Abstract
Increased production of advanced glycosylation end products (AGEs) and augmented oxidative stress may contribute to vascular complications in diabetes. Little is known about the formation and accumulation of AGEs in young patients with type 1 diabetes. The aim of the present study was to investigate whether AGE production and oxidative stress are augmented in young patients with type 1 diabetes at early clinical stages of the disease. Urine samples of 38 patients with type 1 diabetes [mean age (±SD), 12.8 ± 4.5 y; diabetes duration, 5.7 ± 4.3 y; HbA1c, 8.0 ± 1.6%; urinary albumin excretion, 12.6 ± 14.4 mg/g creatinine (Cr)] and those of 60 age-matched healthy control subjects were assayed for AGEs, pentosidine and pyrraline, and markers of oxidative stress, 8-hydroxy-2′-deoxyguanosine (8-OHdG) and acrolein-lysine. Of these four markers, urinary concentrations of pentosidine, 8-OHdG, and acrolein-lysine were significantly higher in the patients with diabetes than in the healthy control subjects. For the patient group, pentosidine correlated significantly with 8-OHdG and acrolein-lysine, and pyrraline correlated significantly with acrolein-lysine. Urinary pentosidine, 8-OHdG, and acrolein-lysine but not pyrraline correlated significantly with urinary albumin excretion. Patients with microalbuminuria (≥15 mg/g Cr) showed significantly higher levels of all four markers than did normoalbuminuric patients and control subjects. The present study indicates that accumulation of AGEs, whose formation is closely linked to oxidative stress, and resultant endothelial dysfunction may start early in the course of type 1 diabetes. This means that the risk of vascular complications may be present at an early age and that the best possible glycemic control should be emphasized from the diagnosis of diabetes.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- AGE:
-
advanced glycosylation end product
- RAGE:
-
advanced glycosylation end product-specific receptor
- 8-OHdG:
-
8-hydroxy-2′-deoxyguanosine
- Cr:
-
creatinine
- ROI:
-
reactive oxygen intermediate
References
Vlassara H, Bucala R, Striker L 1994 Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging. Lab Invest 70: 138–151
Bucala R, Vlassara H 1995 Advanced glycosylation end products in diabetic renal and vascular disease. Am J Kidney Dis 26: 875–888
Suzuki D, Miyata T 1999 Carbonyl stress in the pathogenesis of diabetic nephropathy. Intern Med 38: 309–314
Makita Z, Bucala R, Rayfield EJ, Friedman EA, Kaufman AM, Korbet SM, Barth RH, Winston JA, Fuh H, Manogue KR, Cerami A, Vlassara H 1994 Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure. Lancet 343: 1519–1522
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
Sell DR, Lapolla A, Odetti P, Fogarty J, Monnier VM 1992 Pentosidine formation in skin correlates with severity of complications in individuals with long-standing IDDM. Diabetes 41: 1286–1292
McCance DR, Dyer DG, Dunn JA, Bailie KE, Thorpe SR, Baynes JW, Lyons TJ 1993 Maillard reaction products and their relation to complications in insulin-dependent diabetes mellitus. J Clin Invest 91: 2470–2478
Sugiyama S, Miyata T, Ueda Y, Tanaka H, Maeda K, Kawashima S, van Ypersele de Strihou C, Kurokawa K 1998 Plasma levels of pentosidine in diabetic patients: an advanced glycation end product. J Am Soc Nephrol 9: 1681–1688
Horie K, Miyata T, Maeda K, Miyata S, Sugiyama S, Sakai H, van Ypersele de Strihou C, Monnier VM, Witztum JL, Kurokawa K 1997 Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions: implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J Clin Invest 100: 2995–3004
Vlassara H, Striker LJ, Teichberg S, Fuh H, Li YM, Steffes M 1994 Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats. Proc Natl Acad Sci U S A 91: 11704–11708
