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Nichtenzymatische Glykierung und oxidativer Streß bei chronischen Erkrankungen und Diabetes mellitus

Non-enzymatic glycation and oxidative stress in chronic disease and diabetes mellitus

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Zusammenfassung

□ Moderne Biochemie und Molekularbiologie haben das Verständnis der Pathophysiologie chronischer Erkrankungen wie diabetischer Spätschäden, Morbus Alzheimer, Arteriosklerose und Gefäßschäden durch Beschreibung des Konzeptes „AGE — oxidativer Streß” bereichert.

□ Bei der nichtenzymatischen Glykierungsreaktion reagieren reduzierende Zucker in der offenen Aldehydform mit freien Aminogruppen in Makromolekülen. Dies führt zur Bildung von „Advanced Glycation End products (AGEs)”, die während des normalen Alterns und in verstärktem Maße bei Diabetes mellitus akkumulieren. Oxidationsprozesse, die die Glykierungsreaktionen begleiten, unterstützen die Bildung von AGEs. AGE-Bildung verändert die physikochemischen Eigenschaften von Proteinen, Lipiden und Nukleinsäuren. Darüber hinaus induziert die Bindung von AGEs an spezifische AGE-Rezeptoren intrazelluläre Signalmechanismen. Interaktion von AGEs mit einem der Rezeptoren, RAGE, vermittelt intrazellulär oxidativen Streß, der den Transkriptionsfaktor NF-κB und NF-κB-abhängige Genexpression induziert, die möglicherweise bei diabetischen Spätkomplikationen eine Rolle spielen.

□ Schlußfolgerung

Die Kenntnis der molekularen Grundlagen ermöglicht, das Zusammenspiel verschiedener Pathogene (Radikale, Zytokine, AGE-Proteine, Amyloid-β-Peptide) zu verstehen und oxidativen Streß als einen distal dieser Substanzen angreifenden „gemeinsamen Nenner” zu definieren. Daraus sich ergebende therapeutische Ansätze betreffen nicht nur die Optimierung der Blutzuckerkontrolle und „elegante Moleküle”, wie zum Beispiel AGE-Bildungshemmer und „Cross-link-breaker”, sondern auch gezielte Beratung hinsichtlich einer an Antioxidanzien reichen (und an AGE-Protein armen?) Ernährung, vor allem bei Patienten mit erhöhtem oxidativen Streß.

Abstract

□ New approaches in biochemistry and molecular biology have increased the knowledge on the pathophysiology of chronic diseases as late diabetic complications, Alzheimer’s disease, arteriosclerosis and vascular disease by defining the concept of “AGE-formation and oxidative stress”.

□ Nonenzymatic glycation, in which reducing sugars are covalently bound to free aminogroups of macromolecules, results in the formation of Advanced Glycation End products (AGEs) which accumulate during aging and at accelerated rate during the course of diabetes. Glycation accompanying oxidation processes support AGE-formation. AGE-formation changes the physicochemical properties of proteins, lipids and nucleic acids. In addition, binding of AGEs to specific surface receptors induces cellular signalling and cell activation. Interaction of AGEs with one of the receptors, RAGE, generates intracellular oxidative stress, which results in activation of the transcription factor NF-κB and subsequent gene expression, which might be relevant in late diabetic complications.

□ Conclusion

Knowledge of the basic molecular mechanisms allows to understand the interplay of different inducers such as radicals, cytokines, AGE-proteins and amyloid-β-peptids and to define oxidative stress as a “common endpoint” of cell dysfunction. With respect to therapeutic options it is now possible not only to optimize blood glycemic control, but also to design drugs such as AGE-inhibitors and AGE-“cross-link” breakers. In addition patients with chronic disease associated with increased oxidative stress may benefit from an antioxidant rich (and AGE protein poor?) nutrition.

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Literatur

  1. Abel M, Ritthaler U, Zhang Y, et al. Expression of receptors for advanced glycosylated end products in renal disease. Nephrol Dial Transplant 1995;10:1662–7.

    PubMed  CAS  Google Scholar 

  2. Ahmed MU, Thorpe SR, Baynes JW. Identification of carboxymethyllysine as a degradation product of fructose-lysine in glycosylated protein. J Biol Chem 1986;261:4889–994.

    PubMed  CAS  Google Scholar 

  3. Asayama K, Uchida M, Nakane T. Antioxidants in the serum of children with insulin dependent diabetes mellitus. Free Rad Biol Med 1993;15:597–602.

    Article  PubMed  CAS  Google Scholar 

  4. Baeuerle PA, Baltimore D. NF-kB: ten years after. Cell 1996;87:13–20.

    Article  PubMed  CAS  Google Scholar 

  5. Baumgartl H-J, Hofmann H, Standl E. Erhöhung der Serum-AGEs (“advanced glycosylation endproducts”) bei Rauchem unter den Typ-1-Diabetikern. Diab Stoffw 1996;5:151 abstract.

    Google Scholar 

  6. Baumgartl H-J, Standl E. “Advanced glycation end products” und deren Folge für die diabetische Folgeschäden. Diab Stoffw 1996;5:177–82.

