The Journal of Nutrition

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 youngmenwith 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:

662–666, 2010.


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.

Epidemiological data 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 metabolic syndrome.

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 interest. 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.

Ozanne). 3 Author disclosures: M. S. Martin-Gronert and S. E. Ozanne, no conflicts of


* To whom correspondence should be addressed. E-mail:

662 0022-3166/08 $8.00 ã 2010 American Society for Nutrition. First published online January 27, 2010; doi:10.3945/jn.109.111237.

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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 disease hypothesis.

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.

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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 earlyMay 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 balance.

Molecular mechanisms 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

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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.

Perspectives 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 possibility.

Acknowledgments 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- script.

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