THE ROLE OF OXIDANT STRESS AND GENDER IN THE ERYTHROCYTES ARGININE METABOLISM AND AMMONIA MANAGEMENT IN PATIENTS WITH TYPE 2 DIABETES v1

The erythrocytes are not simply gas transporting cells, but they have a very important role in the regulation and transport of metabolites related to nitrogen metabolism both in healthy subjects and in patients with type 2 DM. The different levels of metabolites are associated with gender differences. We have two particular objectives: 1) To study the differences in the levels of nitrogen metabolites, such ammonium and nitric oxide, and the correlations that exist between them in RBC and serum, in healthy subjects and patients with type 2 DM. And 2) to determine the differences in the levels of nitrogen metabolites, such ammonium and nitric oxide, and the correlations that exist between them in relation to gender in healthy subjects and patients with type 2 DM. 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 (n = 80). We separated serum and red blood cells (RBC) and determined metabolites mainly through colorimetric and spectrophotometric assays. We evaluated changes in the levels and correlations of the main catabolic by-products of blood nitrogen metabolism, as ammonium, nitric oxide (NO), malondialdehyde (MDA), among others. Healthy female and male controls showed a differential blood metabolites distribution involved in arginine metabolism, as ornithine, ammonium, urea and . NO. Patients with DM had increased ammonia, citrulline, urea, uric acid, and ornithine, mainly in the RBC, while the level of arginine was significantly lower in men with type 2 DM. These findings were associated with hyperglycemia, glycosylated hemoglobin (Hb A1C), as well as with levels of RBC’s MDA. Most of the DM-induced alterations in nitrogen-related metabolites seem to be associated with a different RBC capacity for the release of these metabolites and resulting in an abrogation of the gender-related differential management of nitrogen metabolites in healthy subjects. Thisstudy provides the first documented findings giving strong 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 anda characteristic pattern of metabolic disturbances that culminates in a loss of the differential management of nitrogen-related metabolites seen in healthy women and men. Therefore, it is not unlikelythat these characteristic patterns of blood metabolites elicited by type 2 DM might be involved in the specific physiopathology of this disease, and changes in the oxidative status, i.e., increased lipid peroxidation in RBC membranes from diabetic patients, are playing a role in the metabolic alterations found in these blood cells.