Total plasma Nε-(carboxymethyl)lysine and sRAGE levels are inversely associated with a number of metabolic syndrome risk factors in non-diabetic young-to-middle-aged medication-free subjects

Katarína Šebeková 1 , Zora Krivošíková 2  and Martin Gajdoš 2
  • 1 Medical Faculty, Institute of Molecular BioMedicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia
  • 2 Medical Faculty, Department of Clinical and Experimental Pharmacotherapy, Slovak Medical University, Bratislava, Slovakia
Katarína Šebeková, Zora Krivošíková and Martin Gajdoš


Background: Interaction of advanced glycation end products (AGEs) with their specific cell-surface receptor for AGEs (RAGE) induces production of reactive oxygen species, pro-diabetic, pro-inflammatory, and pro-atherogenic responses. The metabolic syndrome (Metsy) imposes a high risk of development of cardiovascular disease and unequivocally predisposes the non-diabetics to type 2 diabetes mellitus. The aim of the study was to investigate the association between circulating soluble RAGE (sRAGE), Nε-(carboxymethyl)lysine (CML) or AGE-associated fluorescence of plasma (AGE-Fl) with the number of manifested Metsy risk factors in young-to-middle-aged medication-free non-diabetic subjects.

Methods: Metsy was classified according to NCEP/ATP III criteria; plasma sRAGE and total CML were determined by ELISA methods and AGE-Fl fluorimetrically.

Results: From among 437 participants aged 33±11 years, 58% were females. In total 174 subjects were Metsy risk factors-free, 142 presented one, 59 presented two risk factors, and 62 suffered from Metsy. Plasma sRAGE and CML/albumin levels decreased with increasing number of Metsy risk factors (p<0.01, both), while AGE-Fl/albumin levels remained similar. Multivariate analysis selected waist circumference as a main determinant of plasma sRAGE as well as CML/albumin levels.

Conclusions: In young-to-middle-aged non-diabetic medication-free subjects plasma total CML/albumin and sRAGE levels decrease prior to the manifestation of Metsy. With regards to RAGE-mediated CML trapping into adipose tissue inducing dysregulation of pro-inflammatory cytokines, adipokines, and the development of obesity-related insulin resistance, and the potential involvement of sRAGE in feedback regulation of the toxic effects of AGE/RAGE-mediated signaling, this early decline might be of clinical impact in development of type 2 diabetes and its complications.

    • Supplemental_Data_PDF
  • 1.

    Miyata T, Wada Y, Cai Z, Iida Y, Horie K, Yasuda Y, et al. Implication of an increased oxidative stress in the formation of advanced glycation end products in patients with end-stage renal failure. Kidney Int 1997;51:1170–81.

  • 2.

    Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl) 2005;83:876–86.

  • 3.

    Nakamura K, Yamagishi SI, Adachi H, Matsui T, Kurita-Nakamura Y, Takeuchi M, et al. Serum levels of soluble form of receptor for advanced glycation end products (sRAGE) are positively associated with circulating AGEs and soluble form of VCAM-1 in patients with type 2 diabetes. Microvasc Res 2008;76: 52–6.

  • 4.

    Goh SY, Cooper ME. The role of advanced glycation end products in progression and complications of diabetes. J Clin Endocrinol Metab 2008;93:1143–52.

  • 5.

    Yamagishi S, Maeda S, Matsui T, Ueda S, Fukami K, Okuda S. Role of advanced glycation end products (AGEs) and oxidative stress in vascular complications in diabetes. Biochim Biophys Acta 2012;1820:663–71.

  • 6.

    Wilson PW, D’Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005;112: 3066–72.

  • 7.

    Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome – An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735–52.

  • 8.

    Sjogren P, Basta G, de Caterina R, Rosell M, Basu S, Silveira A, et al. Markers of endothelial activity are related to components of the metabolic syndrome, but not to circulating concentrations of the advanced glycation end-product N epsilon-carboxymethyl-lysine in healthy Swedish men. Atherosclerosis 2007;195:E168–75.

  • 9.

    Tahara N, Yamagishi S, Matsui T, Takeuchi M, Nitta Y, Kodama N, et al. serum levels of advanced glycation end products (AGEs) are independent correlates of insulin resistance in nondiabetic subjects. Cardiovasc Ther 2012;30:42–8.

  • 10.

    Semba RD, Arab L, Sun K, Nicklett EJ, Ferrucci L. Fat mass is inversely associated with serum carboxymethyl-lysine, an advanced glycation end product, in adults. J Nutr 2011;141:1726–30.

  • 11.

    Tan KC, Shiu SW, Wong Y, Tam X. Serum advanced glycation end products (AGEs) are associated with insulin resistance. Diabetes Metab Res Rev 2011;27:488–92.

  • 12.

