Effect of hyperglycemia on fertility in streptozotocin-induced diabetic male Wistar rats: focus on glucose transporters and oxidative stress

  • Sakti Ronggowardhana Brodjonegoro Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Sardjito General Hospital, Yogyakarta, Indonesia
  • Tanaya Ghinorawa Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Sardjito General Hospital, Yogyakarta, Indonesia
  • Nickanor Kaladius Reumy Wonatorey Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Sardjito General Hospital, Yogyakarta, Indonesia
  • Andy Zulfiqqar Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Sardjito General Hospital, Yogyakarta, Indonesia https://orcid.org/0000-0001-5191-5428
  • Didik Setyo Heriyanto Department of Anatomical Pathology, Faculty of Medicine, Universitas Gadjah Mada, Sardjito General Hospital, Yogyakarta, Indonesia
Keywords: GLUT1, GLUT3, glutathione peroxidase, infertility, MCT4, Nrf2
Abstract viewed: 1650 times
PDF downloaded: 922 times
HTML downloaded: 237 times
EPUB downloaded: 240 times


BACKGROUND Glucose transporters (GLUTs) and oxidant metabolism are associated with the mechanism of infertility. This study evaluated the impact of hyperglycemia on glucose and oxidant metabolisms of Sertoli cells (SCs).

METHODS This study was an animal study to investigate the expression of messenger RNA monocarboxylate transporter 4 (MCT4), GLUT1, GLUT3, nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase, catalase (CAT), and lactate dehydrogenase A (LDHA) of Wistar rats testes that were induced hyperglycemia. Reverse transcription polymerase chain reaction analysis was used. Hyperglycemic state in the Wistar rats was induced by streptozotocin. 24 rats were divided into 3 groups: non-hyperglycemia (control), 2-week, and 4-week hyperglycemic state. All data were collected and analyzed using SPSS version 15.0 (IBM Corp., USA).

RESULTS The expression of glucose transporter (GLUT1 and GLUT3), lactate transporter (MCT4), and cellular defense protein against oxidant (Nrf2 and CAT) was significantly increased in the 2-week and 4-week hyperglycemic state groups with p<0.01, respectively.

CONCLUSIONS Hyperglycemic state affects the metabolism of SCs. Alteration of GLUTs and oxidative metabolism may indicate metabolic alterations by a prolonged exposure to hyperglycemia that may be responsible for diabetes-related male infertility.


  1. Martinez LC, Sherling D, Holley A. The screening and prevention of diabetes mellitus. Prim Care. 2019;46(1):41−52. https://doi.org/10.1016/j.pop.2018.10.006

  2. Rato L, Alves MG, Dias TR, Cavaco JE, Oliveira PF. Testicular metabolic reprogramming in neonatal streptozotocin-induced type 2 diabetic rats impairs glycolytic flux and promotes glycogen synthesis. J Diabetes Res. 2015;2015:973142. https://doi.org/10.1155/2015/973142

  3. Sutanegara D, Darmono, Budhiarta AA. The epidemiology and management of diabetes mellitus in Indonesia. Diabetes Res Clin Pract. 2000;50(2):S9-16. https://doi.org/10.1016/S0168-8227(00)00173-X

  4. Dias TR, Martins AD, Reis VP, Socorro S, Silva BM, Alves MG, et al. Glucose transport and metabolism in sertoli cell: relevance for male fertility. Curr Chem Biol. 2013;7(3):282−93. https://doi.org/10.2174/2212796807999131128125510

  5. Dimova D, Pavlova E, Atanassova N. The role of diabetes mellitus in male reproductive function: review. Acta morphol anthropol. 2017;24(3−4):99−108.

  6. Shayakhmetova GM, Bondarenko LB, Matvienko AV, Kovalenko VM. Reproductive disorders in streptozotocin-treated male rats following co-administration of ethambutol, rifampicin, isoniazid and pyrazinamide. Rom J Diabetes Nutr Metab Dis. 2012;19(4):405−15. https://doi.org/10.2478/v10255-012-0047-8

  7. Schoeller E, Albanna G, Frolova A, H Moley K. Insulin rescues impaired spermatogenesis via the hypothalamic-pituitary-gonadal axis in Akita diabetic mice and restores male fertility. Diabetes. 2012;61(7):1869−78. https://doi.org/10.2337/db11-1527

  8. Gerber J, Heinrich J, Brehm R. Blood-testis barrier and Sertoli cell function: lessons from SCCx43KO mice. Reproduction. 2016;151(2):R15−27. https://doi.org/10.1530/REP-15-0366

  9. Schrade A, Kyrönlahti A, Akinrinade O, Pihlajoki M, Fischer S, Rodriguez VM, et al. GATA4 regulates blood-testis barrier function and lactate metabolism in mouse Sertoli cells. Endocrinology. 2016;157(6):2416-31. https://doi.org/10.1210/en.2015-1927

  10. Mateus I, Feijó M, Espínola LM, Vaz CV, Correia S, Socorro S. Glucose and glutamine handling in the Sertoli cells of transgenic rats overexpressing regucalcin: plasticity towards lactate production. Sci Rep. 2018;8:10321. https://doi.org/10.1038/s41598-018-28668-4

  11. Plaitakis A, Kalef-Ezra E, Kotzamani D, Zaganas I, Spanaki C. The glutamate dehydrogenase pathway and its roles in cell and tissue biology in health and disease. Biology (Basel). 2017;6(1):11. https://doi.org/10.3390/biology6010011

