The role of oxidant stress and gender in the erythrocyte arginine metabolism and ammonia management in patients with type 2 diabetes

OBJECTIVES: To study the differences in the levels of nitrogen metabolites, such as ammonia and nitric oxide and the correlations existing among them in both red blood cells (RBCs) and serum, as well as the possible differences by gender in healthy subjects and patients with type 2 Diabetes Mellitus (DM). DESIGN AND METHODS: This cross-sectional study included 80 patients diagnosed with type 2 DM (40 female and 40 male patients) and their corresponding controls paired by gender (40 female and 40 male). We separated serum and RBC and determined metabolites mainly through colorimetric and spectrophotometric assays. We evaluated changes in the levels of the main catabolic by-products of blood nitrogen metabolism, nitric oxide (NO), and malondialdehyde (MDA). RESULTS: Healthy female and male controls showed a differential distribution of blood metabolites involved in NO metabolism and arginine metabolism for the ornithine and urea formation. Patients with DM had increased ammonia, citrulline, urea, uric acid, and ornithine, mainly in the RBCs, whereas the level of arginine was significantly lower in men with type 2 DM. These findings were associated with hyperglycemia, glycosylated hemoglobin (Hb A(1C)), and levels of RBC’s MDA. Furthermore, most of the DM-induced alterations in nitrogen-related metabolites appear to be associated with a difference in the RBC capacity for the release of these metabolites, thereby causing an abrogation of the gender-related differential management of nitrogen metabolites in healthy subjects. CONCLUSIONS: We found evidence of a putative role of RBC as an extra-hepatic mechanism for controlling serum levels of nitrogen-related metabolites, which differs according to gender in healthy subjects. Type 2 DM promotes higher ammonia, citrulline, and MDA blood levels, which culminate in a loss of the differential management of nitrogen-related metabolites seen in healthy women and men.