Gestational Diabetes During and After Pregnancy

9. Mechanisms Underlying Insulin Resistance in Human Pregnancy and Gestational Diabetes Mellitus

Carrie E. McCurdy  and Jacob E. Friedman

(1)

Department of Pediatrics, University of Colorado Denver, School of Medicine, Aurora, CO, USA

Carrie E. McCurdy

Email: carrie.mccurdy@ucdenver.edu

Abstract

Obesity and pregnancy are associated with a combination of insulin resistance and inflammatory changes that exacerbate, in combination, potentially increasing risk for GDM and subsequent progression to Type 2 diabetes. During mid-pregnancy, skeletal muscle and adipose tissue progressively shift from glucose to fat metabolism, due to insulin resistance associated with placental hormones, primarily placental growth hormone. In 5-10% of the pregnant population, increased inflammatory cytokines, reduced adiponectin, and poor islet function provoke greater insulin resistance leading to gestational diabetes mellitus (GDM). A predominance of negative regulators impacts 3 specific aspects of the insulin receptor signaling pathway during normal pregnancy. These include suppression of insulin receptor β subunit and IRS-1 activation, a loss of IRS-1 protein, and an increase in the p85α subunit of PI 3-kinase, a nutrient sensor that acts as a dominant negative manner to suppress insulin signaling. Human studies demonstrate that a major defect in GDM involves the inability of insulin to stimulate glucose transport into skeletal muscle. The mechanisms for this severe insulin resistance are not completely understood, but involve an unknown post-receptor defect(s), perhaps caused by interaction between inflammation and serine kinases such as p70S6K in skeletal muscle. The majority of these changes are reversible postpartum except in obese GDM women who maintain impaired glucose intolerance. A decrease in IRS1 abundance associated with excessive IRS1 serine phosphorylation, accompanied by increased cytokine expression, underlies a state of chronic insulin resistance in obese GDM women that greatly increases their risk for progression to Type 2 diabetes.

Abbreviations

GDM

Gestational diabetes mellitus

IR

Insulin receptor

IRS1

Insulin receptor substrate

PI 3-Kinase

Phosphatidylinositol 3-kinase

T2DM

Type 2 diabetes mellitus

hPL

human Placental Lactogen

hPGH

human Placental Growth Hormone

GH

Growth hormone

HSL

Hormone sensitive lipase

PD3B

cAMP-Phosphodiesterase 3B

FFA

Free fatty acid

TG

Triglyceride

TNFα

Tumor necrosis factor alpha

IGT

Impaired Glucose tolerance

MAPK

Mitogen-activated protein kinase

PDK1

3-Phosphoinositide-dependent kinase

AMPK

Adenosine monophosphate kinase

PPARα

Peroxisome proliferator-activated receptor alpha

JNK1

cJun N-terminal kinase 1

NFkB

Nuclear factor kappa B

PKCθ

Protein kinase C theta

mTor

Mammalian target of rapamyacin

9.1 Development of Insulin Resistance During Pregnancy

Pregnancy is characterized as an insulin resistant state. While 90–95% of all women retain normal glucose tolerance, approximately 5–10% develop GDM.12 The development of insulin resistance during pregnancy is usually compensated by a considerable increase in insulin secretion. However, in women diagnosed with GDM, insulin resistance is more profound, and this challenge, combined with decreased pancreatic β-cell reserve, triggers impaired glucose tolerance.3 Catalano et al reported the first prospective longitudinal studies in women with normal glucose tolerance using the euglycemic-hyperinsulinemic clamp.4 There was a significant 47% decrease in insulin sensitivity in obese women during late pregnancy and 56% decrease in lean women during pregnancy compared to preconception.4,5 Other investigators have reported that insulin sensitivity significantly decreased (40–80%) with advancing gestation.68 Skeletal muscle is the principal site of whole-body glucose disposal, and along with adipose tissue becomes severely insulin resistant as gestation progresses. Using isolated skeletal muscle fibers from the rectus abdominis obtained during elective caesarian-section or other elective surgery, Friedman et al demonstrated that pregnancy results in a marked 40% reduction in insulin-stimulated glucose transport in skeletal muscle compared to obese nonpregnant women. This impairment is significantly worse in GDM subjects (65% reduced) compared with obese nonpregnant subjects.9 These results are analogous to Garvey et al,10 who measured glucose transport in isolated adipocytes and found a more severe decrease in glucose transport in obese GDM subjects, although these were compared with lean (nonobese) pregnant controls. Regarding basal endogenous (hepatic) glucose production, hepatic glucose output is less suppressed during euglycemic-hyperinsulinemic clamp in lean and obese with GDM compared with each control group.4,5 Overall, these results indicate that all three major insulin target tissues including liver, skeletal muscle, and adipose tissue develop marked insulin resistance in women during normal pregnancy, and to an even greater extent in obese women with GDM.

