IMPACT OF (SODIUM) AMINOPHTHALHYDRAZIDE ON INSULIN+ AND PDX1+ RAT LIVER CELLS IN EXPERIMENTAL MODEL OF DIABETES MELLITUS TYPE I

DOI: 10.22138/2500-0918-2021-18-2-68-77

M.B. Baikenova ¹,², K.V. Sokolova ², I.F. Gette ², I.G. Danilova ²

 

¹ Ural Federal University named after the first President of Russia B.N. Yeltsin,
Yekaterinburg, Russian Federation;
² Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Science,
Yekaterinburg, Russian Federation

Abstract. Aim: to evaluate quantity and functional activity of insulin+ hepatic cells in response to modulation of macrophage functional activity in rats in the modelling of diabetes mellitus type 1. Materials and methods: experiment was carried out on male Wistar rats, which were divided into 3 groups: intact, DM and DM+APH. To model DM alloxan in the dose of 170 mg/kg was injected intraperitoneally, the dose of APH was 2 mg/kg intramuscularly (a total of 20 injections within 30 days). Biochemical, enzyme immunoassay, immunohistochemical and statistical research methods were used. Results: сompare to the DM, in DM+APH group the increasing numbers of insulin+ hepatocytes and insulin+ sinusoidal cells were detected. At the same time, the total number of sinusoidal cells and Pdx1+ liver cells increase in both DM and DM+APH groups. It was found, that the content of insulin in the cytoplasm of insulin+ hepatocytes significantly higher in the DM+APH group, compare to intact and diabetic animals, which indicates the impact of APH at the growth of functional activity of insulin+ hepatocytes. An increase in the expression of insulin in the hepatic cells at the modulation of macrophage activity by APH may contribute to the correction of hyperglycemia in diabetic rats. Conclusion: introduction of APH leads to an increase in the number of insulin+ hepatocytes and their insulin-producing function, as well as insulin+ sinusoidal cells in animals with experimental diabetes. An increase in the total number of sinusoidal hepatic cells when the APH was administered in animals with alloxan-induces DM was revealed. At the same time, the action of APH enhances the expression of Pdx1 — a factor of differentiation for insulin-producing cells in the liver of diabetic animals.

Keywords: diabetes mellitus, liver, immunomodulators, aminophthalhydrazide, insulin+-cells, pdx1+-cells

There is no conflict of interest.
Contact details of the corresponding author:
Madina B. Baikenova
m.b.baikenova@urfu.ru
Received 12.05.2021
For citation:
Baikenova M.B., Sokolova K.V., Gette I.F., Danilova I.G. Impact of (Sodium) Aminophthalhydrazide on Insulin+ and Pdx1+ Rat Liver Cells in Experimental Model of Diabetes Mellitus Type. [Online] Vestn. Ural. Med. Akad. Nauki. = Journal of Ural Medical Academic Science. 2021, Vol. 18, no. 2, pp. 68–77. DOI: 10.22138/2500-0918-2021-18-2-68-77 (In Russ)

