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

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

doi:10.3389/fchem.2021.677621

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.

Highlights

Diabetes mellitus is a group of chronic diseases that could cause severe damage to various organs in human body, leading to disabling and life-threatening health complications (American Diabetes Association, 2019)
We analyzed a panel of 24 plasma samples using a highthroughput integrated proteomic and glycoproteomic analysis protocol described in our recent study (Zhang et al 2019; Figure 1 and Methods)
A total of 32 and 20 differential expressed proteins were identified in type 2 diabetes (T2D) and PDB groups compared to the healthy control (HC) group, which were mainly localized in blood microparticle, immunoglobulin complex, protein–lipid complex, and vesicle lumen components, and involved in antigen binding, immunoglobulin receptor binding, protein activation cascade, complement activation, receptor-mediated endocytosis, and phagocytosis pathways

Summary

Introduction

Diabetes mellitus is a group of chronic diseases that could cause severe damage to various organs in human body, leading to disabling and life-threatening health complications (American Diabetes Association, 2019). It is estimated that 463 million individuals have diabetes mellitus globally in 2019, 90% of which are type 2 diabetes (T2D). By the year 2045, this number is projected to increase to 700 million (Saeedi et al, 2019). Due to its chronic nature, diabetes mellitus causes devastating. Detection may allow the early medical interventions and lifestyle modifications that can largely delay or even prevent the onset of diabetes and its complications (Federation, 2019). New biomarkers that enhance early detection are in urgent need

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