Pharmacotherapeutic aspects of gestational diabetes mellitus against the background of impaired maternal immunity

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Abstract

This article discusses the immune status of the mother in gestational diabetes mellitus (GDM). Normal pregnancy is characterized by a controlled state of the immune system at the early stages of pregnancy. Various immunological mediators adapt to the state of pregnancy, all of which affect maternal and fetal health. GDM, defined as impaired glucose tolerance of any degree during pregnancy, is a serious obstetric complication affecting approximately 5–10% of pregnant women worldwide. Hyperglycemia causes immune dysfunction by negatively affecting neutrophil chemotaxis, macrophage function, and phagocytic responses, making diabetic patients more susceptible to infections and associated comorbidities. The state of pregnancy along with immunological changes, imbalances of innate and adaptive cellular responses present additional health risks. Insulin plays an indispensable role in the treatment of hyperglycemia that occurs in various conditions, including in type I and type II diabetes; insulin has an anti-apoptotic effect and reduces the expression of pro-inflammatory cytokines in human endotoxemic macrophages. Metformin or sulfonylurea derivatives may also be used for the treatment of GDM. Metformin suppresses immune responses mainly through its direct effect on the cellular functions of various types of immune cells. Glyburide enhances the anti-inflammatory response and synergizes with retinoic acid. A better understanding of development if immune dysfunctions during hyperglycemia could lead to new treatments and prevention for infectious diseases and DM2 comorbidities, thereby improving infectious disease outcomes in DM2 patients. These results require further study of the role of drugs such as insulin, metformin, and glyburide in the immunoregulation of the pathophysiology of GDM.

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About the authors

Afak Uldus kyzy Kazimova

Azerbaijan Medical University

Author for correspondence.
Email: afaq_kazimova@list.ru
ORCID iD: 0000-0003-3358-6709

