The importance of pathological insulin resistance and hyperinsulinemia in the pathogenesis of preeclampsia

Aim: to assess dynamic changes in insulin resistance (IR), hyperinsulinemia (HI) and related parameters of carbohydrate and lipid metabolism, endothelial dysfunction, pro-inflammatory and prothrombotic states in pregnancy complicated with preeclampsia (PE).
Materials and Methods. A prospective observational study was conducted consisting of laboratory monitoring 148 high-PE-risk pregnant women comprising Group I - 72 women with overt PE; 36 healthy women with physiological course of pregnancy were included into Group II. All women were assessed level of venous blood glucose, insulin, total cholesterol, high-density lipoproteins (HDL), triglycerides (TG), leptin, placental lactogen, uric acid, tumor necrosis factor-a, C-reactive protein, circulating endothelial cells, fibronectin, nitric oxide metabolites, platelet aggregation at gestational periods 11-14 weeks, 18-21 weeks and 30-34 weeks. We also calculated insulin resistance index, atherogenic coefficient, and TG/HDL ratio, estimating accumulation and distribution of adipose tissue.
Results. There were found physiological changes in IR and HI, lipid, endothelial-hemostasis axis, pro-inflammatory, placental parameters supposed to provide proper fetal energy supply during normal pregnancy. During PE, these parameters were aberrantly elevated starting from early pregnancy stage due to failure of gestational adaptation mechanisms, which acquire important pathogenetic significance therein.
Conclusion. A holistic view at the mechanisms of forming atherogenic transformation of the lipid profile, endothelial dysfunction, pro-inflammatory and prothrombotic status, oxidative stress, hyperuricemia, visceral type of abdominal wall fat deposition as well as correlation analysis data indicate that all such changes were associated with unified pathogenetic arm consisting of pathological IR and HI serving as early baseline mechanisms in PE development.

insulin resistance, hyperinsulinemia, preeclampsia, pathogenesis, fetal energy supply

1. Makisheva R.T. The adaptive meaning of insulin resistance. [Adaptivnyj smysl insulinorezistentnosti]. Vestnik novyh medicinskih tekhnologij. 2016;(1):60-7. (In Russ.). https://doi.org/10.12737/18557.

2. Perederyaeva E.B., Pshenichnikova T.B., Andreeva M.D., Makatsariya A.D. The pathogenetic mechanisms of development of preeclampsia in women with metabolic syndrome. [Patogeneticheskie mekhanizmy razvitiya preeklampsii u zhenshchin s metabolicheskim sindromom]. Akusherstvo, Ginekologia i Reprodukcia. 2015;9(3):54-65. (In Russ.). https://doi.org/10.17749/2070-4968.2015.9.3.054-065.

3. Shagalova N.Ya. Insulin resistance - advantage or harm? [Insulinorezistentnost' - pol'za ili vred?]. Sovremennye problemy nauki i obrazovaniya. 2016;(2):89. (In Russ.).

4. Nolan C.J., Prentki M. Insulin resistance and insulin hypersecretion in the metabolic syndrome and type 2 diabetes: Time for a conceptual framework shift. Diab Vasc Dis Res. 2019;16(2):118-27. https://doi.org/10.1177/1479164119827611.

5. Connor T., Martin S.D., Howlett K.F., McGee S.L. Metabolic remodelling in obesity and type 2 diabetes: pathological or protective mechanisms in response to nutrient excess? Clin Exp Pharmacol Physiol. 2015;42(1):123-8. https://doi.org/10.1111/1440-1681.12315.

6. Dahlmans D., Houzelle A., Jorgensen J.A. et al. Evaluation of muscle microRNA expression in relation to human peripheral insulin sensitivity: a cross-sectional study in metabolically distinct subject groups. Front Physiol. 2017;7:3-11. https://doi.org/10.3389/fphys.2017.00711.

7. Gordiunina S.V. Insulin resistance during pregnancy (a literature review). [Insulinorezistentnost' pri beremennosti (obzor literatury)]. Problemy endokrinologii. 2013;59(5):61-6. (In Russ.).

8. Strizhakov A.N., Timokhina E.V., Ibragimova S.M. et al. A novel approach to the differential prognosis of early and late preeclampsia. [Novye vozmozhnosti differencial'nogo prognozirovaniya rannej i pozdnej preeklampsii]. Akusherstvo, Ginekologia i Reprodukcia. 2018;12(2):55-61. (In Russ.). https://doi.org/10.17749/2313-7347.2018.12.2.055-061.

9. Napso T., Yong H.E.J., Lopez-Tello J., Sferruzzi-Perri A.N. The role of placental hormones in mediating maternal adaptations to support pregnancy and lactation. Front Physiol. 2018;9:1091. https://doi.org/10.3389/fphys.2018.01091.