    Google Scholar 

  7. Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991;40:405–12.

    Article  PubMed  CAS  Google Scholar 

  8. Bierhaus A, Chevion S, Chevion M, et al. Advanced glycation endproducts (AGEs) induced activation of NF-kB is suppressed by a-lipoic acid in cultured endothelial cells. Diabetes 1997;46:1481–90.

    Article  PubMed  CAS  Google Scholar 

  9. Bierhaus A, Illmer T, Kasper M, et al. Advanced glycation endproducts (AGEs) mediated induction of tissue factor in cultured endothelial cells is dependent on RAGE. Circulation 1997;96:2262–71.

    PubMed  CAS  Google Scholar 

  10. Bierhaus A, Ritz E, Nawroth PP. Expression of receptors for advanced glycation end-products in occlusive vascular and renal disease. Nephrol Dial Transplant 1996;11:Suppl 5:87–90. abstract.

    PubMed  CAS  Google Scholar 

  11. Biesalski HK. Antioxidative Vitamine in der Prävention. Deutsch Ärztebl 1995;31:979–83.

    Google Scholar 

  12. Brett J, Schmidt AM, Yan SD, et al. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. Am J Pathol 1993;143:1699–712.

    PubMed  CAS  Google Scholar 

  13. Brownlee M. Advanced protein glycosylation in diabetes and aging. Ann Rev Med 1995;46:223–34.

    Article  PubMed  CAS  Google Scholar 

  14. Brownlee M. Advanced glycation end products in diabetic complications. Curr Opin Endocr Diab 1996;3:291–7.

    Article  CAS  Google Scholar 

  15. Brownlee M, Cerami A, Vlassara H. Advanced glycation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 1988;318:1315–21.

    PubMed  CAS  Google Scholar 

  16. Brownlee M, Vlassara H, Kooney A, et al. Aminoguanidine prevents diabetes-induced arterial wall protein crosslinking. Science 1986;232:1629–32.

    Article  PubMed  CAS  Google Scholar 

  17. Bucala R, Cerami A. Advanced glycosylation: chemistry, biology, and implications for diabetes and aging. Adv Pharmacol 1992;23:1–34.

    Article  PubMed  CAS  Google Scholar 

  18. Bucala R, Makita Z, Koschinsky T, et al. Lipid advanced glycosylation: pathway for lipid oxidation in vivo. Proc Natl Acad Sci USA 1993;90:6434–8.

    Article  PubMed  CAS  Google Scholar 

  19. Bucala R, Makita Z, Vega G, et al. Modification of LDL by advanced glycosylation endproducts contributes to the dyslipidemia of diabetes and renal insufficiency. Proc Natl Acad Sci USA 1994;91:9441–5.

    Article  PubMed  CAS  Google Scholar 

  20. Bucala R, Model P, Cerami A. Modification of DNA by reducing sugars: a possible mechanism for nucleic acid aging and age-related dysfunction in gene expression. Proc Natl Acad Sci USA 1984;81:105–9.

    Article  PubMed  CAS  Google Scholar 

  21. Cameron NE, Cotter MA. Neurovascular dysfunction in diabetic rats. Potential contribution of autoxidation and free radicals using transition metal chelating agents. J Clin Invest 1995;96:1159–63.

    Article  PubMed  CAS  Google Scholar 

  22. Cameron NE, Cotter MA, Dines K, et al. Effects of aminoguanidine on peripheral nerve function and polyol pathway metabolites in streptozotocin-diabetes rats. Diabetologia 1991;35:946–50.

    Article  Google Scholar 

  23. Chappey O, Dosquet C, Wautier M-P, Wautier J-L. Advanced glycation end products, oxidant stress and vascular lesion. Eur J Clin Invest 1997;27:97–108.

    Article  PubMed  CAS  Google Scholar 

  24. Dandona P, Thusu K, Cook S, et al. Oxidative damage to DNA in diabetes mellitus. Lancet 1996;347:444–5.

    Article  PubMed  CAS  Google Scholar 

  25. De Mattia G, Laurenti O, Bravi C, et al. Effect of aldose reductase inhibition on glutathione redox status in erythrocytes of diabetic patients. Metabolism 1994;43:965–8.

    Article  PubMed  Google Scholar 

  26. Drickhammer K. Breaking the curse of the AGEs. Nature 1996;382:211–2.

    Article  Google Scholar 

  27. Dunn JA, Ahmed MU, Mutiashaw MH, et al. Reaction of ascorbate with lysine and protein under autoxidizing conditions: formation of N-epsilon-(carboxymethyl)lysine by reactions between lysine and products of autoxidation of ascorbate. Biochemistry 1990;29:10964–70.

    Article  PubMed  CAS  Google Scholar 

  28. Dunn JA, McCance DR, Thorpe SR, et al. Age-dependent accumulation of N-epsilon-(carboxymethyl) lysine and N-epsilon-(carboxymethyl)-hydroxylysine in human skin collagen. Biochemistry 1991;30:1205–10.

