TY - JOUR

T1 - Multiple glycation sites in blood plasma proteins as an integrated biomarker of type 2 diabetes mellitus

AU - Soboleva, Alena

AU - Mavropulo-Stolyarenko, Gregory

AU - Karonova, Tatiana

AU - Thieme, Domenika

AU - Hoehenwarter, Wolfgang

AU - Ihling, Christian

AU - Stefanov, Vasily

AU - Grishina, Tatiana

AU - Frolov, Andrej

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Type 2 diabetes mellitus (T2DM) is one of the most widely spread metabolic diseases. Because of its asymptomatic onset and slow development, early diagnosis and adequate glycaemic control are the prerequisites for successful T2DM therapy. In this context, individual amino acid residues might be sensitive indicators of alterations in blood glycation levels. Moreover, due to a large variation in the half-life times of plasma proteins, a generalized biomarker, based on multiple glycation sites, might provide comprehensive control of the glycemic status across any desired time span. Therefore, here, we address the patterns of glycation sites in highly-abundant blood plasma proteins of T2DM patients and corresponding age- and gender-matched controls by comprehensive liquid chromatography-mass spectrometry (LC-MS). The analysis revealed 42 lysyl residues, significantly upregulated under hyperglycemic conditions. Thereby, for 32 glycation sites, biomarker behavior was demonstrated here for the first time. The differentially glycated lysines represented nine plasma proteins with half-lives from 2 to 21 days, giving access to an integrated biomarker based on multiple protein-specific Amadori peptides. The validation of this biomarker relied on linear discriminant analysis (LDA) with random sub-sampling of the training set and leave-one-out cross-validation (LOOCV), which resulted in an accuracy, specificity, and sensitivity of 92%, 100%, and 85%, respectively.

AB - Type 2 diabetes mellitus (T2DM) is one of the most widely spread metabolic diseases. Because of its asymptomatic onset and slow development, early diagnosis and adequate glycaemic control are the prerequisites for successful T2DM therapy. In this context, individual amino acid residues might be sensitive indicators of alterations in blood glycation levels. Moreover, due to a large variation in the half-life times of plasma proteins, a generalized biomarker, based on multiple glycation sites, might provide comprehensive control of the glycemic status across any desired time span. Therefore, here, we address the patterns of glycation sites in highly-abundant blood plasma proteins of T2DM patients and corresponding age- and gender-matched controls by comprehensive liquid chromatography-mass spectrometry (LC-MS). The analysis revealed 42 lysyl residues, significantly upregulated under hyperglycemic conditions. Thereby, for 32 glycation sites, biomarker behavior was demonstrated here for the first time. The differentially glycated lysines represented nine plasma proteins with half-lives from 2 to 21 days, giving access to an integrated biomarker based on multiple protein-specific Amadori peptides. The validation of this biomarker relied on linear discriminant analysis (LDA) with random sub-sampling of the training set and leave-one-out cross-validation (LOOCV), which resulted in an accuracy, specificity, and sensitivity of 92%, 100%, and 85%, respectively.

KW - Amadori compounds; biomarkers; glycation; glycation sites; label-free quantification; linear discriminant analysis; mass spectrometry; plasma proteins; type 2 diabetes mellitus

KW - Amadori compounds

KW - biomarkers

KW - glycation

KW - glycation sites

KW - label-free quantification

KW - linear discriminant analysis

KW - mass spectrometry

KW - plasma proteins

KW - type 2 diabetes mellitus

KW - OXIDATION

KW - FRAGMENTATION BEHAVIOR

KW - RISK

KW - MASS-SPECTROMETRY

KW - PEPTIDES

KW - GLUCOSE

KW - ALBUMIN

KW - ASSOCIATION

KW - END-PRODUCTS

KW - RESIDUES

UR - http://www.scopus.com/inward/record.url?scp=85066061355&partnerID=8YFLogxK

UR - http://www.mendeley.com/research/multiple-glycation-sites-blood-plasma-proteins-integrated-biomarker-type-2-diabetes-mellitus

U2 - 10.3390/ijms20092329

DO - 10.3390/ijms20092329

M3 - Article

C2 - 31083443

VL - 20

SP - 1

EP - 25

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 9

M1 - 2329

ER -