    Klenovicsova K, Krivosikova Z, Gajdos M, Sebekova K. Association of sVAP-1, sRAGE, and CML with lactation-induced insulin sensitivity in young non-diabetic healthy women. Clin Chim Acta 2011;412:1842–7.

  • 13.

    Sebekova K, Somoza V, Jarcuskova M, Heidland A, Podracka L. Plasma advanced glycation end products are decreased in obese children compared with lean controls. Int J Pediatr Obes 2009;4:112–8.

  • 14.

    McNulty M, Mahmud A, Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens 2007;20:242–7.

  • 15.

    Tam XH, Shiu SW, Leng L, Bucala R, Betteridge DJ, Tan KC. Enhanced expression of receptor for advanced glycation end-products is associated with low circulating soluble isoforms of the receptor in Type 2 diabetes. Clin Sci (Lond) 2011;120:81–9.

  • 16.

    Basta G, Sironi AM, Lazzerini G, Del Turco S, Buzzigoli E, Casolaro A, et al. Circulating soluble receptor for advanced glycation end products is inversely associated with glycemic control and S100A12 protein. J Clin Endocrinol Metab 2006;91:4628–34.

  • 17.

    Devangelio E, Santilli F, Formoso G, Ferroni P, Bucciarelli L, Michetti N, et al. Soluble RAGE in type 2 diabetes: association with oxidative stress. Free Radic Biol Med 2007;43:511–8.

  • 18.

    Yan XX, Lu L, Peng WH, Wang LJ, Zhang Q, Zhang RY, et al. Increased serum HMGB1 level is associated with coronary artery disease in nondiabetic and type 2 diabetic patients. Atherosclerosis 2009;205:544–8.

  • 19.

    Tan KC, Shiu SW, Chow WS, Leng L, Bucala R, Betteridge DJ. Association between serum levels of soluble receptor for advanced glycation end products and circulating advanced glycation end products in type 2 diabetes. Diabetologia 2006;49:2756–62.

  • 20.

    Grossin N, Wautier MP, Meas T, Guillausseau PJ, Massin P, Wautier JL. Severity of diabetic microvascular complications is associated with a low soluble RAGE level. Diabetes Metab 2008;34:392–5.

  • 21.

    Geroldi D, Falcone C, Emanuele E, D’Angelo A, Calcagnino M, Buzzi MP, et al. Decreased plasma levels of soluble receptor for advanced glycation end-products in patients with essential hypertension. J Hypertens 2005;23:1725–9.

  • 22.

    Derosa G, D’Angelo A, Mugellini A, Pesce RM, Fogari E, Maffioli P. Evaluation of emerging biomarkers in cardiovascular risk stratification of hypertensive patients: a 2-year study. Curr Med Res Opin 2012;28:1435–45.

  • 23.

    Kim OY, Jo SH, Jang Y, Chae JS, Kim JY, Hyun YJ, et al. G allele at RAGE SNP82 is associated with proinflammatory markers in obese subjects. Nutr Res 2009;29:106–13.

  • 24.

    Norata GD, Garlaschelli K, Grigore L, Tibolla G, Raselli S, Redaelli L, et al. Circulating soluble receptor for advanced glycation end products is inversely associated with body mass index and waist/hip ratio in the general population. Nutr Metab Cardiovasc Dis 2009;19:129–34.

  • 25.

    de Giorgis T, D’Adamo E, Giannini C, Chiavaroli V, Scarinci A, Verrotti A, et al. Could receptors for advanced glycation end products be considered cardiovascular risk markers in obese children? Antioxid Redox Signal 2012;17:187–91.

  • 26.

    Falcone C, Emanuele E, D’Angelo A, Buzzi MP, Belvito C, Cuccia M, et al. Plasma levels of soluble receptor for advanced glycation end products and coronary artery disease in nondiabetic men. Arterioscler Thromb Vasc Biol 2005;25:1032–7.

  • 27.

    Koyama H, Yamamoto H, Nishizawa Y. RAGE and soluble RAGE: potential therapeutic targets for cardiovascular diseases. Mol Med 2007;13:625–35.

  • 28.

    McNair ED, Wells CR, Qureshi M, Basran R, Pearce C, Orvold J, et al. Soluble receptors for advanced glycation end products (sRAGE) as a predictor of restenosis following percutaneous coronary intervention. Clin Cardiol 2010;33:678–85.

  • 29.

    National kidney foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1–266.

  • 30.

    Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000;85:2402–10.

  • 31.

    Munch G, Keis R, Wessels A, Riederer P, Bahner U, Heidland A, et al. Determination of advanced glycation end products in serum by fluorescence spectroscopy and competitive ELISA. Eur J Clin Chem Clin Biochem 1997;35:669–77.

  • 32.

    Basta G, Leonardis D, Mallamaci F, Cutrupi S, Pizzini P, Gaetano L, et al. Circulating soluble receptor of advanced glycation end product inversely correlates with atherosclerosis in patients with chronic kidney disease. Kidney Int 2010;77: 225–31.

