title: Increased erythrocytes by-products of arginine catabolism are associated with hyperglycemia and could be involved in the pathogenesis of type 2 diabetes mellitus.
abstract: Diabetes mellitus (DM) is a worldwide disease characterized by metabolic disturbances, frequently associated with high risk of atherosclerosis and renal and nervous system damage. Here, we assessed whether metabolites reflecting oxidative redox state, arginine and nitric oxide metabolism, are differentially distributed between serum and red blood cells (RBC), and whether significant metabolism of arginine exists in RBC. In 90 patients with type 2 DM without regular treatment for diabetes and 90 healthy controls, paired by age and gender, we measured serum and RBC levels of malondialdehyde (MDA), nitrites, ornithine, citrulline, and urea. In isolated RBC, metabolism of L-[(14)C]-arginine was also determined. In both groups, nitrites were equally distributed in serum and RBC; citrulline predominated in serum, whereas urea, arginine, and ornithine were found mainly in RBC. DM patients showed hyperglycemia and increased blood HbA1C, and increased levels of these metabolites, except for arginine, significantly correlating with blood glucose levels. RBC were observed to be capable of catabolizing arginine to ornithine, citrulline and urea, which was increased in RBC from DM patients, and correlated with an increased affinity for arginine in the activities of putative RBC arginase (Km = 0.23±0.06 vs. 0.50±0.13 mM, in controls) and nitric oxide synthase (Km = 0.28±0.06 vs. 0.43±0.09 mM, in controls). In conclusion, our results suggest that DM alters metabolite distribution between serum and RBC, demonstrating that RBC regulate serum levels of metabolites which affect nitrogen metabolism, not only by transporting them but also by metabolizing amino acids such as arginine. Moreover, we confirmed that urea can be produced also by human RBC besides hepatocytes, being much more evident in RBC from patients with type 2 DM. These events are probably involved in the specific physiopathology of this disease, i.e., endothelial damage and dysfunction.
authors.affiliation: Depto. de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Coyoacán, Mexico Distrito Federal, Mexico.
authors.forename: Serafín
authors.initials: S
authors.lastname: Ramírez-Zamora
authors.forename: Miguel L
authors.initials: ML
authors.lastname: Méndez-Rodríguez
authors.forename: Marisela
authors.initials: M
authors.lastname: Olguín-Martínez
authors.forename: Lourdes
authors.initials: L
authors.lastname: Sánchez-Sevilla
authors.forename: Miguel
authors.initials: M
authors.lastname: Quintana-Quintana
authors.forename: Norberto
authors.initials: N
authors.lastname: García-García
authors.forename: Rolando
authors.initials: R
authors.lastname: Hernández-Muñoz
mesh_terms: D000328:Adult; D000368:Aged; D001120:Arginine / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D002247:Carbon Isotopes; D016022:Case-Control Studies; D002956:Citrulline / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006031:Glycosylation; D006454:Hemoglobins / Q000378:metabolism; D006461:Hemolysis; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D009952:Ornithine / Q000097:blood; D018384:Oxidative Stress; D014508:Urea / Q000097:blood
chemical_list: D001786:Blood Glucose; D002247:Carbon Isotopes; D006454:Hemoglobins; D009573:Nitrites; D002956:Citrulline; D009569:Nitric Oxide; D008315:Malondialdehyde; D014508:Urea; D001120:Arginine; D009952:Ornithine