    Article  PubMed  CAS  Google Scholar 

  29. Dyer D, Blackledge J, Thorpe S, et al. Formation of pentosidine during nonenzymatic browning of proteins by glucose: identification of glucose and other carbohydrates as possible precursors of pentosidine in vivo. J Biol Chem 1991;266:11654–60.

    PubMed  CAS  Google Scholar 

  30. Dyer DG, Dunn JA, Thorpe SR, et al. Accumulation of Maillard reaction products in skin collagen in diabetes and aging. J Clin Invest 1993;91:2463–9.

    Article  PubMed  CAS  Google Scholar 

  31. Edelstein D, Brownlee M. Aminoguanidine ameliorates albuminuria in diabetic hypertensive rats. Diabetologia 1992;35:96–7.

    Article  PubMed  CAS  Google Scholar 

  32. Edelstein D, Brownlee M. Mechanistic studies of advanced glycosylation endproduct inhibition by aminoguanidine. Diabetes 1992;41:26–9.

    Article  PubMed  CAS  Google Scholar 

  33. Ellis EN, Good BH. Prevention of glomerular basement membrane thickening by aminoguanidine in experimental diabetes mellitus. Metabolism 1991;40:1016–9.

    Article  PubMed  CAS  Google Scholar 

  34. Fu MX, Requena R, Jenkins A, et al. The advanced glycation end product, Ne-(Carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation re-actions. J Biol Chem 1996;271:9982–6.

    Article  PubMed  CAS  Google Scholar 

  35. Fu M-X, Wells-Knecht KJ, Blackledge JA, et al. Glycation, glycoxydation, and cross-linking of collagen by glucose. Kinetics, mechanisms and inhibition of late stages of the Maillard reaction. Diabetes 1994;43:676–83.

    Article  PubMed  CAS  Google Scholar 

  36. Ghiselli A, Laurenti O, De Mattia G, et al. Salicylate hydroxylation as an early marker of in vivo oxidative stress in diabetic patients. Free Rad Biol Med 1992;13:621–6.

    Article  PubMed  CAS  Google Scholar 

  37. Giardino I, Edelstein D, Brownlee M. Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity: a model for intracellular glycosylation in diabetes. J Clin Invest 1994;94:110–7.

    Article  PubMed  CAS  Google Scholar 

  38. Giardino I, Edelstein D, Brownlee M. BCL-2 expression or antioxidants prevent hyperglycemia-induced formation of intracellular advanced glycation endproducts in bovine endothelial cells. J Clin Invest 1996;97:1422–8.

    Article  PubMed  CAS  Google Scholar 

  39. Giuglianu D, Ceriello A. Oxidative stress and diabetic vascular complications. Diab Care 1996;19:257–67.

    Article  Google Scholar 

  40. Glomb MA, Monnier V. Mechanism of protein modifications by glyoxal and glyceraldehyde, reactive intermediates of the Maillard reaction. J Biol Chem 1995;270:10017–26.

    Article  PubMed  CAS  Google Scholar 

  41. Grandhee SK, Monnier VM. Mechanism of formation of the Maillard protein cross-link pentosidine. J Biol Chem 1991;266:11649–53.

    PubMed  CAS  Google Scholar 

  42. Greten J, Zhang Y, Wiesel R, et al. Expression of receptors for advanced glycation end products in uremia. Nephrol Dial Transpl 1996;11:786–90.

    CAS  Google Scholar 

  43. Griesmacher A, Kindhauser M, Andert SE, et al. Enhanced serum levels of thiobarbituric acid reactive substances in diabetes mellitus. Am J Med 1995;98:469–75.

    Article  PubMed  CAS  Google Scholar 

  44. Grimm S, Bauer MKA, Bacuerle PA, et al. Bcl-2 down-regulates the activity of the transcription factor NF-kB upon apoptosis. J Cell Biol 1996;134:13–23.

    Article  PubMed  CAS  Google Scholar 

  45. Gugliucci A, Bendayan M. Histones from diabetic rats contain increased levels of advanced glycation end products. Biochem Biophys Res Commun 1995;212:56–62.

    Article  PubMed  CAS  Google Scholar 

  46. Hamada Y, Araki N, Horiuchi S, et al. Role of polyol pathway in nonenzymatic glycation. Nephrol Dial Transplant 1996;11:Suppl 5:95–8.

    PubMed  CAS  Google Scholar 

  47. Hammes HP. Neue Therapie der diabetischen Mikroangiopathie. Diabetes J 1996;1:42–5.

    Google Scholar 

  48. Hammes H-P, Brownlee M, Edelstein D, et al. Aminoguanidine inhibits the development of accelerated diabetic retinopathy in the spontaneous hypertensive rat. Diabetologia 1994;37:32–5.

    Article  PubMed  CAS  Google Scholar 

  49. Hammes HP, Martin S, Federlin K, et al. Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy. Proc Natl Acad Sci USA 1991;88:11555–8.

    Article  PubMed  CAS  Google Scholar 

  50. Hipkiss AR, Michaelis J, Syrris P, et al. Carnosine protects against in vitro glycation and cross-linking. Biochem Soc Trans 1994;2:399.

