Molecular mechanisms of insulin resistance in normal pregnancy and gestational diabetes

Prof. L.V. Zhuravlyova, PhD N.V. Sokolnikova, PhD T.A. Rogachova

Kharkiv National Medical University

The purpose of this review article is to analyze current information on the molecular mechanisms of gestational diabetes and the prospects for their use in the further development of new effective treatments for this common pathology. Decreased ability of insulin to bind to its receptor, decreased IRS-1 expression and GLUT-4 translocation, and increased levels of p85α-PI-3 kinase subunits are involved in the development of insulin resistance during pregnancy. In gestational diabetes, there are not only more significant changes of the above mentioned indicators, but also increased levels of pro-inflammatory factors: TNF-α, IL-6, leptin and decreased insulin-sensitizing factors: adiponectin and PPAR-γ. Therapeutic measures aimed at normalizing the secretion of cytokines and adipokines reduce the risk of gestational diabetes mellitus and its complications and require further development

Key Words: gestational diabetes mellitus, insulin resistance, proinflammatory cytokines.

Download.PDF (ukr)

For citing:

1. Журавльова, Л.В., Сокольнікова, Н.В., Рогачова, Т.А. Молекулярні механізми інсулінорезистентності при нормальній вагітності та гестаційному діабеті // Східноєвропейський журнал внутрішньої та сімейної медицини. – 2021. – №1. – С. 22-30. doi: 10.15407/internalmed2021.01.022

2. Zhuravlyova LV, Sokolnikova NV, Rogachova TA. [Molecular mechanisms of insulin resistance in normal pregnancy and gestational diabetes]. Shidnoevr. z. vnutr. simejnoi med. 2021;1:22-30. Ukrainian. doi: 10.15407/internalmed2021.01.022


1. American Diabetes Association Management of Diabetes in Pregnancy. Standards of Medical Care in Diabetes. Diabetes Care. 2020;43 (1):183-192.

2. Sonagra A, Biradar S, K Dattatreya K, Murthy J. Normal pregnancy-a state of insulin resistance. Journal of clinical and diagnostic research. 2014;8 (11):1-3.

3. Petersen M, Shulman G. Mechanisms of Insulin Action and Insulin Resistance. Physiological Reviews. 2018;98(4):2133-2223.

4. Barbour L, McCurdy C, Hernandez T, Kirwan J, Catalano P, Friedman J. Cellular Mechanisms for Insulin Resistance in Normal Pregnancy and Gestational Diabetes. Diabetes Care. 2007;30(Supplement 2):S112-S119.

5. Angueira A, Ludvik A, Reddy T, Wicksteed B, Lowe W, Layden B. New Insights Into Gestational Glucose Metabolism: Lessons Learned From 21st Century Approaches. Diabetes. 2015;64(2):327-334.

6. Abhari F, Ghanbari Andarieh M, Farokhfar A, Ahmady S. Estimating Rate of Insulin Resistance in Patients with Preeclampsia Using HOMA-IR Index and Comparison with Nonpreeclampsia Pregnant Women. BioMed Research International. 2014;2014:1-6.

7. Zhang M, Zhou Y, Zhong J, Wang K, Ding Y, Li L. Current guidelines on the management of gestational diabetes mellitus: a content analysis and appraisal. BMC Pregnancy and Childbirth. 2019;19(1):.

8. Kirwan J, Hauguel-De Mouzon S, Lepercq J, Challier J, Huston-Presley L, Friedman J, Kalhan S, Catalano P. TNF- Is a Predictor of Insulin Resistance in Human Pregnancy. Diabetes. 2002;51(7):2207-2213.

9. Cunningham F, Lenevo K, Bloom S. Williams Obstetrics. 22nd ed. Maternal physiology; 2005. 107-131.

10. Xu J, Zhao Y, Chen Y, Yuan X, Wang J, Zhu H, Lu C. Maternal Circulating Concentrations of Tumor Necrosis Factor-Alpha, Leptin, and Adiponectin in Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis. The Scientific World Journal. 2014;2014:1-12.

