FROM: Creasy and Resnik, Maternal-Fetal Medicine, 2014

Maternal-Fetal Metabolism in Normal and Diabetic Pregnancy

Significant changes in maternal metabolism occur during a normal pregnancy. These
include changes in maternal nutrient metabolism (i.e., carbohydrate, lipid, and protein
metabolism) and changes in factors such as energy expenditure. The overall goal of
these maternal metabolic adaptations is to prepare the woman's body to meet the
increased energy needs of the mother and growth of the fetus in the latter third of
pregnancy, when approximately 70% of fetal growth takes place. 30 However, these
pregnancy metabolic changes take place on the background of a woman's pregestational
metabolic status. For example, if a woman is healthy and lean before conception, there
is an increased need to store adipose tissue in early pregnancy (to meet the increased
energy demands of late gestation) and to develop insulin resistance in late gestation (to
provide nutrients for the growing fetus). If a woman is obese before conception, there is
little need to gain additional adipose tissue, but there is the requirement to provide
nutrients for the fetal growth in late gestation.

Normal Glucose-Tolerant Pregnancy

Glucose homeostasis is primarily a balance between insulin resistance and insulin
secretion. The alterations in insulin resistance affect endogenous glucose production
(primarily hepatic glucose metabolism) and peripheral glucose metabolism, which takes
place in skeletal muscle. In the lean pregnant woman with normal glucose tolerance,
there is a significant 30% increase in basal hepatic glucose production by the third
trimester of pregnancy ( Fig. 59-3 ). This is associated with a significant increase in basal
or fasting insulin concentrations ( Fig. 59-4 ). 31 A decrease in FPG concentrations most
likely results from increasing plasma volumes in early gestation and increased
fetoplacental utilization in late pregnancy. In the postprandial state, increasing insulin
concentrations enhance glucose uptake into skeletal muscle and adipose tissue and
almost completely suppress hepatic glucose production. Although this is the case in lean
women, obese women, even those with normal glucose tolerance, have a decreased
ability for insulin to completely suppress hepatic glucose production in late
pregnancy. 32 These data support the concept of decreased insulin sensitivity in late
gestation that is more severe in obese women compared with non-obese counterparts.

FROM: Creasy and Resnik, Maternal-Fetal Medicine, 2014

Figure 59-3
Alterations in glucose production.Longitudinal changes in total basal endogenous (primarily hepatic)
glucose production (mean SD) from the pregravid state through early gestation (12 to 14 weeks)
and late gestation (34 to 36 weeks).

Figure 59-4
Alterations in insulin resistance.Longitudinal changes in glucose infusion rate (i.e., insulin sensitivity)
in lean women from the pregravid state through early (12 to 14 weeks) and late (34 to 36 weeks)
pregnancy during hyperinsulinemic-euglycemic clamp (mean SD). The asterisk indicates change
over time from pregravid status through late pregnancy (ANOVA).
(Adapted from Catalano PM, Tyzbir ED, Roman NM, etal: Longitudinal changes in insulin release
and insulin resistance in non-obese pregnant women, Am J Obstet Gynecol 165:16671672, 1991.)

FROM: Creasy and Resnik, Maternal-Fetal Medicine, 2014

Peripheral insulin resistance is defined as the decreased ability of insulin to affect
glucose uptake primarily in skeletal muscle and to a lesser degree in adipose tissue.
Various methods are used to assess insulin sensitivity 35 Most of these measures have
identified a significant 50% to 60% decrease in insulin sensitivity in late gestation. 36
The changes in insulin sensitivity during gestation reflect the woman's pregravid insulin
sensitivity status. Lean women usually have greater pregravid insulin sensitivity
compared with overweight or obese women. These differences manifest before
pregnancy, and when evaluated against the metabolic background of pregnancy, the
relationships are similar in late pregnancy, albeit reduced by approximately 50% to 60%
(seeFig. 59-4 ). The decreases in insulin sensitivity in late pregnancy are accompanied by
an increase in insulin response. The insulin response to a glucose load increases
approximately threefold compared with pregravid measures ( Fig. 59-5 ).

Pregnancy Complicated by Diabetes

In both lean and obese women with GDM and mildly elevated FPG levels, there is an
increase in basal endogenous glucose production, similar to that observed in subjects
with normal glucose tolerance, although fasting insulin concentrations, particularly in
late gestation, are greater than in normal glucose-tolerant women ( Fig. 596 ). 37 However, with insulin infusion, the ability of insulin to suppress endogenous

glucose production is decreased in women with GDM compared with a matched control
group (approximately 80% versus 95%).

