Identification of Dysregulated Complement Activation Pathways Driven by N-Glycosylation Alterations in T2D Patients

Yang Zhao; Man Wang; Bo Meng; Ying Gao; Zhichao Xue; Minjun He; You Jiang; Xinhua Dai; Dan Yan; Xiang Fang

doi:10.3389/fchem.2021.677621

Identification of Dysregulated Complement Activation Pathways Driven by N-Glycosylation Alterations in T2D Patients

Front Chem. 2021 Jun 11:9:677621. doi: 10.3389/fchem.2021.677621. eCollection 2021.

Authors

Yang Zhao¹, Man Wang^{1

2}, Bo Meng¹, Ying Gao¹, Zhichao Xue¹, Minjun He¹, You Jiang¹, Xinhua Dai¹, Dan Yan^{2

3

4}, Xiang Fang¹

Affiliations

¹ Center for Advanced Measurement Science, National Institute of Metrology, Beijing, China.
² College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
³ Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
⁴ Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.

Abstract

Diabetes has become a major public health concern worldwide, most of which are type 2 diabetes (T2D). The diagnosis of T2D is commonly based on plasma glucose levels, and there are no reliable clinical biomarkers available for early detection. Recent advances in proteome technologies offer new opportunity for the understanding of T2D; however, the underlying proteomic characteristics of T2D have not been thoroughly investigated yet. Here, using proteomic and glycoproteomic profiling, we provided a comprehensive landscape of molecular alterations in the fasting plasma of the 24 Chinese participants, including eight T2D patients, eight prediabetic (PDB) subjects, and eight healthy control (HC) individuals. Our analyses identified a diverse set of potential biomarkers that might enhance the efficiency and accuracy based on current existing biological indicators of (pre)diabetes. Through integrative omics analysis, we showed the capability of glycoproteomics as a complement to proteomics or metabolomics, to provide additional insights into the pathogenesis of (pre)diabetes. We have newly identified systemic site-specific N-glycosylation alterations underlying T2D patients in the complement activation pathways, including decreased levels of N-glycopeptides from C1s, MASP1, and CFP proteins, and increased levels of N-glycopeptides from C2, C4, C4BPA, C4BPB, and CFH. These alterations were not observed at proteomic levels, suggesting new opportunities for the diagnosis and treatment of this disease. Our results demonstrate a great potential role of glycoproteomics in understanding (pre)diabetes and present a new direction for diabetes research which deserves more attention.

Keywords: N-glycopeptides; complement; diabetes; glycoproteomics; proteomics.