Korean J Physiol Pharmacol.  2014 Feb;18(1):1-14. 10.4196/kjpp.2014.18.1.1.

Advanced Glycation End Products and Diabetic Complications

• Singh VP
• Bali A
• Singh N
• Jaggi AS

• KMID: 2285485
• DOI: http://doi.org/10.4196/kjpp.2014.18.1.1

Abstract

During long standing hyperglycaemic state in diabetes mellitus, glucose forms covalent adducts with the plasma proteins through a non-enzymatic process known as glycation. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis and aging. Glycation of proteins interferes with their normal functions by disrupting molecular conformation, altering enzymatic activity, and interfering with receptor functioning. AGEs form intra- and extracellular cross linking not only with proteins, but with some other endogenous key molecules including lipids and nucleic acids to contribute in the development of diabetic complications. Recent studies suggest that AGEs interact with plasma membrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals. The present review discusses the glycation of plasma proteins such as albumin, fibrinogen, globulins and collagen to form different types of AGEs. Furthermore, the role of AGEs in the pathogenesis of diabetic complications including retinopathy, cataract, neuropathy, nephropathy and cardiomyopathy is also discussed.

Keyword

Advanced glycation end-products; Diabetic complications; Inflammation; Oxidative stress; Plasma proteins

MeSH Terms

Aging
Arthritis, Rheumatoid
Blood Proteins
Cardiomyopathies
Cataract
Cell Membrane
Collagen
Diabetes Complications*
Diabetes Mellitus
Fibrinogen
Free Radicals
Gene Expression
Globulins
Glucose
Glycosylation End Products, Advanced*
Inflammation
Molecular Conformation
Nucleic Acids
Osteoporosis
Oxidative Stress
Blood Proteins
Collagen
Fibrinogen
Free Radicals
Globulins
Glucose
Glycosylation End Products, Advanced
Nucleic Acids

Figure

• 

  Fig. 1 Persistently elevated glucose levels during long standing diabetes induce structural and functional changes in different protein in the body including albumin, globulins, fibrinogen and collagens. Glycation of these proteins is associated with induction of deleterious changes in the body.

• 

  Fig. 2 Formation of advanced glycation end products in three stages i.e., early, intermediate and late stage involving (AGEs). In an early stage, sugars react with a free amino group to form Schiff base which undergoes a rearrangement to a more stable product known as amadori product. In an intermediate stage, amadori product degrades to a variety of reactive dicarbonyl compounds. In the late stage of the glycation process AGEs (irreversible compounds) are formed.

• 

  Fig. 3 Interaction of AGE with RAGE leading to oxidative stress and initiation of inflammation cascade involving activation of MAPK pathway, NF-kB, IL-6, TNF-α, expression of ICAM-1 and VCAM-2 which ultimately leads to diabetic complications.

Reference

1. Forbes JM, Soldatos G, Thomas MC. Below the radar: advanced glycation end products that detour "around the side". Is HbA1c not an accurate enough predictor of long term progression and glycaemic control in diabetes? Clin Biochem Rev. 2005; 26:123–134. PMID: 16648883.

2. Jang C, Lim JH, Park CW, Cho YJ. Regulator of Calcineurin 1 Isoform 4 Is Overexpressed in the Glomeruli of Diabetic Mice. Korean J Physiol Pharmacol. 2011; 15:299–305. PMID: 22128263.

3. Heilig CW, Concepcion LA, Riser BL, Freytag SO, Zhu M, Cortes P. Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype. J Clin Invest. 1995; 96:1802–1814. PMID: 7560072.

4. Fraser DA, Hansen KF. Making sense of advanced glycation end products and their relevance to diabetic complications. Inter Diabetes Monitor. 2005; 17:1–7.

5. Negre-Salvayre A, Salvayre R, Augé N, Pamplona R, Portero-Otín M. Hyperglycemia and glycation in diabetic complications. Antioxid Redox Signal. 2009; 11:3071–3109. PMID: 19489690.

6. Khan N, Bakshi KS, Jaggi AS, Singh N. Ameliorative potential of spironolactone in diabetes induced hyperalgesia in mice. Yakugaku Zasshi. 2009; 129:593–599. PMID: 19420890.

7. Helou C, Marier D, Jacolot P, Abdennebi-Najar L, Niquet-Léridon C, Tessier FJ, Gadonna-Widehem P. Microorganisms and Maillard reaction products: a review of the literature and recent findings. Amino Acids. 2013. [Epub ahead of print].

8. Alikhani M, Alikhani Z, Boyd C, MacLellan CM, Raptis M, Liu R, Pischon N, Trackman PC, Gerstenfeld L, Graves DT. Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone. 2007; 40:345–353. PMID: 17064973.

9. Saito M, Fujii K, Mori Y, Marumo K. Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats. Osteoporos Int. 2006; 17:1514–1523. PMID: 16770520.

10. Nicholl ID, Stitt AW, Moore JE, Ritchie AJ, Archer DB, Bucala R. Increased levels of advanced glycation endproducts in the lenses and blood vessels of cigarette smokers. Mol Med. 1998; 4:594–601. PMID: 9848076.

11. Zheng F, He C, Cai W, Hattori M, Steffes M, Vlassara H. Prevention of diabetic nephropathy in mice by a diet low in glycoxidation products. Diabetes Metab Res Rev. 2002; 18:224–237. PMID: 12112941.

12. Giardino I, Edelstein D, Brownlee M. Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity. A model for intracellular glycosylation in diabetes. J Clin Invest. 1994; 94:110–117. PMID: 8040253.

13. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414:813–820. PMID: 11742414.

14. Brownlee M. Advanced protein glycosylation in diabetes and aging. Annu Rev Med. 1995; 46:223–234. PMID: 7598459.

15. Hammes HP, Alt A, Niwa T, Clausen JT, Bretzel RG, Brownlee M, Schleicher ED. Differential accumulation of advanced glycation end products in the course of diabetic retinopathy. Diabetologia. 1999; 42:728–736. PMID: 10382593.

