Role of insulin resistance in the mechanisms of adaptation and development of disease in postpartum and early neonatal periods

The function of regulation of energy supply to the organism under normal and pathological conditions is provided by an evolutionarily conserved phenomenon of insulin resistance (IR) or a change in tissue sensitivity to insulin [1]. There is an increase in mortality from complications of the so-called diseases of civilization (arterial hypertension, obesity, type 2 diabetes mellitus (DM), variety of cancers) accompanied by IR syndrome or metabolic syndrome (MS), the complexity and uncertainty of the molecular bases of both normal and pathological IR. Therefore, this research area has become one of the most relevant among doctors and scientists, and the results of the studies are of practical value in healthcare. [2].

IR and compensatory hyperinsulinemia play a key role in the mechanisms of adaptation, especially in the transitional periods of life (antenatal, pubertal, gestational, post-reproductive) which are associated with active functional restructuring [3]. The role of pathological IR can be clearly seen in the development of gynecological diseases (precocious puberty, polycystic ovary syndrome (PCOS), endometrial hyperplasia, endometriosis, ovulatory dysfunction, pathological course of perimenopause, endometrial cancer, breast cancer, etc.), obstetric complications (recurrent miscarriage/fetal loss syndrome, gestational diabetes mellitus (GDM), preeclampsia, placental insufficiency, preterm birth), the short-term and long-term pathologies of the postpartum period, the formation of morphofunctional features of the fetus and newborn [4]. In clinical practice, it is necessary to understand the relationship between the phenotypic manifestations of gestational and postpartum IR and hyperinsulinemia. The true causes (genetic, epigenetic, integrative nature) of IR are not clear, since eating disorders, lifestyle, physical inactivity, stress, hormonal dysregulation are only resolving factors. Knowledge of the causes and consequences of pathological IR is extremely important for the development of personalized programs aimed at prevention and treatment of pathologies of the reproductive system.

The methodological basis of the analysis was the study of the Russian and foreign literature on this issue in the databases PubMed, Elibrary.ru, Cochrane, Medline, Hinari, Scopus for the period 2015–2021.

The relationship of insulin resistance with adaptation processes and pathogenesis in the postpartum period

In the postpartum period, there is an involution of gestational changes in all systems of the mother’s body; at the same time, pregnancy and childbirth leave behind “traces” that do not disappear during the woman’s life [5]. The greatest morphofunctional restructuring is observed in the endocrine, reproductive systems and mammary glands. Structural and functional maturation of the mammary glands occurs by the end of pregnancy (gestational mammogenesis); lactogenesis occurs in the first 7–10 days of the postpartum period, reaching its peak during lactopoiesis. During pregnancy the main mechanism of energy and nutrient supply of the fetus refers to normal IR and compensatory hyperinsulinemia which direct the flow of glucose, free fatty acids, amino acids into fetoplacental complex; in the postpartum period this function is performed by breastfeeding [6]. The metabolic effect of prolactin on breast tissue manifests as stimulation of glucose uptake and lipogenesis [7]. Prolactin enhances mRNA transcription, promotes the synthesis of casein and α-lactalbumin and has a systemic effect on carbohydrate and fat metabolism [6, 7]. There are two points of view on the relationship of gestational normal or pathological IR with postpartum IR through prolactin. It is believed that prolactin prolongs the effect of IR which forms in the gestational period under the influence of placental contra-insular factors (hormones, in particular, placental lactogen, pregnancy proteins, oxidative molecules, pro-inflammatory cytokines, etc.), in the postpartum period in non-mammary tissues (liver, muscles, adipose tissue). The mammary glands can absorb more glucose than other organs in case of peripheral IR, regardless of the level of insulin. Such heterogeneity of insulin sensitivity of various organs and systems in the postpartum period increases the availability of biosubstrates for milk secretion [6]. At the stages of lactogenesis and lactopoiesis, milk production becomes the dominant metabolic process in puerperas; this process is characterized by the fact that non-mammary tissues adapt to meet the metabolic needs of the mammary glands through the regulatory influence of IR [7]. The opposite point of view is that systemic mechanisms of increased sensitivity to insulin are activated during lactation. This statement is based on the results of separate observational studies which show that full lactation is associated with a decrease in the incidence of type 2 diabetes in the mother (regardless of ethnicity/race), gestational glucose tolerance and changes in body weight after childbirth [7]. It should be noted that both points of view do not contradict each other since the role of IR in adaptive processes, especially under metabolic load, is clearly seen in the synchronous interaction of vital organs [1].

