Association of IgG N-glycomics with prevalent and incident type 2 diabetes mellitus from the paradigm of predictive, preventive, and personalized medicine standpoint

Objectives Type 2 diabetes mellitus (T2DM), a major metabolic disorder, is expanding at a rapidly rising worldwide prevalence and has emerged as one of the most common chronic diseases. Suboptimal health status (SHS) is considered a reversible intermediate state between health and diagnosable disease. We hypothesized that the time frame between the onset of SHS and the clinical manifestation of T2DM is the operational area for the application of reliable risk assessment tools, such as immunoglobulin G (IgG) N-glycans. From the viewpoint of predictive, preventive, and personalized medicine (PPPM/3PM), the early detection of SHS and dynamic monitoring by glycan biomarkers could provide a window of opportunity for targeted prevention and personalized treatment of T2DM. Methods Case-control and nested case-control studies were performed and consisted of 138 and 308 participants, respectively. The IgG N-glycan profiles of all plasma samples were detected by an ultra-performance liquid chromatography instrument. Results After adjustment for confounders, 22, five, and three IgG N-glycan traits were significantly associated with T2DM in the case-control setting, baseline SHS, and baseline optimal health participants from the nested case-control setting, respectively. Adding the IgG N-glycans to the clinical trait models, the average area under the receiver operating characteristic curves (AUCs) of the combined models based on repeated 400 times fivefold cross-validation differentiating T2DM from healthy individuals were 0.807 in the case-control setting and 0.563, 0.645, and 0.604 in the pooled samples, baseline SHS, and baseline optimal health samples of nested case-control setting, respectively, which presented moderate discriminative ability and were generally better than models with either glycans or clinical features alone. Conclusions This study comprehensively illustrated that the observed altered IgG N-glycosylation, i.e., decreased galactosylation and fucosylation/sialylation without bisecting GlcNAc, as well as increased galactosylation and fucosylation/sialylation with bisecting GlcNAc, reflects a pro-inflammatory state of T2DM. SHS is an important window period of early intervention for individuals at risk for T2DM; glycomic biosignatures as dynamic biomarkers have the ability to identify populations at risk for T2DM early, and the combination of evidence could provide suggestive ideas and valuable insight for the PPPM of T2DM.