Gestational Diabetes During and After Pregnancy

7. Insulin and the Placenta in GDM

Ursula Hiden and G. Desoye 

(1)

Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria

G. Desoye

Email: gernot.desoye@meduni-graz.at

Abstract

Placental development and function are tightly regulated by endocrine, paracrine, and autocrine factors present in the maternal and the fetal circulation and in the placenta. Gestational diabetes (GDM) is associated with a derangement of the concentration of several hormones, cytokines, metabolites, and growth factors in both circulations that may subsequently alter placental morphology and function. One of these is the peptide hormone insulin, which exerts pleiotropic effects on target cells. The placenta is very rich in receptors for insulin and insulin-like growth factors (IGFs) and is therefore susceptible to their concentration changes. This chapter describes general placental alterations in GDM and particularly focuses on the effects of insulin and its signalling components on the placenta.

7.1 Introduction

The placenta is a fetal organ with widespread functions located at the interface between mother and fetus. It transports maternal nutrients to sustain fetal growth, synthesizes hormones and growth factors to facilitate maternal adaptation to pregnancy, represents an immunologic barrier, and dissipates thermic energy resulting from fetal metabolism. Proper function of the placenta is essential to pregnancy outcome. Because of its position between the maternal and fetal compartment, the placenta is susceptible to regulation by hormones, growth factors, and metabolites present in both circulations. These factors, along with their binding proteins and receptors, form a complex network allowing tight control of placental development and function. Any disturbance of this network e.g., by concentration changes in one or several components may also compromise placental functioning.

GDM is associated with alterations in concentrations of a wide range of hormones, growth factors, cytokines, and metabolites in the maternal circulation. Available evidence, though limited, also shows changes in the fetal blood and in the placenta. These include cytokines secreted by adipose tissue, called adipocytokines, insulin, and glucose levels. As a consequence, placentas from GDM pregnancies display various changes in both morphology and function. These changes may represent adaptive responses to the altered maternal and fetal milieu.

In this chapter, the effect of GDM-associated maternal and fetal hyperinsulinemia on the placenta will be discussed. The impact of diabetes and GDM, obesity and diabetes therapies on the placental insulin receptor and its signaling molecules will be elucidated.

7.2 The Human Placenta

The human placenta has a tree-like, villous structure. The terminally differentiated syncytiotrophoblast, a syncytium that is formed from fusion of subjacent, mitotically-active cytotrophoblast cells, covers the surface of all villi. It thus represents the outermost interface of the placenta that is in contact with the maternal circulation. Some villi are physically anchored in the maternal uterus, whereas others freely float in the intervillous space that is filled with maternal blood. The establishment of a proper maternal blood stream into the intervillous space is an important step early in placental development. It depends on the invasion of trophoblast cells into the maternal uterus, followed by remodeling and opening of the maternal uterine spiral arterioles.

Inside the villous core, tissue-resident macrophages, fibroblasts, and placental blood vessels are surrounded by extracellular matrix. The big vessels from the umbilical cord ramify into smaller vessels and capillaries at the tips of the villi and merge again to form the vein of the umbilical cord. Thus, the maternal and the fetal compartments are in contact with different surfaces of the placenta: the microvillous membrane of the syncytiotrophoblast is in contact with the maternal blood, whereas the endothelium of the placental vasculature is in contact with the fetal blood.

The remodeling of the uterine arteries by trophoblasts is completed in the second trimester and, thus, will likely not be affected by GDM that clinically manifests at mid-gestation. However, placental vascularization as well as placental growth continue up to term of gestation and may be affected by the diabetic environment of GDM.

