Linking Diabetes and Nutrition
- What are the findings of the twin studies?
- What did they confirm from the studies about the Dutch Famine?
- Define the following terms:
- Using the definitions above, describe Figure 1.
as soon as possible
The Journal of Nutrition
Symposium: Nutritional Experiences in Early Life as Determinants of the
Adult Metabolic Phenotype
Mechanisms Linking Suboptimal
Early Nutrition and Increased Risk of
Type 2 Diabetes and Obesity1–3
Malgorzata S. Martin-Gronert and Susan E. Ozanne*
Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Addenbrooke’s Hospital,
Cambridge CB2 0QQ, UK
Epidemiological studies have revealed a relationship between poor early growth and development of type 2 diabetes and
other features of metabolic syndrome. The mechanistic basis of this relationship is not known. However, compelling
evidence suggests that early environmental factors, including nutrition, play an important role. Studies of individuals in
utero during a period of famine showed a direct relationship between maternal nutrition and glucose tolerance. Further
evidence has come from studies of monozygotic twins who were discordant for type 2 diabetes. Nutrition during the early
postnatal period has also been shown to have long-term consequences on metabolic health. Excess nutrition and
accelerated growth during the neonatal period has been suggested to be particularly detrimental. Animal models, including
maternal protein restriction, have been developed to elucidate mechanisms linking the early environment and future
disease susceptibility. Maternal protein restriction in rats leads to a low birth weight and development of type 2 diabetes in
the offspring. This is associated with b cell dysfunction and insulin resistance. The latter is associated with changes in
expression of key components of the insulin-signaling cascade in muscle and adipocytes similar to that observed in tissue
from young men with a low birth weight. These differences occur prior to development of disease and thus may represent
molecular markers of early growth restriction and disease risk. The fundamental mechanisms by which these
programmed changes occur remain to be fully defined but are thought to involve epigenetic mechanisms. J. Nutr. 140:
It is well established that poor growth in utero is associated with
increased risk of developing diseases such as type 2 diabetes in
later life (1). There is strong evidence from both human and
animal studies that the early environment and in particular early
nutrition play an important role. However, the molecular
mechanisms by which a phenomenon that occurs in early life
has a phenotypic consequence many years later are only just
starting to emerge.
The first study to link birth weight to increased risk of type 2
diabetes was conducted in a group of men born in Hertfordshire,
UK, who were 64 y old at the time of the study. Those men who
had the lowest birth weight were 6 times more likely to currently
have either impaired glucose tolerance or type 2 diabetes than
those men who were heaviest at birth (2). These findings have
been reproduced in over 40 populations worldwide, including
many ethnic groups. In some of the contemporary cohorts where
there is a high prevalence of maternal obesity, there is also
increased risk of diabetes at the high-birth weight end of the
spectrum. This is thought to reflect the increased risk of diabetes
in the macrosomic offspring of women with gestational diabetes
(3). In addition to type 2 diabetes, similar relationships have
been observed linking birth weight to other conditions such as
cardiovascular disease, insulin resistance, and other features of
The detrimental effects of poor fetal growth on long-term
metabolic health appear to be exaggerated if followed by
accelerated postnatal growth and/or obesity. The initial studies
in the original Hertfordshire cohort found that in 64-y-old
men, the worst glucose tolerance was observed in those who
were in the lowest quartile of birth weight but who were
1 Presented as part of the symposium entitled “Nutritional Experiences in Early
Life as Determinants of the Adult Metabolic Phenotype” at the Experimental
Biology 2009 meeting, April 20, 2009, in New Orleans, LA. This symposium was
sponsored by the ASN and supported by an unrestricted educational grant from
the ASN Nutritional Sciences Council and Milk Specialties Global. The Guest
Editor for this symposium publication was Marta Fiorotto. Guest Editor
disclosure: no conflicts of
2 Supported by the Biotechnology and Biological Sciences Research Council (to
M.S. Martin-Gronert) and a fellowship from the British Heart Foundation (to S.E.
