Zeitschrift für Gerontologie und Geriatrie

, Volume 45, Issue 2, pp 95–101 | Cite as

Proteinglykierung als pathophysiologischer Mechanismus bei Diabetes

  • A. Simm
  • A. Navarrete-Santos
  • B. Hofmann
  • H. Bushnaq
  • N. Nass
Beiträge zum Themenschwerpunkt


Die Inzidenz für Diabetes ist in den letzten Jahren stark gestiegen. Diabetes ist durch erhöhte Zuckerkonzentrationen im Blut gekennzeichnet. Infolge dieser Dysregulation entstehen endogen vermehrt zuckerinduzierte Modifikationen von Proteinen, sog. fortgeschrittene Glykierungsendprodukte („advanced glycation end products“, AGEs), durch chemische, nichtenzymatische Reaktionen. Diese sollen ursächlich zur Pathophysiologie von diabetesassoziierten Folgeerkrankungen beitragen. Die Akkumulation von AGEs im Gewebe kann als Prädiktor für die Prognose von Patienten mit Diabetes dienen. Die gesundheitlichen Effekte der über die Nahrung aufgenommenen AGEs sind dagegen immer noch unklar.


Glykierungsendprodukte Blutglukose Diabetesassoziierte Komplikationen Entzündung Biomarker 

Protein glycation as a pathological mechanism in diabetes


The incidence of diabetes has increased in the recent years. Diabetes is characterized by increased sugar concentrations in the blood. Due to this dysregulation, more carbohydrate-induced modification of proteins – so-called advanced glycation end products (AGEs) – are formed endogenously by non-enzymatic reactions. These are discussed to be at least in part responsible for diabetes-associated diseases. The accumulation of AGEs in the tissue can be used as a biomarker for patient outcome. In contrast, the effects of the uptake of AGEs from nutrition are still unclear.


Advanced glycation end products Blood glucose Diabetes complications Inflammation Biomarkers 



Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.


