ROLE OF FETAL AND INFANT GROWTH IN PROGRAMMING METABOLISM IN LATER LIFE

Biol. Rev. (), , pp. –

Printed in Great Britain

ROLE OF FETAL AND INFANT GROWTH IN PROGRAMMING

METABOLISM IN LATER LIFE

B M. DESAI C. N. HALES

Department of Clinical Biochemistry, University of Cambridge, Cambridge CB QR

(Received June ; revised September ; accepted October )

ABSTRACT

Fetal growth and development is dependent upon the nutritional, hormonal and metabolic

environment provided by the mother. Any disturbance in this environment can modify early

fetal development with possible long-term outcomes as demonstrated by extensive work on

‘programming’. Growth restriction resulting from a deficit in tissue}organ cell number (as

measured by tissue DNA content) is irrecoverable. However, when the cell size (or cell protein

content) is reduced, the effects on growth may not be permanent.

Recent epidemiological studies using archival records of anthropometric measurements

related to early growth in humans have shown strong statistical associations between these

indices of early development and diseases in later life. It has been hypothesised that the

processes explaining these associations involve adaptive changes in fetal organ development in

response to maternal and fetal malnutrition. These adaptations may permanently alter adult

metabolism in a way which is beneficial to survival under continued conditions of malnutrition

but detrimental when nutrition is abundant.

This hypothesis is being tested in a rat model which involves studying the growth and

metabolism in the offspring of rat dams fed a low-protein diet during pregnancy and}or

lactation. Using this rat model, it has been demonstrated that there is :

(i) Permanent growth retardation in offspring nursed by dams fed a low-protein diet.

(ii) Permanent and selective changes in organ growth. Essential organs like the brain and

lungs are relatively protected from reduction in growth at the expense of visceral organs such

as the liver, pancreas, muscle and spleen.

(iii) Programming of liver metabolism as reflected by permanent changes in activities of key

hepatic enzymes of glycolysis and gluconeogenesis (glucokinase and phosphoenolpyruvate

carboxykinase) in a direction which would potentially bias the liver towards a ‘starved’

setting. We have speculated that these changes could be a result of altered periportal and

perivenous regions of the liver which may also affect other aspects of hepatic function.

(iv) Deterioration in glucose tolerance with age.

(v) An increase in the life span of offspring exposed to maternal protein restriction only

during the lactation period, and a decrease in life span when exposed to maternal protein

restriction only during gestation.

These studies show that hepatic metabolism and even longevity can be programmed by

events during early life.

Key words : maternal nutrition, birth weight, nutritional programming, non-insulin-dependent

diabetes.

M. D C. N. H

CONTENTS

I. Introduction . . . . . . . . . . . . . . .

II. Nutrition, growth and development . . . . . . . . . .

() Maternal nutrition and fetal growth . . . . . . . . .

() Fetal adaptation to malnutrition . . . . . . . . . .

III. Programming. . . . . . . . . . . . . . .

() Nutritional programming in animals . . . . . . . . .

() Nutritional programming in humans . . . . . . . . .

() The mechanisms underlying programming . . . . . . . .

IV. Early growth and adult onset diseases . . . . . . . . . .

() Recent epidemiological studies . . . . . . . . . .

() Thrifty phenotype hypothesis . . . . . . . . . . .

() Recent animal studies . . . . . . . . . . . .

V. Conclusions . . . . . . . . . . . . . . .

VI. Acknowledgements . . . . . . . . . . . . .

VII. References . . . . . . . . . . . . . . .

I. INTRODUCTION

Recent epidemiological studies in people whose birth weights were recorded many

years ago suggest links between impaired growth during early life and the development

much later of diseases such as ischaemic heart disease (Barker et al., ), hypertension

(Barker et al., ), diabetes (Hales et al., ) and features of insulin resistance

syndrome (Barker et al., a). The long-term effects of retarded early growth are

proposed to result from maternal and fetal malnutrition at critical periods of fetal or

infant development leading to reduction in the growth of organs and permanent

changes in their metabolism or structure, or both. Furthermore, transition from early

nutrition deprivation to nutrition abundance in later life might reduce the ability to

produce and respond to insulin. The concept may explain the high prevalence of non-

insulin-dependent diabetes (NIDDM) in human populations that have experienced a

transition from an undernourished environment to one of overnutrition, for example,

in the Pima Indian (Bennett et al., ; Jarret, ), Nauruans of the Pacific Islands

(Zimmet et al., ) and migrant populations (Cheah & Tan, ; Zimmet et al.,

; Cohen et al., ). Evidence that maternal and infant undernutrition itself may

be diabetogenic comes mainly from studies in both animals and humans suffering from

protein–energy malnutrition in which functional abnormalities in insulin secretion and

glucose tolerance have been demonstrated (reviewed in Section IV).