10. Rochlani Y., Pothineni N.V., Kovelamudi S., Mehta J.L. Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. Ther Adv Cardiovasc Dis. 2017;11(8):215-25. https://doi.org/10.1177/1753944717711379.

11. Khromylev A.V., Makatsariya A.D. Obesity, metabolic syndrome and thrombophilia. [Ozhirenie, metabolicheskij sindrom i trombofiliya]. Akusherstvo i ginekologiya. (In Russ.). 2017;(10):27-33. https://doi.org/10.18565/aig.2017.10.27-33.

12. Serov V.N. Metabolic syndrome: gynecological problems. [Metabolicheskij sindrom: ginekologicheskie problem]. Akusherstvo i ginekologiya. 2006;(appendix):9-11. (In Russ.).

13. Jyoti B., Steve H., Argyro S. Association between insulin resistance and preeclampsia in obese non-diabetic women receiving metformin. Obstetric Medicine. 2017;10(4):170-3. https://doi.org/10.1177/1753495X17725465.

14. Hypertensive disorders during pregnancy, childbirth and the postpartum period. Preeclampsia Eclampsia. Clinical recommendations (treatment protocol). [Gipertenzivnye rasstrojstva vo vremya beremennosti, v rodah i poslerodovom periode. Preeklampsiya. Eklampsiya. Klinicheskie rekomendacii (Protokol lecheniya)]. Moskva, 2016. 51 s. (In Russ.). Available at: https://rd1.medgis.ru/uploads/userfiles/shared/StandartMed/Protokol-acusher/2.pdf. [Accessed: 15.03.2020].

15. Williams K.J., Wu X. Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward. Atherosclerosis. 2016;247:225-82. https://doi.org/10.1016/j.atherosclerosis.2016.02.004.

16. Erion K.A., Corkey B.E. Hyperinsulinemia: a cause of obesity? Curr Obes Rep. 2017;6(2):178-86. https://doi.org/10.1007/s13679-017-0261-z.

17. Chen X., Stein T.P., Steer R.A., Scholl T.O. Individual free fatty acids have unique associations with inflammatory biomarkers, insulin resistance and insulin secretion in healthy and gestational diabetic pregnant women. BMJ Open Diabetes Res Care. 2019;7(1):e000632. https://doi.org/10.1136/bmjdrc-2018-000632.

18. De Mutsert R., Gast K., Widya R. et al. Associations of abdominal subcutaneous and visceral fat with insulin resistance and secretion differ between men and women: the netherlands epidemiology of obesity study. Metab Syndr Relat Disord. 2018;16(1):54-63. https://doi.org/10.1089/met.2017.0128.

19. Moreno Santillan A.A., Briones Garduno J.C., Diaz de Leon Ponce M.A. Uric acid in pregnancy: new concepts. Contrib Nephrol. 2018;192:110-5. https://doi.org/10.1159/000484285.

20. Brann E., Edvinsson А., Rostedt Punga A. et al. Inflammatory and antiinflammatory markers in plasma: from late pregnancy to early postpartum. Sci Rep. 2019;9(1):1863. https://doi.org/10.1038/s41598-018-38304-w.

21. Serov V.N. Metabolic syndrome (neuro-endocrine syndrome). [Metabolicheskij sindrom (nejroobmenno-endokrinnyj sindrom)]. Medica mente. Lechim s umom. 2015;(1):16-9. (In Russ.).

22. Romantsova T.I., Sych Yu.P. Immunometabolism and metainflammation in obesity. [Immunometabolizm i metavospalenie pri ozhirenii]. Ozhirenie i metabolizm. 2019;16(4):3-17. (In Russ.). https://doi.org/10.14341/omet12218.

23. Khromylev A.V., Makatsariya A.D. The structure of the genetic polymorphisms in patients with metabolic syndrome and a complicated pregnancy in history. [Struktura geneticheskih polimorfizmov u rodil'nic s metabolicheskim sindromom i oslozhnennym techeniem beremennosti v anamneze]. Akusherstvo, Ginekologia i Reprodukcia. 2016;10(3):35-40. (In Russ.). https://doi.org/10.17749/2313-7347.2016.10.2.035-040.

24. Frolova N.A. The evidence of pathogenetic link between embryo(feto)placental insufficiency with early and late preeclampsia. [Obosnovanie patogeneticheskoj svyazi embrio(feto)placentarnoj nedostatochnosti s rannej i pozdnej preeklampsiej]. Aspirantskij vestnik Povolzh'ya. 2015;(1-2):44-53. (In Russ.).