11. El-Bassyouni H, Abdel Raouf S, Farag M, Nawito W, Salman T, Gaber K. Dysregulation of tumor necrosis factor-α and interleukin-6 as predictors of gestational disorders. Middle East Journal of Medical Genetics. 2018;7(2):112.

12. Lepercq J, Cauzac M, Lahlou N, Timsit J, Girard J, Auwerx J, Hauguel-de Mouzon S. Overexpression of placental leptin in diabetic pregnancy: a critical role for insulin. Diabetes. 1998;47(5):847-850.

13. Cseh K, Baranyi É, Melczer Z, Csákány G, Speer G, Kovács M, Gerö G, Karádi I, Winkler G. The pathophysiological influence of leptin and the tumor necrosis factor system on maternal insulin resistance: negative correlation with anthropometric parameters of neonates in gestational diabetes. Gynecological Endocrinology. 2002;16(6):453-460.

14. Altinova A, Toruner F, Bozkurt N, Bukan N, Karakoc A, Yetkin I, Ayvaz G, Cakir N, Arslan M. Circulating concentrations of adiponectin and tumor necrosis factor-α in gestational diabetes mellitus. Gynecological Endocrinology. 2007;23(3):161-165.

15. GAO X, YANG H, ZHAO Y. Variations of tumor necrosis factor-α, leptin and adiponectin in mid-trimester of gestational diabetes mellitus. Chinese Medical Journal. 2008;121(8):701-705.

16. Bozkurt L, Göbl C, Baumgartner-Parzer S, Luger A, Pacini G, Kautzky-Willer A. Adiponectin and Leptin at Early Pregnancy: Association to Actual Glucose Disposal and Risk for GDM-A Prospective Cohort Study. International Journal of Endocrinology. 2018;2018:1-8.

17. McLachlan K, O’Neal D, Jenkins A, Alford F. Do adiponectin, TNFα, leptin and CRP relate to insulin resistance in pregnancy? Studies in women with and without gestational diabetes, during and after pregnancy. Diabetes/Metabolism Research and Reviews. 2006;22(2):131-138.

18. Suryanarayana K, Bhograj A, Nayak A, Murthy N, Dharmalingam M, Kalra P. Serum adiponectin levels in gestational diabetes mellitus. Indian Journal of Endocrinology and Metabolism. 2016;20(6):752.

19. Plows J, Stanley J, Baker P, Reynolds C, Vickers M. The Pathophysiology of Gestational Diabetes Mellitus. International Journal of Molecular Sciences. 2018;19(11):3342.

20. Gomes C, Torloni M, Gueuvoghlanian-Silva B, Alexandre S, Mattar R, Daher S. Cytokine Levels in Gestational Diabetes Mellitus: a Systematic Review of the Literature. American Journal of Reproductive Immunology. 2013;:n/a-n/a.

21. Abell S, De Courten B, Boyle J, Teede H. Inflammatory and Other Biomarkers: Role in Pathophysiology and Prediction of Gestational Diabetes Mellitus. International Journal of Molecular Sciences. 2015;16(12):13442-13473.

22. Greenhill C. The role of adiponectin in gestational diabetes mellitus. Nature Reviews Endocrinology. 2017;13(3):128.

23. Noakes T. So What Comes First: The Obesity or the Insulin Resistance? And Which Is More Important?. Clinical Chemistry. 2018;64(1):7-9.

24. Vernini J, Moreli J, Costa R, Negrato C, Rudge M, Calderon I. Maternal adipokines and insulin as biomarkers of pregnancies complicated by overweight and obesity. Diabetology & Metabolic Syndrome. 2016;8(1):.

25. Emre C. Adipocytokines in Particular Pregnancy Disorders. Annals of Clinical and Laboratory Research. 2015;3(4):.

26. Genc S, Kusku Kiraz Z, Dervisoglu E, Oztop N, Dinccag N, Gurdol F. The Relation Of Oxidative Stress Biomarkers With Proinflammatory Cytokines In Gestational Diabetes. Clinical Investigation. 2017;07(01):.

