Rolf of insulin resistance in the mechanisms of adaptation and development of female reproductive system disease

Regulation of energy supply is one of the most important functions of all living organisms under both physiological and pathological conditions. This function is provided by an evolutionarily conserved phenomenon of insulin re-sistance (IR), which is due to decreased sensitivity of tissues to insulin at its sufficient concentration. In humans the periods of food abundance and insuffi-cient supply of energy often alternated in the process of phylogenetic for-mation of the key mechanisms for controlling cellular energy supply [1, 2]. When J.V. Neel studied the problem of the growing prevalence of obesity in modern civilization, he put forward the theory of the “thrifty” genotype in 1962. According to the theory, IR is the result of natural selection, adipose tis-sue acts as an energy accumulator and the key mechanism of its “recharging” is the selective IR of muscle and liver tissue [3, 4]. IR affects between 15 and 45% of the adult population in the world, with the highest prevalence in Asia (45% in Lebanon, 39% in Thailand) and the lowest in Europe (15.5%) [5]. IR can be physiological and pathological [6, 7]. Despite the wide presence of insulin re-ceptors on the surface of most body cells, the concept of IR is primarily ap-plied to adipocytes, hepatocytes, skeletal muscles, and endothelium [8, 9]. Physiological IR can be considered as peripheral (muscular) and pathological as central (hepatic) [10]. The increased need for energy during starvation, de-hydration, pregnancy, neurometabolic and endocrine disorders, infections re-quires homeostatic versatility and can cause a state of reversible IR involving hormones and cytokines that contribute to the suppression of the action of in-sulin in target tissues [11, 12]. There is evidence of a change in the sensitivity of tissues to insulin in the sleep-wake cycle, the dynamics of the menstrual cy-cle with an increase in IR in phase II, its fluctuations depending on circadian and seasonal biorhythms, age periods of life [13].

Though the physiological effects of IR are important, the attention of cli-nicians is focused on pathological IR, as the pathology associated with it is rapidly expanding [9]. In addition to common metabolic diseases (arterial hy-pertension and atherosclerosis, type 2 diabetes mellitus (DM), non-alcoholic fatty liver disease, metabolic syndrome (MS), polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), etc.), pathological IR is involved in the development of Alzheimer’s and Parkinson’s diseases, rheumatoid ar-thritis, cardiac insufficiency, gout, obstructive sleep apnea, pregnancy compli-cations; it increases the risk of death from cancer (breast, endometrial, colorec-tal cancer) and controls replicative cell aging [14, 15]. The development of IR can be caused by drugs (antiretrovirals, glucocorticoids, oral contraceptives) or factors such as lipodystrophy, genetic defects in the pathways of insulin sig-naling (type A IR) and the synthesis of autoantibodies against the insulin re-ceptor (type B IR) [11, 16].

There is growing evidence in favor of the induction of IR by the gut mi-crobiome which has a significant impact on its barrier function, the breakdown of indigestible food components, the modification of bile acids and other sub-stances, intestinal development and the formation of the immune system in childhood which subsequently may affect the duration of life. These effects promote the release of bacterial proteins, endotoxins, and cytokines into the bloodstream; they cause changes in hundreds of metabolic products, including bile acids, short chain fatty acids, amino acids and many other classes of mole-cules. Together they lead to tissue-specific metabolic dysregulation and activa-tion of immunity, the formation of IR [12, 17].

Since IR and hyperinsulinemia are universal mechanisms in adaptive and pathological processes, it is necessary for the researchers to identify the hidden molecular foundations of these conditions; their understanding may be helpful in offering new theories of development, methods of diagnosis, treatment and prevention of various diseases including pathology of the reproductive system which are closely connected with the general biological phenomenon of IR.

The methodological basis for 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 2013–2021.

Molecular mechanisms of insulin resistance

Due to the complexity of biological systems, it is irrational to explain IR using a single, concise and simple model. The life support systems of the body strive for physiological balance, so the concept of IR should be viewed through the broad prism of homeostasis. Since there was no constant excess of calories during evolution, the physiological consequences of IR could be temporary or accidental. There is no consensus on the underlying cause and pathophysiolo-gy of IR; however, there are some hypotheses (portal, endocrine, ectopic fat accumulation) that IR is a non-random, regular homeostatic mechanism [18, 19].

