МОЛЕКУЛЯРНЫЕ МЕХАНИЗМЫ ФУНКЦИОНИРОВАНИЯ СИСТЕМЫ «МАТЬ–ПЛАЦЕНТА–ПЛОД» ПРИ ОЖИРЕНИИ И ГЕСТАЦИОННОМ САХАРНОМ ДИАБЕТЕ

DOI: https://doi.org/10.29296/24999490-2020-01-02

И.И. Евсюкова, доктор медицинских наук, профессор ФГБНУ «НИИ акушерства, гинекологии и репродуктологии им. Д.О. Отта», Российская Федерация, 199034, Санкт-Петербург, Менделеевская линия, д. 3 E-mail: eevs@yandex.ru

В обзоре представлены данные литературы о влиянии совокупности гормональных и метаболических нарушений в организме женщины, страдающей ожирением и гестационным сахарным диабетом, на функционирование системы «мать–плацента–плод». Показано, что отсутствие при данной патологии циркадного ритма продукции мелатонина ведет к десинхронозу метаболических процессов, гипергликемии, гиперинсулинемии, инсулинорезистентности, гиперлептинемии, гиперлипидемии, активации свободнорадикального окисления, развитию митохондриальной и эндотелиальной дисфункции. Рассмотрены молекулярные механизмы нарушений развития плаценты, синтеза и секреции плацентарных гормонов, эндотелиальных факторов роста и цитокинов. Приведены результаты экспериментальных и клинических исследований особенностей трофической, метаболической, эндокринной и транспортной функций плаценты, лежащих в основе патофизиологических механизмов формирования у плода избыточной массы тела, гиперинсулинизма, изменения качественного состава липопротеидов высокой плотности, высокого содержания в крови свободных жирных кислот, инсулиноподобного фактора роста (IGF-1), маркеров эндотелиальной дисфункции и воспаления. Эпигенетические модификации генома плода лежат в основе нарушений морфофункционального развития мозговых структур, сердечно-сосудистой и других функциональных систем ребенка в раннем онтогенезе и программирования ожирения и метаболического синдрома в последующие годы жизни. Нормализация метаболизма на этапе планирования семьи и в процессе беременности необходима для профилактики неблагоприятных последствий для матери и ребенка.
Ключевые слова: 
беременность, ожирение, гестационный сахарный диабет, плацента, плод

Список литературы: 
  1. Damm P., Houshmand-Oeregaard A., Kelstrup L., Lauenborg J., Mathiesen E.R., Clausen T.D. Gestational diabetes mellitus and long-term consequences for mother and offspring: a view from Denmark. Diabetologia. 2016; 59 (7): 1396–9. https://doi.org/10.1007/s00125-016-3985-5.
  2. Page K.A., Romero A., Buchanan T.A., Xiang A.H. Gestational diabetes mellitus, maternal obesity, and adiposity in offspring. J. Pediatr. 2014; 164 (4): 807–10. https://doi.org/10.1016/j.jpeds.2013.11.063.
  3. Kim S.Y., England J.L., Sharma J.A., Njoroge T. Gestational diabetes mellitus and risk of childhood overweight and obesity in offspring: a systematic review. Exp. Diabetes Res. 2011; 2011: 541308. https://doi.org/10.1155/2011/541308.
  4. Monteiro L.J., Norman J.E., Rice G.E., Illanes S.E. Fetal programming and gestational diabetes mellitus. Placenta. 2016; 48 (Suppl. 1): 54–60. https://doi.org/10.1016/j.placenta.2015.11.015.
  5. Сonnolly N., Anixt J., Manning P., Ping-I Lin D., Marsolo K.A., Bowers K. Maternal metabolic risk factors for autism spectrum disorder-An analysis of electronic medical records and linked birth data. Autism Res. 2016; 9 (8): 829–37. https://doi.org/10.1002/aur.1586.
