Molecular and Cellular Biochemistry

, Volume 305, Issue 1–2, pp 123–131 | Cite as

Plasma methylglyoxal and glyoxal are elevated and related to early membrane alteration in young, complication-free patients with Type 1 diabetes

  • Yingchun Han
  • Edward Randell
  • Sudesh Vasdev
  • Vicki Gill
  • Vereesh Gadag
  • Leigh Anne Newhook
  • Marie Grant
  • Donna Hagerty
Article

Abstract

The reactive aldehydes methylglyoxal and glyoxal, arise from enzymatic and non-enzymatic degradation of glucose, lipid and protein catabolism, and lipid peroxidation. In Type 1 diabetes mellitus (T1DM) where hyperglycemia, oxidative stress, and lipid peroxidation are common, these aldehydes may be elevated. These aldehydes form advanced glycation end products (AGEs) with proteins that are implicated in diabetic complications. We measured plasma methylglyoxal and glyoxal in young, complication-free T1DM patients and assessed activity of the ubiquitous membrane enzyme, Na+/K+ ATPase. A total of 56 patients with TIDM (DM group), 6–22 years, and 18 non-diabetics (ND group), 6–21 years, were enrolled. Mean plasma A1C (%) was higher in the DM group (8.5 ± 1.3) as compared to the ND group (5.0 ± 0.3). Using a novel liquid chromatography-mass spectrophotometry method, we found that mean plasma methylglyoxal (nmol/l) and glyoxal levels (nmol/l), respectively, were higher in the DM group (841.7 ± 237.7, 1051.8 ± 515.2) versus the ND group (439.2 ± 90.1, 328.2 ± 207.5). Erythrocyte membrane Na+/K+ ATPase activity (nmol NADH oxidized/min/mg protein) was elevated in the DM group (4.47 ± 0.98) compared to the ND group (2.16 ± 0.59). A1C correlated with plasma methylglyoxal and glyoxal, and both aldehydes correlated with each other. A high correlation of A1C with Na+/K+ ATPase activity, and a regression analysis showing A1C as a good predictor of activity of this enzyme, point to a role for glucose in membrane alteration. In complication-free patients, increased plasma methylglyoxal, plasma glyoxal, and erythrocyte Na+/K+ ATPase activity may foretell future diabetic complications, and emphasize a need for aggressive management.

Keywords

Type 1 diabetes Methylglyoxal Glyoxal Na+/K+ ATPase activity 

Notes

Acknowledgments

We would like to thank the Canadian Institutes of Health Research Regional Partnership Program, the Janeway Foundation and the Health Care Foundation for funding to carry out this study. We also thank the School of Graduate Studies, Faculty of Medicine, Memorial University for student support for Yingchun Han.

