British Medical Bulletin

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British Medical Bulletin 60:21-32 (2001)
© 2001 Oxford University Press

Type 2 diabetes, the thrifty phenotype – an overview

Robert S Lindsay and Peter H Bennett

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA

	Searching for the causes of type 2 diabetes

Top Footnotes Searching for the causes... The thrifty phenotype Thrifty genotypes and thrifty... Early environmental Influence... Challenges to the thrifty... Why is the thrifty... References

 
Diabetes mellitus is a group of metabolic disorders characterized by chronic hyperglycaemia¹. Within this group, type 2 diabetes describes the form of the disease usually with onset in adult life, and associated with insulin resistance and relative insulin deficiency, as opposed to the absolute deficiency found in type 1 diabetes¹. Type 2 diabetes is of great importance to public health due to the burden of morbidity and mortality associated with this common disease².

Type 2 diabetes is a complex disorder likely to have multiple genetic and environmental causes. Enormous efforts are being made to discover the genetic determinants of the disease. Recently, important additions have been made to our knowledge of the physiology of glucose and energy homeostasis at the molecular level – major advances have been made in our understanding of the mechanisms of insulin action, insulin secretion and control of appetite and energy balance^3,4. In addition, the genetic causes of a number of relatively rare causes of diabetes and obesity – one of the major known risk factors for development of type 2 diabetes – have been discovered, such as the multiple forms of maturity onset diabetes of the young (MODY)⁵ and mutations in leptin⁶ and the leptin receptor⁷, as rare genetic causes of human obesity. It seems likely that these advances, along with efforts to positionally clone candidate genes for type 2 diabetes in a number of populations, will lead in the near future to discovery of the major sources of genetic variation which predispose individuals to develop type 2 diabetes.

At the same time, current evidence confirms the continuing, and at the population level increasing, importance of environmental factors in the development of type 2 diabetes and obesity. The prevalences of these two conditions are rising in populations world-wide^2,8. These increases in prevalence are clearly not caused by changes in the genetic make up of these populations, but indicate the importance of the environment in the development of type 2 diabetes and obesity, and that exposure to adverse environments is increasing. Some of the environmental factors are well known. Availability of calorie rich diets and secular decreases in habitual physical activity have been noted in a number of populations and undoubtedly contribute to the increasing prevalence of obesity and, in turn, type 2 diabetes⁸. Ultimately, the cause of type 2 diabetes is likely to reflect a mix of genetic and environmental causes and, importantly, interactions between genes and environment. In this context, environmental causes of type 2 diabetes, including low levels of physical activity and availability of calorie rich diets, are undoubtedly of major importance. The subject of this issue of this book, however, concerns the evidence for other environmental risk factors, in particular whether environmental factors in early life contribute to later development of type 2 diabetes.

	The thrifty phenotype

Top Footnotes Searching for the causes... The thrifty phenotype Thrifty genotypes and thrifty... Early environmental Influence... Challenges to the thrifty... Why is the thrifty... References

 
The thrifty phenotype hypothesis, introduced by Hales and Barker in 1992⁹, proposed the concept that environmental factors acting in early life, in particular undernutrition, might influence later risk of type 2 diabetes. The hypothesis arose, in large part, from the pioneering work of the MRC Environmental Epidemiology Unit in Southampton which, under the directorship of David Barker, explored the geographical and socio-economic distributions of chronic diseases¹⁰. In particular, they were interested in the temporal relationships of socio-economic conditions and vascular disease: historically, cardiovascular disease was more prevalent in more affluent socio-economic groups, but over time this association appeared to become inverted such that cardiovascular disease became more prevalent in poorer parts of society in countries like the UK. This was linked with the paradox that while on a world-wide basis cardiovascular disease might be considered a disease of ‘affluence’, being concentrated in more prosperous nations, within some of those societies rates of cardiovascular disease were generally highest in the least affluent parts of society¹⁰. This led to the investigation of relationships of early life experiences, measured by factors such as infant mortality and birth weight, to later cardiovascular disease¹⁰.

An association of lower birth weight to later disease was first observed in relation to cardiovascular disease, and subsequently extended to cardiovascular risk factors. Relationships of low birth weight and type 2 diabetes were developed by Barker in collaboration with Hales⁹, and termed the ‘thrifty phenotype hypothesis’. Hales and Barker described the novel association of low birth weight with later development of type 2 diabetes in a cohort of men studied in Hertfordshire, England¹¹. The original observations have now been replicated in several populations¹² and have been extended to examine important antecedents of type 2 diabetes including markers of insulin secretion¹³ and insulin resistance¹⁴.