Significant hemodynamic, metabolic and hormonal gestational changes are a prerequisite for the development or exacerbation of previously asymptomatic diseases, both during pregnancy and in the postpartum period [5, 8]. GDM is a transient condition and an important modifiable risk factor for adverse pregnancy outcomes due to pathological IR and mild compensatory hyperinsulinemia with glucose often returning to normal shortly after delivery. However, women with GDM have a 40% increased risk of developing type 2 diabetes within 10–15 years [9]. Women with GDM often have subclinical metabolic dysfunction prior to conception. Even in normal pregnancy, due to a significant decrease in insulin sensitivity, pregravid (initial) IR becomes aggravated and when combined with dysfunction of β-cell of the pancreas it leads to the development of gestational diabetes and later type 2 diabetes [10]. The subject of the relationship of GDM subtypes (with various degrees of IR) with different phenotypic manifestations and differentiated risk of the postpartum period is under intense research nowadays. GDM with high IR is an unfavorable metabolic profile with high levels of glycemia, body mass index (BMI), blood pressure and atherogenic lipids, pathology of fetoplacental complex, in contrast to women with GDM and moderate glucose tolerance. Risk stratification of women with GDM with high IR makes it possible to predict the nature of hyperglycemia and development of type 2 DM in the postpartum period [11].

GDM is often not only a precursor of type 2 DM, but also a marker of cardiovascular diseases in women [12–14]. The prevention of type 2 diabetes with the help of changes of the postpartum lifestyle and the use of pharmacotherapy in women with GDM has been shown in a number of studies. A systematic review and meta-analysis (2019) presented data on the association of breastfeeding with a reduction in the postpartum risk of GDM progression to type 2 diabetes [14]. In this clinical setting, breastfeeding is valuable as an inexpensive preventive measure to prevent both type 2 diabetes, prediabetes and associated metabolic disorders [13].

The impact of the microbiome on human health is becoming apparent. It has been shown that patients with obesity and type 2 diabetes differ in the composition of the fecal microbiota from healthy controls. In pregnant women, changes in the microflora were recorded from the I to III trimester, as well as in the postpartum period [15]. Microbiota has been proved to be more diversified in late pregnancy compared to the postpartum period. In the later stages of complicated gestation, there is a connection between pathological IR, pro-inflammatory status and their phenotypic manifestations with a decrease in the diversification of the intestinal microbiota [9, 16]. M.K.W. Crusell et al. found an association of GDM with abnormal gut microbiota and similarities with the microbiota of patients with type 2 diabetes [9]. The proven relationship between the microbiome and GDM can be used for postpartum rehabilitation. The gut microbiota is considered to be a biomarker for early detection of GDM and a potential target for modification to reduce the risk of transforming GDM to type 2 diabetes in the postpartum period [17].

Type 2 diabetes is a progressive condition characterized by severe pathological IR and pancreatic β-cell dysfunction, persistent hyperglycemia, dyslipidemia, development of obesity, hypertension, cardiovascular diseases and chronic kidney disease [18]. Pregnancy rates among women with type 2 diabetes have increased by 46% over 10 years and are associated with the risk of congenital anomalies, stillbirth, and neonatal mortality [19]. Every third women with type 2 diabetes showed an increase in pathological IR, atherogenic lipid profile, proinflammatory and antiangiogenic state, endothelial-hemostasiological dysfunction. Such an increase during pregnancy contributes to the progression of type 2 diabetes in the postpartum period, the development of ovulatory dysfunction and infertility and rising cancer risk. Therefore, as a global health problem type 2 diabetes requires the development of secondary preventive measures in the postpartum period due to its metabolic and reproductive complications [20].

