BACKGROUND. Glucose reacts nonenzymatically with proteins in vivo, chemically forming covalently attached glucose-addition products and cross-links between proteins. The excessive accumulation of rearranged late-glucose-addition products, or advanced glycosylation end products (AGEs), is believed to contribute to the chronic complications of diabetes mellitus. METHODS. To elucidate the relation of AGEs to diabetic complications, we used a radioreceptor assay to measure serum and tissue AGEs in diabetic (Types I and Type II) and nondiabetic patients with different levels of renal function. Serum AGEs were measured as a low-molecular-weight (less than or equal to 10 kd) peptide fraction and a high-molecular-weight (greater than 10 kd) protein fraction. RESULTS. The mean (+/- SD) AGE content of samples of arterial-wall collagen from 9 diabetic patients was significantly higher than that of samples from 18 nondiabetic patients (14.5 +/- 5.2 vs. 3.6 +/- 1.5 AGE units per milligram, P less than 0.001). Moreover, diabetic patients with end-stage renal disease had almost twice as much AGE in tissue as diabetic patients without renal disease (21.3 +/- 2.8 vs. 11.5 +/- 1.9 AGE units per milligram, P less than 0.001). The AGE levels in both serum fractions were elevated in the patients with diabetes, and the levels of AGE peptides correlated directly with serum creatinine (P less than 0.001) and inversely with creatinine clearance (P less than 0.005), suggesting that levels of AGE peptides increased with the severity of diabetic nephropathy. In six patients with diabetes who required hemodialysis, the levels of AGE peptides were five times higher than in eight normal subjects (82.8 +/- 9.4 vs. 15.6 +/- 3.4 AGE units per milliliter, P less than 0.001). In another group of diabetic patients the mean serum creatinine level, which decreased by 75 percent during a session of hemodialysis, whereas the level of AGE peptides decreased by only 24 percent. Serum levels of AGE peptides were normal in two patients with normal serum creatinine levels after renal transplantation. CONCLUSIONS. AGEs accumulate at a faster-than-normal rate in arteries and the circulation of patients with diabetes; the increase in circulating AGE peptides parallels the severity of renal functional impairment in diabetic nephropathy.
Source Information
Laboratory of Medical Biochemistry, Rockefeller University, New York, NY 10021.
This article has been cited by other articles:
McIntyre, C. W., John, S. G., Jefferies, H. J.
(2008). Advances in the cardiovascular assessment of patients with chronic kidney disease. NDT Plus
0: sfn146v1-sfn146
[Abstract][Full Text]
Rubio-Ruiz, M. E., Diaz-Diaz, E., Cardenas-Leon, M., Arguelles-Medina, R., Sanchez-Canales, P., Larrea-Gallo, F., Soria-Castro, E., Guarner-Lans, V.
(2008). Glycation does not modify bovine serum albumin (BSA)-induced reduction of rat aortic relaxation: The response to glycated and nonglycated BSA is lost in metabolic syndrome. Glycobiology
18: 517-525
[Abstract][Full Text]
Qian, Y., Feldman, E., Pennathur, S., Kretzler, M., Brosius, F. C. III
(2008). From Fibrosis to Sclerosis: Mechanisms of Glomerulosclerosis in Diabetic Nephropathy. Diabetes
57: 1439-1445
[Full Text]
Craig, M. E., Duffin, A. C., Gallego, P. H., Lam, A., Cusumano, J., Hing, S., Donaghue, K. C
(2008). Plantar Fascia Thickness, a Measure of Tissue Glycation, Predicts the Development of Complications in Adolescents With Type 1 Diabetes. Diabetes Care
31: 1201-1206
[Abstract][Full Text]
Talmor, Y., Golan, E., Benchetrit, S., Bernheim, J., Klein, O., Green, J., Rashid, G.
(2008). Calcitriol blunts the deleterious impact of advanced glycation end products on endothelial cells. Am. J. Physiol. Renal Physiol.
