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The British Journal of Diabetes & Vascular
http://dvd.sagepub.com/content/9/5/208
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DOI: 10.1177/1474651409350273
2009 9: 208 British Journal of Diabetes & Vascular Disease
Anjum Doshani and Justin C Konje
Review: Diabetes in pregnancy: insulin resistance, obesity and placental dysfunction

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Abstract
O
besity in pregnancy is linked to increased mor-
bidity and mortality for mother and baby. The
incidence of gestational diabetes is increased
approximately two to six-fold in women who are over-
weight-obese and the presence of diabetes is a further
metabolic challenge which is associated with adverse
outcomes. Herein the role of obesity is discussed in the
generation of insulin resistance and inflammation and its
contribution to placental dysfunction.
Br J Diabetes Vasc Dis 2009;9:208-212
Key words: placental dysfunction, insulin resistance, obesity.
Introduction
Globally, the World Health Organisation estimates that over
1 billion people are currently overweight, including 800 million
women, and that over 300 million people are obese. More
than 2.5 million deaths annually are weight related and this
could rise to 5 million by 2020.
1

The UK population has grown steadily fatter: 23% of the
UK population is now obese, a three-fold increase since 1980.
2

Obesity is both a major cause of chronic ill health and consid-
ered a disease in its own right.
3
Obesity is increasingly a matter
of concern both in general and in relation to pregnancy. There
are no national data about BMIs of pregnant women in the UK.
BMI, however, varies with age, being higher on average for
older women (table 1).
Obesity is a common finding in most antenatal clinics in the
UK. For example, over the last decade there has been a two-
fold increase in women being recognised as obese at booking.
4

Maternal overweight is associated with an increased risk of
maternal and foetal morbidity and mortality.
There is substantial evidence that obesity in pregnancy
contributes to increased morbidity and mortality for both
mother and baby. For example, the CEMACH report (Why
Mothers Die) found that approximately 35% of women who
died (who had a recordable BMI) in the 20002003 triennia
were obese (i.e. had a BMI 30). The CEMACH Perinatal
Mortality 2005 Report found that approximately 30% of the
mothers who had a stillbirth or a neonatal death were obese.
5
Increased rates of obesity-related morbidity and mortality
are reflected in increased social and financial costs:
Obese women spend an average of 4.83 more days in hos-
pital and the increased levels of complications in pregnancy
and interventions in labour represent a five-fold increase in
cost of antenatal care.
6
The costs associated with newborns are also increased as
the babies born to obese mothers have a 3.5-fold increase
in the admission rate to the neonatal intensive care unit.
Diabetes in pregnancy: insulin resistance,
obesity and placental dysfunction
ANJUM DOSHANI
1
, JUSTIN C KONJE
2
The Author(s), 2009. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/1474651409350273 208
REVIEW
1
Reproductive Sciences Section, Department of Cancer Studies and
Molecular Medicine, University of Leicester, Leicester, UK.
2
Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary,
Leicester, UK.
Correspondence to: Dr Justin C Konje
Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary,
Leicester, LE2 7LX., UK.
Tel: +44 (0)116 252 5826; Fax: +44 (0)116 252 5846
E-mail: jck4@le.ac.uk
Abbreviations and acronyms
BMI body mass index
CEMACH Confidential Enquires into Maternal and Child Health
CRP C-reactive protein
GDM gestational diabetes mellitus
GTT glucose tolerance test
HbA
1C
glycated haemoglobin A
1C
IL interleukin
NICE National Institute for Health and Clinical Excellence
TNF tumour necrosis factor
Table 1. Percentage distribution of body mass index (BMI) in women
in England in 2003
BMI 1624 years 2534 years 3544 years
18.5 7.4 1.0 1.0
18.625.0 61.2 51.8 43.5
25.130.0 18.3 28.3 33.3
30.140.0 11.1 15.1 18.6
> 40 2.0 3.0 3.5
All 100 100 100
Source: Health Survey for England
Information Centre for Health and Social Care. Statistics on Obesity,
Physical Activity and Diet: England, 2006. Leeds: Information Centre,
2006.
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THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 209
REVIEW
Gestational diabetes and obesity
In healthy pregnancy several components of the metabolic
syndrome are acquired including insulin resistance, hypertri-
glyceridaemia, an up-regulation of the inflammatory cascade
and an increase in coagulation factors. These changes are
secondary to the physiological adaptations of pregnancy which
impact substantially not only on carbohydrate and lipid control
pathways but also on vascular endothelial function.
Overweight is a risk factor for impairment of carbohydrate
tolerance both in the non-pregnant state and during preg-
nancy. Recent studies have focused on the association between
obesity and hypertension or diabetes. Even in moderately
overweight subjects (BMI 2530) the incidence of gestational
diabetes is 1.8 to 6.5 times greater than that in normal weight
subjects.
7
In a UK study, women with a BMI > 30 were found
to be 3.6 times more likely to develop GDM than women with
a normal BMI.
8
On the basis of a meta-analysis of the literature, Chu et al.
9