The view that early malnutrition can impair β-cell growth and function is consistent

with early studies on malnourished children from the developing countries, in whom

impaired glucose tolerance was found even after recovery from the nutritional insult

(James & Coore, ; Milner, ). Studies in experimental animals show clearly

that these changes can be reproduced by subjecting either fetal or early postnatal

animals to general protein–calorie malnutrition (Weinkove, Weinkove & Pimstone,

) or, interestingly, to protein deficiency alone (Pimstone, ; Swenne, Crace &

Milner, ). Moreover, the degree of the loss of insulin secretion in protein–calorie

malnutrition is much more severe than would be expected from the degree of reduction

of islet volume (Weinkove et al., ). This, of course, is reminiscent of the situation

in human NIDDM. Poor insulin secretion may occur not only from less β-cells, but

also as a result of abnormal islet structure and vascularization (Snoeck et al., ).

Programming fetal and infant growth

The paradox of the failure of natural selection to eliminate a genetically determined

lethal condition was addressed several years ago by Neel’s ‘ thrifty genotype’ hypothesis

(Neel, ). It suggests that the high incidence of diabetes in Western or recently

affluent societies results from the existence of diabetogenic genes which confer a

survival advantage in the condition of subsistence living, although are detrimental to

survival under conditions of overnutrition.

Hales & Barker () have proposed a hypothesis concerning the aetiology of

NIDDM, the ‘thrifty phenotype’ which provides an alternative to the ‘thrifty

genotype’ hypothesis. The essence of this hypothesis is that poor fetal and early

postnatal nutrition imposes mechanisms of nutritional thrift upon the growing

individual. One of the major long-term consequences of inadequate early nutrition is

suggested to be impaired development of the endocrine pancreas and increased

susceptibility to the development of NIDDM.

II. NUTRITION, GROWTH AND DEVELOPMENT

Growth and development of the mammalian embryo and fetus is a highly complicated

sequence of events whereby a single-cell zygote develops into a complex yet organized,

multicellular, multisystem, fully developed animal. Tissue or organ development

involves three different processes, namely, ‘hyperplasia’ also known as replication or

proliferation; differentiation, which involves the orderly and programmed migration of

cells into definable tissues and organ rudiments; and, ‘hypertrophy’, in which the cells

increase in size and acquire the capacity to synthesize macromolecules for specialized

functions. In mammals, as in many other species, the major part of the developmental

process pertaining to cell division occurs during intrauterine life. In some organs and

tissues, it continues after birth. For example, at birth, a virtually full complement of

brain neurones and of renal glomeruli are present (Hinchliffe et al., a) and

available data suggest that at the age of yr at least half the adult complement of β-cells

is present (Stefan et al., ).

Fetal growth and development is controlled by two major factors, namely, genetic

factors as determined by the fetal genome, and environmental factors, such as maternal

nutrition, that alter the expression of the fetal genome. Recent studies into the control

of fetal growth appear to suggest that the genome regulates the growth and development

of the fetus in a predetermined pathway in which specific genes are turned on and off

at specific stages of fetal development, and the environmental factors influence growth

by their effect on this normal pattern of genetic expression (Han, ).

() Maternal nutrition and fetal growth

The relationship between the diet of the mother and the well-being of the fetus and

infant continues to be a matter of great importance, uncertainty and controversy. It has

been known for many years that birth weight is strongly maternally determined and

that genetic factors play a relatively weak role (Carr-Hill et al., ). In Walton &

Hammond’s () well-known experiments, in which Shetland and Shire horses were

crossed, the foals were smaller at birth when a Shetland pony was the mother than when

a Shire horse was the mother. As the genetic composition of the two crosses was similar,

this implied that the Shetland mother had constrained the growth of the fetus. These

M. D C. N. H

findings from cross-breeding experiments are supported by recent embryo-transfer

experiments. Once again, the size at birth of animal embryos removed from their

mothers’ uteri is related to the size of the uterus into which they are transferred (Snow,

).

In human studies, comparisons of birth weights of half-siblings show that those

related through the mother tend to have similar birth weights whereas those related

through the father do not (Morton, ). Ounsted & Ounsted () showed that the

mothers of growth-retarded babies had themselves had low mean birth weight. Further

studies have shown that the birth weight of mothers is not only related to that of their

children but also to that of the subsequent generation (Hackman et al., ; Klebanoff,

Meirik & Berendes, ; Emmanuel et al., ). This has led to the conclusion that

mothers constrain fetal growth and that the degree of constraint they exert is set when

they themselves are in utero (Ounsted, Scott & Ounsted, ).

‘Maternal constraint ’ is thought to reflect the limited capacity of the mother to

deliver nutrients to her fetus, which in turn limits the growth of the fetus (McCance &

Widdowson, ; Gluckman et al., ). From human (Eastman & Jackson, ;

Hackman et al., ) and animal (Owens, Owens & Robinson, ; Zeman, ;

Chow & Lee, ) studies, it is known that both the plane of nutrition at the onset of

pregnancy (previous nutritional exposure) and the nutrition during the pregnancy itself

can exert an influence on fetal growth. Not only this, but possibly the nutritional status

of the mother’s own mother in the past may influence fetal growth as demonstrated by

a study of survivors of the Dutch ‘hunger winter’. A famine occurred in the western

part of the Netherlands during the Second World War (Stein & Susser, ). It began

in October after the German occupation forces imposed an embargo on all

transport and food supplies – a reprisal for a general strike. It ended suddenly, in May