The protective role of physiological IR is most clearly seen in physical activity which is accompanied by increased glycogenolysis and gluconeogene-sis in the liver, increased synthesis of free fatty acids in adipose tissue and in-creased utilization of the obtained energy substrates by muscles [20]. Various changes (increased sensitivity to insulin in skeletal muscles and IR of adipose tissue and liver) are caused by the dual action of the myokine interleukin (IL)-6 released in response to a decrease in the glycogen reserve in the myocyte; moreover, this effect is associated with a sudden short-term increase in IL-6, in contrast to the persistent high level in people with a pathology with proin-flammatory status [21, 22]. The effect of IL-6 on adipocytes leads to the sup-pression of the transmembrane glucose transporter GLUT-4 and inhibition of the insulin-1 receptor substrate (IRS-1) which is a key link in the intracellular transmission of the insulin signal by activating the phosphorylation of its ser-ine residues (Ser36, Ser38, Ser111); all these processes result in the increase in lipolysis [23]. In hepatocytes, IL-6 promotes gluconeogenesis, glycogenolysis, and suppression of glycogenogenesis by activating glycogen phosphorylase and SOSC-3 synthesis blocking the insulin signal [15, 22]. An increase in the utilization of energy substrates in skeletal muscles is mediated by the action of IL-6 on AMP kinase and insulin-independent stimulation of PKB/Akt (protein kinase B/serine-threonine kinase) which leads to activation of the mechanisms of intracellular insulin transduction [24].

The main reasons for the formation of pathological IR are the presence of an excess of energy substrates, adipose tissue, genetic defects leading to functional deficiency of insulin signaling pathway molecules (IRS, PKB/Akt, PI3Ks, glycogen synthetase, hormone-sensitive lipase), glucose transporters in the cell (GLUT) [25, 26]. However, a number of authors argue that IR develops using similar mechanisms: in physiological processes it is localized (peripheral IR), short-term and has a reverse development when the influencing factor is removed; in pathological processes IR is persistent and regular changes which occur as “vicious upward spiral” lead to the processes resulting in the devel-opment of various diseases [27]. An important role in closing the “vicious cir-cle” belongs to compensatory chronic hyperinsulinemia which becomes patho-logical. It has been shown that the permanent effect of elevated doses of insulin on adipocytes causes a dose-dependent decrease in insulin receptors on the cell surface and impaired glucose transport [7].

Each mechanism of pathological IR induces it either through toxic me-tabolites from nutrients (DAG, ceramide, acylcarnitine, BCAA), excessive use of food (ER stress, oxidative stress) or in response to intracellular inflamma-tion and oxidative stress. The described mitochondrial dysfunction in individu-als with IR contributes to a positive energy balance and lipid accumulation. In-flammation of adipose tissue stimulates lipolysis and the increase in substrate delivery to tissues. Therefore, it is worth considering an integrated IR model where several reactions, for example, excess of nutrients, synthesis of placental hormones with atherogenic dyslipidemia during gestation, pathological chang-es (reduction of postmenopausal sex steroids, endocrine pathology, etc.) con-tribute to ectopic accumulation of lipids and subsequent insulin resistance [18, 23].

A natural model for studying the underlying cause of IR is type 2 diabe-tes. T.M. Batista et al. [28] demonstrated the mechanisms of IR induction us-ing muscle samples and primary cultured myoblasts obtained from people with type 2 DM. Defects in insulin signaling at the level of AKT/GSK3/FOXO1 phosphorylation, reduced glucose uptake and changes in mitochondrial respi-ration similar to defects in type 2 diabetes in vivo were objectified. The data of global phosphoproteomics showed that these defects are part of a multidimen-sional network of signaling changes, including more than 1000 Ser/Thr phos-phorylation sites on more than 700 different proteins. Only a small proportion of these abnormalities are associated with traditional insulin-regulated phos-phorylation. The greatest number of changes occurred in pathways outside the signaling pathway of the latter. The results indicate that there is a primary cel-lular defect underlying IR. The identification of the cause of this defect at the cellular level will help to understand the pathogenesis of diseases and provide opportunities for new treatment methods [18, 24].

Insulin resistance in women with pathology of the reproductive system

Estrogens play a protective role in metabolic health of women, especially in relation to the distribution of body fat mass, fatty acid mobilization, glucose response of various tissues and organs. A decrease in estrogen levels can sig-nificantly affect energy metabolism and overall metabolic homeostasis [1]. In comparison with premenopausal women, postmenopausal women are much more likely to have increased insulin resistance. Menopause is a potential risk factor for IR regardless of age, probably due to a decrease in circulating estro-gens. The women in the post-reproductive period have been proved to be more susceptible to the development of dyslipidemia, weight gain and impaired glu-cose tolerance [8, 29]. IR directly stimulates the production of androgens by the cells of the ovarian theca. This process can lead to premature puberty in children in case of hyperinsulinemia accompanied by IR. The reaction of ovari-an tissues to hyperinsulinemia implements a cascade of hormonal disorders with a change in reciprocal relationships in the hierarchy of the reproductive system. Recent literature suggests that precocious puberty is a precursor to ovarian hyperandrogenism in adolescence and contributes to the development of PCOS in adulthood [30].