Alterations in insulin sensitivity.Longitudinal changes

in insulin sensitivity during clamp 40mUm 2min 1 insulin infusion in obese women (mean SD).
GDM, gestational diabetes mellitus; Pg, difference between groups; Pt, individual longitudinal
changes with time. Figure 59-6

FROM: Creasy and Resnik, Maternal-Fetal Medicine, 2014

If insulin sensitivity is estimated before conception or after delivery, there is a
significant decrease in women who go on to develop GDM, compared with normal
glucose-tolerant women. 38 During pregnancy, the percentage decrease in insulin
sensitivity is approximately the same in women with GDM as in matched controls (i.e.,
50% to 60%). The decreased insulin sensitivity observed during pregnancy in the
woman who develops GDM is a function of her pregravid metabolic status. The
increased glucose concentrations represent the inability of pancreatic beta cells to
normalize glucose levels ( Fig. 59-7 ).

Figure 59-7
Insulin sensitivity and secretion relationships in normal women and women with gestational diabetes
mellitus (GDM).Prehepatic insulin secretion was assessed during steady-state hyperglycemia using
plasma insulin and C-peptide concentrations and C-peptide kinetics in individual patients.
(From Buchanan TA: Pancreatic -cell defects in gestational diabetes: implications for the
pathogenesis and prevention of type 2 diabetes, J Clin Endocrinol Metab 86:989993, 2001.)

The relationship between insulin sensitivity and insulin response has been characterized
as a hyperbolic curve or, when multiplied, as the disposition index. A curve that is
shifted to the left can be plotted for individuals who go on to develop GDM. Whether
insulin resistance precedes beta cell defects or occurs concomitantly is not known with
certainty. However, Buchanan proposed that insulin resistance causes beta cell
dysfunction in susceptible individuals. 39 The increased risk of T2DM in women who
formerly had GDM may be a function of decreasing insulin sensitivity (i.e., worsening
insulin resistance) exacerbated by increasing age, adiposity, and the inability of the beta
cells to fully compensate.

FROM: Creasy and Resnik, Maternal-Fetal Medicine, 2014

Mechanisms of Insulin Resistance
Insulin resistance is defined as a condition in which physiologic insulin concentrations
elicit decreased biologic response in target tissues. The action of insulin in target cells
requires the orchestrated activation of complex molecular steps. Autophosphorylation of
the insulin receptor on tyrosine residues is the initial mandatory step allowing
recruitment and activation of downstream effectors such as insulin receptor substrate-1
(IRS-1). The mechanisms responsible for pregnancy-induced insulin resistance have
been characterized at the molecular level. In normal pregnancy, the ability of the insulin
receptor to transduce an intracellular signal is diminished. In late pregnancy, skeletal
muscle IRS-1 content is lower than in nonpregnant women. 42 The downregulation of
IRS-1 closely parallels the decreased ability of insulin to stimulate 2-deoxyglucose
uptake in skeletal muscle. In GDM, the insulin receptor also displays a decreased ability
to undergo tyrosine phosphorylation. The decreased receptor phosphorylation, which
results in 25% less glucose transport activity, is not found in pregnant women with
normal glucose tolerance.
The insulin resistance of pregnancy is almost completely reversed shortly after delivery,
consistent with the marked decrease in insulin requirements clinically in women
managed on insulin. 43 The placenta has long been suspected of producing hormonal
factors related to these adaptations in maternal metabolism. The strongest candidates
include maternal cortisol and placenta-derived hormones such as human placental
lactogen (HPL), progesterone, and estrogen. 43 44 45 46 Tumor necrosis factor- (TNF-)
and other cytokines produced by the placenta can be released locally as well as in the
maternal systemic circulation. 45
Despite decades of intensive research, direct proof of how placental factors modify
insulin action in maternal tissues has not been obtained. The role of TNF- in insulin
resistance was first revealed in studies investigating how TNF- impairs insulin
action. 47 Since then, a wide variety of factors, including nutrients such as fatty acids and
amino acids, have been found to induce insulin resistance through IRS-1 serine
phosphorylation. 48 In pregnant women, circulating TNF- concentrations had an
inverse correlation with insulin sensitivity, as estimated from clamp studies. 49 In the
third trimester, increased circulating free fatty acids may also contribute to the insulin
resistance. 50