estimated that the risk of developing GDM is about two, four,
and eight times higher among overweight, obese, and severely
obese women, respectively, compared with normal weight
pregnant women.
Insulin resistance, obesity and diabetes
Insulin resistance and obesity are important pathophysiological
contributors to both GDM and type 2 diabetes.
10,11
Recent
evidence suggests that inflammation is a central feature of the
insulin resistance syndrome that is also linked to obesity. For
example, physiological studies
12
using intravenous glucose
tolerance tests or euglycaemic hyperinsulinaemic clamps
found a direct association between the degree of insulin resis-
tance and levels of inflammatory markers. Inflammatory cyto-
kines, such as TNF-a and IL-6, which are secreted by adipose
tissue and are constitutively elevated in the serum of obese
subjects,
13
have been shown to induce insulin resistance.
14

Women with polycystic ovary syndrome, which is associated
with insulin resistance, obesity, and increased risk of GDM and
type 2 diabetes, also demonstrate increased levels of inflam-
matory markers.
15
A high-fat diet induced adipocyte hypertro-
phy which caused a decrease in the expression and secretion
of adiponectin (an insulin sensitising hormone) and an increase
in glucocorticoids (insulin resistant hormones) leading to insu-
lin resistance.
16
In normal pregnancy insulin resistance develops and assists
in the provision of substrates for energy for the baby. This insu-
lin resistance leads to higher levels of glucose and free fatty
acids; this effect is counterbalanced, however, by increased
secretion of maternal insulin. In 24% of women, the pancre-
atic insulin response is inadequate and gestational diabetes
ensues.
The underlying pathophysiology of gestational diabetes can
be viewed as a function of decreased maternal insulin sensitivity
or increased insulin resistance. Insulin resistance classically refers
to an impairment of the degree to which a given quantity of
insulin lowers plasma glucose, both by stimulating glucose
uptake in insulin-sensitive tissues (predominantly skeletal muscle),
and by inhibiting hepatic glucose output. Although insulin resist-
ance is primarily related to glucose metabolism, other nutrients
are also involved. Insulin resistance results in the inability of insulin
to suppress lipolysis and a decreased ability to suppress amino
acid turnover. The regional distribution of fat was suggested to
modulate the response to an oral glucose load in obese pregnant
women.
17
In this study, insulin areas under the curve after an oral
glucose tolerance test during the second and third trimester of
pregnancy and in the postpartum period were significantly higher
in pregnant women with upper body obesity than in pregnant
women with lower body obesity and in lean pregnant women.
No epidemiological investigation of the importance of regional
distribution of fat as a risk factor for gestational diabetes has
been undertaken so far, but weight excess clearly increases the
risk of overt impartment of carbohydrate intolerance in pregnant
women.
Placenta and insulin resistance
Placental hormones
The placenta is a complex organ that fulfils several roles during
foetal growth. It separates the maternal and foetal circulations,
with which it is in contact through different surfaces, i.e. the
syncytiotrophoblast exposes the placenta to the maternal circu-
lation and the endothelium is in contact with foetal blood.
Because of this unique position, the placenta is exposed to the
regulatory influence of hormones, cytokines, growth factors,
and substrates present in both circulations and, hence, may be
affected by changes in any of these.
The human placenta expresses virtually all known cytokines
including TNF-a, resistin and leptin, which are also produced by
adipose cells. The discovery that some of these adipokines are
key players in the regulation of insulin action suggests possible
novel interactions between the placenta and adipose tissue in
understanding pregnancy-induced insulin resistance. The inter-
play between the two systems becomes more evident in GDM.