, when the Allied armies liberated the Netherlands. An account of the famine,

written immediately after liberation, stated that ‘the average food intake from all

sources, including extra-legal, in October was approximately calories. This

was reduced to calories or less in April ’. Dutch women who were born in

Amsterdam during and after the famine, and who experienced famine during the first

and second trimesters of their intrauterine lives, have been followed up. Although they

themselves had normal birth weight the mean birth weight of their own babies was

reduced (Lumey, ). In this study, clear effects on the reproductive outcomes are

seen in the generation following an environmental exposure in utero. Furthermore, a

study on Swedish women has shown that women who were themselves small for

gestational age (growth retarded in utero) had an increased risk of giving birth to either

intrauterine growth retarded or preterm infants, again emphasizing the importance of

maternal factors and the intrauterine milieu. Moreover, women who were preterm at

birth did not demonstrate a similar risk (Klebanoff, Meirik & Berendes ). Studies

on pregnant women from developing countries indicate that women with low pre-

pregnancy weight and short stature had infants with low birth weight (Kramer, ).

Therefore, adverse maternal nutrition can be viewed as a long-term environmental

adversity affecting the rapidly developing fetus, and the process of adaptation to this

milieu could be considered as a response to this adversity.


() Fetal adaptation to malnutrition

The plasticity of the fetus enables it to adapt to conditions of adverse maternal

nutrition by reducing its growth and development (Widdowson & McCance, ;

Owens et al., ). Whilst adaptation allows a highly effective means of survival under

the situation of nutritional deprivation, it raises a number of issues which need to be

addressed. First, what are the limits of this adaptation, and at what point does it break

down? For instance, the simplest way of adapting to undernutrition is to reduce body

weight, thereby reducing the use of substrates which leads to a fall in basal metabolic

rate. However, there is obviously a limit below which weight loss becomes excessive,

and morbidity and mortality increases. Secondly, what are the costs of the adaptation?

Almost by definition, adaptation confers benefts compared with the unadapted state,

but it also usually involves costs. A number of studies have shown that undernutrition

causes a reduction in cell numbers in certain organs which is irrecoverable (Widdowson,

; Winick, ; Hinchliffe et al., ). Thirdly, what kind of relationship does the

adapting organism’s response have to the stress imposed? Does any degree of growth

deficit carry some risk? And finally, what are the mechanisms involved?

III. PROGRAMMING

The possibility that nutrition in early life could influence a propensity to adult

diseases invokes the concept of ‘programming’. The principle that the nutritional,

hormonal, and metabolic environment provided by the mother may permanently change

the structure and physiology of her offspring was established long ago. Recently, Lucas

() defined programming as a process whereby a stimulus or insult, at a critical or

sensitive period of development, has lasting or lifelong significance.

There are four essential principles which underlie the concept of programming. (i)

Nutritional (or non-nutritional) manipulations cause different effects at different times

in early life. (ii) Rapidly growing fetuses and neonates are more vulnerable to these

manipulations. (iii) Manipulation in early life has permanent effects. (iv) The permanent

effects include reduced cell numbers, altered organ structure and resetting of hormonal

axes.

() Nutritional programming in animals

Animal evidence for programming during critical periods of development dates back

over years (Spalding, ). Non-nutritional influences, for example, hormonal

signals operating during critical periods, also have numerous programming effects. The

classic example of such a phenomenon is the exposure of female rats at a critical period

of fetal life to a single exogenous dose of testosterone, which permanently reorientated

sexual behaviour (Angelbeck & Du Brul, ). A similar dose of testosterone in -

day-old females had no effect. Thus, there is a critical time at which the animal’s sexual

physiology is sensitive and can be permanently changed. Exposure of animals to an

excess of thyroxine during the neonatal period changes the pituitary-hypothalamic

responses linked to the secretion of thyroid-stimulating hormone in later life (Besa &

Pascula-Leone, ).

Some of the earliest work relating developmental physiology to nutrition and to its

outcome were the studies of McCance and Widdowson. Employing the ‘ large and small

M. D C. N. H

litter ’ technique, they produced cohorts of well-nourished and undernourished

suckling animals which subsequently paved the way for future studies. The intriguing

features of their studies were that the rats raised in large litters were small at weaning,

continued to eat less and remained smaller as adults. Also, these studies provided some

of the early information linking chronological, somatic and behavioural development in

retarded growth. More precisely, they identified critical stages of development at which

interference with an animal’s growth could have permanent and far-reaching

consequences (McCance & Widdowson, , ; Widdowson & McCance, ,

).

