The role of enzymes of the glyoxalase system in relation to complications in type II diabetes mellitus
Keywords:Glyoxalase I, Glyoxalase II, Lactate, Aldose reductase
Background: Metabolism of methylglyoxal by the glyoxalase system may be linked to the development of diabetic complications. It was considered worthwhile to find out whether changes observed in the levels of glyoxalase I, glyoxalase II, aldose reductase & D-lactate are prognostic indicators for the development of complications of diabetes or merely reflect the result of changes associated with complications.
Methods: The glyoxalase system was characterized in erythrocytes of blood samples from patients with type II diabetes mellitus (n=177), and normal healthy control subjects (n=40). Diabetics were divided into 3 main groups based on presence or absence of complications.
Results: The concentrations of RBC glyoxalase I, glyoxalase II, aldose reductase, and D-lactate were significantly increased in all groups of diabetic patients, (P <0.001) relative to controls. Comparison between groups showed maximum rise of enzymes in group I and group III (P <0.001); and maximum rise of D-lactate in group III (P <0.001). Within the groups of patients with complications, enzyme levels were markedly increased in patients with IHD/PVD (ischaemic heart disease/peripheral vascular disease) and decreased in patients with nephropathy.
Conclusion: Results of this study suggests a positive relationship between increased activity of erythrocyte enzymes of glyoxalase system and poor or moderate glycemic control. The increased enzyme levels in patients without complications indicate their role as prognostic markers for development of complications. Molecular mechanisms for development of Nephropathy appear to be different from those of Neuropathy and Retinopathy.
Sarah Wild, Gojka Rojlic, Anders Green, Richard Sicree, Hilary King. Global prevalence of diabetes. Diabetes Care. 2004 May;27(5):1047-53.
Kaveeshwar SA, Cornwall J. The current state of diabetes mellitus in India. Australas Med J. 2014;7(1):45-8.
Vander Jagt DL. Methylglyoxal, diabetes mellitus and diabetic complications Drug Metabol Drug Interact. 2008;23(1-2):93-124.
Antony C. McLellan, Paul J. Thornalley, Jonathan Benn, Peter H. Sonksen. Glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications. Clin Sci. 1994;87:21-9.
Vander Jagt DL, Robinson B, Taylor KK, Hunsaker LA. Reduction of Trioses by NADPH dependent aldo-keto reductases. Aldose reductase, methylglyoxal, and diabetic complications. J Biol Chem. 1992;267(7):4364-9.
Thornalley PJ. Modification of the glyoxalase system in human red cells by glucose in vitro. Biochem J. 1988;254:751-5.
Naila Rabbani, Paul J. Thornalley. The critical role of methylglyoxal and glyoxalase I in diabetic nephropathy. Diabetes. 2014 Jan;63:291-9.
Trinder P. Determination of blood glucose using an oxidoperoxidase system with noncaricinigenic chromogen. J Clin Pathol. 1969 Mar;22(2):158-61.
Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia. 2003 Jan;46(1):3-19.
Ratliff DM, Vander Jagt DJ, Eaton RP, Vander Jagt DL. Increased levels of methylglyoxal-metabolizing enzymes in mononuclear and polymorphonuclear cells from insulin-dependent diabetic patients with diabetic complications: aldose reductase, glyoxalase I, and glyoxalase II--a clinical research center study. J Clin Endocrinol Metab. 1996 Feb;81(2):488-92.
Vander Jagt DL, Robinson B, Taylor KK, Hunsaker LA. Reduction of trioses by NADPH-dependent aldo-keto reductases. Aldose reductase, methylglyoxal, and diabetic complications. J Biol Chem. 1992 Mar;267(7):4364-9.
McLellan AC, Phillips SA, Thornalley PJ. The assay of methylglyoxal in biological systems by derivatization with 1,2-diamino-4,5-dimethoxybenzene. Anal Biochem. 1992 Oct;206(1):17-23.
Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001 Dec;414(6865):813-20.
Kador PF, Kinoshita JH. Role Kador of aldose reductase in the development of diabetes-associated complications. Am J Med. 1885;79(Suppl 5A):8-12.
International Diabetes Federation. New IDF Worldwide definition of the metabolic syndrome. Press Conference. 1st International congress on prediabetes and the metabolic syndrome. Brerlin, Germany, April 14, 2005. Available At: www.idf.org.
David L. Vander Jagt, Lucy A. Hunsaker. Methylglyoxal metabolism and diabetic complications: roles of aldose reductase, glyoxalase I, betaine aldehyde dehydrogenase. Chemico-Biol Interact. 2003;2:143-4.
Brandt RB, Siegel SA, Waters MG, Bloch MH. Spectrophotometric assay for D-lactate in plasma. Anal Biochem. 1980 Feb;102(1):39-46.
Kees Olieman, Elbert de Vries. Determination of D- and L-lactate in fermented dairy products with HPLC. Netherlands Milk Dairy J. 1988;42(2):111.
Beisswenger PJ, Howell SK, Touchette AD, Lal S, Szwergold BS. Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes. 1999 Jan;48(1):198-202.
Thornalley PJ, Hooper NI, Jennings PE, Florkowski CM, Jones AF, Lunec J, et al. The human red blood cell glyoxalase system in diabetes mellitus. Diabetes Res Clin Pract. 1989 Aug;7(2):115-20.
McLellan AC, Phillips SA, Thornalley PJ. Fluorimetric assay of D-lactate. Anal Biochem. 1992 Oct;206(1):12-6.
Thornalley PJ. Modification of the glyoxalase system in human red blood cells by glucose in vitro. Biochem J. 1988 Sep;254(3):751-5.
Atkins TW, Thornalley PJ. Fluorimetric assay of D-lactate. Med Sci Res. 1989;11:777-8.
Chandalia M, Abate N, Garg A, Stray-Gundersen J, Grundy SM. Relationship between generalized and upper body obesity to insulin resistance in Asian Indian men. J Clin Endocrinol Metab. 1999 Jul;84(7):2329-35.
Nishimura C, Saito T, Ito T, Omori Y, Tanimoto T. High levels of erythrocyte aldose reductase and diabetic retinopathy in NIDDM. Diabetologia. 1994 Mar;37(3):328-30.
Oishi N, Kubo E, Takamura Y, Maekawa K, Tanimoto T, Akagi Y. Correlation between erythrocyte aldose reductase level and human diabetic retinopathy. Br J Ophthalmol. 2002 Dec;86(12):1363-6.
Reddy GB, Satyanarayana A, Balakrishna N, Ayyagari R, Padma M, Viswanath K, et al. Erythrocyte aldose reductase activity and sorbitol levels in diabetic retinopathy. Mol Vis. 2008 Mar;14:593-601.
Chung SS, Chung SK. Aldose reductase in diabetic microvascular complications. Curr Drug Targets. 2005 Jun;6(4):475-86.
Enas EA, Yusuf S, Mehta JL. Prevalence of coronary artery disease in Asian Indians. Am J Cardiol. 1992 Oct;70(9):945-9.