27. Gonzalez Y, Herrera M, Soldevila G, Garcia-Garcia L, Fabián G, Pérez-Armendariz E, Bobadilla K, Guzmán-Beltrán S, Sada E, Torres M. High glucose concentrations induce TNF-α production through the down-regulation of CD33 in primary human monocytes. BMC Immunology. 2012;13(1):19.

28. Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, Quagliaro L, Ceriello A, Giugliano D. Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans. Circulation. 2002;106(16):2067-2072.

29. Amirian A, Mahani M, Abdi F. Role of interleukin-6 (IL-6) in predicting gestational diabetes mellitus. Obstetrics & Gynecology Science. 2020;63(4):407-416.

30. Kramer C, Campbell S, Retnakaran R. Gestational diabetes and the risk of cardiovascular disease in women: a systematic review and meta-analysis. Diabetologia. 2019;62(6):905-914.

31. Olson A. Regulation of GLUT4 and Insulin-Dependent Glucose Flux. ISRN Molecular Biology. 2012;2012:1-12.

32. Kroder G, Bossenmaier B, Kellerer M, Capp E, Stoyanov B, Mühlhöfer A, Berti L, Horikoshi H, Ullrich A, Häring H. Tumor necrosis factor-alpha- and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on insulin signaling.. Journal of Clinical Investigation. 1996;97(6):1471-1477.

33. Kang J, Boonanantanasarn K, Baek K, Woo K, Ryoo H, Baek J, Kim G. Erratum: Institutions, Correspondence, Figures & Legends Correction. Hyperglycemia increases the expression levels of sclerostin in a reactive oxygen species- and tumor necrosis factor-alpha-dependent manner. Journal of Periodontal & Implant Science. 2015;45(4):156.

34. Fuster J, Ouchi N, Gokce N, Walsh K. Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease. Circulation Research. 2016;118(11):1786-1807.

35. Wei W, Zhang X. Expression of ADP and TNF-α in patients with gestational diabetes mellitus and its relationship with pregnancy outcomes. Experimental and Therapeutic Medicine. 2020;20: 2184-2190.

36. Vesentini G, Barbosa A, Damasceno D, Marini G, Piculo F, Matheus S, Hallur R, Nunes S, Catinelli B, Magalhães C, Costa R, Abbade J, Corrente J, Calderon I, Rudge M. Alterations in the structural characteristics of rectus abdominis muscles caused by diabetes and pregnancy: A comparative study of the rat model and women. PLOS ONE. 2020;15(4):e0231096.

37. Colomiere M, Permezel M, Lappas M. Diabetes and obesity during pregnancy alter insulin signalling and glucose transporter expression in maternal skeletal muscle and subcutaneous adipose tissue. Journal of Molecular Endocrinology. 2009;44(4):213-223.

38. Tumurbaatar B, Poole A, Olson G, Makhlouf M, Sallam H, Thukuntla S, Kankanala S, Ekhaese O, Gomez G, Chandalia M, Abate N. Adipose Tissue Insulin Resistance in Gestational Diabetes. Metabolic Syndrome and Related Disorders. 2017;15(2):86-92.

39. Sykiotis G, Papavassiliou A. Serine Phosphorylation of Insulin Receptor Substrate-1: A Novel Target for the Reversal of Insulin Resistance. Molecular Endocrinology. 2001;15(11):1864-1869.

40. Sevillano J, de Castro J, Bocos C, Herrera E, Ramos M. Role of Insulin Receptor Substrate-1 Serine 307 Phosphorylation and Adiponectin in Adipose Tissue Insulin Resistance in Late Pregnancy. Endocrinology. 2007;148(12):5933-5942.

41. Draznin B. Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85 : The Two Sides of a Coin. Diabetes. 2006;55(8):2392-2397.

42. Catalano P. Trying to understand gestational diabetes. Diabetic Medicine. 2014;31(3):273-281.

43. Gao Y, She R, Sha W. Gestational diabetes mellitus is associated with decreased adipose and placenta peroxisome proliferator-activator receptor γ expression in a Chinese population. Oncotarget. 2017;8(69):113928-113937.