16. Hsieh CL, Yang MH, Chyau CC, Chiu CH, Wang HE, Lin YC, Chiu WT, Peng RY. Kinetic analysis on the sensitivity of glucose- or glyoxal-induced LDL glycation to the inhibitory effect of Psidium guajava extract in a physiomimic system. Biosystems. 2007; 88:92–100. PMID: 16806668.

17. Yonekura H, Yamamoto Y, Sakurai S, Watanabe T, Yamamoto H. Roles of the receptor for advanced glycation endproducts in diabetes-induced vascular injury. J Pharmacol Sci. 2005; 97:305–311. PMID: 15750291.

18. Cooper ME, Bonnet F, Oldfield M, Jandeleit-Dahm K. Mechanisms of diabetic vasculopathy: an overview. Am J Hypertens. 2001; 14:475–486. PMID: 11368471.

19. Turk Z, Ljubic S, Turk N, Benko B. Detection of autoantibodies against advanced glycation endproducts and AGE-immune complexes in serum of patients with diabetes mellitus. Clin Chim Acta. 2001; 303:105–115. PMID: 11163030.

20. Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991; 40:405–412. PMID: 2010041.

21. Baynes JW. The Maillard hypothesis on aging: time to focus on DNA. Ann N Y Acad Sci. 2002; 959:360–367. PMID: 11976210.

22. Monnier VM, Nagaraj RH, Portero-Otin M, Glomb M, Elgawish AH, Sell DR, Friedlander MA. Structure of advanced Maillard reaction products and their pathological role. Nephrol Dial Transplant. 1996; 11(Suppl 5):20–26. PMID: 9044302.

23. Lapolla A, Traldi P, Fedele D. Importance of measuring products of non-enzymatic glycation of proteins. Clin Biochem. 2005; 38:103–115. PMID: 15642271.

24. Kikuchi S, Shinpo K, Takeuchi M, Yamagishi S, Makita Z, Sasaki N, Tashiro K. Glycation--a sweet tempter for neuronal death. Brain Res Brain Res Rev. 2003; 41:306–323. PMID: 12663085.

25. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes. 1999; 48:1–9. PMID: 9892215.

26. Sima AA, Sugimoto K. Experimental diabetic neuropathy: an update. Diabetologia. 1999; 42:773–788. PMID: 10440118.

27. Simm A, Wagner J, Gursinsky T, Nass N, Friedrich I, Schinzel R, Czeslik E, Silber RE, Scheubel RJ. Advanced glycation endproducts: a biomarker for age as an outcome predictor after cardiac surgery? Exp Gerontol. 2007; 42:668–675. PMID: 17482402.

28. Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988; 318:1315–1321. PMID: 3283558.

29. Ahmed N. Advanced glycation endproducts--role in pathology of diabetic complications. Diabetes Res Clin Pract. 2005; 67:3–21. PMID: 15620429.

30. Stitt AW. The maillard reaction in eye diseases. Ann N Y Acad Sci. 2005; 1043:582–597. PMID: 16037281.

31. 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. PMID: 15220206.

32. Yamamoto Y, Doi T, Kato I, Shinohara H, Sakurai S, Yonekura H, Watanabe T, Myint KM, Harashima A, Takeuchi M, Takasawa S, Okamoto H, Hashimoto N, Asano M, Yamamoto H. Receptor for advanced glycation end products is a promising target of diabetic nephropathy. Ann N Y Acad Sci. 2005; 1043:562–566. PMID: 16037279.

33. Jono T, Kimura T, Takamatsu J, Nagai R, Miyazaki K, Yuzuriha T, Kitamura T, Horiuchi S. Accumulation of imidazolone, pentosidine and N(epsilon)-(carboxymethyl) lysine in hippocampal CA4 pyramidal neurons of aged human brain. Pathol Int. 2002; 52:563–571. PMID: 12406185.

34. Rother KI. Diabetes treatment--bridging the divide. N Engl J Med. 2007; 356:1499–1501. PMID: 17429082.

35. Evans TW. Review article: albumin as a drug--biological effects of albumin unrelated to oncotic pressure. Aliment Pharmacol Ther. 2002; 16(Suppl 5):6–11. PMID: 12423448.

36. Rondeau P, Bourdon E. The glycation of albumin: structural and functional impacts. Biochimie. 2011; 93:645–658. PMID: 21167901.

37. Iberg N, Flückiger R. Nonenzymatic glycosylation of albumin in vivo. Identification of multiple glycosylated sites. J Biol Chem. 1986; 261:13542–13545. PMID: 3759977.

38. Barnaby OS, Cerny RL, Clarke W, Hage DS. Comparison of modification sites formed on human serum albumin at various stages of glycation. Clin Chim Acta. 2011; 412:277–285. PMID: 21034726.

39. Hasan NA. Effects of trace elements on albumin and lipoprotein glycation in diabetic retinopathy. Saudi Med J. 2009; 30:1263–1271. PMID: 19838431.

40. Rubenstein DA, Yin W. Glycated albumin modulates platelet susceptibility to flow induced activation and aggregation. Platelets. 2009; 20:206–215. PMID: 19437339.

41. Unoki H, Bujo H, Yamagishi S, Takeuchi M, Imaizumi T, Saito Y. Advanced glycation end products attenuate cellular insulin sensitivity by increasing the generation of intracellular reactive oxygen species in adipocytes. Diabetes Res Clin Pract. 2007; 76:236–244. PMID: 17097186.

42. Unoki H, Yamagishi S. Advanced glycation end products and insulin resistance. Curr Pharm Des. 2008; 14:987–989. PMID: 18473850.

43. Singh NR, Rondeau P, Bourdon E. Identification of upregulated low molecular weight proteins in human adipocytes treated with glycoxidized albumin. Open Obes J. 2010; 2:110–115.

