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ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)
DOI: https://doi.org/10.15407/fz

Fiziologichnyi Zhurnal

(English title: Physiological Journal)

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2025; 71(4): 22-28


CYTOKINE-INDUCED CHANGES IN GLUCOSE UPTAKE AND PYRUVATE KINASE ACTIVITY IN ORGANOTYPIC CULTURES

A.V. Shkuropat1, V.A. Shvets1, I.V. Golovchenkо1, O.M. Hasiuk1

  1. Kherson State University
DOI: https://doi.org/10.15407/fz71.04.022


Abstract

Glucose uptake is regulated by the activity of glucose trans- porters (GLUT), which are influenced by various factors. The effects of interleukin-2 (IL-2) on glucose uptake remain con- troversial, while erythropoietin is known for its anti-apoptotic properties and glucose-lowering effects. This study aimed to evaluate the impact of IL-2 and erythropoietin on glucose up- take and pyruvate kinase M2 (PKM2) activity in organotypic cultures of brain, liver, and skeletal muscle. Organotypic cul- tures were prepared from white laboratory mice and incubated with IL-2 (5000 and 7500 IU/ml), erythropoietin (13, 6.5, and 1.3 IU/ml), or left untreated (control). Among all tissues, liver cultures exhibited the lowest glucose uptake. IL-2 increased glucose uptake in all culture types, while erythropoietin en- hanced uptake only in skeletal muscle cultures. PKM2 activity was cytokine- and tissue-dependent: low-dose IL-2 elevated PKM2 activity in liver and skeletal muscle cultures, whereas high-dose erythropoietin reduced PKM2 activity in skeletal muscle. These findings suggest that erythropoietin may activate GLUT4 in skeletal muscle, while IL-2 may act via GLUT1 across all tissue types, possibly involving other mechanisms. The observed increase in PKM2 activity under IL-2 stimula- tion may indicate a shift toward aerobic metabolism, while erythropoietin-induced decreases in PKM2 activity may reflect a shift toward glycolytic pathway.

Keywords: interleukin-2; erythropoietin; cytokines; organotypic cultures; liver; skeletal muscles; brain; glucose absorption intensity; PKM2; glucose transporter; GLUT