REFERENCES
1. Verbovaja N.I., Dolgih Ju.A., Verbovoj A.F., Galkin R.A. Microvascular complications of diabetes mellitus. Endocrinology: news, opinions, training. 2019; 8 (4): 44–54. doi: 10.24411/2304-9529-2019-14006. (in Russian)
2. Information bulletin of the World Health Organization. January 2015 report. (in Russian)
3. Picardi A., D’Avola D., V. U. Gentilucci Galati G., Fiori E., Spataro S., Afeltra A. Diabetes in chronic liver disease: from old concepts to new evidence. Metabolism Research and Reviews. 2006; 22(4): 274-283. https://doi.org/10.1002/dmrr.636
4. Kalmykova Z.A., Kononenko I.V., Majorov A.Ju. Diabetes mellitus and chronic liver disease. Part 1: general mechanisms of etiology and pathogenesis. Therapeutic archive. 2019; 10: 106-111. DOI: 10.26442/00403660.2019.10.000165. (in Russian)
5. Manna P, Das J, Ghosh J, Sil PC. Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IkappaBalpha/NF-kappaB, MAPKs, and mitochondria-dependent pathways: Prophylactic role of arjunolic acid. Free Radic Biol Med. 2010; 48:1465–84. doi: 10.1016/j.freeradbiomed.2010.02.025.
6. Leclercq A., Morais A. S., Schroyen B., Hul N., Geerts A. Insulin resistance in hepatocytes and sinusoidal liver cells: Mechanisms and consequences. 2007; 47(1): 142-156. https://doi.org/10.1016/j.jhep.2007.04.002
7. Krenkel, O., Tacke, F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017; 17: 306–321. https://doi.org/10.1038/nri.2017.11.
8. Li P., He K., Li J., Liu Z., Gong J. The role of Kupffer cells in hepatic diseases. Molecular Immunology. 2017; 85:222-229. https://doi.org/10.1016/j.molimm.2017.02.018
9. Kazankov, K., Jørgensen, S.M.D., Thomsen, K.L. et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2019; 16: 145–159. https://doi.org/10.1038/s41575-018-0082-x.
10. Kojima H., Fujimiya M., Matsumura K., Nakahara T., Hara M., Chan L. Extrapancreatic insulin producing cells in multiple organs in diabetes. PNAS. 2004; 101(8): 2458-2463. https://doi.org/10.1073/pnas.0308690100
11. Danilova I. G., Bulavintceva T. S., Gette I. F., Medvedeva S.Yu., Emelyanov V. V., Abidov M. T. Partial recovery from alloxan-induced diabetes by sodium phthalhydrazide in rats. Biomedicine & Pharmacotherapy. 2017; 95: 103-110. https://doi.org/10.1016/j.biopha.2017.07.117.
12. Andrali S. S., Smapley M. L., Vanderford N. L., Ozcan S., Glucose regulation of insulin gene expression in pancreatic β-cells. Biochemical Journal. 2008; 415(1): 1–10.
13. Ohlsson H, Karlsson K, Edlund T. IPF1, ahomeodomain-containing transactivator of the insulin gene. 1993; 12: 4251-4259.
14. Oster A., Jensen J., Serup P., Galante P., Madsen O. D, Larsson L.I. Rat endocrine pancreatic development in relation to two homeobox gene products (Pdx-1 and Nkx 6.1). J Histochem Cytochem.1998; 46: 707-715.
15. Danilova I.G., Gette I.F. A method for modeling alloxan diabetes. Invention patent №2534411; 2014. (in Russian)
16. Hewitt SM, Baskin DG, Frevert CW, Stah lWL, Rosa-Molinar E. Controls for immunohistochemistry: the Histochemical Society’s standards of practice for validation of immunohistochemic alassays. J Histochem Cytochem. 2014; 62(10): 693–697. doi:10.1369/0022155414545224.
17. Seeberger KL, Anderson SJ, Ellis CE, Yeung TY, Korbutt GS. Identification and differentiation of PDX1 β-cell progenitors within the human pancreatic epithelium. World J Diabetes. 2014; 5(1): 59–68. doi:10.4239/wjd.v5.i1.59.
18. George L. Kumar, Lars Rudbeck. Под редакцией Г.А. Франка и П. Г. Малькова. Immunohistochemical methods (Иммуногистохимические методы): – М., 2011: 224-227.
19. Mendes-Braz M., Martins J. O. Diabetes Mellitus and Liver Surgery: The Effect of Diabetes on Oxidative Stress and Inflammation. Mediators of Inflammation. 2019; 2018: 11-22. https://doi.org/10.1155/2018/2456579
20. Tang D., Cao L., Burkhardt B. R., Xia C., Litherland S. A., Atkinson M. A., Yang L. In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow. Diabetes Jul. 2004; 53(7): 1721-1732. DOI:10.2337/diabetes.53.7.1721
21. Jacobs F., Wisse E., Geest B. The Role of Liver Sinusoidal Cells in Hepatocyte-Directed Gene Transfer. 2010; 176(1): 14-21. https://doi.org/10.2353/ajpath.2010.090136
22. Hui H., Perfetti R. Рancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood. European Journal of Endocrinology. 2002; 146 (2): 129-141, doi: 10.1530/eje.0.1460129
23. Koblas T., Leontovyc I, Loukotova S., Kosinova L. Saudek F. Reprogramming of Pancreatic Exocrine Cells AR42J Into Insulin-producing Cells Using mRNAs for PDX1, Ngn3, and MafA Transcription Factors. Official journal of the American Society of Gene & Cell Therapy. 2016; 5:1-12.

Authors
Madina B. Baikenova
Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences
Junior researcher
106 Pervomaiskaya str. Yekaterinburg Russian Federation 620049
Ural Federal University named after the first President of Russia B.N. Yeltsin
PhD student
19 Mira str. Yekaterinburg Russian Federation 620002
m.b.baikenova@urfu.ru

Ksenia V. Sokolova
Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences
Junior researcher
106 Pervomaiskaya str. Yekaterinburg Russian Federation 620049
kssocolova@bk.ru

Irina F. Gette
Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences
Candidate of Science in Biology, Senior Researcher
106 Pervomaiskaya str. Yekaterinburg Russian Federation 620049
i.goette@yandex.ru

Irina G. Danilova
Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences
Doctor of Biological Science, Associate Professor, Head of the Laboratory of Morphology and Biochemistry
106 Pervomaiskaya str. Yekaterinburg Russian Federation 620049
ig-danilova@yandex.ru

 

Лицензия Creative Commons

 

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

 
 
 

Authorization