Skip to main content
SpringerLink
Log in

Clinical Potential of Advanced Glycation End-Product Inhibitors in Diabetes Mellitus

  • Leading Article
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Non-enzymatic accumulation of advanced glycation end-products (AGE) is to some extent a physiologic consequence of tissue aging. On the other hand, circulating AGE and tissue deposits mark the course of diabetes mellitus as well as a variety of other vascular or degenerative diseases. AGE generation is paralleled by oxidative damage and lipid peroxidation within target tissue, with features of inflammation through the involvement of monocytes/macrophages expressing receptors for glycated macromolecules. Over the past 15 years, a wealth of data concerning the pharmacology of AGE have been gathered through animal and human investigations, targeting their likely contribution to the progression of diabetic and non-diabetic vascular damage. Several agents have been shown to interfere with the formation of AGE or AGE precursors, bind to tissue receptors, or promote breakdown of deposits. The first and most studied inhibitor, aminoguanidine, has shown extensive beneficial effects in experimental models of diabetic vascular damage, recently entering phase I–III clinical investigation. Newer anti-AGE agents include pyridoxamine and the so-called ‘amadorins’, cross-link breakers, AGE binders and receptor antagonists.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I

Similar content being viewed by others

References

  1. Grandhee SK, Monnier VM. Mechanism of formation of the Maillard protein cross-link pentosidine. J Biol Chem 1991; 266: 11654–60

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Monnier VM, Nagaraj RH, Portero-Otin M, et al. Structure of advanced Maillard reaction products and their pathological role. Nephral Dial Transplant 1996; 11 Suppl. 5: 20–6

    Article  CAS  Google Scholar 

  4. Porte Jr D, Schwartz MW. Diabetic complications: why is glucose potentially toxic? Science 1996; 272: 699–700

    Article  PubMed  CAS  Google Scholar 

  5. Onorato JM, Jenkins AJ, Thorpe SR, et al. Pyridoxamine, an inhibitor of advanced glycation reactions, also inhibits advanced lipoxidation reactions: mechanism of action of pyridoxamine. J Biol Chem 2000; 275: 21177–84

    Article  PubMed  CAS  Google Scholar 

  6. Degenhardt TP, Alderson NL, Arrington DD, et al. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney Int 2002; 61: 939–50

    Article  PubMed  CAS  Google Scholar 

  7. El Khoury J, Thomas C, Loike J, et al. Macrophages adhere to glucose-modified basement membrane collagen IV via their scavenger receptors. J Biol Chem 1994; 269: 10197–200

    PubMed  CAS  Google Scholar 

  8. Schmidt AM, Hori O, Cao R, et al. RAGE: a novel cellular receptor for advanced glycation end products. Diabetes 1996; 45 Suppl. 3: S77–80

    Article  PubMed  CAS  Google Scholar 

  9. Makino H, Shikata K, Hironaka K, et al. Ultrastructure of nonenzymatically glycated mesangial matrix in diabetic nephropathy. Kidney Int 1995; 48: 517–26

    Article  PubMed  CAS  Google Scholar 

  10. Schmidt AM, Hofmann M, Taguchi A, et al. RAGE: a multiligand receptor contributing to the cellular response in diabetic vasculopathy and inflammation. Semin Thromb Hemost 2000; 26: 485–93

    Article  PubMed  CAS  Google Scholar 

  11. 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 U S A 1997; 94: 6474–9

    Article  PubMed  CAS  Google Scholar 

  12. Raj DS, Choudhury D, Welbourne TC, et al. Advanced glycation endproducts: a nephrologist’s perspective. Am J Kidney Dis 2000; 35: 365–80

    Article  PubMed  CAS  Google Scholar 

  13. Yanagisawa K, Makita Z, Shiroshita K, et al. Specific fluorescence assay for advanced glycation end products in blood and urine of diabetic patients. Metabolism 1998; 47: 1348–53

    Article  PubMed  CAS  Google Scholar 

  14. Floridi A, Antolini F, Galli F, et al. Daily haemodialysis improves indices of protein glycation. Nephral Dial Transplant 2002; 17: 871–8

    Article  CAS  Google Scholar 

  15. Sakata N, Imanaga Y, Meng J, et al. Increased advanced glycation end products in atherosclerotic lesions of patients with end-stage renal disease. Atherosclerosis 1999; 142: 67–77

    Article  PubMed  CAS  Google Scholar 

  16. Bucala R. What is the effect of hyperglycemia on atherogenesis and can it be reversed by aminoguanidine? Diabetes Res Clin Pract 1996; 30S: 123–30