Both the low birth weight and thrifty phenotype hypotheses were born into what might be considered a hostile environment, consequently they generated enormous controversy. Because of this, and their implications in several fields of medicine, the hypotheses will already be familiar to practitioners in endocrinology, cardiology and respiratory disease, but they also have broader implications important to other fields. Research stimulated by the thrifty phenotype hypothesis has led to an increased understanding of the plasticity of early human development, and highlighted how this plasticity might contribute to later human disease. The number of fields of medicine and basic biology influenced by these hypotheses is attested to by the range of topics included in this issue.

In this introduction, we will not recapitulate the evidence for and against the different parts of the thrifty phenotype hypothesis, as these topics are covered in detail in later chapters, but rather highlight the contribution we feel it has made to our understanding of the pathophysiology of diabetes and in stimulating further research.

	Thrifty genotypes and thrifty phenotypes

Top Footnotes Searching for the causes... The thrifty phenotype Thrifty genotypes and thrifty... Early environmental Influence... Challenges to the thrifty... Why is the thrifty... References

 
While the theme of this issue is the thrifty phenotype, it is appropriate to first consider an older hypothesis – ‘the thrifty genotype’ – in contra-distinction to which the name of the ‘thrifty phenotype’ is derived. While overall, the two hypotheses are very different, they share important features. Both address the basic mechanisms which underlie the aetiology of such a common disease as type 2 diabetes. Both have been important in stimulating further research.

In 1962, Neel introduced the thrifty genotype hypothesis, addressing the aetiology of diabetes (the distinctions between type 1 and type 2 diabetes had not been defined at that time) and obesity from the perspective of evolutionary biology¹⁵. Neel proposed that predisposition to diabetes might arise because of genetic variations which were advantageous in certain environmental situations but were later rendered disadvantageous – and disease causing – in different environments. More specifically, that human variations which were favourable in populations facing challenges of episodic undernutrition might be disadvantageous when food supplies became abundant: in Neel's words¹⁵ ‘a thrifty genotype rendered detrimental by progress’. In particular, Neel proposed that the increased fat storage would be accomplished by alteration of the threshold and amount of insulin release in response to meals (‘the fast insulin trigger’) and that this predisposed to diabetes and obesity.

While much of the physiological basis provided in the original paper has been superseded¹⁶, the general hypothesis has proven attractive in providing potential explanations for subsequent observations concerning the epidemiology of type 2 diabetes. Firstly, as type 2 diabetes is such a common condition, it seems plausible that genetic variation predisposing to diabetes might have been associated with selective advantage at some point over the course of human evolution. Neel's hypothesis suggests one potential mechanism for this. Secondly, it provides a possible explanation for why the propensity to diabetes varies greatly among populations. The prevalence of type 2 diabetes is profoundly different in different ethnic groups. The highest known prevalence of type 2 diabetes occurs in the Pima Indian population of Arizona, among whom over 60% of adults develop the disease¹⁷. Other American Indian groups as well as Polynesian and Micronesian populations also have very high prevalence of type 2 diabetes, followed by migrant Asian Indians². Undoubtedly some of these differences relate to non-genetic factors, particularly with regard to contemporary environmental influences on physical activity and nutritional intake. It is also likely that differences in underlying genetic predisposition to type 2 diabetes exist between ethnic groups. Again, Neel's hypothesis provides a potential explanation for this: differences in genetic predisposition to diabetes being the result of different forces of selection due to nutritional circumstance in the various populations.

The thrifty phenotype hypothesis proposes a very different aetiological model for type 2 diabetes. In this model, undernutrition acts not as a selection pressure acting over many generations to alter the genetic make up of the population, but rather as an early environmental influence acting in an individual to increase risk of type 2 diabetes⁹. In Neel's hypothesis, entire populations have an increased predisposition to type 2 diabetes – because of genetic selection, they are better adapted to different nutritional circumstances than those they experience today. In the thrifty phenotype hypothesis, maladaptive responses occur as a result of environmentally induced alteration of physiology in the early life of the individual. Both hypotheses offer explanations of why the frequency of diabetes and obesity may differ in different populations and why predisposition to diabetes is common, albeit by very different mechanisms.

