REVIEW

The Thrifty Phenotype Hypothesis: HowDoes it Look After 5 Years?C. N. Hales, M. Desai, S. E. Ozanne

Department of Clinical Biochemistry, University of Cambridge,Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QR

KEY WORDS Non-insulin-dependent diabetes Thrifty phenotype hypothesisGenetic basis Nutrition Maternal diet

study published in the same year by a different groupIntroductionof workers looking for evidence of a genetic influence

Swinburn1 in his interesting commentary on the status controlling the insulin response to glucose in man. Iseliusafter 30 years of the Thrifty Genotype hypothesis of the et al.5 reported from a study of 155 families that theaetiology of non-insulin-dependent diabetes (NIDDM) sibling environment had a large effect on the parametersconcludes: ‘The underlying logic of the Thrifty Genotype of insulin secretion which they studied.hypothesis remains widely accepted . . .’. We acknowl- A number of studies have found that in families withedge that the great majority of people concerned with NIDDM the condition is more likely to be transmittedthe aetiology of NIDDM believe that the condition is to the offspring if the mother is affected rather than theprimarily genetically determined but may be modulated father.3 While stronger maternal transmission could haveby environmental factors, particularly those relating to a genetic basis such as that resulting from a geneticenergy balance in adult life. In reviewing the present change in mitochondria or the sex-specific imprinting ofstatus of an alternative, namely the Thrifty Phenotype gene expression, these observations are also consistenthypothesis (suggesting a key role for nutritionally induced with the major factor being the fetal and infant environ-changes in fetal and possibly infant growth)2 we shall ment provided by the mother.begin by questioning whether there really are anylonger good reasons to suppose that NIDDM is stronglygenetically determined. The arguments which have been Bimodal Distribution of Blood Glucosebrought forward to substantiate the genetic basis of

ConcentrationsNIDDM mainly relate to: the familial aggregation of thecondition; the bimodal distribution of fasting and 2 hpost-load blood glucose concentrations in some popu- In certain populations with a very high prevalence oflations; the variation in prevalence of NIDDM in NIDDM, blood glucose concentrations either fasting orpopulations with differing degrees of racial admixture 2 h after an oral glucose load, have been found to beand, finally (and believed by many, most conclusively), bimodally distributed and this has been interpreted asvery high concordance rates in monozygotic twins. We

evidence for a genetic effect.6 A bimodal distributionconsider each of these pieces of evidence in turn beforehas not been found in all populations, however, althoughreviewing the current status of the Thrifty Phenotypeit could be argued that in populations with a relativelyhypothesis.low prevalence it might be difficult to detect.3 On theother hand, it is equally possible that a bimodalFamilial Aggregationdistribution reflects the fact that there is a rapid transitionfrom moderate to more severe glucose intolerance. InMany would agree that this phenomenon, which is wellthis model less time is spent in the intermediate state ofrecognized and generally accepted,3 is the weakest pieceglucose intolerance. There are certainly known mech-of evidence. Indeed a careful review of the data inanisms which could induce rapidly deteriorating glucoseseveral family studies shows it to be rather moretolerance. Chronically elevated blood glucose concen-consistent with the aggregation having an environmentaltrations have a detrimental effect on glucose-inducedrather than genetic basis. Beaty et al.,4 in a study of 794insulin secretion—the so-called ‘glucose toxicity’ effect.7first degree relatives of subjects with NIDDM, found thatIt might be expected therefore that once a critical levelthe number of affected siblings contributed more toof glucose intolerance had been reached the detrimentalpredicting NIDDM in the relative than did the numbereffect on insulin secretion would rapidly induce pro-of affected parents. The results suggested a strong within-gression to still worse glucose tolerance.generation component which might reflect environmental

factors. A very similar conclusion emerged from another

189CCC 0742–3071/97/030189–07$17.50 1997 by John Wiley & Sons, Ltd. DIABETIC MEDICINE, 1997; 14: 189–195

REVIEWMexican Americans’. It is almost certain that the averageRacial Admixturebirth weight would be lower in this poor community.