According to the study of S.E. Power et al., women with impaired insulin sensitivity have a higher frequency of operative delivery which leads to a higher risk of infectious and inflammatory postpartum diseases [21]. K. Benhalima et al. showed that women with pathological IR gave preterm birth more frequently which was accompanied by purulent-septic complications with its subsequent treatment; the patients also experienced iron deficiency anemia and neonatal hypoglycemia [22]. The authors concluded that impaired sensitivity to insulin was associated with infectious and inflammatory complications of the postpartum period both after preterm and full-term delivery.

Cardiovascular diseases in women are a serious threat not only during pregnancy, but also in the postpartum period causing up to 18% of deaths worldwide [23].

Postpartum hypertension, both gestational and de novo, can provoke all maternal complications and negative outcomes, such as eclampsia, disseminated intravascular coagulation (DIC) syndrome, pulmonary edema, HELLP syndrome, hemorrhage and thrombosis with manifestations of organ and systemic failure [23, 24]. Most cases of postpartum hypertension are due to gestational or chronic hypertension and preeclampsia. The removal of the placenta as an inducer of pathological IR, hyperinsulinemia and secondary associated inflammatory and thrombotic statuses, oxidative stress, hyperleptinemia, leptin resistance, hypersympathicotonia, antiangiogenic effects is a therapeutic measure for these conditions. In 50–85% of pregnant women with hypertension, blood pressure returns to normal by day 7 after delivery. In some cases, hypertension in the postpartum period can persist from 6 to 12 weeks which is more common in women with severe preeclampsia, high BMI, early gestational hypertension. Every fourth woman with gestational hypertension needs antihypertensive treatment two years after the end of pregnancy [23].

Postpartum preeclampsia is increasingly recognized as an important cause of maternal morbidity and mortality in the postpartum period. It remains unclear whether postpartum preeclampsia (eclampsia) represents a separate entity from preeclampsia during pregnancy. There is a need to improve the terminology regarding preeclampsia immediately after delivery (within the first 48 hours) and postpartum preeclampsia with delayed onset, namely from 48 hours to 6 weeks after delivery. Most reports of postpartum preeclampsia are limited to a small number of observations; according to the literature, its prevalence ranges from 0.3% to 7.5% of all pregnancies [25, 26]. Postpartum preeclampsia is accompanied by the development of diabetogenic and atherogenic mechanisms during pregnancy which are aimed at energy and nutrients supply of the fetus, and by long-term antiangiogenic and endothelial and hemostasiological disorders. Therefore, postpartum preeclampsia may be associated with a higher risk of maternal morbidity, though it remains an understudied complication [24, 27]. Understanding the mechanisms of increase in pathological IR, hyperinsulinemia and associated alternative factors of the postpartum period is important for developing measures to reduce maternal morbidity and mortality among puerperas [24, 26, 27].

Pathological IR accompanies not only type 2 diabetes, but also non-diabetic chronic kidney disease (CKD) increasing this way the risk of cardiovascular diseases, premature death, progression of renal failure. The mechanisms underlying pathological IR in CKD are not fully understood. The study by W. Cao et al. showed involvement of CKD in the pathogenesis of the renal/adipose-cerebral-peripheral sympathetic reflex which activates the RAS/ROS axis to stimulate IR through local inflammation and impaired Glut4 metabolism [28]. The relationship between CKD and pathological IR and hyperinsulinemia characteristic of preeclampsia is also complex and ambiguous. On the one hand, preeclampsia may be a cause or marker of CKD in the future, on the other hand, patients with CKD have an increased incidence of preeclampsia and many predisposing factors, such as diabetes, obesity, MS, and hypertension, which are common in preeclampsia and CKD. Preeclampsia is actually a clinical indicator of kidney disease. In the classical sense, renal dysfunction associated with preeclampsia is reversible within 1–3 months after delivery regardless of their severity, but this may not occur in all patients. Therefore, it is necessary to conduct prospective cohort studies which are probably the only way to determine the risks associated with CKD and make it possible to differentiate the consequences of preeclampsia: whether it is an underlying kidney disease or a lesion associated with the pathogenesis of secondary multiple lesions. In this regard, interdisciplinary postpartum monitoring of women with preeclampsia can be an effective measure for the prevention of cardiovascular and kidney diseases [29].

