Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Aug 15;100(4):839–846. doi: 10.1172/JCI119599

Age-dependent increase in ortho-tyrosine and methionine sulfoxide in human skin collagen is not accelerated in diabetes. Evidence against a generalized increase in oxidative stress in diabetes.

M C Wells-Knecht 1, T J Lyons 1, D R McCance 1, S R Thorpe 1, J W Baynes 1
PMCID: PMC508256  PMID: 9259583

Abstract

The glycoxidation products Nepsilon-(carboxymethyl)lysine and pentosidine increase in skin collagen with age and at an accelerated rate in diabetes. Their age-adjusted concentrations in skin collagen are correlated with the severity of diabetic complications. To determine the relative roles of increased glycation and/or oxidation in the accelerated formation of glycoxidation products in diabetes, we measured levels of amino acid oxidation products, distinct from glycoxidative modifications of amino acids, as independent indicators of oxidative stress and damage to collagen in aging and diabetes. We show that ortho-tyrosine and methionine sulfoxide are formed in concert with Nepsilon-(carboxymethyl)lysine and pentosidine during glycoxidation of collagen in vitro, and that they also increase with age in human skin collagen. The age-adjusted levels of these oxidized amino acids in collagen was the same in diabetic and nondiabetic subjects, arguing that diabetes per se does not cause an increase in oxidative stress or damage to extracellular matrix proteins. These results provide evidence for an age-dependent increase in oxidative damage to collagen and support previous conclusions that the increase in glycoxidation products in skin collagen in diabetes can be explained by the increase in glycemia alone, without invoking a generalized, diabetes-dependent increase in oxidative stress.