294: F1059-F1064
[Abstract][Full Text]
Murakami, R., Murakami, S., Tsushima, R., Ueda, C., Mikami, K., Ebina, T., Kumasaka, R., Nakamura, N., Okumura, K.
(2008). Glycaemic control and serum intact parathyroid hormone levels in diabetic patients on haemodialysis therapy. Nephrol Dial Transplant
23: 315-320
[Abstract][Full Text]
Cheung, A. K., Greene, T., Leypoldt, J. K., Yan, G., Allon, M., Delmez, J., Levey, A. S., Levin, N. W., Rocco, M. V., Schulman, G., Eknoyan, G., for HEMO Study Group,
(2008). Association between Serum 2-Microglobulin Level and Infectious Mortality in Hemodialysis Patients. CJASN
3: 69-77
[Abstract][Full Text]
Wu, T., Willett, W. C., Rifai, N., Rimm, E. B.
(2007). Plasma Fluorescent Oxidation Products as Potential Markers of Oxidative Stress for Epidemiologic Studies. Am J Epidemiol
166: 552-560
[Abstract][Full Text]
Cai, W., He, J. C., Zhu, L., Chen, X., Wallenstein, S., Striker, G. E., Vlassara, H.
(2007). Reduced Oxidant Stress and Extended Lifespan in Mice Exposed to a Low Glycotoxin Diet: Association with Increased AGER1 Expression. Am. J. Pathol.
170: 1893-1902
[Abstract][Full Text]
Meerwaldt, R., Lutgers, H. L., Links, T. P., Graaff, R., Baynes, J. W., Gans, R. O.B., Smit, A. J.
(2007). Skin Autofluorescence Is a Strong Predictor of Cardiac Mortality in Diabetes. Diabetes Care
30: 107-112
[Abstract][Full Text]
Schramm, J. C., Dinh, T., Veves, A.
(2006). Microvascular changes in the diabetic foot.. INT J LOW EXTREM WOUNDS
5: 149-159
[Abstract]
Huebschmann, A. G., Regensteiner, J. G., Vlassara, H., Reusch, J. E.B.
(2006). Diabetes and Advanced Glycoxidation End Products.. Diabetes Care
29: 1420-1432
[Full Text]
Stam, F., Schalkwijk, C. G., van Guldener, C., ter Wee, P. M., Stehouwer, C. D. A.
(2006). Advanced glycation end-product peptides are associated with impaired renal function, but not with biochemical markers of endothelial dysfunction and inflammation, in non-diabetic individuals. Nephrol Dial Transplant
21: 677-682
[Abstract][Full Text]
Cheung, A. K., Rocco, M. V., Yan, G., Leypoldt, J. K., Levin, N. W., Greene, T., Agodoa, L., Bailey, J., Beck, G. J., Clark, W., Levey, A. S., Ornt, D. B., Schulman, G., Schwab, S., Teehan, B., Eknoyan, G., for HEMO Study Group,
(2006). Serum beta-2 Microglobulin Levels Predict Mortality in Dialysis Patients: Results of the HEMO Study. J. Am. Soc. Nephrol.
17: 546-555
[Abstract][Full Text]
Galkina, E., Ley, K.
(2006). Leukocyte Recruitment and Vascular Injury in Diabetic Nephropathy. J. Am. Soc. Nephrol.
17: 368-377
[Abstract][Full Text]
Meerwaldt, R., Hartog, J. W.L., Graaff, R., Huisman, R. J., Links, T. P., den Hollander, N. C., Thorpe, S. R., Baynes, J. W., Navis, G., Gans, R. O.B., Smit, A. J.
(2005). Skin Autofluorescence, a Measure of Cumulative Metabolic Stress and Advanced Glycation End Products, Predicts Mortality in Hemodialysis Patients. J. Am. Soc. Nephrol.
16: 3687-3693
[Abstract][Full Text]
Nakagawa, K., Oak, J.-H., Higuchi, O., Tsuzuki, T., Oikawa, S., Otani, H., Mune, M., Cai, H., Miyazawa, T.
