Author Identifier

Xiaohong Chen: https://orcid.org/0000-0003-1476-4020

Date of Award

2025

Document Type

Thesis - ECU Access Only

Publisher

Edith Cowan University

Degree Name

Doctor of Philosophy

School

School of Medical and Health Sciences

First Supervisor

Wei Wang

Second Supervisor

Lois Balmer

Third Supervisor

Manshu Song

Fourth Supervisor

Yongsong Chen

Abstract

Background. Insulin resistance, a fundamental pathophysiological feature of metabolic disorders, is primarily driven by adipose tissue inflammation. However, reliable biomarkers capturing the underlying immunometabolic processes remain limited. IgG N-glycosylation regulates inflammatory responses and has been implicated in metabolic diseases, yet its specific role in insulin resistance requires further investigation. This PhD aimed to identify the role of IgG N-glycosylation in insulin resistance and its associated inflammatory processes.

Methods. IgG N-glycosylation profiles were analysed in 313 human participants 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 insulin resistance (HOMA-IR ≥ 2.69 without diabetes, n = 155), and severe insulin resistance (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 insulin resistance-related inflammatory markers, including tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), and adiponectin. Mediation analysis was performed to evaluate the contribution of IgG N-glycans to insulin resistance via inflammation. Ordinal logistic regression was used to assess the association between IgG N-glycans and insulin resistance severity, with discriminative power evaluated using receiver operating characteristic curves. To validate the dynamic changes in IgG N-glycosylation and its mechanistic role during insulin resistance progression, a longitudinal observational study was conducted in insulin-resistant rat models. Both group-specific and time-specific alterations in IgG N-glycosylation profiles were analysed using a linear mixed-effects model. To further investigate potential mechanisms, adipose tissue inflammation was evaluated through macrophage infiltration and inflammatory markers (TNF-α, IL-6, CRP, and adiponectin), while insulin signalling in adipocytes was assessed via the expression of the insulin receptor, insulin receptor substrate-1 (IRS-1), and glucose transporter-4 (GLUT4).

Results. Pro-inflammatory IgG N-glycoforms, characterized by reduced sialylation and galactosylation, along with increased bisecting N-acetylglucosamine, were observed as insulin resistance severity increased in humans. Significant correlations between human IgG N-glycans and inflammatory markers were observed across the insulin-sensitive (r = 0.599, p < 0.05), mild insulin resistance (r = 0.461, p < 0.05), and severe insulin resistance (r = 0.666, p < 0.01) groups. Human IgG N-glycosylation significantly influenced insulin resistance (β = 0.406, p < 0.001), partially via modulating inflammatory markers. 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 insulin resistance risk in humans, with respective area under the curves (AUCs) of 0.752, 0.683, and 0.764 for the insulin-sensitive, mild insulin resistance, and severe insulin resistance groups. These findings were mirrored in insulin-resistant rat models, where stage-specific changes in IgG N-glycosylation were observed during insulin resistance progression: an initial increase in galactosylated and sialylated glycans (anti-inflammatory) during early glucose impairment, followed by a transition toward reduced galactosylation and sialylation (pro-inflammatory) at later stages. These changes coincided with enhanced adipose tissue inflammation, as evidenced by increased macrophage infiltration, elevated TNF-α, IL-6, and CRP, and reduced adiponectin. Additionally, impaired insulin signalling was observed in adipocytes, characterized by decreased expression of the insulin receptor, IRS-1, and GLUT-4.

Conclusion. IgG N-glycosylation contributes to insulin resistance by modulating inflammatory responses and undergoes dynamic, stage-specific alterations during insulin resistance development, serving as an immunometabolic modulator. Pro-inflammatory IgG N-glycoforms are associated with adipose tissue inflammation and may play a critical role in initiating insulin resistance. Glycoforms FA2[6]G1 and A2G2S2 emerge as protective biomarkers, offering potential for predicting and preventing insulin resistance.

Comments

Author also known as Sharon Chen

DOI

10.25958/b41k-rc63

Access Note

Access to this thesis is embargoed until 7th August 2030

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Available for download on Wednesday, August 07, 2030

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