44. Valcourt U, Merle B, Gineyts E, Viguet-Carrin S, Delmas PD, Garnero P. Non-enzymatic glycation of bone collagen modifies osteoclastic activity and differentiation. J Biol Chem. 2007; 282:5691–5703. PMID: 17142454.

45. Dunn EJ, Philippou H, Ariëns RA, Grant PJ. Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus. Diabetologia. 2006; 49:1071–1080. PMID: 16538489.

46. Jörneskog G, Hansson LO, Wallen NH, Yngen M, Blombäck M. Increased plasma fibrin gel porosity in patients with Type I diabetes during continuous subcutaneous insulin infusion. J Thromb Haemost. 2003; 1:1195–1201. PMID: 12871319.

47. Lund T, Svindland A, Pepaj M, Jensen AB, Berg JP, Kilhovd B, Hanssen KF. Fibrin(ogen) may be an important target for methylglyoxal-derived AGE modification in elastic arteries of humans. Diab Vasc Dis Res. 2011; 8:284–294. PMID: 21844128.

48. Kennedy DM, Skillen AW, Self CH. Glycation of monoclonal antibodies impairs their ability to bind antigen. Clin Exp Immunol. 1994; 98:245–251. PMID: 7955529.

49. Lapolla A, Fedele D, Garbeglio M, Martano L, Tonani R, Seraglia R, Favretto D, Fedrigo MA, Traldi P. Matrix-assisted laser desorption/ionization mass spectrometry, enzymatic digestion, and molecular modeling in the study of nonenzymatic glycation of IgG. J Am Soc Mass Spectrom. 2000; 11:153–159. PMID: 10689668.

50. Austin GE, Mullins RH, Morin LG. Non-enzymic glycation of individual plasma proteins in normoglycemic and hyperglycemic patients. Clin Chem. 1987; 33:2220–2224. PMID: 3690840.

51. Bork P, Holm L, Sander C. The immunoglobulin fold. Structural classification, sequence patterns and common core. J Mol Biol. 1994; 242:309–320. PMID: 7932691.

52. Ahmad S, Moinuddin , Khan RH, Ali A. Physicochemical studies on glycation-induced structural changes in human IgG. IUBMB Life. 2012; 64:151–156. PMID: 22241644.

53. Said G, Guilbert M, Millerot-Serrurot E, Van Gulick L, Terryn C, Garnotel R, Jeannesson P. Impact of carbamylation and glycation of collagen type I on migration of HT1080 human fibrosarcoma cells. Int J Oncol. 2012; 40:1797–1804. PMID: 22378540.

54. Avery NC, Bailey AJ. The effects of the Maillard reaction on the physical properties and cell interactions of collagen. Pathol Biol (Paris). 2006; 54:387–395. PMID: 16962252.

55. Sanguineti R, Storace D, Monacelli F, Federici A, Odetti P. Pentosidine effects on human osteoblasts in vitro. Ann N Y Acad Sci. 2008; 1126:166–172. PMID: 18448811.

56. Wang X, Shen X, Li X, Agrawal CM. Age-related changes in the collagen network and toughness of bone. Bone. 2002; 31:1–7. PMID: 12110404.

57. Yuen A, Laschinger C, Talior I, Lee W, Chan M, Birek J, Young EW, Sivagurunathan K, Won E, Simmons CA, McCulloch CA. Methylglyoxal-modified collagen promotes myofibroblast differentiation. Matrix Biol. 2010; 29:537–548. PMID: 20423729.

58. Kemeny SF, Figueroa DS, Andrews AM, Barbee KA, Clyne AM. Glycated collagen alters endothelial cell actin alignment and nitric oxide release in response to fluid shear stress. J Biomech. 2011; 44:1927–1935. PMID: 21555127.

59. Titov VN, Khokhlova NV, Shiriaeva IuK. Glucose, glycotoxins, and protein glycation products: the role in pathogensis. Klin Med (Mosk). 2013; 91:15–24. PMID: 23789446.

60. Pageon H, Zucchi H, Rousset F, Monnier VM, Asselineau D. Skin aging by glycation: lessons from the reconstructed skin model. Clin Chem Lab Med. 2014; 52:169–174. PMID: 23770560.

61. Han D, Yamamoto Y, Munesue S, Motoyoshi S, Saito H, Win MT, Watanabe T, Tsuneyama K, Yamamoto H. Induction of receptor for advanced glycation end products by insufficient leptin action triggers pancreatic β-cell failure in type 2 diabetes. Genes Cells. 2013; 18:302–314. PMID: 23410183.

62. Vlassara H, Li YM, Imani F, Wojciechowicz D, Yang Z, Liu FT, Cerami A. Identification of galectin-3 as a high-affinity binding protein for advanced glycation end products (AGE): a new member of the AGE-receptor complex. Mol Med. 1995; 1:634–646. PMID: 8529130.

63. Ohgami N, Nagai R, Ikemoto M, Arai H, Miyazaki A, Hakamata H, Horiuchi S, Nakayama H. CD36, serves as a receptor for advanced glycation endproducts (AGE). J Diabetes Complications. 2002; 16:56–59. PMID: 11872368.

64. Thornalley PJ. Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs. Cell Mol Biol (Noisy-le-grand). 1998; 44:1013–1023. PMID: 9846883.

65. Yan SD, Zhu H, Zhu A, Golabek A, Du H, Roher A, Yu J, Soto C, Schmidt AM, Stern D, Kindy M. Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nat Med. 2000; 6:643–651. PMID: 10835680.

66. Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999; 97:889–901. PMID: 10399917.

67. Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hori O, Ogawa S, Stern DM, Schmidt AM. Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature. 2000; 405:354–360. PMID: 10830965.

68. Chavakis T, Bierhaus A, Al-Fakhri N, Schneider D, Witte S, Linn T, Nagashima M, Morser J, Arnold B, Preissner KT, Nawroth PP. The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med. 2003; 198:1507–1515. PMID: 14623906.