Cand.Sci. (Med.), Teaching Assistant at the Department of Pharmacology

Azerbaijan, Baku

Sh. M.k. Polukhova

Azerbaijan Medical University

Email: afaq_kazimova@list.ru
Azerbaijan, Baku

References

  1. Mor G., Cardenas I., Abrahams V., et al. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci. 2011;1221(1):80–7. doi: 10.1111/j.1749-6632.2010.05938.x.
  2. Zare F., Seifati S., Mahdi Dehghan-Manshadi M. Preimplantation Factor (PIF): a peptide with various functions. JBRA. Assist Reprod. 2020;24(2):214–18. doi: 10.5935/1518-0557.20190082.
  3. Billington W. The immunological problem of pregnancy: 50 years with the hope of progress. A tribute to peter Medawar. J Reprod Immunol. 2003;60:1–11. doi: 10.1016/S0165-0378(03)00083-4.
  4. Deshmukh H., Way S. Immunological basis for recurrent fetal loss and pregnancy complications. Ann Rev Pathol. 2019;14:185–210. doi: 10.1146/annurev-pathmechdis-012418-012743.
  5. Kampmann U., Madsen R., Skajaa O., et al. Gestational diabetes: A clinical update. World J Diab. 2015;6:1065–72. Doi: 110.4239/wjd.v6.i8.1065.
  6. Berbudi A., Rahmadika N., Tjahjadi A.I., et al. Type 2 diabetes and its impact on the immune system. Curr Diabetes Rev. 2020;16:442–49. doi: 10.2174/1573399815666191024085838.
  7. Tessaro G., Ayala S., Nolasco L., et al. Insulin influences LPS-Induced TNF-α and IL-6 release through distinct pathways in mouse macrophages from different compartments. Cell Physiol Biochem. 2017;42(5):2093–104. doi: 10.1159/000479904.
  8. Hotamisligil S., Shargill S., Spiegelman M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87–91. doi: 10.1126/science.7678183.
  9. Halberg N., Wernstedt-Asterholm I., Scherer E. The adipocyte as an endocrine cell. Endocrinol Metab. Clin North Am. 2008;37(3):753–68. doi: 10.1016/j.ecl.2008.07.002.
  10. Ferracini M., Martins O., Campos M., et al. Impaired phagocytosis by alveolar macrophages from diabetic rats is related to the deficient coupling of LTs to the Fc γ R signaling cascade. Mol Immunol. 2010;47(11–12):1974–80. doi: 10.1016/j.molimm.2010.04.018.
  11. Ruholamin S., Eshaghian S., Allame Z. Neonatal outcomes in women with gestational diabetes mellitus treated with metformin in compare with insulin: A randomized clinical trial. J Res Med Sci. 2014;19:970–75.
  12. American Diabetes Association. Standards of medical care in diabetes-2014. Diab Care. 2014;37(Suppl. 1):14–80.
  13. Crowther A., Hiller E., Moss R., et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352:2477–86. doi: 10.1056/NEJMoa042973.
  14. Stenninger E., Flink R., Eriksson B., et al. Long term neurological dysfunction and neonatal hypoglycaemia after diabetic pregnancy. Arch Dis Child Fetal Neonatal Ed. 1998;79:174–79. doi: 10.1136/fn.79.3.F174.
  15. Daskalakis G., Marinopoulos S., Krielesi V., et al. Placental pathology in women with gestational diabetes Comparative Study. Acta Obstet Gynecol Scand. 2008;87(4):403–7. doi: 10.1080/00016340801908783.
  16. Correa-Silva S., Alencar A., Moreli J., et al. Hyperglycemia induces inflammatory mediators in the human chorionic villous. Cytokine. 2018;111:41–8. doi: 10.1016/j.cyto.2018.07.020.
  17. Angelo A., Neves C., Lobo T., et al. Monocyte profile in peripheral blood of gestational diabetes mellitus patients. Cytokine. 2018;107:79–84. doi: 10.1016/j.cyto.2017.11.017.
  18. Aktulay A., Engin-Ustun Y., Ozkan M., et al. Gestational diabetes mellitus seems to be associated with inflammation. Acta Clin Croat. 2015;54:475–78.
  19. Liu W., Lou X., Zhang Z., et al. Association of neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, mean platelet volume with the risk of gestational diabetes mellitus. Gynecol Endocrinol. 2020;37(2):1–3. doi: 10.1080/09513590.2020.1804549.
  20. De Castro C., Franca E., Fagundes D., et al. Characterization of natural killer cells and cytokines in maternal placenta and fetus of diabetic mothers. J Immunol Res. 2016;2016:7154524. doi: 10.1155/2016/7154524.
  21. Blumer I., Hadar E., Hadden D., et al. Diabetes and pregnancy: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013;98:4227–49. doi: 10.1210/jc.2013-2465.
  22. Plitas G., Rudensky A. Regulatory T cells: Differentiation and function. Cancer Immunol Res. 2016;4:721–25. doi: 10.1158/2326-6066.CIR-16-0193.