7.3 Insulin Therapy and Antidiabetic Drugs

When dietary management fails to achieve adequate glucose control, the therapeutic use of insulin has been regarded as the most physiological and safe way to treat hyperglycemia in GDM. This is because free insulin cannot cross the placenta.1 However, insulin complexed to anti-insulin antibodies has been detected in cord blood suggesting transplacental transport of insulin bound to maternal antibodies via placental Fc-receptors.2 By this route insulin escapes degradation by placental insulinases.3

Most diabetic pregnant women treated with porcine insulin are reported to have anti-insulin antibodies. Their prevalence depends on duration of the disease and on the kind of insulin administered.4 Thus, in patients with insulin-treated pregestational diabetes, anti-insulin antibodies will occur, although even GDM women treated with insulin produce anti-insulin IgG.5 Higher levels of insulin antibodies have been found when animal insulin is used for therapy as compared with human insulin.6 The biological effect of the maternally-derived insulin in the fetal circulation is unclear. The presence of maternal anti-insulin antibody levels does not correlate with birth weight or fetal metabolic disorders.5

In recent years, insulin analogs such as insulin lispro7 and insulin aspart8 are often used. They do not increase insulin antibody levels. Hence, they do not utilize the transplacental transport mechanism via Fc-receptors and are not detectable in the fetal circulation.

The use of glucose-lowering oral agents in pregnancy has raised discussion and concern because of limited data on their short- and long-term risk for the fetus and neonate, respectively. The suitability of several classes of antidiabetic agents for treatment of diabetes in pregnancy has been determined in ex vivo perfusion of human placentas. The PPAR-gamma agonists thiazolidinediones (rosiglitazone, pioglitazone), alpha-glucosidase inhibitors (acarbose) and biguanides (metformin) readily cross the placental barrier.9 Nevertheless, metformin and acarbose have been used increasingly for GDM therapy. Various studies showed no consistent evidence for an increase in adverse maternal or neonatal consequences.10 However, the use of compounds crossing the placenta has to be considered very critically.

Exenatide, a synthetic exendin-4 with incretin effect stimulating insulin secretion is transported across the placenta in negligible amounts, resulting in insignificant exposure to the fetus.11 The sulfonylureas glipizide and glyburide block ATP-sensitive potassium channels in β-cells and thus stimulate insulin secretion. Both show little or no transport across the placenta.12 Although the potential transport of these drugs across the placenta has been studied, almost no information is available on potential effects of these drugs on the placenta itself. It is conceivable that some cellular processes and placental functions are modified by drugs in the maternal circulation. In the single study to examine this question, glipizide induced a dose-dependent upregulation of placental insulin receptors (IR) in vitro13 (Fig. 7.1), and may alter placental function. Glyburide is safe and has been used for the treatment of GDM.12

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Fig. 7.1

Amount of insulin receptors (IR) on isolated placental trophoblasts after 48 h treatment with glipizide shows a dose-dependent increase (a). The affinity of receptors towards insulin remains stable upon glipizide treatment (b). Data taken from13

7.4 Hyperglycemia, Hyperinsulinemia and Proinflammatory Cytokines

Hyperglycemia in the fetal circulation produces hyperinsulinemia in the fetal compartment. In GDM women treated with insulin, maternal plasma insulin levels are also elevated.14 The elevated insulin levels in the maternal and fetal circulation will particularly affect placental development, because of the high expression of IR15 on both placental surfaces.16

Adipocytokines, biologically active peptides, profoundly influence insulin sensitivity, contribute to insulin resistance, and produce a proinflammatory state. They appear to be involved in the development of obesity-mediated adverse effects on glucose and lipid metabolism17 and may represent a molecular link between increased adiposity and impaired insulin sensitivity.

Several adipocytokines display altered levels in the maternal or fetal circulation in GDM pregnancies. Tumor necrosis factor alpha (TNF-α) has elevated and reduced levels in the maternal and fetal circulation, respectively,18whereas, plasma leptin is increased in mother19 and fetus20 and placental leptin production is increased GDM.20 Furthermore, decreased plasma levels of maternal adiponectin in GDM have been reported.21 Resistin levels are lower in infants born to mothers with GDM.22 Thus, adiposity may further influence and promote insulin resistance in pregnancy in general and in GDM in particular, ultimately leading to maternal and, hence, fetal hyperglycemia.

7.5 Morphological Alteration of the Placenta in GDM

The placenta in GDM is characterized by a variety of morphological and functional changes reviewed in detail elsewhere.2324

GDM first appears in the second half of gestation when fundamental steps in placental development such as placentation and opening of the uterine spiral arteries have been completed. However, central placental functions and processes such as nutrient transport, synthesis of hormones and growth factors, as well as placental growth and vascularization may still be influenced by metabolic derangements in both circulations. Ultimately, these lead to changes in placental morphology observed at term of gestation.

