Serum levels of essential and non-essential trace elements in type 2 diabetic patients with rheumatoid arthritis in Western Iran

Bahiraee, Omid; Babaei, Sara; Manoochehri, Zohreh; Ahmadi Joybari, Turaj; Mansouri, Borhan; Mansourisarabbadieh, Armin

doi:10.22034/emt.2026.601747.1004

Serum levels of essential and non-essential trace elements in type 2 diabetic patients with rheumatoid arthritis in Western Iran

Document Type : Original Article

Authors

Omid Bahiraee ¹

Sara Babaei ²

Zohreh Manoochehri ³

Turaj Ahmadi Joybari ¹

Borhan Mansouri ³

Armin Mansourisarabbadieh ²

¹ Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran

² Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran

³ Substance Abuse Prevention Research Center, Research Institute for Health, Kermanshah University of Medical Sciences, Kermanshah, Iran

10.22034/emt.2026.601747.1004

Abstract

Background and Objectives: Type 2 diabetes mellitus (T2DM) and rheumatoid arthritis (RA) are chronic inflammatory diseases with significant comorbidities. Trace elements play vital roles in metabolic and immune functions, and their imbalance may contribute to disease pathogenesis. This study aimed to evaluate serum levels of essential and non-essential trace elements in T2DM patients with RA in western Iran.
Methods: This case-control study included 100 T2DM patients, 100 T2DM patients with RA, and 100 healthy controls aged 35–65 years from Ravansar city in western Iran. Serum concentrations of arsenic (As), cadmium (Cd), lead (Pb), and zinc (Zn) were measured using inductively coupled plasma mass spectrometry (ICP-MS). Moreover, statistical analyses were performed using IBM SPSS Statistics version 25 and R version 4.5.2.
Results: Our findings showed that T2DM patients had significantly higher age and BMI (p = 0.014 and p < 0.001, respectively). In T2DM patients without RA, serum arsenic, cadmium, copper, and lead concentrations were significantly higher, while zinc was lower, compared with controls (all p < 0.05). A similar pattern was observed in the small RA-positive subgroup (higher As, Cd, Cu, and Pb; lower Zn), but due to the very small sample size (10 vs. 5), these findings are merely descriptive and exploratory, and no conclusion regarding statistical significance can be drawn.
Conclusion: Serum arsenic, cadmium, and lead were higher, and zinc was lower, in T2DM patients compared with healthy controls. However, due to the small sample size and limited complete cases, these findings should be considered exploratory and interpreted cautiously.

Highlights

Higher serum As, Cd, Cu, and Pb, and lower Zn in T2DM patients.
Higher RA prevalence in T2DM patients than controls, but not significant.
Similar trace element patterns in the small RA-positive subgroup.
Findings are exploratory and need confirmation in larger studies.

Keywords

Diabetes mellitus type 2

Rheumatoid arthritis

Serum

Trace elements

Subjects

Environmental Health & Epidemiology

[1] Patel R, Sina RE, Keyes D. Lifestyle Modification for Diabetes and Heart Disease Prevention (Archived). 2024 Feb 12. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 36251831.

[2] Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320(13):1360-1372. http://doi.org/10.1001/jama.2018.13103

[3] American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes—2021. Diabetes Care. 2021;44(Supplement 1):S15-S33. http://doi.org/10.2337/dc21-S002

[4] International Diabetes Federation. IDF Diabetes Atlas. 10th ed. Brussels, Belgium: International Diabetes Federation; 2021.

[5] Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14(2):88-98. http://doi.org/10.1038/nrendo.2017.151

[6] Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023-2038. http://doi.org/10.1016/S0140-6736(16)30173-8

[7] McInnes IB, Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet. 2017;389(10086):2328-2337. http://doi.org/10.1016/S0140-6736(17)31472-1

[8] England BR, Thiele GM, Anderson DR, Mikuls TR. Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. BMJ. 2018;361:k1036. http://doi.org/10.1136/bmj.k1036

[9] Nicolau J, Lequerré T, Bacquet H, Vittecoq O. Rheumatoid arthritis, insulin resistance, and diabetes. Joint Bone Spine. 2017;84(4):411-416. http://doi.org/10.1016/j.jbspin.2016.09.001

[10] Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th ed. New York: WH Freeman; 2002.