  6. Cахарный диабет и репродуктивная система женщины.: руководство для врачей. Под ред. Э.К. Айламазяна. М.: ГЭОТАР-Медиа, 2017. 428. [Diabetes mellitus and reproductive system of women. (red. E.K. Ailamazyan). M.: GEOTAR-Media, 2017; 428 (in Russian)].
  7. Liu B., Geng H., Yang J., Zhang Y., Deng L. at AL. Early pregnancy fasting plasma glucose and lipid concentrations in pregnancy and association to offspring size: a retrospective cohort study. BMC Pregnancy Childbirth. 2016; 16: 56. https://doi.org/10.11`86/s12884-016-0846-7.
  8. Gabbay-Benziv R., Baschat A.A. Gestational diabetes as one of the «great obstetrical syndromes», – the maternal, placental, and fetal dialog. Best. Pract. Res. Clin. Obstet.Gynaecol. 2015; 29 (2): 150–5. https://doi.org/10.1015/jbpobgyn.2014.04.025.
  9. Айламазян Э.К., Евсюкова И.И., Ярмолинская М.И. Роль мелатонина в развитии гестационного сахарного диабета. Журн. акуш. жен. болезней. 2018; 67 (1): 87–91. [Ailamazyan E.K., Evsyukova I.I., Yarmolinskaya M.I. The role of melatonin in development of gestation diabetes mellitus.Journal of Obstetrics and Women’s Diseases. 2018; 67 (1): 87–91 (in Russian)]
  10. Pirozzi F.F., Bonini-Domingos C.R., Ruiz M.A. Metabolic Actions of Melatonin on Obesity and Diabetes: A Light in the Darkness. Cell. Biol. Res. Ther. 2015; 4 (2): 2–6. http://dx.doi.org/10.4172/2324-9293.1000119.
  11. Piccinetti C.C., Migliarini B., Olivotto I., Coletti G., Amici A., Carnevali O. Appetite regulation: the central role of melatonin in Danio rerio. Horm. Behav. 2010; 58 (5): 780–5. https://doi.org/10.1016/j.yhbeh.2010.07.013.
  12. Lardone P.J., Alvarez-Sanchez N., Guerrero J.M., Carrillo-Vico A. Melatonin and glucose metabolism: clinical relevance. Curr. Pharm. Des. 2014; 20 (30): 4841–53. PMID: 24251676.
  13. Soderquist F., Hellstrom P.M., Cunningham J.L. Human gastroenteropancreatic expression of melatonin and its receptors MT1` and MT2. PLoS One. 2015; 10 (3): e0120195. https://doi.org/10.1371/journal.pone.0120195.
  14. Peschke E., Bahr I., Muhlbauer E. Experimental and clinical aspects of melatonin and clock genes in diabetes. J. Pineal Res. 2015; 59 (1): 1–23. https://doi.org/10.1111/jpi.12240.
  15. Alonso-Vale M.I., Andreotti S., Mukai P.Y, Borges-Silva C.D., Peres S.B., Cipolla-Neto J., Lima F.B. Melatonin and the circadian entrainment of metabolic and hormonal activities in primary isolated adipocytes. J. Pineal Res. 2008; 45 (4): 422–9. https://doi.org/10.1111/j.1600-079X.2008.00610.x.
  16. Szewczyk-Golec K., Wozniak A., Reiter R.J. Inter-relationships of the chronobiotic, melatonin, with leptin and adiponectin: implications for obesity. J. Pineal Res. 2015; 59 (3): 277–91. https://doi.org/1./1111/jpi.12257.
  17. Asher G., Sassone-Corsi P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell. 2015; 161 (1): 84–92. https://doi.org/10.1016/j.cell.2015.03.015.
  18. Cipolla-Neto J., Amaral F.G., Afeche S.C., Tan D.X., Reiter R.J. Melatonin, energy metabolism, and obesity: a review. J. Pineal Res. 2014; 56 (4): 371–81. https://doi.org/10.1111/jpi.12137.
  19. Plano S.A., Casiraghi L.P., Garcia Moro P., Paladino N., Golombek D.A., Chiesa J.J. Circadian and metabolic effects of light: implications in weight homeostasis and health. Front. Neurol. 2017; 8: 558. https://doi.org/10.3389/fneur.2017.00558. eCollection 2017.