	Early environmental Influence before and after the thrifty phenotype

Top Footnotes Searching for the causes... The thrifty phenotype Thrifty genotypes and thrifty... Early environmental Influence... Challenges to the thrifty... Why is the thrifty... References

 
The basic concept advanced by the thrifty phenotype hypothesis is that human disease may arise due to early environmental effects whose influence to cause disease is only expressed much later in life. Thus, the influences of the environmental exposure are not confined to the time frame in which they are experienced but may continue to act through the life of the organism and long after an adverse exposure has ended. As a further refinement of this hypothesis, it is proposed that certain key developmental windows exist during which exposures ‘set’ physiological systems and thus lead to long-term consequences. This concept has been termed¹⁸ environmental ‘programming’.

When the thrifty phenotype hypothesis was proposed, this concept was not new to the field of metabolic disease in humans. The importance of the early environment had already been invoked as an explanation of increased propensity to diabetes in offspring of diabetic mothers – a very different early nutritional model to that proposed in the thrifty phenotype hypothesis. As early as 1960, White made fundamental observations regarding the high prevalence of abnormal glucose tolerance in offspring of diabetic mothers¹⁹. Around the same time, Pedersen developed the hypothesis that early overexposure to glucose in utero resulted in organomegaly and excessive growth that might then predispose to subsequent diabetes²⁰. Frienkel then extended this hypothesis to propose that overexposure to a range of intermediary metabolites, most importantly glucose and amino acids, might act in the long-term to alter metabolism and lead to human disease²¹, a concept he termed fuel mediated teratogenesis. Pettitt and colleagues then showed that both obesity²² and type 2 diabetes²³ were more prevalent in the offspring of mothers who had had diabetes during pregnancy- suggesting that predisposition to these conditions had arisen as a consequence of the intra-uterine environment.

Similarly, in the field of obesity it had already been proposed that influences in early life might be important in later predisposition to obesity. In 1972, Brook proposed that obesity might be influenced by events in utero²⁴, following the concept of the time that adipocyte differentiation occurred primarily in the intra-uterine period. Stein and Susser explored the influence of early undernutrition, due to exposure to war time famine, on later predisposition to obesity, finding that exposure to famine early in intra-uterine life was associated with an increase in later obesity²⁵.

A variety of observations and hypotheses regarding long-term influences of hormonal exposure on endocrine axes had also been established in experimental animals. The best known of these is the example of plasticity in the hypothalamic–pituitary–gonadal axis. Since the 1960s, it had been recognized that there is a ‘window’ in the first 10 days of post-natal life in which exposure of a new-born female rat to a single pulse of testosterone leads to reduced fertility in adult life²⁶. This arises because androgen exposure or non-exposure at this stage of development permanently alters hypothalamic responses to a male or female pattern respectively^26,27, a phenomenon the authors called ‘imprinting’, borrowing the term from behavioural psychology²⁸.

The thrifty phenotype hypothesis has also been important in stimulating later, different hypotheses addressing how the environment in early life might act to influence later disease. The presence or absence of breast feeding in early life has been proposed to influence later development and predisposition to disease. Pettitt et al observed that breast-feeding in the first 2 months of life was associated with a lower risk of development of type 2 diabetes in the Pima population²⁹. Such a protective effect of breast-feeding has also been observed for childhood obesity³⁰.

	Challenges to the thrifty phenotype

Top Footnotes Searching for the causes... The thrifty phenotype Thrifty genotypes and thrifty... Early environmental Influence... Challenges to the thrifty... Why is the thrifty... References

 
In part, the evidence for the thrifty phenotype rests upon the observation of associations of later human disease and lower birth weight. Initially, this basic observation was widely challenged, but has now been replicated in several separate studies and populations. More recently others, most notably Hattersley, have explored whether that association might arise not because of environmental insults in utero, but because of a genetic connection between lower birth weight and later diabetes³¹, as discussed elsewhere in this issue. Maturity onset diabetes of the young (MODY) was originally described as a syndrome of early onset non-insulin dependent diabetes with a clinical features more typical of type 2 than type 1 diabetes and with an autosomal dominant pattern of inheritance³². It is now known that MODY is caused by a range of genetic mutations⁵. Hattersley et al demonstrated that one of the causes of MODY – mutation of the glucokinase gene – when present in the fetus is also associated with lower birth weight as well as later diabetes³³. While the frequency of this mutation is too low to explain the associations seen in the populations described by Barker and Hales, it does demonstrate the potential for genetic mechanisms to underpin associations of birth weight and later disease. Insulin is a major promoter of growth in utero³¹. Consequently, genes which affect either insulin secretion or insulin resistance might well influence both fetal growth and subsequently development of diabetes³¹. Indeed, disruption of a variety of genes involved in insulin secretion or signalling, such as IRS-2, are known in animal models to result in alteration of fetal growth³⁴. Does variation in such genes result in alteration of birth weight in human populations? At present, the evidence is limited, although in a single study common variants of several candidates genes did not appear to influence birth weight³⁵.