9.1.1 Hormone and Metabolic Factors Contributing to Insulin Resistance in Pregnancy and GDM

Beginning in mid-pregnancy, placental-derived hormones reprogram maternal physiology to achieve an insulin resistant state, reducing insulin sensitivity ∼50% in the last trimester (Fig.9.1). These hormones also contribute to altered β-cell function. Human placental lactogen (hPL) increases up to 30-fold throughout pregnancy and induces insulin release from the pancreas; studies outside of pregnancy find that they can cause peripheral insulin resistance.1112 Another major hormone implicated in insulin resistance during pregnancy is human placental growth hormone (hPGH). hPGH increases 6–8-fold during gestation and replaces normal pituitary growth hormone (GH) in the maternal circulation by ∼20 weeks gestation.13 Because hPGH is difficult to assay in human serum, and the gene is absent in other species, the potential role of hPGH in pregnancy-induced insulin resistance is not well studied. Much like the well documented effects of excess normal GH on insulin sensitivity however, over-expression of hPGH in transgenic mice comparable to levels seen in the third trimester of pregnancy causes severe peripheral insulin resistance.14 The impact of hPGH on the insulin signaling cascade in skeletal muscle has been studied in vivo and in vitro in both skeletal muscle and adipose tissue, and appears to interfere with insulin signaling by a unique mechanism involving PI 3-kinase,1517 as discussed below. One other potentially important hormone, which increases about 2.5-fold in pregnancy, is maternal cortisol.18 Glucocorticoids are well known to interfere with insulin signaling in skeletal muscle by postreceptor mechanisms and could, in addition to hPGH, be involved in suppressing insulin sensitivity in pregnancy.19

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Fig. 9.1

A rise in placental hormones suppresses maternal insulin sensitivity to shuttle necessary fuels to the fetus. Increased production of placental hormones, including pGrowth Hormone, pLactogen, leptin, and potentially TNFα, act on maternal insulin-responsive tissues, the liver, skeletal muscle, and adipose tissue, to decrease insulin responsiveness. In adipose tissue, insulin’s ability to suppress hormone-sensitive lipase (HSL) and stimulate adipose tissue LPL activity results in increased maternal free fatty acids (FFA) and a production of maternal triglycerides (TG) to the placenta for fetal use. In addition to placental hormones, the increased flux of FFA from maternal adipose tissue negatively impacts insulin signaling in both liver and skeletal muscle. In skeletal muscle, there is a reduction in insulin-stimulated glucose uptake and, in the liver, insulin fails to suppress glucose production. In combination, the insulin resistance in maternal liver and skeletal muscle in late pregnancy accelerates fuel availability to the fetus. In GDM, prior insulin resistance is compounded by the normal insulin resistance of pregnancy, resulting in a greater shunting of excess fuels to the fetus, which can lead to fetal overgrowth