The effects of IR caused by hyperinsulinemia on the central mechanisms of regulation of the reproductive system are the increase in the sensitivity of pituitary cells to gonadotropin releasing hormone with an increase in LH secre-tion and imbalance of gonadotropins, which leads to anovulation, oligomenor-rhea, hyperandrogenism and polycystic ovarian structure [1, 13]. The women with chronic anovulation and hyperandrogenism should be considered at high risk for metabolic disorders associated with IR. Ovarian steroidogenesis ac-companied by IR leads not only to an excess of androgens, but also to the mo-notonous nature of estradiol secretion with an increase in the half-life of LH. In addition, IR and hyperinsulinemia contribute to a decrease in the concentration of sex steroid-binding globulin, which leads to an increase in the fraction of ac-tive androgens and insulin-like growth factor-1 (IGF-1) [8, 31]. Consequently, the peripheral effects of hyperinsulinemia associated with IR lead to an im-pairment of the synthesis of sex steroids, an increase in gonadotropin-stimulating effects.

PCOS is a common gynecological endocrine disorder diagnosed in 8–13% of women and accompanied by infertility [2, 25, 32]. In addition, PCOS is associated with a higher risk of metabolic disorders, including impaired glucose tolerance, type 2 diabetes, dyslipidemia and cardiovascular disease [33, 34]. According to the studies, PCOS has a multifactorial origin, which includes ge-netic and neuroendocrine causes, lifestyle, immune and metabolic dysfunctions. One of the main pathological changes in PCOS is IR, which can be present both with increased and normal body weight [35, 36]. Given the strong rela-tionship between the gut microbiome and IR, it is critical to further identify and analyze specific functional bacterial profiles associated with the develop-ment of PCOS. This will allow the clinicians to find out whether manipulation of the gut microbiota can be useful for personalized treatment of PCOS [17].

IR transformed into type 2 DM, chronic hypertension, obesity, MS can be considered as an active independent risk factor for oncopathology of the re-productive system organs (“the deadly quartet”) [37, 38]. The receptor hetero-geneity of the endometrium in hyperplastic processes and precancerous endo-metrium was proved by histochemical studies; it is expressed in the impair-ment of the receptor status due to receptors for sex steroids and insulin [13, 39]. Similar studies of ectopic endometrium in endometriosis also revealed sig-nificant characteristics in the functioning of the insulin/IGF-1 system: the rela-tive IR of the endometrium is due to a decrease in the expression of insulin re-ceptors and an increase in IGF-1 receptors in the endometrium [40]. Conse-quently, both systemic IR and its local manifestations play a significant role in the mechanisms of the development of reproductive system pathology. The study of systemic IR is aimed at new approaches to the prediction and preven-tion of gynecological diseases with an unfavorable prognosis.

Both insulin resistance and MS (insulin resistance syndrome) are power-ful risk factors for the development of cardiovascular disease and type 2 diabe-tes [41]. The prevalence of IR and MS varies from 20 to 45% in different pop-ulations [6, 8]. Although there are strong lifestyle factors for the development of both IR and MS, the role of genetic traits is becoming increasingly clear. Re-cently, progress has been made in the identification of genetic loci associated with IR and MS [11, 12]. Some of them were shown to be involved directly in the bioeffects of insulin and glucose metabolism, while further studies are re-quired to determine the functional relationships between genetic variants and the action of insulin. Identification of evidence for the involvement of genetic factors in the mechanisms of IR is difficult: phenotypes (IR and MS) depend on lifestyle and environmental factors that must be taken into account when studying the underlying genetic structure; moreover, phenotype IR is difficult to quantify due to the fact that there is no direct relationship between the level of circulating insulin and IR severity [40].

The knowledge of the genetic markers IR and MS and their use in clinical practice are promising tasks for the prediction and management of conditions that determine the quality and duration of life, such as type 2 diabetes, cardio-vascular diseases, oncopathology.

Insulin resistance is a universal regulator of energy and nutrient needs during pregnancy and childbirth. The basic mechanism of fetal energy supply

The causes and mechanisms of IR during pregnancy are complex and are not fully understood [42]. Like the hormone insulin, resistance to it is one of the earliest, ancient regulatory functions of the body, which is a universal find-ing of evolution. The development of IR during pregnancy is due to the need to limit the use of glucose by the mother in order to provide a sufficient amount of energy and nutrients for the growing fetus, which requires glucose as the main source of energy [43–45]. It is known that the degree of maternal IR is related to the degree of glucose flow from mother to fetus. There is a decrease in insulin sensitivity by 50–60% during pregnancy [42]. Protein synthesis, en-ergy production and cellular activity significantly increase in the embryo- (feto-) placental complex due to the mechanisms of IR compensation. These mecha-nisms include increased activity of the neuroendocrine system, ligand synthe-sis, autocrine, paracrine, intracrine, and juxtacrine regulation of cell metabo-lism [46].

IR mechanisms characteristic of normal pregnancy are similar to those that occur in non-pregnant patients with type 2 DM [47]. Pregnancy is charac-terized by switching the cellular energy supply of the mother’s body from the carbohydrate component, namely glucose, to fat which is more favorable for the growth and development of the fetus. Recent studies have shown that physiological gestation is accompanied by a statistically significant increase in IR indices, insulin levels and lipid profile indicators which can be suggestive of a diabetogenic and atherogenic shift in metabolism with the formation of phys-iological IR and hyperinsulinemia [8, 10]. This fact indicates that normal preg-nancy is similar to the functional phase of insulin resistance syndrome. The dysmetabolic pattern which is revealed during normal gestation, as well as moderate pro-inflammatory and hypercoagulable conditions, activation of the endothelial-platelet link in case of failure of permanent mechanisms of adapta-tion may lead to structural disorders and act as prerequisites for complications of gestation [44]. Unlike the maternal organism, the consumption of energy and nutrients occurs extremely efficiently in the uterine-placental-fetal com-plex; it is ensured by the production and compensatory effect of hormones, pregnancy proteins, cytokines, oxidative molecules, etc. on IR [2, 37]. Due to uneven IR in the functional system “mother-placenta-fetus”, the nutritional processes in the fetus and in the placenta differ by two and three orders, re-spectively, compared with such target organs as the uterus and mammary glands. These facts confirm the importance of the regulatory and uneven nature of the influence of IR on different organs and systems [27, 43]. In the dynamics of a normal pregnancy, IR compensation is most vulnerable in the placenta; the manifestations are its aging and a decrease in the production of proteins and enzymes, growth factors and energy generation. There is an opinion that placental decompensation of IR is one of the inducers of the onset of labor [46]. The energy supply of the contractile activity of the myometrium during childbirth is carried out by the formation of ATP in the same way as during contraction of skeletal muscles. Increased synthesis of glucocorticoids in partu-rient women contributes to an increase in IR by regulating glycogenolysis in the placenta and liver, gluconeogenesis and glycemia. A natural preventive measure for possible hypoglycemia is the activation of the sympathetic-adrenal system with a decrease in insulin concentration. An increase in the level of the latter by the end of the second stage of labor reflects the activity of the para-sympathetic division of the autonomic nervous system [37]. In general, the change in IR, the degree of its compensation in the dynamics of gestation and childbirth indicates the compensatory-adaptive nature of the processes.

According to the study results, the pathophysiological precursors for the development of obstetric pathology lie in the regularities of the development of normal pregnancy aimed at the primary energy and nutrients supply of the fe-tus through the formation of physiological IR and compensatory hyperinsu-linemia [44]. Disruption of gestational adaptation to placental contra-insular factors (placental lactogen, cortisol, progesterone, estrogens, TNF-α, “pregnan-cy zone” proteins, etc.) leads to a severe escalation of physiological changes with transformation into pathogenetic links of gestational complications, the nosological orientation of which is provided by deviations of gene networks, epigenetic dysregulation, somatic pathology [2, 43, 45]. In recent years, the studies have confirmed the relationship of pathological IR with spontaneous miscarriage, threatened miscarriage, fetal loss syndrome, placental insufficien-cy, fetal growth retardation, preeclampsia, thromboembolic complications, premature detachment of the normally located placenta, postterm pregnancy, gestational diabetes (GDM) [1, 37, 47]. It is believed that the dominant view on the development of endotheliosis in preeclampsia is placental ischemia due to limited gestational metamorphosis of the spiral arteries. However, a number of studies have shown the role of IR, hyperinsulinemia, leptin and dyslipidemia in the formation of oxidative stress and endothelial-hemostasiological disorders in preeclampsia [6, 48]. The nature of the metabolic pattern in pregnant wom-en confirms the position “pregnancy is a natural model of MS” [44, 47]. In non-pregnant women, these metabolic markers are most significant in the de-velopment of MS, type 2 diabetes, essential hypertension and its complications [8, 12]. According to meta-analyses, the development of the above complica-tions is associated with preeclampsia, as well as in chronic kidney disease, ear-ly strokes and heart attacks, vascular dementia and severe metabolic disorders postmenopausal women [1, 49]. In addition, it is worth noting that IR syn-drome is the cause of essential hypertension in 80% of people all over the world, while reduced insulin sensitivity is not only the basic mechanism for the energy and nutrients supply of the fetus, but also the leading mechanism for the development of gestational hypertension [41, 46]. According to the results of recent studies, the basic pathophysiological mechanisms of preeclampsia development are pathological IR, hypersinsulinemia, which realize their action through associated atherogenic dyslipidemia, hyperleptinemia and hyperu-ricemia, meta-inflammation and immunometabolic disorders, oxidative stress, prothrombotic status, hypersympathicotonia, antiangiogenic state. They lead to structural and functional destabilization of the vascular endothelium fol-lowed by the manifestation of a symptom complex in the form of hyperten-sion, proteinuria and multiple organ failure [37, 43]. The presence of addition-al alternative factors, such as placental ischemia, immune, infectious, toxic, gene deviations, epigenetic dysregulation, contributes to the basic (dysmetabol-ic) mechanisms of pathogenesis and determines the duration of the clinical manifestation of preeclampsia [27, 45].

A holistic view of the changes that occur during pregnancy shows that trophoblast invasion and the formation of IR are processes of the same order. Their aim is to create local conditions for the energy supply of the fetus using cytotrophoblastic transformation of the spiral arteries and systemic conditions through switching the energy supply of the pregnant woman from carbohy-drate to fatty component with a predominant flow of glucose to the fetus. A different combination of their physiological or impaired formation leads to var-ious major obstetric syndromes in different periods [21, 49].

Currently, there is an active search for the causes of endothelial dysfunc-tion during pregnancy. There is a point of view that gestational endotheliosis can be a manifestation of pathological IR and hyperinsulinemia and the sys-temic inflammatory response associated with them, disturbances in the system of hemostasis and fibrinolysis and oxidative stress [2, 48, 50].

Placental contra-insular factors are undoubtedly a stress test in compari-son with GDM in pregnant women with primary defects in cellular response to insulin stimuli. Hyperglycemia in GDM is associated with increased maternal and fetal morbidity and high mortality rates [37]. The results of the examina-tion of pregnant women with pregnancy-induced hypertension and pregnant women with GDM show that insulin levels are significantly lower in GDM as-sociated with pathological IR than in gestational hypertension, which may ex-plain the differences between “hypertensive” and “hyperglycemic” phenotypes of complicated pregnancy with similar underlying mechanisms, namely patho-logical IR and hyperinsulinemia [40, 42]. Given the importance of IR for phys-iological and pathophysiological processes at various levels of insulin, it is practically important to objectify its effect on organs and systems. In this sphere, special attention is paid to the assessment of glomerular filtration rate, postprandial glycemia and manifestations of endothelial dysfunction [46].

Therefore, an in-depth study of the role of IR as a regulatory and con-necting link in the functioning of individual body systems makes it possible to get a more detailed and holistic understanding of adaptive processes during normal pregnancy and the pathogenetic mechanisms of its complications and to form a systematic view of gestation mechanisms.

Conclusion

IR is an evolutionarily conserved mechanism for the regulation and redistribu-tion of energy in the body. However, due to the changes in agricultural tech-nology and lifestyle, excess energy is currently redistributed and stored as a bi-ological resource, which subsequently leads to neuroendocrine and metabolic disorders. The key role of IR as an integrator of metabolism, growth, and life expectancy is obvious, while IR can act both as a protective and pathological mechanism. Cardiovascular pathology associated with pathological IR is the third most common cause of death among other deaths caused by complica-tions of chronic non-communicable diseases. IR has a significant impact on the adaptation processes and the formation of the pathology of the female repro-ductive system. The general biological approach to considering the role of the IR phenomenon that is vital for the balance of reciprocal relationships in a complex hierarchically built reproductive system and for the normal function-ing of the mother-placenta-fetus system makes it possible to explain the adap-tive processes and pathogenetic mechanisms in gynecological and obstetric disorders, to develop a comprehensive view from the perspective of the closely interrelated functioning of individual body systems.

Thus, despite significant achievements and growing interest in the prob-lem, it is important to understand that there is still much to learn in this area in order to improve approaches to predicting, preventing and personalizing the treatment of IR-associated diseases and implement the 5P’s model of the cur-rent stage of medicine.