DOI: http://dx.doi.org/10.18203/2320-6012.ijrms20150245

Erythrocyte enzymes of Glyoxalase system as indicators of beneficial effects of antihyperglycemic agents in Type 2 Diabetes

Vinay Patke, Sarvesh Saroj

Abstract


Background: Methylglyoxal (MG), a product of sustained hyperglycemia, is a reactive carbonyl toxin responsible for development of complications in diabetes. Glyoxalase system detoxify MG to prevent complications. Some antihyperglycemic agents, may inhibit deleterious effects of MG by independent mechanisms. It was considered worthwhile to identify such agents and to find out whether changes observed in the erythrocyte levels of Glyoxalase I, Glyoxalase II, Aldose Reductase & D-Lactate are indicators of the beneficial effects through their direct action on MG, or merely a result of good glycemic control in response to treatment.

Methods: The glyoxalase system was characterized in erythrocytes of blood samples from patients with Type 2 Diabetes (n = 147), and normal healthy control subjects (n = 40). Diabetics were divided into groups based on presence or absence of complications; & further divided into subgroups based on medication with sulphonylurea, metformin, insulin and combination therapy.

Results: Erythrocyte Glyoxalase I, Glyoxalase II, Aldose Reductase, and D-Lactate levels significantly increased in all diabetics, (p<0.001) relative to controls. A maximum rise of enzymes in T2D with complications was observed as compared to patients without complications (p<0.001). Inadequate glycemic control was observed in all diabetics, and enzyme levels significantly declined in groups treated with metformin, either as monotherapy or in combination with insulin.

Conclusions: Enzymes of Glyoxalase system indicate beneficial effects of metformin. Metformin reduces MG and minimizes worsening glycemic control leading to complications. Metformin renders protection through mechanism independent of its antihyperglycemic action.

 


Keywords


Glyoxalase, Lactate, Aldose Reductase, Metformin

Full Text:

PDF

References


The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development & progression of long term complications in insulin-dependent diabetes mellitus. N Eng J Med. 1993;329:977-86.

Vander Jagt DL Robinson B, Taylor KK, Hunsaker LA. Reduction of trioses by NADPH – dependent aldo-keto reductase: aldose reductase, methylglyoxal, & diabetic complications. J Biol Chem 1992;167:4364-9.

Baskaran S, Balasubramanian KA. Effect of methylglyoxal on protein thiol & amino groups in isolated rat enterocytes and colonocytes and activity of various brush border enzymes. Indian J Biochem Biophy. 1990;27:13-17.

Antony C. McLellan, Paul J. Thornalley, Jonathan Benn and Peter H. Sonksen Glyoxalase System in Clinical Diabetes Mellitus and Correlation with Diabetic Complications. Clin Sci. 1994;87:21-29.

Thornalley P. The glyoxalase system: new developments towards functional Characterization of a metabolic pathway fundamental to biological life. Biochem J. 1990;269:1–11.

Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: Principles of pathogenesis and therapy. Lancet. 2005;365(9467):1333–46.

Aquilante CL. Sulfonylurea pharmacogenomics in Type 2 diabetes: the influence of drug target and diabetes risk polymorphisms. Expert Rev Cardiovasc Ther. 2010;8(3):359–72.

Lo TWC, Selwood T, and Thornalley PJ. The reaction of methylglyoxal with Aminoguanidine under physiological conditions and prevention of methylglyoxal binding to plasma proteins. Biochem Pharmacol. 1994,48:1865–70.

Hirsh J, Petrakova E, Feather M. The reaction of some dicarbonyl sugars with Amino guanidine. Carbohydr Res. 1992,232:125–30.

Zimmerman G, Meistrell M, Bloom O, Cockroft K, Bianchi M, Risucci D, Broome J, Farmer P, Cerami A, Vlassara H: Neurotoxicity of advanced glycosylation end products during focal stroke and neuroprotective effects of aminoguanidine. Proc Natl Acad Sci USA. 1995;92:3744–8.

Thornalley PJ. Modification of the glyoxalase system in human red blood cells by Glucose in vitro. Biochem J. 1988;254(3):751-5.

P. Trinder. Determination of Blood Glucose using an oxidoperoxidase System with noncaricinigenic chromogen. J Clin Path. 1969;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;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. 81(2):488-92.

Vander Jagt DL, Robinson B, Taylor KK, Hunsaker LA. Reduction of trioses by NADPH-dependent aldo-keto reductase. Aldose reductase, methylglyoxal, and Diabetic Complications Biol Chem. 1992;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;206(1):17-23.

Beisswenger PJ, Howell SK, Touchette AD, Lal S, Szwergold BS. Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes. 1999;48(1):198-202.

Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193–203.

Kador PF, Kinoshita JH. Role Kador of aldose reductase in the development of diabetes-associated complications. Am J Med. 1885;79(5A):8-12.

International Diabetes Federation. Nerw IDF Worldwide definition of the metabolic syndrome. Press Conference. 1st International congress on prediabetes and the metabolic syndrome. Brerlin, Germany, 2005.

Jagt DLV, Hunsaker LA. Methylglyoxal metabolism and diabetic complications: Roles of Aldose Reductase, Glyoxalase I, Betaine aldehyde dehydrogenase. Chemico-Bioilogical Interactions. 2003, 143-144.

Leibowitz G, Cerasi E: Sulfonylurea treatment of NIDDM patients with cardiovascular disease: a mixed blessing? Diabetologia. 1996;39:503-14.

Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813-20.

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;84(7):2329-35.

Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574-9.

Faure P, Rossini E, Wiernsperger N. An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats. Diabetes 1999;48:353-7.

Beisswenger P, Rugiero-Lopez D. Metformin inhibition of glycation processes. Diabetes Metab. 2003;29(6S):95-103.

Anedda A, Rial E, Barroso G. Metformin induces oxidative stress in white adipocytes and raises uncoupling proten levels. J Endocrinol. 2008;199:33-40.

Hulisz DT, Bonfiglio MF, Murray RD: Metformin-associated lactic acidosis. J Am Board Fam Pract. 1998;11:233-6.

Rojas LBA, Gomes MB. Diabetology & Metabolic Syndrome. 2013;5:6.