Effect of Gestational Diabetes Mellitus on the Growth, Development, and Stem Cells of Offspring : Maternal-Fetal Medicine

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Effect of Gestational Diabetes Mellitus on the Growth, Development, and Stem Cells of Offspring

Zhang, Meihua1; Ma, Munan2; Wang, Jinping1; Wang, Yijun2; Yang, Xinrui1; Fu, Songtao2,3,4,∗

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Maternal-Fetal Medicine 5(1):p 31-35, January 2023. | DOI: 10.1097/FM9.0000000000000130
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The development of a cellular organism begins with a zygote and follows a sequence of events. Importantly, in multicellular organisms, stem cells possess the ability to differentiate. The stem cell niche is a specialized and dynamic microenvironment, playing a critical role in maintaining the properties of stem cells.1 Over the years, various important aspects of the stem cell niche have been revealed, including cell–cell interaction, cell–extracellular matrix interaction, and a large number of signaling factors. It was found that a high-glucose microenvironment significantly affects the biological activity of stem cells.2 Gestational diabetes mellitus (GDM) only occurs during pregnancy. The reported morbidity rate associated with GDM ranges from 1% to 14% worldwide; in China, this rate ranges from 1% to 5% and has significantly increased in recent years.3 GDM causes severe impairment to the health status of offspring and leads to several complications, such as macrosomia, respiratory distress syndrome, polycythemia, hyperbilirubinemia, cardiovascular diseases, congenital abnormality, etc.4 A study also indicated that GDM consistently influences the long-term health status of offspring, and is an underlying risk factor for glucose metabolism disorder, obesity, high blood pressure, and cognitive dysfunction.5 However, the exact mechanisms involved in this process remain unknown. In this review, we discuss the effects of GDM on the growth, development, and stem cells of offspring.

Effects of GDM on fetal health status

GDM increases the risk of fetal overweight and obesity

In pregnant women with GDM, the long-term intrauterine high-glucose environment stimulates the proliferation of islet cells and insulin secretion, resulting in hyperinsulinism and fetal macrosomia. A study demonstrated that fetuses exposed to the GDM environment during pregnancy may present insulin sensitivity during childhood.6 Moreover, hyperglycemia and hyperinsulinism increase fat and protein storage in offspring, resulting in overgrowth; they also influence the risk of overweight and obesity during early childhood.7,8 Another study also demonstrated that even offspring of GDM women with a normal birthweight are at a high risk of developing obesity by the age of 10 years.9 Therefore, glucose management is important during pregnancy.

GDM causes abnormal fetal carbohydrate and lipid metabolism

Fetal energy metabolism can be affected by the high-glucose environment of GDM. Offspring of women with GDM showed abnormal expression of insulin-related pathway-controlling genes; fetal glucose metabolism was also abnormal.10 Large amounts of nutrients were used to maintain the level of metabolism, resulting in an increased risk of fetal hypoglycemia. Research also indicated that brain cells cannot maintain the normal oxidation process at low levels of blood glucose. This increases the likelihood that offspring will develop neurological diseases, such as brain damage. Therefore, intervention in women with GDM before pregnancy is of great importance.

Moreover, GDM causes abnormal lipid metabolism, such as a decrease in high-density lipoprotein and an increase in total cholesterol, triglycerides, and low-density lipoprotein.11 Zhang et al.12 demonstrated that the male offspring of hyperglycemic rats had high birth weight, significant weight gain, and elevated levels of triglycerides. These findings indicated that GDM may be a high risk factor for hepatic lipid metabolic diseases.

GDM causes fetal hypoxia and distress

Pathological changes were found in placenta capillaries due to the intrauterine high-glucose environment. These alterations significantly affect the blood supply and eventually cause fetal hypoxia. A study demonstrated that the changes in placental structure, particularly the microvilli in GDM, are consistent with those observed in fetal hypoxia, indicating that GDM can cause hypoxia.13 In addition, hyperinsulinemia induces metabolism acceleration, resulting in a relative hypoxic state.14 Fetal distress produces large amounts of erythropoietin and increases the number of nucleated erythrocytes (ie, 2–3–fold higher compared with that noted in fetuses born to healthy pregnant women). The oxygen content in blood increases after birth, a large amount of red blood cells are damaged, and bilirubin is released, eventually leading to neonatal hyperbilirubinemia.15

The development of the fetal respiratory system occurs at a relatively late stage. Glucocorticoids can promote the maturation of alveolar surfactant, maintain lung surface tension, and improve fetal lung function. However, excessive insulin causes glucocorticoid antagonism and reduces the secretion of fetal alveolar surfactant. These effects impair the development of the neonatal respiratory system, leading to neonatal asphyxia.