A well known placental alteration in GDM is the increase in placental weight.25 This is paralleled by an increase in fetal weight, resulting from excessive fat accumulation.26 The reason for the elevated weight of placenta and fetus are unclear, although changes in transplacental transport may be implicated.

In addition to augmented growth, gross placental structure may be altered in GDM predominantly as a result of an enlargement of placental surface and exchange areas; i.e., the syncytiotrophoblast and the placental endothelium as a result of hyperproliferation and hypervascularization.27 Their underlying mechanisms are not clear, but maternal hyperinsulinemia early in gestation is a candidate for increased trophoblast proliferation28 and for inducing structural modifications.29 However, other maternal growth factors are likely to contribute.

The greater placental capillary surfaces may result from feto-placental counter regulatory mechanisms to fetal hypoxia. Presence of fetal hypoxia can be deduced from the elevated fetal erythropoietin levels often observed in the fetuses of diabetic women30 and may result from changes in GDM. The low oxygen levels may have profound consequences for fetus and placenta and upregulate expression of proangiogenic factors such as VEGF and FGF-2 in the feto-placental compartment hence stimulating placental vascularization.31,32 Hypervascularization resulting from stimulated vascular branching is a common feature of the placenta in GDM.33

7.6 Functional Alteration of the Placenta in GDM

7.6.1 Gene Expression

Comparison of gene expression of placentas from obese women with insulin-treated GDM with those from healthy controls, revealed 435 genes differentially expressed. Most of these were related to inflammatory pathways, which may reflect the obesity of these mothers.34 A more recent study measured gene expression in total placental tissue from normal and nonobese GDM subjects. Among 22,215 genes surveyed, the expression of 66 genes was altered. Their functions were predominantly related to immune response, and development and regulation of cell death.35 These differences in gene expression arise from the interaction of the maternal and fetal diabetic milieu with the placenta, including altered levels of hormones, growth factors, and metabolites. For instance, insulin in a concentration similar to that present in fetal cord plasma in GDM alters the expression of 146 genes on primary placental endothelial cells.36 These gene expression studies will help reveal biological processes that are most affected by GDM and thus will contribute to improving our understanding for the mechanisms underlying changes in placental phenotype associated with GDM.

7.6.2 Placental Transport

The transporting epithelium in the human placenta is the syncytiotrophoblast with its microvillous plasma membrane bathing in the maternal blood in the intervillous space. At specialized sites, the syncytiotrophoblast basal membrane is in contact with the endothelial cells lining the fetal capillary. These sites are the key structures across which all nutrients such as glucose, amino acids, and lipids destined for the fetus have to be transported.

The increased transplacental glucose flux underlying fetal hyperglycemia is not accounted for by changes in glucose transporter expression because perfusion experiments demonstrate an unaltered or even reduced glucose transfer across the placenta in diet- and insulin-treated GDM, respectively.3738 This suggests the steeper maternal-fetal glucose gradient as the driving force for the enhanced glucose fluxes across the placenta in GDM. The unchanged concentration differences of glucose between umbilical arteries and vein in GDM39 support this notion.

Conflicting data exist on amino acid transport systems in GDM. Upregulation of the placental syncytiotrophoblast system A amino-acid transporter, which transports alanine, serine, proline, and glutamine, has been observed40although not uniformly.4142 As amino acid transport systems are complex and several transporter systems exist with overlapping specificity, conclusions from one transport system may not apply to general amino acid transport. Future studies measuring amino acid transport in placental perfusion using GDM placentas would allow better identification of potential GDM-associated changes in the transport and help to elucidate the role of amino acid transport in fetal adiposity.