  20. Reiter R.J., Tan D.X., Korkmaz A., Ma S. Obesity and metabolic syndrome: association with chronodisruption, sleep deprivation, and melatonin suppression. An. Med. 2012; 44 (6): 564–77. https://doi.org/10.3109/07853890.2011.586365.
  21. Buonfiglio D., Parthimos R., Dantas R., Silva R.C., Gomes G., Andrade-Silva J., Ramos-Lobo A., Amaral F.G., Matos R., Sinésio J.Jr., Motta-Teixeira L.C., Donato J.Jr., Reiter R.J., Cipolla-Neto J. Melatonin Absence Leads to Long-Term Leptin Resistance and Overweight in Rats. Front Endocrinol (Lausanna). 2018; 9: 122. https://doi.org/10.3389/fendo.2018.00122. eCollection 2018.
  22. Fenzl A., Kiefer F.W. Brown adipose tissue and thermogenesis. Horm. Mol. Biol. Clin. Invest. 2014; 19 (1): 25–37. https://doi.org/10.1515/hmbci-2014-0022.
  23. Tan D.X., Manchester L.C., Fuentes-Broto L., Paredes S.D., Reiter R.J. Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity. Obes. Rev. 2011; 12 (3): 167–88. https://doi.org/10.1111/j.1467-789X.2010.00756.x.
  24. Silha J.F., Krsek M., Skrha J.V., Sucharda P., Nyomba B. L. G., Murphy L.J. Plasma resistin, adiponectin and leptin level in lean and obese subjects: correlations with insulin resistance. Eur. J. Endocrinol. 2003; 149 (4): 331–5. PMID: 14514348. Online version via http://www.eje.org.
  25. Sobrevia L., Salsoso R., Fuenzalida B., Barros E., Toledo L.,Silva L., Pizarro C., Subiabre M., Villalobos R., Araos J., Toledo F., González M., Gutiérrez J., Farias M., Chiarello D.I., Pardo F., Leiva A. Insulin Is a Key Modulator of Fetoplacental Endothelium Metabolic Disturbances in Gestational Diabetes Mellitus. Front. Physiol. 2016; 7: 119. https://doi.org/10.3389/fphys.2016.00119. Published online 2016.
  26. Lui K., Wu H.-Y., Xu Y.-H. Study on the relationship between the expression of IGF-1 in umbilical cord blood and abnormal glucose metabolism during pregnancy. Europ. Rev. Med. Pharmacol. Sci. 2017; 21 (4): 647–51. PMID: 28272722.
  27. Sferruzzi-Perri A.N., Owens J.A, Pringle K.G, Roberts C.T. The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth. J. Physiol. 2011; 589 (Pt 1): 7–20. https://doi.org/10.1113/jphysiol.2010.198622.
  28. Roith D.L. The Insulin – Like Growth Factor System. Exper. Diab. Res. 2003; 4 (4): 205–12. https://doi.org/10.1080/15438600390249664.
  29. Montelongo A., Lasuncion M.A., Pallardo E., Herrera E. Longitudinal study of plasma lipoproteins and hormones during pregnancy in normal and diabetic women. Diabetes. 1992; 41 (12): 1651–9. https://doi.org/10.2337/diab.41.12.1651.
  30. Sharafati-Chaleshtori R., Shirzad H., Rafiean-Kopaei M., Soltani A. Melatonin and human mitochondrial diseases. J. Res. Med. Sci. 2017; 22 (2): 1–11. https://doi.org/10.4103/1735-1995.199092.
  31. Tamura H., Nakamura Y., Terron M.P., Flores L.J., Manchester L.C., Tan D-X., Sugino N., Reiter R.J. Melatonin and pregnancy in the human. Reprod. Toxicol. 2008; 25 (3): 291–303. https://doi.org/10.16/j.reprotox.2008.03.005.