(2005). Ion-trap tandem mass spectrometric analysis of Amadori-glycated phosphatidylethanolamine in human plasma with or without diabetes. J. Lipid Res.
46: 2514-2524
[Abstract][Full Text]
Bohlender, J. M., Franke, S., Stein, G., Wolf, G.
(2005). Advanced glycation end products and the kidney. Am. J. Physiol. Renal Physiol.
289: F645-F659
[Abstract][Full Text]
Natarajan, S., Liao, Y., Sinha, D., Cao, G., McGee, D. L., Lipsitz, S. R.
(2005). Sex Differences in the Effect of Diabetes Duration on Coronary Heart Disease Mortality. Arch Intern Med
165: 430-435
[Abstract][Full Text]
Thomas, M. C., Tikellis, C., Kantharidis, P., Burns, W. C., Cooper, M. E., Forbes, J. M.
(2004). The Role of Advanced Glycation in Reduced Organic Cation Transport Associated with Experimental Diabetes. J. Pharmacol. Exp. Ther.
311: 456-466
[Abstract][Full Text]
Wautier, J.-L., Schmidt, A. M.
(2004). Protein Glycation: A Firm Link to Endothelial Cell Dysfunction. Circ. Res.
95: 233-238
[Abstract][Full Text]
Endemann, D. H., Schiffrin, E. L.
(2004). Endothelial Dysfunction. J. Am. Soc. Nephrol.
15: 1983-1992
[Abstract][Full Text]
Svensson, M., Eriksson, J. W., Dahlquist, G.
(2004). Early Glycemic Control, Age at Onset, and Development of Microvascular Complications in Childhood-Onset Type 1 Diabetes: A population-based study in northern Sweden. Diabetes Care
27: 955-962
[Abstract][Full Text]
Li, J. H., Wang, W., Huang, X. R., Oldfield, M., Schmidt, A. M., Cooper, M. E., Lan, H. Y.
(2004). Advanced Glycation End Products Induce Tubular Epithelial-Myofibroblast Transition through the RAGE-ERK1/2 MAP Kinase Signaling Pathway. Am. J. Pathol.
164: 1389-1397
[Abstract][Full Text]
Lieuw-A-Fa, M. L. M., van Hinsbergh, V. W. M., Teerlink, T., Barto, R., Twisk, J., Stehouwer, C. D. A., Schalkwijk, C. G.
(2004). Increased levels of N{epsilon}-(carboxymethyl)lysine and N{epsilon}-(carboxyethyl)lysine in type 1 diabetic patients with impaired renal function: correlation with markers of endothelial dysfunction. Nephrol Dial Transplant
19: 631-636
[Abstract][Full Text]
Trovati, M., Cavalot, F.
(2004). Optimization of Hypolipidemic and Antiplatelet Treatment in the Diabetic Patient with Renal Disease. J. Am. Soc. Nephrol.
15: S12-20
[Abstract][Full Text]
Galler, A., Muller, G., Schinzel, R., Kratzsch, J., Kiess, W., Munch, G.
(2003). Impact of Metabolic Control and Serum Lipids on the Concentration of Advanced Glycation End Products in the Serum of Children and Adolescents With Type 1 Diabetes, as Determined by Fluorescence Spectroscopy and N{epsilon}-(Carboxymethyl)Lysine ELISA. Diabetes Care
26: 2609-2615
[Abstract][Full Text]
Locatelli, F., Canaud, B., Eckardt, K.-U., Stenvinkel, P., Wanner, C., Zoccali, C.
(2003). Oxidative stress in end-stage renal disease: an emerging threat to patient outcome. Nephrol Dial Transplant
18: 1272-1280
[Abstract][Full Text]
Suliman, M. E., Heimburger, O., Barany, P., Anderstam, B., Pecoits-Filho, R., Rodriguez Ayala, E., Qureshi, A. R., Fehrman-Ekholm, I., Lindholm, B., Stenvinkel, P.
(2003). Plasma Pentosidine Is Associated with Inflammation and Malnutrition in End-Stage Renal Disease Patients Starting on Dialysis Therapy. J. Am. Soc. Nephrol.
