engleski

Biogenesis of methylglyoxal-adducts is associated with LDL and triglyceride levels: implications for diabetic atherosclerosis

Aims Protein glycation leading to AGEs is enhanced in diabetes by increases in blood glucose per se, and collaterally, by endogenous production of reactive carbonyls. Low weight alpha-dicarbonyls are formed as glycolytic intermediates during metabolic conversion of glucose and/or during lipid peroxidation. Among AGE precursors, methylglyoxal (MG) is considered as one of the key intermediates. We hypothesized it to be a common product of both carbonyl and oxidative stress, and investigated the MG biogenesis in relation to glycemic and lipid status in diabetic patients. Methods Serum and urine MG-adduct content was measured by DELFIA method in 88 diabetic patients and 20 controls. Fasting (FG) and postprandial (PPG) glucose level, HbA1c, glucose profile M-index, LDL and HDL cholesterol, plasma triglyceride and homocysteine levels were determined. Results Significant positive relationship was observed between serum level of MG-adducts and LDL (r=0.31 p=0.003) whereas fasting glucose correlated inversely (r= -0.33 p=0.001) as well as postprandial glucose (r= -0.23 p=0.041) and HbA1c (r= -0.22 p=0.036). Similarly, significant correlations were also found between urinary levels of MG-adducts and postprandial glucose (r= -0.28 p=0.023), serum triglycerides (r=0.31 p=0.003), homocystein (r=0.57 p=0.0007), HDL (r= -0.28 p=0.007) and urine albumine/creatinine ratio (r=0.53 p=0.002). Multiple linear regression was performed using serum or urine MG-adducts as dependent variable and HbA1c, fasting and postprandial glucose, LDL, HDL, triglycerides, serum creatinine, homocystein and urine albumine/creatinine ratio as independent variables. Of these, only LDL-cholesterol and FG were independently associated with MG-adducts in serum (p<0.00046), whereas urine albumine/creatinine ratio, PPG, HDL and triglycerides were independently associated with urine MG-adducts (p<0.011). Patients with LDL-cholesterol >3.0 mmol/l, had a higher serum level of MG-adducts (616+/-400 ugEq/ml (range 183-2066) vs 424+/-237 ugEq/ml (53-1370) ; p=0.026). In addition, significant correlation between homocysteine and urinary excretion of MG-adducts (r=0.8 ; p=0.02) was recorded in patients with a history of macrovascular disease. Conclusion A highly significant relationship between LDL and MG-adduct production, as well as tight correlation between triglycerides and urinary MG-adduct excretion suggest that lipoxidation and glyceraldehyde-3-phosphate route, along with the glycolytic pathway, might be an important source in MG generation. The glycotoxin methylglyoxal seems to be a common factor linking the two dominant metabolic changes in diabetes, hyperglycemia and intensive lipolysis, with vascular pathobiochemistry of diabetes.

Diabetes; Atherosclerosis; Lipoprotein; Glycation adduct; Methylglyoxal

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