Furthermore, GDM can cause a wide range of vascular effects, including damage to umbilical artery endothelio-cytes and narrowing of the fallopian tube. These effects also lead to insufficient blood supply, fetal ischemia and hypoxia, intrauterine respiratory distress, embryocardia disappearance, and fetal death.16,17

GDM causes fetal cardiac abnormalities

Animal studies showed that the blood pressure of hyperglycemic pregnant female mice was higher compared with that of the healthy group. These data suggested that prolonged exposure to an intrauterine high-glucose environment may increase the rate of hypertension in offspring.18 A follow-up study19 also indicated that the blood pressure of offspring of women with GDM was significantly higher than that measured in the healthy group. Another study also reported that male offspring of women with GDM are more likely to develop high systolic blood pressure than female offspring.20 However, the association between diastolic blood pressure and maternal GDM was not statistically significant. Thus, further investigation is warranted to confirm this relationship.

Adenosine 5′-monophosphate-activated protein kinase (AMPK), a key molecule in the regulation of bioenergy metabolism, avoids oxidation of fatty acids and alleviates myocardial ischemia–reperfusion (I/R) injury. There was no significant difference in heart rate-pressure product observed between the normal pregnancy and GDM groups before I/R.18 However, following I/R, the heart rate-pressure product was significantly reduced and the systolic function of the heart was impaired in the GDM group. Furthermore, after I/R, the level of AMPK and acetyl-coenzyme A phosphorylation in the GDM group was lower than that recorded in the normal pregnancy group. These findings suggested that the intrauterine high-glucose environment of GDM may be an important factor in myocardial injury caused by the incomplete activation of AMPK.

Moreover, GDM induces cardiomyocyte hypertrophy by affecting cell differentiation.21 A high-glucose environment increases the synthesis of cardiac proteins, glycogen, and fat in the heart, leading to cardiac enlargement. At the same time, the fetal ventricular wall and ventricular septal is thickened, the cardiac chamber is decreased, and myocardial compliance is relatively weakened, eventually causing cardiac dysfunction.22 It has been demonstrated that the changes in the function and structure of the heart can persist in infancy.23 Therefore, effective prediction of GDM and appropriate clinical intervention are important for reducing the risk of myocardial diseases. Moreover, modest exercise during pregnancy can significantly reduce the risk of congenital heart defects by reducing the levels of oxidative stress.24

Abnormal electrocardiograms have also been observed in offspring of pregnant women with GDM, revealing arrhythmias, a widened QRS time, and increased QRS voltage. Moreover, the rate of an abnormal fetal electrocardiogram in pregnant women with GDM reaches 56%, which is markedly higher than that recorded in the healthy group.25

GDM impairs the development of the fetal nervous system and intelligence

Intellectual development is an important part of neonatal development. Fraser et al.26 investigated 723,775 males aged 16–18 years, and concluded that GDM was associated with a decline in cognitive ability. Adane et al.27 reported that the negative effects on the development of cognitive ability are directly linked to the severity of GDM. Moreover, Wang et al.28 showed that the scores of fine movement, adaptation, language, social skills, and total development quotient of offspring of women with GDM were lower than those noted in the healthy group. Thus, clinical attention should be paid to the intellectual development of offspring of women with GDM. Continuous monitoring and interventions should be carried in the early stage of the disease to prevent cognitive impairment.

The advanced neural structures of the fetus begin to form at mid-to-late gestation. At this stage, an intrauterine high-glucose and high-ketone environment will lead to abnormal brain development or serious brain nerve injury in the fetus, and cause cognitive and behavioral dysfunction. In the absence of intervention for the correction of the levels of blood glucose, damage to brain tissue occurs. This causes permanent injury and seriously threatens neural development in the brains of newborns.29

Research showed that the levels of blood glucose in pregnant women with GDM influence the probability of nervous system abnormalities in their newborns. Hyper-glycemia also induces oxidative stress response, promotes the production of reactive oxygen species, and causes perinatal nervous system malformation.30 Meanwhile, endoplasmic reticulum stress can also damage the function of autophagy, disrupt the normal signal transduction of nerve epithelial cells, lead to cell apoptosis, and eventually cause neural tube defects.31 Antenatal screening can assist in the identification of some neural malformations. Effective control of diabetes is important in reducing the risk of fetal neural malformations.32

We summarized the effects of GDM on the growth and development of offspring (Table 1). According to the evidence, GDM exerts significant and long-term effects on the growth and development of offspring.

