, 39:946 | Cite as

The role of glycation cross-links in diabetic vascular stiffening

  • T. J. Sims
  • L. M. Rasmussen
  • H. Oxlund
  • A. J. Bailey


Previous studies have shown that biomechanical analysis of aorta from diabetic subjects reveals a marked increase in stiffness compared to aorta from age-matched control subjects. In the present paper we have proposed that this increased stiffness can be attributed to glycation-induced inter-molecular cross-links based on a direct analysis of the two known glycation cross-links, the fluorescent pentosidine and the non-fluorescent NFC-1. There was a significant difference in the increase in concentration of both cross-links with increasing age for both the intima (p<0.0025) and the media (p<0.0005) from the diabetic compared to the control subjects, but no correlation with the mature enzymic cross-link hydroxylysyl-pyridinoline. Finally, we have obtained a significant correlation of stiffness with both glycation cross-links (NFC-1, r=0.86; p<0.005 and pentosidine r=0.75, p<0.05), but the concentration of NFC-1 is about 50 times greater than that of pentosidine, indicating that it is the major glycation cross-link responsible for the stiffening of the aorta.


Diabetes mellitus glycation cross-links vascular stiffening 



Advanced glycation end-product


furoyl-furanyl imidazole




  1. 1.
    Banga JD, Sixma JJ (1984) Diabetes mellitus, vascular disease and thrombosis. Clinics in Haematology 15: 465–492Google Scholar
  2. 2.
    Garcia MJ, McNamara T, Kannell WB (1974) Morbidity and mortality in diabetes in the Framingham population; sixteen year follow-up study. Diabetes 23: 105–111PubMedGoogle Scholar
  3. 3.
    Kannell WB, McGee DL (1979) Diabetes and cardiovascular disease. The Framingham Study. JAMA 241: 2035–2038CrossRefGoogle Scholar
  4. 4.
    Baynes JW, Monnier VW (1989) The Maillard reaction in aging, diabetes and nutrition. Prog Chem Biol Res 304: 1–410Google Scholar
  5. 5.
    Pongor S, Ulrich PC, Benscath FA, Cerami A (1984) Aging of proteins: isolation and identification of a fluorescent chromophore from the reaction of polypeptides with glucose. Proc Natl Acad Sci USA 81: 2684–2688PubMedCrossRefGoogle Scholar
  6. 6.
    Njoroge FG, Fernades AA, Monnier VM (1988) Mechanism of formation of the putative advanced glycosylation and protein cross-link 2-(2-furoyl)-4-(5)-(2-furanyl)-1H-imidazole. J Biol Chem 263: 10646–10652PubMedGoogle Scholar
  7. 7.
    Chang JCF, Ulrich PC, Bucala R, Cerami A (1985) Detection of advanced glycosylation products bound to protein in situ. J Biol Chem 260: 7970–7974PubMedGoogle Scholar
  8. 8.
    Ahmed MU, Thorpe SR, Baynes JW (1986) Identification of N-carboxymethyllysine as a degradation product of fructoselysine in glycated proteins. J Biol Chem 261: 4889–4894PubMedGoogle Scholar
  9. 9.
    Portero-Otin M, Najaraj RH, Monnier VM (1995) Chromatographic evidence for pyrraline formation during protein glycation in vitro and in vivo. Biochim Biophys Acta 1247: 74–80PubMedGoogle Scholar
  10. 10.
    Sell DR, Monnier VM (1989) Structure elucidation of a senesescence cross-link from human extracellular matrix. J Biol Chem 264: 21597–21602PubMedGoogle Scholar
  11. 11.
    Bailey AJ, Sims TJ, Avery NC, Halligan EP (1995) Non-enzymic glycation of fibrous collagen: reaction products of glucose and ribose. Biochem J 305: 385–390PubMedGoogle Scholar