[11] Komarova T, McKeating D, Perkins AV, Tinggi U. Trace element analysis in whole blood and plasma for reference levels in a selected Queensland population, Australia. Int J Environ Res Public Health. 2021;18(5):2652. http://doi.org/10.3390/ijerph18052652

[12] Moksnes MR, Hansen AF, Wolford BN, Thomas LF, Rasheed H, Simić A, et al. A genome-wide association study provides insights into the genetic etiology of 57 essential and non-essential trace elements in humans. Commun Biol. 2024;7(1):432. http://doi.org/10.1038/s42003-024-06116-0

[13] Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. Exp Suppl. 2012;101:133-164. http://doi.org/10.1007/978-3-7643-8340-4_6

[14] Satarug S, Garrett SH, Sens MA, Sens DA. Cadmium, environmental exposure, and health outcomes. Environ Health Perspect. 2010;118(2):182-190. http://doi.org/10.1289/ehp.0901234

[15] Navas-Acien A, Guallar E, Silbergeld EK, Rothenberg SJ. Lead exposure and cardiovascular disease—a systematic review. Environ Health Perspect. 2007;115(3):472-482. http://doi.org/10.1289/ehp.9785

[16] Vaziri ND. Mechanisms of lead-induced hypertension and cardiovascular disease. Am J Physiol Heart Circ Physiol. 2008;295(2):H454-H465. http://doi.org/10.1152/ajpheart.00158.2008

[17] Prozialeck WC, Edwards JR, Nebert DW, Woods JM, Barchowsky A, Atchison WD. The vascular system as a target of metal toxicity. Toxicol Sci. 2008;102(2):207-218. http://doi.org/10.1093/toxsci/kfm263

[18] Salehi N, Manoochehri Z, Nakhaee S, Janjani H, Ahmadi A, Mansouri B. The association of mineral element concentrations and dietary habits with the risk of cardiovascular diseases: A random forest analysis. Environ Med Toxicol. 2026;1(1):13-21. http://doi.org/10.22034/emt.2026.598803.1000

[19] Garner RE, Levallois P. Associations between cadmium levels in blood and urine, blood pressure and hypertension among Canadian adults. Environ Res. 2017;155:64-72. http://doi.org/10.1016/j.envres.2017.01.018

[20] Evans DM, Zhu G, Dy V, Heath AC, Madden PA, Kemp JP, et al. Genome-wide association study identifies loci affecting blood copper, selenium and zinc. Hum Mol Genet. 2013;22(19):3998-4006. http://doi.org/10.1093/hmg/ddt239

[21] Liao KP, Liu J, Lu B, Solomon DH, Kim SC. Association between lipid levels and major adverse cardiovascular events in rheumatoid arthritis compared to non-rheumatoid arthritis patients. Arthritis Rheumatol. 2015;67(8):2004-2010. http://doi.org/10.1002/art.39165

[22] Moradinazar M, Pasdar Y, Najafi F, Shahsavari S, Shakiba E, Hamzeh B, et al. Association between dyslipidemia and blood lipids concentration with smoking habits in the Kurdish population of Iran. BMC Public Health. 2020;20:1-10. http://doi.org/10.1186/s12889-020-09723-0

[23] Ayeneh Pour A, Moradinazar M, Samadi M, Hamzeh B, Najafi F, Karimi S, et al. Association of Dietary Inflammatory Index with cardiovascular disease in Kurdish adults: results of a prospective study on Ravansar non-communicable diseases. BMC Cardiovasc Disord. 2020;20:1-8. http://doi.org/10.1186/s12872-020-01668-x

[24] Menke A, Guallar E, Cowie CC. Metals in urine and diabetes in U.S. adults. Diabetes. 2016;65(1):164-171. http://doi.org/10.2337/db15-0918

[25] Filippini T, Wise LA, Vinceti M. Cadmium and type 2 diabetes mellitus: a systematic review and meta-analysis of prospective cohort studies. Environ Int. 2022;158:106986. http://doi.org/10.1016/j.envint.2021.106986

[26] Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44-84. http://doi.org/10.1016/j.biocel.2006.07.001

[27] He K, Xun P, Liu K, Morris S, Reis J, Guallar E. Mercury exposure in young adulthood and incidence of diabetes later in life. Diabetes Care. 2013;36(6):1584-1589. http://doi.org/10.2337/dc12-1842