Nakamura S, Makita Z, Ishikawa S, Yasumura K, Fujii W, Yanagisawa K, Kawata T, Koike T 1997 Progression of nephropathy in spontaneous diabetic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation. Diabetes 46: 895–899
Yoshihara K, Nakamura K, Kanai M, Nagayama Y, Takahashi S, Saito N, Nagata M 1998 Determination of urinary and serum pentosidine and its application to elder patients. Biol Pharm Bull 21: 1005–1008
Yoshihara K, Kiyonami R, Shimizu Y, Beppu M 2001 Determination of urinary pyrraline by solid-phase extraction and high performance liquid chromatography. Biol Pharm Bull 24: 863–866
Toyokuni S 1999 Reactive oxygen species-induced molecular damage and its application in pathology. Pathol Int 49: 91–102
Uchida K, Kanematsu M, Sakai K, Matsuda T, Hattori N, Mizuno Y, Suzuki D, Miyata T, Noguchi N, Niki E, Osawa T 1998 Protein-bound acrolein: potential markers for oxidative stress. Proc Natl Acad Sci U S A 95: 4882–4887
Uchida K 1999 Current status of acrolein as a lipid peroxidation product. Trends Cardiovasc Med 9: 109–113
Omata N, Tsukahara H, Ito S, Ohshima Y, Yasutomi M, Yamada A, Jiang M, Hiraoka M, Nambu M, Deguchi Y, Mayumi M 2001 Increased oxidative stress in childhood atopic dermatitis. Life Sci 69: 223–228
Satoh K, Yamada S, Koike Y, Igarashi Y, Toyokuni S, Kumano T, Takahata T, Hayakari M, Tsuchida S, Uchida K 1999 A 1-hour enzyme-linked immunosorbent assay for quantitation of acrolein- and hydroxynonenal-modified proteins by epitope-bound casein matrix method. Anal Biochem 270: 323–328
The Diabetes Control and Complications Trial Research Group 1993 The effect of intensive treatment of diabetes on the development and progression of long-term complications of insulin-dependent diabetes mellitus. N Engl J Med 329: 977–986
Baynes JW, Thorpe SR 1999 Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48: 1–99
Berg TJ, Bangstad HJ, Torjesen PA, Osterby R, Bucala R, Hanssen KF 1997 Advanced glycation end products in serum predict changes in the kidney morphology of patients with insulin-dependent diabetes mellitus. Metabolism 46: 661–665
Berg TJ, Clausen JT, Torjesen PA, Dahl-Jorgensen K, Bangstad HJ, Hanssen KF 1998 The advanced glycation end product Nε-(carboxymethyl)lysine is increased in serum from children and adolescents with type 1 diabetes. Diabetes Care 21: 1997–2002
Chiarelli F, de Martino M, Mezzetti A, Catino M, Morgese G, Cuccurullo F, Verrotti A 1999 Advanced glycation end products in children and adolescents with diabetes: relation to glycemic control and early microvascular complications. J Pediatr 134: 486–491
Chiarelli F, Catino M, Tumini S, Cipollone F, Mezzetti A, Vanelli M, Verrotti A 2000 Advanced glycation end products in adolescents and young adults with diabetic angiopathy. Pediatr Nephrol 14: 841–846
Misselwitz J, Franke S, Kauf E, John U, Stein G 2002 Advanced glycation end products in children with chronic renal failure and type 1 diabetes. Pediatr Nephrol 17: 316–321
Beisswenger PJ, Moore LL, Curphey TJ 1993 Relationship between glycemic control and collagen-linked advanced glycosylation end products in type 1 diabetes. Diabetes Care 16: 689–694
Dominguez C, Ruiz E, Gussinye M, Carrascosa A 1998 Oxidative stress at onset and in early stages of type 1 diabetes in children and adolescents. Diabetes Care 21: 1736–1742
Elhadd TA, Kennedy G, Hill A, McLaren M, Newton RW, Greene SA, Belch JJF 1999 Abnormal markers of endothelial cell activation and oxidative stress in children, adolescents and young adults with type 1 diabetes with no clinical vascular disease. Diabetes Metab Res Rev 15: 405–411
Telci A, Cakatay U, Salman S, Satman I, Sivas A 2000 Oxidative protein damage in early stage type 1 diabetic patients. Diabetes Res Clin Pract 50: 213–223
Yan SD, Schmidt AM, Anderson GM, Zhang J, Brett J, Zou YS, Pinsky D, Stern D 1994 Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem 269: 9889–9897
