1. The metabolism of methylglyoxal by the glyoxalase system may be linked to the development of diabetic complications. The glyoxalase system was characterized in blood samples from patients with insulin-dependent diabetes mellitus (n = 43), patients with non-insulin-dependent diabetes mellitus (n = 107) and 21 normal healthy control subjects. 2. The concentrations of glyoxalase metabolites, methylglyoxal, S-D-lactoylglutathione and D-lactate, were increased in diabetic patients, relative to normal control subjects: methylglyoxal [median, range (n) pmol/g], insulin-dependent patients, 470.7, 85.6-1044.3 (42), P < 0.001, non-insulin-dependent patients, 286.8, 54.7-2370 (105), P < 0.001, control subjects, 79.8, 25.3-892.9 (21); S-D-lactoylglutathione [mean +/- SD (n)pmol/10(6) erythrocytes], combined diabetic patients, 3.37 +/- 0.85 (24), control subjects 4.76 +/- 1.95 (8) P < 0.05; D-lactate [mean +/- SD or median, range (n)nmol/g], insulin dependent patients, median 18.3, 5.7-57.4 (42), P < 0.001, non-insulin-dependent patients, 20.0 +/- 8.9, 2.6-48.4 (105), P < 0.001, control subjects 9.7 +/- 4.3, 1.8-19.7 (21). The reduced glutathione concentrations in blood samples from the insulin-dependent and non-insulin-dependent diabetic patient groups were not different from the control group values (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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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.