High-Throughput Human Complement C3 N-Glycoprofiling Identifies Markers of Early Onset Type 1 Diabetes Mellitus in...

Area of Science:

• Biochemistry
• Immunology
• Metabolomics

Background:

• Children with new-onset type 1 diabetes (T1D) exhibit elevated oligomannose glycans in plasma proteins.
• The complement component C3, a major plasma protein, is exclusively glycosylated with oligomannose structures and has been linked to T1D.
• Glycosylation changes can influence inflammatory responses, prompting investigation into C3 glycosylation in T1D.

Purpose of the Study:

• To characterize the N-glycosylation profile of C3 in children with T1D compared to healthy siblings.
• To assess the potential of C3 N-glycans as biomarkers for T1D risk stratification.

Main Methods:

• Developed a high-throughput workflow for protein-specific N-glycosylation profiling of human C3 using concanavalin A lectin enrichment and LC-MS analysis.
• Analyzed plasma samples from 61 newly diagnosed T1D children and 84 unaffected siblings from the Danish Childhood Diabetes Register.
• Utilized regression modeling to evaluate the discriminative power of C3 N-glycans between T1D cases and controls.

Main Results:

• Significant alterations in C3 N-glycan profiles were observed in children with T1D.
• T1D was associated with an increased proportion of high-mannose, unprocessed glycan structures on C3.
• A C3 glycan-based regression model demonstrated strong discriminative power (AUC = 0.879) between early-onset T1D and healthy siblings.

Conclusions:

• The study confirms previous findings of altered plasma high-mannose glycans in recent-onset T1D.
• C3 N-glycome alterations are implicated in the pathogenesis of T1D.
• The developed C3 glycan-based model shows promise for assessing T1D risk in pediatric populations.