    Google Scholar 

  51. Hirsch J, Baines CL, Feather MS. X-ray structures of a 3-amino-5-and a 3-amino-6-substituted triazine, producedas a result of reaction of 3-deoxy-D-erythrhexo-2-ulose (3-deoxyglucosone) with aminoguanidine. J Carbohydr Chem 1992;11:891–901.

    Article  CAS  Google Scholar 

  52. Hofmann M, Bierhaus A, Zumbach M, et al. Schlechte diabetische Stoffwechselkontrolle führt zur Aktivierung des Transskriptionsfaktors NF-kB. Diab Stoffw 1997;6:Suppl 1:105. abstract.

    Google Scholar 

  53. Hori O, Brett J, Slattery T, et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. J Biol Chem 1995;270:25752–61.

    Article  PubMed  CAS  Google Scholar 

  54. Hujiberts MSP, Wolffenbuttel BRH, Boudier HA, et al. Aminoguanidine treatment increases elasticity and decreases fluid filtration of large arteries from diabetic rats. J Clin Invest 1993;92:1407–11.

    Article  Google Scholar 

  55. Hunt JV, Dean RT, Wolff SP. Hydroxyl radical production and autoxidative glycosylation: glucose autoxidation as the cause of protein damage in the experimental glycation model of diabetes and aging. Biochem J 1988:256:205–12.

    PubMed  CAS  Google Scholar 

  56. Hunt JV, Smith CCT, Wolff SP. Autoxidative glycosylation and possible involvement of peroxides and free radicals in LDL modifications. Diabetes 1990;39:1420–4.

    Article  PubMed  CAS  Google Scholar 

  57. Jiang ZY, Woolard ACS, Wolff SP. Hydrogen peroxide production during experimental protein glycation. FEBS Lett 1990;268:69–71.

    Article  PubMed  CAS  Google Scholar 

  58. Karpen CW, Cataland S, Dorisson TM, et al. Production of 12-hydroyeicosatetraenoic acid and vitamin E status in platelets from type I human diabetic subjects. Diabetes 1985;34:526–31.

    Article  PubMed  CAS  Google Scholar 

  59. Khatami M, Suldan Z, David I, Li W, et al. Inhibitory effects of pyridoxal phosphate, ascorbate and aminoguanidine on nonenzymatic browning. Life Sci 1988; 43:1725–31.

    Article  PubMed  CAS  Google Scholar 

  60. Kihara M, Schmelzer JD, Poduslo JF, et al. Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology and oxygene free radicals. Proc. Natl Acad Sci USA 1991;88:6107–11.

    Article  PubMed  CAS  Google Scholar 

  61. Knecht KJ, Dunn JA, McFarland KF, et al. Effect of diabetes and aging on carboxymethyllysine levels in human urine. Diabetes 1991;40:190–6.

    Article  PubMed  CAS  Google Scholar 

  62. Koschinsky T, He CJ, Mitsuhashi T, et al. Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy. Proc Natl Acad Sci USA 1997;94:6474–9.

    Article  PubMed  CAS  Google Scholar 

  63. Krantz S, Salazar R, Brandt R, et al. Purification and partial amino acid sequencing of a fructosyllysine-specific binding protein from cell membranes of the monocyte-like cell line U937. Biochim Biophys Acta 1995;1266:109–12.

    Article  PubMed  Google Scholar 

  64. Kushi L, Folsom AR, Prineas RJ, et al. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med 1996;18:1156–62.

    Article  Google Scholar 

  65. Ledl F, Schleicher E. Die Maillard-Reaktion in Lebensmitteln und im menschlichen Körper — neue Ergebnisse zu Chemie, Biochemie und Medizin. Angewandte Chemie 1990;102:597–634.

    Article  CAS  Google Scholar 

  66. Leonhardt W, Hanefeld M, Lattke P, et al. Vitamin E-Mangel und Oxidierbarkeit der Low-Density-Lipoproteine bei Typ-I- und Typ-II-Diabetes: Einfluß der Qualität der Stoffwechselkontrolle. Diab Stoffw 1997;6: Suppl 2: 24–8.

    Google Scholar 

  67. Lewis BS, Harding JJ. The effects of aminoguanidine on the glycation (nonenzymatic glycosylation) of lens proteins. Exp Eye Res 1990;50:463–7.

    Article  PubMed  CAS  Google Scholar 

  68. Li Y-M, Steffes M, Donnelly T, et al. Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor aminoguanidine. Proc Natl Acad Sci USA 1996;93:3902–7.

    Article  PubMed  CAS  Google Scholar 

  69. Li Y-M, Tan A-X, Vlassara H. Antibacterial activity of lysozyme and lactoferrin is inhibited by binding of advanced glycation-modified proteins to a conserved motif. Nat Med 1995;1:1057–61.

    Article  PubMed  CAS  Google Scholar 

  70. Li YM, Wojciehowicz D, Gilmore P, et al. Molecular identity and tissue distribution of advanced glycation endproduct receptors: relationship of p60 to OST-48 and 80KH membrane proteins. Proc Natl Acad Sci USA 1996;93:11047–52.