Author disclosures: M. S. Martin-Gronert and S. E. Ozanne, no conflicts of
* To whom correspondence should be addressed. E-mail: firstname.lastname@example.org.
662 0022-3166/08 $8.00 ã 2010 American Society for Nutrition.
First published online January 27, 2010; doi:10.3945/jn.109.111237.
currently obese (BMI .28) (2). A study of 7-y-old South
Africans revealed that those children with low birth weights
who underwent rapid childhood weight gain had the worst
glucose tolerance (4). Rapid growth during early life has also
been associated with increased risk of cardiovascular disease. A
study in Finland showed that the highest death rate from
coronary heart disease occurred in men who were thin at birth
but whose weight caught up postnatally such that they had an
average or above average body mass from the age of 7 y (5). In
terms of obesity risk, accelerated postnatal growth appears to
be particularly detrimental even in individuals who had a
normal birth weight (6).
Developmental origins of health and disease hypothesis
In light of the epidemiological data, Nick Hales and David
Barker proposed what they termed the thrifty phenotype
hypothesis in 1992 to explain the relationships between patterns
of early growth and long-term health (7). This suggested that the
relationships between birth weight and metabolic disease arose
because of the response of a growing fetus to a suboptimal
nutritional environment. Central to this hypothesis was the
suggestion that during times of nutritional deprivation, the
growing fetus adopts a number of strategies to maximize its
chances of survival postnatally in similar conditions of poor
nutrition (Fig. 1). Such adaptations include the preservation of
brain growth at the expense of other tissues such as skeletal
muscle and the endocrine pancreas, and the programming of
metabolism in a manner that would encourage storage of
nutrients when they were available. This has no detrimental
effect and is in fact beneficial to survival if the fetus is born into
conditions of poor nutrition. Thus, in populations where there
is chronic malnutrition, these adaptations are beneficial and
prevalence of metabolic disease is low. However, detrimental
consequences of developmental programming were proposed to
arise if the fetus was born into conditions that differed from
those experienced in utero. The imbalance between the early and
postnatal environments may then conflict with the programming
that occurred during fetal life and predispose the offspring to the
subsequent development of metabolic diseases in adulthood.
The ideas suggested within the thrifty phenotype hypothesis
have been expanded and modified in the 17 y since its proposal.
To reflect the evidence that the critical periods of vulnerability to
environmental influences extend beyond the fetal period, the
concept that events in early life affect long-term health is now
generally referred to as the developmental origins of health and
Evidence from human studies
Some of the strongest evidence in support of the role of the
environment in underlying the relationship between fetal growth
and type 2 diabetes has come from the study of twins. A study of
middle-aged twins in Denmark revealed that, in both monozy-
gotic (identical) and dizygotic (nonidentical) twin pairs who
were discordant for type 2 diabetes, the diabetic twin had a
significantly lower birth weight than their normoglycemic co-
twin (8). If it is assumed that the monozygotic twins are
genetically identical then the difference in birth weight must be
related to the fetal environment. A second study of twins in Italy
who were significantly younger (mean age 32 y) than the cohort
in Demark revealed similar findings. These studies thus provide
strong evidence for the importance of a nongenetic intrauterine
factor in the development of type 2 diabetes in later life.
Assessing the impact of maternal nutrition on the health of
offspring in humans is difficult. However, investigations involv-
FIGURE 1 Developmental programming of type 2
diabetes and cardiovascular disease.