Wautier JL, Wautier MP, Schmidt AM, Anderson GM, Hori O, Zoukourian C, Capron L, Chappey O, Yan SD, Brett J, Guillausseau PJ, Stern D 1999 Advanced glycation end products (AGEs) on the surface of diabetic erythrocytes bind to the vessel wall via a specific receptor inducing oxidant stress in the vasculature: a link between surface-associated AGEs and diabetic complications. Proc Natl Acad Sci U S A 91: 7742–7746
Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM 1997 Activation of the receptor for advanced glycation end products triggers a p21ras-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 272: 17810–17814
Urata Y, Yamaguchi M, Higashiyama Y, Ihara Y, Goto S, Kuwano M, Horiuchi S, Sumikawa K, Kondo T 2002 Reactive oxygen species accelerate production of vascular endothelial growth factor by advanced glycation end products in RAW264.7 mouse macrophages. Free Radic Biol Med 32: 688–701
Lal MA, Brismar H, Eklof AC, Aperia A 2002 Role of oxidative stress in advanced glycation end product-induced mesangial cell activation. Kidney Int 61: 2006–2014
Witko-Sarsat V, Friedlander M, Capeillere-Blandin C, Nguyen-Khoa T, Nguyen AT, Zingraff J, Jungers P, Descamps-Latscha B 1996 Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 49: 1304–1313
Miyata T, Wada Y, Cai Z, Iida Y, Horie K, Yasuda Y, Maeda K, Kurokawa K, van Ypersele de Strihou C 1997 Implication of an increased oxidative stress in the formation of advanced glycation end products in patients with end-stage renal failure. Kidney Int 51: 1170–1181
Miyata T, Inagi R, Asahi K, Yamada Y, Horie K, Sakai H, Uchida K, Kurokawa K 1998 Generation of protein carbonyls by glycoxidation and lipoxidation reactions with autoxidation products of ascorbic acid and polyunsaturated fatty acids. FEBS Lett 437: 24–28
Dyer DG, Blackledge JA, Thorpe SR, Baynes JW 1991 Formation of pentosidine during nonenzymatic browning of proteins by glucose: identification of glucose and other carbohydrates as possible precursors of pentosidine in vivo. J Biol Chem 266: 11654–11660
Hayase F, Nagaraj RH, Miyata S, Njoroge FG, Monnier VM 1989 Aging of proteins: immunological detection of a glucose-derived pyrrole formed during Maillard reaction in vivo. J Biol Chem 264: 3758–3764
Rodriguez-Garcia J, Requena JR, Rodriguez-Segade S 1998 Increased concentrations of serum pentosidine in rheumatoid arthritis. Clin Chem 44: 250–255
Schiekofer S, Balletshofer B, Andrassy M, Bierhaus A, Nawroth PP 2000 Endothelial dysfunction in diabetes mellitus. Semin Thromb Hemost 26: 503–511
Pomilio M, Mohn A, Verrotti A, Chiarelli F 2002 Endothelial dysfunction in children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 15: 343–361
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported in part by a research grant from the Ministry of Education, Science and Culture of Japan.
Rights and permissions
About this article
Cite this article
Tsukahara, H., Sekine, K., Uchiyama, M. et al. Formation of Advanced Glycosylation End Products and Oxidative Stress in Young Patients with Type 1 Diabetes. Pediatr Res 54, 419–424 (2003). https://doi.org/10.1203/01.PDR.0000076662.72100.74
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/01.PDR.0000076662.72100.74
This article is cited by
-
Advanced glycation end products as predictors of renal function in youth with type 1 diabetes
Scientific Reports (2021)
-
Advanced oxidation protein products promote NADPH oxidase-dependent β-cell destruction and dysfunction through the Bcl-2/Bax apoptotic pathway
Laboratory Investigation (2017)
-
The pentosidine concentration in human blood specimens is affected by heating
Amino Acids (2013)
-
Integrated analysis of miRNA and mRNA reveals that acrolein modulates GPI anchor biosynthesis in human primary endothelial cells
BioChip Journal (2013)
-
Evaluation of N ε-(3-formyl-3,4-dehydropiperidino)lysine as a novel biomarker for the severity of diabetic retinopathy
Diabetologia (2008)