Our own work has also examined whether genetic influences might underpin some of the associations of birth weight and diabetes in the American Indian populations. The Pima population of Arizona have an extremely high prevalence of obesity and type 2 diabetes – an increase that is believed to reflect both current environmental influences, such as reduced levels of exercise and inappropriately high caloric intake, as well as genetic predisposition to both type 2 diabetes and obesity. In the Pima, we have demonstrated that both low and high birth weight are associated with an increased later risk of type 2 diabetes (Fig. 1)³⁶ . High birth weight principally reflects influences of maternal diabetes in pregnancy both to increase birth weight and to increase likelihood of type 2 diabetes in later life³⁷. As an alternative to both the thrifty genotype and thrifty phenotype hypotheses, we have suggested that the association of low birth weight with type 2 diabetes in the Pima population might reflect selective survival of low birth weight infants, with genetically determined metabolic characteristics that were also related to the later development of diabetes³⁶. Such an advantage in utero and infancy could represent a powerful selective force over the course of human evolution.

View larger version (12K): [in this window] [in a new window]   Fig. 1 The relation of birth weight and later prevalence of type 2 diabetes in the Pima population. Prevalence of type 2 diabetes is adjusted for age using the direct method using the age distribution of 1179 subjects, and presented as mean and 68% confidence intervals. Redrawn from McCance et al36.

 
More recently, we have examined relationships of parental diabetes to low birth weight. If the association between low birth weight and later diabetes is due to genetic effects, then the parents of low birth weight offspring should themselves be at a greater risk of diabetes³⁸. Conversely, the absence of such effects would be more consistent with the notion that early environmental influences were a cause of diabetes in these lower birth weight offspring. In the Pima, lower birth weight is indeed associated with parental diabetes, but in fact solely with diabetes in fathers ( Fig. 2). Furthermore, the ability of low birth weight to predict later diabetes in offspring appears to depend on the presence of diabetes in fathers³⁸. These observations appear to strengthen the case for a genetic link between low birth weight and type 2 diabetes. The particular association with paternal diabetes has also led us to consider whether genomic imprinting – differential expression of genes depending on parent of origin – might be a determining factor in the low-birth weight diabetes relationship³⁸. Imprinting is known to act in syndromic causes of obesity and diabetes such as Prader-Willi syndrome and transient neonatal diabetes mellitus (TNDM: OMIM 601410). Intriguingly, the majority of currently recognised imprinted genes appear to influence pathways involving fetal growth or placental development^39,40. If low birth weight is associated with type 2 diabetes secondary to genetic influences, might this arise through actions of imprinted genes on both fetal growth and glucose homeostasis? Others have made similar proposals. Recently, type 2 diabetes has been associated with a genetic polymorphism on chromosome 11p found close to the insulin gene (INS VNTR III), but only if the associated allele was transmitted from the father⁴¹. The authors concluded that an imprinted gene in this region might be acting to increase the risk of type 2 diabetes⁴¹.

View larger version (11K): [in this window] [in a new window]   Fig. 2 Mean birth weight of children divided by last known diabetes status of their parent. Groups: Neither, neither parent ever diagnosed with diabetes; Both, both parents diagnosed with diabetes; Mother Only and Father Only, mother or father diabetic. respectively, second parent non-diabetic. Values are expressed as mean ± SEM. General linear model consistent with a significant effect of parental diabetes diagnosis on birth weight (P <0.001) and independent effects of both maternal (post hoc Student Newman Keuls, P <0.0001) and paternal (Student Newman Keuls, P <0.001) diabetes status. Redrawn from Lindsay et al38.