Almost all fatty acids circulate in esterified form in triglycerides, phospholipids, and cholesterol esters. Together with apolipoproteins and lipid-soluble vitamins they are complexed in lipoproteins. GDM does not significantly alter maternal cholesterol levels, but maternal as well as fetal hypertriglyceridemia, particularly in the VLDL and HDL fraction, has been a well known feature of GDM.43,44 At present the mechanism of fatty acid transport across the placental barrier is still not fully understood. The lipoproteins have to bind to LDL, HDL, and VLDL receptors on the syncytiotrophoblast surface. Subsequently, they are either endocytosed (LDL45) or depleted of cholesterol (HDL46). In addition, endothelial lipase alone47 or in concert with other yet unidentified lipases, hydrolyzes maternal triglycerides. The released free fatty acids will then be taken up by and transferred across the trophoblast, a complex process involving several fatty acids transport molecules and binding proteins.4849 Cellular membranes of GDM placentas contain a higher proportion of these fatty acids. Several scenarios may be involved: selective uptake and intermediate storage of these fatty acids into the placenta, their increased placental synthesis, their reduced conversion into eicosanoids and/or their decreased release into the fetal circulation.50 The fetal concentrations of arachidonic acid and docosahexaenoic acid are reduced in GDM,51whereas those in the mothers are unchanged.52 A more detailed analysis found these changes only in the arterial, but not in the venous, cord plasma coming from the placenta. This indicates that altered fetal metabolism of long-chain fatty acids rather than altered placental transport account for alteration of fatty acids in the fetal circulation in GDM.53

7.6.3 Oxygen Delivery in Diabetes

Several utero-placental alterations in GDM are unfavorable for oxygen delivery to the fetus. A higher proportion of glycosylated hemoglobin,54 which has a stronger binding affinity for oxygen than nonglycosylated hemoglobin, will impair oxygen delivery to the placenta. This may be further augmented by a reduced utero-placental blood flow, especially without tight glycemic control of the mothers.55In the placenta, thickening of the trophoblast basement membrane is frequently found. It mainly results from increased amounts of collagen.5657 Collectively, these changes may lead to reduced oxygen delivery to the fetus. In addition, fetal demand for oxygen may be increased, because of hyperinsulinemia- and hyperglycemia-induced stimulation of the fetal aerobic metabolism. In the situation of imbalanced fetal oxygen demand and maternal supply, fetal hypoxia may ensue. Elevated fetal plasma erythropoietin levels in GDM pregnancies may reflect such imbalance.30

7.7 Insulin Effects in the Human Placenta

The placenta is a rich source of IR and has served as the tissue of origin for isolation of the receptor protein. The IR distribution pattern in the placenta is complex and varies with gestational age. In the first trimester IRs are mainly expressed on the trophoblasts and are thus in contact with the maternal circulation, whereas at term most IRs are located at the placental endothelium and are directed toward the fetal blood. At this stage of gestation the trophoblast contains only a modest IR amount, located at the microvillous membrane. This change in IR location during gestation may reflect a change in control of insulin-dependent processes in the placenta from the mother early in gestation to the fetus later in gestation. For obvious reasons, IR expression in placentas from uncomplicated pregnancies at mid-gestation has not been investigated, leaving unresolved the question of which distinct time period in gestation this change in location occurs. Hence, insulin target cells at the time period of the clinical manifestation of GDM and for the initial effects of hyperinsulinemia on placental processes is unknown.

Although IR expression in the trophoblast decreases toward term of gestation, several insulin effects have been reported in isolated term trophoblasts, mainly relating to transport function and hormone synthesis. Insulin stimulates the uptake of the amino-acid analog α-aminoisobutyric acid, a synthetic substrate for the system A amino acid transporter.58,59 This is an isolated finding and a general conclusion on GDM-associated alterations in transplacental amino acid transport remains to be established.

Insulin’s endocrine activity affects the synthesis and secretion of placental hormones. Trophoblast estradiol-β secretion is downregulated60,61 paralleled by the inhibition of aromatase (CYP19A1), the enzyme that catalyzes the last step in estrogen biosynthesis.62 The effect of GDM on maternal estrogen levels is controversial. Couch et al44 found elevated levels of β-estradiol in plasma of women with diet-treated GDM, while others reported reduced levels, when women were insulin-treated,63 or no change.6465

Moreover, insulin upregulates placental lactogen (hPL) secretion from isolated trophoblasts.6061 Since more than 99% of hPL is released into the maternal circulation, higher maternal hPL concentrations in insulin-treated GDM women would be expected. However, plasma levels are rather reduced at term,63 suggesting additional regulators of circulating hPL levels beyond insulin, and IGF-I may be a candidate. Insulin also reduces the expression of placental growth hormone in choriocarcinoma cells used as trophoblast models.66 This is an interesting finding because placental growth hormone can induce insulin resistance.67