In concert with this work were the studies of Winick and colleagues which put

forward a hypothesis to explain growth retardation. They suggested that essentially

growth encompasses two stages, namely, cell division and cell enlargement. In a series

of studies on malnourished rats from birth until days of age, they demonstrated that

the cellular effects of malnutrition depend upon the phase of growth of the animals at

the time of onset of malnutrition. Very early in life, malnutrition would impede cell

division, organ growth and differentiation which may be irrecoverable. Later in life, it

would lead to changes in cell composition and cell size (Winick & Noble, ; Winick,

Fish & Rosso, ; Winick ). Conversely, overfeeding rats by raising the animals

in litters of – pups compared to – pups during the proliferative phase of growth

caused acceleration of the rate of cell division, and produced a higher DNA content per

organ (Winick & Noble, ). Thus, these studies collectively indicate that a reduced

supply of nutrients during early life (prenatal and postnatal) interferes with the rate of

cell multiplication in the various organs and that the effect is proportionally more

deleterious in tissues with a faster rate of cell multiplication.

Nutritional programming has been demonstrated convincingly in a range of

mammals, such as rats, mice, sheep, pigs and primates. It has further been shown that

poor nutrition may permanently programme the structure and physiology of a range of

organs and tissues, although such effects may remain latent until the animal is mature.

For instance, nutrition at a vulnerable period of brain development has permanent

effects on brain size, with the cerebellum being more affected than the cerebrum, brain

cell number (Winick, ) and performance (Katz, ; Smart, ).

Early studies have unequivocally demonstrated that alteration of cholesterol

metabolism during development, either by changing the amount or composition of the

diet or by giving cholestyramine which sequesters bile salts and increases cholesterol

excretion, has permanent effects. Thus, treatment of rat dams during gestation up-

regulated cholesterol synthesis in the adult offspring, whereas treatment of the dams

after birth permanently changed the body’s capacity to excrete cholesterol in bile

(Innis, , ; Little & Hahn, ).

The age at which an animal is weaned also appears to have a longlasting influence on

metabolism. Rats that are weaned prematurely have a raised plasma cholesterol

concentration in later life, which becomes apparent only after months (Hahn & Kirby,

).

Mott, Lewis & McGill () have shown that early overfeeding in primates may

programme later obesity and that breast-fed and bottle-fed baboons have long-term

differences in their lipid metabolism and in the degree of atherosclerosis. Similarly,

Duff & Snell () have shown that overnutrition in rats caused by litter manipulation


resulted in alteration in hepatic enzyme activities that reflected an increased capacity

for lipid synthesis by the liver.

These results raise the question of where the ‘memory’ of the early event had been

stored in the intervening period and further demonstrate that early diet could play a role

in the later development of disease states that have considerable significance in humans.

In addition, recent studies on rats have shown that the quality of nutrition in early

life could have permanent consequences on carbohydrate metabolism. For instance,

maternal protein-undernourished fetuses show long-term morphological changes in β-

cells (Snoeck et al., ), insulin secretion (Dahri et al., ), blood pressure

(Langley & Jackson ) and hepatic metabolism (Desai et al., ; Ozanne et al., ).

() Nutritional programming in humans

Given the evidence for programming in general and the evidence for nutritional

programming in mammals, the same phenomena in humans might be predicted.

Childhood obesity may predispose to adult obesity (Charney et al., ). This is

supported by animal data cited above (Mott, Lewis & McGill, ). Paradoxically,

however, early starvation of mothers may also be followed by adult obesity in offspring.

Among men born during the Dutch ‘hunger winter’ of –, those whose mothers

were exposed to famine in the first half of gestation became obese as adults (Stein &

Susser, ; Ravelli, Stein & Susser, ). It is thought that, during early gestation,

hypothalamic control of appetite becomes set in relation to body size (Widdowson &

McCance, ). An inappropriate setting of the hypothalamus could have led to

obesity in men whose mothers were exposed to famine in utero. Alternatively, early

nutrition could influence the adipocyte number (Faust et al., ) or size (Lewis et al.,

).

Recently, Hinchcliffe et al. () have shown that asymmetrical retardation

(disproportionate growth) is associated with a substantial reduction in the number of

nephrons, and that there is no postnatal compensation for this.

Iron deficiency in infancy, common both in the West and in developing countries, is

related to poor developmental performance (Ankett et al., ), which could have

long-lasting consequences (Dallman, Siimes & Stekel, ; Walter et al., ).

A prospective dietary study on preterm infants undertaken by Lucas & Morley

() has shown that a brief period of early dietary management has a major impact

about years later on brain growth, neurodevelopment and bone mineralization.

Compared to formula feed, human milk appeared to promote brain growth, brain

development and bone mineralisation in these infants.

() The mechanisms underlying programming

Collectively, the animal and human studies provide convincing evidence that

nutrition at a critical or sensitive period in early life may influence a wide variety of

metabolic, developmental and pathological processes in adulthood. If this is so, defining

the mechanisms involved could be crucial to understanding the pathogenesis of adult

disease. Some programming events may have immediate effects, for example, neuronal

growth at a critical stage with subsequent failure of catch-up. Other programming

effects, as cited previously, are deferred. In this instance, the question is how the

M. D C. N. H

memory of early events is stored and later expressed, despite continuous cellular

replication and replacement. Lucas () has postulated three cellular mechanisms. It

could occur at the level of an individual gene, with induction or repression of gene

expression. Another possibility is a permanent reduction in cell numbers. Alternatively,

specific individual cells might be deleted or clonally expanded.