Diabetes and the placenta
In diabetes, the placenta undergoes a variety of structural and
functional changes.
18
Their nature and

extent depend on a range
of variables including the quality of glycaemic control achieved
during the critical periods in placental development, the modal-
ity of treatment, and the time period of severe departures from
the excellent metabolic control of a non-diabetic environment.
Diabetes at the beginning of pregnancy may have long-term
effects on placental development. These adaptive responses of
the placenta to the diabetic environment, such as buffering
excess maternal glucose or increased vascular resistance, may
help limit foetal growth within a normal range. If the duration
or extent of the diabetic insult, including maternal hyperglycae-
mia, hyperinsulinaemia, or dyslipidaemia, exceeds the placental
capacity to mount adequate responses, then excessive foetal
growth may ensue. Diabetic insult at the later stages in gesta-
tion, such as may occur in gestational diabetes, will foremost
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210 VOLUME 9 ISSUE 5
.
SEPTEMBER/OCTOBER 2009
REVIEW
lead to short-term changes in a variety of molecules for key
functions including gene expression.
19
The diabetic environment can be regarded as a network of
substances (hormones, nutrients, cytokines) with altered con-
centrations. The current view is that the abnormal maternal
metabolic environment may generate stimuli within the adipose
tissue and the placental cells resulting in the increased produc-
tion of inflammatory cytokines whose expression is minimal in
normal pregnancy. One leading hypothesis is that changes in
circulating adiponectin, leptin, TNF-a, and resistin link inflam-
mation to metabolic changes which ultimately enhance insulin
resistance in the mother. Likewise, the foetal environment is also
changed in diabetes, and elevated levels of insulin, leptin, and
other cytokines have been well documented. Concentrations of
leptin, an adipocyte-derived molecule, were more than two-fold
higher in obese women.
20
Mohamed-Ali et al.
21
and other researchers have shown
high concentrations of IL-6 and CRP in obese pregnant women,
implicating

adiposity as a key factor in low-grade chronic
inflammation. They found that IL-6 was 50% higher, and CRP
was

almost double, in obese pregnant women, relative to lean
women. High CRP correlates with endothelial dysfunction

and
impaired insulin sensitivity
12
in non-pregnant populations and
predicts the risk for type 2 diabetes in women.
22
Thus,

obesity-
driven inflammation in pregnancy could be implicated

in the
pathogenesis of pre-eclampsia and GDM.
23

Insulin stimulates foetal aerobic glucose metabolism and
hence this will

increase the oxygen demand of the foetus.
Reduced oxygen delivery to the intervillous

space, as a result
of the higher oxygen affinity of glycated

haemoglobin,
24

thickening of the placental basement membrane
25
and
reduced utero-placental or foeto-placental blood flow
26
will
result in foetal hypoxaemia.
27
Hypoxia is a potent stimulator
of hypoxia-sensitive transcription factors (e.g. hypoxia induc-
ible factor 1a) which

will therefore lead to the stimulated
expression and synthesis of a variety

of molecules, some of
which are key players, especially in angiogenesis.
28
Diabetic pregnancies are associated with elevated foetal
levels of fibroblast growth factor-2 which will stimulate

placen-
tal angiogenesis and lead to the hypercapillarisation seen in
placentas of type 1 diabetic pregnancies.
29
Reports on

GDM are
conflicting.
30,31
Some, but not all, studies have reported longi-
tudinal vascular growth and enhanced branching

angiogenesis,
which may reflect different gestational ages at onset of GDM

either within or after the critical developmental

stages of vascu-
logenesis and angiogenesis.
32
Placenta and cytokines
The placenta is also a source and a target for the cytokines as
discussed above.

The type and the location of the cytokine
receptors present

on the placental cells will determine whether
signals are generated by the placenta, maternally (presumably
adipose-derived), or by the foetus. This emphasises the possibil-
ity

of an external control of placental function that can become
dysregulated when the cytokine levels are augmented, such as

in GDM or obesity.
33
One leading hypothesis is that increased TNF-a, leptin and
resistin

contribute to enhancing insulin resistance in the GDM
mother.
34
In addition, adiponectin may be implicated in the
loss of insulin sensitivity with advancing gestation in normal
pregnancy and in pregnancy with GDM through a decrease in
maternal adiponectin concentrations.
35,36