In line with its lipogenic effects in other tissues the combination of insulin and fatty acids upregulate adipophilin expression in trophoblasts.68 Adipophilin is a protein implicated in cellular fatty acid uptake and storage of neutral lipids in adipocytes. Hence, elevated adipophilin levels along with the lipogenic activity of insulin may contribute to elevated storage of triglycerides in GDM placentas.69

Despite the high amounts of IR on placental endothelial cells at term of gestation,15 no distinct insulin effects on these cells have been identified so far, apart from a general regulation of gene expression.36Interestingly, the IRs are particularly expressed at branching sites of placental capillaries with high proliferative activity.70 This suggests that the general insulin effect on vascular endothelium such as the activation of endothelial NO synthase (eNOS) and subsequent expression of proangiogenic factors such as VEGFA,71 ultimately promoting angiogenesis and vascularization, may also be operative in the placenta.70

The GDM-associated elevation of insulin levels in the fetal and – if insulin treated – also in the maternal circulation14 may contribute to placental changes observed in GDM in vivo. The insulin-induced increase in amino acid transport may sustain fetal overgrowth in GDM. The upregulated VEGFA expression in the endothelial cells may contribute to the diabetes-associated placental hypervascularization (cf. above).

7.8 Placental Insulin Receptor Expression in Normal and Diabetic Pregnancy

The amount of IR can be regulated by ambient insulin concentrations. Hence, it comes as no surprise that in GDM IR protein is also changed in total placental tissue and on trophoblast membranes.14,23 The alterations depend on the type of diabetes and on the treatment modality and, obviously on maternal obesity. Whereas mild forms of GDM treated with a restriction in nutrient uptake down-regulate trophoblast IRs, severe insulin-treated cases show an upregulation of IRs on trophoblast membranes similar to Type 1 diabetes14 (Fig. 7.2). In GDM, IR expression in total placental tissue depends on the metabolic control. Whereas well controlled insulin-treated GDM reveals no change,72 in poorly controlled or even untreated GDM, insulin receptor expression is down-regulated.73,74

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Fig. 7.2

Diabetes alters the number of IR on trophoblast plasma membranes. Diet-treated GDM reduces insulin receptor numbers, whereas insulin-treated GDM and Type 1 diabetes increase the amount of trophoblast IR. Data taken from13

The mechanisms accounting for the changes in IR in diabetes are unknown. Among several scenarios these may be the result of the different maternal insulin levels in diet- vs. insulin-treated GDM cases14 or of elevated glucocorticoid levels75,76 which, similar to other tissues,77 may up-regulate IR expression in the more severe cases of GDM and in T1DM.

7.9 Insulin Resistance in GDM

Insulin resistance is a common phenomenon in the second half of normal pregnancy resulting from the insulin-antagonizing action of various pregnancy-related hormones. In GDM, insulin resistance cannot be sufficiently compensated for by maternal insulin production and as a consequence hyperglycemia arises. Insulin resistance emerges from elevated levels of cytokines and hormones counter-acting IR signaling and from altered expression levels of components of the insulin signaling cascade.78 Both will result in reduced insulin action. In GDM, maternal levels of the cytokine TNFα are increased.18Plasma levels of leptin are elevated in the maternal19,79 and the fetal20circulation. Both interfere with IR signal transduction. TNFα impairs IR signaling by inhibition of IR substrate 1 (IRS1) activity, whereas hyperleptinemia leads to insulin resistance by activation of SOCS (suppressor of cytokine signaling) proteins, which, ultimately, attenuate leptin and IR signaling.80

The placenta expresses TNFα and leptin receptors and hence, may also be a target of the weakening effects of TNFα and leptin on insulin signaling. The role of the pregnancy-related hormones such as estrogen, progesterone, prolactin, and human placental lactogen in the development of the accentuated insulin resistance of GDM is unclear as they do not significantly correlate with insulin resistance.81

In addition to factors counteracting insulin signaling, altered activation or expression of components of the IR signaling cascade in the insulin target cells may contribute to insulin resistance. Also in GDM, alterations in activation, phosphorylation or expression of proteins related to insulin signaling in classical insulin target tissues (adipose tissue78,82; skeletal muscle78,83) have been shown. In the placenta, only limited data about insulin resistance or alteration in insulin signaling resulting from GDM are available.7284 However, these are restricted to measurements of total IR-protein phosphorylation and do not include information on activation or inhibition of site-specific insulin signaling by i.e., phosphorylation of tyrosine or serine residues, respectively. This information is important because signaling may be induced or inhibited depending on the phosphorylation site.