69. Stern DM, Yan SD, Yan SF, Schmidt AM. Receptor for advanced glycation endproducts (RAGE) and the complications of diabetes. Ageing Res Rev. 2002; 1:1–15. PMID: 12039445.

70. Kislinger T, Fu C, Huber B, Qu W, Taguchi A, Du Yan S, Hofmann M, Yan SF, Pischetsrieder M, Stern D, Schmidt AM. N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem. 1999; 274:31740–31749. PMID: 10531386.

71. Xie J, Reverdatto S, Frolov A, Hoffmann R, Burz DS, Shekhtman A. Structural basis for pattern recognition by the receptor for advanced glycation end products (RAGE). J Biol Chem. 2008; 283:27255–27269. PMID: 18667420.

72. Schmidt AM, Hori O, Chen JX, Li JF, Crandall J, Zhang J, Cao R, Yan SD, Brett J, Stern D. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest. 1995; 96:1395–1403. PMID: 7544803.

73. Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999; 97:889–901. PMID: 10399917.

74. Hudson BI, Bucciarelli LG, Wendt T, Sakaguchi T, Lalla E, Qu W, Lu Y, Lee L, Stern DM, Naka Y, Ramasamy R, Yan SD, Yan SF, D'Agati V, Schmidt AM. Blockade of receptor for advanced glycation endproducts: a new target for therapeutic intervention in diabetic complications and inflammatory disorders. Arch Biochem Biophys. 2003; 419:80–88. PMID: 14568011.

75. Yan SD, Schmidt AM, Anderson GM, Zhang J, Brett J, Zou YS, Pinsky D, Stern D. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem. 1994; 269:9889–9897. PMID: 8144582.

76. Neumann A, Schinzel R, Palm D, Riederer P, Münch G. High molecular weight hyaluronic acid inhibits advanced glycation endproduct-induced NF-kappaB activation and cytokine expression. FEBS Lett. 1999; 453:283–287. PMID: 10405161.

77. Zhang Q, Ames JM, Smith RD, Baynes JW, Metz TO. A perspective on the Maillard reaction and the analysis of protein glycation by mass spectrometry: probing the pathogenesis of chronic disease. J Proteome Res. 2009; 8:754–769. PMID: 19093874.

78. Halliwell B. The wanderings of a free radical. Free Radic Biol Med. 2009; 46:531–542. PMID: 19111608.

79. Li YM, Mitsuhashi T, Wojciechowicz D, Shimizu N, Li J, Stitt A, He C, Banerjee D, Vlassara H. Molecular identity and cellular distribution of advanced glycation endproduct receptors: relationship of p60 to OST-48 and p90 to 80K-H membrane proteins. Proc Natl Acad Sci U S A. 1996; 93:11047–11052. PMID: 8855306.

80. Jung HA, Jung YJ, Yoon NY, Jeong da M, Bae HJ, Kim DW, Na DH, Choi JS. Inhibitory effects of Nelumbo nucifera leaves on rat lens aldose reductase, advanced glycation endproducts formation, and oxidative stress. Food Chem Toxicol. 2008; 46:3818–3826. PMID: 18952135.

81. Frank RN. Diabetic retinopathy. N Engl J Med. 2004; 350:48–58. PMID: 14702427.

82. Chen M, Curtis TM, Stitt AW. Advanced glycation end products and diabetic retinopathy. Curr Med Chem. 2013; 20:3234–3240. PMID: 23745547.

83. Zong H, Ward M, Madden A, Yong PH, Limb GA, Curtis TM, Stitt AW. Hyperglycaemia-induced pro-inflammatory responses by retinal Müller glia are regulated by the receptor for advanced glycation end-products (RAGE). Diabetologia. 2010; 53:2656–2666. PMID: 20835858.

84. Stitt AW, Curtis TM. Diabetes-related adduct formation and retinopathy. J Ocul Biol Dis Infor. 2011; 4:10–18. PMID: 23272270.

85. Zong H, Ward M, Stitt AW. AGEs, RAGE, and diabetic retinopathy. Curr Diab Rep. 2011; 11:244–252. PMID: 21590515.

86. Curtis TM, Hamilton R, Yong PH, McVicar CM, Berner A, Pringle R, Uchida K, Nagai R, Brockbank S, Stitt AW. Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products. Diabetologia. 2011; 54:690–698. PMID: 21116609.

87. Miller AG, Zhu T, Wilkinson-Berka JL. The Renin-angiotensin system and advanced glycation end-products in diabetic retinopathy: impacts and synergies. Curr Clin Pharmacol. 2013; 8:285–296. PMID: 23173957.

88. Berner AK, Brouwers O, Pringle R, Klaassen I, Colhoun L, McVicar C, Brockbank S, Curry JW, Miyata T, Brownlee M, Schlingemann RO, Schalkwijk C, Stitt AW. Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology. Diabetologia. 2012; 55:845–854. PMID: 22143324.

89. Ai J, Liu Y, Sun JH. Advanced glycation end-products stimulate basic fibroblast growth factor expression in cultured Müller cells. Mol Med Rep. 2013; 7:16–20. PMID: 23129015.

90. Nagaraj RH, Linetsky M, Stitt AW. The pathogenic role of Maillard reaction in the aging eye. Amino Acids. 2012; 42:1205–1220. PMID: 20963455.

91. Choudhuri S, Dutta D, Sen A, Chowdhury IH, Mitra B, Mondal LK, Saha A, Bhadhuri G, Bhattacharya B. Role of N-ε- carboxy methyl lysine, advanced glycation end products and reactive oxygen species for the development of nonproliferative and proliferative retinopathy in type 2 diabetes mellitus. Mol Vis. 2013; 19:100–113. PMID: 23378723.