Table 1 - Effects of gestational diabetes mellitus on fetal growth and development.
System Symptom Cause
Physical development Overweight, obesity Hyperglycemia and hyperinsulinism cause fat and protein storage
Metabolism Hypoglycemia, abnormal lipid metabolism Large amount of nutrition consumed to maintain metabolism level
Respiratory Fetal hypoxia, neonatal asphyxia, intrauterine respiratory distress Pathological changes in capillaries, changes in placental structure, hyperinsulinemia causes metabolism acceleration and glucocorticoid antagonism
Cardiovascular Hypertension, myocardial injury, cardiac functional and structural abnormalities, electrocardiogram-detected abnormalities An intrauterine high-glucose environment causes hypertension, incomplete activation of AMPK, cell differentiation, and cardiac abnormalities
Nervous Cognitive ability decline, brain nerve injury, nervous system malformation A high-glucose and high-ketone environment induces oxidative stress, as well as the production of ROS and endoplasmic reticulum stress
AMPK: Adenosine 5′-monophosphate-activated protein kinase; ROS: Reactive oxygen species.

Effect of GDM on progeny stem cells, growth, and development

Stem cells have unique self-renewal ability and strong differentiation potency. Owing to variations in their differentiation potency, they are classified into pluripotent, multipotent, and unipotent stem cells. The microenvironment also plays an important role in stem cell differentiation, regulating their survival and functioning by producing factors.33 These factors activate the signaling pathway and eventually lead to stem cell differentiation, proliferation, or apoptosis.1 Overall, a considerable body of evidence supports the hypothesis that the level of maternal metabolism during gestation can reprogram the metabolic parameters of offspring.

Algaba-Chueca et al.34 isolated amniotic mesenchymal stem cells (AMSCs) from the placentas of pregnant women with GDM and normal glucose tolerance. The results showed that, in the GDM-AMSC group, the proliferation and osteogenic potential decreased, whereas the invasive and chemotactic capacity increased. These findings indicated that GDM may affect the health of offspring by exerting an effect on stem cell function. Gene expression analyses revealed that the expression levels of inflammatory mediators decreased in GDM-AMSCs, and these factors are associated with the development of insulin resistance, type 2 diabetes, obesity, and atherosclerosis.35 Importantly, exposure of control AMSCs to a GDM-like environment in vitro resulted in similar effects to those observed in GDM-AMSCs.36 A study also found that the expression of inflammatory genes in AMSCs was associated with maternal insulin sensitivity and fetal metabolic parameters. These findings indicated that GDM causes metabolic dysfunction in offspring by impacting the function of stem cells.34

The effect of a high-glucose microenvironment on stem cells in diabetes has been widely investigated through in vitro experiments; it is hypothesized that similar pathological phenomena may occur in GDM progeny. An intrauter-ine high-glucose environment also increases the apoptosis of stem cells and accelerates senescence. It has been shown that the proliferation and differentiation abilities of progeny stem cells were decreased in such an environment.5 The accumulation of advanced glycosylation end products in a high-glucose microenvironment leads to changes in the biological activities of adipose-derived stem cells through various pathways, including cell surface markers, proliferation, migration, multi-lineage differentiation, secretory function, and tissue repair ability.2

Effects of GDM on the bone marrow mesenchymal stem cells (BMSCs) of offspring

Osteoblasts play an important role in bone growth, and most of them are derived from multipotent BMSCs. BMSCs have multidirectional differentiation potential and self-renewal ability, which are important for bone formation and bone tissue regeneration. An intrauterine high-glucose environment can cause BMSC aging. A study showed that oxidative stress caused by hyperglycemia can damage the DNA structure, trigger damage response, or directly regulate aging-related signaling pathways to promote cellular senescence.37 Another study also indicated that the proliferative and migratory ability of BMSCs in the high-glucose group were significantly decreased, while the rate of apoptosis was increased.38 Moreover, a high-glucose environment may reduce the osteogenic differentiation ability of BMSCs.