  1. 1.
    Centers for Disease Control and Prevention (2007) National surveillance data. CDC, Atlanta/GA. http://apps.nccd.cdc.gov/DDTSTRS/NationalSurvData.aspx. Zugegriffen: 23.09.2011Google Scholar
  2. 2.
    Olshansky SJ et al (2005) A potential decline in life expectancy in the United States in the 21st century. N Engl J Med 352(11):1138–1145PubMedCrossRefGoogle Scholar
  3. 3.
    Nass N, Simm A (2009) Advanced glycation end products (AGEs) in diabetes. Abhandlungen Sächsische Akademie der Wissenschaften zu Leipzig 65(3):63–75Google Scholar
  4. 4.
    Maillard LC (1912) Action des acides amines sur les sucres: formation des melanoidines par voie methodique. CR Acad Sci Ser 154:66–68Google Scholar
  5. 5.
    Nass N et al (2007) Advanced glycation end products, diabetes and ageing. Z Gerontol Geriatr 40(5):349–356PubMedCrossRefGoogle Scholar
  6. 6.
    Bunn HF, Higgins PJ (1981) Reaction of monosaccharides with proteins: possible evolutionary significance. Science 213(4504):222–224PubMedCrossRefGoogle Scholar
  7. 7.
    Sebekova K et al (2001) Plasma levels of advanced glycation end products in healthy, long-term vegetarians and subjects on a western mixed diet. Eur J Nutr 40(6):275–281PubMedCrossRefGoogle Scholar
  8. 8.
    Sato T et al (2006) TAGE (toxic AGEs) theory in diabetic complications. Curr Mol Med 6(3):351–358PubMedCrossRefGoogle Scholar
  9. 9.
    Mericq V et al (2010) Maternally transmitted and food-derived glycotoxins: a factor preconditioning the young to diabetes? Diabetes Care 33(10):2232–2237PubMedCrossRefGoogle Scholar
  10. 10.
    Cai W et al (2007) Reduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet: association with increased AGER1 expression. Am J Pathol 170(6):1893–1902PubMedCrossRefGoogle Scholar
  11. 11.
    Sebekova K, Somoza V (2007) Dietary advanced glycation endproducts (AGEs) and their health effects – PRO. Mol Nutr Food Res 51(9):1079–1084PubMedCrossRefGoogle Scholar
  12. 12.
    Stolzing A et al (2006) Degradation of glycated bovine serum albumin in microglial cells. Free Radic Biol Med 40(6):1017–1027PubMedCrossRefGoogle Scholar
  13. 13.
    Nass N et al (2010) Glycation of PDGF results in decreased biological activity. Int J Biochem Cell Biol 42(5):749–754PubMedCrossRefGoogle Scholar
  14. 14.
    O’Harte FP et al (1996) Identification of the site of glycation of human insulin. Peptides 17(8):1323–1330CrossRefGoogle Scholar
  15. 15.
    Bartling B et al (2009) Age-associated changes of extracellular matrix collagen impair lung cancer cell migration. Faseb J 23(5):1510–1520PubMedCrossRefGoogle Scholar
  16. 16.
    Konova E et al (2004) Age-related changes in the glycation of human aortic elastin. Exp Gerontol 39(2):249–254PubMedCrossRefGoogle Scholar
  17. 17.
    Hernebring M et al (2006) Elimination of damaged proteins during differentiation of embryonic stem cells. Proc Natl Acad Sci USA 103(20):7700–7705PubMedCrossRefGoogle Scholar
  18. 18.
    Vlassara H (2001) The AGE-receptor in the pathogenesis of diabetic complications. Diabetes Metab Res Rev 17(6):436–4343PubMedCrossRefGoogle Scholar
  19. 19.
    Schmidt AM et al (2000) RAGE: a multiligand receptor contributing to the cellular response in diabetic vasculopathy and inflammation. Semin Thromb Hemost 26(5):485–493PubMedCrossRefGoogle Scholar
  20. 20.
    Sourris KC, Forbes JM (2009) Interactions between advanced glycation end-products (AGE) and their receptors in the development and progression of diabetic nephropathy – are these receptors valid therapeutic targets. Curr Drug Targets 10(1):42–50PubMedCrossRefGoogle Scholar
  21. 21.
    Bierhaus A, Humpert PM, Nawroth PP (2006) Linking stress to inflammation. Anesthesiol Clin 24(2):325–340PubMedCrossRefGoogle Scholar
  22. 22.
    Dronavalli S, Duka I, Bakris GL (2008) The pathogenesis of diabetic nephropathy. Nat Clin Pract Endocrinol Metab 4(8):444–452PubMedCrossRefGoogle Scholar
  23. 23.
    Vlassara H (1994) Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats. Proc Natl Acad Sci USA 91(24):11704–11708PubMedCrossRefGoogle Scholar
  24. 24.
    YamamotoY et al (2001) Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice. J Clin Invest 108(2):261–268Google Scholar
  25. 25.
    Iacobini C et al (2005) Development of age-dependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice. Am J Physiol Renal Physiol 289(3):611–621CrossRefGoogle Scholar
  26. 26.
    Myint KM et al (2006) RAGE control of diabetic nephropathy in a mouse model: effects of RAGE gene disruption and administration of low-molecular weight heparin. Diabetes 55(9):2510–2522PubMedCrossRefGoogle Scholar
  27. 27.
    Miyata T et al (1998) Renal catabolism of advanced glycation end products: the fate of pentosidine. Kidney Int 53(2):416–422PubMedCrossRefGoogle Scholar
  28. 28.
    Forbes JM et al (2001) Renoprotective effects of a novel inhibitor of advanced glycation. Diabetologia 44(1):108–114PubMedCrossRefGoogle Scholar
  29. 29.
    Bhattacharyya J et al (2007) Effect of a single AGE modification on the structure and chaperone activity of human alphaB-crystallin. Biochemistry 46(50):14682–14692PubMedCrossRefGoogle Scholar
  30. 30.
