Role of Glucose Derived Reactive Metabolites in Diabetic Nephropathy

Abstract

Discovery of differences in the formation of triose phosphate intermediates (TPint) and methylglyoxal (MG) by cell metabolism between mouse strains with identical levels of hyperglycemia suggested prospective importance to diabetes complications. To assess the possible relevance of triose phosphates [glyceraldehyde-3-phosphate and dihydroxyacetone phosphate] in modulating diabetic nephropathy (DN) in type 1 diabetes mellitus (T1DM) patients. A case–control study was conducted among 131 unrelated T1DM with (59 patients) or without nephropathy (72 patients) and 146 non-diabetic controls. Using red blood cells, metabolites of glyoxalase system and triose phosphates were analyzed in deproteinated hemolysate samples. Suitable descriptive statistics was used for different variables. Cross-sectional measures of TPint/mol of glucose in red blood cells were significantly increased in nephropathy cohort relative to diabetic patients with normal albumin excretion/healthy controls (p < 0.0001) and a concomitant increase in MG (R2: 0.3721; p < 0.0001) was observed. Decreased glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity correlated with increased MG levels (R2: 0.0841; p: 0.0259, Table 1) and TPint (R2: 0.0676; p: 0.0467; Table 1) in the DN cohort, but not in either diabetic group with normal albumin excretion or healthy controls. The concentration of d-lactate and activity of glyoxalase I in RBCs were increased markedly in the DN cohort as compared to other studied groups (p < 0.05). The surrogate markers for oxidative stress (thiobarbituric acid reactive substances and glutathione) in DN cohort were all within the range observed in the other studied groups. Diabetic patients who have an elevated levels of intracellular TPint and consequently the chronic exposure to high MG concentrations appears to be susceptible to the development of renal diabetic complications, despite good glycemic control and possibly related to modification of GAPDH by environmental factors or inherent differences. Table 1 Correlation coefficients for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) with various biochemical measurements Healthy controls Diabetic patients with normal AER Diabetic nephropathy patients with macroalbuminuria R2 p R2 p R2 p HbA1c (%) 0.012 0.1783 0.0282 0.1584 0.017 0.319 Hemosylate glucose (nmol/mgHb) 0.0046 0.4148 0.0065 0.4988 0.0153 0.3494 TPint (nmol/mgHb) 0.0166 0.1207 0.0050 0.5534 0.0676 0.0467 MG (nmol/mgHb) 0.0021 0.5814 0.0037 0.6107 0.0841 0.0259 GSH 0.0059 0.3556 0.0077 0.4623 0.0065 0.542 TBARS 0.0028 0.5252 0.0019 0.7136 0.0088 0.4789 HbA1C glycated hemoglobin, TPint triose phosphate intermediates, MG methylglyoxal, GSH reduced glutathione, TBARS thiobarbituric acid reactive substances