    Article  Google Scholar 

  17. Schalkwijk CG, Ligtvoet N, Twaalfhoven H, et al. Amadori albumin in type 1 diabetic patients: correlation with markers of endothelial function, association with diabetic nephropathy, and localization in retinal capillaries. Diabetes 1999; 48: 2446–53

    Article  PubMed  CAS  Google Scholar 

  18. Schmidt AM, Yan SD, Wautier JL, et al. Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res 1999; 84: 489–97

    Article  PubMed  CAS  Google Scholar 

  19. Stitt AW, He C, Vlassara H. Characterization of the advanced glycation endproduct receptor complex in human vascular endothelial cells. Biochem Biophys Res Commun 1999; 256: 549–56

    Article  PubMed  CAS  Google Scholar 

  20. Pugliese G, Pricci F, Iacobini C, et al. Accelerated diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice. FASEB J 2001; 15: 2471–9

    Article  PubMed  CAS  Google Scholar 

  21. Ohgami N, Nagai R, Ikemoto M, et al. CD36, a member of class B scavenger receptor family, is a receptor for advanced glycation end products. Ann N Y Acad Sci 2001; 947: 350–5

    Article  PubMed  CAS  Google Scholar 

  22. Lalla E, Lamster IB, Feit M, et al. Blockade of RAGE suppresses periodontitisassociated bone loss in diabetic mice. J Clin Invest 2000; 105: 1117–24

    Article  PubMed  CAS  Google Scholar 

  23. Goova MT, Li J, Kislinger T, et al. Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice. Am J Pathol 2001; 159: 399–403

    Article  Google Scholar 

  24. Park L, Raman KG, Lee KJ, et al. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat Med 1998; 4: 1025–31

    Article  PubMed  CAS  Google Scholar 

  25. Huttunen HJ, Fages C, Rauvala H. Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem 1999; 274: 19919–24

    Article  PubMed  CAS  Google Scholar 

  26. Huang JS, Guh JY, Hung WC, et al. Role of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) cascade in advanced glycation end-product-induced cellular mitogenesis in NRK-49F cells. Biochem J 1999; 342: 231–8

    Article  PubMed  CAS  Google Scholar 

  27. Malherbe P, Richards JG, Gaillard H, et al. cDNA cloning of a novel secreted isoform of the human receptor for advanced glycation end products and characterization of cells co-expressing cell-surface scavenger receptors and Swedish mutant amyloid precursor protein. Brain Res Mol Brain Res 1999; 71: 159–70

    Article  PubMed  CAS  Google Scholar 

  28. Lander HM, Tauras JM, Ogiste JS, et al. Activation of the receptor for advanced glycation end products triggers a p21(ras) dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 1997; 272: 17810–4

    Article  PubMed  CAS  Google Scholar 

  29. Sugimoto H, Shikata K, Wada J, et al. Advanced glycation end products-cytokinenitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-alpha and inducible nitric oxide synthase in diabetic rat glomeruli. Diabetologia 1999; 42: 878–86

    Article  PubMed  CAS  Google Scholar 

  30. Skolnik EY, Yang Z, Makita Z, et al. Human and rat mesangial cell receptors for glucose-modified proteins: potential role in kidney tissue remodelling and diabetic nephropathy. J Exp Med 1991; 174: 931–9

    Article  PubMed  CAS  Google Scholar 

  31. Crowley ST, Brownlee M, Edelstein D, et al. Effects of nonenzymatic glycosylation of mesangial matrix on proliferation of mesangial cells. Diabetes 1991; 40: 540–7

    Article  PubMed  CAS  Google Scholar 

  32. Ziyadeh FN, Han DC, Cohen JA, et al. Glycated albumin stimulates fibronectin gene expression in glomerular mesangial cells: involvement of the transforming growth factor-β system. Kidney Int 1998; 53: 631–8

    Article  PubMed  CAS  Google Scholar 

  33. Menè P, Pascale C, Bernardini S, et al. Effects of advanced glycation endproducts on [Ca2+]i signalling of cultured human mesangial cells. J Am Soc Nephrol 1999; 10: 1478–86

    PubMed  Google Scholar 

  34. Ivanov GI, Chaushev TA, Dakovska LN, et al. Increased adhesion of lymphoid cells to glycated proteins. Int J Biochem Cell Biol 1999; 31: 797–804

    Article  PubMed  CAS  Google Scholar 

  35. Suzuki D, Miyata T, Saotome N, et al. Immunohistochemical evidence for an increased oxidative stress and carbonyl modification of proteins in diabetic glomerular lesions. J Am Soc Nephrol 1999; 10: 822–32

    PubMed  CAS  Google Scholar 

  36. Youssef S, Nguyen DT, Soulis T, et al. Effect of diabetes and aminoguanidine therapy on renal advanced glycation end-product binding. Kidney Int 1999; 55: 907–16

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  38. Loske C, Neumann A, Cunningham AM, et al. Cytotoxicity of advanced glycation endproducts is mediated by oxidative stress. J Neural Transm 1998; 105: 1005–15

    Article  PubMed  CAS  Google Scholar 

  39. Price DL, Rhett PM, Thorpe SR, et al. Chelating activity of advanced glycation end-product inhibitors. J Biol Chem 2001; 276: 48967–72

    Article  PubMed  CAS  Google Scholar 

  40. Abdel-Rahman E, Bolton WK. Pimagedine: a novel therapy for diabetic nephropathy. Expert Opin Investig Drugs 2002; 11: 565–74

    Article  PubMed  CAS  Google Scholar 

  41. Brownlee M, Vlassara H, Kooney A, et al. Aminoguanidine prevents diabetesinduced arteriole wall protein cross-linking. Science 1986; 232: 1629–32

    Article  PubMed  CAS  Google Scholar 

  42. Picard S, Parthasarathy S, Fruebis J, et al. Aminoguanidine inhibits oxidative modification of low density lipoprotein and the subsequent increase in uptake by macrophage scavenger receptor. Proc Natl Acad Sci U S A 1992; 89: 6876–80

    Article  PubMed  CAS  Google Scholar 

  43. Kern TS, Engerman RL. Pharmacological inhibition of diabetic retinopathy: aminoguanidine and aspirin. Diabetes 2001; 50: 1636–42

    Article  PubMed  CAS  Google Scholar 

  44. Kelly DJ, Gilbert RE, Cox AJ, et al. Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy. J Am Soc Nephrol 2001; 12: 2098–107

    PubMed  CAS  Google Scholar 

  45. Sugimoto H, Shikata K, Wada J, et al. Advanced glycation end products-cytokinenitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-alpha and inducible nitric oxide synthase in diabetic rat glomeruli. Diabetologia 1999; 42: 878–86

    Article  PubMed  CAS  Google Scholar 

  46. Brown CD, Zhao ZH, Thomas LL, et al. Effects of erythropoietin and aminoguanidine on red blood cell deformability in diabetic azotemic and uremic patients. Am J Kidney Dis 2001; 38: 1414–20

    Article  PubMed  CAS  Google Scholar 

  47. Ziolo MT, Katoh H, Bers DM. Expression of inducible nitric oxide synthase depresses beta-adrenergic-stimulated calcium release from the sarcoplasmic reticulum in intact ventricular myocytes. Circulation 2001; 104: 2961–6

    Article  PubMed  CAS  Google Scholar 

  48. Whittier F, Spinowitz B, Wuerth JP, et al. Pimagidine (PG) safety profile in patients with type 1 diabetes mellitus (DM). J Am Soc Nephrol 1999; 10: 184A

    Google Scholar 

  49. Freedman BJ, Wuerth JP, Cartwright K, et al. Design and baseline characteristics for the aminoguanidine clinical trial in overt type 2 diabetic nephropathy (ACTION II). Control Clin Trials 1999; 20: 493

    Article  PubMed  CAS  Google Scholar 

  50. Viberti GC, Slama G, Pozza G, et al. Early closure of European Pimagedine Trial. Lancet 1997; 350: 214–5

    Article  PubMed  CAS  Google Scholar 

  51. Rahbar S, Yernini KK, Scott S, et al. Novel inhibitors of advanced glycation endproducts. Biochem Biophys Res Commun 1999; 262: 651–6

    Article  PubMed  CAS  Google Scholar 

  52. Khalifah RG, Baynes JW, Hudson BG. Amadorins: novel post-Amadori inhibitors of advanced glycation reactions. Biochem Biophys Res Commun 1999; 257: 251–8

    Article  PubMed  CAS  Google Scholar 

  53. Bonnefont-Rousselot D. Antioxidant and anti-AGE therapeutics: evaluation and perspectives. J Soc Biol 2001; 195: 391–8

    PubMed  CAS  Google Scholar 

  54. Rabbar S, Natarajan R, Yemeni K, et al. Evidence that pioglitazone, metformin and pentoxyfilline are inhibitors of glycation. Clin Chim Acta 2000; 301: 65

    Article  Google Scholar 

  55. Miyata T, Ueda Y, Asahi K, et al. Mechanism of the inhibitory effect of OPB-9195 [(+/-)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-yla cetanilide] on advanced glycation end product and advanced lipoxidation end product formation. J Am Soc Nephrol 2000; 11: 1719–25

    PubMed  CAS  Google Scholar 

  56. Miyata T, Ueda Y, Yamada Y, et al. Accumulation of carbonyl stress accelerates the formation of pentosidine, an advanced glycation end product: carbonyl stress uin uremia. J Am Soc Nephrol 1998; 9: 2349–56

    PubMed  CAS  Google Scholar 

  57. Wada R, Nishizawa Y, Yagihashi N, et al. Effects of OPB-9195, anti-glycation agent, on experimental diabetic neuropathy. Eur J Clin Invest 2001; 31: 513–20

    Article  PubMed  CAS  Google Scholar 

  58. Tsuchida K, Makita Z, Yamagishi S, et al. Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195. Diabetologia 1999; 42: 579–88

    Article  PubMed  CAS  Google Scholar 

  59. Seidler NW, Yeargans GS. Effects of thermal denaturation on protein glycation. Life Sci 2002; 70: 1789–99

    Article  PubMed  CAS  Google Scholar 

  60. Cohen MP, Masson N, Hud E, et al. Inhibiting albumin glycation ameliorates diabetic nephropathy in the db/db mouse. Exp Nephrol 2000; 8: 135–43

    Article  PubMed  CAS  Google Scholar 

  61. Vasan S, Foiles PG, Founds HW. Therapeutic potential of AGE inhibitors and breakers of AGE protein cross-links. Expert Opin Investig Drugs 2001; 10: 1977–87

    Article  PubMed  CAS  Google Scholar 

  62. Asif M, Egan J, Vasan S, et al. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci U S A 2000; 97: 2809–13

    Article  PubMed  CAS  Google Scholar 

  63. Vaitkevicius PV, Lane M, Spurgeon H, et al. A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys. Proc Natl Acad Sci U S A 2001; 98: 1171–5

    Article  PubMed  CAS  Google Scholar 

  64. Kass DA, Shapiro EP, Kawaguchi M, et al. Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation 2001; 104: 1464–70

    Article  PubMed  CAS  Google Scholar 

  65. Lyford J. Selected highlights from the 50th Annual Scientfic Session of the American College of Cardiology, Orlando USA March 2001, 18-21. Curr Control Trials Cardiovasc Med 2001 March; 2: 85–9

    Article  PubMed  Google Scholar 

  66. Alteon’s hypertension drug fails to achieve main gaol in Phase IIb trials. Pharma Marketletter 2003 Jul 28; 19

  67. Forbes JM, Soulis T, Thallas V, et al. Renoprotective effects of a novel inhibitor of advanced glycation. Diabetologia 2001; 44: 108–14

    Article  PubMed  CAS  Google Scholar 

  68. Cohen MP, Sharma K, Jin Y, et al. Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists: a novel treatment strategy. J Clin Invest 1995; 95: 2338–45

    Article  PubMed  CAS  Google Scholar 

  69. Zheng F, Cai W, Mitsuhashi T, et al. Lysozyme enhances renal excretion of advanced glycation endproducts in vivo and suppresses adverse age-mediated cellular effects in vitro: a potential AGE sequestration therapy for diabetic nephropathy? Mol Med 2001; 7: 737–47

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Funded in part by grants from the Italian Ministry of University and Research (MIUR) to Paolo Menè. The authors have no conflicts of interest directly relevant to the content of this article.

Author information

Authors and Affiliations

  1. Cattedra di Nefrologia, Dipartimento di Scienze Cliniche, Policlinico Umberto I, Viale del Policlinico 155, Rome, 00161, Italy

    Paolo Mené, Francescaromana Festuccia & Francesco Pugliese

Authors
  1. Paolo Mené
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francescaromana Festuccia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesco Pugliese
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paolo Mené.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mené, P., Festuccia, F. & Pugliese, F. Clinical Potential of Advanced Glycation End-Product Inhibitors in Diabetes Mellitus. Am J Cordiovosc Drugs 3, 315–320 (2003). https://doi.org/10.2165/00129784-200303050-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00129784-200303050-00002

Keywords

Search

Navigation