IV. EARLY GROWTH AND ADULT ONSET DISEASES

() Recent epidemiological studies

Epidemiological and animal studies have suggested that long-term health can be

influenced by events in early life. Early evidence came from geographical studies which

revealed differences in disease rates in different places or at different times. Forsdahl

() first reported from Norway that a close correlation existed between current death

rates from ischaemic heart disease and past infant mortality rates in different areas of

the country. However, the current infant mortality rate was less strongly related to

current ischaemic heart disease deaths. This was attributed to adverse influences in

childhood and adolescence, associated with poor living standards, which increased

susceptibility to other influences associated with affluence and encountered in later life.

These observations were confirmed in the UK by Williams, Roberts & Davies

(). Moreover, in their study, there was an equally good correlation between past

and present infant mortality and ischaemic heart disease deaths, thus they questioned

the role of living conditions in early life. It is possible in the UK (unlike Norway) that

geographical variations in infant mortality persist (Markowe, ).

In , studies from different areas of England and Wales reported that infant

mortality in – predicted the incidence of death from ischaemic heart disease in

– (Barker & Osmond, ). It was suggested that the mechanisms which linked

infant mortality and later ischaemic heart disease could be operating during fetal life.

Moreover, since infant mortality is known to be strongly and inversely related to birth

weight (McCormick, ; Dollfus et al., ), it became important to determine

whether birth weight itself was related to ischaemic heart disease.

Therefore, Barker and his colleagues undertook a search for old records of birth

weight and discovered a few populations in the United Kingdom where such records

existed, stretching back for over years. In certain places, such as Hertfordshire,

Preston and Sheffield, records existed of early anthropometry such as birth weight,

weight at yr, head circumference and abdominal circumference for people who are

currently in the age range – yr. This was followed by a more detailed series of

studies which established statistical links between indices of infant and fetal growth and

the risk of death from ischaemic heart disease and hypertension. For example, in a

group of Hertfordshire men, death from ischaemic heart disease increased as birth

weight or weight at yr decreased (Barker et al., ). Subsequent studies showed

linkages of indices of early growth with hypertension (Barker et al., ), plasma

fibrinogen concentration, factor VII (Barker et al., ), cholesterol and apolipoprotein

B (Fall et al., ). These associations parallel those with death rates from ischaemic

heart disease in that high body weight in early life is associated with a low incidence of

each risk factor. The associations are strong and graded, and are independent of social

class, either at birth or currently, and of influences in adult lifestyle such as smoking and

alcohol consumption.


A striking feature of these findings is that different risk factors are related to different

patterns of early growth. It was observed that adult blood pressure increased in relation

to decreasing birth weight but not independently to weight at yr. The strongest

predictor of adult blood pressure was seen in adults who at birth had a large placenta

in relation to birth weight (Barker et al., ). Plasma fibrinogen concentrations were

related in men to weight at yr but not to birth weight. In fact, those babies who were

short in relation to head size tended to develop hypertension and high plasma

fibrinogen concentrations (Barker et al., ). Increased placental size has been

implicated as a sign of maternal, and possibly fetal, malnutrition. This is supported by

a study from Oxford which showed that maternal anaemia is associated with increased

placental size and with an increased ratio of placental weight to birth weight (Godfrey

et al., ).

In view of the known association between ischaemic heart disease, hypertension and

NIDDM, and the fact that very rapid growth of β-cells of the islets of Langerhans

occurs during fetal life (at least in rats), the possibility that loss of glucose tolerance

could itself be a consequence of poor early growth and development was explored.

In the same population of Hertfordshire men of mean age years, glucose tolerance

(either judged by the h plasma glucose concentration at the end of the test or the

percentage of men with impaired glucose tolerance or newly discovered NIDDM) was

strongly related to birth weight. The smallest infants had the worst glucose tolerance.

Furthermore, these men had an eightfold increased risk of having impaired glucose

tolerance or NIDDM if their weight at yr was equal to or less than ± kg compared

with those whose weight at yr was equal to or greater than ± kg (Hales et al., ).

This was true in each social class and at each level of body weight. A similar relationship

with birth weight was seen in men and women of mean age from Preston (Phipps et

al., ). These trends were barely changed by adjustments for duration of gestation,

and therefore reflected differences in fetal growth rates.

Recent advances in assay methodology make it possible to measure specifically

plasma concentrations of the precursor of insulin, – split proinsulin (Sobey et al.,

; Temple et al., ). A raised plasma – split proinsulin concentration is

thought to indicate β-cell dysfunction (see Fig. ). Concentrations of plasma – split

proinsulin were higher in Hertfordshire men with lower birth weight and weight at yr

of age. Therefore, this suggests that the relationship between low birth weight and

NIDDM depends partly on impaired β-cell function. This interpretation is consistent

with the occurrence of impaired development of the endocrine pancreas in babies with

intrauterine growth retardation (Van Assche et al., ). However, in studies of

middle-aged adults, no strong relationships between indices of β-cell function and early

anthropometry have been observed (Phillips et al., b ; Alvarsson, Efendic & Grill,

). The lack of such correlations may reflect the adaptation of β-cell responses to

insulin resistance in later adult life. There is a relationship between min plasma

glucose levels and birth weight in young men (Robinson et al., ) which is consistent

with this conclusion.

