Maternal pregestational diabetes as an factor in the genesis of congenital malformations of the fetus

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Abstract

This review article summarizes the results of modern clinical studies performed domestically or abroad, which provide information on maternal pregestational diabetes (type 1 or 2) shaping a spectrum of congenital malformations of the fetus. Advances in the treatment of diabetes mellitus have reduced the risk of fetal congenital malformations in pregnant women with the disease, but an increase in its incidence among women of childbearing age indicates that this cause of congenital malformations is becoming more relevant every year. This review article presents four diabetes-mediated pathways for the genesis of fetal congenital malformations: those associated with metabolic imbalance or oxidative stress, genetically mediated and caused by insufficient inhibition of apoptosis. Thus, based on clinical studies and meta-analysis over the past ten years, it has been demonstrated that women with pregestational diabetes mellitus are at the highest risk of developing fetal congenital malformations. Achievement of diabetes compensation and physiological nutritional status in such patients determines the favorable course of all stages of pregnancy.

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About the authors

Nodari D. Shengelia

Center for Family Planning and Reproduction

Email: nod802210@yandex.ru
ORCID iD: 0000-0003-0677-494X
SPIN-code: 7495-9480

MD

Russian Federation, 3 Mendeleevskaya Line, Saint Petersburg, 199034

Olesya N. Bespalova

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Email: shiggerra@mail.ru
ORCID iD: 0000-0002-6542-5953
SPIN-code: 4732-8089
Scopus Author ID: 57189999252
ResearcherId: D-3880-2018

MD, Dr. Sci. (Med.)

Russian Federation, 3 Mendeleevskaya Line, Saint Petersburg, 199034

Margarita O. Shengelia

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Author for correspondence.
Email: bakleicheva@gmail.com
ORCID iD: 0000-0002-0103-8583
SPIN-code: 7831-2698
Scopus Author ID: 57203248029
ResearcherId: AGN-5365-2022

MD

Russian Federation, 3 Mendeleevskaya Line, Saint Petersburg, 199034

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Supplementary files

Supplementary Files
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1. Fig. 1. Balance of p53 activity upon Pax3 expression. Before differentiation, early embryonic cells are proliferative (self-renewing), have the potential to differentiate into many cell types (pluripotent), and fuel metabolism is predominantly anaerobic (glycolytic). After terminal differentiation, cells become non-proliferative (post-mitotic) and can no longer differentiate into other cell types (fixed cell type), and fuel metabolism is predominantly aerobic (oxidative). p53 activation promotes terminal cell differentiation. Pax3 may be required to balance p53 activity by maintaining the characteristics of undifferentiated cells until the developmental stage at which terminal differentiation should occur. In addition to neuroepithelium and neural crest, progenitor cells of other embryonic organs may contain other regulators of the phenotype of undifferentiated cells [10]

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2. Fig. 2. Biochemical / molecular pathway in which maternal hyperglycemia can cause birth defects. Excessive glucose transported to the embryo is actively metabolized. The increased glycolytic flux stimulates the synthesis of glucosamine-6-phosphate, which inhibits the activity of glucose-6-phosphate dehydrogenase, which reduces the synthesis of nicotinamide adenine dinucleotide phosphate and subsequently reduces the synthesis of reduced glutathione. Also, active glucose uptake stimulates the diacylglycerol / protein kinase pathway, which is able to inhibit the synthesis of nicotinamide adenine dinucleotide phosphate and reduced glutathione. Increased glucose metabolism, including aerobic metabolism, increases oxygen consumption faster than it can be delivered, which stimulates superoxide production. The increased production of superoxide increases the production of hydrogen peroxide, which, due to the reduced availability of reduced glutathione, leads to an increase in the production of the hydroxyl radical rather than water. The resulting oxidative stress suppresses the expression of critical regulatory genes (such as Pax3) and promotes derepression of the cell cycle regulator (such as p53), leading to apoptosis. The loss of a critical mass of organ progenitor cells that are at the stage of active formation leads to the formation of congenital malformations of the fetus [27]. NADP+ — nicotinamide adenine dinucleotide phosphate; NADPH is reduced form of NADP+ Сигнальный путь мембранных фосфолипидов Membrane phospholipid signaling pathways

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3. Fig. 3. Possible targets for the prevention of diabetic embryopathy. Maternal hyperglycemia leads to increased oxidative stress through the production of reactive oxygen species, partly produced by mitochondria. The reactive oxygen species produced cause membrane damage, which in turn activates programmed cell death through pro-apoptotic proteins. Upregulation of pro-apoptotic proteins leads to endoplasmic stress and cell death. Abnormal apoptosis causes malformations of the main organ systems of the developing fetus [23]

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