Plasma N-glycome shows continuous deterioration as the diagnosis of insulin resistance approaches

Abstract

IntroductionPrediction of type 2 diabetes mellitus (T2DM) and its preceding factors, such as insulin resistance (IR), is of great importance as it may allow delay or prevention of onset of the disease. Plasma protein N-glycome has emerged as a promising predictive biomarker. In a prospective longitudinal study, we included patients with a first diagnosis of impaired glucose metabolism (IR or T2DM) to investigate the N-glycosylation’s predictive value years before diabetes development.Research design and methodsPlasma protein N-glycome was profiled by hydrophilic interaction ultra-performance liquid chromatography in 534 TwinsUK participants free from disease at baseline. This included 89 participants with incident diagnosis of IR or T2DM during the follow-up period (7.14±3.04 years) whose last sample prior to diagnosis was compared using general linear regression with 445 age-matched unrelated controls. Findings were replicated in an independent cohort. Changes in N-glycome have also been presented in connection with time to diagnosis.ResultsEight groups of plasma N-glycans were different between incident IR or T2DM cases and controls (p<0.05) after adjusting for multiple testing using Benjamini-Hochberg correction. These differences were noticeable up to 10 years prior to diagnosis and are changing continuously as becoming more expressed toward the diagnosis. The prediction model was built using significant glycan traits, displaying a discriminative performance with an area under the receiver operating characteristic curve of 0.77.ConclusionsIn addition to previous studies, we showed the diagnostic potential of plasma N-glycome in the prediction of both IR and T2DM development years before the clinical manifestation and indicated the continuous deterioration of N-glycome toward the diagnosis.

Multi-block data integration analysis for identifying and validating targeted N-glycans as biomarkers for type II diabetes mellitus

“…Thus, we explored the N-glycan traits whose expression were different in cases and controls. The present study validates that of Cvetko et al 36 and Clemens et al 35 , we identified GPs 34, 32, 26, 31, 36 and 30 to be highly expressed in T2DM in the first principal axis and on the second principal axis, GPs 38, 1, 2, 25 and 20 were dominant in T2DM. Sialylated glycans (GP26, GP32, GP35 and GP36) are expressed on a1-acid glycoprotein, whereas GP18 and GP20 originates from glycoproteins a-antitrypsin.…”

“…First, the GST2D score was used to predict T2DM development 6–8 years before clinical manifestation 35 . In another study, Cvetko et al 36 reported that individuals who were healthy at baseline but developed insulin resistance and T2DM over time, were characterised by complex and highly branched N-glycan structures. Specifically, the study identified alterations in eight N-glycans: GP10, GP16, GP18, GP19, GP20, GP26, GP32 and GP34 36 ; with GP 32 and GP34 being the most significant in the continuum of insulin resistance and T2DM.…”

“…In another study, Cvetko et al 36 reported that individuals who were healthy at baseline but developed insulin resistance and T2DM over time, were characterised by complex and highly branched N-glycan structures. Specifically, the study identified alterations in eight N-glycans: GP10, GP16, GP18, GP19, GP20, GP26, GP32 and GP34 36 ; with GP 32 and GP34 being the most significant in the continuum of insulin resistance and T2DM. Increasing evidence shows that T2DM patients can be distinguished from healthy individuals depending on the composition of their respective total N-glycome 5 , 18 .…”

Comparison of self-sampling blood collection for N-glycosylation analysis

“…Many studies have investigated glycan changes in various disorders, such as inflammation, aging, cancer, autoimmune diseases [ 9 – 11 ]. Studies have reported glycans as very responsive to mentioned conditions, sometimes even years before its onset [ 12 , 13 ], making glycans powerful potential biomarkers.…”

In a pursuit of optimal glycan fluorescent label for negative MS mode for high-throughput N-glycan analysis

“…Besides serving constructive, storing, or protective roles, with evolution, glycans became increasingly more complex and began to acquire other functional roles crucial for complex organisms ( Lauc et al, 2014 ). Improper glycosylation underlies many diseases ( Freeze, 2006 ) and some glycans may be used as novel predictive or diagnostic biomarkers for some of them ( Cvetko et al, 2021 ). Therefore, it is important to include high-throughput glycan analysis in different studies to have a complete picture of what is happening.…”