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Multiple Glycation Sites in Blood Plasma Proteins As an Integrated Biomarker of Type 2 Diabetes Mellitus

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Multiple Glycation Sites in Blood Plasma Proteins As an Integrated Biomarker of Type 2 Diabetes Mellitus International Journal of Molecular Sciences Article Multiple Glycation Sites in Blood Plasma Proteins as an Integrated Biomarker of Type 2 Diabetes Mellitus 1,2, 1, 3,4 Alena Soboleva y , Gregory Mavropulo-Stolyarenko y, Tatiana Karonova , Domenika Thieme 5, Wolfgang Hoehenwarter 5 , Christian Ihling 6, Vasily Stefanov 1, Tatiana Grishina 1 and Andrej Frolov 1,2,* 1 Department of Biochemistry, St. Petersburg State University, 199034 Saint Petersburg, Russia; [email protected] (A.S.); [email protected] (G.M.-S.); [email protected] (V.S.); [email protected] (T.G.) 2 Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, D-06120 Halle (Saale), Germany 3 Almazov National Medical Research Centre, 197341 Saint Petersburg, Russia; [email protected] 4 Department of Faculty Therapy, The First Pavlov St. Petersburg State Medical University, 197022 Saint Petersburg, Russia 5 Proteome Analytics Research Group, Leibniz Institute of Plant Biochemistry, D-06120 Halle (Saale), Germany; [email protected] (D.T.); [email protected] (W.H.) 6 Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, D-06120 Halle (Saale), Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-0-345-5582-1350 These authors contributed equally to this work. y Received: 15 March 2019; Accepted: 7 May 2019; Published: 10 May 2019 Abstract: 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. Keywords: Amadori compounds; biomarkers; glycation; glycation sites; label-free quantification; linear discriminant analysis; mass spectrometry; plasma proteins; type 2 diabetes mellitus 1. Introduction Diabetes is an ubiquitously spread disease with a worldwide occurrence exceeding 387 million in 2014, and expected to reach 592 million by the year 2035 [1]. Among the total number of cases, more than 90% are represented by the type 2 diabetes mellitus (T2DM), characterized with impaired insulin action and/or insulin secretion [2]. As the onset of the early metabolic alterations (insulin tolerance and Int. J. Mol. Sci. 2019, 20, 2329; doi:10.3390/ijms20092329 www.mdpi.com/journal/ijms Int.Int. J. Mol. Sci. 2019, 20, x 2329 FOR PEER REVIEW 22 of of 2526 tolerance and hyperglycaemia) is asymptomatic, vascular diabetic complications are often revealed hyperglycaemia)at the moment of is T2DM asymptomatic, diagnosis vascular [3]. Hence, diabetic early complications discovery of areT2DM, often or revealed even preceding at the moment changes of T2DMin glucose diagnosis metabolism, [3]. Hence, would early essentially discovery increase of T2DM, therapy or even precedingefficiency changesand reduce in glucose the costs metabolism, required wouldfor the essentially treatment increase of diabetic therapy complications efficiency and [4]. reduce Obviously, the costs even required minor for changes the treatment in blood of diabeticglucose complicationsconcentrations [4might]. Obviously, affect the even rates minor of blood changes protei inn blood glycation glucose [5], concentrationsi.e., interaction mightof glucose affect with the ratesfree amino of blood groups protein of glycationproteins, yielding [5], i.e., interactionfructosylamines, of glucose also withknown free as amino Amadori groups compounds of proteins, [6] yielding(Figure fructosylamines,1). Their further also degradation known as Amadoriresults in compounds the formation [6] (Figure of a highly1). Their heterogenic further degradation group of resultsadvanced in the glycation formation end of aproducts highly heterogenic (AGEs) [7], group known of advancedfor their glycationpro-inflammatory end products impact (AGEs) in the [7], knowndevelopment for their of pro-inflammatoryvascular diabetic complications impact in the development[8,9]. However, of vascularalthough diabetic AGEs are complications well-established [8,9]. However,biomarkers although of diabetic AGEs complications are well-established [10], Am biomarkersadori compounds of diabetic