The association between early growth and NIDDM raised the possibility of whether

the combination of reduced glucose tolerance, hypertension and hypertriglyceridaemia,

components of what is now referred to as the ‘ insulin resistance syndrome’ or

‘syndrome X’, could be linked to birth weight. When Hertfordshire men with the

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32-33 split proinsulin

CN 32

31

6564

Proinsulinconvertase 3

Carboxypeptidase H

des-31-32 split proinsulin


Carboxypeptidase H

C

AB

C-peptide

Insulin

Carboxypeptidase H

des-64-65 split proinsulin


65-66 split proinsulin

Carboxypeptidase H


Fig. . Insulin production from proinsulin. Insulin is produced from its precursor molecule proinsulin,

and the major route is via the – split proinsulin pathway. The proportion of circulating proinsulin

rises in non-insulin-dependent diabetes patients, the cause of which is thought to be a pancreatic β-cell

defect. Possible mechanisms for the defect are reviewed by Rhodes & Alarcon ().

insulin resistance syndrome were examined for a relationship with birth weight, it was

found that when those with a birth weight equal to or less than ± kg were compared

with those whose birth weight was greater than ± kg, the former had an -fold

increased risk of having features of the insulin resistance syndrome. A similar degree

of increased risk was found in both men and women in Preston (Barker et al., a).

It has recently been shown that adult insulin resistance, as judged from the initial rate


of fall of plasma glucose levels after a bolus injection of insulin, was related to an index

of thinness at birth. Thus, infants of low ponderal index (weight divided by length

cubed) were most insulin resistant as adults. Adult obesity was an added risk such that

infants who were thin at birth and obese (as judged by body mass index) as adults were

approximately twice as insulin resistant as those who were heavier at birth but thin as

adults (Phillips et al., a). The processes which link thinness at birth with insulin

resistance in adult life are not known. Studies of patients with NIDDM, using

euglycaemic clamp, have shown that peripheral tissues, particularly skeletal muscle, are

an important site of insulin resistance (DeFronzo, ). Muscle biopsies have shown

that insulin resistance is associated with a lower density of capillaries in muscle, a lesser

proportion of Type muscle fibres and a greater proportion of Type B fibres (Lillioja

et al., ). Babies born at term with a low ponderal index have a reduced mid-arm

circumference which implies that they have a low muscle bulk as well as less

subcutaneous fat (Robinson et al., ). The authors therefore suggested that thinness

in fetal life may be associated with abnormalities in muscle structure and function that

persist into adult life and interfere with the ability of insulin to promote glucose uptake.

These observations have been independently confirmed in divergent populations.

For example, the relationship of low birth weight to increased risk of adult NIDDM

has been confirmed in Pima Indians (McCance et al., ) and the relationship of low

birth weight to features of the insulin resistance syndrome has been confirmed in

Mexican Americans (Valdez et al., ) and in Swedish men (Lithell et al., ).

Interestingly, in the Pima Indians, there is also an increased risk associated with higher

birth weight (McCance et al., ). Presumably, this is because a large proportion of

pregnancies are associated with gestational diabetes which is also a factor known to

predispose to subsequent NIDDM in the offspring. Earlier work on rats which had

diabetes expeirmentally induced during pregnancy has also shown that there are long-

term consequences to the offspring – mild diabetes during pregnancy was associated

with decreased insulin secretion in the offspring whereas severe diabetes caused insulin

resistance (Van Assche, Aerts & Holemans, ; Holemans, Aerts & Van Assche,

).

Additional evidence that processes leading to NIDDM operate early in life is the

finding that individuals with impaired glucose tolerance are significantly shorter than

those with normal glucose tolerance in East Anglia in England (Williams et al., ).

Confirmation of this association has also been observed in a very different population

in Tanzania in which impaired glucose tolerance was found to be more common in

shorter individuals, even though the population was underweight by Western standards

and NIDDM itself very uncommon (Swai et al., ).

Studies on younger populations, including children aged and years from

Salisbury (Law et al., ), and -year-old men in Southampton (Robinson et al.,

) show a similar association between fetal growth, blood pressure and insulin

response to that observed previously in older people. Therefore, these associations

provide further evidence that the pathogenesis of NIDDM is set in sequence in early

life, and that metabolism becomes impaired within a few years of birth.

The variations in birth weight in the Hertfordshire and Preston studies may be

markers of more subtle but more important changes in organ structure and function

which determine later disease. For example, recent studies have shown that raised

M. D C. N. H

serum cholesterol concentrations in adult life are associated with impaired growth

during late gestation. It is suggested that impaired fetal growth leads to under-

development of the liver and a resultant permanent change in low-density lipoprotein

cholesterol metabolism (Barker et al., b).

Hence, the findings are reproducible and applicable to widely different ethnic groups

and may provide important insights into the underlying pathogenic processes. In order

to incorporate these findings into a pathogenic mechanism leading to impaired glucose

tolerance, NIDDM and insulin resistance syndrome, it is necessary to understand the

major processes determining fetal growth and development. These associations between

early growth and long-term health are thought to reflect ‘programming’, whereby

influences which impair fetal growth have permanent effects on the structure and

function of particular organs and tissues.