    Article  PubMed  CAS  Google Scholar 

  71. Maillard LC. Action des acides amines sur les sucres; formation des melanoides par voie methodique. C R Acad Sci 1912:154:66.

    CAS  Google Scholar 

  72. Makita Z, Bucala R, Rayfield EJ, et al. Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure. Lancet 1994;343:1519–22.

    Article  PubMed  CAS  Google Scholar 

  73. Makita Z, Radoff S, Rayfield EJ, et al. Advanced glycosylation endproducts in patients with diabetic nephropathy. N Engl J Med 1991; 325:836–42.

    PubMed  CAS  Google Scholar 

  74. Makita Z, Vlassara H, Cerami A, et al. Immunochemical detection of advanced glycosylation endproducts in vivo. J Biol Chem 1992;267:5133–8.

    PubMed  CAS  Google Scholar 

  75. Makita Z, Vlassara H, Rayfield E, et al. Hemoglobin-AGE: a circulating marker of advanced glycosylation. Science 1992;258:651–3.

    Article  PubMed  CAS  Google Scholar 

  76. Makita Z, Yanagisawa K, Kuwajima S, et al. Advanced glycation endproducts and diabetic nephropathy. J Diab Compl 1995;9:265–8.

    Article  CAS  Google Scholar 

  77. Mattson MP, Rydel RE. Amyloid ox-tox transducers. Nature 1996;382:674–5.

    Article  PubMed  CAS  Google Scholar 

  78. McLellan AC, Thornalley PJ, Benn J, et al. Glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications. Clin Sci Colch 1994;87: 21–9.

    PubMed  CAS  Google Scholar 

  79. Miyata T, Hori O, Zhang J, et al. The receptor for advanced glycation end products (RAGE) is a central mediator of the interaction of AGE-beta-2 microglobulin with human mononuclear phagocytes via an oxidant sensitive pathway. J Clin Invest 1996;98:1088–94.

    Article  PubMed  CAS  Google Scholar 

  80. Miyata T, Inagi R, Ilida Y, et al. Involvement of beta-2-microglobulin modified with advanced glycation end products in the pathogenesis of hemodialysis associated amyloidosis. J Clin Invest 1994;93:521–8.

    Article  PubMed  CAS  Google Scholar 

  81. Miyazaki S, Niwa T, Morit T, et al. Advanced glycation end products are associated with beta-2-microglobulin amyloidosis. Am J Nephr 1995;15.

  82. Monnier V. The Maillard reaction in aging, diabetes and nutrition. NIH conference. Baynes JW, Monnier V, eds. New York: Liss, 1988:1–22.

    Google Scholar 

  83. Monnier VM, Ceramo A. Nonenzymatic browning in vivo: possible process for aging on long lived proteins. Science 1981;211:491–3.

    Article  PubMed  CAS  Google Scholar 

  84. Monnier VM, Sell DR, Nagaraj RH, et al. Maillard reaction-mediated molecular damage to extracellular matrix and other tissue proteins in diabetes, aging and uremia. Diabetes 1992;41:3–41.

    Google Scholar 

  85. Mullarkey CJ, Edelstein D, Brownlee M. Free radical generation by early glycation products a mechanism for accelerated atherogenesis in diabetes. Biochem Biophys Res Commun 1990;173:932–9.

    Article  PubMed  CAS  Google Scholar 

  86. Münch G, Taneli Y, Schraven E, et al. The cognitionenhancing drug Tenilsetam is an inhibitor of protein crosslinking by advanced glycosylation. J Neural Transm 1994;8:193–208.

    Article  Google Scholar 

  87. Münch G, Thome J, Foley P, et al. Advanced glycation endproducts in ageing and Alzheimer’s disease. Brain Res Rev 1997;23:134–43.

    Article  PubMed  Google Scholar 

  88. Nagamatsu M, Nickander KK, Schmelzer JD, et al. Lipoic acid improve nerve blood flow, reduces oxidative stress and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care 1995;18:1160–7.

    Article  PubMed  CAS  Google Scholar 

  89. Nagaraj R, Monnier V. Protein modification by the degradation products of ascorbate: formation of a novel pyrrole from the Maillard reaction of L-threose with proteins. Biochim Biophys Acta 1995;1253:75–84.

    PubMed  Google Scholar 

  90. Nakamura S, Makita Z, Ishikawa S, et al. Progression of nephropathy in spontaneous diabetic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation. Diabetes 1997;46:895–9.

    Article  PubMed  CAS  Google Scholar 

  91. Nakayama H, Taneda S, Kuwajima S, et al. Production and characterisation of antibodies to advanced glycation products on proteins. Biochem Biophys Res Commun 1989;162:740–5.

    Article  PubMed  CAS  Google Scholar 

  92. Neeper M, Schmidt AM, Brett J, et al. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 1992;267:14998–15004.

    PubMed  CAS  Google Scholar 

  93. Nicholls K, Mandel TE. Advanced glycosylation end-products in experimental murine diabetic nephropathy: efect of islet isografting and of aminoguanidine. Lab Invest 1989;60:486–91.