7.10 GDM Alters Placental Insulin Receptor Signaling Components

Basically, insulin activates two main signaling pathways: the phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) and the mitogen-activated protein kinase (MAPK) pathway. The PI3K/PKB pathway induces the metabolic effects of insulin such as translocation of GLUT4 glucose transporters, glycogen and protein synthesis. The PI3K is composed of a regulatory 85-kDa subunit and a catalytic 110-kDa subunit. The MAPK pathway stimulates proliferation, migration and angiogenesis.85 Gene knock out experiments in mice and isolated cells in vitro strongly suggest that MAPK signaling is mainly activated via insulin receptor substrate 1 (IRS1) whereas insulin receptor substrate 2 (IRS2) plays a key role in the regulation of carbohydrate metabolism.86 Thus, expression changes of any insulin signaling component may affect insulin receptor signal transduction and, ultimately, insulin effects.

Obesity and GDM are associated with altered expression of several downstream components of the insulin signaling pathway in the placenta (Fig. 7.3). When obesity is associated with GDM, or vice versa, the changes are more pronounced. A reduction of IRS1 expression is a common feature in skeletal muscle and adipose tissue in women with GDM.78 The obese, nondiabetic women have higher plasma insulin levels than the nonobese group, whereas the glucose levels are normal. This indicates that the elevated insulin levels in obesity with normal glucose tolerance may already induce changes in the placental insulin signaling pathway similar to but less severe than those observed in insulin-treated GDM. Alternatively, or in addition, the inflammation associated with obesity and GDM may contribute as well.

A160858_1_En_7_Fig3_HTML.gif

Fig. 7.3

Altered expression of placental insulin signaling components in nonobese and obese women without or with insulin-treated GDM. The pathway illustrated is one of several insulin signaling cascades resulting in GLUT4 translocation to the plasma membrane. Obesity alone alters the expression of IRS2 and PI3K p85α (second pathway) vs. healthy, nonobese controls (first pathway). Placentas from insulin-treated non obese women with GDM showed additional changes in IRS1, PI3K p85α and GLUT4 (third pathway). Similar changes to those found in insulin-treated nonobese GDM were found in obese insulin-treated GDM. Insulin concentrations refer to those measured in the late third trimester; *indicates significant difference from controls. The red and green color indicates upregulation and downregulation vs. control, respectively. According to data from72

7.11 Conclusion

Because of the presence of IR on the maternal and fetal surface the placenta is a target tissue of insulin in both circulations. Whereas various effects of insulin have been identified in isolated placental cells, their relevance remains to be shown in vivo. GDM is a condition associated with exacerbated maternal insulin resistance. To date, presence and character of insulin resistance in the placenta in GDM has not been determined, and the few existing studies present conflicting data on insulin receptor autophosphorylation. Elevated levels of TNFα and leptin in the maternal and/or fetal circulation may impair insulin signaling and alter levels of insulin signaling molecules. This then may modify insulin effects in GDM and produce changes observed in placentas obtained from GDM women.

Only few studies exist that define treatment modality or even distinguish between diet-treated and insulin-treated GDM cases, and between placentas from obese and nonobese women. Over the years, it has become clear that these represent different groups with different degrees of metabolic derangement. Furthermore, obesity, even with normal glucose tolerance, is associated with a change in the levels of insulin signaling components in the placenta, which resembles changes observed in insulin-treated GDM and, therefore, may represent a modest form of inflammatory response of the placenta. Placental alterations associated with maternal obesity might represent a stage preceding placental alterations in GDM. In order to understand the effect of GDM on the placenta, it appears of central importance to define and distinguish between these groups. A detailed analysis of the placental response to the diabetic environment is still pending.

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