Full Text

The Full Text of this article is available as a PDF (217.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baynes J. W. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991 Apr;40(4):405–412. doi: 10.2337/diab.40.4.405. [DOI] [PubMed] [Google Scholar]
  2. Beisswenger P. J., Moore L. L., Brinck-Johnsen T., Curphey T. J. Increased collagen-linked pentosidine levels and advanced glycosylation end products in early diabetic nephropathy. J Clin Invest. 1993 Jul;92(1):212–217. doi: 10.1172/JCI116552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brot N., Weissbach H. Biochemistry and physiological role of methionine sulfoxide residues in proteins. Arch Biochem Biophys. 1983 May;223(1):271–281. doi: 10.1016/0003-9861(83)90592-1. [DOI] [PubMed] [Google Scholar]
  4. Cameron N. E., Cotter M. A. Potential therapeutic approaches to the treatment or prevention of diabetic neuropathy: evidence from experimental studies. Diabet Med. 1993 Aug-Sep;10(7):593–605. doi: 10.1111/j.1464-5491.1993.tb00131.x. [DOI] [PubMed] [Google Scholar]
  5. Ceriello A., dello Russo P., Amstad P., Cerutti P. High glucose induces antioxidant enzymes in human endothelial cells in culture. Evidence linking hyperglycemia and oxidative stress. Diabetes. 1996 Apr;45(4):471–477. doi: 10.2337/diab.45.4.471. [DOI] [PubMed] [Google Scholar]
  6. Cotter M. A., Love A., Watt M. J., Cameron N. E., Dines K. C. Effects of natural free radical scavengers on peripheral nerve and neurovascular function in diabetic rats. Diabetologia. 1995 Nov;38(11):1285–1294. doi: 10.1007/BF00401760. [DOI] [PubMed] [Google Scholar]
  7. Dyer D. G., Blackledge J. A., Thorpe S. R., Baynes J. W. 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 Jun 25;266(18):11654–11660. [PubMed] [Google Scholar]
  8. Dyer D. G., Dunn J. A., Thorpe S. R., Bailie K. E., Lyons T. J., McCance D. R., Baynes J. W. Accumulation of Maillard reaction products in skin collagen in diabetes and aging. J Clin Invest. 1993 Jun;91(6):2463–2469. doi: 10.1172/JCI116481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Elgawish A., Glomb M., Friedlander M., Monnier V. M. Involvement of hydrogen peroxide in collagen cross-linking by high glucose in vitro and in vivo. J Biol Chem. 1996 May 31;271(22):12964–12971. doi: 10.1074/jbc.271.22.12964. [DOI] [PubMed] [Google Scholar]
  10. Fu M. X., Knecht K. J., Thorpe S. R., Baynes J. W. Role of oxygen in cross-linking and chemical modification of collagen by glucose. Diabetes. 1992 Oct;41 (Suppl 2):42–48. doi: 10.2337/diab.41.2.s42. [DOI] [PubMed] [Google Scholar]
  11. Fu M. X., Requena J. R., Jenkins A. J., Lyons T. J., Baynes J. W., Thorpe S. R. The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions. J Biol Chem. 1996 Apr 26;271(17):9982–9986. doi: 10.1074/jbc.271.17.9982. [DOI] [PubMed] [Google Scholar]
  12. Fu M. X., Wells-Knecht K. J., Blackledge J. A., Lyons T. J., Thorpe S. R., Baynes J. W. Glycation, glycoxidation, and cross-linking of collagen by glucose. Kinetics, mechanisms, and inhibition of late stages of the Maillard reaction. Diabetes. 1994 May;43(5):676–683. doi: 10.2337/diab.43.5.676. [DOI] [PubMed] [Google Scholar]
  13. Giugliano D., Ceriello A., Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care. 1996 Mar;19(3):257–267. doi: 10.2337/diacare.19.3.257. [DOI] [PubMed] [Google Scholar]
  14. Grandhee S. K., Monnier V. M. Mechanism of formation of the Maillard protein cross-link pentosidine. Glucose, fructose, and ascorbate as pentosidine precursors. J Biol Chem. 1991 Jun 25;266(18):11649–11653. [PubMed] [Google Scholar]
  15. Harman D. Role of free radicals in aging and disease. Ann N Y Acad Sci. 1992 Dec 26;673:126–141. doi: 10.1111/j.1749-6632.1992.tb27444.x. [DOI] [PubMed] [Google Scholar]
  16. Huggins T. G., Wells-Knecht M. C., Detorie N. A., Baynes J. W., Thorpe S. R. Formation of o-tyrosine and dityrosine in proteins during radiolytic and metal-catalyzed oxidation. J Biol Chem. 1993 Jun 15;268(17):12341–12347. [PubMed] [Google Scholar]
  17. Jiang Z. Y., Woollard A. C., Wolff S. P. Hydrogen peroxide production during experimental protein glycation. FEBS Lett. 1990 Jul 30;268(1):69–71. doi: 10.1016/0014-5793(90)80974-n. [DOI] [PubMed] [Google Scholar]
  18. Keegan A., Walbank H., Cotter M. A., Cameron N. E. Chronic vitamin E treatment prevents defective endothelium-dependent relaxation in diabetic rat aorta. Diabetologia. 1995 Dec;38(12):1475–1478. doi: 10.1007/BF00400609. [DOI] [PubMed] [Google Scholar]
  19. Knecht K. J., Dunn J. A., McFarland K. F., McCance D. R., Lyons T. J., Thorpe S. R., Baynes J. W. Effect of diabetes and aging on carboxymethyllysine levels in human urine. Diabetes. 1991 Feb;40(2):190–196. doi: 10.2337/diab.40.2.190. [DOI] [PubMed] [Google Scholar]
  20. Kunisaki M., Bursell S. E., Clermont A. C., Ishii H., Ballas L. M., Jirousek M. R., Umeda F., Nawata H., King G. L. Vitamin E prevents diabetes-induced abnormal retinal blood flow via the diacylglycerol-protein kinase C pathway. Am J Physiol. 1995 Aug;269(2 Pt 1):E239–E246. doi: 10.1152/ajpendo.1995.269.2.E239. [DOI] [PubMed] [Google Scholar]