References

  1. 1.
    World Health Organization (2006) Diabetes Fact Sheet. 312 www.who.int/mediacentre/factsheet/fs312/en/print.html (accessed March 29, 2007)Google Scholar
  2. 2.
    American Diabetes Association (2007) All about diabetes. www.diabetes.org/about-diabetes.jsp (accessed March 29, 2007)Google Scholar
  3. 3.
    Thornalley PJ, Langborg AM, Minhas HS (1999) Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem J 344:109–116PubMedCrossRefGoogle Scholar
  4. 4.
    Thornalley PJ (2005) Dicarbonyl intermediates in the maillard reaction. Ann NY Acad Sci 1043:111–117PubMedCrossRefGoogle Scholar
  5. 5.
    Phillips SA, Thornalley PJ (1993) The formation of methylgyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal. Eur J Biochem 212:101–105PubMedCrossRefGoogle Scholar
  6. 6.
    Wells-Knecht KJ, Zyzak DV, Litchfield JE, Thorpe SR, Baynes JW (1995) Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose. Biochem 34:3702–3709CrossRefGoogle Scholar
  7. 7.
    Beisswenger PJ, Howell SK, O’Dell RM, Wood ME, Touchette AD, Szwergold BS (2001) Alpha-Dicarbonyls increase in the postprandial period and reflect the degree of hyperglycemia. Diabetes Care 24:726–732PubMedCrossRefGoogle Scholar
  8. 8.
    Chang KC, Paek KS, Kim HJ, Lee YS, Yabe-Nishimura C, Seo HG (2002) Substrate-induced up-regulation of aldose reductase by methylglyoxal, a reactive oxoaldehyde elevated in diabetes. Mol Pharmacol 61:1184–1191PubMedCrossRefGoogle Scholar
  9. 9.
    Kalapos MP (1999) Methylglyoxal in living organisms. Chemistry, biochemistry, toxicology and biological implications. Toxic Let 110:145–175CrossRefGoogle Scholar
  10. 10.
    Jay D, Hitomi H, Griendling KK (2006) Oxidative stress and diabetic cardiovascular complications. Free Rad Biol Med 41:183–192CrossRefGoogle Scholar
  11. 11.
    Kershnar AK, Daniels SR, Imperatore G, Palla SL, Petitti DB, Petitti DJ, Marcovina S, Dolan LM, Hamman RF, Liese AD, Pihoker C, Rodriguez BL (2006) Lipid abnormalities are prevalent in youth with Type 1 and Type 2 diabetes: the search for diabetes in youth study. J Pediatr 149:314–319PubMedCrossRefGoogle Scholar
  12. 12.
    O’Brien PJ, Siraki AG, Shangari N (2005) Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health. Crit Rev Toxicol 35:609–662PubMedCrossRefGoogle Scholar
  13. 13.
    Thornalley PJ, Battah S, Ahmed N, Karachalias N, Agalou S, Babaei-Jadidi R, Dawnay A (2003) Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spec. Biochem J 375:581–592PubMedCrossRefGoogle Scholar
  14. 14.
    Zeng J, Davies MJ (2005) Evidence for the formation of adducts and S-(carboxymethyl)cysteine on reaction of α-dicarbonyl compounds with thiol groups on amino acids, peptides, and proteins. Chem Res Toxicol 18:1232–1241PubMedCrossRefGoogle Scholar
  15. 15.
    Morgan PE, Dean RT, Davies MJ (2002) Inactivation of cellular enzymes by carbonyls and protein-bound glycation/glycoxidation products. Arch Biochem Biophys 403:259–269PubMedCrossRefGoogle Scholar
  16. 16.
    Park YS, Koh YH, Takahashi M, Miyamoto Y, Suzuki K, Dohmae N, Takio K, Honke K, Taniguchi N (2003) Identification of the binding site of methylglyoxal on glutathione peroxidase: methylglyoxal inhibits glutathione peroxidase activity via binding to glutathione binding sites Arg 184 and 185. Free Rad Res 37:205–211CrossRefGoogle Scholar
  17. 17.
    Bidasee KR, Zhang Y, Shao CH, Wang M, Patel KP, Dincer UD, Besch HR Jr (2004) Diabetes increases formation of advanced glycation end products on sarco(endo)plasmic reticulum Ca2+-ATPase. Diabetes 53:463–473PubMedCrossRefGoogle Scholar
