Mechanisms of Insulin Resistance during Pregnancy

Abstract

Pregnancy is physiologically associated with a gradual increase in insulin resistance, which acts as a physiologic adaptive mechanism to ensure the adequate supply of glucose to the rapidly growing fetus. However, an early adaptive increase in beta-cell glucose sensitivity and beta-cell insulin secretion maintains glucose homeostasis during normal pregnancy. Potential mechanisms behind gestational insulin resistance include hormonal, placental, and genetic or epigenetic factors, as well as the increase in visceral adipose tissue, alterations in gut microbiota, and the concurrent presence of overweight or obesity. In some instances, defects in beta-cell adaptive mechanisms occur, resulting in a substantial exacerbation of insulin resistance and in the possible development of gestational diabetes mellitus (GDM). This chapter aims to provide readers with a basic knowledge of the physiologic adaptations and the possible dysregulations of glucose homeostasis and insulin sensitivity during pregnancy. Indeed, this knowledge is critical to properly identifying women at risk for maternal and/or fetal metabolic complications and tailoring the prevention and treatment strategies for this population. We also briefly discuss the potential factors and molecular/cellular mechanisms accounting for gestational insulin resistance and GDM pathophysiology.

1. Introduction

Pregnancy is a unique metabolic event characterized by a series of biochemical, anatomical, and physiological changes aiming to ensure the adequate nourishment of the fetus and to prepare the maternal body for lactation. The pregnancy of a healthy woman is physiologically associated with resistance to the action of insulin on glucose uptake and consumption by maternal peripheral tissues [1, 2]. Insulin resistance during pregnancy serves as a physiological adaptation aimed to subsidize the adequate supply of carbohydrates to the rapidly growing fetus, which uses glucose as the main energy source [2]. Data from normal pregnancies of nondiabetic overweight or obese women demonstrated that resistance to the action of insulin on lipolysis and fat oxidation develops during late gestation and disappears postpartum [3]. Yet, during pregnancy, there is a coexisting balance between the physiologic insulin resistance and an adaptive increase in beta-cell insulin production.

This chapter aims to provide readers with a basic knowledge of the physiologic adaptations and the possible dysregulations of glucose homeostasis and insulin sensitivity during pregnancy. Indeed, this knowledge is critical for identifying women at risk for maternal and/or fetal metabolic complications. We also provide a brief overview of the potential factors and molecular/cellular mechanisms accounting for gestational insulin resistance and gestational diabetes mellitus (GDM) pathophysiology, although these are still not entirely clear.

2. Placental hormones and insulin resistance during pregnancy

The placenta undoubtedly plays a critical role in the development of gestational insulin resistance, as it is supported by the fact that glucose homeostasis rapidly restores after the placental expulsion at delivery [2]. The placenta secretes a series of pregnancy-specific hormones called “placental hormones” (e.g., human chorionic gonadotropin (hCG), human placental lactogen (hPL), and human placental growth hormone (hPGH) into the maternal circulation. These hormones and other hormones (e.g., prolactin) are believed to represent a major factor in reprogramming maternal physiology to achieve an insulin-resistant state [4]. Particularly in mid and late pregnancy, there is a substantial rise in insulin resistance that may be secondary to the marked increase in the production of such hormones [5, 6].

In normal pregnancy, the short half-life of many of the placental hormones in the maternal circulation and the weakening of their effects within 24–48 hours after delivery (accompanied by the reversal of insulin resistance) support the role of these hormones in the development of gestational insulin resistance [7, 8]. Interestingly, this also explains why mothers with type 1 diabetes mellitus (T1DM) experience a rapid decline in insulin requirements (toward pre-pregnancy levels) 1 or 2 days after delivery [2, 9]. Moreover, the circulating concentrations of other non-pregnancy-specific hormones (e.g., prolactin, progesterone, estradiol, and cortisol) increase significantly during pregnancy. The increasing amounts of progesterone, cortisol, and prolactin may also contribute to the post-binding defect in insulin action observed during pregnancy [6, 10]. However, no single hormone has been found to completely account for gestational insulin resistance [2].