Similar to its effect on skeletal muscle, placental hormones interfere with insulin-stimulated glucose uptake into adipose tissue for esterification, as well as interfere with insulin’s ability to suppress lipolysis through the enzyme hormone-sensitive lipase (HSL).20 The normal suppression of lipolysis involves insulin-mediated phosphorylation of cAMP-phosphodiesterase 3B (PDE3B), which causes a reduction in cAMP levels to suppress lipolysis. The decrease in cAMP levels inhibits the activity of HSL, thereby reducing triglyceride (TG) breakdown in adipocytes, principally during early pregnancy. In late pregnancy, failure to fully inhibit lipolysis results in increased release of free fatty acids (FFA), which in obese individuals with GDM results in elevated fasting FFA.20 Thus, insulin resistance in adipose tissues plays an important role in increasing circulating FFA that can accumulate in nonadipose depots, like skeletal muscle and the liver, enhancing insulin resistance in the mother, as well as providing fuel for the growth of the fetus. In women with pre-existing obesity, insulin resistance prior to gestation worsens further during pregnancy and this can lead to an elevation in maternal/fetal TG, which may play an important role in excessive adiposity in babies born to overweight/obese mothers.21

9.1.2 New Factors Involved in Insulin Resistance in Pregnancy

During pregnancy, the placenta and adipose tissue become significant sources of many cytokines and adipocytokines, whose expression is dysregulated by maternal diabetes and obesity.2223 Tumor necrosis factor alpha (TNF-α) is a cytokine produced not only from monocytes and macrophages within the adipocyte, but from T cells, neutrophils, and fibroblasts within the placenta. Obese animals and humans show a positive correlation between TNF-α levels and body mass index (BMI) and hyperinsulinemia.2425 Infusion of TNFα, results in increased insulin resistance in rat and in human skeletal muscle cells incubated in culture.26 27 Although the concentration of circulating TNFα in plasma of obese patients is extremely low compared with that found in burn patients and patients with cachexia, recent evidence indicates that skeletal muscle expresses TNFα mRNA and that it may act in a paracrine fashion.2627 Studies report that changes in insulin sensitivity from early (22–24w) to late gestation (34–36w) are correlated with changes in plasma TNFα (r = 0.45) and that circulating TNFα may be produced by the placenta to exacerbate insulin resistance, through mechanisms discussed below. Lastly, there appears to be a local fivefold increase in TNFα mRNA in skeletal muscle from obese women with GDM that persists postpartum which could be involved in producing chronic local subclinical inflammation and insulin resistance in this population.28

Adiponectin is a secreted globular protein synthesized exclusively in adipocytes and has been shown to correlate highly with whole-body insulin sensitivity through its receptors in skeletal muscle and liver.29Adiponectin can increase glucose uptake in skeletal muscle and suppress hepatic glucose production through its effect on stimulation of AMP Kinase.30 Studies have also demonstrated that adiponectin stimulates fatty acid oxidation through activation of peroxisome proliferator-activated receptor alpha (PPARα) in liver and skeletal muscle.31 Adiponectin levels are reduced in GDM patients, which could contribute to the reduced insulin sensitivity in women with GDM.32

Plasma leptin levels are elevated significantly in pregnant women compared with nonpregnant women.3334 Masuzaki et al found that plasma leptin levels were elevated significantly during second trimester and remained high during the third trimester.35 Plasma leptin levels 24-h after placental delivery were reduced below those measured during the first trimester. Highman et al34 showed that maternal plasma leptin increased significantly during early pregnancy, before any major changes in body fat and resting metabolic rate, suggesting that pregnancy is a leptin-resistant state. In humans, the higher leptin levels in umbilical veins than in umbilical arteries, and the marked decreased during the neonatal period, suggests that the placenta is one of the major sources of leptin in the fetal circulation.36 This is in contrast to mouse and rat pregnancies, which show an increase in plasma leptin levels during pregnancy but no increase in leptin mRNA in the placentas,37 suggesting that leptin production may be differentially regulated across species during pregnancy. Cord blood leptin levels are positively correlated with birth weight and ponderal index (kg/m3), but also with length and head circumference.3839 Cord leptin levels, but not insulin, were negatively related to weight gain from birth to 4 months.38 Leptin may thus have an important role for fetal growth and maternal glucose metabolism. Whether leptin directly regulates fetal growth, or regulates insulin signaling and energy balance during pregnancy, remains an unanswered question.

