Document Type : Research articles


1 Biology Department, Medical Biotechnology Research Center, Ashkezar Branch, Islamic Azad University, Ashkezar, Yazd, Iran

2 Department of Internal Medicine, Kashan University of Medical Sciences, Kashan, Iran


Background: One of the major long-term complications of diabetes mellitus (DM) is diabetic nephropathy (DN) characterized by persistent albuminuria and a progressive renal dysfunction.
Objectives: The aim of this trial was to determine the effects of selenium supplementation on the levels of genes expression associated with insulin, lipid and inflammatory markers in diabetic hemodialysis patients.
Methods: This randomized, double-blind, placebo-controlled clinical trial was done on forty diabetic hemodialysis patients. The study subjects were divided into two groups by random to take either 200 µg/day selenium (n=20) or placebo (n=20) during 24 weeks.
Results: Selenium intake led to upregulation of peroxisome proliferator-activated receptor gamma (PPAR-?) (1.08+0.22 vs. 0.93+0.18 fold change, P=0.049), LDL-receptor (1.06+0.14 vs. 0.90+0.16 fold change, P=0.008) and transforming the growth of factor beta (TGF-?) (1.15+0.18 vs. 0.91+0.20 fold change, P=0.002) in the levels of gene expression. In comparison with placebo, in this intervention also reduction of gene expression of tumor necrosis factor alpha (TNF-?) (0.90+0.19 vs. 1.08+0.19 fold change, P=0.014) and interleukin-1 (IL-1) (1.00+0.11 vs. 1.12+0.15 fold change, P=0.020) were detected. In this study, gene expression of vascular endothelial growth factor (VEGF) (1.02+0.13 vs. 0.96+0.18 fold change, P=0.333) and (IL-8) (0.98+0.20 vs. 1.03+0.17 fold change, P=0.458) were not affected by selenium supplementation.
Conclusion: Selenium supplementation during 24 weeks had positive effects on gene expression associated with metabolic status inflammatory markers in diabetic hemodialysis patients.


  1. Koye DN, Shaw JE, Reid CM, Atkins RC, Reutens AT, Magliano DJ. Incidence of chronic kidney disease among people with diabetes: a systematic review of observational studies. Diabet Med. 2017;34(7):887-901. doi: 10.1111/dme.13324. [PubMed: 28164387].
  2. Park YH, Song JH, Choi GW, Kim HJ. Predictors of complication following lower extremity amputation in diabetic end-stage renal disease. Nephrol. 2017;23(6): 518-22. doi: 10.1111/nep.13066.
  3. Solini A, Ferrannini E. Pathophysiology, prevention and management of chronic kidney disease in the hypertensive patient with diabetes mellitus. J Clin Hypertens. 2011;13(4): 252-57. doi: 10.1111/j.1751-7176.2011.00446.x. [PubMed: 21466620].
  4. Domingueti CP, Sant'Ana Dusse LM, das Graças Carvalho M, de Sousa LP, Gomes KB, Fernandes AP. Diabetes mellitus: The linkage between oxidative stress, inflammation, hypercoagulability and vascular complications. J Diabetes Complications. 2016;30(4):738-45. doi: 10.1016/j.jdiacomp.2015.12.018. [PubMed: 26781070].
  5. Jin YP, Su XF, Yin GP, Xu XH, Lou JZ, Chen JJ et al.. Blood glucose fluctuations in hemodialysis patients with end stage diabetic nephropathy. J Diabetes Complications. 2015;29(3): 395-9. doi: 10.1016/j.jdiacomp.2014.12.015. [PubMed: 25681043].
  6. Arora MK, Singh UK. Molecular mechanisms in the pathogenesis of diabetic nephropathy: an update. Vascul Pharmacol. 2013;58(4): 259-71. doi: 10.1016/j.vph.2013.01.001. [PubMed: 23313806].
  7. Al-Kafaji G, Golbahar J. High glucose-induced oxidative stress increases the copy number of mitochondrial DNA in human mesangial cells. Biomed Res Int. 2013;2013:1-8. doi: 10.1155/2013/754946. [PubMed: 23984405].
  8. Oldfield MD, Bach LA, Forbes JM, Nikolic-Paterson D, McRobert A, Thallas V, et al. Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). J Clin Invest. 2001;108(12):1853-63. doi: 10.1172/JCI11951. [PubMed: 11748269].
  9. Papadopoulou-Marketou N, Chrousos GP, Kanaka-Gantenbein C. Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis. Diabetes Metab Res Rev. 2017;33(2). doi: 10.1002/dmrr.2841.[PubMed: 27457509].
  10. Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci. 2013;124(3):139-52. doi: 10.1042/CS20120198. [PubMed: 23075333].