might complications suit better [ 10for], Amadoriglycemic compoundscontrol and early might diagnostics suit better forof T2DM glycemic [11]. control and early diagnostics of T2DM [11]. FigureFigure 1.1. EarlyEarly andand advancedadvanced glycationglycation inin humanhuman bloodblood plasma.plasma. TheThe majormajor pathwayspathways ofof advancedadvanced glycationglycation endend product product (AGE) (AGE) formation: formation: monosaccharide monosaccharide autoxidation autoxidation (Wolff-pathway), (Wolff-pathway), autoxidation ofautoxidation aldimins (Namiki-pathway), of aldimins (Namiki-pathway), polyol pathway, poly autoxidationol pathway, of Amadori autoxidation products of Amadori (Hodge-pathway), products and(Hodge-pathway), non-oxidative pathway.and non-oxidative pathway. FastingFasting plasma glucose (FPG) is the preferredpreferred diagnosticdiagnostic parameter, but an increaseincrease ofof bloodblood glucoseglucose is also detected in patients susufferingffering fromfrom other diseases besides diabetes mellitus [12]. [12]. Currently,Currently, thethe blood blood content content of hemoglobinof hemoglobin isoform, isoform, HbA 1cHbA, glycated1c, glycated by the by N-terminus the N-terminus of its α -chainof its (α>-chain6.5% of (˃ the6.5% total of hemoglobinthe total hemoglobin fraction), isfraction), one of the is one principle of the diagnostic principle criteriadiagnostic of this criteria disease of [this13] anddisease an e [13]fficient and tool an ofefficient long-term tool (60–90 of long-term days) glycemic (60–90 days) control glycemic [14]. However, control HbA [14].1c However,does not deliverHbA1c anydoes information not deliver about any short-terminformation alterations about short-term in plasma glucosealterations concentrations in plasma accompanyingglucose concentrations the onset ofaccompanying metabolic syndrome the onset [15 of]. Inmetabolic contrast, syndrome short-living [1 plasma5]. In contrast, proteins provideshort-living a good plasma possibility proteins to decreaseprovide a the good time possibility dimensions to ofdecrease glycemic the control. time di Thus,mensions human of serumglycemic albumin control. (HSA), Thus, the human major serum blood plasmaalbumin protein (HSA), with the amajor half-life blood of 21 plasma days, can protein be used with as aa marker half-life of of T2DM 21 days, [16]. can Its globalbe used glycation as a marker rates canof T2DM be quantitatively [16]. Its global assigned glycation by anrates array can of be enzymatic quantitatively [17], colorimetricassigned by [an18 ],array immunochemical of enzymatic [17], [19], electrophoreticcolorimetric [18], [20 ],immunochemical and chromatographic [19], [electrop21] methods.horetic Importantly, [20], and chromato the levelsgraphic of HSA glycation[21] methods. vary fromImportantly, 1% and 10%the levels in healthy of HSA individuals glycation to vary 20% from to 90% 1% inand patients 10% in with healthy diabetes individuals [22]. However, to 20% to as 90% the glycationin patients rates with at diabetes individual [22]. lysyl However, residues as in the the glyc HSAation molecule rates at di individualffer essentially lysyl [23 residues], the sensitivity in the HSA of themolecule potential differ glycation essentially sites [23], to short-term the sensitivity changes of the of blood potential glucose glycation levels sites might to also short-term be different. changes of bloodIn this glucose context, levels the monitoringmight also be of different. glycation rates at specific glycation sites might be advantageous in comparison to the quantification of global glycation levels. Therefore during the last decade, Int. J. Mol. Sci. 2019, 20, 2329 3 of 25 mass spectrometry was intensively employed in the establishment of such techniques [24–26]. In all cases, analytics relied on the bottom-up proteomic approach, based on nano-scaled liquid chromatography-mass spectrometry (nanoLC-MS) and tandem mass spectrometry (MS/MS). Thus, we showed that only some HSA lysyl residues are differentially glycated in plasma of T2DM patients, whereas glycation rates at other potential modification sites seemed to not
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