  32. Lenna S., Han R., Trojanowska M. Endoplasmic reticulum stress and endothelial dysfunction. IUBMB Life. 2014; 66 (8): 530–7. https://doi.org/10.1002/jub.1292.
  33. Sanchez-Vera I., Bonet B., Viana M., Quintanar A., Martin M.D., Blanco P., Donnay S., Albi M. Changes in plasma lipids and increased low density lipoprotein susceptibility to oxidation in pregnancies complicated by gestational diabetes: consequences of obesity. Metab. Clin. Exp. 2007; 56 (11): 1527–33. https://doi.org/10.1016/j.metabol.2007.06.020.
  34. Liong S., Lappas M. Endoplasmic reticulum stress is increased in adipose tissue of women with gestational diabetes. PLoS ONE. 2015; 10 (4): e0122633. https://doi.org/10.1371/journal.pone.0122633.
  35. Colomiere M., Permezel M., Lappas M. Diabetes and obesity during pregnancy alter insulin signaling and glucose transporter expression in maternal skeletal muscle and subcutaneous adipose tissue. J. Mol. Endocrinol. 2010; 44 (4): 213–23. https://doi.org/10.1677/JME-09-0091.
  36. Евсюкова И.И., Кветной И.М. Мелатонин и циркадные ритмы в системе мать-плацента-плод. Молекулярная медицина. 2018; 16 (6): 9–13. [Evsyukova I.I., Kvetnoy I.M. Melatonin and circadian rhythms in the system «mother-placenta-fetus». Molekulyarnaya meditsina. 2018; 16 (6): 9–13 (in Russian). https://doi.org/10.29296/24999490-2018-06-02.
  37. Reiter R.J., Tan D.X., Korkmaz A., Rosales-Corral S.A. Melatonin and stabile circadian rhythms optimize maternal, placental and fetal physiology. Hum. Reprod. Update. 2014; 20 (2): 293–307. https://doi.org/10.1093/humupd/dmt054.
  38. Nakamura N.Y., Tamura H., Kashida S., Takayama H., Yagamata Y., Karube A., Sugino N., Kato H. Changes of serum melatonin level and its relationship to feto-placental unit during pregnancy. J. Pineal Res. 2001; 30 (1): 29–33. PMID 11168904
  39. Iwasaki S., Nakazawa K., Sacai J., Kometani K., Iwashita M., Yoshimura Y., Maruyama I. Melatonin as local regulator of human placental function. J. Pineal Res. 2005; 39: 261–5. https://doi.org/10.1111/j.1600-079X.2005.00244.x.
  40. Desoye G. The Human Placenta in Diabetes and Obesity: Friend or Foe? The 2017 Norbert Freinkel Award Lecture. Diabetes Cart. 2018; 41 (7): 1362–9. https://doi.org/10.2337/dci17-0045.
  41. Grissa O., Yessoufou A., Mrisak I., Hichami A., Amoussou-guenou D., Grissa A., Djrolo F., Moutairou K., Miled A., Khairi H., Zaouali M., Bougmiza I., Zbidi A., Tabka Z., Khan N.A. Growth factor concentrations and their placental mRNA expression are modulated in gestational diabetes mellitus :possible interactions with macrosomia. BMC Pregnancy and Childbirth. 2010; 10: 7. https://doi.org/10.1186/1471-2393-10-7.
  42. Hahn D., Blaschitz A., Korgun E.T., Lang I., Desoye G., Skofitsch G., Dohr G. From maternal glucose to fetal glycogen: expression of key regulators in the human placenta. Mol. Hum. Reprod. 2001; 7 (12): 1173–8. https://doi.org/10.1093/molehr/7.12.1173
  43. Lolmede K., Durand de Saint Front V., Galitzky J., Lafontan M., Bouloumie A. Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes. Int J. Obes. Relat. Metab. Disord. 2003; 27 (10): 1187–95. https://doi.org/10.1038/sj.ijo.0802407
  44. Jarmuzek P., Wielgos M., Bomba-Opon D. Placental pathologic changes in gestational diabetes mellitus. Neuro. Endocrinol. Lett. 2015; 36 (2): 101–5. PMID:26071574.