  21. Makita Z., Radoff S., Rayfield E. J., Yang Z., Skolnik E., Delaney V., Friedman E. A., Cerami A., Vlassara H. Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med. 1991 Sep 19;325(12):836–842. doi: 10.1056/NEJM199109193251202. [DOI] [PubMed] [Google Scholar]
  22. McCance D. R., Dyer D. G., Dunn J. A., Bailie K. E., Thorpe S. R., Baynes J. W., Lyons T. J. Maillard reaction products and their relation to complications in insulin-dependent diabetes mellitus. J Clin Invest. 1993 Jun;91(6):2470–2478. doi: 10.1172/JCI116482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Oberley L. W. Free radicals and diabetes. Free Radic Biol Med. 1988;5(2):113–124. doi: 10.1016/0891-5849(88)90036-6. [DOI] [PubMed] [Google Scholar]
  24. Papanastasiou P., Grass L., Rodela H., Patrikarea A., Oreopoulos D., Diamandis E. P. Immunological quantification of advanced glycosylation end-products in the serum of patients on hemodialysis or CAPD. Kidney Int. 1994 Jul;46(1):216–222. doi: 10.1038/ki.1994.262. [DOI] [PubMed] [Google Scholar]
  25. Requena J. R., Fu M. X., Ahmed M. U., Jenkins A. J., Lyons T. J., Baynes J. W., Thorpe S. R. Quantification of malondialdehyde and 4-hydroxynonenal adducts to lysine residues in native and oxidized human low-density lipoprotein. Biochem J. 1997 Feb 15;322(Pt 1):317–325. doi: 10.1042/bj3220317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sagara M., Satoh J., Wada R., Yagihashi S., Takahashi K., Fukuzawa M., Muto G., Muto Y., Toyota T. Inhibition of development of peripheral neuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine. Diabetologia. 1996 Mar;39(3):263–269. doi: 10.1007/BF00418340. [DOI] [PubMed] [Google Scholar]
  27. Schmidt A. M., Hori O., Brett J., Yan S. D., Wautier J. L., Stern D. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb. 1994 Oct;14(10):1521–1528. doi: 10.1161/01.atv.14.10.1521. [DOI] [PubMed] [Google Scholar]
  28. Sell D. R., Lapolla A., Odetti P., Fogarty J., Monnier V. M. Pentosidine formation in skin correlates with severity of complications in individuals with long-standing IDDM. Diabetes. 1992 Oct;41(10):1286–1292. doi: 10.2337/diab.41.10.1286. [DOI] [PubMed] [Google Scholar]
  29. Sell D. R., Monnier V. M. End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen. J Clin Invest. 1990 Feb;85(2):380–384. doi: 10.1172/JCI114449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Stadtman E. R. Role of oxidized amino acids in protein breakdown and stability. Methods Enzymol. 1995;258:379–393. doi: 10.1016/0076-6879(95)58057-3. [DOI] [PubMed] [Google Scholar]
  31. Van Dam P. S., Van Asbeck B. S., Erkelens D. W., Marx J. J., Gispen W. H., Bravenboer B. The role of oxidative stress in neuropathy and other diabetic complications. Diabetes Metab Rev. 1995 Oct;11(3):181–192. doi: 10.1002/dmr.5610110303. [DOI] [PubMed] [Google Scholar]
  32. Vlassara H., Bucala R., Striker L. Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging. Lab Invest. 1994 Feb;70(2):138–151. [PubMed] [Google Scholar]
  33. Vogt W. Oxidation of methionyl residues in proteins: tools, targets, and reversal. Free Radic Biol Med. 1995 Jan;18(1):93–105. doi: 10.1016/0891-5849(94)00158-g. [DOI] [PubMed] [Google Scholar]
  34. Watkins N. G., Neglia-Fisher C. I., Dyer D. G., Thorpe S. R., Baynes J. W. Effect of phosphate on the kinetics and specificity of glycation of protein. J Biol Chem. 1987 May 25;262(15):7207–7212. [PubMed] [Google Scholar]
  35. Wells-Knecht M. C., Huggins T. G., Dyer D. G., Thorpe S. R., Baynes J. W. Oxidized amino acids in lens protein with age. Measurement of o-tyrosine and dityrosine in the aging human lens. J Biol Chem. 1993 Jun 15;268(17):12348–12352. [PubMed] [Google Scholar]
  36. Wells-Knecht M. C., Thorpe S. R., Baynes J. W. Pathways of formation of glycoxidation products during glycation of collagen. Biochemistry. 1995 Nov 21;34(46):15134–15141. doi: 10.1021/bi00046a020. [DOI] [PubMed] [Google Scholar]
  37. Williamson J. R., Chang K., Frangos M., Hasan K. S., Ido Y., Kawamura T., Nyengaard J. R., van den Enden M., Kilo C., Tilton R. G. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes. 1993 Jun;42(6):801–813. doi: 10.2337/diab.42.6.801. [DOI] [PubMed] [Google Scholar]
  38. Wolff S. P., Dean R. T. Glucose autoxidation and protein modification. The potential role of 'autoxidative glycosylation' in diabetes. Biochem J. 1987 Jul 1;245(1):243–250. doi: 10.1042/bj2450243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wolff S. P., Jiang Z. Y., Hunt J. V. Protein glycation and oxidative stress in diabetes mellitus and ageing. Free Radic Biol Med. 1991;10(5):339–352. doi: 10.1016/0891-5849(91)90040-a. [DOI] [PubMed] [Google Scholar]
  40. Zyzak D. V., Richardson J. M., Thorpe S. R., Baynes J. W. Formation of reactive intermediates from Amadori compounds under physiological conditions. Arch Biochem Biophys. 1995 Jan 10;316(1):547–554. doi: 10.1006/abbi.1995.1073. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES