Diabetes Metab J.  2018 Jun;42(3):188-195. 10.4093/dmj.2017.0105.

The Role of Advanced Glycation End Products in Diabetic Vascular Complications

• Rhee SY
• Kim YS

• KMID: 2413980
• DOI: http://doi.org/10.4093/dmj.2017.0105

Abstract

In cases of chronic hyperglycemia, advanced glycation end-products (AGEs) are actively produced and accumulated in the circulating blood and various tissues. AGEs also accelerate the expression of receptors for AGEs, and they play an important role in the development of diabetic vascular complications through various mechanisms. Active interventions for glucose and related risk factors may help improve the clinical course of patients by reducing AGEs. This review summarizes recent updates on AGEs that have a significant impact on diabetic vascular complications.

Keyword

Diabetes complications; Glycation end products, advanced; Receptor for advanced glycation end products

MeSH Terms

Diabetes Complications
Diabetic Angiopathies*
Glucose
Glycosylation End Products, Advanced*
Humans
Hyperglycemia
Risk Factors
Glucose
Glycosylation End Products, Advanced

Figure

• 

  Fig. 1 Suggested mechanism of advanced glycation end-products (AGEs) in diabetic vascular complications. RAGE, receptor for advanced glycation end-product; NF-κB, nuclear factor κB; RAS, renin-angiotensin system; TZD, thiazolidinediones; GLP-1, glucagon like peptide-1; DPP-4, dipeptidylpeptide-4; sRAGE, soluble receptor for advanced glycation end-product; ROS, reactive oxygen species; eNOS, endothelial nitric oxide synthase; NADPH, nicotinamide adenine dinucleotide phosphate; IL, interleukin; TNF-α, tumor necrosis factor α.

Reference

1. Vlassara H, Palace MR. Diabetes and advanced glycation endproducts. J Intern Med. 2002; 251:87–101.

2. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA. 2003; 290:2159–2167.

3. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359:1577–1589.

4. Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: a review. Diabetologia. 2001; 44:129–146.

5. Yamagishi S, Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm Des. 2005; 11:2279–2299.

6. Koska J, Saremi A, Howell S, Bahn G, De Courten B, Ginsberg H, Beisswenger PJ, Reaven PD. VADT Investigators. Advanced glycation end products, oxidation products, and incident cardiovascular events in patients with type 2 diabetes. Diabetes Care. 2018; 41:570–576.

7. Lo TW, Westwood ME, McLellan AC, Selwood T, Thornalley PJ. Binding and modification of proteins by methylglyoxal under physiological conditions. A kinetic and mechanistic study with N alpha-acetylarginine, N alpha-acetylcysteine, and N alpha-acetyllysine, and bovine serum albumin. J Biol Chem. 1994; 269:32299–32305.

8. Ahmed N, Thornalley PJ, Dawczynski J, Franke S, Strobel J, Stein G, Haik GM. Methylglyoxal-derived hydroimidazolone advanced glycation end-products of human lens proteins. Invest Ophthalmol Vis Sci. 2003; 44:5287–5292.

9. Uribarri J, Cai W, Sandu O, Peppa M, Goldberg T, Vlassara H. Diet-derived advanced glycation end products are major contributors to the body's AGE pool and induce inflammation in healthy subjects. Ann N Y Acad Sci. 2005; 1043:461–466.

10. Yamagishi S, Ueda S, Okuda S. Food-derived advanced glycation end products (AGEs): a novel therapeutic target for various disorders. Curr Pharm Des. 2007; 13:2832–2836.

11. Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP. AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res. 1998; 37:586–600.

12. Naka Y, Bucciarelli LG, Wendt T, Lee LK, Rong LL, Ramasamy R, Yan SF, Schmidt AM. RAGE axis: animal models and novel insights into the vascular complications of diabetes. Arterioscler Thromb Vasc Biol. 2004; 24:1342–1349.

13. Schmidt AM, Stern D. Atherosclerosis and diabetes: the RAGE connection. Curr Atheroscler Rep. 2000; 2:430–436.

14. Xu B, Ji Y, Yao K, Cao YX, Ferro A. Inhibition of human endothelial cell nitric oxide synthesis by advanced glycation end-products but not glucose: relevance to diabetes. Clin Sci (Lond). 2005; 109:439–446.

15. Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest. 1991; 87:432–438.

16. Yamagishi S, Nakamura N, Suematsu M, Kaseda K, Matsui T. Advanced glycation end products: a molecular target for vascular complications in diabetes. Mol Med. 2015; 21:Suppl 1. S32–S40.

17. Treins C, Giorgetti-Peraldi S, Murdaca J, Van Obberghen E. Regulation of vascular endothelial growth factor expression by advanced glycation end products. J Biol Chem. 2001; 276:43836–43841.

18. Chung NA, Lydakis C, Belgore F, Li-Saw-Hee FL, Blann AD, Lip GY. Angiogenesis, thrombogenesis, endothelial dysfunction and angiographic severity of coronary artery disease. Heart. 2003; 89:1411–1415.

19. Yamagishi S, Adachi H, Takeuchi M, Enomoto M, Furuki K, Matsui T, Nakamura K, Imaizumi T. Serum level of advanced glycation end-products (AGEs) is an independent determinant of plasminogen activator inhibitor-1 (PAI-1) in nondiabetic general population. Horm Metab Res. 2007; 39:845–848.

20. Yamagishi S. Role of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) in vascular damage in diabetes. Exp Gerontol. 2011; 46:217–224.

21. Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol. 2014; 18:1–14.

22. Takenaka K, Yamagishi S, Matsui T, Nakamura K, Imaizumi T. Role of advanced glycation end products (AGEs) in thrombogenic abnormalities in diabetes. Curr Neurovasc Res. 2006; 3:73–77.

23. Chait A, Bornfeldt KE. Diabetes and atherosclerosis: is there a role for hyperglycemia? J Lipid Res. 2009; 50:Suppl. S335–S339.

24. Wei Q, Ren X, Jiang Y, Jin H, Liu N, Li J. Advanced glycation end products accelerate rat vascular calcification through RAGE/oxidative stress. BMC Cardiovasc Disord. 2013; 13:13.

25. Cipollone F, Iezzi A, Fazia M, Zucchelli M, Pini B, Cuccurullo C, De Cesare D, De Blasis G, Muraro R, Bei R, Chiarelli F, Schmidt AM, Cuccurullo F, Mezzetti A. The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Circulation. 2003; 108:1070–1077.

26. Cheng CL, Tang Y, Zheng Z, Liu X, Ye ZC, Wang C, Lou TQ. Advanced glycation end-products activate the renin-angiotensin system through the RAGE/PI3-K signaling pathway in podocytes. Clin Invest Med. 2012; 35:E282.

27. Geronikaki A, Gavalas A, Dislian V, Giannoglou G. Inhibition of renin-angiotensin system and advanced glycation end products formation: a promising therapeutic approach targeting on cardiovascular diseases. Cardiovasc Hematol Agents Med Chem. 2007; 5:249–264.

28. Gleissner CA, Galkina E, Nadler JL, Ley K. Mechanisms by which diabetes increases cardiovascular disease. Drug Discov Today Dis Mech. 2007; 4:131–140.

29. Yamagishi S, Nakamura K, Matsui T, Noda Y, Imaizumi T. Receptor for advanced glycation end products (RAGE): a novel therapeutic target for diabetic vascular complication. Curr Pharm Des. 2008; 14:487–495.

30. Nakamura K, Yamagishi S, Adachi H, Kurita-Nakamura Y, Matsui T, Yoshida T, Imaizumi T. Serum levels of sRAGE, the soluble form of receptor for advanced glycation end products, are associated with inflammatory markers in patients with type 2 diabetes. Mol Med. 2007; 13:185–189.

31. Berg TJ, Snorgaard O, Faber J, Torjesen PA, Hildebrandt P, Mehlsen J, Hanssen KF. Serum levels of advanced glycation end products are associated with left ventricular diastolic function in patients with type 1 diabetes. Diabetes Care. 1999; 22:1186–1190.

32. Yonekura H, Yamamoto Y, Sakurai S, Petrova RG, Abedin MJ, Li H, Yasui K, Takeuchi M, Makita Z, Takasawa S, Okamoto H, Watanabe T, Yamamoto H. Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem J. 2003; 370(Pt 3):1097–1109.

33. Nakamura K, Yamagishi S, Adachi H, Kurita-Nakamura Y, Matsui T, Yoshida T, Sato A, Imaizumi T. Elevation of soluble form of receptor for advanced glycation end products (sRAGE) in diabetic subjects with coronary artery disease. Diabetes Metab Res Rev. 2007; 23:368–371.

34. Hanford LE, Enghild JJ, Valnickova Z, Petersen SV, Schaefer LM, Schaefer TM, Reinhart TA, Oury TD. Purification and characterization of mouse soluble receptor for advanced glycation end products (sRAGE). J Biol Chem. 2004; 279:50019–50024.