The relevance of studies of mixed race populations tothe genetic origins of NIDDM is that the interbreeding Twinsof races with a high prevalence of NIDDM with thosewith a low prevalence should produce a graded reduction Early studies of the concordance rates for NIDDM in

monozygotic twins described rates approximating toof prevalence according to the ‘dilution’ of the diabetes-prone races genes with the genes of races with a low 100 %. These observations are probably the single most

important factor leading to the present general beliefprevalence. In a number of studies of this nature thisprediction appears to have been fulfilled.8–10 However that NIDDM is genetically determined. It is now accepted

that the early studies, depending as they did on recruit-even when the data clearly match the predictions of thegenetic hypothesis (and this is not always the case—see ment from diabetes clinics, suffered from this ascertain-

ment bias towards concordance. Subsequent studies havebelow), the interpretation of the data is likely to beconfounded by the differing socio-economic circum- shown lower concordance rate (see below). Furthermore

while low concordance rates for a given conditionstances of the different racial admixtures. As a generalrule it is observed that the higher the proportion of strongly argue against a dominant role for genetic factors

in the aetiology of that condition, high concordancethe aboriginal race, the lower the socio-economiccircumstances of the population. It is observed both in rates are merely compatible with a possible genetic

determination and do not prove it. This is particularlythe UK11 and the USA12 that populations in poorer socio-economic circumstances have more NIDDM. It is relevant clear when one starts to envisage a role for the early,

fetal and infant, environment in the aetiology of ain the context of this review to note that there is aconsiderable disparity in birth weight and infant mortality disease. Monozygotic twins, unlike dizygotic twins,

frequently share the same placenta. Thus if fetal nutritionbetween black and white infants in the USA.13–15

Brousseau et al.8 studied North American Indian Tribes is an issue this may be more concordant in mono- thanin dizygotic twins.in North Dakota according to their mixture with the

white population. They found that the prevalence of For all these reasons the data from twin studies relatingto NIDDM deserves very close scrutiny. A recent andNIDDM fell as the degree of Indian inheritance declined.

However neither the nutritional or the socio-economic probably the largest of such studies was reported fromFinland and involved 13 888 twin pairs of the samestatus of the groups was reported nor the prevalence of

obesity. Serjeantson et al.9 studied the population of sex.17 The concordance rate for NIDDM among monozyg-otic twins was 34 % and for dizygotic twins 16 %. MuchNauru with respect to the relation of foreign admixture

to the prevalence of diabetes. They concluded that there larger differences for concordance rates between mono-and dizygotic twins for insulin-dependent diabeteswas a much higher prevalence of NIDDM in full-blooded

Nauruans than in those of mixed race. However, this (IDDM) were observed (23 % versus 5 %, respectively).It was concluded that hereditability for IDDM was greaterdifference was only observed in those over 60 years of

age of whom only 29 people were studied, including than NIDDM. Unfortunately due to the very large numberof subjects involved it was not possible to subject theonly 5 in the ‘foreign’ HLA category. If one summed the

figures for NIDDM and impaired glucose tolerance (IGT), twins to glucose tolerance tests. Undoubtedly thereforesome of the twins recorded as non-diabetic could havethe numbers show that 21 out of 23 ‘pure’ Nauruans

had either NIDDM or IGT, and 5 out of 6 ‘foreign’ been misclassified. Equally it is highly possible that pairsof twins, neither of whom were detected as beingadmixed Nauruans came into this combined category.

No data were presented as to the socio-economic diabetic by the use of records, would on testing haverevealed new sets of discordant twins. In addition therecircumstances of the present or previous generation or

the obesity of the people studied. is no reason why such an error of detection should bemore applicable to mono- than to dizygotic twins. IndeedThe most comprehensive study in this area was carried

out by Gardner et al.10 who examined 1423 Mexican if anything one would expect the converse to be thecase. Thus there is a relatively small difference in theAmericans and Anglos in three San Antonio neighbour-

hoods. The per cent native American admixture of concordance rate for NIDDM between mono- anddizygotic twins. It is also conceivable that this differenceMexican Americans was estimated from skin colour

measurements. It was found that the NIDDM rates in can be accounted for by the greater early environmentalconcordance of monozygotic twins.Mexican Americans paralleled the proportion of native

