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J Clin Invest. Jun 1993; 91(6): 2470–2478.
PMCID: PMC443307

Maillard reaction products and their relation to complications in insulin-dependent diabetes mellitus.

Abstract

Glycation, oxidation, and browning of proteins have all been implicated in the development of diabetic complications. We measured the initial Amadori adduct, fructoselysine (FL); two Maillard products, N epsilon-(carboxymethyl) lysine (CML) and pentosidine; and fluorescence (excitation = 328 nm, emission = 378 nm) in skin collagen from 39 type 1 diabetic patients (aged 41.5 +/- 15.3 [17-73] yr; duration of diabetes 17.9 +/- 11.5 [0-46] yr, [mean +/- SD, range]). The measurements were related to the presence of background (n = 9) or proliferative (n = 16) retinopathy; early nephropathy (24-h albumin excretion rate [AER24] > or = 20 micrograms/min; n = 9); and limited joint mobility (LJM; n = 20). FL, CML, pentosidine, and fluorescence increased progressively across diabetic retinopathy (P < 0.05, P < 0.001, P < 0.05, P < 0.01, respectively). FL, CML, pentosidine, and fluorescence were also elevated in patients with early nephropathy (P < 0.05, P < 0.001, P < 0.01, P < 0.01, respectively). There was no association with LJM. Controlling for age, sex, and duration of diabetes using logistic regression, FL and CML were independently associated with retinopathy (FL odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.01-1.12, P < 0.05; CML OR = 6.77, 95% CI = 1.33-34.56, P < 0.05) and with early nephropathy (FL OR = 1.05, 95% CI = 1.01-1.10, P < 0.05; CML OR = 13.44, 95% CI = 2.00-93.30, P < 0.01). The associations between fluorescence and retinopathy and between pentosidine and nephropathy approached significance (P = 0.05). These data show that FL and Maillard products in skin correlate with functional abnormalities in other tissues and suggest that protein glycation and oxidation (glycoxidation) may be implicated in the development of diabetic retinopathy and early nephropathy.