14: 1614-1622
[Abstract][Full Text]
Morcos, M., Sayed, A. A.R., Bierhaus, A., Yard, B., Waldherr, R., Merz, W., Kloeting, I., Schleicher, E., Mentz, S., Abd el Baki, R. F., Tritschler, H., Kasper, M., Schwenger, V., Hamann, A., Dugi, K. A., Schmidt, A.-M., Stern, D., Ziegler, R., Haering, H. U., Andrassy, M., van der Woude, F., Nawroth, P. P.
(2002). Activation of Tubular Epithelial Cells in Diabetic Nephropathy. Diabetes
51: 3532-3544
[Abstract][Full Text]
Zatz, R., Noronha, I. L., Fujihara, C. K.
(2002). Experimental and clinical rationale for use of MMF in nontransplant progressive nephropathies. Am. J. Physiol. Renal Physiol.
283: F1167-F1175
[Abstract][Full Text]
Baggio, B., Budakovic, A., Vestra, M. D., Saller, A., Bruseghin, M., Fioretto, P.
(2002). Effects of Cigarette Smoking on Glomerular Structure and Function in Type 2 Diabetic Patients. J. Am. Soc. Nephrol.
13: 2730-2736
[Abstract][Full Text]
Tan, K. C.B., Chow, W.-S., Ai, V. H.G., Metz, C., Bucala, R., Lam, K. S.L.
(2002). Advanced Glycation End Products and Endothelial Dysfunction in Type 2 Diabetes. Diabetes Care
25: 1055-1059
[Abstract][Full Text]
Yamagishi, S.-i., Inagaki, Y., Okamoto, T., Amano, S., Koga, K., Takeuchi, M., Makita, Z.
(2002). Advanced Glycation End Product-induced Apoptosis and Overexpression of Vascular Endothelial Growth Factor and Monocyte Chemoattractant Protein-1 in Human-cultured Mesangial Cells. J. Biol. Chem.
277: 20309-20315
[Abstract][Full Text]
Nakagawa, J., Ishikura, S., Asami, J., Isaji, T., Usami, N., Hara, A., Sakurai, T., Tsuritani, K., Oda, K., Takahashi, M., Yoshimoto, M., Otsuka, N., Kitamura, K.
(2002). Molecular Characterization of Mammalian Dicarbonyl/L-Xylulose Reductase and Its Localization in Kidney. J. Biol. Chem.
277: 17883-17891
[Abstract][Full Text]
Floridi, A., Antolini, F., Galli, F., Fagugli, R. M., Floridi, E., Buoncristiani, U.
(2002). Daily haemodialysis improves indices of protein glycation. Nephrol Dial Transplant
17: 871-878
[Abstract][Full Text]
Sacks, D. B., Bruns, D. E., Goldstein, D. E., Maclaren, N. K., McDonald, J. M., Parrott, M.
(2002). Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus. Clin. Chem.
48: 436-472
[Abstract][Full Text]
Horl, W. H.
(2002). Hemodialysis Membranes: Interleukins, Biocompatibility, and Middle Molecules. J. Am. Soc. Nephrol.
13: S62-71
[Abstract][Full Text]
Bierhaus, A., Schiekofer, S., Schwaninger, M., Andrassy, M., Humpert, P. M., Chen, J., Hong, M., Luther, T., Henle, T., Kloting, I., Morcos, M., Hofmann, M., Tritschler, H., Weigle, B., Kasper, M., Smith, M., Perry, G., Schmidt, A.-M., Stern, D. M., Haring, H.-U., Schleicher, E., Nawroth, P. P.
(2001). Diabetes-Associated Sustained Activation of the Transcription Factor Nuclear Factor-{kappa}B. Diabetes
50: 2792-2808
[Abstract][Full Text]
Kanauchi, M., Tsujimoto, N., Hashimoto, T.
