Background: Little is known about enzymatic N-glycosylation in type 2 diabetes, a common posttranslational modification of proteins influencing their function and integrating genetic and environmental influences. We sought to gain insights into N-glycosylation to uncover yet unexplored pathophysiological mechanisms in type 2 diabetes. Methods: Using a high-throughput MALDI-TOF mass spectrometry method, we measured N-glycans in plasma samples of the DiaGene case-control study (1583 cases and 728 controls). Associations were investigated with logistic regression and adjusted for age, sex, body mass index, high-density lipoprotein-cholesterol, non-high-density lipoprotein-cholesterol, and smoking. Findings were replicated in a nested replication cohort of 232 cases and 108 controls. Results: Eighteen glycosylation features were significantly associated with type 2 diabetes. Fucosylation and bisection of diantennary glycans were decreased in diabetes (odds ratio (OR) = 0.81, p = 1.26E-03, and OR = 0.87, p = 2.84E-02, respectively), whereas total and, specifically, alpha2,6-linked sialylation were increased (OR = 1.38, p = 9.92E-07, and OR = 1.40, p = 5.48E-07). Alpha2,3-linked sialylation of triantennary glycans was decreased (OR = 0.60, p = 6.38E-11). Conclusions: While some glycosylation changes were reflective of inflammation, such as increased alpha2,6-linked sialylation, our finding of decreased alpha2,3-linked sialylation in type 2 diabetes patients is contradictory to reports on acute and chronic inflammation. Thus, it might have previously unreported immunological implications in type 2 diabetes. General significance: This study provides new insights into N-glycosylation patterns in type 2 diabetes, which can fuel studies on causal mechanisms and consequences of this complex disease.

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Keywords Diabetes complications, diabetes mellitus, inflammation, MALDI-TOF-MS, N-glycosylation, Sialic acid
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Journal Biochimica et Biophysica Acta - General Subjects
Dotz, V. (Viktoria), Lemmers, R.F.H. (Roosmarijn F.H.), Reiding, K.R, Hipgrave-Ederveen, A, Lieverse, A, Mulder, M.T, … van Hoek, M. (2018). Plasma protein N-glycan signatures of type 2 diabetes. Biochimica et Biophysica Acta - General Subjects, 1862(12), 2613–2622. doi:10.1016/j.bbagen.2018.08.005