In addition, some placental hormones can also influence other canonical hormonal axes in light of their structural similarity to hormones found in the nonpregnant state [2]. For instance, circulating concentrations of hPGH (which differs from pituitary growth hormone by 13 amino acids) increase six- to eightfold during gestation. Thus, hPGH gradually replaces the function of the pituitary growth hormone (GH) during pregnancy [4, 11]. Unlike GH, hPGH is secreted tonically rather than in a pulsatile fashion [2, 12]. This results in maternal serum levels of hPGH comparable to circulating levels observed in acromegaly (e.g., 10 times higher than GH outside pregnancy). Hence, hPGH may exert the same diabetogenic effects of the pituitary GH, resulting in insulin resistance and hyperinsulinemia, reduced insulin-stimulated glucose uptake and glycogenesis, and impaired insulin-mediated suppression of hepatic glucose production [2, 13]. Accordingly, transgenic mice overexpressing hPGH to levels comparable to those observed in the third trimester of pregnancy exhibit severe peripheral insulin resistance [14]. Concerning the molecular mechanisms behind insulin resistance in skeletal muscle in response to elevated hPGH values, it has been shown that hPGH increases the expression of the p85α subunit of phosphatidylinositol 3-kinase (PI3K) in skeletal muscle [4]. In turn, the increase in the p85α subunit of PI3K acts as a dominant-negative competitor to forming a PI3K heterodimer with the p110 subunit, thus inhibiting the PI3K activity and attenuating the insulin signaling downstream [4, 15]. Conversely, data on the potential role of hPL and hCG in the pathophysiology of gestational insulin resistance are less univocal [4, 10, 16].

3. Other factors linked to insulin resistance during pregnancy

Apart from increased secretion of placental hormones and non-pregnancy-specific hormones, other factors have been linked to the pathophysiology of gestational insulin resistance. In this regard, the potential relationship between the placenta and insulin resistance has been suggested to be mediated via the secretion of different pro-inflammatory cytokines and adipokines and/or via the release of other substances from the placenta into the maternal circulation [2, 4]. Obesity and other pregnancy-related factors (e.g., exosomes secreted from both the placenta and adipose tissue, specific genetic polymorphisms, epigenetic factors, pregnancy-related increase in visceral adiposity, and altered gut microbiota composition) can further explain the changes observed in insulin sensitivity throughout pregnancy [4, 17, 18, 19].

3.1 Obesity and gestational insulin resistance

Obesity represents a growing public health problem that is increasingly affecting women of childbearing age and pregnant women. More than half of all pregnant women in the United States are considered obese, with 8% being extremely obese [20]. Obese pregnant women are likely to experience several complications during pregnancy, as they exhibit a higher risk for GDM, hypertension, and preeclampsia [21].

Increases in maternal fat mass (seen in both lean and obese pregnant women) and obesity play a central role in the development of insulin resistance during pregnancy [22]. As a consequence of increased insulin resistance, lipid metabolism is also affected during pregnancy; it is characterized by a two- or threefold increase in triglyceride and cholesterol concentrations in late gestation [2]. The impaired insulin-mediated suppression of lipolysis (secondary to insulin resistance) also leads to a substantial increase in circulating values of free fatty acids (FFAs) [2, 23], which can result in lipotoxicity, inflammation, endothelial dysfunction, reduced trophoblast invasion, and consequently reduced placental metabolism and function, particularly in obese women who are more prone to central fat accumulation (central obesity) [24].

Insulin resistance during pregnancy can be particularly exacerbated in the presence of preexisting or concomitant conditions (including diabetes, obesity, and physical inactivity), thus posing serious clinical implications for pregnancy outcomes and long-term morbidity for the mother and offspring [2]. For instance, obese women exhibit increased insulin resistance and increased insulin response, as well as higher circulating inflammatory cytokine values compared with nonobese women both before and during pregnancy. The aberrant increase in insulin resistance secondary to maternal obesity leads to a parallel increase in the risk of developing metabolic syndrome-like disorders during pregnancy, such as hypertension, coagulation disorders, hyperlipidemia, glucose intolerance, and GDM [25]. Importantly, an exuberant increase in gestational insulin resistance can also lead to a surplus of lipids and glucose, resulting in fetal overnutrition and subsequent increased risk of metabolic disease later in life [13]. In this regard, excess nutrient supply, suboptimal in utero metabolic environment, and alterations in placental gene expression, inflammation and metabolism may also induce metabolic dysfunctions in the offspring, thus generating a vicious cycle of transgenerational obesity and diabetes [24, 26].

4. Glucose homeostasis and changes in insulin sensitivity during pregnancy

Fetal growth and development depend on multidirectional interactions between the mother, the placenta, and the fetus (maternal-placental-fetal triad). In the context of glucose homeostasis, proper maternal metabolic adaptations are needed to ensure nutrient stores for the fetus and to meet the maternal nutrient requirements. Adequate glucose regulation is essential for guaranteeing maternal and fetal health during the three pregnancy trimesters. In this regard, pregnancy is characterized by two distinct physiologic phases, namely: i) an early anabolic phase, which takes place during the early gestational period (specifically, during the first and second pregnancy trimesters) when there is an increase in nutrient storage and deposition of lipids in maternal tissues; ii) a late catabolic phase, which occurs during the third trimester and is characterized by a marked reduction in insulin sensitivity (insulin resistance) and by enhanced adipose tissue lipolysis [27]. Insulin resistance changes over time during gestation, increasing substantially in the last half of the pregnancy and becoming severe in women with maternal diabetes [2].

During the anabolic phase, the mother stores nutrients to meet the maternal, fetal, and placental energy demands of the future catabolic phase (late gestation) and lactation [27, 28]. In particular, the early stages of pregnancy are characterized by increased beta-cell insulin secretion, while insulin sensitivity may decrease, increase, or even remain unchanged during this period [4, 29]. Following the mid stages of pregnancy, fetal glucose requirements start to increase, prompting the placenta to produce hormones (such as hPGH, hPL, and prolactin) that increase maternal insulin resistance and hepatic glucose production in the effort to preserve the maternal to fetal glucose gradient [30, 31]. In late gestation, maternal metabolism shifts to a catabolic state. This catabolic state results in augmented insulin resistance, enhanced lipolysis (due to reduced insulin-mediated suppression of lipolysis), increased hepatic glucose production, reduced maternal adipose tissue depots, and increased postprandial FFA levels. Overall, there is a reduction of insulin-mediated peripheral glucose disposal (by 40–60% compared with pre-pregnancy levels), which is aimed to allow a greater glucose transport across the placenta [30].

In late gestation, insulin action is particularly decreased in skeletal muscle. As the number of insulin receptors on the skeletal muscle cell surface remains unchanged during the entire pregnancy, the reduced insulin sensitivity is considered to be due to a post-receptor defect in insulin signaling cascade causing a consequential decreased ability of insulin to promote glucose transporter 4 (GLUT4) translocation from the cytoplasm to the myocyte surface and to mediate the subsequent glucose uptake in muscle cells [23]. In pregnant women with normal glucose tolerance, reversal of insulin resistance postpartum is accompanied by enhanced skeletal muscle insulin signaling due to increased expression of skeletal muscle insulin receptor substrate 1 (IRS-1) and downregulation of the p85α subunit of PI3K [32]. These changes allow for greater p85/p110 binding to IRS-1 and play a major role in the metabolic adaptation to normal human pregnancy and restoration of insulin sensitivity postpartum [32]. The p85 regulatory unit of PI3K is a key effector enzyme for stimulating glucose uptake in insulin-sensitive tissues. PI3K is composed of the p85 regulatory unit and a catalytic subunit called p110, which need to form a p85-p110 heterodimer and bind to IRS-1 for PI3K activation. Under the action of hPGH, the p85 monomer is selectively overexpressed and competes with the active p85-p110 heterodimer in a dominant-negative fashion for binding to IRS-1, thus decreasing the IRS-1-associated PI3K activity [13]. In turn, this reduction in PI3K activity results in the attenuation of the final step of the insulin signaling pathway, namely in the reduction of GLUT4 translocation from the cytoplasm to the plasma membrane [13].

4.1 Placental glucose transport and physiologic beta-cell adaptation to gestational insulin resistance

The rate of glucose transfer across the human placenta is directly proportional to the maternal-fetal glucose gradient up to maternal glucose concentrations that are well above the physiologic range [33]. As the fetus has very little capacity for gluconeogenesis, maternal glucose represents the main energy source for the placenta and the fetus. Maternal glucose is crucial for normal fetal metabolism and growth [34, 35].

However, passive diffusion of glucose across the placenta is insufficient to meet fetal glucose needs. Thus, facilitated diffusion using a variety of glucose transporters is required for this purpose. Glucose transporters (GLUTs) are members of the GLUT gene family of facilitated-diffusion transporters. They are embedded in the microvillous (maternal-facing) and basal (fetal-facing) membranes of the syncytiotrophoblast, which is the main placental barrier layer [36]. While eight members of the GLUT family have been described in human placental tissue, only glucose transporter 1 (GLUT1) protein has been identified in the syncytium. Basal membrane GLUT1 expression is upregulated over pregnancy, increased in diabetic pregnancy, and reduced in chronic hypoxia, while microvillous membrane GLUT1 expression remains unaffected [36]. It has been reported that transporter saturation in the perfused placenta occurs with glucose concentrations above 20 mmol/L (360 mg/dL) [37].

As we previously mentioned, there is a coexisting balance between physiologic insulin resistance and an adaptive increase in beta-cell insulin production during pregnancy. In early pregnancy, the endocrine pancreas anticipates the increase in insulin resistance that occurs late in pregnancy through an early increase in beta-cell insulin secretion. As peripheral tissues become progressively more resistant to insulin during normal pregnancy, maternal euglycemia is maintained through a 200–250% compensatory increase in maternal pancreatic insulin secretion [4].

This adaptive increase in insulin secretion may occur through different mechanisms. Lowering the threshold for glucose-stimulated insulin secretion (increased beta-cell glucose sensitivity) is the primary mechanism of the adaptation of pancreatic islets to the increased demand for insulin under normal blood glucose concentrations during pregnancy [38]. In addition, there is an increase in beta-cell mass that occurs via beta-cell hyperplasia and hypertrophy processes and via upregulation of insulin synthesis and secretion [39, 40, 41]. Placental lactogens have also been suggested to play an important role in beta-cell adaptation during pregnancy, as these hormones increase beta-cell insulin secretion and beta-cell proliferation and survival, and lower the threshold for glucose-stimulated insulin secretion [42].

Interestingly, a pregnancy-induced increase in C-peptide concentrations (associated with improved metabolic control during pregnancy) has also been demonstrated in women with long-term T1DM, even in women with undetectable C-peptide concentrations in early pregnancy [43]. This phenomenon may be related to different factors, such as: i) pregnancy-induced growth promoting factors influencing the rejuvenation of the beta cells; ii) suppression of the immune system; and iii) improvement in metabolic control leading to reduced beta-cell glucotoxicity [44, 45].

5. Defective beta-cell adaptation during pregnancy and gestational diabetes mellitus (GDM)

Gestational Diabetes Mellitus (GDM) is defined as glucose intolerance of various degrees with onset or first recognition during pregnancy, which is not clearly preexisting diabetes [46]. GDM is one of the most common pregnancy complications, affecting around 2–10% of pregnancies in the United States [47]. GDM is believed to result from pancreatic beta-cell dysfunction in women with preexisting insulin resistance [48]. In particular, defects in beta-cell adaptive mechanisms (through which pancreatic islets adapt to the increased gestational insulin demand) lead to the development of GDM. Compared with women with normal glucose tolerance, women who develop GDM undergo a similar degree of reduction in insulin sensitivity and insulin-mediated whole-body glucose disposal with advancing pregnancy (about 50% reduction) [4]. However, women with GDM fail to overcome peripheral insulin resistance with a proper compensatory increase in endogenous insulin secretion [22].

The reduction in insulin receptor tyrosine kinase phosphorylation and receptor tyrosine kinase activity is observed in pregnant women with normal glucose tolerance and in women with GDM. Yet, the latter group does not exhibit a significant improvement in insulin resistance postpartum [2, 22]. The altered reversal of insulin resistance postpartum in women with previous GDM is likely due to inflammation-induced impairment of peripheral insulin sensitivity secondary to the action of placental hormones and pro-inflammatory cytokines and adipokines (such as leptin, adiponectin, tumor necrosis factor alpha (TNF-α), interleukin-6, resistin) affecting the post-receptor insulin signaling pathway [2, 4, 5]. Notably, TNF-α (a pro-inflammatory cytokine produced from monocytes, macrophages, T-cells, neutrophils, fibroblasts, adipocytes, but also from the placenta) has been suggested as a crucial driver of insulin resistance in both pregnant women with normal glucose tolerance and women with GDM, which acts by inhibiting the insulin receptor tyrosine kinase activity via serine phosphorylation of IRS-1 [2, 4, 5, 22, 49]. Additionally, alterations in the placental structure may also negatively influence glucose homeostasis during pregnancy. Indeed, it has been shown that the placental abnormalities most consistently associated with maternal diabetes are represented by an increased incidence of villous immaturity, increased measures of angiogenesis, and increased placental weight [50]. Also, comorbidities such as diabetes and obesity may further negatively impact the placental function and the insulin signaling in the placental tissue [51]. Specific alterations in placental function have been described in the placentas of obese women as compared with the placentas of lean women, namely reduced mitochondrial respiration and adenosine triphosphate (ATP) generation in trophoblast [52].

Friedman et al. [53] examined rectus abdominis muscle biopsies obtained during cesarean section from pregnant women with normal glucose tolerance, pregnant women with GDM, and nonpregnant women undergoing elective surgery (nonpregnant controls). Authors found that insulin resistance to glucose transport during pregnancy is associated with a reduction in IRS-1 tyrosine phosphorylation, mainly due to decreased expression of IRS-1 protein. Yet, in women with GDM, there was also a decrease in tyrosine phosphorylation of the insulin receptor beta-subunit that contributed to further decreases in glucose transport activity [53]. Accordingly, Chu et al. [54] found that PI3K activity in adipose tissue of patients with GDM was significantly decreased to 82.89% compared with the control group and negatively correlated with the HOMA-IR (Homeostatic Model Assessment for Insulin Resistance).

Women with a history of GDM exhibit an increased 35–60% risk of developing type 2 diabetes mellitus (T2DM) over 10–20 years after pregnancy [47]. Moreover, GDM is associated with an increased risk of fetal complications (macrosomia, polyhydramnios, neonatal hypoglycemia, shoulder dystocia, respiratory-distress syndrome, increased perinatal mortality) and maternal complications (hypertension, preeclampsia, increased risk of cesarean delivery) [47, 55]. One of the most common and serious complications of GDM is macrosomia, which arises from maternal hyperglycemia. High maternal glucose levels cross the placenta and cause fetal hyperglycemia, which, in turn, stimulates the release of insulin by the fetal beta-cells and causes hyperinsulinemia, resulting in subsequent macrosomia (as insulin anabolic properties induce an increased growth rate of fetal tissues) [47]. It is worth reminding that insulin is present in the fetal pancreas as early as the 10th gestational week and in fetal plasma from the 12th gestational week [56, 57, 58].

Many risk factors for the development of GDM are similar to those for T2DM. These risk factors include overweight and obesity, excessive gestational weight gain, advanced maternal age, multiparity, family history of T2DM or GDM, polycystic ovary syndrome (PCOS), physical inactivity, GDM in the previous pregnancy, certain ethnicities (including Asian ethnicity), a previous macrosomic child, Westernized diet, genetic polymorphisms, and intrauterine environment (low or high birth weight) [48, 59, 60, 61, 62, 63, 64, 65].

Screening for GDM should be performed particularly in at-risk women through a 2-hour, 75-g oral glucose tolerance test (OGTT) performed at 24–28 weeks of gestation. According to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria, the diagnosis of GDM is made if at least one value of plasma glucose concentration is equal to or exceeds the thresholds of 92 mg/dL, 180 mg/dL, and 153 mg/dl (for fasting, 1-hour and 2-hour post-glucose load glucose values, respectively) after performing a 75-g OGTT [66]. All patients with any risk factor for GDM should receive healthy lifestyle counseling to address modifiable risk factors, such as excessive weight gain and physical inactivity, to prevent GDM [67].

Management of established GDM involves lifestyle intervention consisting of diet counseling aimed at limiting glycemic excursions and ensuring appropriate weight gain (weight control), coupled with self-monitoring of blood glucose (SMBG) and promotion of safe and insulin-sensitizing physical activity regimens. Indeed, it is well known that physical exercise induces a rapid increase in the rate of glucose uptake in the contracting skeletal muscles. This augmented membrane glucose transport capacity is due to the recruitment of GLUT4 transporters to the sarcolemma [68].

Pharmacotherapy is usually started when lifestyle intervention alone fails to lead to adequate glucose control in women with GDM. Pharmacological treatment of GDM involves the use of oral antidiabetic medications (metformin or glibenclamide) or, more frequently, exogenous insulin therapy [69, 70]. Indeed, insulin therapy is considered the first-line pharmacologic therapy for GDM, as insulin does not cross the placenta to a significant degree. Fasting hyperglycemia is treated with basal (long-acting) insulin analogs, while postprandial hyperglycemia is treated with rapid-acting (prandial) insulin analogs. Prandial and basal insulin can be used separately or in combination, based on the individual glycemic profile [71].

Remarkably, appropriate treatment of GDM has been shown to reduce the risk of both maternal and fetal complications of GDM, such as macrosomia, large for gestational age newborns, shoulder dystocia, cesarean section, preeclampsia, and respiratory distress syndrome [72]. Finally, prevention and adequate management of GDM are critical to stop the vicious cycle that increases the risk of developing metabolic dysfunctions such as obesity and diabetes in the offspring [26, 73, 74].

6. Conclusions

Normal pregnancy is physiologically characterized by a progressive increase in insulin resistance, which acts as a physiological adaptation aimed to ensure the adequate supply of glucose to the rapidly growing fetus. However, an early adaptive increase in beta-cell glucose sensitivity and beta-cell insulin secretion ensures the maintenance of glucose homeostasis in normal pregnancy. Potential mechanisms underlying the gestational insulin resistance include hormonal, placental, and genetic or epigenetic factors, as well as the increase in visceral adipose tissue, alterations in gut microbiota, and the possible concurrent presence of overweight or obesity. In some instances, defects in beta-cell adaptive mechanisms occur, leading to substantial exacerbation of insulin resistance and possible development of GDM. A basic knowledge of the physiologic adaptations and the possible dysregulations of glucose homeostasis and insulin sensitivity during pregnancy is critical for identifying women who are at risk for maternal and/or fetal metabolic complications and for properly tailoring the prevention and treatment strategies for this population.

Conflict of interest

The authors declare no conflict of interest.

Author contributions

MI conceived and wrote the manuscript. ML and NP equally contributed to writing the manuscript. AF, DDM, and CR revised different parts of the manuscript. All authors have read and agreed to the published version of the manuscript.