92. Chilelli NC, Burlina S, Lapolla A. AGEs, rather than hyperglycemia, are responsible for microvascular complications in diabetes: A "glycoxidation-centric" point of view. Nutr Metab Cardiovasc Dis. 2013; 23:913–919. PMID: 23786818.

93. Stitt AW. The role of advanced glycation in the pathogenesis of diabetic retinopathy. Exp Mol Pathol. 2003; 75:95–108. PMID: 12834631.

94. Vasan S, Foiles P, Founds H. Therapeutic potential of breakers of advanced glycation end product-protein crosslinks. Arch Biochem Biophys. 2003; 419:89–96. PMID: 14568012.

95. Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem. 1992; 267:14998–15004. PMID: 1378843.

96. Bucciarelli LG, Wendt T, Qu W, Lu Y, Lalla E, Rong LL, Goova MT, Moser B, Kislinger T, Lee DC, Kashyap Y, Stern DM, Schmidt AM. RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice. Circulation. 2002; 106:2827–2835. PMID: 12451010.

97. Chibber R, Molinatti PA, Rosatto N, Lambourne B, Kohner EM. Toxic action of advanced glycation end products on cultured retinal capillary pericytes and endothelial cells: relevance to diabetic retinopathy. Diabetologia. 1997; 40:156–164. PMID: 9049475.

98. Tanaka N, Yonekura H, Yamagishi S, Fujimori H, Yamamoto Y, Yamamoto H. The receptor for advanced glycation end products is induced by the glycation products themselves and tumor necrosis factor-alpha through nuclear factor-kappa B, and by 17beta-estradiol through Sp-1 in human vascular endothelial cells. J Biol Chem. 2000; 275:25781–25790. PMID: 10829018.

99. Yamagishi S, Amano S, Inagaki Y, Okamoto T, Koga K, Sasaki N, Yamamoto H, Takeuchi M, Makita Z. Advanced glycation end products-induced apoptosis and overexpression of vascular endothelial growth factor in bovine retinal pericytes. Biochem Biophys Res Commun. 2002; 290:973–978. PMID: 11798169.

100. Yamagishi S, Hsu CC, Taniguchi M, Harada S, Yamamoto Y, Ohsawa K, Kobayashi K, Yamamoto H. Receptor-mediated toxicity to pericytes of advanced glycosylation end products: a possible mechanism of pericyte loss in diabetic microangiopathy. Biochem Biophys Res Commun. 1995; 213:681–687. PMID: 7646524.

101. Stitt AW, Hughes SJ, Canning P, Lynch O, Cox O, Frizzell N, Thorpe SR, Cotter TG, Curtis TM, Gardiner TA. 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. 2004; 47:1735–1746. PMID: 15502926.

102. Moore TC, Moore JE, Kaji Y, Frizzell N, Usui T, Poulaki V, Campbell IL, Stitt AW, Gardiner TA, Archer DB, Adamis AP. The role of advanced glycation end products in retinal microvascular leukostasis. Invest Ophthalmol Vis Sci. 2003; 44:4457–4464. PMID: 14507893.

103. Mamputu JC, Renier G. Advanced glycation end-products increase monocyte adhesion to retinal endothelial cells through vascular endothelial growth factor-induced ICAM-1 expression: inhibitory effect of antioxidants. J Leukoc Biol. 2004; 75:1062–1069. PMID: 15020646.

104. Antonetti DA, Barber AJ, Khin S, Lieth E, Tarbell JM, Gardner TW. Penn State Retina Research Group. Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Diabetes. 1998; 47:1953–1959. PMID: 9836530.

105. Nakamura N, Hasegawa G, Obayashi H, Yamazaki M, Ogata M, Nakano K, Yoshikawa T, Watanabe A, Kinoshita S, Fujinami A, Ohta M, Imamura Y, Ikeda T. Increased concentration of pentosidine, an advanced glycation end product, and interleukin-6 in the vitreous of patients with proliferative diabetic retinopathy. Diabetes Res Clin Pract. 2003; 61:93–101. PMID: 12951277.

106. Joussen AM, Poulaki V, Mitsiades N, Cai WY, Suzuma I, Pak J, Ju ST, Rook SL, Esser P, Mitsiades CS, Kirchhof B, Adamis AP, Aiello LP. Suppression of Fas-FasL-induced endothelial cell apoptosis prevents diabetic blood-retinal barrier breakdown in a model of streptozotocin-induced diabetes. FASEB J. 2003; 17:76–78. PMID: 12475915.

107. Podestà F, Romeo G, Liu WH, Krajewski S, Reed JC, Gerhardinger C, Lorenzi M. Bax is increased in the retina of diabetic subjects and is associated with pericyte apoptosis in vivo and in vitro. Am J Pathol. 2000; 156:1025–1032. PMID: 10702418.

108. Caldwell RB, Caldwell Bartoli M, Behzadian MA, El-Remessy AE, Al-Shabrawey M, Platt DH, Caldwell RW. Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab Res Rev. 2003; 19:442–455. PMID: 14648803.

109. Hashim Z, Zarina S. Advanced glycation end products in diabetic and non-diabetic human subjects suffering from cataract. Age (Dordr). 2011; 33:377–384. PMID: 20842534.

110. Pollreisz A, Schmidt-Erfurth U. Diabetic cataract-pathogenesis, epidemiology and treatment. J Ophthalmol. 2010; 2010:608751. PMID: 20634936.

111. Harding JJ, Egerton M, van Heyningen R, Harding RS. Diabetes, glaucoma, sex, and cataract: analysis of combined data from two case control studies. Br J Ophthalmol. 1993; 77:2–6. PMID: 8435392.

112. Luthra M, Balasubramanian D. Nonenzymatic glycation alters protein structure and stability. A study of two eye lens crystallins. J Biol Chem. 1993; 268:18119–18127. PMID: 8349689.