 
The role of genes and environment in determining associations of low birth weight with later disease is by no means settled. The strictly genetic interpretation is challenged by twin studies of Poulsen et al who have demonstrated that in identical twins the smaller twin is more likely to develop type 2 diabetes⁴². Given that identical twins share all of their genes, the authors interpret this as evidence that an environmental effect acting on the smaller twin is increasing risk of metabolic disease – lending support to the environmental hypothesis of Hales and Barker. On the other hand, a recent report of a considerably larger series of monozygotic twins (together with a contemporary series of dizygotic twins) failed to find any relationship between birth weight and either blood pressure or glucose intolerance among the twin pairs⁴³. This report casts doubt on the hypothesis that environmental effects on intra-uterine growth per se are important determinants of low birth weight-blood pressure and low birth weight-glucose intolerance relationships.

A second challenge to the thrifty phenotype hypothesis comes from those who accept the importance of early environmental influences on both birth weight and later disease, but question whether undernutrition is the specific critical environmental determinant. The role of nutrition in altering pancreatic insulin secretion and insulin resistance had been addressed by a large number of studies in animal models – some of which are reviewed in this issue. A number of human populations who have been subject to periods of undernutrition because of deprivation during World War II have also been examined to assess whether maternal undernutrition during pregnancy resulted in long-term consequences for the children. Children born during famine in Holland (survivors of ‘the Dutch Hunger Winter’) were found to have significantly higher 2-h plasma glucose concentrations⁴⁴. By contrast, children whose mothers survived the siege of Leningrad appeared to have no long-term effect on blood glucose, although the authors comment on the difficulty of ascertaining the extent of exposure to famine in this group, especially when pregnant women may have had preferential access to food⁴⁴. (Further discussion of these two war-time famines is given by Prentice in this issue.) While the Dutch study would support the hypothesis that undernutrition during pregnancy can lead to metabolic consequences, the second raises doubts as to whether such effects may only be exerted in the most extreme circumstances, making undernutrition unlikely to be instrumental in the aetiology of most cases of type 2 diabetes. Other authors have sought to explain the findings of low birth weight in terms of other early environmental insults, including the actions of glucocorticoids in utero to increase predisposition to type 2 diabetes⁴⁵.

	Why is the thrifty phenotype hypothesis important? Future challenges

Top Footnotes Searching for the causes... The thrifty phenotype Thrifty genotypes and thrifty... Early environmental Influence... Challenges to the thrifty... Why is the thrifty... References

 
We do not know yet how great a role early nutrition plays in the generation of later diabetes. One cannot doubt, however, the enormous importance of the thrifty phenotype hypothesis in stimulating research examining the aetiology of this common disease.

The high prevalence of type 2 diabetes seen in many populations lends additional importance to both the thrifty phenotype and thrifty genotype. On a clinical level, any hypothesis attempting to understand the aetiology of such a common disease is important if new understanding emanates which helps to prevent or treat the disease in the future. On a more fundamental level, it is hard to believe that the mechanisms underlying such a common disease will not also reflect upon normal physiology. If fetal programming is a key mechanism in the generation of diabetes, it is likely that such a mechanism will play a part in programming normal metabolism – with implications for other aspects of physiology. The thrifty phenotype has also stimulated researchers to re-address concepts of the plasticity of human responses, hormonal and physiological, in the face of environmental insults and the way that such insults may exert permanent effects on the organisms. It serves to remind us that despite the recent triumphs of genetics and molecular biology, an understanding of environmental influences and how genes and the environment interact is likely to be critical to our understanding of many common, chronic human diseases. Finally, and of greatest challenge to the medical and public health community, if early environment influences later disease, it obliges all health professionals involved in early human development to re-appraise their goals. Perhaps in the future we will have to place more emphasis on the long-term, and possibly unexpected, effects of interventions taken in early life. Early environmental influences on later disease may carry implications for all clinicians, but may be most important for those who develop health policy addressing the health and nutrition of mothers and children.

	Footnotes

Top Footnotes Searching for the causes... The thrifty phenotype Thrifty genotypes and thrifty... Early environmental Influence... Challenges to the thrifty... Why is the thrifty... References

 
Correspondence to: Dr Peter H Bennett, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 East Indian School Road, Phoenix, AZ 85014, USA

	References

Top Footnotes Searching for the causes... The thrifty phenotype Thrifty genotypes and thrifty... Early environmental Influence... Challenges to the thrifty... Why is the thrifty... References

 

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