    PubMed  CAS  Google Scholar 

  94. Njorge FG, Monnier VM. The chemistry of the maillard reaction under physiological conditions: a review. Prog Clin Biol Res 1989;304:85–107.

    Google Scholar 

  95. Nourooz-Zadeh J, Halliwell B, Tritschler H, et al. Decreased lipid standardised plasma a-tocopherol in non-insulin dependent diabetes mellitus. Diab Stoffw 1997;6:Suppl 2:20–3.

    Google Scholar 

  96. Nourooz-Zadeh J, Tajaddini-Samadi J, McCarthy S, et al. Elevated levels of authentic plasma hydroperoxides in NIDDM. Diabetes 1995;44:1054–8.

    Article  PubMed  CAS  Google Scholar 

  97. Odetti PR, Borgoglio A, De Pascale A, et al. Prevention of diabetes-increased aging effect on rat collagen-linked flurescence by aminoguanidine and rutin. Diabetes 1990;39:796–801.

    Article  PubMed  CAS  Google Scholar 

  98. Ou P, Wolff SP. Aminoguanidine: a drug proposed for the prophylaxis in diabetes inhibits catalase and generates hydrogen peroxide in vitro. Biochem Pharmacol 1993;43:1139–44.

    Article  Google Scholar 

  99. Oxlund H, Andreassen TT. Aminoguanidine treatment reduces the increase in collagen stability of rats with experimental diabetes mellitus. Diabetolgia 1992;35:75–8.

    Google Scholar 

  100. Palinski W, Koschinsky T, Butler SW, et al. Immunological evidence for the presence of advanced glycation end products in atherosclerotic lesions of euglycemic rabbits. Arterioscl Thromb Vasc Biol 1995;15:571–82.

    PubMed  CAS  Google Scholar 

  101. Papoulis A, Youssef A, Bucala R. Identification of N2-(1-carboxyethyl) guanine (CEG) as a guanine advanced glycosylation end product. Biochemistry 1995;34:648–55.

    Article  PubMed  CAS  Google Scholar 

  102. Philis-Tsimikas A, Parthasarathy S, Picard S, et al. Aminoguanidine has both pro-oxidant and antioxidant activity toward LDL. Arterioscler Thromb Vasc Biol 1995;15:367–76.

    PubMed  CAS  Google Scholar 

  103. Picard S, Parthasarathy S, Fruebis J, et al. Aminoguanidine inhibits oxidative modifications of low density lipoprotein and the subsequent increase in uptake by macrophage scavenger receptors. Proc Natl Acad Sci USA 1991;89:6876–80.

    Article  Google Scholar 

  104. Pryor WA, Godber SS. Noninvasive measures of oxidative stress status in humans. Free Rad Biol Med 1991;10:177–84.

    Article  PubMed  CAS  Google Scholar 

  105. Rabini RA, Fumelli P, Galassi R, et al. Increased suspectibility of lipid peroxidation of low-density lipoproteins and erythrocyte membranes from diabetic patients. Metabolism 1994;43:1470–4.

    Article  PubMed  CAS  Google Scholar 

  106. Radoff S, Cerami A, Vlassara H. Isolation of a surface binding protein specific for advanced glycosylation end products from the murine macrophage derived cell line RAW 264.7. Diabetes 1990;39:1510–8.

    Article  PubMed  CAS  Google Scholar 

  107. Radoff S, Makita Z, Vlassara H. Radioreceptor assay for advanced glycosylation end products. Diabetes 1991;40: 1731–8.

    Article  PubMed  CAS  Google Scholar 

  108. Radoff S, Vlassara H, Cerami A. Characterisation and isolation of a macrophage receptor for advanced glycosylation end products. Arch Biochem Biophys 1988;263:418–23.

    Article  PubMed  CAS  Google Scholar 

  109. Reinauer H. Biochemistry of protein glycation in diabetes mellitus. Klin Lab 1993;39:984–7.

    CAS  Google Scholar 

  110. Ritthaler U, Deng Y, Zhang Y, et al. Expression of receptors for advanced glycation end products in peripheral occlusive vascular disease. Am J Pathol 1995;146:688–94.

    PubMed  CAS  Google Scholar 

  111. Ritz E, Deppisch R, Nawroth P. Toxicity of uraemia — does it come of AGE? Nephrol Dial Transplant 1994;9:1–2.

    PubMed  CAS  Google Scholar 

  112. Robinson B, van der Jagd DL, Taylor KK, et al. A new integrative theory of diabetic complications. Clin Res 1992;40:81A

    Google Scholar 

  113. Sakata N, Meng J, Jinn S, et al. Nonenzymatic glycatin and extractability of collagen in human atherosclerotic plaques. Atherosclerosis 1995;116:63–75.

    Article  PubMed  CAS  Google Scholar 

  114. Schmidt AM, Hori O, Breet J, Yan SD, et al. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfumction in the pathogenesis of vascular lesions. Arterioscler Thromb 1994;14:1521–8.