References

  1. Israelsen WJ, Vander Heiden MG. Pyruvate kinase: Function, regulation and role in cancer. Semin Cell Dev Biol. 2015 Jul;43:43-51. doi: 10.1016/j.semcdb.2015.08.004. PMID: 26277545. CrossRef PubMed PubMedCentral
  2. Beschasnyi SP , Hasiuk OM. The carbon monoxide donor, topiramate, and blockers of aquaporine receptors decrease myocardial ischemia-reperfusion injiry. Fiziol Zh. 2021;67(5):30-8. doi: 10.15407/fz67.05.030. CrossRef
  3. Cayla J, Lavoie C, Gareau R, Duvallet A. Effects of recombinant erythropoietin (r-HuEPO) on plasma glucose concentration in endurance-trained rats. Acta Physiol Scand. 1999;166(3):247-9. doi: 10.1046/j.1365- 201x.1999.00565.x. CrossRef PubMed
  4. Bialik S, Cryns VL, Drincic A, Miyata S, Wollowick AL, Srinivasan A, Klitsis RN. The mitochondrial apoptotic pathway is activated by serum and glucose deprivation in cardiac myocytes. Circ Res. 1999;85:403-14. PMID: 10473670; doi: 10.1161/01.res.85.5.403. CrossRef PubMed
  5. Moley KH, Mueckler MM. Glucose transport and apoptosis. Apoptosis. 2000;5(2):99-105. doi: 10.1023/a:1009697908332. CrossRef.1023/A:1009697908332 PubMed
  6. Shim H, Chun YS, Lewis BC, Dang CV. A unique glucosedependent apoptotic pathway induced by c-myc. Proc Natl Acad Sci USA. 1998;95:1511-6. PMID: 9465046; PMCID: PMC19067; doi: 10.1073/pnas.95.4.1511. CrossRef PubMed PubMedCentral
  7. Venge P, Moberg L, Björnsson E, Bergström M, Långström B, Håkansson L. Mechanisms of basal and cytokine-induced uptake of glucose in normal human eosinophils: relation to apoptosis. Respirat Med. 2003 Oct;97(10):1109-19. PMID: 14561018; doi: 10.1016/ s0954-6111(03)00143-4. CrossRef.1016/S0954-6111(03)00143-4 PubMed
  8. Shkuropat A V , Shvets V A, Golovchenkо IV , Prosiannikova YaM. Influence of biologically active substances on synthesis function and cellular destruction of hepatocytes in vitro. Fiziol Zh. 2022;68(5):60-6. doi: 10.15407/ fz68.05.060. CrossRef
  9. Altenberg B, Greulich KO. Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics. 2004;84(6):1014-20. doi: 10.1016/j. ygeno.2004.08.010 CrossRef PubMed
  10. Ghosal J, Chakraborty M, Biswas T, Ganguly CK, Datta AG. Effect of erythropoietin on the glucose transport of rat erythrocytes and bone marrow cells. Biochem Med Metab Biol. 1987;38(2):134-41. doi: 10.1016/0885- 4505(87)90072-7. CrossRef.1016/0885-4505(87)90072-7 PubMed
  11. Yang W, Lu Z. Pyruvate kinase M2 at a glance. J Cell Sci. 2015 May 1;128(9):1655-60. doi: 10.1242/jcs.166629. PMID: 25770102. А.В. Шкуропат, В.А. Швець, І.В. Головченко, О.М. Гасюк 28
  12. Zachée P, Staal GEJ, Rijksen G, De Bock R, Couttenye MM, De Broe ME. Pyruvate kinase deficiency and delayed clinical response to recombinant human erythropoietin treatment. Lancet. 33(8650): 1327-8. CrossRef.1016/S0140-6736(89)92718-9 PubMed
  13. Harnish MJ, Lange T, Dimitrov S, Born J, Fehm HL. Differential regulation of human blood glucose level by interleukin-2 and -6. Exp Clin Endocrinol Diabetes. 2005;113(1):43-8. doi: 10.1055/s-2004-830526. CrossRef PubMed
  14. Michiels C, Minet E, Michel G, Mottet D, Piret JP, Raes M. HIF-1 and AP-1 cooperate to increase gene expression in hypoxia: role of MAP kinases. IUBMB Life. 2001 Jul;52(1-2):49-53. PMID: 11795593; doi: 10.1080/15216540252774766. CrossRef PubMed
  15. Bindon C, Czerniecki M, Ruell P, Edwards A, McCarthy WH, Harris R, Hersey P. Clearance rates and systemic effects of intravenously administered interleukin 2 (IL-2) containing preparations in human subjects. Br J Cancer. 1983;47(1):123-33. doi: 10.1038/bjc.1983.15. CrossRef PubMed PubMedCentral
