Negative Association between Erythrocyte Reduced Glutathione Concentration and Diabetic Complications

Abstract

1. Multiple logistic regression analysis of biochemical and clinical variables in diabetic patients was performed to identify those associated with the presence of diabetic complications (retinopathy, neuropathy and nephropathy). 2. The presence of diabetic complications correlated positively with duration of diabetes and patients age and negatively with the concentration of reduced glutathione in erythrocytes. Individually, retinopathy, neuropathy and nephropathy correlated with duration of diabetes, but retinopathy also correlated positively with haemoglobin A1C in diabetic patients. In insulin-dependent patients, the concentration of methylglyoxal was also in the logistic model for retinopathy and diabetic complications, but the logistic regression coefficient was not significant. 3. Multiple linear regression analysis indicated that erythrocyte reduced glutathione concentration correlated negatively with D-lactate concentration and positively with duration of diabetes in insulin-dependent patients and correlated negatively with glucose concentration in non-insulin-dependent diabetic patients. 4. In non-diabetic subjects, erythrocyte glyoxalase I activity correlated positively with methylglyoxal concentration. There was no similar correlation in diabetic patients. In insulin-dependent patients, methylglyoxal concentration correlated positively with duration of diabetes. 5. Glyoxal and methylglyoxal are detoxified by the glyoxalase system with reduced glutathione as co-factor. The concentration of reduced glutathione may be decreased by oxidative stress and by decreased in situ glutathione reductase activity in diabetes mellitus. A reduced concentration of reduced glutathione may predispose diabetic patients to oxidative damage and to alpha-oxoaldehydemediated glycation by decreasing the in situ glyoxalase I activity. Recent studies of vascular endothelial cells in vitro have suggested that alpha-oxoaldehydes detoxified by glyoxalase I are the major precursors of advanced glycation end products implicated in the development of diabetic complications. The role of these factors in the development of diabetic complications and the prospective prevention of diabetic complications by supplementation of reduced glutathione and/or alpha-oxoaldehyde-scavenging agents now deserve investigation.

Oxidative stress status in patients with diabetes mellitus: relationship to diet

“…The clinical relevance of this possibility is illustrated by the results of a large survey of diabetic patients in which serum uric acid was independently associated with an increased presence of coronary heart disease (Rathmann et al, 1993). Similarly, decrease in GSH has been related to severity of diabetic complications (Thornalley et al, 1996).…”

Oxidative Stress in Type II Diabetes Mellitus and the Role of the Endogenous Antioxidant Glutathione

“…When loss of GSH occurs, due to an increased rate of these reactions, it is important that the metabolic machinery in RBCs react with an increased rate of GSH synthesis. As mentioned above some authors report unchanged or elevated GSH concentrations in the RBCs of NIDDM patients (Caren and Carne 1951;Matsubara, Ferreira et al 1992;Sinclair, Girling et al 1992;Di Simplicio, De Giorgio et al 1995;Laaksonen, Atalay et al 1996;Thornalley, McLellan et al 1996;Atalay, Laaksonen et al 1997;Straface, Rivabene et al 2002;Nwose, Jelinek et al 2006;Ozkilic, Cengiz et al 2006). A second group of authors report decreased GSH concentrations in NIDDM (Bono, Caimi.G et al 1986;Murakami, K. et al 1989;Yoshida, Hirokawa et al 1995;Vijayalingam, Parthiban et al 1996;Seghrouchni, Drai et al 2002;Memisogullari, Taysi et al 2003;Sailaja, Baskar et al 2003;Constantin, Constantinescu et al 2005;Sampathkumar, Balasubramanyam et al 2005).…”

“…But if GSH concentrations are decreased, the tendency to form hemithioacetal, and flux via the glyoxylase pathway is diminished, and methylglyoxal will accumulate. Methylglyoxal is increased threefold in NIDDM patients, despite significantly increased activity of the glyoxalase I enzyme and this was found to be associated with complications of the disease (Thornalley, McLellan et al 1996). The oxoaldehyde glyoxal can also be produced from a slow non-enzymatic autoxidation of glucose (Abordo, Minhas et al 1999).…”

“…Quite a few authors report unchanged or elevated GSH concentrations in RBCs in diabetes (Matsubara, Ferreira et al 1992;Sinclair, Girling et al 1992;Di Simplicio, De Giorgio et al 1995;Laaksonen, Atalay et al 1996). Glutathione is protective in oxidative stress as it forms conjugates with reactive products of lipid peroxidation such as HNE, and it participates in the conversion of methyglyoxal to Dlactate, and scavenges O 2 •-and H 2 O 2 generated by AGEs (Yoshida, Hirokawa et al 1995;Thornalley, McLellan et al 1996;Griffith and Mulcahy 1999;Beard, Shangari et al 2003;Beisswenger, Howell et al 2003;Robertson, Harmon et al 2003;Constantin, Constantinescu et al 2005;Iles and Liu 2005;Gil, Siems et al 2006). When loss of GSH occurs, due to an increased rate of these reactions, it is important that the metabolic machinery in RBCs react with an increased rate of GSH synthesis.…”

Transmembrane electron transfer in diabetic nephropathy.

“…Reduced GSH concentration in erythrocytes showed negative correlations with short-and meanterm metabolic control parameters, such as fasting plasma glucose and fructosamine, rather than with long-term HbA 1c . Discrepancies among reports with regard to erythrocyte GSH in diabetes and its relationship with metabolic parameters and diabetic complications (16)(17)(18)(19) usually have been ascribed to differences in glycemic control, which was on average worse in our complicated groups. However, this finding does not explain the difference in erythrocyte GSH content between the nephropathy and retinopathy groups who showed similar metabolic control.…”