  18. 18.
    Lee HJ, Howell SK, Sanford RJ, Beisswenger PJ (2005) Methylglyoxal can modify GAPDH activity and structure. Ann NY Acad Sci 1043:135–145PubMedCrossRefGoogle Scholar
  19. 19.
    Jia X, Olson DJH, Ross ARS, Wu L (2006) Structural and functional changes in human insulin induced by methylglyoxal. FASEB J 20:E871–E879CrossRefGoogle Scholar
  20. 20.
    Horiuchi S, Sakamoto Y, Sakai M (2003) Scavenger receptors for oxidized and glycated proteins. Amino Acids 25:283–292PubMedCrossRefGoogle Scholar
  21. 21.
    Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP (2005) Understanding RAGE, the receptor for advanced glycation end products. J Mol Med 83:876–886PubMedCrossRefGoogle Scholar
  22. 22.
    Xu B, Chibber R, Ruggerio D, Kohner E, Ritter J, Ferro A (2003) Impariment of vascular endothelial nitric oxide synthase activity by advanced glycation end products. FASEB J 17:1289–1291PubMedCrossRefGoogle Scholar
  23. 23.
    Bidasee KR, Nallani K, Yu Y, Cocklin RR, Zhang Y, Wang M, Dincer UD, Besch HR Jr (2003) Chronic diabetes increases advanced glycation end products on cardiac ryanodine receptors/calcium-release channels. Diabetes 52:1825–1836PubMedCrossRefGoogle Scholar
  24. 24.
    Ferretti G, Bacchetti T,Marchionni C, Calderelli L, Curatola G (2001) Effect of glycation of high density lipoproteins on their physiochemical properties and on paraoxonase activity. Acta Diabetol 38:163–169PubMedCrossRefGoogle Scholar
  25. 25.
    Iijima K, Murata M, Takahara H, Irie S, Fujimoto D (2000) Identification of Nω-carboxymethylarginine as a novel acid-labile advanced glycation end product in collagen. Biochem J 347:23–27PubMedCrossRefGoogle Scholar
  26. 26.
    Cohen MP, Shea E, Chen S, Shearman CW (2003) Glycated albumin increases oxidative stress, activates NF-κB and extracellular signal-regulated kinase (ERK), and stimulates ERK-dependent transformating growth factor-β1 production in macrophage RAW cells. J Lab Clin Med 141:242–249PubMedCrossRefGoogle Scholar
  27. 27.
    Rashid G, Benchetrit S, Fishman D, Bernheim J (2004) Effect of advanced glycation end-products on gene expression and synthesis of TNF-α and endothelial nitric oxide synthase by endothelial cells. Kid Int 66:1099–1106CrossRefGoogle Scholar
  28. 28.
    Rodriguez-Manas L, Angulo J, Vallejo S, Peiro C, Sanchez-Ferrer A, Cercas E, Lopez-Doriga P, Sanchez-Ferrer CF (2003) Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature. Diabetologia 46:556–566PubMedGoogle Scholar
  29. 29.
    Wautier JL, Schmidt AM (2004) Protein glycation. A firm link to endothelial cell dysfunction. Circ Res 95:233–238PubMedCrossRefGoogle Scholar
  30. 30.
    Kislinger T, Tanji N, Wendt T, Qu W, Lu Y, Ferran LJ, Taguchi A, Olson K, Bucciarelli L, Goova M, Hofmann MA, Cataldegirmen G, D’Agati V, Pischetsrieder M, Stern DM, Schmidt AM (2001) Receptor for advanced glycation end products medicates inflammation and enhanced expression of tissue factor in vasculature of diabetic apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 21:905–910PubMedGoogle Scholar
  31. 31.
    Scivittaro V, Ganz MB, Weiss MF (2000) AGEs induce oxidative stress and activate protein kinase C-BII in neonatal mesangial cells. Am J Physiol (Renal Physiol) 278:F676–F683Google Scholar
  32. 32.
    Wu L (2005) The pro-oxidant role of methylglyoxal in mesenteric artery smooth muscle cells. Can J Physiol Pharmacol 83:63–68PubMedCrossRefGoogle Scholar
  33. 33.
    Rosca MG, Mustata TG, Kinter MT, Ozdemir AM, Kern TS, Szweda LI, Brownlee M, Monnier VM, Weiss MF (2005) Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am J Physiol (Renal Physiol) 289:420–430CrossRefGoogle Scholar
