitive to the presence of diabetes and MS. Serum N-glycan levels could therefore provide a non-invasive alternative marker for T2DM and MS.

Increased plasma N-glycome complexity is associated with higher risk of type 2 diabetes

“…Their great variability within populations and the significant heritability rate gives them great potential in risk assessments. Changes in the glycosylation of plasma proteins have been studied in many different diseases, including type 2 diabetes mellitus [8]. These changes have been confirmed in both individuals with diabetes and db/db mice [9,10].…”

Influence of diabetes on natriuretic peptide thresholds in screening for Stage B heart failure

“…It has been suggested recently that under normal conditions proBNP is glycosylated as mechanism to limit its processing to functional BNP, and during heart failure the degree of proBNP glycosylation is reduced which results in an increase in proBNP processing to active BNP (Vodovar et al, 2014). In the context of diabetes it has been shown that serum and tissue glycosylation signatures differ compared with non-diabetic profiles (Testa et al, 2015, Ravida et al, 2015. Therefore a possible link may exist between glycosylation mediated reduction in circulating BNP in diabetics compared with non-diabetics in a Stage B heart failure population, a concept that would warrant investigation.…”

N‐glycome signatures in human plasma: associations with physiology and major diseases

“…and Testa et al . showed somewhat contradictory results on changes of two different core‐fucosylated diantennary glycan species. Although both studies were similar with regard to the detection of glycan species after desialylation, the low resolution of both techniques bearing the risk of overlapping peaks and the low sample size used in Itoh et al .…”