  45. Leiva A., Fuenzalida B., Barros E., Sobrevia B., Salsoso R., Sáez T., Villalobos R., Silva L., Chiarello I., Toledo F., Gutiérrez J., Sanhueza C., Pardo F., Sobrevia L. Nitric Oxide is a Central Common Metabolite in Vascular Dysfunction Associated with Diseases of Human Pregnancy. Curr. Vasc. Pharmacol. 2016; 14 (3): 237–59. PMID: 26899560.
  46. Kelley D.E., He J., Menshokova E.V., Ritov V.B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. 2002; 51 (10): 2944–50. https://doi.org/10.2337/diabetes.51.10.2944
  47. Hauguel-de Mouzon S., Guerre-Millio M. The placenta cytokine network and inflammatory signals. Placenta. 2006; 27 (8): 794–8. https://doi.org/10.1016/j.placenta.2005.08.009
  48. Siwetz M., Blaschitz A., El-Heliebi A., Hiden U., Desoye G., Huppertz B., Gauster M. TNF-α alters the inflammatory secretion profile of human first trimester placenta. Lab. Invest. 2016; 96 (4): 428–38. https://doi.org/10.1038/labinvest.2015.159.
  49. Khodabandehloo H., Gordani-Fruzjaee S., Panahi G., Meshkani R. Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction. Transl. Res. 2016; 167 (1): 228–56. https://doi.org/10.1016/j.trsl.2015.08.011.
  50. Aye I.L., Jansson T., Powell T.L. TNF-α stimulates System A amino acid transport in primary human trophoblast cells mediated by p38 MARK signaling. Physiol. Rep. 2015; 3 (10): pii:e12594. https://doi.org/10.14814/phy2.12594.
  51. Jones H.N., Jansson T., Powell T.L. IL-6 stimulates system A amino acid transporter activity in trophoblast cells throught STATS and increased expression of SNAT2. Am. J. Physiol. Cell. Physiol. 2009; 297 (5): 1228–35. https://doi.org/10.1152/ajpcell.00195.2009.
  52. Lager S., Jansson N., Olsson A.L., Wennergren M., Jansson T., Powell T.L. Effect of IL-6 and TNF-α on fatty acid aptake in cultured human primary trophoblast cells. Placenta. 2011; 32 (2): 121–7. https://doi.org/10.1016/j.placenta.2010.10.012.
  53. Tessier D.R., Ferraro Z.M., Gruslin A. Role of leptin in pregnancy: consequences of maternal obesity. Placenta. 2013; 34 (3): 205–11. https://doi.org/10.1016/j.placenta.2012.11.035.
  54. Feng H., Su R., Song Y., Wang C., Lin L., Ma J., Yang H. Positive Correlation between Enhanced Expression of TLR4/MyD88/NF-Kb with Insulin Resistance in Placentae of Gestational Diabetes Mellitus. PLoS ONE. 2016; 11 (6): e0157185. https://doi.org/10.1371/journal.pone.o157185.
  55. Howell K.R., Powell T.L. Effects of maternal obesity on placental function and fetal development. Reproduction. 2017; 153 (3): 97–108. https://doi.org/10.1530/REP-16-0495.
  56. Lager S., Gaccioli F., Ramirez V.I., Jones H.N., Jansson T., Powell T.L. Oleic acid stimulated system A amino acid transport in primary human trophoblast cells mediated by toll-like receptor 4. J. Lipid. Res. 2013; 54 (3): 725–33. https://doi.org/10.1111/j.1471-0528.2010.02569.x.
  57. Larque E., Pagan A., Pietro M.T., Blanco J.E., Gil-Sanchez A. et al. Placental fatty acid transder: a key factor in fetal growth. Ann. Nutr. Metab. 2014; 64 (3–4): 247–53. https://doi.org/10.1159/000365028.