  12. 12.
    Fu M, Knetch KJ, Thorpe SR, Baynes JW (1992) Role of oxygen in cross-linking and chemical modification of collagen by glucose. Diabetes 41: 42–48PubMedGoogle Scholar
  13. 13.
    Wolff SP, Dean RT (1987) Glucose oxidation and protein modification. Biochem J 245: 243–250PubMedGoogle Scholar
  14. 14.
    Brownlee M (1992) Non-enzymatic glycosylation of macromolecules. Prospects of pharmacological modulation. Diabetes 41: 57–60PubMedGoogle Scholar
  15. 15.
    Oxlund H, Andreassen TT (1992) Aminoguanidine treatment reduces the increase in collagen stability of rats with experimental diabetes mellitus. Diabetologia 35: 19–25PubMedCrossRefGoogle Scholar
  16. 16.
    Hirsch J, Petrakova E, Feather MS, Barnes CC (1995) The reaction of d-glucose with aminoguanidine. Carbohydrate Res 267: 17–25CrossRefGoogle Scholar
  17. 17.
    Paul GP, Bailey AJ (1996) Glycation of collagen. The basis of its central role in the late complications of diabetes mellitus. Intern J Biochem Cell Biol (In press)Google Scholar
  18. 18.
    Hocks APG, Ruisson CM, Hick P, Reneman RS (1985) Transcutaneous detection of relative changes in artery diameter. Ultrasound Med Biol 11: 51–59CrossRefGoogle Scholar
  19. 19.
    Thordason H, Neubauer B (1987) Arterial wall stiffness in insulin-dependent diabetes. An echocardiographic study. Diabet Med 3: 449–454CrossRefGoogle Scholar
  20. 20.
    Brownlee M, Vlassara H, Kooney A, Ulrich P, Cerami A (1986) Aminoguanidine prevents diabetic induced arterial wall protein cross-linking. Science 232: 1629–1632PubMedCrossRefGoogle Scholar
  21. 21.
    Airaksinen KEJ, Salmela PI, Linnaluoto MK, Ikaheimo MJ, Ryhanen LJ (1993) Diminished arterial elasticity in diabetes: association with fluorescent advanced glycosylation end-products in collagen. Cardiovascular Res 27: 942–945CrossRefGoogle Scholar
  22. 22.
    Oxlund H, Rasmussen LM, Andreassen TT, Heickendorff L (1989) Increased aortic stiffness in patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 32: 748–752PubMedCrossRefGoogle Scholar
  23. 23.
    Andreassen TT, Seyer-Hansen K, Bailey AJ (1981) Thermal stability, mechanical properties and reducible cross-links of rat tail tendon in experimental diabetes. Biochim Biophys Acta 677: 313–317PubMedGoogle Scholar
  24. 24.
    Sims TJ, Bailey AJ (1992) Quantitative analysis of collagen and elastin cross-links using a single column system. J Chromatog 582: 49–55CrossRefGoogle Scholar
  25. 25.
    Bailey AJ, Sims TJ, Avery NC, Miles CA (1993) Chemistry of collagen cross-links. Biochem J 296: 489–496PubMedGoogle Scholar
  26. 26.
    Bannister DW, Burns AB (1970) Adaptation of the Bergman and Loxley technique for hydroxyproline determination of the autoanalyser. Analyst 95: 596–600PubMedCrossRefGoogle Scholar
  27. 27.
    Bailey AJ (1995) The non-enzymic glycation of elastin. Ciba Foundation Symposium 192. The molecular biology and pathology of elastin. John Wiley, Chichester, pp 304–306Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • T. J. Sims
    • 1
  • L. M. Rasmussen
    • 2
  • H. Oxlund
    • 2
  • A. J. Bailey
    • 1
  1. 1.Collagen Research Group, Division of Molecular and Cellular BiologyUniversity of BristolLangfordUK
  2. 2.Department of Connective Tissue Biology, Institute of AnatomyUniversity of AarhusAarhusDenmark

Personalised recommendations