American genes. However as we have pointed out More recently there has been an early report ofstudies involving the Danish Twin Register.18 This studyelsewhere the NIDDM rates also closely paralleled the

socio-economic circumstances of the groups studied, addressed the weaknesses of previous twin studies byfirstly using random recruitment of twins ascertainedbeing highest in the poorest communities.16 Indeed

the authors themselves point out, ‘that other, as yet through a population based twin registry and, secondly,by performing standard oral glucose tolerance tests onunidentified factors associated with low socio-economic

status could also contribute to excess NIDDM in barrio all subjects. The study thus far has confirmed the small

190 C.N. HALES ET AL.

REVIEWdifference in concordance rates for NIDDM between been that it is likely that those born in a low social class

will remain in this class as adults. Thus it is suggestedmono- and dizygotic twins at 33 % and 23 %, respect-ively. This difference was not significant in the number the association with poor early growth really reflects

adverse circumstances as an adult which are the realof pairs studied (total of 62). If the sum of twins withNIDDM or IGT was calculated then the difference causative factors. It is of course impossible to examine

this suggestion without the definition of what thesebetween mono- and dizygotic twins became significant(46 % and 28 %, respectively) but retained less than a adverse circumstances might be. Smoking and alcohol

consumption can certainly be eliminated as possibilities.factor of 2 in a total of 155 pairs studied. It wasconcluded that, ‘The data indicate a weak genetic Other observations which support the early origins of

the link came from studies in children. Seven-year-oldcomponent in NIDDM per se compared with previousstudies’. The authors do not discuss the possibility that children in the UK show higher 30 minute plasma

glucose concentrations after an oral glucose load inthis supposed ‘genetic’ component might really bedue to greater in utero environmental concordance in relation to their increasing thinness at birth.25 In India,

an oral glucose tolerance test study of 379 4-year-oldmonozygotic twins. It is also important to rememberthat, since twins have lower birth weights than singletons, children whose birth weights were recorded in Pune

showed 30 minute glucose and insulin concentrationsif the cause of the reduction in birth weight reflects thefactors which cause low birth weight in singleton to be higher in those of lowest birth weight.26

Following these initial studies, other investigationspregnancies twins are more likely to develop NIDDM.This again will increase concordance for a non-genetic have examined these relationships in a wide variety of

different populations around the world. These studiesreason. The authors also addressed the issue of whetherbirth weight differences might relate to discordance in have confirmed the findings (Table 1). We are not aware

of any findings to the contrary. It is of interest that themono- and dizygotic twins. They found that in both setsof discordant twins birth weights were significantly lower relationship between birth weight and NIDDM in the

Pima Indians is U-shaped. This population has a highin the NIDDM twin compared with the discordant non-diabetic twin. They conclude: ‘our study supports an prevalence of gestational diabetes which in turn is

associated with an abnormally elevated birth weight (butimportant role of intrauterine malnutrition for the develop-ment of NIDDM later in life. The intrauterine component as macrosomia not as normal growth). It has been shown

both in animals and humans that the offspring of ais independent of genotype and may not be explainedby gestational age, maternal height, birth order or sex’. diabetic pregnancy are themselves more at risk of

developing NIDDM as adults.35 This presumably explainsWhile more and larger studies of NIDDM in twins areclearly required, it is apparent that at present such studies the upturn of the association between birth weight and

adult diabetes in the Pima Indians. The authors of thisdo not provide a strong basis of support for thegenetic hypothesis. paper propose that the relationship between low birth

weight and adult NIDDM is genetic rather than environ-mental in origin.27 They suggest that since there is aThe Thrifty Phenotype Hypothesishigh infant mortality among those of low birth weight,those who are of low birth weight and survive into adultThe origin of this proposal lies in epidemiological studies

linking indices of poor early fetal and infant growth to life are genetically predisposed to do so. The recentobservation18 that in pairs of monozygotic twins discor-NIDDM, IGT, and the insulin resistance syndrome

(or syndrome X).19–24 Archival records of early life dant for NIDDM, the twins with diabetes have asignificantly lower birth weight is evidence against thisanthropometry have shown that reduced birth weight,

weight at 1 year and thinness at birth are strongly hypothesis. Thus it seems most probable that there issomething linked to low birth weight which predisposesassociated with an increased susceptibility to NIDDM

and IGT in adult life and to insulin resistance. The to loss of glucose tolerance and the insulin resistancesyndrome and that this factor is environmental.strongest relationships were found between birth weight

and the presence of the insulin resistance syndrome as It has been argued that whatever the cause of the lowbirth weight which underlies this relationship it cannotdefined by the loss of glucose tolerance, hypertension,

and a raised plasma triglyceride concentration. These be a major cause of NIDDM since so few of the totalpopulation with NIDDM had a low birth weight.1,27 Thisrelationships were found to be enhanced by adult obesity.