  34. 34.
    Hammes HP, Brownlee M, Schleicher E, Bretzel RG (1999) Diabetic retinopathy risk correlates with intracellular concentrations of the glycoxidation product Nε-(carboxymethyl)lysine independently of glycohaemoglobin concentration. Diabetologia 42:603–607PubMedCrossRefGoogle Scholar
  35. 35.
    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 17:316–321PubMedCrossRefGoogle Scholar
  36. 36.
    Lieuw-A-Fa MLM, Van Hinsbergh VWM, Teerlink T, Barto R, Twisk J, Stehouwer CDA, Schalkwijk CG (2004) Increased levels of Nε-(carboxymethyl)lysine and Nε-(carboxyethyl)lysine in type 1 diabetic patients with impaired renal function: correlation with markers of endothelial dysfunction. Nephrol Dial Transplant 19:631–636PubMedCrossRefGoogle Scholar
  37. 37.
    Hwang JS, Shin CH, Yang SW (2005) Clinical implications of Nε-(carboxymethyl)lysine, advanced glycation end product, in children and adolescents with type 1 diabetes. Diabetes Obes Metab 7:263–267PubMedCrossRefGoogle Scholar
  38. 38.
    Raccah D, Fabreguettes C, Azulay JP, Vague P (1996) Erythrocyte NA+-K+-ATPase activity, metabolic control, and neuropathy in IDDM patients. Diabetes Care 19:564–568PubMedCrossRefGoogle Scholar
  39. 39.
    Mimura M, Makino H, Kanatsuka A, Asai T, Yoshida S (1994) Reduction of erythrocyte (Na(+)-K)ATPase activity in type 2 (non-insulin-dependent) diabetic patients with microalbuminuria. Horm Met Res 26:33–38CrossRefGoogle Scholar
  40. 40.
    Djemli-Shipkolye A, Coste T, Raccah D, Vague P, Pieroni G, Gerbi A (2001) Na,K-ATPase alterations in diabetic rats: relationship with lipid metabolism and nerve physiological parameters. Cell Mol Biol 47:297–304PubMedGoogle Scholar
  41. 41.
    Tsimaratos M, Coste TC, Djemli-Shipkolye A, Daniel L, Shipkolye F, Vague P, Raccah D (2001) Evidence of time-dependent changes in renal medullary Na,K-ATPase activity and expression in diabetic rats. Cell Mol Biol 47:239–245Google Scholar
  42. 42.
    Koc B, Erten V, Yilmaz MI, Sonmez A, Kocar IH (2003) The relationship between red blood cell NA/K-ATPase activities and diabetic complications in patients with type 2 diabetes mellitus. Endocrine 21:273–278PubMedCrossRefGoogle Scholar
  43. 43.
    Clinical Practice Guidelines Expert Committee of Canadian Diabetes Association (2003) Clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 27:SGoogle Scholar
  44. 44.
    Vasarhelyi B, Szabo T, Ver A, Tulassay T (1997) Measurement of Na+/K+-ATPase activity with an automated analyzer. Clin Chem 43:1986–1987PubMedGoogle Scholar
  45. 45.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  46. 46.
    McLellan AC, Thornalley PJ, Benn J, Sonksen PH (1994) Glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications. Clin Sci 87:21–29PubMedGoogle Scholar
  47. 47.
    Nemet I, Turk Z, Duvnjak L, Varga-Defterdarovic L (2005) Humoral methylglyoxal level reflects glycemic fluctuation. Clin Biochem 38:379–383PubMedCrossRefGoogle Scholar
  48. 48.
    Odani H, Shinzato T, Matsumoto Y, Usami J, Maeda K (1999) Increase in three α1 β-dicarbonyl compound levels un human uremic plasma: specific in vivo determination on intermediates in advanced maillard reaction. Biochem Biophys Res Comm 256:89–93PubMedCrossRefGoogle Scholar
  49. 49.
    Lapolla A, Flamini R, Vedova AD, Senesi A, Reitano R, Fedele D, Basso E, Seraglia R, Traldi P (2003) Glyoxal and methylglyoxal levels in diabetic patients: quantitive determination by a new GC/MS method. Clin Chem Lab Med 41:1166–1173PubMedCrossRefGoogle Scholar