  58. Yang X., Li M., Haghiac M., Catalano P.M., O’Tierney-Ginn P., Hauguel-de Mouzon S. Causal relationship between obesity-related traits and TLR4-driven responses at the maternal-fetal interface. Diabetologia. 2016; 59 (11): 2459–66. https://doi.org/10.1007/s00125-016-4073-6.
  59. Jia L., Vianna C.R., Fukuda M., Berglund E.D., Liu C. et al. Hepatocyte Toll-like receptor 4 regulates obesity- induced inflammation and insulin resistance. Nat. Commun. 2014; 5: 3878. https://doi.org/10.1038/ncomms4878.
  60. Subiabre M., Villalobos-Labra R., Silva L., Fuentes G., Toledo F., Sobrevia L. Role of insulin, adenosin, and adipokine receptors in the fetoplacental vascular dysfunction in gestational diabetes mellitus. Biochim. Biophys. Acta Mol. Basis Dis. 2019; pii:S0925-4439 (18) 30513–1. https://doi.org/10.1016/jbbadis.2018.12.021.
  61. Avagliano L., Mascherpa M., Massa V., Doi P., Bulfamante G.P. Fetal pancreatic Langerhans islets size in pregnancies with metabolic disorders. J. Matern. Fetal. Neonatal.Med. 2018; 6: 1–6. https://doi.org/10.1080/14767058.2018.1468878.
  62. Sreckovic I., Birner-Gruenberger R., Besenboeck C., Milijkovic M., Stojakovic T., Scharnagl H., Marsche G., Lang U., Kotur-Stevuljevic J., Jelic-Ivanovic Z., Desoye G., Wadsack C. Gestational diabetes melliyus modulates neonatal high-density lipoprotein composition and its functional heterogeneity. Biochim. Biophys. Acta. 2014; 1841 (11): 1619–27. https://doi.org/10.1016/j.bbalip.2014.07.021.
  63. Castillo-Castrejon M., Powell T.L. Placental Nutrient Transport in Gestational Diabetic Pregnancies. Front. Endocrinol (Lausanne). 2017; 8: 306. https://doi.org/10.3389/fendo.2017.00306. eCollection 2017.
  64. Patel N., Hellmuth C., Uhl O., Godfrey K., Briley A., Welsh P., Pasupathy D., Seed P.T., Koletzko B., Poston L. Cord Metabolic Profiles in Obese Pregnant Women: Insights Into Offspring Growth And Body Composition. J. Clin. Endocrinol. Metab. 2018; 103 (1): 346–55. https://doi.org/10.1210/jc.2017.-00876.
  65. Cassidy F.C., Charalambous M. Genomic imprinting, growth and maternal-fetal interactions. J. Exp. Biol. 2018; 221 (Pt.Suppl.1.): pii: jeb164517. https://doi.org/10.1242/jeb.164517.
  66. Hajj N., Pliushch G., Schneider E., Dittrich M., Muller T., Korenkov M., Aretz M., Zechner U., Lehnen H., Haaf T. Metabolic programming of MEST DNA methylation by intrauterine exposure to gestational diabetes mellitus. Diabetes. 2013; 62 (4): 1320–8. https://doi.org/10.2337/ab12-0289.
  67. Peng Y., Yu S., Li H., Xiang H., Peng J., Jiang S. MicroRNAs: emerging roles in adipogenesis and obesity. Cell. Signal. 2014; 26 (9): 1888–96. https://doi.org/10.1016/j.cellsig.2014.05.006.
  68. McCloskey K., Ponsonby A.L., Collier F., Allen K., Tang M.L.K., Carlin J.B., Saffery R., Skilton M.R., Cheung M., Ranganathan S., Dwyer T., Burgner D., Vuillermin P. The association between higher maternal pre-pregnancy body mass index and increased birth weight, adiposity and inflammation in the newborn. Pediatr. Obes. 2018; 13 (1): 46–53. https://doi.org/10.1111/ijpo.12187.
  69. Redman C.W., Staff A.C. Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity. Am.J. Obstet. Gynecol. 2015; 213. (Suppl. 4): 9–11. https://doi.org/10.1016/j.ajog.2015.08.003.