It has been suggested that since lower birth weights conclusion is unwarranted for the following reasons. Itis not the low birth weight per se which is causingare a feature of poor socio-economic circumstances it is

the latter factor which really links the association. Against NIDDM. Low birth weight is simply a crude surrogateindex of high exposure to some environmental conditionthis is the fact that the effect of low birth weight is

independent of social class. In other words although low not yet fully identified. The relationship between birthweight and NIDDM in the English population is continu-birth weight is undoubtedly more common among those

in a poorer social class, it is equally apparent that low ous across the birth weight range but decreases withincreasing birth weight. For example, babies of a perfectlybirth weight is detrimental in the present context even

in those of higher social class. Another concern has ‘normal’ birth weight registered as say 7.0 lb (3.2 kg)

191THRIFTY PHENOTYPE HYPOTHESIS AFTER 5 YEARS

REVIEWTable 1. Studies confirming a linkage between poor early growth and loss of glucose tolerance and/or the presence of the insulinresistance syndrome

Population Reference

Pima Indians, USA McCance et al. (1994)27

Mexican Americans and non-Hispanic whites, USA Valdez et al. (1994)28

Men in Sweden Leon et al. (1996)29

Men in Sweden Lithell et al. (1996)30

School children in Jamaica Forrester et al. 199631

Glucose intolerant women in pregnancy, UK Olah (1996)32

Health professional men, USA Curhan et al. (1996)33

Twins in Denmark Vaag et al. (1996)18

Australian Aborigines Hoy et al. (1996)34

have been more exposed than those of 9 lb (4 kg). It is related to maternal energy and protein consumption.38

We have nevertheless decided in the first instance topossible that a baby of 7.0 lb which goes on to haveNIDDM would under conditions of optimum nutrition pursue the exploration of an animal model in which

pregnant and lactating rat dams are exposed to a purelyhave reached a weight of 9.0 lb. The other possibility isthat a weight of 7.0 lb in some infants disguises a growth protein deficient isocaloric diet.39 We shall briefly review

our and others’ findings to date from this research aimeddefect which would have been revealed by more subtletests of structure and function. For example, the baby at testing aspects of the Thrifty Phenotype hypothesis.may be long but thin or it may have achieved goodhead growth but be short despite having an apparently Maternal Low Protein Rat Model‘normal’ weight. It is at present impossible to make ameaningful calculation of the proportion of NIDDM Early studies by Hoet and colleagues looked at the

effects of feeding pregnant rats a low protein diet. Thiswhich may be accounted for by a poor fetal and infantenvironment. If one goes to the other extreme of weight revealed that maternal protein deficiency caused fetal

growth retardation and thus pups with a lower birthand takes account of the very low prevalence of NIDDMand the insulin resistance syndrome in those English weight. These neonates had reduced b-cell proliferation,

islet size, and vascularization.39 It was subsequentlyadults who were babies of birth weight greater than9.5 lb (4.3 kg)19,20 then it is possible to imagine that shown that offspring from protein restricted mothers,

maintained on a low protein diet to the adult age ofquite a high proportion of these conditions is associatedwith something involved in early growth. seventy days had reduced glucose tolerance, associated

with reduced insulin secretion.40It is of course critically important to try to define whatit is that is associated with reduced early growth and We modified the experimental protocol described

above to focus specifically on consequences of maternalNIDDM. In the Thrifty Phenotype hypothesis we drewattention to a poor maternal protein intake as one dietary manipulation. Rat dams were fed either a control