113. Beswick HT, Harding JJ. Conformational changes induced in lens alpha- and gamma-crystallins by modification with glucose 6-phosphate. Implications for cataract. Biochem J. 1987; 246:761–769. PMID: 3689329.

114. Kumar MS, Reddy PY, Kumar PA, Surolia I, Reddy GB. Effect of dicarbonyl-induced browning on alpha-crystallin chaperone-like activity: physiological significance and caveats of in vitro aggregation assays. Biochem J. 2004; 379:273–282. PMID: 14711370.

115. Gul A, Rahman MA, Hasnain SN, Salim A, Simjee SU. Could oxidative stress associate with age products in cataractogenesis? Curr Eye Res. 2008; 33:669–675. PMID: 18696342.

116. Ookawara T, Kawamura N, Kitagawa Y, Taniguchi N. Site-specific and random fragmentation of Cu,Zn-superoxide dismutase by glycation reaction Implication of reactive oxygen species. J Biol Chem. 1992; 267:18505–18510. PMID: 1326527.

117. Ramalho JS, Marques C, Pereira PC, Mota MC. Role of glycation in human lens protein structure change. Eur J Ophthalmol. 1996; 6:155–161. PMID: 8823589.

118. Franke S, Dawczynski J, Strobel J, Niwa T, Stahl P, Stein G. Increased levels of advanced glycation end products in human cataractous lenses. J Cataract Refract Surg. 2003; 29:998–1004. PMID: 12781289.

119. O'Connor AS, Schelling JR. Diabetes and the kidney. Am J Kidney Dis. 2005; 46:766–773. PMID: 16183435.

120. Giacchetti G, Sechi LA, Rilli S, Carey RM. The renin-angiotensin-aldosterone system, glucose metabolism and diabetes. Trends Endocrinol Metab. 2005; 16:120–126. PMID: 15808810.

121. Marshall SM. Recent advances in diabetic nephropathy. Postgrad Med J. 2004; 80:624–633. PMID: 15537844.

122. Wolf G. New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur J Clin Invest. 2004; 34:785–796. PMID: 15606719.

123. Cooper ME. Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia. 2001; 44:1957–1972. PMID: 11719827.

124. Bohlender JM, Franke S, Stein G, Wolf G. Advanced glycation end products and the kidney. Am J Physiol Renal Physiol. 2005; 289:F645–F659. PMID: 16159899.

125. 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. PMID: 22386936.

126. Zhou J, Chan L, Zhou S. Trigonelline: a plant alkaloid with therapeutic potential for diabetes and central nervous system disease. Curr Med Chem. 2012; 19:3523–3531. PMID: 22680628.

127. 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. PMID: 23159951.

128. Fukami K, Yamagishi S, Kaifu K, Matsui T, Kaida Y, Ueda S, Takeuchi M, Asanuma K, Okuda S. Telmisartan inhibits AGE-induced podocyte damage and detachment. Microvasc Res. 2013; 88:79–83. PMID: 23648312.

129. Forbes JM, Cooper ME, Oldfield MD, Thomas MC. Role of advanced glycation end products in diabetic nephropathy. J Am Soc Nephrol. 2003; 14(8 Suppl 3):S254–S258. PMID: 12874442.

130. Bai P, Phua K, Hardt T, Cernadas M, Brodsky B. Glycation alters collagen fibril organization. Connect Tissue Res. 1992; 28:1–12. PMID: 1628485.

131. Mott JD, Khalifah RG, Nagase H, Shield CF 3rd, Hudson JK, Hudson BG. Nonenzymatic glycation of type IV collagen and matrix metalloproteinase susceptibility. Kidney Int. 1997; 52:1302–1312. PMID: 9350653.

132. Nyengaard JR, Chang K, Berhorst S, Reiser KM, Williamson JR, Tilton RG. Discordant effects of guanidines on renal structure and function and on regional vascular dysfunction and collagen changes in diabetic rats. Diabetes. 1997; 46:94–106. PMID: 8971088.

133. Krishnamurti U, Rondeau E, Sraer JD, Michael AF, Tsilibary EC. Alterations in human glomerular epithelial cells interacting with nonenzymatically glycosylated matrix. J Biol Chem. 1997; 272:27966–27970. PMID: 9346947.

134. Charonis AS, Tsilbary EC. Structural and functional changes of laminin and type IV collagen after nonenzymatic glycation. Diabetes. 1992; 41(Suppl 2):49–51. PMID: 1526336.

135. Walton HA, Byrne J, Robinson GB. Studies of the permeation properties of glomerular basement membrane: cross-linking renders glomerular basement membrane permeable to protein. Biochim Biophys Acta. 1992; 1138:173–183. PMID: 1547278.

136. Kelly DJ, Gilbert RE, Cox AJ, Soulis T, Jerums G, Cooper ME. Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy. J Am Soc Nephrol. 2001; 12:2098–2107. PMID: 11562408.

137. Kim YS, Kim BC, Song CY, Hong HK, Moon KC, Lee HS. Advanced glycosylation end products stimulate collagen mRNA synthesis in mesangial cells mediated by protein kinase C and transforming growth factor-beta. J Lab Clin Med. 2001; 138:59–68. PMID: 11433229.

138. Huang JS, Guh JY, Chen HC, Hung WC, Lai YH, Chuang LY. Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. J Cell Biochem. 2001; 81:102–113. PMID: 11180401.

139. Oldfield MD, Bach LA, Forbes JM, Nikolic-Paterson D, McRobert A, Thallas V, Atkins RC, Osicka T, Jerums G, Cooper ME. Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). J Clin Invest. 2001; 108:1853–1863. PMID: 11748269.

140. Riser BL, Denichilo M, Cortes P, Baker C, Grondin JM, Yee J, Narins RG. Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis. J Am Soc Nephrol. 2000; 11:25–38. PMID: 10616837.