In addition, the interaction between diabetes and the bone marrow microenvironment has attracted considerable attention. Mobilopathy refers to changes in the bone marrow microenvironment and its function caused by diabetic microangiopathy, neuropathy, fat deposition, inflammation, and bone resorption. These alterations impair the proliferation, multidirectional differentiation, and other functions of BMSCs, as well as worsen the occurrence and development of various complications associated with diabetes. Cell biology studies have shown a decline in circulating hematopoietic stem cells, endothe-lial progenitor cells, and other precocious cell types in the bone marrow, as well as impairment of the function of bone marrow-derived progenitor cells.39,40

Extensive pathological changes in the bone marrow and the shortage of circulating stem cells may be linked to the progression of diabetes and death. In diabetes, myeloid hematopoiesis is dominant in bone marrow tissue, while stem cell lines are inhibited. The mobilization of mesenchy-mal stem cells (MSCs) is reduced, whereas that of myeloid cells is enhanced. These effects result in pro-inflammatory conditions and sustained inflammation in the body.41

GDM significantly affects the proliferation and differentiation abilities of the stem cells of offspring

Epidemiological and clinical evidence has shown that exposure of the fetus to hyperglycemia during pregnancy is associated with several diseases. Nevertheless, the underlying mechanisms of maternal and fetal diabetes remain poorly understood.42 Barker et al.43 hypothesized that exposure to an adverse environment leads to programmed adaptation in the fetus and influences the multidirectional differentiation ability of stem cells.

High glucose levels significantly inhibited the prolifer-ative ability of osteoblasts, and induced the differentiation of osteoblasts to adipogenesis. Diabetes can lead to abnormal bone metabolism in humans and animals, affect bone structure and bone mass, lead to osteoporosis and insufficient bone regeneration, and increase the risk of fracture.44 Yang et al.45 showed that long-term cultivation of MSCs in the presence of high glucose levels reduced the cartilage and increased the adipose tissue. The enhanced adipogenic capacity may cause metabolic dysfunction in infants of women with GDM.

Neural stem cells are neural tissue-specific stem cells with strong ability for replication and differentiation. Zhang et al.46 simulated the internal environment of diabetes, and found DNA fragmentation in neural stem cells in a high-glucose environment. Moreover, the rate of apoptosis was significantly increased, indicating that high glucose induces the apoptosis of neural stem cells. Other findings have shown that GDM causes aberrant differentiation of astrocytes in the mouse embryonic brain.47

Amrithraj et al.5 revealed that GDM significantly affects the proliferation of human umbilical cord-derived stem cells. Kong et al.42 found that GDM decreased the proliferative rate of umbilical cord MSCs, and reported premature death of these cells cultured in medium with a high concentration of glucose.

In conclusion, hyperglycemia in pregnant women with GDM exerts a series of effects on fetal stem cells (eg, reduction of the increment and storage of stem cells, damage to stem cells, adipogenic differentiation, and premature maturation). However, the effects of GDM in pregnant women on the differentiation ability of stem cells should be further investigated.


An intrauterine high-glucose environment significantly affects the growth and development of important systems in the human body. Offspring of women with GDM are more likely to be overweight, obese, have an abnormal metabolism, and develop dysfunctions of important organs and systems. The use of effective clinical methods can help reduce the harm to offspring.

An intrauterine high-glucose environment can lead to changes in the multi-differentiation proficiency of intra-corporal stem cells. This was demonstrated by their decreased proliferative and osteogenic ability, increased adipogenic abilities and rate of apoptosis, and occurrence of premature death. Abnormal cell mobilization results in pro-inflammatory conditions and long-term inflammation in the body. However, thus far, few studies investigated the effects of GDM on progeny stem cells, growth, and development. Therefore, further studies are warranted.

According to the available evidence, stem cells may be a reliable predictor of the long-term effects of GDM on offspring. The implementation of effective methods for the prevention and treatment of GDM will assist in improving the function of stem cells of offspring, and reduce the long-term consequences to growth and development.



Conflicts of Interest



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Diabetes, gestational; Growth and development; Offspring; Stem cells

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