    PubMed  CAS  Google Scholar 

  115. Schmidt AM, Mora R, Cao R, et al. The endothelial cell binding site for advanced glycation end products consists of a complex: an integral membrane protein and a lactoferrin-like polypeptide. J Biol Chem 1994;269:9882–8.

    PubMed  CAS  Google Scholar 

  116. Schmidt AM, Vianna M, Gerlach M, et al. Isolation and characterisation of binding proteins for advanced glycation end products from lung tissue which are present on the endothelial surface. J Biol Chem 267 (1992), 14987–97.

    PubMed  CAS  Google Scholar 

  117. Schmidt AM, Yan SD, Stern DM. The dark side of glucose. Nature Med 1995;1:1002–4.

    Article  PubMed  CAS  Google Scholar 

  118. Sell DR, Monnier V. End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen. J Clin Invest 1990;85:380–4.

    Article  PubMed  CAS  Google Scholar 

  119. Simone-Schnaß I, Rosak C, Tritschler HJ, et al. Alpha-Tocopherolaufnahme und -zufuhr bei Typ-II-Diabetikern. Diab Stoffw 1997;6:Suppl 2:16–9.

    Google Scholar 

  120. Sinclair AJ, Girling AJ, Gray L, et al. Disturbed handling of ascorbic acid in diabetic patients with and without microangiopathy during high dose ascorbate supplementation. Diabetologia 1991;34:171–5.

    Article  PubMed  CAS  Google Scholar 

  121. Sinclair AJ, Taylor PB, Lunec J, et al. Low plasma ascorbate in patients with type 2 diabetes mellitus consuming adaequate dietary vitamin C. Diabet Med 1994;11:893–8.

    Article  PubMed  CAS  Google Scholar 

  122. Soulis-Liparota T, Cooper M, Papazoglou D, et al. Retardation by aminoguanidine of development of albuminuria, mesangial expansion and tissue fluorescence in streptozocin-induced diabetic rats. Diabetes 1991;40:1328–34.

    Article  PubMed  CAS  Google Scholar 

  123. Srivastava S, Joshi CS, Sethi PP, et al. Altered platelet function in non-insulin-dependent diabetes mellitus (NIDDM). Thromb Res 1994:76:451–61.

    Article  PubMed  CAS  Google Scholar 

  124. Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781–6.

    Article  PubMed  CAS  Google Scholar 

  125. Stevens VJ, Rouzer CA, Monnier VM, et al. Diabetic cataract formation: potential role of glycosylation of lens crystallins. Proc Natl Acad Sci USA 1978;75:2918–22.

    Article  PubMed  CAS  Google Scholar 

  126. Suzuki YJ, Tsuchiya M, Packer L. Lipoate prevents glucose-induced protein modifications. Free Radic Res Commun 1992;17:211–7.

    Article  PubMed  CAS  Google Scholar 

  127. Takara K, Horiuchi S, Araki M, et al. Endocytic uptake of nonenzymatically glycosylated proteins is mediated by a scavenger receptor for aldehyde-modified proteins. J Biol Chem 1988;263:14819–25.

    Google Scholar 

  128. Takata K, Horiuchi S, Araki N, et al. Scavenger receptor of human leukemia cell line (THP-1) and murine macrophages for nonenzymatically glycosylated proteins. Biochim Biophys Acta 1989;986:18–26.

    Article  PubMed  CAS  Google Scholar 

  129. Tilton R, Chang K, Hasan K, et al. Prevention of vascular dysfunction by guanidines. Diabetes 1993;43: 221–32.

    Article  Google Scholar 

  130. Traber MG. Relationship of plasma and dietary vitamin E. Diab Stoffw 1997;6:Suppl 2:11–5.

    Google Scholar 

  131. Vasan S, Zhang X, Zhang X, et al. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature 1996;382:275–8.

    Article  PubMed  CAS  Google Scholar 

  132. Vlassara H. Advanced glycation in diabetic renal and vascular disease. Kidney Int 1995;48:Suppl 51:43–4.

    Google Scholar 

  133. Vlassara H. Protein glycation in the kidney: role in diabetes and aging. Kidney Int 1996;49:1795–1804.

    Article  PubMed  CAS  Google Scholar 

  134. Vlassara H. Advanced glycation end-products and atherosclerosis. Ann Med 1996;28:419–26.

    Article  PubMed  CAS  Google Scholar 

  135. Vlassara H. Pathogenesis of diabetic nephropathy, advanced glycation and new therapy. Med Klin 1997;92:Suppl 1:29–34.

    Article  Google Scholar 

  136. Vlassara H, Brownlee M, Cerami A. High affinity receptor mediated uptake and degradation of glucose modified proteins: a potential mechanism for the removal of senscent macromolecules. Proc Natl Acad Sci USA 1985;82:5588–92.

    Article  PubMed  CAS  Google Scholar 

  137. Vlassara H, Brownlee M, Cerami A. The novel macrophage receptor for glucose-modified proteins is distinct from previously described scavenger-receptors. J Exp Med 1986;164:1301–9.

