The impact of insulin resistance on placental environment in pregnancies complicated with gestational diabetes mellitus

1. Introduction

Gestational diabetes mellitus (GDM) is a pregnancy-related disease which involves both short-term and long-term serious maternal and fetal consequences^(1,2). The condition is defined as a state of hyperglycemia caused by a compromised insulin secretion first identified during pregnancy⁽³⁾, especially in the second trimester⁽⁴⁾.

According to the World Health Organization (WHO, 2013), there is a worldwide consensus regarding the screening and diagnosis of gestational diabetes mellitus⁽⁵⁾. The main recommendation involves undergoing the oral glucose tolerance test (OGTT) performed with 75 g oral glucose, between 24 and 28 weeks of pregnancy⁽⁶⁾. The test is positive if the fasting plasma glucose levels dosed à jeun (≥5.1 mmol/L), at 1 hour (≥10 mmol/L), and/or at 2 hours (≥8.5mmol/L) overcome the cutoff values specified before. Following the International Diabetes Federation, the prevalence of gestational diabetes mellitus is approximately 14%, which represents almost 20 million births per year⁽⁷⁾. There have also been recorded certain variations, depending on the geographical region⁽⁸⁾. Regarding incidence, the scientists have documented higher values in socioeconomically deprived areas⁽⁹⁾; however, it seems that the incidence grows in parallel with the advancement of maternal age and Body Mass Index (BMI).

Moreover, the widening percentage of obese population, especially amongst women of reproductive age, had a consistent contribution. It seems that the promotor of gestational diabetes mellitus is a damaged carbohydrate metabolism in association with pancreatic beta cell dysfunction⁽⁷⁾. These metabolic changes have direct repercussions on the placental morphology and function, which will negatively impact the intrauterine environment⁽¹⁰⁾.  

2. Materials and method

The aim of this literature review is to synthesize the relationship between insulin resistance, which characterizes gestational diabetes mellitus, and the morphological and functional changes that take place in the placental microenvironment.

PubMed, NCBI and Medical Journals were searched for studies written in English regarding the placental impact of insulin resistance in women diagnosed with gestational diabetes mellitus. The literature reviewed was published between January 2018 and April 2024.

The publications were selected taking into account the year of publication and the novelty they came with. The keywords used were: “placenta”, “insulin resista­nce”, “gestational diabetes mellitus”, “pregnancy”, and “histopathology”.

3. Risk factors

The onset of gestational diabetes mellitus is promoted by a cohort of risk factors, of which we can mention diabetes background, history of gestational diabetes mellitus, macrosomia in previous pregnancies⁽¹¹⁾, obesity (BMI >25 kg/m²)⁽¹²⁾, ethnicity and advanced maternal age (above 35 years old)⁽¹³⁾. Interestingly, researchers found an association between gestational diabetes mellitus and increased levels of TPOAb.  Although it’s not clear yet if the TPOAb increases before or after the insulin resistance onset, they certainly have a participation on the disease progress. Moreover, experts recommend the TPOAb screening to be performed from early stages of pregnancy⁽¹⁴⁾. Risk factors related to lifestyle, like physical activity and nutritional aspects, are also important. Also, considering that the literature describes cases of gestational diabetes mellitus developed at nulliparous patients in the absence of any risk factors, genetic susceptibility should also be taken into account. Furthermore, it represents the background over which the other risk factors overlap⁽¹⁵⁾. Regarding environmental factors, domestic violence and an unsuitable familial environment may play an important role. The biochemical substrate is the disturbance of the hypothalamus-pituitary-adrenal axis which increases cortisol plasma concentration and contributes to insulin resistance⁽¹⁶⁾.

It must be noticed that the prevalence of the aforementioned factors differs according to race and geographical region⁽¹⁷⁾. Just as importantly, aspects like polycystic ovary syndrome⁽¹⁸⁾ and several drugs, especially antipsychotic and corticosteroids, must be recorded^(19,20).