[28] Navas-Acien A, Silbergeld EK, Sharrett R, Calderon-Aranda E, Selvin E, Guallar E. Metals in urine and peripheral arterial disease. Environ Health Perspect. 2005;113(2):164-169. http://doi.org/10.1289/ehp.7385

[29] Feng J, Wang H, Jing Z, Wang Y, Wang W, Jiang Y, Sun W. Relationships of the trace elements zinc and magnesium with diabetic nephropathy-associated renal functional damage in patients with type 2 diabetes mellitus. Front Med. 2021;8:626909. http://doi.org/10.3389/fmed.2021.626909

[30] Jayawardena R, Ranasinghe P, Galappatthy P, Malkanthi R, Constantine G, Katulanda P. Effects of zinc supplementation on diabetes mellitus: a systematic review and meta-analysis. Diabetol Metab Syndr. 2012;4(1):13. http://doi.org/10.1186/1758-5996-4-13

[31] Chausmer AB. Zinc, insulin and diabetes. J Am Coll Nutr. 1998;17(2):109-115. http://doi.org/10.1080/07315724.1998.10718735

[32] Kremer JM, Bigaouette J. Nutrient intake of patients with rheumatoid arthritis is deficient in pyridoxine, zinc, copper, and magnesium. J Rheumatol. 1996;23(6):990-994.

[33] Flora SJ. Arsenic-induced oxidative stress and its reversibility. Free Radic Biol Med. 2011;51(2):257-281. http://doi.org/10.1016/j.freeradbiomed.2011.04.008

[34] Cuypers A, Plusquin M, Remans T, Jozefczak M, Keunen E, Gielen H, et al. Cadmium stress: an oxidative challenge. Biometals. 2010;23(5):927-940. http://doi.org/10.1007/s10534-010-9329-x

[35] Filippin LI, Vercelino R, Marroni NP, Xavier RM. Redox signalling and the inflammatory response in rheumatoid arthritis. Clin Exp Immunol. 2008;152(3):415-422. http://doi.org/10.1111/j.13652249.2008.03634.x

[36] Prozialeck WC, Woods J. The vascular endothelium as a target of cadmium toxicity. Life Sci. 2006;79(16):1493-1506. http://doi.org/10.1016/j.lfs.2006.05.021

[37] Rorsman P, Renström E. Insulin granule dynamics in pancreatic beta cells. Diabetologia. 2003;46(8):1029-1045. http://doi.org/10.1007/s00125-003-1153-1

[38] Gonick HC, Ding Y, Bondy SC, Ni Z, Vaziri ND. Lead-induced hypertension: interplay of nitric oxide and reactive oxygen species. Hypertension. 1997;30(6):1487-1492. http://doi.org/10.1161/01.HYP.30.6.1487

[39] Faure P, Roussel AM, Martinie M, Favier A. Insulin resistance and zinc deficiency. In: Zinc and Human Health. 2011:107-125.

[40] Beletate V, El Dib RP, Atallah ÁN. Zinc supplementation for the prevention of type 2 diabetes mellitus in adults with insulin resistance. Cochrane Database Syst Rev. 2007;(3):CD005525. http://doi.org/10.1002/14651858.CD005525.pub2

[41] Prasad AS. Zinc: mechanisms of host defense. J Nutr. 2007;137(5):1345-1349. http://doi.org/10.1093/jn/137.5.1345

[42] Xin L, Yang X, Cai G, Fan D, Xia Q, Liu L, Hu Y, Ding N, Xu S, Wang L, Li X, Zou Y, Pan F. Serum levels of copper and zinc in patients with rheumatoid arthritis: A meta-analysis. Biol Trace Elem Res. 2015 Nov;168(1):1-10. http://doi.org/10.1007/s12011-015-0325-4

[43] Wang H, Zhang R, Shen J, Jin Y, Chang C, Hong M, Guo S, He D. Circulating level of blood iron and copper associated with inflammation and disease activity of rheumatoid arthritis. Biol Trace Elem Res. 2023 Jan;201(1):90-97. http://doi.org/10.1007/s12011-022-03148-z

[44] Youssef AA, Wood B, Baron DN. Serum copper: a marker of disease activity in rheumatoid arthritis. J Clin Pathol. 1983 Jan;36(1):14-17. http://doi.org/10.1136/jcp.36.1.14