The Fetal Origins of Type 2 Diabetes Mellitus
L ike other living creatures, human beings are
“plastic” in early life and are molded by the
environment. Although the growth of a fetus is in-
fluenced by its genes, studies in humans and animals
suggest that this growth is usually limited by the
environment, particularly by the nutrients and oxy-
gen the fetus receives (1). There are many possible
evolutionary advantages in the tendency of the body
to remain plastic during development rather than
have its development driven only by genetic instruc-
tions acquired at conception (2). Studies in animals
show that a fetus may adapt to malnutrition by
altering hormone production or the sensitivity of
tissues to these hormones (3, 4). Among the hor-
mones that regulate fetal growth, and hence the
requirements for nutrients, insulin has a central role
(5). The fetus can alter its metabolism (for example,
by switching from glucose to amino acid oxidation)
(4). It can redistribute its cardiac output to protect
key organs, especially the brain. Slowing of growth
is also an adaptive function because it reduces the
requirements for substrate. Unlike physiologic ad-
aptations in adulthood, adaptations during develop-
ment tend to lead to permanent changes in the
structure and function of the body. Experiments
show that even minor modifications to the diet of
pregnant animals may be followed by lifelong
changes in the offspring in ways that can be related
to human disease (for example, elevated blood pres-
sure and altered glucose–insulin metabolism) (6). At
a molecular level, such “programmed” changes may
reflect the alteration of gene expression in utero by
nutrient availability, acting directly on the cell or
through hormonal signals.
In the early 1990s, a study in Hertfordshire, En-
gland (7), was the first to show that persons with
low birthweights had higher rates of type 2 diabetes
later in life. The study was part of a research pro-
gram investigating the fetal origins hypothesis,
which states that coronary heart disease, stroke,
type 2 diabetes, and hypertension originate from
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adaptations that the fetus makes to malnutrition;
these adaptations cause permanent changes in the
body’s structure and physiology (3, 8). The Hert-
fordshire study entailed examination of men and
women born from 1911 through 1930 whose size at
birth and in infancy was recorded. Later studies in
Europe and the United States (9, 10) also examined
detailed birth records and confirmed the association
between low birthweight and the development of
type 2 diabetes or reduced glucose tolerance. Al-
though birthweight serves as a marker of fetal
growth and nutrition, it is crude. The same birth-
weight may be the result of many different paths of
growth (11). More detailed measurements of body
size at birth, when available, may give insights into
the adaptations made by the fetus. For example,
low-birthweight babies who are thin tend to be in-
sulin resistant as children and adults and are there-
fore likely to develop type 2 diabetes. This suggests
that thin babies responded to malnutrition in utero
through endocrine and metabolic changes (3, 9, 12).
In this issue, Rich-Edwards and colleagues (13)
report the results of the largest study in this area to
date. Women in the Nurses’ Health Study were able
to obtain their birthweights, and the incidence of
type 2 diabetes among these women was ascertained
by a mailed questionnaire. When data were adjusted
for current body mass index and age, the risk for
type 2 diabetes across the range of birthweights
decreased twofold; this finding was similar to those
in previous studies (7). A useful feature of the
Nurses’ Health Study is that it has collected infor-
mation on childhood socioeconomic status and adult
lifestyle factors. The associations with birthweight
changed little after adjustment for these factors,
providing further evidence that they reflect pro-
cesses linked to intrauterine growth rather than the
confounding effects of influences after birth.
The Nurses’ Health Study also throws further
light on a question that is often raised. Because
mothers who have gestational diabetes tend to de-
liver babies with high birthweight, who are them-
selves at increased risk for type 2 diabetes, why is
• Volume 130 • Number 4 (Part 1)
 not high birthweight associated with type 2 diabe-
tes? The answer is that it is, but only in the off-
spring of mothers with gestational diabetes. In the
Pima Indians, among whom diabetes in pregnancy is
unusually common, the association between birth-
weight and type 2 diabetes is U-shaped. The asso-
ciation with high birthweight is abolished when the
offspring of mothers with gestational diabetes are
excluded. Similarly, in the Nurses’ Health Study,
exclusion of mothers who had a history of diabetes
at any age strengthened the association of type 2
diabetes with low birthweight and led to a fourfold
decrease in the risk for type 2 diabetes across the
range of birthweights.
In a study in Mysore, South India (14), men and
women who had low birthweights tended to be in-
sulin resistant; however, short, fat babies of heavier
mothers tended to develop type 2 diabetes and were
both insulin resistant and insulin deficient, with a
low 30-minute insulin increment. These findings
have led to a novel explanation for the current
epidemic of type 2 diabetes in urban and migrant
Indian populations. Widespread fetal malnutrition
in the Indian population, whose average birthweight
is only 2.9 kg, predisposes them to insulin resis-
tance. After moving to an urban area, a person’s
level of physical activity tends to decrease. Young
women who are no longer required to do agricul-
tural work or walk long distances to fetch water and
firewood may gain weight and therefore become
more insulin resistant. These women would be less
able to maintain glucose homeostasis during preg-
nancy, even at relatively low levels of obesity, and
could become hyperglycemic (although not neces-
sarily diabetic). Their children, who would be ex-
posed to high circulating glucose concentrations in
utero, may have impaired pancreatic b-cell develop-
ment and become insulin deficient. These ideas
need to be confirmed by further studies in India. It
is known, however, that maternal hyperglycemia,
even within the normal range, is associated with
increased fetal birthweight (macrosomia) without in-
creased fetal length (15). In addition, women with
gestational diabetes have babies who tend to be
macrosomic and are at increased risk for type 2
diabetes as adults.
During the past 10 years, some persons have
argued that the associations between low birth-
weight and cardiovascular disease and type 2 diabe-
tes in later life are the results of confounding vari-
ables (16, 17). Their voices are now seldom heard.
Furthermore, as Rich-Edwards and colleagues (13)
remark, results of experiments on animals directly
support the fetal origins hypothesis. So how should
we proceed? It seems that the strategy described by
the National Institutes of Health (18) is to ignore
the issue. Others, however, will recognize the pos-
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sible importance of these findings in preventing type
2 diabetes. If the disease is a deferred consequence
of successful adaptation in utero, then its primary
prevention lies in protecting fetal development. Con-
tinuing epidemiologic studies will need to use better
markers of fetal development than birthweight. Fur-
thermore, we now know that the fetus can be pro-
grammed by nutritional influences that do not influ-
ence size at birth. Persons who were in utero during
the Dutch famine in 1944 and 1945 now have re-
duced glucose tolerance and evidence of insulin re-
sistance, but these changes are independent of the
modest effect of famine on birthweight (19).
The mechanisms by which undernutrition and re-
tarded growth in utero lead to lifelong changes in
glucose–insulin metabolism need to be explored.
Studies of children in Europe, Jamaica, and India
suggest that these mechanisms still operate today
(20, 21). Further clinical and basic science research
may therefore be a matter of urgency and cannot be
deferred until we learn whether genetics offers so-
lutions to the worldwide epidemic of type 2 diabetes.
David J.P. Barker, MD, PhD, FRS
University of Southampton
Southampton SO16 6YD, United Kingdom
Requests for Reprints: David J.P. Barker, MD, PhD, FRS, MRC
Environmental Epidemiology Unit, University of Southampton,
Southampton General Hospital, Southampton SO16 6YD,
United Kingdom.
Ann Intern Med. 1999;130:322-324.
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© 1999 American College of Physicians–American Society of Internal
Medicine

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