Currently, IR is considered to be the leading basic pathophysiological factor underlying the metabolic (neurotransmitter-endocrine) syndrome [18, 30]. The works of Academician of the Russian Academy of Sciences V.N. Serov played a great role in the development of the concept of the role of pathological IR and chronic hyperinsulinemia in the formation of pathology of the female reproductive system, in particular, the influence of gestational pathological IR on the state of metabolism in the postpartum period. In the second half of the XX century the Russian scientist identified and described postpartum MS developing in women after pregnancy complicated by preeclampsia and determined its negative impact on the reproductive, endocrine and cardiovascular systems of the body [30].

Despite the lack of consensus on the definition of MS and criteria for its diagnosis, it is characterized by a combination of risk factors such as abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, prothrombotic and pro-inflammatory state, higher glucose levels, and factors undoubtedly associated with increased risk of developing chronic diseases such as type 2 diabetes and cardiovascular diseases. The syndrome has a complex and multifaceted origin and is the focus of attention of numerous scientists [31].

An increased risk of MS manifestations after childbirth is associated with hypertensive disorders during pregnancy, aggravated by parity, regardless of age. This circumstance can be explained by the repeated long-term effect of pathological IR associated with gestational hypertension on the woman’s body during each subsequent pregnancy. There is increasing evidence that cardiometabolic markers after pregnancy-induced hypertension, preeclampsia persist in the postpartum period. In addition, hypertensive disorders during pregnancy without underlying aberrations may contribute to the manifestation of abnormal metabolic profiles postpartum, some of which lead to MS. Maternal BMI and blood pressure are the main factors of MS in the postpartum period [32].

MS in the postpartum period is often accompanied by an imbalance in the gut microbiota causing an inflammatory response in the body by destroying the intestinal barrier and increasing pathological IR at the expense of metabolites that affect host metabolism and hormone release; vicious circle that contributes to the continuous progression of MS has formed. Therefore, the gut microbiota may be a novel aspect of MS prevention in the postpartum period [33].

Numerous multicenter studies on millions of women who have undergone preeclampsia showed the common causes of long-term deaths in these patients with patients suffering from MS. Similar patterns in the development of MS and preeclampsia which consist in an increase in diabetogenic and atherogenic disorders associated with pathological IR and chronic hyperinsulinemia, determine the development of common cardiometabolic diseases and their complications in the long term [8, 34].

Given the growing severity of cardiovascular and metabolic diseases, as well as the availability of risk reduction strategies in the first year after childbirth, all women with clinical and laboratory manifestations of pathologic IR should be studied in terms of potential MS which can affect reproductive potential and quality of life in the post-reproductive age [32].

The significance of insulin resistance in the formation of the «mother-newborn» dyad and health in the postnatal period

The concept of fetal programming was first proposed by D. Barker and K. Hales (1998) and was developed in the ontogenetic theory of health and disease initiation (DOHaD). According to this theory, metabolic reprogramming of the fetus is due to an unfavorable intrauterine environment through epigenetic mechanisms and causes metabolic diseases in adulthood [35, 36]. The studies have shown a significant causal relationship between hypertension, coronary artery disease, obesity, MS, deaths due to acute cardiovascular diseases in adulthood and fetal growth retardation, preterm birth and low/overweight at birth which are markers of an increased risk of pathological IR [25, 37]. According to A.M. Vaiserman, both low (<2.5 kg) and high (>4.5 kg) birth weights can be predictors of short lifespan, while normal weight is a predictor of maximum lifespan. There is strong evidence linking fetal growth retardation followed by postnatal catch-up growth with various aspects of MS, type 2 diabetes and cardiovascular diseases in adulthood. In contrast, fetal macrosomia is associated with a high risk of developing non-diabetic obesity and cancer later in life. Evolutionary modification of epigenetic patterns is considered to be a central mechanism in determining such developmentally programmed phenotypes. The axis of growth hormone/insulin-like growth factor, the processes associated with IR are the key driving force of these patterns of development [38].