Resistin, a 114-amino acid polypeptide has been shown to
contribute to obesity and insulin resistance.
37
However, whether
other hormones of pregnancy or one major hormone is respon-
sible for insulin resistance of pregnancy remains unresolved.
Obesity and its clinical sequlae in the
pregnant woman
Obesity is a major contributing factor to the two most common
medical risks in pregnancy: diabetes and hypertension. The asso-
ciations between pre-gestational and gestational diabetes,
adverse pregnancy and race have been well documented in the
literature. Pregnant women with pre-gestational type 1 and type
2 diabetes are more likely to have Caesarean deliveries, macro-
somic infants, congenital malformations and preterm deliver-
ies.
38
GDM has also been associated with adverse pregnancy
outcomes, including pre-term birth, macrosomia and associated
shoulder dystocia, and Caesarean deliveries.
39
Although both
pre-gestational and gestational diabetes are strongly associated
with higher birth weights, in the presence of diabetes-associated
vascular disease birth weight may be restricted. Women with
GDM have a 2050% chance of developing type 2 diabetes in
the 510 years after pregnancy, and their offspring are at
increased risk of developing diabetes and obesity later in life.
40

Managing diabetes in pregnancy
Women with diabetes planning to become pregnant should be
counselled about the importance of establishing good glycaemic
control (HbA
1C
< 6.1%) before conception and maintaining this
control (fasting blood glucose 3.55.9 mmol/L; 1-h postprandial
blood glucose < 7.8 mmol/L) throughout pregnancy in order to
reduce the risk of miscarriage, congenital malformation, stillbirth
and neonatal death. Women with HbA
1c
> 10% should be
strongly advised to avoid pregnancy. In women planning to
become pregnant it is also advisable to substitute drugs, such as
angiotensin-converting enzyme inhibitors and angiotensin II
receptor antagonists, for agents which are not contraindicated in
pregnancy.
41
The management of diabetes (type 1, type 2 and GDM) and
its complications in pregnancy and during the postnatal period
are described in a recent NICE guideline (no. 63).
41
Conclusion
Maternal overweight and obesity are associated with adverse
maternal and foetal outcomes. Inflammatory cytokines are
secreted by adipose tissue and contribute to the insulin resis-
tance of pregnancy, thereby increasing the metabolic burden
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THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 211
REVIEW
in mothers with diabetes and promoting the development
of GDM in women who lack compensatory islet beta cell
capacity.
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Key messages

Maternal overweight is associated with an increased
risk of maternal and foetal morbidity and mortality
Obesity and insulin resistance are important contribu-
tors to GDM and type 2 diabetes
Inflammatory cytokines, e.g. TNF-a and IL-6, which are
secreted by adipose tissues, have been shown to induce
insulin resistance
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SEPTEMBER/OCTOBER 2009
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38. Ray JG, Vermeulen MJ, Shapiro JL, Kenshole AB. Maternal and neona-
tal outcomes in pregestational and gestational diabetes mellitus, and
the influence of maternal obesity and weight gain: the deposit study.
Q J Med 2001;94:347-56.
39. Hedderson MM, Ferrara A, Sacks DA. Gestational diabetes mellitus
and lesser degrees of pregnancy hyperglycemia: association with
increased risk of spontaneous preterm birth. Obstet Gynecol
2003;102:850-6.
40. Gillman MW, Rifas-Shiman S, Berkey CS et al. Maternal gestational
diabetes, birth weight, and adolescent obesity. Pediatrics 2003;
111:e221-6.
41. National Institute for Health and Clinical Excellence. Diabetes in
pregnancy: management of diabetes and its complications from pre-
conception to the postnatal period. London: NICE, 2008. http://
guidance.nice.org.uk/CG63 (Accessed September 2009).
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frequent undesirable effect of insulin therapy. Local
allergy is common and usually resolves. Systemic
allergy is rare but potentially more serious since severe
cases may be life-threatening. Lipodystrophy is
uncommon. For full details of these and other side-
effects, please see the Summary of Product Characteristics,
which is available at http://emc.medicines.org.uk/
Legal Category: POM
Date of Preparation or Last Review: May 2009
Full Prescribing Information is Available From:
Eli Lilly and Company Limited, Lilly House, Priestley
Road, Basingstoke, Hampshire, RG24 9NL. Telephone:
Basingstoke (01256) 315 999
Adverse events should be reported.
Reporting forms and information
can be found at www.yellowcard.gov.uk
Adverse events should also be reported
to Eli Lilly and Company Limited
(Telephone 0870 240 1125).
UKHMG00105 September 2009
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