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Selected References

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  • Kennedy L, Baynes JW. Non-enzymatic glycosylation and the chronic complications of diabetes: an overview. Diabetologia. 1984 Feb;26(2):93–98. [PubMed]
  • Merimee TJ. Diabetic retinopathy. A synthesis of perspectives. N Engl J Med. 1990 Apr 5;322(14):978–983. [PubMed]
  • Greene DA, Lattimer SA, Sima AA. Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. N Engl J Med. 1987 Mar 5;316(10):599–606. [PubMed]
  • Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991 Apr;40(4):405–412. [PubMed]
  • Lyons TJ. Oxidized low density lipoproteins: a role in the pathogenesis of atherosclerosis in diabetes? Diabet Med. 1991 Jun;8(5):411–419. [PubMed]
  • Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA. 1988 Nov 18;260(19):2864–2871. [PubMed]
  • Chase HP, Jackson WE, Hoops SL, Cockerham RS, Archer PG, O'Brien D. Glucose control and the renal and retinal complications of insulin-dependent diabetes. JAMA. 1989 Feb 24;261(8):1155–1160. [PubMed]
  • McCance DR, Hadden DR, Atkinson AB, Archer DB, Kennedy L. Long-term glycaemic control and diabetic retinopathy. Lancet. 1989 Oct 7;2(8667):824–828. [PubMed]
  • D'Antonio JA, Ellis D, Doft BH, Becker DJ, Drash AL, Kuller LH, Orchard TJ. Diabetes complications and glycemic control. The Pittsburgh Prospective Insulin-Dependent Diabetes Cohort Study Status Report after 5 yr of IDDM. Diabetes Care. 1989 Nov-Dec;12(10):694–670. [PubMed]
  • McCance DR, Hadden DR, Atkinson AB, Johnston H, Kennedy L. The relationship between long-term glycaemic control and diabetic nephropathy. Q J Med. 1992 Jan;82(297):53–61. [PubMed]
  • Feldt-Rasmussen B, Mathiesen ER, Deckert T. Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes. Lancet. 1986 Dec 6;2(8519):1300–1304. [PubMed]
  • Brinchmann-Hansen O, Dahl-Jørgensen K, Sandvik L, Hanssen KF. Blood glucose concentrations and progression of diabetic retinopathy: the seven year results of the Oslo study. BMJ. 1992 Jan 4;304(6818):19–22. [PMC free article] [PubMed]
  • Strowig S, Raskin P. Glycemic control and diabetic complications. Diabetes Care. 1992 Sep;15(9):1126–1140. [PubMed]
  • Schnider SL, Kohn RR. Effects of age and diabetes mellitus on the solubility and nonenzymatic glucosylation of human skin collagen. J Clin Invest. 1981 Jun;67(6):1630–1635. [PMC free article] [PubMed]
  • Yue DK, McLennan S, Delbridge L, Handelsman DJ, Reeve T, Turtle JR. The thermal stability of collagen in diabetic rats: correlation with severity of diabetes and non-enzymatic glycosylation. Diabetologia. 1983 Apr;24(4):282–285. [PubMed]
  • Hamlin CR, Kohn RR, Luschin JH. Apparent accelerated aging of human collagen in diabetes mellitus. Diabetes. 1975 Oct;24(10):902–904. [PubMed]
  • Dyer DG, Dunn JA, Thorpe SR, Bailie KE, Lyons TJ, McCance DR, Baynes JW. Accumulation of Maillard reaction products in skin collagen in diabetes and aging. J Clin Invest. 1993 Jun;91(6):2463–2469. [PMC free article] [PubMed]
  • Dunn JA, McCance DR, Thorpe SR, Lyons TJ, Baynes JW. Age-dependent accumulation of N epsilon-(carboxymethyl)lysine and N epsilon-(carboxymethyl)hydroxylysine in human skin collagen. Biochemistry. 1991 Feb 5;30(5):1205–1210. [PubMed]
  • Lyons TJ, Kennedy L. Non-enzymatic glycosylation of skin collagen in patients with type 1 (insulin-dependent) diabetes mellitus and limited joint mobility. Diabetologia. 1985 Jan;28(1):2–5. [PubMed]
  • Vishwanath V, Frank KE, Elmets CA, Dauchot PJ, Monnier VM. Glycation of skin collagen in type I diabetes mellitus. Correlation with long-term complications. Diabetes. 1986 Aug;35(8):916–921. [PubMed]
  • Lyons TJ, Bailie KE, Dyer DG, Dunn JA, Baynes JW. Decrease in skin collagen glycation with improved glycemic control in patients with insulin-dependent diabetes mellitus. J Clin Invest. 1991 Jun;87(6):1910–1915. [PMC free article] [PubMed]
  • Lyons TJ, Kennedy L. Effect of in vitro non-enzymatic glycosylation of human skin collagen on susceptibility to collagenase digestion. Eur J Clin Invest. 1985 Jun;15(3):128–131. [PubMed]
  • Sell DR, Lapolla A, Odetti P, Fogarty J, Monnier VM. Pentosidine formation in skin correlates with severity of complications in individuals with long-standing IDDM. Diabetes. 1992 Oct;41(10):1286–1292. [PubMed]
  • Monnier VM, Sell DR, Abdul-Karim FW, Emancipator SN. Collagen browning and cross-linking are increased in chronic experimental hyperglycemia. Relevance to diabetes and aging. Diabetes. 1988 Jul;37(7):867–872. [PubMed]
  • Kohn RR, Cerami A, Monnier VM. Collagen aging in vitro by nonenzymatic glycosylation and browning. Diabetes. 1984 Jan;33(1):57–59. [PubMed]
  • Dominiczak MH, Bell J, Cox NH, McCruden DC, Jones SK, Finlay AY, Percy-Robb IW, Frier BM. Increased collagen-linked fluorescence in skin of young patients with type I diabetes mellitus. Diabetes Care. 1990 May;13(5):468–472. [PubMed]