The concept of fetal and newborn hyperglycemia in pregnant women with GDM suggests that fetal hyperglycemia is due to intrauterine hyperglycemia, which contributes to the induction of macrosomia. In addition, fetal/newborn hyperglycemia provokes neonatal hypoglycemia after birth [18]. It is suggested that neonatal hyperglycemia may be not only a transient phenomenon caused by neonatal hyperglycemia, but may also reflect intrauterine/neonatal IR which subsequently leads to MS. Fetal and neonatal hyperglycemia may be associated with maternal obesity, high weight gain, a high-fat diet, or an increase in pathological IR. Also, fetal/newborn hyperglycemia can occur in patients with GDM with good glucose control [39, 40]. Therefore, IR of the fetus and newborn may be associated with both pathological IR which is accompanied by GDM and with pathological IR caused by other different factors in pregnant women. The term “large for gestational age” is associated with reduced fetal sensitivity to insulin. Fetal IR programming is induced by abnormal activation of inflammation, adipokines and the endoplasmic reticulum [37]. Epigenetic programming of resistance to insuline is associated with an epigenetic modifying enzyme, pro-inflammatory factors, the nature of intracellular insulin signals, regulation of energy balance and mRNA. Global epigenetic changes across the entire genome are associated with IR. Blood DNA methylation levels in newborns are associated with sensitivity to insulin during early childhood. Higher changes in DNA methylation in the neonatal adiponectin gene were reported in the GDM group [41].

One of the mechanisms underlying pathological IR is the perinatal preparation of the intestinal microbiota of the fetus and newborn. The first microbial colonization of the gastrointestinal tract was believed to occur during the passage of the fetus through the birth canal. However, recent studies have shown that meconium contains bacterial DNA and specific bacteria; this fact suggests that colonization of the gastrointestinal tract of the fetus depends on the mother [42]. Colonization of the newborn’s gut is critical for healthy growth as it affects IR and hyperinsulinemia regulation, hyperinsulinemia function, metabolism, immunity and brain development. The importance of microbiome control should be taken into account when choosing strategies for the use of dietary supplements to support the intestinal microbiota of a child, especially in risk groups for obesity and impaired insulin resistance [41, 43].

Resistance to insulin is biologically important as it is a necessary adaptation process which satisfies the needs of the fetus and placenta in energy and nutrients. Its significance is illustrated by the data showing that in normal gestation IR of the mother in the middle of pregnancy positively correlates with the body weight of the newborn at birth [39]. However, there is a lack of studies on the relationship between maternal IR before pregnancy and neonatal weight. A study by Y. Wei et al. showed an association between maternal glucose levels, HOMA-IR before conception, and weight of neonates at birth in low-birth-weight infants [44]. The study of Z. Wang et al. showed that pathological IR of the mother is significantly associated with the birth weight of the newborn [4]. Maternal obesity is associated with neonatal and childhood obesity, in turn, childhood obesity is associated with premature death and disability in adulthood [39]. While maternal IR and fasting glucose levels are positively associated with neonatal obesity, the role of maternal triglycerides and non-esterified fatty acids in the development of neonatal obesity remains controversial. A.L. Shapiro et al. reported that HOMA-IR, glucose but not triglycerides and non-esterified fatty acids at 24–32 weeks’ gestation mediated the association between maternal BMI and neonatal obesity [40, 45]. Women with obesity and/or GDM have larger fetuses as early as 20 weeks of gestation which correlates with fetal hyperglycemia and hyperinsulinemia [2].

Newborn girls have been found to be more resistant to insulin than boys and the mechanisms underlying the relationship between maternal metabolism and neonatal obesity may differ depending on gender [45]. In a longitudinal DALI study, R.A. Lima et al. showed that resistance to insulin in obese women is associated with neonatal obesity; higher IR in early pregnancy is associated with greater degree of obesity in boys, while in girls this association with IR was observed in the middle of pregnancy. The authors believe that the formation of the “mother-newborn” dyad should be improved taking into account the gender of the fetus [39].