35. Uribarri J, Woodruff S, Goodman S, Cai W, Chen X, Pyzik R, Yong A, Striker GE, Vlassara H. Advanced glycation end products in foods and a practical guide to their reduction in the diet. J Am Diet Assoc. 2010; 110:911–916.

36. Luevano-Contreras C, Chapman-Novakofski K. Dietary advanced glycation end products and aging. Nutrients. 2010; 2:1247–1265.

37. Liu G, Zong G, Hu FB, Willett WC, Eisenberg DM, Sun Q. Cooking methods for red meats and risk of type 2 diabetes: a prospective study of U.S. Women. Diabetes Care. 2017; 40:1041–1049.

38. Luevano-Contreras C, Garay-Sevilla ME, Wrobel K, Malacara JM, Wrobel K. Dietary advanced glycation end products restriction diminishes inflammation markers and oxidative stress in patients with type 2 diabetes mellitus. J Clin Biochem Nutr. 2013; 52:22–26.

39. Wu CH, Huang SM, Lin JA, Yen GC. Inhibition of advanced glycation endproduct formation by foodstuffs. Food Funct. 2011; 2:224–234.

40. Kwok JM, Ma CC, Ma S. Recent development in the effects of statins on cardiovascular disease through Rac1 and NADPH oxidase. Vascul Pharmacol. 2013; 58:21–30.

41. Ishibashi Y, Yamagishi S, Matsui T, Ohta K, Tanoue R, Takeuchi M, Ueda S, Nakamura K, Okuda S. Pravastatin inhibits advanced glycation end products (AGEs)-induced proximal tubular cell apoptosis and injury by reducing receptor for AGEs (RAGE) level. Metabolism. 2012; 61:1067–1072.

42. Yamagishi S. Possible involvement of advanced glycation end products in carry-over benefits of atorvastatin in ASCOT-BPLA. Eur Heart J. 2008; 29:1922.

43. Yamagishi S, Nakamura K, Matsui T. Potential utility of telmisartan, an angiotensin II type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity for the treatment of cardiometabolic disorders. Curr Mol Med. 2007; 7:463–469.

44. Yamagishi S, Nakamura K, Matsui T. Regulation of advanced glycation end product (AGE)-receptor (RAGE) system by PPAR-gamma agonists and its implication in cardiovascular disease. Pharmacol Res. 2009; 60:174–178.

45. Coughlan MT, Thallas-Bonke V, Pete J, Long DM, Gasser A, Tong DC, Arnstein M, Thorpe SR, Cooper ME, Forbes JM. Combination therapy with the advanced glycation end product cross-link breaker, alagebrium, and angiotensin converting enzyme inhibitors in diabetes: synergy or redundancy? Endocrinology. 2007; 148:886–895.

46. Ihm SH, Chang K, Kim HY, Baek SH, Youn HJ, Seung KB, Kim JH. Peroxisome proliferator-activated receptor-gamma activation attenuates cardiac fibrosis in type 2 diabetic rats: the effect of rosiglitazone on myocardial expression of receptor for advanced glycation end products and of connective tissue growth factor. Basic Res Cardiol. 2010; 105:399–407.

47. Ojima A, Ishibashi Y, Matsui T, Maeda S, Nishino Y, Takeuchi M, Fukami K, Yamagishi S. Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression. Am J Pathol. 2013; 182:132–141.

48. Nakashima S, Matsui T, Takeuchi M, Yamagishi SI. Linagliptin blocks renal damage in type 1 diabetic rats by suppressing advanced glycation end products-receptor axis. Horm Metab Res. 2014; 46:717–721.

49. Matsui T, Nakashima S, Nishino Y, Ojima A, Nakamura N, Arima K, Fukami K, Okuda S, Yamagishi S. Dipeptidyl peptidase-4 deficiency protects against experimental diabetic nephropathy partly by blocking the advanced glycation end products-receptor axis. Lab Invest. 2015; 95:525–533.

50. Thornalley PJ, Yurek-George A, Argirov OK. Kinetics and mechanism of the reaction of aminoguanidine with the alpha-oxoaldehydes glyoxal, methylglyoxal, and 3-deoxyglucosone under physiological conditions. Biochem Pharmacol. 2000; 60:55–65.

51. Soulis-Liparota T, Cooper M, Papazoglou D, Clarke B, Jerums G. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat. Diabetes. 1991; 40:1328–1334.

52. Forbes JM, Yee LT, Thallas V, Lassila M, Candido R, Jandeleit-Dahm KA, Thomas MC, Burns WC, Deemer EK, Thorpe SR, Cooper ME, Allen TJ. Advanced glycation end product interventions reduce diabetes-accelerated atherosclerosis. Diabetes. 2004; 53:1813–1823.