OBJECTIVES: This study aimed at evaluating the serum redox status in type 2 diabetes mellitus (T2DM) accompanied with an imbalance in iron concentrations. METHODS: Diabetic patients were grouped according to serum iron levels [normal (DNFe), low (DLFe), and high (DHFe)], and their clinical and redox parameters [total sulfhydryl groups (tSH), uric acid (UA), and total bilirubin (tBILI) as non-enzymatic antioxidants, and malondialdehyde (MDA) and advanced oxidation products of proteins (AOPP) as markers of oxidative stress] were determined. RESULTS: Glucose and HbA1c levels in the T2DM patients did not differ in function of serum iron. T2DM was associated with reduced tSH levels. In the diabetic patients, tSH, UA, and tBILI negatively correlated with MDA, as well as HbA1c with UA. Accordingly, AOPP and MDA were higher in the diabetic groups compared to the controls. The reduced antioxidant capacity was particularly pronounced in the DLFe group, which was further characterized by lower levels of UA and tBILI compared to the other groups. Subsequently, the level of MDA in the DLFe group was higher compared to the DNFe and DHFe groups. The positive correlation between serum iron levels and the antioxidants UA and tBILI, in conjunction with the negative correlation between serum iron levels and the markers of oxidative stress in the diabetic patients, corroborated the indication that comparatively higher level of oxidative stress is present when T2DM coexists with decreased iron levels. CONCLUSIONS: T2DM-associated redox imbalance is characterized by a decrease in serum total sulfhydryl groups and low serum iron-associated reduction in uric acid and total bilirubin levels, accompanied by increased oxidative stress markers. The relatively noninvasive and simple determination of these parameters may be of considerable interest in monitoring the pathophysiological processes in T2DM patients, and may provide useful insights into the effects of potential therapeutic or nutritional interventions.

Department of Physiology Institute of Biology Faculty of Natural Sciences and Mathematics Ss Cyril and Methodius University Skopje Republic of Macedonia

Institute for Preclinical and Clinical Pharmacology and Toxicology Medical Faculty Ss Cyril and Methodius University Skopje Republic of Macedonia

University Clinic for Maxillofacial Surgery Medical Faculty Ss Cyril and Methodius University Skopje Republic of Macedonia

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Cabiscol E, Ros J. Oxidative damage to proteins: structural modifications and consequences in cell function. In: Dalle-Donne I, Scaloni A, Butterfield DA, editors. Redox proteomics: from protein modifications to cellular dysfunction and disease. Hoboken: John Wiley & Sons, Inc; 2006. p. 399-471.

Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438. doi: 10.1155/2014/360438. PubMed DOI

Hunt J, Smith C, Wolff S. Autoxidative glycosylation and possible involvement of peroxides and free radicals in LDL modification by glucose. Diabetes. 1990;39(11):1420-4.

Halliwell B, Gutteridge JM. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol. 1990;186:1-85.

Fernández-Real JM, Manco M. Effects of iron overload on chronic metabolic diseases. Lancet Diabetes Endocrinol. 2014;2(6):513-26.

Toxqui L, Piero AD, Courtois V, Bastida S, SanchezMuniz FJ, Vaquero MP. [Iron deficiency and overload: Implications in oxidative stress and cardiovascular health]. Nutr Hosp 2010;25(3):350-65. Spanish

Van Campenhout A, Van Campenhout C, Lagrou AR, Abrams P, Moorkens G, Van Gaal L, et al. Impact of diabetes mellitus on the relationships between iron-, inflammatory- and oxidative stress status. Diabetes Metab Res Rev. 2006;22(6):444-54.

Ganjifrockwala F, Joseph J, George G. Decreased total antioxidant levels and increased oxidative stress in South African type 2 diabetes mellitus patients. JEMDSA. 2017;22(2):21-5.