9.1.3 Cellular Pathways Underlying Insulin Resistance in Pregnancy and GDM

In nonpregnant individuals, obesity is described as a low-grade inflammatory condition associated with an increased production of proinflammatory factors that originate from macrophage infiltration of adipose tissue.40 Women with GDM, particularly those who are diagnosed early in pregnancy, have more severe insulin resistance that is not specifically related to pregnancy.4 5 Further, in women with a history of GDM, there is a significantly increased risk of the subsequent development of Type 2 diabetes (T2DM), estimated to be about 2–3% per year of follow-up.41 Thus, it seems likely that in most women, GDM represents an unmasking of the genetic predisposition of T2DM, induced by the hormonal milieu of pregnancy, often together with the inflammatory state of obesity. This section will focus on the cellular impairments in insulin signaling underlying the insulin resistance of normal pregnancy and the mechanisms that define the excessive insulin resistance found in GDM.

9.1.3.1 The IR/IRS is a Critical Node in the Insulin Signaling Network and is Inhibited in Human Pregnancy and GDM

Insulin stimulates growth and affects metabolism through two major pathways: the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI 3-kinase) pathway. The MAPK pathway is mainly involved in insulin-mediated growth effects, while the activation of PI 3-kinase is critical for insulin-mediated metabolic effects like glucose uptake, glycogen synthesis, and regulation of protein translation initiation.42 It should be noted that in states of insulin resistance, the mitogenic aspects of insulin signaling through the MAPK pathway is often not dampened, while insulin signaling through the PI 3-kinase pathway for glucose metabolism is severely impaired.43 There are three major molecules/nodes involved in the insulin signaling pathway for glucose uptake in skeletal muscle and adipose tissue, and for insulin suppression of lipolysis in adipose tissue and suppression of hepatic glucose production. A critical node is defined as a point in a signaling network that is essential for the biological function of receptor signaling pathway but also allows for crosstalk between pathways that can fine-tune the response to insulin.44

The insulin receptor (IR)/insulin receptor substrate (IRS) tandem is the first critical node in the insulin signaling cascade (Fig.9.2a). The IR is composed of two extracellular alpha subunits, each linked by disulfide bonds to an intracellular beta subunit that can act as a tyrosine kinase. Insulin binding causes a conformational change in the IR and leads activation and auto (self) phosphorylation of the beta subunit of the IR. The autophosphorylation of the IR on tyrosine leads to recruitment and binding of intracellular substrates. Six of the known substrates belong to the IRS protein family, which bind to IR via pleckstrin-homology and phosphotyrosine-binding domains. IRS proteins (IRS1–6) have unique tissue distribution and signaling functions.45 IRS1 and IRS2 are the mostly widely distributed, with IRS1 playing a major role in skeletal muscle and adipose signaling for glucose transport. Once insulin binds, the IRS is recruited to bind to the IR, and IRS proteins are tyrosine phosphorylated on up to 20 known sites, thereby serving as large docking proteins for subsequent downstream targets of the IR.