4. Insulin resistance

Pregnancy is a natural process that is accompanied by multiple physiological, biochemical and metabolic changes designed to sustain a normal fetal development⁽²¹⁾. All metabolic lines shift from the very beginning under the influence of the placental hormones⁽²²⁾. Regarding carbohydrates, the first weeks of pregnancy are characterized by a decreased fasting plasma glucose and a high insulin sensitivity, a dynamic which will reverse as the pregnancy advances. This shift is stimulated by the hormones and bioactive proteins produced physiologically by the placenta. This mechanism has consequences which will reflect on the pancreatic b-cells, causing processes of hypertrophy and hyperplasia⁽²³⁾.

Thus, pregnancy itself is accompanied by a physiological increased insulin resistance, especially during the second and the third trimesters, having the purpose of sustaining fetal growth and providing fatty acids through lipolysis processes⁽²⁴⁾.

This environment of insulin resistance is first determined by an increase in placental anti-insulinogenic peptides such as placental growth hormone, progesterone, tumor necrosis factor a (TNF-a), and cortisol. In parallel, b-cells function is upregulated through prolactin and human placental lactogen (hPL) growth, which will stimulate the expansion of b-cell mass as an adaptative response, designed to maintain homeostasis⁽²⁵⁾. 

From a molecular approach, the literature mentions the alteration of many metabolic pathways, such as the metabolism of ketone bodies and asparagine, beta-oxidation and glycolysis, an event that has a major contribution on the onset of insulin resistance. Furthermore, TLR4/NF-kB signaling pathway is indispensable for the onset of gestational diabetes mellitus⁽²⁶⁾. T-cell death-associated gene 51 (TDAG51) downregulation seems to promote adipogenesis, hepatic steatosis, weight gain and insulin resistance. Sterol regulatory element-binding protein 1 (SREBP-1) is another transcription factor that regulates the structure of insulin receptor and, also, the expression of genes that are participating in insulin signaling pathways. Its abnormal expression was associated with the pathogenesis of gestational diabetes mellitus⁽²⁷⁾. Immunological factors are also involved, some of them being proinflammatory cytokines, tumor necrosis factor (TNF), adipokines, interleukins, leptin and visfatin⁽²⁸⁾. Leptin is an adipokine produced by the adipose tissue involved in the control of lipidic and carbohydrates metabolism and, also, insulin sensitivity. There are numerous studies that outline the effect of LEP G2548A polymorphism in the onset of the disease⁽²⁹⁾. Distortions of the insulin signaling pathways, genetic alterations of the insulin receptor encoding, and proinflammatory cytokines are the promotors of gestational diabetes mellitus^(28,30).

5. Genetic and epigenetic involvement

In the past few years, genetics and epigenetics have become a subject of great interest regarding their participation in the onset of gestational diabetes mellitus. Apart from deepening the pathophysiological mechanisms, they have also provided new perspectives regarding the detection of women who will develop cardiometabolic condition after child birth⁽³¹⁾. It seems that gestational diabetes mellitus results from the interaction between genetic, epigenetic and environmental factors. Studies revealed the presence of certain genes which alter the normal function of pancreatic b-cells and their endocrine role. The most relevant of them are HNF1A, HNF4A, HNF1B, GCK, IPFI/PDX1, CAPN10, KCNJII, INSR, GLUT4/SCLA4 and ABCC8. Furthermore, epigenetics has its significant contribution, histone modification, DNA methylation and microRNA gene silencing being the main contributors⁽³²⁾.

Placenta has its own epigenetic arrangement, influencing both the mother’s metabolism and the fetal outcome. Gestational diabetes mellitus determines epigenetic changes in the placenta, such as miRNA expression alteration and DNA methylation, both affecting placental function. DNA methylation is a biochemical reaction that involves the transfer of a methyl group to a cytosine base, under the catalytic effect of DNA methyltransferase enzyme, determining the appearance of 5-methylcytosine in the whole genome⁽³³⁾. It has been noticed that women diagnosed with gestational diabetes mellitus have a predisposition to MEG3 hypermethylation, as a placental adaptive response to hyperglycemic intrauterine environment^(34,35).