Schillern EEM, Pasch A, Feelisch M, Waanders F, Hendriks HS, Mencke R, et al. Serum free thiols in type 2 diabetes mellitus: a prospective study. J Clin Transl Endocrinol. 2019;16:100182. doi: 10.1016/j.jcte.2019.100182. PubMed DOI

Mahboob M, Rahman MF, Grover P. Serum lipid peroxidation and antioxidant enzyme levels in male and female diabetic subjects. Singapore Med J. 2005;46(7):322-4.

Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15(7):539-53.

Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968;25:192-205.

Yagi K. Simple assay for the level of total lipid peroxides in serum or plasma. Methods Mol Biol. 1998;108:101-6.

Taylor EL, Armstrong KR, Perrett D, Hattersley AT, Winyard PG. Optimisation of an advanced oxidation protein products assay: its application to studies of oxidative stress in diabetes mellitus. Oxid Med Cell Longev. 2015;2015:496271. doi: 10.1155/2015/496271. PubMed DOI

Ganesh S, Dharmalingam M, Marcus S. Oxidative stress in type 2 diabetes with iron deficiency in asian indians. J Med Biochem. 2012;31(2):115-20.

Erkus E, Aktas G, Kocak MZ, Duman TT, Atak BM. Serum bilirubin level is associated with diabetic control in type 2 diabetes mellitus. Blood Heart Circ. 2018;2(2). doi: 10.15761/BHC.1000132. DOI

Ceriello A, Bortolotti N, Falleti E, Taboga C, Tonutti L, Crescentini A, et al. Total radical-trapping antioxidant parameter in NIDDM patients. Diabetes Care. 1997;20(2):194-7.

DiNicolantonio JJ, McCarty MF, O'Keefe JH. Antioxidant bilirubin works in multiple ways to reduce risk for obesity and its health complications. Open Heart. 2018;5(2):e000914. doi: 10.1136/openhrt-2018-000914. PubMed DOI

Saha A, Adak S, Chowdhury S, Bhattacharyya M. Enhanced oxygen releasing capacity and oxidative stress in diabetes mellitus and diabetes mellitus-associated cardiovascular disease: a comparative study. Clin Chim Acta. 2005;361(1-2):141-9.

Pandey KB, Mishra N, Rizvi SI. Protein oxidation biomarkers in plasma of type 2 diabetic patients. Clin Biochem. 2010;43(4-5):508-11.

Beutler E, Hoffbrand AV, Cook JD. Iron deficiency and overload. Hematology Am Soc Hematol Educ Program. 2003:40-61.

Sánchez MVJ, García GJL, Velasco PM, Flores HS, Belmont ML, Orozco MJV, et al. [National consensus for the diagnosis and treatment of anemia in childhood and adolescence]. Pediatr Mex. 2012;14(2):71-85. Spanish.

Fernández-Real JM, López-Bermejo A, Ricart W. Cross-talk between iron metabolism and diabetes. Diabetes. 2002;51(8):2348-54.

Liu J, Li Q, Yang Y, Ma L. Iron metabolism and type 2 diabetes mellitus: a meta-analysis and systematic review. J Diabetes Investig. 2020;11(4):946-55.

Zaka-Ur-Rab Z, Adnan M, Ahmad SM, Islam N. Effect of oral iron on markers of oxidative stress and antioxidant status in children with iron deficiency anaemia. J Clin Diagn Res. 2016;10(10):SC13-9.

Deokar S, Rai P, Bakshi A, Rai A. Study of biochemical markers in iron deficiency anemia. Int J Res Med Sci. 2013;1(4):541-4.

Liu Q, Sun L, Tan Y, Wang G, Lin X, Cai L. Role of iron deficiency and overload in the pathogenesis of diabetes and diabetic complications. Curr Med Chem. 2009;16(1):113-29.

Peng YF, Wei YS. Associations between serum bilirubin levels and essential trace elements status in an adult population. Oncotarget. 2017;8(46):81315-20.

Ghio AJ, Ford ES, Kennedy TP, Hoidal JR. The association between serum ferritin and uric acid in humans. Free Radic Res. 2005;39(3):337-42.

Swaminathan S, Fonseca VA, Alam MG, Shah SV. The role of iron in diabetes and its complications. Diabetes Care. 2007;30(7):1926-33.