() Thrifty phenotype hypothesis

The proposed role of the fetal environment in the pathogenesis of non-insulin-

dependent diabetes and its associated features has been incorporated into the ‘thrifty

phenotype’ hypothesis (Hales & Barker, ). The essence of this hypothesis is that

poor fetal nutrition imposes growth and developmental constraints and changes upon

the fetus which may be considered as achieving metabolic thrift. It is envisaged that the

changes adopted serve at least two functions. First, they operate by selective nutritional

distribution between organs, such that the overall brain growth and development is

preserved relative to certain other organs such as the liver and pancreas. Secondly, the

changes which occur adapt metabolism in postnatal life, such that the chances of

survival under conditions of poor nutrition postnatally are enhanced. There is a

growing body of work on experimental animals which strongly supports the existence

of such mechanisms.

A further development of the ‘thrifty phenotype’ hypothesis is the proposal that

whilst these adaptive changes are beneficial to survival under conditions of poor

nutrition, they may be detrimental under conditions of normal or overnutrition. Under

these conditions, there would be a reduced ability to produce and respond to insulin

with subsequent increased risk of impaired glucose tolerance or NIDDM. Other

changes may also be entrained, leading to hypertension and disordered lipid metabolism

depending on the timing and type of nutrient deficiency. It is envisaged that poor

nutrition during early life need not inevitably lead to NIDDM in adult life. It is rather

the transition from nutritional deprivation to nutritional abundance which leads to the

metabolic conflicts resulting in NIDDM.

This hypothesis also draws particular attention to the potential role of fetal amino

acid deficiency in the aetiology of NIDDM. This is because of the key role of amino

acids as substrates for fetal energy production and their being essential for fetal growth

(reviewed by Jones, ). Furthermore, insulin, a major fetal growth hormone

(Fowden, ), is predominantly regulated by amino acids rather than by glucose

during fetal life. Hence, both the growth of β-cells and the triggering of insulin

secretion are affected.


() Recent animal studies

In recent years, the key role of nutritional protein in ensuring proper development

of the islets of Langerhans has been demonstrated by Hoet, Remacle and their

colleagues in Louvain. It has been shown that pregnant rats fed a diet containing

slightly less than half the normal protein content produced pups with reduced neonatal

β-cell proliferation as measured by tritiated thymidine levels, islet size and

vascularization (Snoeck et al., ). The reduced vascularization may relate to

observations in an earlier study in which impairment of insulin secretion following

protein–calorie deficiency was found to be more severe than would have been expected

from the reduction in numbers of islet cells alone (Weinkove et al., ). In other

studies, rats weaned on a low-protein diet for only weeks produced an insulin

response to glucose that was permanently impaired, leading to the suggestion that ‘early

malnutrition may predispose to diabetes’ (Swenne et al., ). It was subsequently

shown that offspring from protein-restricted mothers, maintained on low protein to the

adult age of d had reduced glucose tolerance, associated with reduced insulin

secretion. A group of animals fed normally after birth had an intermediate response

(Dahri et al., ).

Other studies have shown that prenatal exposure to a maternal low-protein diet

induced hypertension in the young adult offspring (Langley & Jackson, ). The

finding that the activity of placental enzyme β-hydroxy-steroid dehydrogenase,

which protects the fetus from deleterious effects of maternal corticosteroids, was lower

in these maternal-protein-restricted offspring suggested a role for glucocorticoid

hormones (Phillips et al., ).

We have studied the offspring of protein-restricted rats during pregnancy and}or

lactation. Permanent growth retardation was seen in offspring nursed by mothers on a

low-protein diet despite the fact that they were weaned on a normal % protein diet.

Conversely, a complete catch-up in growth was demonstrated by offspring born to

protein-restricted mothers but subsequently nursed by mothers fed an adequate

protein diet (Fig. ). Sex-dependent, selective and permanent organ weight changes

were also observed. For instance, the brain and lungs were relatively protected from

reduction in growth whilst the liver and pancreas were more disadvantaged in these

offspring at days of age (i.e. before weaning) (Table ). In -week-old male rats

which had been weaned on a normal diet, the relative weight of muscle was significantly

lower whereas in the female rats, the relative weight of the pancreas was increased

(Desai et al., ).

At days postpartum, changes in liver enzyme activity in the offspring from low-

protein-fed mothers (approximately % decrease in glucokinase and about %

increase in phosphoenolpyruvate carboxykinase) shifted the enzyme setting of the liver

by a factor of % in favour of glucose production rather than utilization. These

changes were still apparent in adult offspring, demonstrating permanency (Desai et al.,

). It is known that glucokinase and phosphoenolpyruvate carboxykinase are

predominantly located in different metabolic zones of the liver. The former is expressed

around the perivenous zone and the latter around the periportal zone (Jungermann &

Katz, ). We have therefore hypothesized that, during development, different

hepatic cells may have multiplied differentially according to the nutritional status of the

M. D C. N. H

0

100

200

300

400

500

600

Bo

dy w

eig

ht

(g)

0 8 24 32 40 48

Weeks

Female rats

0

100

200

300

400

500

600

Bo

dy w

eig

ht

(g)

0 8 24 32 40 48

Weeks

Male rats

700

800

900

16

16

Fig. . Effects of maternal low-protein diet on growth of male and female rat offspring. Mean body

weights of male and female offspring until weeks of age are shown. For clarity, no error bars are shown.

