Abstract
BACKGROUND: Reliable biomarkers capturing immunometabolic processes in insulin resistance (IR) remain limited. IgG N-glycosylation modulates immune responses and reflects metabolic disorders, yet its role in IR remains unclear. This study investigated its potential for early detection, risk stratification, and targeted prevention within the framework of predictive, preventive, and personalised medicine (PPPM/3PM). METHODS: A total of 313 participants were categorized into three groups based on the homeostatic model assessment for insulin resistance (HOMA-IR): insulin-sensitive (HOMA-IR < 2.69 without diabetes, n = 75), mild IR (HOMA-IR ≥ 2.69 without diabetes, n = 155), and severe IR (HOMA-IR ≥ 2.69 with type 2 diabetes, n = 83). Canonical correlation analysis was conducted to explore the overall relationship between IgG N-glycosylation and IR-related inflammation, indicated by tumour necrosis factor-α, interleukin- 6, C-reactive protein, and adiponectin. Mediation analysis was performed to evaluate the effect of IgG N-glycans on IR. Ordinal logistic regression was used to assess the association between IgG N-glycans and IR severity, with discriminative power evaluated using receiver operating characteristic curves. RESULTS: Pro-inflammatory IgG N-glycoforms, characterized by reduced sialylation and galactosylation, along with increased bisecting N-acetylglucosamine, were observed as IR severity increased. IgG N-glycosylation significantly correlated with inflammatory markers in the insulin-sensitive (r = 0.599, p < 0.05), mild (r = 0.461, p < 0.05), and severe (r = 0.666, p < 0.01) IR groups. IgG N-glycosylation significantly influenced IR (β = 0.406) partially via modulation of inflammation. Increased glycoforms FA2[6]G1 (OR: 0.86, 95% CI: 0.78-0.96) and A2G2S2 (OR: 0.88, 95% CI: 0.82-0.94) were associated with a lower IR risk, with respective area under the curves (AUCs) of 0.752, 0.683, and 0.764 for the insulin sensitive, mild, and severe IR groups. CONCLUSIONS: IgG N-glycosylation contributes to IR by modulating inflammatory responses. Glycoforms FA2[6]G1 and A2G2S2 emerge as protective biomarkers, offering potential for predicting and preventing IR through primary prevention strategies within the PPPM framework. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-025-00410-x.