During gestation, a higher level of inflammatory mediators, for example, reflected by the concentration of TNFα, an IR mediator, is associated with an increase in IR in a pregnant woman [26]. Despite the fact that the placenta is the main source of TNFα entering the maternal circulation, a small amount of the mediator passes to the fetus. The placenta releases pro-inflammatory cytokines to cause the necessary increase in IR to enhance the delivery of nutrients to the fetus. In the case of normal pregnancy, IR may reflect the balance of the transfer of energy and nutrients between mother and fetus to optimize fetal health [46]. According to the study by S. Faleschini et al., high maternal IR is associated with a lower level of TNFα in cord blood, which reflects placental optimization of nutrient balance in favor of the fetus [47]. Studies on the effect of pathological IR in pregnant women with GDM on the inflammatory status of newborns and the course of the neonatal period have shown that there is a high probability of neonatal hypoglycemia and respiratory distress syndrome in newborns [1, 47, 48].

In recent years, the attention of researchers has been attracted by the possibility of a comprehensive assessment of the most important systemic processes, in particular, the relationship of biological rhythms and mechanisms for providing energy and building materials. A.N. Strizhakov et al. (2017) in his study demonstrated the relationship between the dynamics of melatonin, the development of metabolic processes, changes in sensitivity to insulin in the “mother-newborn” dyad under the normal conditions and in case of impaired formation of biorhythms in the early neonatal period and deviations in the concentration of insulin, glucose, and the HOMA-IR index. The improvement of care for newborns which is aimed at the timely formation of ultradian, circadian and infradian biorhythms has been shown to reduce significantly the frequency of metabolic disorders during adaptation of newborns, restoration of the “mother-newborn” dyad [49].

The influence of pathological IR on the development of congenital fetal pathology in women before conception is studied: the mechanisms of the formation of such congenital malformations as neural tube defects, defects of the abdominal wall, malformations of large vessels remain understudied; however, it is highly likely that disturbances in glucose metabolism contribute to the development of certain malformations [25].

Birth creates serious metabolic problems for the newborn. After the umbilical cord is clamped, the continuous transplacental supply of glucose is sharply disrupted, so the newborn uses its endogenous production until exogenous food intake is established. Then the newborn has to adapt to alternating periods of feeding and fasting. These problems are solved by well-planned metabolic and hormonal adaptive changes, IR and hyperinsulinemia. Although this adaptation is not as great as adaptive changes in the cardiorespiratory system, it is just as complex and necessary for survival in the extrauterine environment [3, 50].

Therefore, a deep understanding of the correlation of metabolic adaptation processes in the “mother-fetus-newborn” system, scientific reasoning of personalized care programs in the postnatal period will significantly reduce the frequency of metabolic disorders, optimize the restoration of the “mother-newborn” dyad, and have a beneficial effect on the development of this biological system.

Conclusion

To date, reliable scientific data have already been accumulated on the relationship of normal and pathological IR, compensatory and chronic hyperinsulinemia before conception and during pregnancy with the adaptive mechanisms of the formation of the biological system “mother-newborn”, antenatal programming of metabolic and immune processes, the course of transient conditions, body weight and malformations of newborns, gender, biorhythms of functional indicators of life support systems, characteristics of pathogenesis in the postpartum period. Pregnancy is currently considered to be a natural model of MS, and the leading role in switching the cellular energy supply of the pregnant woman from carbohydrate to fat component in order to optimize the energy and nutrient supply of the fetus belong to IR. In the postpartum period in the postpartum period, this reorganization accompanied by an increasing pathological IR can lead to metabolic dysfunction both in the mother and the newborn in the short and long term with impaired lactogenesis and lactopoiesis, the transformation of GDM into type 2 diabetes, the development of infectious and inflammatory diseases, hypertension, obesity, MS, CKD. These pathological conditions negatively affect reproductive potential, reduce the quality of life of a woman in post-reproductive age, and can cause disability and death.

Deep knowledge of the multifaceted mechanisms of adaptation and pathogenesis in the female reproductive system in all periods of life, their close relationship through the universal regulatory functions of energy and nutrients control require an interdisciplinary approach to the development of personalized programs for risk stratification, primary prevention and rehabilitation aimed at reducing the phenotypic manifestations of hereditary and acquired high-risk factors.