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Fig. 9.2

Insulin signaling for glucose uptake. (a) Insulin binds to its receptor causing a conformational change in the receptor that activates its intrinsic tyrosine kinase activity. Activation of the tyrosine kinase leads to auto-phosphorylates on tyrosine residues of the beta-chain of the insulin receptor (IR). Tyrosine phosphorylation of IR recruits IR substrate 1/2 (IRS1/2) proteins to bind at these tyrosine residues on IR. IRS proteins are then phosphorylated on tyrosine residues by IR and act as large docking proteins for downstream signaling. The key regulatory (p85) subunit of PI 3-kinase (p85–p110) binds to tyrosine phosphorylated IRS allowing IR to tyrosine phosphorylate p85 and activate the catalytic (p110) subunit. Increased PI 3-kinase activity leads to activation of several downstream signaling proteins which phosphorylate and activate Akt. Akt activation is required for translocation of GLUT4 to the plasma membrane. Translocation of GLUT4 to the membrane allows glucose to enter the cells. (b) With GDM several of the key steps in insulin signaling for glucose transport are suppressed by a predominance of negative regulatory mechanisms. (Points 1/2) Serine phosphorylation of both the IR and IRS block tyrosine phosphorylation on IR and IRS1/2 leading to a decrease in IR-IRS1/2 association and recruitment of PI 3-kinase. Activation of serine kinases can be caused by an upregulation in inflammatory cytokines, like TNFα, or due to increased nutrient flux into the cell that can cause negative feedback on IRS-1. (Point 2) Increased serine phosphorylation on IRS1/2 promotes protein degradation and decreases the abundance of IRS1/2. (Point 3) In both pregnancy and GDM, pGH is upregulated, which increases the expression of the regulatory (p85) subunit of PI 3-kinase. Increased p85 competes with the enzymatically functional p85–p110 for binding sites on IRS1/2, thereby acting in a dominant negative fashion to dampen the effect of insulin to promote PI 3-kianse activity and, ultimately leading to (Point 4) a decrease in insulin-stimulated glucose uptake into skeletal muscle and adipose tissue

Initial studies of mechanisms for pregnancy induced insulin resistance investigated the IR/IRS critical node. Most studies have found no significant decrease in insulin ability to bind its receptor and no decrease in IR abundance in pregnancy or GDM.46 47 However, in both pregnant rats and in obese pregnant humans, there is a significant decrease in insulin-stimulated tyrosine phosphorylation (activation) of the IR and in IRS1.9 47 In GDM, compared with normal pregnancy, tyrosine phosphorylation of IR and IRS1 was even further reduced.948 The decrease in tyrosine phosphorylation of IR and IRS1 in response to insulin during pregnancy is likely due to impaired IR tyrosine kinase activity as opposed to upregulation of a protein tyrosine phosphatase that dephosphorylate these proteins.48 - 50 The reduction in IR activity is reversible postpartum in women with normal glucose tolerance, but not obese GDM subjects who continue to gain weight postpartum.2851

9.1.3.2 Negative Regulation of Insulin Signaling by Serine Phosphorylation at IR and IRS in Pregnancy and GDM

In contrast to phosphorylation on tyrosine, phosphorylation at serine residues on both IR and IRS proteins dampen the insulin signaling cascade by three mechanisms (Fig.9.2b): (1) chronic serine phosphorylation can induce a conformational change in the IR or IRS that prevents ATP from phosphorylating tyrosine residues on the IR/IRS necessary for full activity, (2) the reduced level of tyrosine phosphorylation prevents association between IR/IRS and docking of PI 3-kinase to IRS, and (3) increased serine phosphorylation on IRS can trigger IRS protein degradation by the proteosomal degradation pathway.52,53

Using an in vitro assay on isolated IR from skeletal muscle that were pretreated with an alkaline phosphatase to dephosphorylate serine/threonine residues, there was a significant improvement in insulin’s ability to stimulate tyrosine kinase activity in IR from skeletal muscle of obese pregnant and GDM women.48 This implicates excessive serine phosphorylation as an underlying cause of the reduction in IR activity during pregnancy. Increased serine phosphorylation can be due to activation of a number of stress kinase signaling pathways induced by inflammatory cytokines or increased flux of fatty acids into cells. TNFα a potent activator of serine kinases in skeletal muscle, is increased in plasma during pregnancy, and is highly correlated with the severity of insulin resistance in pregnancy.2854 Another possible mediator of serine kinase activation may be FFAs, which are elevated in pregnancy due to a failure to adequately suppress lipolysis late in pregnancy.2055