  • 33.

    Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res 2004;63:582–92.

  • 34.

    Fu MX, Requena JR, Jenkins AJ, Lyons TJ, Baynes JW, Thorpe SR. The advanced glycation end product, N-(epsilon)(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions. J Biol Chem 1996;271:9982–6.

  • 35.

    Schillaci G, Pirro M. C-reactive protein in hypertension: clinical significance and predictive value. Nutr Metab Cardiovasc Dis 2006;16:500–8.

  • 36.

    van der Velde M, Bello AK, Brantsma AH, El Nahas M, Bakker SJ, de Jong PE, et al. Do albuminuria and hs-CRP add to the International Diabetes Federation definition of the metabolic syndrome in predicting outcome? Nephrol Dial Transplant 2012;27:2275–83.

  • 37.

    Semba RD, Beck J, Sun K, Egan JM, Carlson OD, Varadhan R, et al. Relationship of a dominant advanced glycation end product, serum carboxymethyl-lysine, and abnormal glucose metabolism in adults: the Baltimore longitudinal study of aging. J Nutr Health Aging 2010;14:507–13.

  • 38.

    Gaens KH, Niessen PM, van Greevenbroek MM, van der Kallen CH, Niessen HW, Rensen SR, et al. Nε-Carboxymethyllysine–RAGE axis: a novel link between obesity, inflammation and insulin resistance. 11th Maillard Reaction Symposium, Nancy, France. 2012:200–1.

  • 39.

    Miller AA, De Silva TM, Jackman KA, Sobey CG. Effect of gender and sex hormones on vascular oxidative stress. Clin Exp Pharmacol Physiol 2007;34:1037–43.

  • 40.

    Ide T, Tsutsui H, Ohashi N, Hayashidani S, Suematsu N, Tsuchihashi M, et al. Greater oxidative stress in healthy young men compared with premenopausal women. Arterioscler Thromb Vasc Biol 2002;22:438–42.

  • 41.

    Somoza V, Wenzel E, Weiss C, Clawin-Radecker I, Grubel N, Erbersdobler HF. Dose-dependent utilisation of casein-linked lysinoalanine, N(epsilon)-fructoselysine and N(epsilon)-carboxymethyllysine in rats. Mol Nutr Food Res 2006;50:833–41.

  • 42.

    Delgado-Andrade C, Tessier FJ, Niquet-Leridon C, Seiquer I, Navarro MP. Study of the urinary and faecal excretion of N (epsilon)-carboxymethyllysine in young human volunteers. Amino Acids 2012;43:595–602.

  • 43.

    McNair ED, Wells CR, Qureshi AM, Basran R, Pearce C, Orvold J, et al. Modulation of high sensitivity C-reactive protein by soluble receptor for advanced glycation end products. Mol Cell Biochem 2010;341:135–8.

  • 44.

    Koyama H, Shoji T, Yokoyama H, Motoyama K, Mori K, Fukumoto S, et al. Plasma level of endogenous secretory RAGE is associated with components of the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol 2005;25: 2587–93.

  • 45.

    Yonekura H, Yamamoto Y, Sakurai S, Petrova RG, Abedin MJ, Li H, et al. 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;370:1097–109.

  • 46.

    Yamagishi S, Adachi H, Nakamura K, Matsui T, Jinnouchi Y, Takenaka K, et al. Positive association between serum levels of advanced glycation end products and the soluble form of receptor for advanced glycation end products in nondiabetic subjects. Metabolism 2006;55:1227–31.

  • 47.

    Galichet A, Weibel M, Heimann CW. Calcium-regulated intramembrane proteolysis of the RAGE receptor. Biochem Biophys Res Commun 2008;370:1–5.

  • 48.

    Zhang L, Bukulin M, Kojro E, Roth A, Metz VV, Fahrenholz F, et al. Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases. J Biol Chem 2008;283:35507–16.

  • 49.

    Gopal P, Rutten EP, Dentener MA, Wouters EF, Reynaert NL. Decreased plasma sRAGE levels in COPD: influence of oxygen therapy. Eur J Clin Invest 2012;42:807–14.

  • 50.

    Mokan M, Galajda P, Pridavkova D, Tomaskova V, Sutarik L, Krucinska L, et al. Prevalence of diabetes mellitus and metabolic syndrome in Slovakia. Diabetes Res Clin Pract 2008;81:238–42.

Purchase article
Get instant unlimited access to the article.
Log in
Already have access? Please log in.

Log in with your institution

Journal + Issues

Clinical Chemistry and Laboratory Medicine ( CCLM) publishes articles on novel teaching and training methods applicable to laboratory medicine. CCLM welcomes contributions on the progress in fundamental and applied research and cutting-edge clinical laboratory medicine. It is one of the leading journals in the field, with an impact factor of over three. CCLM is the official journal of nine national clinical societies and associated with EFLM.