(2001). Advanced Glycation End Products in Nondiabetic Patients With Coronary Artery Disease. Diabetes Care
24: 1620-1623
[Abstract][Full Text]
COHEN, G., RUDNICKI, M., WALTER, F., NIWA, T., HÖRL, W. H.
(2001). Glucose-Modified Proteins Modulate Essential Functions and Apoptosis of Polymorphonuclear Leukocytes. J. Am. Soc. Nephrol.
12: 1264-1271
[Abstract][Full Text]
Stein, G., Franke, S., Mahiout, A., Schneider, S., Sperschneider, H., Borst, S., Vienken, J.
(2001). Influence of dialysis modalities on serum AGE levels in end-stage renal disease patients. Nephrol Dial Transplant
16: 999-1008
[Abstract][Full Text]
Kiuchi, K, Nejima, J, Takano, T, Ohta, M, Hashimoto, H, BAXTER, G F
(2001). Increased serum concentrations of advanced glycation end products: a marker of coronary artery disease activity in type 2 diabetic patients. Heart
85: 87-91
[Abstract][Full Text]
Amano, S., Kaji, Y., Oshika, T., Oka, T., Machinami, R., Nagai, R., Horiuchi, S.
(2001). Advanced glycation end products in human optic nerve head. Br. J. Ophthalmol.
85: 52-55
[Abstract][Full Text]
Pinto-Sietsma, S.-J., Mulder, J., Janssen, W. M.T., Hillege, H. L., de Zeeuw, D., de Jong, P. E.
(2000). Smoking Is Related to Albuminuria and Abnormal Renal Function in Nondiabetic Persons. ANN INTERN MED
133: 585-591
[Abstract][Full Text]
MIYATA, T., UEDA, Y., ASAHI, K., IZUHARA, Y., INAGI, R., SAITO, A., VAN YPERSELE DE STRIHOU, C., KUROKAWA, K.
(2000). Mechanism of the Inhibitory Effect of OPB-9195 [({+/-})-2-Isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide] on Advanced Glycation End Product and Advanced Lipoxidation End Product Formation. J. Am. Soc. Nephrol.
11: 1719-1725
[Abstract][Full Text]
MIYATA, T., KUROKAWA, K., VAN YPERSELE DE STRIHOU, C.
(2000). Advanced Glycation and Lipoxidation End Products: Role of Reactive Carbonyl Compounds Generated during Carbohydrate and Lipid Metabolism. J. Am. Soc. Nephrol.
11: 1744-1752
[Full Text]
Kaji, Y., Usui, T., Oshika, T., Matsubara, M., Yamashita, H., Araie, M., Murata, T., Ishibashi, T., Nagai, R., Horiuchi, S., Amano, S.
(2000). Advanced Glycation End Products in Diabetic Corneas. IOVS
41: 362-368
[Abstract][Full Text]
Moreno, P. R., Fallon, J. T., Murcia, A. M., Leon, M. N., Simosa, H., Fuster, V., Palacios, I. F.
(1999). Tissue characteristics of restenosis after percutaneous transluminal coronary angioplasty in diabetic patients. J Am Coll Cardiol
34: 1045-1049
[Abstract][Full Text]
Henle, T., Deppisch, R., Beck, W., Hergesell, O., Hansch, G. M., Ritz, E.
(1999). Advanced glycated end-products (AGE) during haemodialysis treatment: discrepant results with different methodologies reflecting the heterogeneity of AGE compounds. Nephrol Dial Transplant
14: 1968-1975
[Abstract][Full Text]
MENÈ, P., PASCALE, C., TETI, A., BERNARDINI, S., CINOTTI, G. A., PUGLIESE, F.
(1999). Effects of Advanced Glycation End Products on Cytosolic Ca2+ Signaling of Cultured Human Mesangial Cells. J. Am. Soc. Nephrol.
10: 1478-1486
[Abstract][Full Text]
Davidson, M. B., Schriger, D. L., Peters, A. L., Lorber, B.
(1999). Relationship Between Fasting Plasma Glucose and Glycosylated Hemoglobin: Potential for False-Positive Diagnoses of Type 2 Diabetes Using New Diagnostic Criteria. JAMA
281: 1203-1210
[Abstract][Full Text]
Wang, X., Bucala, R., Milne, R.