Increased basal serine phosphorylation of IRS1, specifically at IRS1 (S307 mice/S312 humans) has recently been observed in skeletal muscle from mouse and humans with GDM.28,5051 Although the specific serine kinase responsible for increased IR/IRS1 serine phosphorylation during pregnancy is not known, several possible candidates have been identified, including increased activation of JNK1 NFkB, PKCθ and p70 S6 Kinase.53,56 In a genetic mouse model of spontaneous GDM (Leprdb/+ heterozygous mouse), the increase in IRS1(S307/312) serine phosphorylation during pregnancy corresponded to an upregulation in basal and insulin-stimulated phosphorylation of p70 S6Kinase (Thr421/Ser424), but not PKCλ/ζ.50 Similar results showing increased phosphorylation on IRS1(Ser307/312) and increased phosphorylation of p70 S6 kinase were reported recently in skeletal muscle biopsies obtained from pregnant GDM subjects compared with pregnant control subjects matched for obesity.57 The increase in p70 S6 kinase 1 (S6K) is normally a major downstream effector of the mammalian target of rapamycin (mTOR) and PI 3-kinase pathway, primarily implicated in the control of protein synthesis, cell growth, and proliferation in response to insulin. However, S6K phosphorylation also operates, at least partly, by counteracting positive signals induced by hormones and nutrients and thus might be involved in suppressing IRS-1 function due to nutrient excess through serine phosphorylation of IRS1.58,59

The changes in IR and IRS1 observed in pregnancy are generally reversible in women who return to normal glucose tolerance postpartum, suggesting a pregnancy-specific mechanism.51 However, the increase in IRS1 serine phosphorylation remained elevated in former GDM subjects with impaired glucose tolerance (IGT) postpartum.28,57 Increased serine phosphorylation on IRS1 is associated with degradation of the protein in skeletal muscle9,4750and in adipose tissue,20 particularly in GDM subjects, and contributes to the severe insulin resistance to glucose uptake. Taken together, these data suggest that a persistence in IRS1 serine phosphorylation in skeletal muscle may underlie chronic insulin resistance in GDM women and, in some cases, is likely to underlie their increased risk for progression to type 2 diabetes.

9.1.3.3 PI 3-Kinase is Suppressed in States of Insulin Resistance by a Dominant Negative Mechanism

PI 3-kinase is a class IA heterodimer composed of a regulatory subunit that binds to IRS proteins and a catalytic subunit. There are at least five known protein isoforms of the regulatory subunit encoded on three separate genes that were identified by molecular weight (p85α and its splice variants p55α and p50α, p85β and p55γ) and three isoforms of the catalytic subunit (p110α, p110β and p110γ), all of which have unique tissue distribution and signaling functions.6062 The regulatory subunits p85α and p85β are ubiquitously expressed in tissues with the p85α subunit making up 65–75% of the regulatory subunit pool.63 Interestingly, the pool of regulatory subunits exists in excess of the pool of catalytic subunits and because unbound p85α monomers compete for the same IRS1 binding sites as the holoenzyme (p85–p110), the monomers can inhibit PI 3-kinase activity by preventing binding of catalytically functional heterodimers (p85–p110). Therefore, the activity of the PI 3-kinase holoenzyme (and therefore insulin sensitivity) can be controlled by the ratio of the abundance of the regulatory to catalytic subunits. Thus, it was discovered that decreasing any of the regulatory subunits by genetic deletion in mouse models or by siRNA in cell models leads to enhanced PI 3-kinase activity and downstream signaling,64,65 whereas an increase in the expression of p85α paradoxically reduces insulin-stimulated PI 3-kinase activity.1766 In human studies, p85α abundance is increased 1.5–2-fold in obese pregnant as compared with obese nonpregnant control in skeletal muscle and adipose tissue biopsies920,28 and returned to normal levels postpartum.28,51 No difference was noted between control pregnant and GDM in the level of increase in p85α, suggesting the increased p85α is a mechanism for the normal insulin resistance of pregnancy. Interestingly, in transgenic mice engineered to over-express hPGH variant there is a lean phenotype with extreme insulin resistance.14 This is associated with a significant increase in p85α subunit of PI 3-kinase and striking decrease in IRS-1-associated PI 3-kinase activity in skeletal muscle.15 Conversely, mice with a heterozygous deletion of p85α are protected from GH-induced insulin resistance in skeletal muscle,17demonstrating that the level of p85α is inversely related to PI 3-kinase activity and insulin sensitivity. Thus, p85α may be acting as a dominant negative during pregnancy, and can be viewed as a potential nutrient or hormonal sensor in skeletal muscle.