Groups and had significantly lower body weights compared to Groups and . ^, Group : Offspring

of mothers fed a % protein diet during pregnancy and lactation; D, Group : Offspring of mothers

fed an % protein diet during pregnancy and lactation; E, Group : Offspring of others fed a %

protein diet during pregnancy but nursed by mothers fed an % protein diet ; _, Group : Offspring of

mothers fed an % diet during pregnancy and then nursed by mothers on a % protein diet. At weeks

of age, all offspring were weaned on a % protein diet and remained on this diet till weeks of age.


Table . Selective changes in organ growth in offspring of rats fed a low-protein diet

(The body and organ weights of -day-old offspring from groups , and (see legend to Fig. for details) are

expressed as percentage Group weights. Groups and show similar reduction in body weight whereas Group

exhibits partial recovery. In all three groups, the brain and lung are relatively preserved, the kidney and thymus

show similar weight reduction to the body whereas the pancreas, liver, muscle and spleen are more disadvantaged.

The heart is the only organ which shows variation in reduction in weight depending upon when the exposure to

the maternal low-protein diet occurred.)

Percentage of control weight

Organs Group Group Group

Body

Brain

Lung

Heart

Kidney

Thymus

Pancreas

Liver

Spleen

Muscle

fetus, resulting in the population of perivenous cells being contracted and that of

periportal cells being expanded. Consistent with this, we found that the activity of

another perivenous enzyme, glutamine synthetase, decreased and another periportal

enzyme, carbomyl phosphate synthetase, increased in the offspring from low-protein-

fed mothers (Desai et al., ). These livers when isolated and perfused with glucagon

and insulin showed a marked resistance to the action of insulin in inhibiting glucagon-

stimulated glucose output (Ozanne et al., ). The offspring of rat dams protein-

restricted during pregnancy and lactation were not glucose intolerant at months of

age. However, at months of age, the worsening of glucose tolerance in these offspring

was more extensive than that of control offspring. In the former group of offspring, this

was mainly attributable to insulin resistance in the males and insulin deficiency in the

females (Hales et al., ). This reflects the human situation in which males are more

insulin resistant than females (Phillips et al., a).

We also investigated the influence of a maternal low-protein diet on longevity in the

offspring (Hales et al., ). Our findings show that a brief period of exposure to

lactating dams which have been protein deprived has a beneficial effect on longevity.

This brief period is also capable of permanently reducing the growth trajectory of

offspring. Conversely, a highly detrimental effect on longevity was observed when the

pups growth was retarded in utero, but was then accelerated as a result of good postnatal

nutrition by being suckled by unrestricted mothers. The rate of growth of such pups

when expressed relative to their initial body weight was faster than in the controls

during early life. On the other hand, longevity was unchanged when the pups growth

was retarded in utero and the same rate of growth was maintained during the postnatal

period by being nursed by the same low-protein-fed mothers (Fig. ). It has been

known for many years that undernutrition increases longevity in a variety of animals

(Berg and Simms, ). Our findings demonstrate that nutrition during the first three

weeks of postnatal life affects not only growth but also longevity in rats.

M. D C. N. H

0

200

600

400

Bo

dy w

eig

ht/

weig

ht

at

day 3

(%

)

0 7 21 28

Days

14

800

Fig. . Rate of growth until days of age of offspring of female rats fed on a low-protein diet. Growth

rate of offspring from four groups (see legend to Fig. for details) is shown. The body weights at ,

and days of age are expressed as a percentage of the body weight on day following birth. The postnatal

growth rate was constant in groups and , whereas in group it was significantly lower, and in group

it was significantly accelerated.

V. CONCLUSION

The concept that events in early life could play a major role in determining health in

later life may be intuitively difficult to accept initially. Nevertheless, there is good

evidence that appropriate nutritional supplementation before conception, and during

pregnancy may reduce the risk of some birth defects. Perhaps the most convincing

argument that can be made for the need to consider maternal nutrition as a critical

modulator of embryonic development is the observation that maternal iodine

supplementation has eradicated the occurrence of iodine deficiency-induced cretinism

(iodine-deficiency-associated developmental defects) (Dunn, ). In addition,

adverse maternal nutrition which has an immediate and visible impact on the outcome

of pregnancy is seen in the case of folate deficiency and spina bifida (Rosenberg, ).

VI. ACKNOWLEDGEMENTS

Our work discussed in this article has been supported by the British Diabetic Association, the Medical Research

Council and the Parthenon Trust. We thank D. Hutt, A. Flack, A. Wayman and L. Smith of Dunn Nutritional

Laboratory, Animal Unit for their invaluable assistance.

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