3.1.2 Research progress of N-Glycomics in diabetic patients
Type 1 diabetes mellitus (T1DM): Bermingham et al. retrospectively selected 818 T1DM patients with a large annual loss of glomerular filtration rate, and analyzed the relationship between the relative abundance of 39 serum N-glycans and diabetes-related clinical indicators. It was found that with the increase of glycated hemoglobin A1c (HbA1c), the relative abundance of simple diantennary N-glycan (NA2) gradually decreased. The relative abundance of complex multi-branched, galactosylated and sialylated N-glycans gradually increased, and the corresponding N-glycan levels also changed significantly with the decrease of blood glucose levels after treatment, and returned to healthy controls[40-42]. Another study found that multi-branched N-glycans are closely related to the occurrence of autoimmune diseases, which may be related to the pathogenesis of T1DM[43, 44]. Rudman et al. analyzed the serum N-glycans of 1917 children and adolescents with T1DM from DanDiabKids (Denmark), and found that the relative abundance of galactosylated N-glycans in serum decreased significantly, and the proportion of bisecting N-acetyl-D-(+)-glucosamine (GlcNAc) and high mannose structure increased significantly. A logistic regression model was established using serum N-glycans to identify children with T1DM. The area under the receiver operating characteristic curve (AUC) was 0.915. The model is helpful to identify high-risk individuals of T1DM at an early stage, and then prevent the progression of T1DM through timely intervention, which has certain clinical practical value[45, 46].
In addition, studies have found that a variety of sugar synthesis-related genes are associated with the pathogenesis of T1DM.For example, the fucosyltransferase 2 gene has been identified as a T1DM pathogenic gene[47]. Different levels of gene expression lead to the differentiation of glycan synthesis process, which is manifested as the change of glycan structure or quantity. It can be seen that the change of N-glycan is closely related to the occurrence of T1DM, and the purpose of early warning or auxiliary diagnosis of T1DM can be achieved by detecting the change of serum N-glycan profile. It is expected that more and more in-depth research in the future can explore the potential clinical application value of N-glycan profile in diabetes.
Type 2 diabetes mellitus (T2DM): Dotz et al. analyzed the serum N-glycan profiles of 1583 T2DM patients and 728 healthy controls, and found that 18 N-glycans and derived traits were closely related to T2DM, among which the change of sialylation modification was the most prominent. The degree of overall sialic acid modification in the T2DM group was higher than that in the control group. The double-antenna α2,6-linked sialic acid-modified N-glycan increased, while the three-antenna α2,3-linked sialic acid-modified N-glycan decreased.
In addition, the proportion of fucosylation and flat typing in dual-antenna N-glycans also decreased. Keser et al. conducted a glycomics study on a 10-year follow-up cohort (FinRisk cohort) from Finland, and found that individuals with T2DM had a decrease in low-branched N-glycans, an increase in multi-branched N-glycans, and an increase in galactose and sialylated N-glycans. The overall performance is an increase in the structural complexity of N-glycans. Similar trends were observed in T2DM high-risk populations and populations with elevated HbA1c, indicating that the increased complexity of N-glycans is closely related to the development of T2DM and poor blood glucose control[48-50].
Testa et al. found that the relative abundance of α1,6/3-linked monogalactosylated core fucosylated double-antenna N-glycans in the T2DM group was significantly lower than that in the healthy control group, while digalactosylated NA2 was significantly increased. The changes of α1,3-linked monogalactosylated core fucosylated double-antenna N-glycans and NA2 were more significant in T2DM patients with complications. The former was considered to be closely related to diabetic macroangiopathy[41-43]. Similar to the results of T1DM-related studies, the changes of N-glycans in the serum of T2DM patients are generally characterized by increased branching and modification[51], but the changes of NA2 are more complex[52]. The proportion of fucosylation modification is reduced, and the proportion of modified N-glycans such as galactose and sialic acid is also quite different. In summary, serum N-glycans in patients with T2DM have changed to a certain extent, and N-glycans may become biomarkers for early diagnosis of T2DM and complications[53], but further research is still needed.