Developmental programming of type 2 diabetes 663
ing individuals conceived during conditions of famine have
provided direct evidence of the consequential effects that
maternal nutrition during gestation and lactation has on the
overall health of the adult offspring. The Dutch famine, which
occurred in the western part of The Netherlands at the end of
World War II, was a short, defined period of famine lasting
~5 mo from late November 1944 to early May 1945. Prior to the
onset of the famine, the affected area of The Netherlands
consisted of a reasonably well-nourished population. The
occurrence of this abrupt famine therefore granted researchers
a unique opportunity to retrospectively study the effect of
maternal nutrition on offspring’s glucose tolerance. Compared
with individuals born the year before the famine, those who
were in utero during the famine had higher plasma glucose levels
2 h after a standard oral glucose tolerance test (9). These glucose
levels were highest in those individuals who had been exposed to
the famine during the final trimester of pregnancy and then
became obese in adult life. This study therefore provided direct
evidence that poor maternal nutrition leads to increased
susceptibility to type 2 diabetes in the offspring. It also supports
the hypothesis that the greatest risk of developing metabolic
diseases exists when there is a marked conflict between the
environmental conditions experienced in utero and that expe-
rienced in adult life.
Evidence from animal models
Animal models have been invaluable in proving proof of concept
of the phenomenon of developmental programming. A number
of animal models, including both large animals (e.g. sheep) and
small animals (e.g. rats and mice) have been established to
investigate the effects of the early environment on long-term
health [reviewed in (10)]. In the rat, maternal protein restriction,
maternal calorie restriction, maternal anemia, intrauterine
artery ligation, and fetal exposure to glucocorticoids result in
features of the metabolic syndrome in the offspring. The
phenotypic outcomes of these insults are very similar, suggesting
that they act through common pathways. One of the most
extensively studied rodent models is that of maternal protein
restriction. Dams are fed a low- (8%) protein diet during
pregnancy and lactation to induce growth restriction in the
offspring [reviewed in (11)]. The level of protein restriction is a
mild insult to the animals, because it results in only a modest
reduction in birth weight and does not affect litter size. The
offspring are weaned onto a standard diet containing 20%
protein. These animals are compared to control offspring born
to mothers fed a control diet containing 20% protein. The low-
protein (LP) offspring undergo an age-dependent loss of glucose
tolerance and demonstrate both b-cell dysfunction and insulin
resistance and by 17 mo of age have frank diabetes [reviewed in
(11)]. The insulin resistance is associated with reductions in
expression of a number of key insulin signaling proteins,
including the p110b catalytic subunit of phosphatidyl inositol
3-kinase in adipose tissue and protein kinase C z in skeletal
muscle (12,13). The profile of insulin signaling protein expres-
sion in muscle and adipose tissue from LP offspring demon-
strates strikingly similar deficiencies to those in tissues from
humans with a low birth weight (14,15). The differences in
protein expression occur prior to development of insulin
resistance, suggesting that they are not consequences of hyper-
insulinemia or hyperglycemia but play a role in determining
future susceptibility to insulin resistance, cardiovascular disease,
and type 2 diabetes.
A modification of the maternal protein restriction model has
enabled the assessments of the differential effects of reduced
growth at different stages of early development. The cross
fostering of LP offspring to control-fed dams for the period of
lactation results in a rapid growth during this period (recuper-
ated offspring) and excess weight gain postweaning (16). In
contrast, crossing control offspring to LP-fed dams during
lactation slows growth and permanently reduces body size (16).
This suggests that, as in humans, early postnatal life represents a
critical time window for determination of long-term energy
Extensive human and animal studies provide strong evidence
that a suboptimal environment during early life affects long-
term health and risk of diseases such as type 2 diabetes. A major
research focus in this field is therefore to define the molecular
mechanisms by which an event that occurs in early life has
phenotypic consequences many months later following multiple
rounds of cell division.
One area of immense interest is in the role of epigenetic
modifications in mediating the long-term effects of early-life
insults on gene transcription (17–19). Epigenetics refers to
modifications of DNA and proteins packaging the DNA
(histones) that regulate gene activity. Examples of such modi-
fications include DNA methylation and post-translational mod-
ifications of histone tails such as methylation, acetylation,
phosphorylation, and ubiquitination. It is known that cytosine
methylation within CpG dinucleotides of DNA acts in concert
with other chromatin modifications to heritably maintain
specific genomic regions in a transcriptionally silent state (20).