    Fong DS et al (2004) Retinopathy in diabetes. Diabetes Care 27 (Suppl 1):84–87CrossRefGoogle Scholar
  31. 31.
    Khan ZA, Chakrabarti S (2007) Cellular signaling and potential new treatment targets in diabetic retinopathy. Exp Diabetes Res 2007:31867PubMedCrossRefGoogle Scholar
  32. 32.
    Madsen-Bouterse SA, Kowluru RA (2008) Oxidative stress and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Rev Endocr Metab DisordGoogle Scholar
  33. 33.
    Barile GR, Schmidt AM (2007) RAGE and its ligands in retinal disease. Curr Mol Med 7(8):758–765PubMedCrossRefGoogle Scholar
  34. 34.
    Stitt AW et al (1997) Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats. Am J Pathol 150(2):523–531PubMedGoogle Scholar
  35. 35.
    Amano S et al (2001) Advanced glycation end products in human optic nerve head. Br J Ophthalmol 85(1):52–55PubMedCrossRefGoogle Scholar
  36. 36.
    Stitt AW et al (2004) Substrates modified by advanced glycation end-products cause dysfunction and death in retinal pericytes by reducing survival signals mediated by platelet-derived growth factor. Diabetologia 47(10):1735–1746PubMedCrossRefGoogle Scholar
  37. 37.
    Chen AS et al (2004) Pyridoxal-aminoguanidine adduct is more effective than aminoguanidine in preventing neuropathy and cataract in diabetic rats. Horm Metab Res 36(3):183–187PubMedCrossRefGoogle Scholar
  38. 38.
    Ino-ue M, Ohgiya N, Yamamoto M (1998) Effect of aminoguanidine on optic nerve involvement in experimental diabetic rats. Brain Res 800(2):319–322PubMedCrossRefGoogle Scholar
  39. 39.
    Mazzone T, Chait A, Plutzky J (2008) Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet 371(9626):1800–1809PubMedCrossRefGoogle Scholar
  40. 40.
    Brownlee M et al (1986) Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science 232(4758):1629–1632PubMedCrossRefGoogle Scholar
  41. 41.
    Vlassara H et al (1995) Advanced glycation endproducts promote adhesion molecule (VCAM-1, ICAM-1) expression and atheroma formation in normal rabbits. Mol Med 1(4):447–456PubMedGoogle Scholar
  42. 42.
    Endemann G et al (1993) CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem 268(16):11811–11816PubMedGoogle Scholar
  43. 43.
    Ohgami N et al (2003) Advanced glycation end products (AGE) inhibit scavenger receptor class B type I-mediated reverse cholesterol transport: a new crossroad of AGE to cholesterol metabolism. J Atheroscler Thromb 10(1):1–6PubMedCrossRefGoogle Scholar
  44. 44.
    Park L et al (1998) Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat Med 4(9):1025–1031PubMedCrossRefGoogle Scholar
  45. 45.
    Koyama Y et al (2008) Soluble receptor for advanced glycation end products (RAGE) is a prognostic factor for heart failure. J Card Fail 14(2):133–139PubMedCrossRefGoogle Scholar
  46. 46.
    Koyama H et al (2005) Plasma level of endogenous secretory RAGE is associated with components of the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol 25(12):2587–2593PubMedCrossRefGoogle Scholar
  47. 47.
    Koyama H et al (2007) Low circulating endogenous secretory receptor for AGEs predicts cardiovascular mortality in patients with end-stage renal disease. Arterioscler Thromb Vasc Biol 27(1):147–153PubMedCrossRefGoogle Scholar
  48. 48.
    Pahl HL (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18(49):6853–6866PubMedCrossRefGoogle Scholar
  49. 49.
    Wellen KE, Hotamisligil GS (2005) Inflammation, stress, and diabetes. J Clin Invest 115(5):1111–1119PubMedGoogle Scholar
  50. 50.
    Bartling B et al (2011) Effect of diabetes mellitus on the outcome of patients with resected non-small cell lung carcinoma. Gerontology 57(6):497–501PubMedCrossRefGoogle Scholar
  51. 51.
    Bartling B et al (2011) Prognostic potential and tumor growth-inhibiting effect of plasma advanced glycation end products in non-small cell lung carcinoma. Mol Med 17(9–10):980–989Google Scholar
  52. 52.
    Schleicher ED, Wagner E, Nerlich AG (1997) Increased accumulation of the glycoxidation product N(epsilon)-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest 99(3):457–468PubMedCrossRefGoogle Scholar
  53. 53.
    Sell DR, Kleinman NR, Monnier VM (2000) Longitudinal determination of skin collagen glycation and glycoxidation rates predicts early death in C57BL/6NNIA mice. Faseb J 14(1):145–156PubMedGoogle Scholar
  54. 54.
    Aso Y et al (2000) Serum concentrations of advanced glycation endproducts are associated with the development of atherosclerosis as well as diabetic microangiopathy in patients with type 2 diabetes. Acta Diabetol 37(2):87–92PubMedCrossRefGoogle Scholar
  55. 55.
    Haus JM et al (2007) Collagen, cross-linking, and advanced glycation end products in aging human skeletal muscle. J Appl Physiol 103(6):2068–2076PubMedCrossRefGoogle Scholar
  56. 56.
    Meerwaldt R et al (2007) Skin autofluorescence is a strong predictor of cardiac mortality in diabetes. Diabetes Care 30(1):107–112PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • A. Simm
    • 1
  • A. Navarrete-Santos
    • 1
  • B. Hofmann
    • 1
  • H. Bushnaq
    • 1
  • N. Nass
    • 1
  1. 1.Klinik und Poliklinik für Herz und ThoraxchirurgieUniversitätsklinikum Halle (Saale)HalleDeutschland

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