  11. Navarro-González JF, Mora-Fernández C. The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol. 2008;19(3): 433-42. doi: 10.1681/ASN.2007091048. [PubMed: 18256353].
  12. Keane WF. The role of lipids in renal disease: future challenges. Kidney Int Suppl. 2000;75:27-31. [PubMed: 10828758].
  13. Zhang Y, Guan Y. PPAR-gamma agonists and diabetic nephropathy. Curr Diab Rep. 2005;5(6): 470-75. doi: 10.1007/s11892-005-0057-5. [PubMed: 16316600].
  14. Jia Z, Sun Y, Yang G, Zhang A, Huang S, Heiney KM, et al. New Insights into the PPAR γ Agonists for the Treatment of Diabetic Nephropathy. PPAR Res. 2014;2014: 1-7. doi: 10.1155/2014/818530. [PubMed: 24624137].
  15. Zachara BA, Gromadzińska J, Wasowicz W, Zbróg Z. Red blood cell and plasma glutathione peroxidase activities and selenium concentration in patients with chronic kidney disease: a review. Acta Biochim Pol. 2006;53(4):663-77. [PubMed: 17160142].
  16. Ashley N, Ogawa-Wong AN, Berry MJ, Seale LA. Selenium and Metabolic Disorders: An Emphasis on Type 2 Diabetes Risk. Nutrients. 2016;8:1-19. doi: 10.3390/nu8020080.
  17. Beytut E, Erişir M, Aksakal M. Effects of additional vitamin E and selenium supply on antioxidative defence mechanisms in the kidney of rats treated with high doses of glucocorticoid. Cell Biochem Funct. 2004;22(1):59-65. doi: 10.1002/cbf.1053. [PubMed: 14695656].
  18. Boosalis MG.The role of selenium in chronic disease. Nutr Clin Pract. 2008;23(2):152-60. doi: 10.1177/0884533608314532. [PubMed: 18390782].
  19. Sedighi O, Makhlough A, Shokrzadeh M, Hoorshad S. Association between plasma selenium and glutathione peroxidase levels and severity of diabetic nephropathy in patients with type two diabetes mellitus. Nephrourol Mon. 2014;6(5): 1-4. doi: 10.5812/numonthly.21355. [PubMed: 25695036].
  20. Zhu C, Zhang S, Song C, Zhang Y, Ling Q, Hoffmann PR, et al. Selenium nanoparticles decorated with Ulva lactuca polysaccharide potentially attenuate colitis by inhibiting NF-κB mediated hyper inflammation. J Nanobiotechnology. 2017;15(1):1-15. doi: 10.1186/s12951-017-0252-y. [PubMed: 28270147].
  21. Donma MM, Donma O. Promising link between selenium and peroxisome proliferator activated receptor gamma in the treatment protocols of obesity as well as depression. Med Hypotheses. 2016;89:79-83. doi: 10.1016/j.mehy.2016.02.008. [PubMed: 26968915].
  22. Asemi Z, Zare Z, Shakeri H, Sabihi SS, Esmaillzadeh A. Effect of multispecies probiotic supplements on metabolic profiles, hs-CRP, and oxidative stress in patients with type 2 diabetes. Ann Nutr Metab. 2013;63(1-2): 1-9. doi: 10.1159/000349922. [PubMed: 23899653].
  23. Hasani M, Djalalinia S, Sharifi F, Varmaghani M, Zarei M, Abdar ME, et al. Effect of Selenium Supplementation on Lipid Profile: A Systematic Review and Meta-Analysis. Horm Metab Res. 2018;50(10):715-27. doi: 10.1055/a-0749-6655. [PubMed: 30312982].
  24. Bahmani F, Kia M, Soleimani A, Asemi Z, Esmaillzadeh A. Effect of Selenium Supplementation on Glycemic Control and Lipid Profiles in Patients with Diabetic Nephropathy. Biol Trace Elem Res. 2016;172(2): 282-89. doi: 10.1007/s12011-015-0600-4. [PubMed: 26686847].
  25. Zadeh Modarres S, Heidar Z, Foroozanfard F, Rahmati Z, Aghadavod E, Asemi Z. The Effects of Selenium Supplementation on Gene Expression Related to Insulin and Lipid in Infertile Polycystic Ovary Syndrome Women Candidate for In Vitro Fertilization: a Randomized, Double-Blind, Placebo-Controlled Trial. Biol Trace Elem Res. 2018;183(2):218-25. doi: 10.1007/s12011-017-1148-2. [PubMed: 28875327].
  26. Karamali M, Dastyar F, Badakhsh MH, Aghadavood E, Amirani E, Asemi Z. The Effects of Selenium Supplementation on Gene Expression Related to Insulin and Lipid Metabolism, and Pregnancy Outcomes in Patients with Gestational Diabetes Mellitus: a Randomized, Double-Blind, Placebo-Controlled Trial. Biol Trace Elem Res. 2020;195(1): 1-8. doi: 10.1007/s12011-019-01818-z. [PubMed: 31317471].