141. Twigg SM, Cao Z, MCLennan SV, Burns WC, Brammar G, Forbes JM, Cooper ME. Renal connective tissue growth factor induction in experimental diabetes is prevented by aminoguanidine. Endocrinology. 2002; 143:4907–4915. PMID: 12446618.

142. Twigg SM, Chen MM, Joly AH, Chakrapani SD, Tsubaki J, Kim HS, Oh Y, Rosenfeld RG. Advanced glycosylation end products up-regulate connective tissue growth factor (insulin-like growth factor-binding protein-related protein 2) in human fibroblasts: a potential mechanism for expansion of extracellular matrix in diabetes mellitus. Endocrinology. 2001; 142:1760–1769. PMID: 11316739.

143. Tanji N, Markowitz GS, Fu C, Kislinger T, Taguchi A, Pischetsrieder M, Stern D, Schmidt AM, D'Agati VD. Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol. 2000; 11:1656–1666. PMID: 10966490.

144. Yamamoto Y, Kato I, Doi T, Yonekura H, Ohashi S, Takeuchi M, Watanabe T, Yamagishi S, Sakurai S, Takasawa S, Okamoto H, Yamamoto H. Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice. J Clin Invest. 2001; 108:261–268. PMID: 11457879.

145. Stopper H, Schinzel R, Sebekova K, Heidland A. Genotoxicity of advanced glycation end products in mammalian cells. Cancer Lett. 2003; 190:151–156. PMID: 12565169.

146. Habib AA, Brannagan TH 3rd. Therapeutic strategies for diabetic neuropathy. Curr Neurol Neurosci Rep. 2010; 10:92–100. PMID: 20425233.

147. El-Mesallamy HO, Hamdy NM, Ezzat OA, Reda AM. Levels of soluble advanced glycation end product-receptors and other soluble serum markers as indicators of diabetic neuropathy in the foot. J Investig Med. 2011; 59:1233–1238.

148. Jack M, Wright D. Role of advanced glycation endproducts and glyoxalase I in diabetic peripheral sensory neuropathy. Transl Res. 2012; 159:355–365. PMID: 22500508.

149. Sato K, Tatsunami R, Yama K, Tampo Y. Glycolaldehyde induces cytotoxicity and increases glutathione and multidrug-resistance-associated protein levels in Schwann cells. Biol Pharm Bull. 2013; 36:1111–1117. PMID: 23811560.

150. Wada R, Yagihashi S. Role of advanced glycation end products and their receptors in development of diabetic neuropathy. Ann N Y Acad Sci. 2005; 1043:598–604. PMID: 16037282.

151. Wada R, Nishizawa Y, Yagihashi N, Takeuchi M, Ishikawa Y, Yasumura K, Nakano M, Yagihashi S. Effects of OPB-9195, anti-glycation agent, on experimental diabetic neuropathy. Eur J Clin Invest. 2001; 31:513–520. PMID: 11422401.

152. Sugimoto K, Nishizawa Y, Horiuchi S, Yagihashi S. Localization in human diabetic peripheral nerve of N(epsilon)-carboxymethyllysine-protein adducts, an advanced glycation endproduct. Diabetologia. 1997; 40:1380–1387. PMID: 9447944.

153. Wada R, Yagihashi S. AGE Research. AGEs and diabetic neuropathy. 2004. p. 109–119.

154. Sekido H, Suzuki T, Jomori T, Takeuchi M, Yabe-Nishimura C, Yagihashi S. Reduced cell replication and induction of apoptosis by advanced glycation end products in rat Schwann cells. Biochem Biophys Res Commun. 2004; 320:241–248. PMID: 15207727.

155. Williams SK, Howarth NL, Devenny JJ, Bitensky MW. Structural and functional consequences of increased tubulin glycosylation in diabetes mellitus. Proc Natl Acad Sci U S A. 1982; 79:6546–6550. PMID: 6959136.

156. Vlassara H, Brownlee M, Cerami A. Nonenzymatic glycosylation of peripheral nerve protein in diabetes mellitus. Proc Natl Acad Sci U S A. 1981; 78:5190–5192. PMID: 6946466.

157. Santini SA, Cotroneo P, Marra G, Manto A, Giardina B, Mordente A, Greco AV, Martorana GE, Magnani P, Ghirlanda G. NA⁺/K⁺ ATPase impairment and experimental glycation: the role of glucose autoxidation. Free Radic Res. 1996; 24:381–389. PMID: 8733942.

158. 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. PMID: 1991829.

159. Amore A, Cirina P, Mitola S, Peruzzi L, Gianoglio B, Rabbone I, Sacchetti C, Cerutti F, Grillo C, Coppo R. Nonenzymatically glycated albumin (Amadori adducts) enhances nitric oxide synthase activity and gene expression in endothelial cells. Kidney Int. 1997; 51:27–35. PMID: 8995714.

160. Schmidt AM, Hasu M, Popov D, Zhang JH, Chen J, Yan SD, Brett J, Cao R, Kuwabara K, Costache G, et al. Receptor for advanced glycation end products (AGEs) has a central role in vessel wall interactions and gene activation in response to circulating AGE proteins. Proc Natl Acad Sci U S A. 1994; 91:8807–8811. PMID: 8090728.

161. Bell DS. Diabetic cardiomyopathy. Diabetes Care. 2003; 26:2949–2951. PMID: 14514607.

162. Montagnani M. Diabetic cardiomyopathy: how much does it depend on AGE? Br J Pharmacol. 2008; 154:725–726. PMID: 18414387.

163. Ma H, Li SY, Xu P, Babcock SA, Dolence EK, Brownlee M, Li J, Ren J. Advanced glycation endproduct (AGE) accumulation and AGE receptor (RAGE) up-regulation contribute to the onset of diabetic cardiomyopathy. J Cell Mol Med. 2009; 13:1751–1764. PMID: 19602045.

164. 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. PMID: 19902320.

165. Bodiga VL, Eda SR, Bodiga S. Advanced glycation end products: role in pathology of diabetic cardiomyopathy. Heart Fail Rev. 2013; [Epub ahead of print].