Different epigenetic states on identical DNA sequences can
therefore lead to alternative gene expression levels.
Several studies have shown that nutritional influences in early
life can induce permanent alterations in epigenetic modifica-
tions. Studies in mice that carry the epigenetically sensitive allele
Agouti viable yellow (Avy) demonstrated that when Avy
pregnant dams were fed a diet supplemented with methyl
donors and cofactors, they tended to have offspring that were
pseudo-agouti and lean rather than yellow and obese as seen in
offspring of normally fed dams (21). Global changes in DNA
methylation were observed in sheep that experienced alterations
in vitamin B and methionine during the periconceptional period
(22). In addition, supplementation of the diet of pregnant mice
with methyl donors altered methylation of genes implicated in
allergic airway disease (23). Maternal protein restriction has
been shown to alter the methylation status of the promoters of
the glucocorticoid receptor (24), PPARa (25), and the angio-
tensin receptor (26) with parallel changes in gene expression.
More recent studies have shown that histone modifications can
also be influenced by the early environment. Intrauterine artery
ligation, a model of placental insufficiency, leads to changes in
both DNA methylation and histone acetylation in the PDX-
1 promoter (27). Alterations in histone modifications have also
been implicated in mediating the effect of caloric restriction
during the second half of pregnancy on the programmed
reduction of GLUT4 expression in the offspring (28). Recent
studies have demonstrated that maternal diet can influence
epigenetic marks in humans. These revealed that individuals
who were exposed to famine in utero during the Dutch Hunger
Winter had altered methylation of the insulin-like growth factor
2 gene in white blood cells in adulthood (29).
An alternative mechanism by which environmental factors at
critical periods of development could have long-term phenotypic
consequences is through permanent structural changes in key
organs. If a certain nutrient or hormone is essential at a critical
period of development for growth and differentiation of a tissue,
inappropriate levels of this factor will have permanent structural
consequences. There are several examples in rodent models of
developmental programming to suggest that the perinatal
environment can have large and lasting effects on brain
development. For example, treatment of neonatal rat pups
during the second postnatal week of life with high levels of
insulin was shown to induce permanent changes in hypotha-
lamic morphology, notably causing a reduction in the density of
neurons within the ventromedial hypothalamus (30). This
region of the hypothalamus has been implicated in regulation
of satiety. Thus, structural alterations in this area of the brain
could contribute to the excess weight gain and glucose intoler-
ance in adult rats that were administered insulin in early life.
Altered levels of leptin during perinatal life have also been
implicated as an important programming factor (31). During
early neonatal life in rodents, there is a surge in plasma leptin
concentrations. The functional significance of this surge is
unknown; however, the action of leptin during this period is very
different to that in adult life. Whereas in the adult brain, leptin
acts on hypothalamic circuitry that affects food intake and
energy expenditure, evidence from rodents suggests that in the
first few weeks of postnatal life leptin is ineffective at modulat-
ing these pathways. During this period, leptin has an important
neurotrophic role. It has been shown that leptin can stimulate
neurite outgrowth from arcuate nucleus explants from d4-old
neonatal mice (32). Furthermore, the greatly reduced density of
projections from the arcuate nucleus to the downstream para-
ventricular nucleus in the leptin-deficient ob/ob mice can be
restored to wild-type levels by administration of leptin from
postnatal d 4 to 12.
There is now little doubt that fetal and early postnatal life are
important time periods for the determination of future risk of
type 2 diabetes, obesity, and other features of the metabolic
syndrome. These conditions represent major health care issues
of the 21st century in both the developed and developing world.
Understanding the fundamental mechanisms underlying the
Developmental Origins of Health and Disease is therefore
critical. Once we understand such processes, targeted interven-
tion and ultimately prevention strategies may become a feasible
M.S.M-G. and S.E.O. wrote the paper, M.S.M-G. produced
the figure, and S.E.O. had the primary responsibility for final
content. Both authors read and approved the final manu-
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