  27. Hu X, Chandler JD, Orr ML, Hao L, Liu K, Uppal K, et al. Selenium Supplementation Alters Hepatic Energy and Fatty Acid Metabolism in Mice. J Nutr. 2018;148(5):675-84. doi: 10.1093/jn/nxy036. [PubMed: 29982657].
  28. Dhingra S, Bansal MP. Hypercholesterolemia and apolipoprotein B expression: regulation by selenium status. Lipids Health Dis. 2005;4:1-13. doi: 10.1186/1476-511X-4-28. [PubMed: 16271152].
  29. Gandhi UH, Kaushal N, Ravindra KC, Hegde S, Nelson SM, Narayan V, et al. Selenoprotein-dependent up-regulation of hematopoietic prostaglandin D2 synthase in macrophages is mediated through the activation of peroxisome proliferator-activated receptor (PPAR) gamma. J Biol Chem. 2011;286(31):27471-82. doi: 10.1074/jbc.M111.260547. [PubMed: 21669866].
  30. Wang S, Dougherty EJ, Danner RL. PPARγ signaling and emerging opportunities for improved therapeutics. Pharmacol Res. 2016;111:76-85. doi: 10.1016/j.phrs.2016.02.028. [PubMed: 27268145].
  31. McKenzie RC, Arthur JR, Beckett GJ. Selenium and the regulation of cell signaling, growth, and survival: molecular and mechanistic aspects. Antioxid Redox Signal. 2002;4(2): 339-51. doi: 10.1089/152308602753666398. [PubMed: 12006185].
  32. Shin DJ, Osborne TF. Thyroid hormone regulation and cholesterol metabolism are connected through Sterol Regulatory Element-Binding Protein-2 (SREBP-2). J Biol Chem. 2003;278(36):34114-8. doi: 10.1074/jbc.M305417200. [PubMed: 12829694].
  33. Kong WJ, Liu J, Jiang JD. Human low-density lipoprotein receptor gene and its regulation. J Mol Med. 2006;84(1):29-36. doi: 10.1007/s00109-005-0717-6. [PubMed: 16292665].
  34. Ju W, Li X, Li Z, Wu GR, Fu XF, Yang MX, et al. The effect of selenium supplementation on coronary heart disease: A systematic review and meta-analysis of randomized controlled trials. J Trace Elem Med Biol. 2017;44:8-16. doi: 10.1016/j.jtemb.2017.04.009. [PubMed: 28965605].
  35. Sedighi O, Zargari M, Varshi G. Effect of selenium supplementation on glutathione peroxidase enzyme activity in patients with chronic kidney disease: a randomized clinical trial. Nephrourol Mon. 2014;6(3): 1-4. doi: 10.5812/numonthly.17945. [PubMed: 25032143].
  36. Jamilian M, Samimi M, Afshar Ebrahimi F, Aghadavod E, Mohammadbeigi R, Rahimi M, et al. Effects of Selenium Supplementation on Gene Expression Levels of Inflammatory Cytokines and Vascular Endothelial Growth Factor in Patients with Gestational Diabetes. Biol Trace Elem Res. 2018;181(2):199-206. doi: 10.1007/s12011-017-1045-8. [PubMed: 28528475].
  37. Heidar Z, Hamzepour N, Zadeh Modarres S, Mirzamoradi M, Aghadavod E, Pourhanifeh MH, et al. The Effects of Selenium Supplementation on Clinical Symptoms and Gene Expression Related to Inflammation and Vascular Endothelial Growth Factor in Infertile Women Candidate for In Vitro Fertilization. Biol Trace Elem Res. 2020;193(2):319-25. doi: 10.1007/s12011-019-01715-5. [PubMed: 30963410].
  38. Gao XJ, Tang B, Liang HH, Yi L, Wei ZG. Selenium deficiency induced an inflammatory response by the HSP60-TLR2-MAPKs signalling pathway in the liver of carp. Fish Shellfish Immunol. 2019;87: 688-94. doi: 10.1016/j.fsi.2019.02.017. [PubMed: 30769078].
  39. Dai L, Golembiewska E, Lindholm B, Stenvinkel P. End-Stage Renal Disease, Inflammation and Cardiovascular Outcomes. Contrib Nephrol. 2017;191: 32-43. doi: 10.1159/000479254. [PubMed: 28910789].
  40. Liu Z, Qu Y, Wang J, Wu R. Selenium Deficiency Attenuates Chicken Duodenal Mucosal Immunity via Activation of the NF-κb Signaling Pathway. Biol Trace Elem Res. 2016;172(2): 465-73. doi: 10.1007/s12011-015-0589-8. [PubMed: 26728795].