166. Rodrigues B, Cam MC, Kong J, Goyal RK, McNeill JH. Strain differences in susceptibility to streptozotocin-induced diabetes: effects on hypertriglyceridemia and cardiomyopathy. Cardiovasc Res. 1997; 34:199–205. PMID: 9217891.

167. Flier JS, Mueckler MM, Usher P, Lodish HF. Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science. 1987; 235:1492–1495. PMID: 3103217.

168. Taegtmeyer H. Energy metabolism of the heart: from basic concepts to clinical applications. Curr Probl Cardiol. 1994; 19:59–113. PMID: 8174388.

169. Thornalley PJ, Langborg A, Minhas HS. Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem J. 1999; 344(Pt 1):109–116. PMID: 10548540.

170. Lagadic-Gossmann D, Buckler KJ, Le Prigent K, Feuvray D. Altered Ca²⁺ handling in ventricular myocytes isolated from diabetic rats. Am J Physiol. 1996; 270:H1529–H1537. PMID: 8928857.

171. Trost SU, Belke DD, Bluhm WF, Meyer M, Swanson E, Dillmann WH. Overexpression of the sarcoplasmic reticulum Ca²⁺-ATPase improves myocardial contractility in diabetic cardiomyopathy. Diabetes. 2002; 51:1166–1171. PMID: 11916940.

172. Bidasee KR, Zhang Y, Shao CH, Wang M, Patel KP, Dincer UD, Besch HR Jr. Diabetes increases formation of advanced glycation end products on Sarco(endo)plasmic reticulum Ca2+- ATPase. Diabetes. 2004; 53:463–473. PMID: 14747299.

173. Ren J, Gintant GA, Miller RE, Davidoff AJ. High extracellular glucose impairs cardiac E-C coupling in a glycosylation-dependent manner. Am J Physiol. 1997; 273:H2876–H2883. PMID: 9435627.

174. Smit AJ, Lutgers HL. The clinical relevance of advanced glycation endproducts (AGE) and recent developments in pharmaceutics to reduce AGE accumulation. Curr Med Chem. 2004; 11:2767–2784. PMID: 15544475.

175. Kass DA, Shapiro EP, Kawaguchi M, Capriotti AR, Scuteri A, deGroof RC, Lakatta EG. Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation. 2001; 104:1464–1470. PMID: 11571237.

176. Posch K, Simecek S, Wascher TC, Jürgens G, Baumgartner-Parzer S, Kostner GM, Graier WF. Glycated low-density lipoprotein attenuates shear stress-induced nitric oxide synthesis by inhibition of shear stress-activated L-arginine uptake in endothelial cells. Diabetes. 1999; 48:1331–1337. PMID: 10342824.

177. Brett J, Schmidt AM, Yan SD, Zou YS, Weidman E, Pinsky D, Nowygrod R, Neeper M, Przysiecki C, Shaw A, Migheli A, Stern D. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. Am J Pathol. 1993; 143:1699–1712. PMID: 8256857.

178. Striker LJ, Striker GE. Administration of AGEs in vivo induces extracellular matrix gene expression. Nephrol Dial Transplant. 1996; 11(Suppl 5):62–65. PMID: 9044310.

179. Throckmorton DC, Brogden AP, Min B, Rasmussen H, Kashgarian M. PDGF and TGF-beta mediate collagen production by mesangial cells exposed to advanced glycosylation end products. Kidney Int. 1995; 48:111–117. PMID: 7564067.

180. Petrova R, Yamamoto Y, Muraki K, Yonekura H, Sakurai S, Watanabe T, Li H, Takeuchi M, Makita Z, Kato I, Takasawa S, Okamoto H, Imaizumi Y, Yamamoto H. Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes. J Mol Cell Cardiol. 2002; 34:1425–1431. PMID: 12393002.

181. Cui XP, Li BY, Gao HQ, Wei N, Wang WL, Lu M. Effects of grape seed proanthocyanidin extracts on peripheral nerves in streptozocin-induced diabetic rats. J Nutr Sci Vitaminol (Tokyo). 2008; 54:321–328. PMID: 18797155.

182. Shi X, Liao S, Mi H, Guo C, Qi D, Li F, Zhang C, Yang Z. Hesperidin prevents retinal and plasma abnormalities in streptozotocin-induced diabetic rats. Molecules. 2012; 17:12868–12881. PMID: 23117428.

183. Kawai T, Takei I, Tokui M, Funae O, Miyamoto K, Tabata M, Hirata T, Saruta T, Shimada A, Itoh H. Effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy in patients with type 2 diabetes, in relation to suppression of N(ɛ)-carboxymethyl lysine. J Diabetes Complications. 2010; 24:424–432. PMID: 19716319.

184. Stefanska B. Curcumin ameliorates hepatic fibrosis in type 2 diabetes mellitus - insights into its mechanisms of action. Br J Pharmacol. 2012; 166:2209–2211. PMID: 22452372.

185. Elseweidy MM, Elswefy SE, Younis NN, Zaghloul MS. Pyridoxamine, an inhibitor of protein glycation, in relation to microalbuminuria and proinflammatory cytokines in experimental diabetic nephropathy. Exp Biol Med (Maywood). 2013; 238:881–888. PMID: 23970406.

186. Sohn E, Kim J, Kim CS, Lee YM, Jo K, Shin SD, Kim JH, Kim JS. The Extract of Litsea japonica Reduced the Development of Diabetic Nephropathy via the Inhibition of Advanced Glycation End Products Accumulation in db/db Mice. Evid Based Complement Alternat Med. 2013; 2013:769416. PMID: 23781268.

187. Quan HY, Kim do Y, Chung SH. Korean red ginseng extract alleviates advanced glycation end product-mediated renal injury. J Ginseng Res. 2013; 37:187–193. PMID: 23717171.