  50. 50.
    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 15:405–411PubMedCrossRefGoogle Scholar
  51. 51.
    Mostafa AA, Randell EW, Vasdev SC, Gill VD, Han Y, Gadag V, Raouf AA, El Said H (2007) Plasma protein advanced glycation end products, carboxymethyl cysteine and carboxyethyl cysteine, are elevated and related to nephropathy in patients with diabetes. Mol Cell Biochem, doi. 10.1007/s11010-007-9422-9Google Scholar
  52. 52.
    Baldini P, Incerpi S, Lambert-Gardini S, Spinedi A, Luly P (1989) Membrane lipid alterations and Na+-pumping activity in erythrocytes from IDDM and NIDDM subjects. Diabetes 38:825–831PubMedCrossRefGoogle Scholar
  53. 53.
    Besch W, Blucher H, Bettin D, Wolf E, Michaelis D, Kohnert KD (1995) Erythrocyte sodium–lithium countertransport, adenosine triphosphatase activity and sodium-potassium fluxes in insulin-dependent diabetes. Int J Clin Lab Res 25:104–109PubMedCrossRefGoogle Scholar
  54. 54.
    Finotti P, Palatini P (1986) Reduction of erythrocyte (Na+-K+)ATPase activity in Type 1 (insulin-dependent) diabetic subjects and its activation by homologous plasma. Diabetologia 29:623–628PubMedCrossRefGoogle Scholar
  55. 55.
    Jannot MF, Raccah D, Dufayet de la Tour D, Coste T, Vague P (2002) Genetic and environment regulation of NA/K adenosine triphosphatase activity in diabetic patients. Metabolism 51:284–291PubMedCrossRefGoogle Scholar
  56. 56.
    Deak B, Dobos M, Kocsis I, Krikovszky D, Tordai A, Madacsy L, Tulassay T, Vasarhelyi B (2003) HbA1c levels and erythrocyte transport functions in complication-free type 1 diabetic children and adolescents. Acta Diabetol 40:9–13PubMedCrossRefGoogle Scholar
  57. 57.
    Stark G (2005) Functional consequences of oxidative membrane damage. J Membrane Biol 205:1–16CrossRefGoogle Scholar
  58. 58.
    Chang CT, Wu MS, Tian YC, Chen KH, Yu CC, Liao CH, Hung CC, Yang CW (2007) Enhancement of epithelial sodium channel expression in renal cortical collecting duct cells by advanced glycation end products. Nephrol Dian Transplant 22:722–731CrossRefGoogle Scholar
  59. 59.
    Barbagallo M, Gupta RK, Resnick LM (1993) Independent effects of hyperinsulinemia and hyperglycemia on intracellular sodium in normal human red cells. Am J Hypertens 6:264–267PubMedGoogle Scholar
  60. 60.
    Vasdev S, Ford CA, Parai S, Longerich L, Gadag V (2000) Dietary alpha-lipoic acid supplementation lowers blood pressure in spontaneously hypertensive rats. J Hypertens 18:567–573PubMedCrossRefGoogle Scholar
  61. 61.
    Midaoui AEL, Elimadi A, Wu L, Haddad PS, de Champlain J (2003) Lipoic acid prevents hypertension, hyperglycemia and the increase in heart mitochondrial superoxide production. Am J Hypertens 16:173–179PubMedCrossRefGoogle Scholar
  62. 62.
    Foster TS (2007) Efficacy and safety of α-lipoic acid supplementation in the treatment of symptomatic diabetic neuropathy. Diabetes Edu 33:111–117CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Yingchun Han
    • 1
  • Edward Randell
    • 1
  • Sudesh Vasdev
    • 2
  • Vicki Gill
    • 2
  • Vereesh Gadag
    • 3
  • Leigh Anne Newhook
    • 4
  • Marie Grant
    • 5
  • Donna Hagerty
    • 5
  1. 1.Department of Laboratory MedicineMemorial UniversitySt. John’sCanada
  2. 2.Discipline of Medicine, Health Sciences CentreMemorial UniversitySt. John’sCanada
  3. 3.Division of Community HealthMemorial UniversitySt. John’sCanada
  4. 4.Department of Pediatrics, Faculty of MedicineMemorial UniversitySt. John’sCanada
  5. 5.Eastern HealthSt. John’sCanada

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