  16. Mikolás E, Cseh J, Pap M, Szijárto IA, Balogh A, Laczy B, Bekő V, Fisi V, Molnár GA, Mérei A, Szeberényi J, Wittmann I. Effects of erythropoietin on glucose metabolism. Hormon Metab Res. 2012;44(4):279-85. doi: 10.1055/s-0032-1301901. CrossRef PubMed
  17. Peng B, Kong G, Yang C, Ming Y . Erythropoietin and its derivatives: from tissue protection to immune regulation. Cell Death Disease. 2020;11(2). doi: 10.1038/s41419- 020-2276-8. CrossRef PubMed PubMedCentral
  18. Chakrabarti R, Jung CY , Lee TP, Liu H, Mookerjee BK. Changes in glucose transport and transporter isoforms during the activation of human peripheral blood lymphocytes by phytohemagglutinin. J Immunol. 1994 Mar 15;152(6):2660-8. PMID: 8144874. CrossRef PubMed
  19. Golovchenkо IV, Shkuropat AV. Features of cerebral circulation under conditions of motor and sensor deprivation. Fiziol Zh. 2020;66(4):30-6. doi: 10.15407/fz66.04.030. CrossRef
  20. Tang Z, Sun X, Huo G, Xie Y, Shi Q, Chen S, Wang X, Liao Z. Protective effects of erythropoietin on astrocytic swelling after oxygen-glucose deprivation and reoxygenation: mediation through AQP4 expression and MAPK pathway. Neuropharmacology. 2013 Apr;67:8-15. PMID: 23142737; doi: 10.1016/j.neuropharm.2012.10.017. CrossRef PubMed
  21. Michelle Furtado L, Poon V , Klip A. GLUT4 activation: thoughts on possible mechanisms. Acta Physiol Scand. 2003 Aug;178(4):287-96. PMID: 12864733; doi: 10.1046/j.1365-201X.2003.01160.x. CrossRef PubMed
  22. Shvets V, Shkuropat A, Prosiannikova Y, Golovchenko I. Effect of Interleukin-2 on the humoral link of immunity during physical activity. J Phys Educat Sport. 2020;20(Supplement issue 6):3153-9.
  23. Mulukutla BC, Yongky A, Le T, Mashek DG, Hu W.-S. Regulation of glucose metabolism - a perspective from cell bioprocessing. Trends Biotechnol. 2016;34(8):638- 51. doi: 10.1016/j.tibtech.2016.04.012. CrossRef PubMed
  24. Patel NS, Nandra KK, Thiemermann C. Bench-to-bedside review: Erythropoietin and its derivatives as therapies in critical care. Critical Care. 2012;16(4):229. doi: 10.1186/ cc11315. CrossRef PubMed PubMedCentral
  25. Mulukutla BC, Khan S, Lange A, Hu WS. Glucose metabolism in mammalian cell culture: new insights for tweaking vintage pathways. Trend Biotechnol. 2010 Sep;28(9):476-84. PMID: 20691487; doi: 10.1016/j. tibtech.2010.06.005. CrossRef PubMed
  26. Tang Z, Sun X, Shi Q, Wang X, Xie Y, Huo G, Liao Z. Beneficial effects of carbamylated erythropoietin against oxygen-glucose deprivation/reperfusion-induced astrocyte swelling: Proposed molecular mechanisms of action. Neurosci Lett. 2012;530(1):23-8. doi: 10.1016/j. neulet.2012.09.029. CrossRef PubMed
  27. Pan Y, Yang XH, Guo LL, Gu YH, Qiao QY, Jin HM. Erythropoietin reduces insulin resistance via regulation of its receptor-mediated signaling pathways in db/db mice skeletal muscle. Int J Biol Sci. 2017 Oct 17;13(10):1329- 40. PMID: 29104499; PMCID: PMC5666531; doi: 10.7150/ijbs.19752. CrossRef PubMed PubMedCentral
  28. Miljus N, Massih B, Weis MA, Rison JV, Bonnas CB, Sillaber I, Ehrenreich H, Geurten BR, Heinrich R. Neuroprotection and endocytosis: erythropoietin receptors in insect nervous systems. J Neurochem. 2017 Apr;141(1):63-74. PMID: 28142212; doi: 10.1111/ jnc.13967. CrossRef PubMed
  29. 29.He H, Wu T, Xiong J, Chen K, Mo Z. Effect of erythropoietin on the proliferation and apoptosis of neonatal porcine islet cells. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2010 Nov;35(11):1115-22. PMID: 21131731; doi: 10.3969/j.issn.1672-7347.2010.11.001.
  30. Malhotra R, Brosius FC. Glucose uptake and glycolysis reduce hypoxia-induced apoptosis in cultured neonatal rat cardiac myocytes. J Biol Chem. 1999;274:12567-75. doi: 10.1074/jbc.274.18.12567. CrossRef PubMed

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