Type 2 Diabetes Mellitus is Associated with the Immunoglobulin G N-Glycome through Putative Proinflammatory Mechanisms in an Australian Population

Abstract

Type 2 diabetes mellitus (T2DM) is a common complex trait arising from interactions among multiple environmental, genomic, and postgenomic factors. We report here the first attempt to investigate the association between immunoglobulin G (IgG) N-glycan patterns, T2DM, and their clinical risk factors in an Australian population. N-glycosylation of proteins is one of the most frequently observed co-and posttranslational modifications, reflecting, importantly, the real-time status of the interplay between the genomic and postgenomic factors. In a community-based case-control study, 849 participants (217 cases and 632 controls) were recruited from an urban community in Busselton, Western Australia. We applied the ultraperformance liquid chromatography method to analyze the composition of IgG N-glycans. We then conducted Spearman's correlation analyses to explore the association between glycan biomarker candidates and clinical risk factors. We performed area under the curve (AUC) analysis of the receiver operating characteristic curves by fivefold cross-validation for clinical risk factors, IgG glycans, and their combination. Two directly measured and four derived glycan peaks were significantly associated with T2DM, after correction for extensive clinical confounders and false discovery rate, thus suggesting that IgG N-glycan traits are highly correlated with T2DM clinical risk factors. Moreover, adding the IgG glycan profiles to fasting blood glucose in the logistic regression model increased the AUC from 0.799 to 0.859. The AUC for IgG glycans alone was 0.623 with a 95% confidence interval 0.580-0.666. In addition, our study provided new evidence of diversity in T2DM complex trait by IgG N-glycan stratification. Six IgG glycan traits were firmly associated with T2DM, which reflects an increased proinflammatory and biological aging status. In summary, our study reports novel associations between the IgG N-glycome and T2DM in an Australian population and the putative role of proinflammatory mechanisms. Furthermore, IgG N-glycomic alterations offer future prospects as inflammatory biomarker candidates for T2DM diagnosis, and monitoring of T2DM progression to cardiovascular disease or renal failure.

Glycosylation Biomarkers Associated with Age-Related Diseases and Current Methods for Glycan Analysis

“…Furthermore, protein-glycan interactions are also known to play a role in many processes affecting disease progression [ 5 ]. For instance, aberrant glycosylation is often present in patients with cancer [ 6 , 7 ], diabetes and inflammation [ 8 , 9 ].…”

“…Diseases are also driven by many diverse factors, including genetic variants, epigenetic dysregulation and environmental influences. Glycosylation, among other post-translational modifications (PTMs), can reflect the real-time status of these complex interactions and can provide potential diagnostic and prognostic biomarkers for multifactorial diseases [ 8 , 10 ]. Glycosylation is known to be altered in the process of ageing.…”

Associations between plasma protein, IgG and IgA N-glycosylation and metabolic health markers in pregnancy and gestational diabetes

“…Our data revealed that metabolic parameters related to insulin levels and insulin resistance signi cantly associate with two distinct N-glycan structures -FA2B and A2G2S2. Herein, the FA2B structure negatively associates with insulin levels, but the same structure has been previously found to be increased in type 2 diabetes [30,31]. This might be attributed to the fact that type 2 diabetes pathogenesis, apart from insulin resistance, also involves defects of insulin-producing β-cells, responsible for decreased insulin production and secretion.…”

Variation of IgG N‐linked glycosylation profile in diabetic retinopathy

“…The results above were largely in consistent with previous studies of IgG glycosylation profiles in type 2 diabetes and its related factors. Previous studies have reported that complex glycan structures with bisecting GlcNAc were highly associated with some inflammatory diseases, reflecting a body status of pro-inflammation [11,27]. IgG proteins were sensitive to biological inflammatory stress and the variation of IgG glycans could reverse its anti-inflammation function [28,29].…”