Regarding microRNAs, they play an important role in the genesis of metabolic disorders. miRNAs dysregulations, such as miR-137 and miR-21-3p, are strongly associated with gestational diabetes mellitus⁽³⁶⁾. They also develop an altered response in the omental adipocytes, predisposing to insulin resistance. Performing plasma dosages, the scientists noticed an increased expression of upregulated microRNA-20a-5p, 17-5p and 16-5p; thus, they proposed them as a diagnostic tool for gestational diabetes⁽³⁷⁾.

Histone modification includes a spectrum of chemical reactions that can be determined by environmental factors or bioactive substances. Reactions such as acetylation, SUMOylation, methylation, phosphorylation and ubiquitylation modify the expression of IG2BP2, MTNR1B and IGF2BP2, genes involved in the control of insulin homeostasis^(38,39).

Arachidonic acid metabolites, especially epoxyeicosatrienoic acids (EETs) synthesized via CYP2J2, CYP2C9, CYP2C8 and EPHX2, are involved in glucose metabolism and insulin sensitivity homeostasis. It seems that the polymorphisms of these genes can perturb carbohydrates homeostasis⁽⁴⁰⁾.

Besides the aforementioned factors, others, like transcription factor 7-like 2 (TCF7L2), potassium voltage-gated KQT-like subfamily member 1 (KCNQ1), insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), melatonin receptor 1B (MTNR1B), glucokinase (GCK), CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1), insulin receptor substrate-1 (IRS1), peroxisome proliferator-activated receptor gamma (PPARG), adrenoceptor beta 3 (ADRB3) and adiponectin (ADIPOQ), belong to the genetic background of gestational diabetes mellitus⁽³⁸⁾.  

6. Biohumoral placental alteration

Placenta is a cross-functional organ which mediates the molecule transportation between the maternal and fetal compartment. Also, it is designed to function as an endocrine gland, synthesizing and secreting bioactive peptides in both compartments^(41,42).

A spectrum of maternal circulating factors, such as leptin, insulin and insulin-like growth factor, have been shown to reshape placental nutrients metabolism in pregnancies complicated by insulin resistance⁽⁴³⁾. Previous studies revealed that increased leptin levels in the early stages of pregnancy were associated with a higher risk of developing gestational diabetes mellitus later in pregnancy⁽⁴⁴⁾. According to literature, leptin amplifies GLUT1 and Aquaporin-9 expression, thus accelerating the rate of glucose absorption and gluconeogenesis. Also, through PI3K and the JACK-STAT signaling cascade, leptin stimulates placental amino-acid absorption⁽⁴³⁾.

Regarding the immunological adjustments, normal pregnancies are characterized by a shift from proinflammatory to an anti-inflammatory milieu. In gestational diabetes mellitus, the balance tilts to a proinflammatory placental environment through an increased concentration of proinflammatory cytokines IL-6, IL-8, IL-1b, CRP and TNF-a, and the decrease of anti-inflammatory ones, especially IL-4 and IL-10^(45,46). Regarding peripheral blood, researchers have noticed a higher concentration of IFN-g, Th2, Th17, CD4⁺ and CD8⁺ T lymphocytes. In addition, diminished levels of cytotoxic T lymphocytes and T regulators cells were registered⁽⁴⁷⁾.

To summarize, it seems that gestational diabetes mellitus is endorsed by the alteration of many placental genes which will lead to protein conformational adjustments. These biochemical distortions reflect on the placental morphology, producing histopathological changes which will be further discussed⁽⁴⁸⁾.
 

7. Histopathological adjustments

Literature reveals that morphological placental changes appear despite a rigorous glycemic control. It seems that six out of seven women will develop vascular dysfunction regardless of the diabetes severity⁽⁴⁹⁾. Placenta is an important barometer that can provide information concerning the fetal environment. An adequate placental development is mandatory for a regular fetal growth. The placentas obtained from pregnancies complicated by gestational diabetes mellitus suffered both structural and functional changes. Those changes are determined either by the hyperglycemic milieu, or by an abnormal trophoblastic invasion, oxidative stress or chronic inflammation, all of them being specific to diabetes mellitus^(10,50).