  23. La Rocca C., Carbone F., Longobardi S., et al. The immunology of pregnancy: Regulatory T cells control maternal immune tolerance toward the fetus Immunol Lett. 2014;162:41–8. doi: 10.1016/j.imlet.2014.06.013.
  24. Schober L., Radnai D., Spratte J., et al. The role of regulatory T cell (Treg) subsets in gestational diabetes mellitus. Clin Exp Immunol. 2014;177:76–85. doi: 10.1111/cei.12300.
  25. Ghanim H., Mohanty P., Deopurkar R., et al. Acute modulation of toll-like receptors by insulin. Diab Care. 2008;31:1827–31. doi: 10.2337/dc08-0561.
  26. Van Niekerk G., Christowitz C., Conradie D., et al. Insulin as an immunomodulatory hormone. Cytokine Growth Factor Rev. 2020;52:34–44. doi: 10.1016/j.cytogfr.2019.11.006.
  27. Leffler M., Hrach T., Stuerzl M., et al. Insulin attenuates apoptosis and exerts anti-inflammatory effects in endotoxemic human macrophages. J Surg Res. 2007;143:398–406. doi: 10.1016/j.jss.2007.01.030.
  28. Dandona P., Ghanim H., Green K., et al. Insulin infusion suppresses while glucose infusion induces Toll-like receptors and high-mobility group-B1 protein expression in mononuclear cells of type 1 diabetes patients. Am J Physiol Metab. 2013;304:E810–18. doi: 10.1152/ajpendo.00566.2012.
  29. Petersen M., Shulman G. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98:2133–223. doi: 10.1152/physrev.00063.2017.
  30. Vanky E., Zahlsen K., Spigset O., et al. Placental passage of metformin in women with polycystic ovary syndrome. Fertil. Steril. 2005;83:1575–78. doi: 10.1016/j.fertnstert.2004.11.051.
  31. Singh A., Singh R. Metformin in gestational diabetes: An emerging contender. Indian. J Endocrinol Metab. 2015;19:236–44. doi: 10.4103/2230-8210.149317.
  32. Schuiveling M., Vazirpanah N., Radstake T., et al. Metformin, a new era for an old drug in the treatment of immune mediated disease. Curr Drug Targets. 2018;19:945–59. doi: 10.2174/1389450118666170613081730.
  33. Nath N., Khan M., Paintlia M., et al. Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J Immunol. 2009;182(12):8005–14. doi: 10.4049/jimmunol.0803563.
  34. Shi W., Xiao D., Wang L., et al. Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell. Death Dis. 2012;3:e275. doi: 10.1038/cddis.2012.13.
  35. Jing Y., Wu F., Li D. Metformin improves obesity-associated inflammation by altering macrophages polarization. Mol Cell Endocrinol. 2018;461:256–64. doi: 10.1016/j.mce.2017.09.025.
  36. Vasamsetti S., Karnewar S., Kanugula A., et al. Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diab. 2015;64(6):2028–41. doi: 10.2337/db14-1225.
  37. Krysiak R., Gdula-Dymek A., Okopien B. Monocyte-suppressing effect of high-dose metformin in fenofibrate-treated patients with impaired glucose tolerance. Pharmacol Rep. 2013;65(5):1311–16. doi: 10.1016/S1734-1140(13)71489-0.
  38. Cameron A., Morrison V., Levin D., et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res. 2016;119(5):652–65. doi: 10.1161/CIRCRESAHA.116.308445.
  39. Xiao H., Ma X., Feng W., et al. Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. Cardiovasc Res. 2010;87(3):504–13. doi: 10.1093/cvr/cvq066.
  40. Ursini F., Russo E., Pellino G., et al. Metformin and Autoimmunity: A “New Deal” of an Old Drug. Front Immunol. 2018;9:1236. doi: 10.3389/fimmu.2018.01236.
  41. Refuerzo J. Oral hypoglycemic agents in pregnancy. Obstet Gynecol Clin North Am. 2011;38:227–34. doi: 10.1016/j.ogc.2011.02.013.
  42. Gui J., Liu Q., Feng L. Metformin vs insulin in the management of gestational diabetes. A meta-analysis. PLoS One. 2013;8:e64585. doi: 10.1371/journal.pone.0064585.
  43. Glueck C., Goldenberg N., Pranikoff J., et al. Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. Hum Reprod. 2004;19:1323–30. doi: 10.1093/humrep/deh263.
  44. Lin Y., Liu P., Pook K., et al. Glyburide and retinoic acid synergize to promote wound healing by anti-inflammation and RIP140 degradation. Sci Rep. 2018;8:834. doi: 10.1038/s41598-017-18785-x.
  45. Moore L., Clokey D. Rappaport V. Metformin compared with glyburide in gestational diabetes: A randomized controlled trial. Obstet Gynecol. 2010;115:55–9. doi: 10.1097/AOG.0b013e3181c52132.

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