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      Dicarbonyls and Advanced Glycation End-Products in the Development of Diabetic Complications and Targets for Intervention

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          Abstract

          Advanced glycation end-products (AGEs) are non-enzymatic protein and amino acid adducts as well as DNA adducts which form from dicarbonyls and glucose. AGE formation is enhanced in diabetes and is associated with the development of diabetic complications. In the current review, we discuss mechanisms that lead to enhanced AGE levels in the context of diabetes and diabetic complications. The methylglyoxal-detoxifying glyoxalase system as well as alternative pathways of AGE detoxification are summarized. Therapeutic approaches to interfere with different pathways of AGE formation are presented.

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          Effect of collagen turnover on the accumulation of advanced glycation end products.

          Nicole Verzijl, Jeroen DeGroot, Suzanne R Thorpe … (2000)
          Collagen molecules in articular cartilage have an exceptionally long lifetime, which makes them susceptible to the accumulation of advanced glycation end products (AGEs). In fact, in comparison to other collagen-rich tissues, articular cartilage contains relatively high amounts of the AGE pentosidine. To test the hypothesis that this higher AGE accumulation is primarily the result of the slow turnover of cartilage collagen, AGE levels in cartilage and skin collagen were compared with the degree of racemization of aspartic acid (% d-Asp, a measure of the residence time of a protein). AGE (N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, and pentosidine) and % d-Asp concentrations increased linearly with age in both cartilage and skin collagen (p < 0.0001). The rate of increase in AGEs was greater in cartilage collagen than in skin collagen (p < 0.0001). % d-Asp was also higher in cartilage collagen than in skin collagen (p < 0.0001), indicating that cartilage collagen has a longer residence time in the tissue, and thus a slower turnover, than skin collagen. In both types of collagen, AGE concentrations increased linearly with % d-Asp (p < 0.0005). Interestingly, the slopes of the curves of AGEs versus % d-Asp, i.e. the rates of accumulation of AGEs corrected for turnover, were identical for cartilage and skin collagen. The present study thus provides the first experimental evidence that protein turnover is a major determinant in AGE accumulation in different collagen types. From the age-related increases in % d-Asp the half-life of cartilage collagen was calculated to be 117 years and that of skin collagen 15 years, thereby providing the first reasonable estimates of the half-lives of these collagens.
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            Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry.

            Roya Babaei-Jadidi, Paul Thornalley, Sinan Battah … (2003)
            Glycation of proteins forms fructosamines and advanced glycation endproducts. Glycation adducts may be risk markers and risk factors of disease development. We measured the concentrations of the early glycation adduct fructosyl-lysine and 12 advanced glycation endproducts by liquid chromatography with tandem mass spectrometric detection. Underivatized analytes were detected free in physiological fluids and in enzymic hydrolysates of cellular and extracellular proteins. Hydroimidazolones were the most important glycation biomarkers quantitatively; monolysyl adducts (N(epsilon)-carboxymethyl-lysine and N(epsilon)-1-carboxyethyl-lysine) were found in moderate amounts, and bis(lysyl)imidazolium cross-links and pentosidine in lowest amounts. Quantitative screening showed high levels of advanced glycation endproducts in cellular protein and moderate levels in protein of blood plasma. Glycation adduct accumulation in tissues depended on the particular adduct and tissue type. Low levels of free advanced glycation endproducts were found in blood plasma and levels were 10-100-fold higher in urine. Advanced glycation endproduct residues were increased in blood plasma and at sites of vascular complications development in experimental diabetes; renal glomeruli, retina and peripheral nerve. In clinical uraemia, the concentrations of plasma protein advanced glycation endproduct residues increased 1-7-fold and free adduct concentrations increased up to 50-fold. Comprehensive screening of glycation adducts revealed the relative and quantitative importance of alpha-oxoaldehyde-derived advanced glycation endproducts in physiological modification of proteins-particularly hydroimidazolones, the efficient renal clearance of free adducts, and the marked increases of glycation adducts in diabetes and uraemia-particularly free advanced glycation endproducts in uraemia. Increased levels of these advanced glycation endproducts were associated with vascular complications in diabetes and uraemia.
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              Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking.

              Melanie P. Ulrich, H Vlassara, A Cerami … (1986)
              Age-associated increases in collagen cross-linking and accumulation of advanced glycosylation products are both accelerated by diabetes, suggesting that glucose-derived cross-link formation may contribute to the development of chronic diabetic complications as well as certain physical changes of aging. Aminoguanidine, a nucleophilic hydrazine compound, prevented both the formation of fluorescent advanced nonenzymatic glycosylation products and the formation of glucose-derived collagen cross-links in vitro. Aminoguanidine administration to rats was equally effective in preventing diabetes-induced formation of fluorescent advanced nonenzymatic glycosylation products and cross-linking of arterial wall connective tissue protein in vivo. The identification of aminoguanidine as an inhibitor of advanced nonenzymatic glycosylation product formation now makes possible precise experimental definition of the pathogenetic significance of this process and suggests a potential clinical role for aminoguanidine in the future treatment of chronic diabetic complications.
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                Author and article information

                Contributors
                Casper G. Schalkwijk: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 05 May 2017
                Publication date Collection: May 2017
                Volume: 18
                Issue: 5
                Electronic Location Identifier: 984
                Affiliations
                [1 ]Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, 69120 Heidelberg, Germany; thomas.fleming@ 123456med.uni-heidelberg.de (T.F.); peter.nawroth@ 123456med.uni-heidelberg.de (P.P.N.)
                [2 ]Department of Nuclear Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany
                [3 ]German Center for Diabetes Research (DZD), 85764 Munich-Neuherberg, Germany
                [4 ]Joint Heidelberg-IDC Translational Diabetes Program, Helmholtz Center, 85764 Munich-Neuherberg, Germany; stephan.herzig@ 123456helmholtz-muenchen.de
                [5 ]Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany; marc.freichel@ 123456pharma.uni-heidelberg.de
                [6 ]Molecular Medicine Partnership Unit, University of Heidelberg, 69120 Heidelberg, Germany; martina.muckenthaler@ 123456med.uni-heidelberg.de
                [7 ]Institute for Diabetes and Cancer (IDC), Helmholtz Center, 85764 Munich-Neuherberg, Germany
                Author notes
                Article
                Publisher ID: ijms-18-00984
                DOI: 10.3390/ijms18050984
                PMC ID: 5454897
                PubMed ID: 28475116
                SO-VID: c05cae30-79bc-4f72-afb7-38e952004d1c
                Copyright © © 2017 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 25 January 2017
                Date accepted : 02 May 2017
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: advanced glycation end-products,diabetes,glyoxalase,aldose reductase,methylglyoxal,glyoxal,3-deoxyglucosone
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: advanced glycation end-products, diabetes, glyoxalase, aldose reductase, methylglyoxal, glyoxal, 3-deoxyglucosone

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