9.1.3.4 Akt is the Third Critical Node in the Insulin Signaling Pathway

Perhaps the most critical mediator for insulin action immediately downstream of PI 3-Kinase is 3-phosphoinositide-dependent kinase 1 (PDK1), which is responsible for activation of Akt and aPKCζ. Akt (or PKB) is a serine/threonine kinase that signals most of insulin’s metabolic actions downstream of PI3K, including activation of glucose transport, increasing protein synthesis and increasing glycogen synthesis in skeletal muscle, and suppression of gluconeogenesis in liver. In skeletal muscle and adipose tissue, insulin stimulates PI 3-Kinase to phosphorylate kinase 1 (PDK1), which is responsible for activation of Akt and aPKCζ. Activation of Akt requires phosphorylation of a threonine residue by PDK1 and a serine residue by the mTor/Rictor complex (mTORC1). There are three Akt isoforms (Akt1–3) with distinct but partially redundant signaling functions.67 In contrast to the other isoforms, only loss of Akt2 function results in dysregulation of glucose metabolism and insulin resistance.68 - 70 In signaling for glucose transport, Akt phosphorylates and inhibits AS160, a Rab-GTPase, permitting GLUT4 translocation to the plasma membrane. In skeletal muscle and adipose tissue from pregnant subjects, Akt levels are normal (unpublished observations), as are the levels of insulin-responsive glucose transporter GLUT4.9

9.2 Summary: Postpartum and Beyond

The impact of GDM on both the health of the mother and the offspring has been shown to last well beyond delivery. Women with a history of GDM are at much higher risk of developing T2DM,41 while children born to these GDM mothers have an increased risk of childhood obesity and early onset of T2DM.71,72 With GDM increasing rapidly due to the maternal obesity epidemic, identification of the major defects in the insulin signaling pathway during pregnancy is essential for understanding what factors (genetic and environmental) trigger excessive insulin resistance. These triggers may underlie excess fuel transfer to the fetus and the vicious cycle of maternal diabetes transmission to the offspring. Whether our efforts should be focused on reducing maternal adipose tissue inflammation or simply improving skeletal muscle insulin signaling as a therapeutic target is still an open question. Human studies have shown that a major defect in GDM involves the inability of insulin to stimulate glucose transport into skeletal muscle. The mechanisms for this severe insulin resistance are not completely understood, but involve a defect in the IR, IRS1, and an unknown post-receptor defect(s), perhaps caused by interaction between inflammation and serine kinases in skeletal muscle and adipose tissue. In obese women, there is an upregulation in inflammatory cytokines and adipokines that are thought to increase serine phosphorylation of the IRS proteins, while in women with GDM this defect is more severe and more likely to persist postpartum. Although potential candidates for both the inflammatory cytokine mediator(s) and the activated serine kinase have been identified, there is still very little understanding of what initiates these defects during pregnancy and beyond. A persistent dampening in skeletal muscle insulin signaling in cultured myocytes or adipocytes from GDM women, for example, would be an excellent candidate for a primary genetic or perhaps epigenetic mechanism that contributes to insulin resistance of GDM women. Future questions to be addressed include: What is the contribution of skeletal muscle TNFα production as a mechanism for greater insulin resistance in women with GDM? What is the role of the p70 S6 kinase-1 signaling pathway as a potential mediator of maternal insulin resistance independent of PI 3-kinase? Is the infiltration of macrophage into skeletal muscle or adipose tissue accelerated by pregnancy, and if so by what mechanism? Ultimately, answers to these questions should provide us with a better understanding of the cellular factors that trigger human GDM.

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