(1998). Epitopes close to the apolipoprotein B low density lipoprotein receptor-binding site are modified by advanced glycation end products. Proc. Natl. Acad. Sci. USA
95: 7643-7647
[Abstract][Full Text]
Wautier, J.-L., Guillausseau, P.-J.
(1998). Diabetes, advanced glycation endproducts and vascular disease. Vasc Med
3: 131-137
[Abstract]
Bierhaus, A., Hofmann, M. A, Ziegler, R., Nawroth, P. P
(1998). AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res
37: 586-600
[Abstract][Full Text]
Rodriguez-Garcia, J., Requena, J. R., Rodriguez-Segade, S.
(1998). Increased concentrations of serum pentosidine in rheumatoid arthritis. Clin. Chem.
44: 250-255
[Abstract][Full Text]
Gaster, B., Hirsch, I. B.
(1998). The Effects of Improved Glycemic Control on Complications in Type 2 Diabetes. Arch Intern Med
158: 134-140
[Abstract][Full Text]
Cerami, C., Founds, H., Nicholl, I., Mitsuhashi, T., Giordano, D., Vanpatten, S., Lee, A., Al-Abed, Y., Vlassara, H., Bucala, R., Cerami, A.
(1997). Tobacco smoke is a source of toxic reactive glycation products. Proc. Natl. Acad. Sci. USA
94: 13915-13920
[Abstract][Full Text]
Wrobel, K., Wrobel, K., Garay-Sevilla, Ma. E., Nava, L. E., Malacara, J. M.
(1997). Novel analytical approach to monitoring advanced glycosylation end products in human serum with on-line spectrophotometric and spectrofluorometric detection in a flow system. Clin. Chem.
43: 1563-1569
[Abstract][Full Text]
Koschinsky, T., He, C.-J., Mitsuhashi, T., Bucala, R., Liu, C., Buenting, C., Heitmann, K., Vlassara, H.
(1997). Orally absorbed reactive glycation products (glycotoxins): An environmental risk factor in diabetic nephropathy. Proc. Natl. Acad. Sci. USA
94: 6474-6479
[Abstract][Full Text]
Wagenknecht, L. E., D'Agostino, R. Jr, Savage, P. J., O'Leary, D. H., Saad, M. F., Haffner, S. M.
(1997). Duration of Diabetes and Carotid Wall Thickness : The Insulin Resistance Atherosclerosis Study (IRAS). Stroke
28: 999-1005
[Abstract][Full Text]
Visona, A., Lusiani, L., Bonanome, A., Beltramello, G., Confortin, L., Papesso, B., Costa, F., Pagnan, A.
(1995). Wall Thickening of Common Carotid Arteries in Patients Affected by Noninsulin-Dependent Diabetes Mellitus: Relationship to Microvascular Complications. ANGIOLOGY
46: 793-799
[Abstract]
Bucala, R., Mitchell, R., Arnold, K., Innerarity, T., Vlassara, H., Cerami, A.
(1995). Identification of the Major Site of Apolipoprotein B Modification by Advanced Glycosylation End Products Blocking Uptake by the Low Density Lipoprotein Receptor. J. Biol. Chem.
270: 10828-10832
[Abstract][Full Text]
Palinski, W., Koschinsky, T., Butler, S. W., Miller, E., Vlassara, H., Cerami, A., Witztum, J. L.
(1995). Immunological Evidence for the Presence of Advanced Glycosylation End Products in Atherosclerotic Lesions of Euglycemic Rabbits. Arterioscler. Thromb. Vasc. Bio.
15: 571-582
[Abstract][Full Text]
Makita, Z, Vlassara, H, Rayfield, E, Cartwright, K, Friedman, E, Rodby, R, Cerami, A, Bucala, R
(1992). Hemoglobin-AGE: a circulating marker of advanced glycosylation. Science
258: 651-653
[Abstract]
Previous