  • Monnier VM, Kohn RR, Cerami A. Accelerated age-related browning of human collagen in diabetes mellitus. Proc Natl Acad Sci U S A. 1984 Jan;81(2):583–587. [PMC free article] [PubMed]
  • Fu MX, Knecht KJ, Thorpe SR, Baynes JW. Role of oxygen in cross-linking and chemical modification of collagen by glucose. Diabetes. 1992 Oct;41 (Suppl 2):42–48. [PubMed]
  • Brownlee M, Vlassara H, Cerami A. Nonenzymatic glycosylation and the pathogenesis of diabetic complications. Ann Intern Med. 1984 Oct;101(4):527–537. [PubMed]
  • Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988 May 19;318(20):1315–1321. [PubMed]
  • Monnier VM, Vishwanath V, Frank KE, Elmets CA, Dauchot P, Kohn RR. Relation between complications of type I diabetes mellitus and collagen-linked fluorescence. N Engl J Med. 1986 Feb 13;314(7):403–408. [PubMed]
  • Oimomi M, Maeda Y, Baba S, Iga T, Yamamoto M. Relationship between levels of advanced-stage products of the Maillard reaction and the development of diabetic retinopathy. Exp Eye Res. 1989 Aug;49(2):317–320. [PubMed]
  • Makita Z, Radoff S, Rayfield EJ, Yang Z, Skolnik E, Delaney V, Friedman EA, Cerami A, Vlassara H. Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med. 1991 Sep 19;325(12):836–842. [PubMed]
  • Fujimori E. Cross-linking and fluorescence changes of collagen by glycation and oxidation. Biochim Biophys Acta. 1989 Oct 5;998(2):105–110. [PubMed]
  • Ahmed MU, Thorpe SR, Baynes JW. Identification of N epsilon-carboxymethyllysine as a degradation product of fructoselysine in glycated protein. J Biol Chem. 1986 Apr 15;261(11):4889–4894. [PubMed]
  • Ahmed MU, Dunn JA, Walla MD, Thorpe SR, Baynes JW. Oxidative degradation of glucose adducts to protein. Formation of 3-(N epsilon-lysino)-lactic acid from model compounds and glycated proteins. J Biol Chem. 1988 Jun 25;263(18):8816–8821. [PubMed]
  • Dunn JA, Patrick JS, Thorpe SR, Baynes JW. Oxidation of glycated proteins: age-dependent accumulation of N epsilon-(carboxymethyl)lysine in lens proteins. Biochemistry. 1989 Nov 28;28(24):9464–9468. [PubMed]
  • Sell DR, Monnier VM. Structure elucidation of a senescence cross-link from human extracellular matrix. Implication of pentoses in the aging process. J Biol Chem. 1989 Dec 25;264(36):21597–21602. [PubMed]
  • Sell DR, Monnier VM. End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen. J Clin Invest. 1990 Feb;85(2):380–384. [PMC free article] [PubMed]
  • Dyer DG, Blackledge JA, Thorpe SR, Baynes JW. 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. 1991 Jun 25;266(18):11654–11660. [PubMed]
  • Rosenbloom AL, Silverstein JH, Lezotte DC, Richardson K, McCallum M. Limited joint mobility in childhood diabetes mellitus indicates increased risk for microvascular disease. N Engl J Med. 1981 Jul 23;305(4):191–194. [PubMed]
  • Grgic A, Rosenbloom AL, Weber FT, Giordano B, Malone JI, Shuster JJ. Joint contracture--common manifestation of childhood diabetes mellitus. J Pediatr. 1976 Apr;88(4 Pt 1):584–588. [PubMed]
  • MIRSKY IA, FUTTERMAN P, BROHKAHN RH. The quantitative measurement of vibratory perception in subjects with and without diabetes mellitus. J Lab Clin Med. 1953 Feb;41(2):221–235. [PubMed]
  • Oberley LW. Free radicals and diabetes. Free Radic Biol Med. 1988;5(2):113–124. [PubMed]
  • 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 Feb;87(2):432–438. [PMC free article] [PubMed]
  • Hogan M, Cerami A, Bucala R. Advanced glycosylation endproducts block the antiproliferative effect of nitric oxide. Role in the vascular and renal complications of diabetes mellitus. J Clin Invest. 1992 Sep;90(3):1110–1115. [PMC free article] [PubMed]
  • Brownlee M, Vlassara H, Kooney A, Ulrich P, Cerami A. Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science. 1986 Jun 27;232(4758):1629–1632. [PubMed]
  • Hammes HP, Martin S, Federlin K, Geisen K, Brownlee M. Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11555–11558. [PMC free article] [PubMed]
  • 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 Oct;40(10):1328–1334. [PubMed]
  • Yagihashi S, Kamijo M, Baba M, Yagihashi N, Nagai K. Effect of aminoguanidine on functional and structural abnormalities in peripheral nerve of STZ-induced diabetic rats. Diabetes. 1992 Jan;41(1):47–52. [PubMed]
  • Rohrbach DH, Hassell JR, Kleinman HK, Martin GR. Alterations in the basement membrane (heparan sulfate) proteoglycan in diabetic mice. Diabetes. 1982 Feb;31(2):185–188. [PubMed]
  • Yue DK, Swanson B, McLennan S, Marsh M, Spaliviero J, Delbridge L, Reeve T, Turtle JR. Abnormalities of granulation tissue and collagen formation in experimental diabetes, uraemia and malnutrition. Diabet Med. 1986 May;3(3):221–225. [PubMed]
  • Cohen MP, Klepser H, Wu VY. Undersulfation of glomerular basement membrane heparan sulfate in experimental diabetes and lack of correction with aldose reductase inhibition. Diabetes. 1988 Oct;37(10):1324–1327. [PubMed]

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