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Description: This is a 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 of the main catabolic by- products of blood nitrogen metabolism, nitric oxide (NO), malondialdehyde (MDA). Main results are that healthy female and male controls showed a differential blood metabolites distribution involved in NO metabolism and in arginine metabolism for the ornithine and urea formation. 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, and 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. 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. Key words: Ammonia, Arginine, Urea, Glycemia, Glycosylated hemoglobin (Hb A1C), Arginase activity.