FROM: Creasy and Resnik, Maternal-Fetal Medicine, 2014

The cooperation of inflammatory and metabolic factors in blunting the effects of insulin
has recently gained attention. The term metabolic inflammation is applied to
situations of low-grade chronic inflammation observed in several metabolic disorders
such as obesity and diabetes. 51 Adipose tissue plays an essential role in initiation of the
inflammatory response. Not only is it a storage depot for excess calories, but it also
actively releases fatty acids and secretes a variety of adipocytokines. Pregnancy in a
woman with obesity and GDM is a state of metabolic inflammation. 52 Macrophages
originating from the maternal systemic circulation invade maternal adipose tissue and
the placenta, increasing local and systemic release of proinflammatory cytokines. 53
Altogether, these observations suggest that in pregnancy the expanding adipose tissue
mass is a primary cause of systemic insulin resistance and that the resulting altered
homeostasis, inflammation, and insulin resistance propagate to skeletal muscle and the
liver. 54

Placental Transport: (from Gabbe, Normal and Problem

Pregnancy, 2012)
Glucose
Placental permeability for D-glucose is at least 50 times the value predicted on the
basis of size and lipid solubility. 9 Thus, specialized transport mechanisms must be
available on both the microvillous and basal membranes. Membrane proteins
facilitating the translocation of molecules across cell membranes are
termed transporters. The primary human placental glucose transporter is
GLUT1, 10 a sodium-independent transporter, as compared to the sodiumdependent transporters found in adult kidney and intestine. This transporter, in
contrast to that found in human adipocytes (GLUT4), is not insulin sensitive. The
placental D-glucose transporter is saturable at high substrate concentrations; 50% saturation is
observed at glucose levels of approximately 5 mM (90 mg/dL). Thus, glucose transfer from
mother to fetus is not linear, and transfer rates decrease as maternal glucose concentration
increases. This effect is reflected in fetal blood glucose levels following maternal sugar loading.

Lipids
Esterified fatty acids (triglycerides) are present in maternal serum as components of
chylomicrons and very-low-density lipoproteins (VLDLs). Before transfer across the
placenta, lipoprotein lipase interacts with these particles, releasing free fatty acids,

FROM: Creasy and Resnik, Maternal-Fetal Medicine, 2014

which, due to their hydrophobic nature, are relatively insoluble in plasma and circulate
bound to albumin. As a result, fatty acid transfer involves dissociation from maternal
protein, subsequent association with placental proteins, first at the plasma membrane
(FABPpm), then after transfer into the cell (thought to be via FAT/CD36 and FATP)
with intracytoplasmic binding proteins. Transfer out of the syncytiotrophoblast is less
well worked out, but is thought to occur via interaction with FAT/CD36 and FATP,
which are present at both the microvillous and basolateral placental membrane
surfaces.
Early studies documented that placental fatty acid transfer increases logarithmically
with decreasing chain length (C16 to C8) and then declines somewhat for C6 and C4.
More recent work, however, has clarified the fact that essential fatty acids are, in
general, transferred more efficiently than are nonessential fatty acids. Such selectivity
may also relate to the composition of triglycerides in maternal serum, as lipoprotein
lipase preferentially cleaves fatty acids in the two positions. In general, fatty acids
transferred to the fetus reflect maternal serum lipids and diet. There is also evidence
that the placental secretion of leptin, a hormone generally secreted by
adipocytes, may promote maternal lipolysis, thus providing both placenta
and fetus the means by which to ensure an adequate lipid supply.

Receptor-Mediated Endocytosis/Exocytosis
Endocytosis, via the clatharin-dependent endocytosis pathway, has long
been known to occur within the placenta. Placental endocytosis plays a
critical role in cell signaling; examples include insulin and EGF receptors,
protein recycling (receptors, transporters), substrate transfer (LDL
receptor), and transcytosis (immunoglobulin, taken up by endocytosis, and
transferred from the maternal to the fetal circulation). The general
mechanisms underlying these processes include postligand binding, cell entry, and
processing. Following ligand binding, the receptors aggregate on the cell surface and
collect in specialized membrane structures termed clatharin-coated pits (Figure 2-3 ).
These coated pits invaginate, pinch off, and enter the cell to form vesicles, which fuse to
form endosomes. The endosomes move deeper into the cytoplasm where the lower
endosome pH facilitates ligand separation from its receptor.

FROM: Creasy and Resnik, Maternal-Fetal Medicine, 2014

The fate of ligand and receptor differs depending on the specific substrate:
Although insulin receptor is probably recycled to the cell surface, maternal
insulin does not reach the fetal circulation due to lysosomal degradation