  12. Darbandi M, Darbandi S, Agarwal A, Sengupta P, Durairajanayagam D, Henkel R, et al. Reactive oxygen species and male reproductive hormones. Reprod Biol Endocrinol. 2018;16(1):87. https://doi.org/10.1186/s12958-018-0406-2

  13. Guzel E, Arlier S, Guzeloglu-Kayisli O, Tabak MS, Ekiz T, Semerci N, et al. Endoplasmic reticulum stress and homeostasis in reproductive physiology and pathology. Int J Mol Sci. 2017;18(4):792. https://doi.org/10.3390/ijms18040792

  14. Yu B, Huang Z. Variations in antioxidant genes and male infertility. Biomed Res Int. 2015;2015:513196. https://doi.org/10.1155/2015/513196

  15. Do MH, Hur J, Choi J, Kim Y, Park HY, Ha SK. Spatholobus suberectus ameliorates diabetes-induced renal damage by suppressing advanced glycation end products in db/db mice. Int J Mol Sci. 2018;19(9):2774. https://doi.org/10.3390/ijms19092774

  16. Deeds MC, Anderson JM, Armstrong AS, Gastineau DA, Hiddinga HJ, Jahangir A, et al. Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models. Lab Anim. 2011;45(3):131-40. https://doi.org/10.1258/la.2010.010090

  17. Chidlow G, Wood JP, Graham M, Osborne NN. Expression of monocarboxylate transporters in rat ocular tissues. Am J Physiol Cell Physiol. 2005;288(2):C416-28. https://doi.org/10.1152/ajpcell.00037.2004

  18. Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53:401-26. https://doi.org/10.1146/annurev-pharmtox-011112-140320

  19. Singh RP, Sastry KV, Pandey NK, Shit NG, Agarwal R, Singh R, et al. Molecular characterization and expression of LDHA and LDHB mRNA in testes of Japanese Quail (Coturnix japonica). Asian-Aust J Anim Sci. 2011;24(8):1060-8. https://doi.org/10.5713/ajas.2011.10263

  20. Afifi M, Almaghrabi OA, Kadasa NM. Ameliorative effect of zinc oxide nanoparticles on antioxidants and sperm characteristics in streptozotocin-induced diabetic rat testes. Biomed Res Int. 2015;2015:153573. https://doi.org/10.1155/2015/153573

  21. Almeer RS, Soliman D, Kassab RB, AlBasher GI, Alarifi S, Alkahtani S, et al. Royal jelly abrogates cadmium-induced oxidative challenge in mouse testes: involvement of the Nrf2 pathway. Int J Mol Sci. 2018;19(12):3979. https://doi.org/10.3390/ijms19123979

  22. Kianifard D, Sadrkhanlou RA, Hasanzadeh S. The ultrastructural changes of the sertoli and leydig cells following streptozotocin induced diabetes. Iran J Basic Med Sci. 2012;15(1):623-35.

  23. Wang X, Yang X, Zhong X, Wang Z, Xue S, Yu W, et al. Percutaneous nephrolithotomy under ultrasound guidance in patients with renal calculi and autosomal dominant polycystic kidney disease: a report of 11 cases. Adv Urol. 2017;2017:3483172. https://doi.org/10.1155/2017/3483172

  24. Xu Y, Lei H, Guan R, Gao Z, Li H, Wang L, et al. Studies on the mechanism of testicular dysfunction in the early stage of a streptozotocin induced diabetic rat model. Biochem Biophys Res Commun. 2014;450(1):87-92. https://doi.org/10.1016/j.bbrc.2014.05.067

  25. Liu B, Zhang X, Qin M, Song A, Cui T, Wang C. Malfunction of Sertoli cell secretion leads to testicular damage in diabetic rats. Int J Clin Exp Med. 2016;9(6):9316-21.

  26. Jiang T, Huang Z, Lin Y, Zhang Z, Fang D, Zhang DD. The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes. 2010;59(4):850-60. https://doi.org/10.2337/db09-1342

  27. Kobayashi T, Miyazaki T, Natori M, Nozawa S. Protective role of superoxide dismutase in human sperm motility: superoxide dismutase activity and lipid peroxide in human seminal plasma and spermatozoa. Hum Reprod. 1991;6(7):987-91. https://doi.org/10.1093/oxfordjournals.humrep.a137474

  28. La Vignera S, Condorelli RA, Vicari E, D'Agata R, Salemi M, Calogero AE. High levels of lipid peroxidation in semen of diabetic patients. Andrologia. 2012;44 Suppl 1:565-70. https://doi.org/10.1111/j.1439-0272.2011.01228.x

  29. Sindhu RK, Koo JR, Roberts CK, Vaziri ND. Dysregulation of hepatic superoxide dismutase, catalase and glutathione peroxidase in diabetes: response to insulin and antioxidant therapies. Clin Exp Hypertens. 2004;26(1):43-53. https://doi.org/10.1081/CEH-120027330

  30. Bhattacharya SM, Ghosh M, Nandi N. Diabetes mellitus and abnormalities in semen analysis. J Obstet Gynaecol Res. 2014;40(1):167-71. https://doi.org/10.1111/jog.12149

How to Cite
Brodjonegoro SR, Ghinorawa T, Wonatorey NKR, Zulfiqqar A, Heriyanto DS. Effect of hyperglycemia on fertility in streptozotocin-induced diabetic male Wistar rats: focus on glucose transporters and oxidative stress. Med J Indones [Internet]. 2021Jul.8 [cited 2024Apr.15];30(3):177-81. Available from: http://mji.ui.ac.id/journal/index.php/mji/article/view/4635
Basic Medical Research