(20 % protein) or an isocaloric low (8 %) protein dietpossible factor. We chose low protein because of themany human and animal studies of a low protein intake during pregnancy and lactation. In addition two ‘crossov-

er’ groups were included to enable a separate evaluationshowing its detrimental effects on insulin productionand glucose homeostasis,2 and also because protein is of the effects of maternal protein restriction during

gestation alone or lactation alone. All offspring weregenerally a relatively scarce and expensive foodstuff formany populations and for deprived communities within weaned onto a control (20 %) protein diet at 21 days of

age.41 At this stage striking changes in activity ofaffluent populations. In highlighting low maternal dietaryprotein as a possible contributor to poor fetal growth it key enzymes involved in glucose homeostasis were

observed.42 Hepatic glucokinase (GK) activity was con-was not intended to exclude the involvement of otherdietary deficiencies alone or in combination. There are siderably reduced (approximately 50 %) and hepatic

phosphoenolpyruvate carboxykinase (PEPCK) activity wascertainly many well-documented examples of dietarydeficiencies during pregnancy, both in the developing significantly increased (approximately 100 %) in the

offspring exposed to maternal low protein diet duringand developed countries, as reviewed in a recentinternational conference.36 It is possible that, rather than gestation. No changes were observed in the offspring

exposed to maternal low protein diet during lactation,a problem of pure protein deficiency, it may be the ratioof early carbohydrate/energy consumption to protein suggesting that the maternal nutrition during fetal life

plays a critical role in determining hepatic enzymecontent of the diet which is of greatest importance.37

We have observed that the concentration of insulin-like activities in the offspring. This is of particular interestgiven that neither GK or PEPCK are expressed until aftermolecules in human cord blood, used as an indirect

measure of b-cell growth and function, are significantly birth. These changes were still apparent at 11 months

192 C.N. HALES ET AL.

REVIEWof age indicating that events during fetal life can have who do develop IDDM, the majority will not have the

strongest genetic predisposing factors.49–51permanent effects on adult glucose metabolism. Thelivers of these low protein offspring also showed a Other good examples of situations where genetic

factors play some role in susceptibility and response tomarked resistance to the action of insulin to inhibitglucagon stimulated glucose output during an ex vivo infection but would not by any stretch of imagination

be thought of as causative are in infectious diseases.liver perfusion.43 Other recent studies by Holness andSugden have shown that these low protein offspring have Immunity to viral, mycobacterial, and protozoal infections

is genetically linked to class I MHC molecules (reviewedlower glucose utilization in fast twitch muscle andadipose tissue compared to controls.44 This suggests that in Bell and McMichael52). Our concern is that in what

has been described as the ‘triumphalism’ of the modernall insulin sensitive tissues are permanently affected bypoor maternal nutrition during early life. genetics53 we are swept along by a tide of elegant

techniques and lod scores and our attention is divertedWe performed glucose tolerance tests on the controland low protein offspring at three different ages, 6 weeks, from the really important factors.

We conclude that there is strong evidence that3 months, and 15 months. At both 6 weeks and 3months of age the low protein offspring were more environmental, probably nutritional factors operating in

early (fetal and possibly infant) life play a major causativeglucose tolerant than controls. However the low proteinoffspring showed a greater deterioration of glucose role in NIDDM. Furthermore since such an aetiological

process is tractable it is important that a concerted efforttolerance with age than controls. This resulted in thelow protein offspring having a significantly worse glucose be made to identify the factors and mechanisms involved

so that steps can be taken to prevent this disease. Thetolerance in late adult life (15 months of age). In malesthis glucose intolerance was mainly attributable to insulin Thrifty Phenotype hypothesis continues to provide a

conceptual basis for this research.resistance whereas in the females, to insulin deficiency.45

This reflects the human situation in which males aremore insulin resistant than females.23

Other studies using similar low protein models have Acknowledgementsshown that prenatal exposure to maternal low proteindiet induced hypertension in the young adult offspring.46 Our reasearch discussed in this article has been supportedThe authors found that the activity of the placental by the British Diabetic Association, Medical Researchenzyme 11 b-hydroxy-steroid dehydrogenase, which Council, and Parthenon Trust. We are grateful for helpfulprotects the fetus from deleterious effects of maternal comments from P. Bingley and S. O’Rahilly and thankcorticosteroids, was lower in these maternal protein L. Creswell for skilled secretarial assistance.restricted offspring and suggested glucocorticoid hor-mones may be involved.47

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