    Article  PubMed  CAS  Google Scholar 

  138. Vlassara H, Brownlee M, Cerami A. Specific macrophage receptor activity for advanced glycosylation end products inversely correlates with insulin levels in vivo. Diabetes 1988;37:456–61.

    Article  PubMed  CAS  Google Scholar 

  139. Vlassara H, Brownlee M, Manogue KR, et al. Cachectin/TNF and IL1 induced by glucose-modified proteins: role in normal tissue remodelling. Science 1988;240:1546–8.

    Article  PubMed  CAS  Google Scholar 

  140. Vlassara H, Bucala R, Striker L. Pathogenic effects of advanced glycosylation: biochemical, biological and clinical implications for diabetes and aging. Lab Invest 1994;70:138–51.

    PubMed  CAS  Google Scholar 

  141. Vlassara H, Fuh H, Donnelly T, et al. Advanced glycation endproducts promote adhesion molecule (VCAM-1, ICAM-1) expression and atheroma formation in normal rabbits. Mol Med 1995;1:447–56.

    PubMed  CAS  Google Scholar 

  142. Vlassara H, Li Y-M, Imani F, et al. Identification of galectin-3 as a high affinity binding protein for advanced glycation end products (AGEs): a new member of the AGE-receptor complex. Mol Med 1996;1:634–46.

    Google Scholar 

  143. Vlassara H, Striker LJ, Teichberg S, et al. Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats. Proc Natl Acad Sci USA 1994;91:11704–8.

    Article  PubMed  CAS  Google Scholar 

  144. Wautier JL, Wautier MP, Schmidt AM, et al. Advanced glycation end products (AGEs) on the surface of diabetic erythrocytes bind to the vessel wall via a specific receptor inducing oxidant stress in the vasculature: a link between surface-associated AGEs and diabetic complications. Proc Natl Acad Sci USA 1994;91:7742–6.

    Article  PubMed  CAS  Google Scholar 

  145. Wautier JL, Zoukourian C, Chappey O, et al. Receptormediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Invest 1996;97:238–43.

    Article  PubMed  CAS  Google Scholar 

  146. Wells-Knecht KJ, Lyons TJ, Lyons TJ, et al. 3-Desoxyfructose concentrations are increased in human plasma and urine in diabetes. Diabetes 1994;443:1152–6.

    Article  Google Scholar 

  147. Wells-Knecht KJ, Zyzak DV, Litchfield JE, et al. Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose. Biochemistry 1995;34:3702–9.

    Article  PubMed  CAS  Google Scholar 

  148. Wells-Knecht M, Thorpe SR, Baynes JW. Pathways of formation of glycoxidation products during glycation of collagen. Biochemistry 1995;34:15134–141.

    Article  PubMed  CAS  Google Scholar 

  149. Wisotzky J, Sommer M, Schubert K, et al. Die Akkumulation von AGEs im Alterungsprozeß, bei Diabetes mellitus und bei der chronischen Niereninsuffizienz. Med Klin 1996;91:454–7.

    CAS  Google Scholar 

  150. Yagihashi S, Kamijo M, Baba M, et al. Effects of aminoguanidine on functional and structural abnormalitis in peripheral nerve of STZ-induced diabetic rats. Diabetes 1992;41:47–52.

    Article  PubMed  CAS  Google Scholar 

  151. Yan SD, Chen X, Fu J, et al. RAGE and amyloid-b-peptide neurotoxicity in Alzheimer’s disease. Nature 1996;382:685–91.

    Article  PubMed  CAS  Google Scholar 

  152. Yan SD, Schmidt AM, Anderson GM, et al. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem 1994;269:9889–97.

    PubMed  CAS  Google Scholar 

  153. Yan S-D, Yan SF, Chen X, et al. Non-enzymatically glycated tau in Alzheimer’s disease induceds neuronal oxidant stress resulting in cytokine gene expression and release of amyloid b-peptide. Nat Med 1995;1:693–9.

    Article  PubMed  CAS  Google Scholar 

  154. Yang CW, Vlassara H, Peten EP, et al. Advanced glycation endproducts upregulate gene expression found in diabetic glomerular disease. Proc Natl Acad Sci USA 1994;91:9436–40.

    Article  PubMed  CAS  Google Scholar 

  155. Yang Z, Makita Z, Horii Y, et al. Two novel rat liver membrane proteins that bind advanced glycosylation endoproducts: relationship to macrophage receptor for glucose-modified proteins. J Exp Med 1991;174: 515–24.

    Article  PubMed  CAS  Google Scholar 

  156. Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant a-lipoic acid. Diabetologia 1995;38: 1425–33.

    Article  PubMed  CAS  Google Scholar 

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  1. Innere Medizin I, Endokrinologie und Stoffwechsel der Universität Heidelberg, Bergheimer Straße 58, D-69115, Heidelberg, Deutschland

    Peter P. Nawroth & Reinhard Ziegler

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Nawroth, P.P., Bierhaus, A., Vogel, G.E. et al. Nichtenzymatische Glykierung und oxidativer Streß bei chronischen Erkrankungen und Diabetes mellitus. Med Klin 94, 29–38 (1999). https://doi.org/10.1007/BF03044692

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