It was found that placentas obtained from women diagnosed with diabetes were larger and weighed more than the ones obtained from normal pregnancies⁽⁵¹⁾. Placental shape has also encountered some changes, most of the placentas being oval or irregular⁽⁴⁹⁾. Also, the surface area, volume, central thickness and number of cotyledons were increased⁽⁵²⁾.

Regarding the microscopic aspects, they included stiffen basement membrane and irregular blood vessels with inflated endothelial cells, often with narrowed or even obstructed vascular lumen. Histological features, like relief tortuosity⁽⁵³⁾, immature villi, vascular thrombosis, diffuse calcification, villous congestion, inflammation and necrosis, are often present⁽⁵⁴⁾. Other characteristics described were an increased volume of the cyto- and syncytiotrophoblast, an expanded intervillous space, extended fibrinoid areas and collagen fibers, glycogen storage and a higher apoptotic index⁽⁵²⁾.

Regarding electron microscopy, the microvilli from the surface of syncytiotrophoblast cells appeared dis­organized, shortened and dispersed⁽⁵⁵⁾.

This structural reshape leads to various degrees of placental dysfunction which will place these pregnancies in the high-risk category⁽⁴⁹⁾.

8. Clinical outcome

Gestational diabetes mellitus is a pregnancy-associated condition with potential severe consequences, impacting both the mother and the fetus⁽⁵⁶⁾. Regarding short-term fetal complications, these include fetal growth abnormalities, such as macrosomia, intrauterine growth restriction, small-for-gestational-age fetuses, an increased risk of fetal structural faults^(57,58), and iron deficiency anemia⁽⁵⁹⁾. In terms of long-term complications, among them there can be mentioned the increased risks of developing a cohort of metabolic related conditions, cardiovascular disease, metabolic syndrome, obesity, and type 2 diabetes⁽⁵⁷⁾.

Interestingly, fetal consequences are more serious in women who did not receive insulin treatment compared to those who did. Therefore, children born from mothers who underwent insulin treatment were predisposed to develop respiratory distress and jaundice. Also, they had an increased rate of neonatal intensive care unit admission. On the other hand, babies who were born from mothers who did not undertake insulin treatment experienced complications such as an increased rates of caesarean delivery, preterm parturition, and low Apgar scores⁽⁶⁰⁾. Excepting polyhydramnios⁽⁶¹⁾ and pregnancy-induced hypertension, most maternal conditions are long-term complications. Besides type 2 diabetes, which develops in approximately half of cases within ten years from the moment of childbirth, the other ones progress in the following decades – mainly dyslipidemia, insulin resistance, coronary artery calcification, and atherosclerosis⁽⁶²⁾. 
 

9. Conclusions

Gestational diabetes mellitus is a pregnancy-related disease which is diagnosed in the second trimester by performing OGTT. It is characterized by an impaired insulin sensitivity that leads to a fetal hyperglycemic environment. All the metabolic and biohumoral alterations are triggered by certain signaling pathways, phenomena which overlap on the individual background. The result is represented by an impaired placental morphology, including immature villi, vascular thrombosis, diffuse calcification, inflammation, and necrosis. All these will influence the pregnancy course, determining premature birth, impaired fetal growth, still births, shoulder dystocia, and an increased caesarean section delivery rate. Furthermore, on the long term, both the mother and the baby are exposed to an increased risk of developing type 2 diabetes, metabolic syndrome, and cardiometabolic disease. Despite everything known up to now, there are many things to be researched about, especially the possibilities of preventing the long-term complications. 

Corresponding author: Nicolae-Gabriel Marina, e-mail: nicolae-gabriel.marina@rez.umfcd.ro

Conflict of interests: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.