British Medical Bulletin

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British Medical Bulletin 60:89-101 (2001)
© 2001 Oxford University Press

The role of genetic susceptibility in the association of low birth weight with type 2 diabetes

Timothy M Frayling and Andrew T Hattersley

Department of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter, UK

	Abstract

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 
We suggest that altered fetal growth and type 2 diabetes may be two phenotypes of the same genotype – in other words the ‘thrifty phenotype’ is the result of a ‘thrifty genotype’. Supporting this there is strong evidence that paternal factors and, therefore, genes influence fetal growth and that these paternal genes affecting fetal growth may also alter diabetes risk. Further study is needed to determine whether common gene variants can explain the association between reduced birth weight and increased risk of type 2 diabetes. If the genetic hypothesis is true, common diabetes genes are likely to have subtle effects on insulin secretion and/or action and, therefore, subtle effects on fetal growth. Large cohorts of infants and their parents will be required – probably in the region of thousands rather than hundreds – to identify gene variants that may explain the association between reduced birth weight and increased risk of type 2 diabetes. All previously described associations between birth weight and type 2 diabetes have required many hundreds of subjects and it is likely that the geneticists and the ‘programmists’ are trying to identify very subtle physiological effects.

	Introduction

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 
There is no doubt that low birth weight is associated with adult disorders characterised by insulin resistance such as type 2 diabetes, hypertension, dyslipidaemia and coronary heart disease^1–3. However, the mechanism of this established association is still uncertain and controversial. For the past decade, research has principally focused on the role of the intra-uterine environment. It has been proposed that undernutrition in utero results in a permanent re-programming of the fetal metabolism¹. Genetic factors are not part of this thrifty phenotype hypothesis, but there is a significant body of evidence suggesting that they are important both as determinants of birth weight and adult diseases like type 2 diabetes. We have proposed a hypothesis that low birth weight and type 2 diabetes are two phenotypes of the same insulin resistant genotype (Fig. 1)⁴. In this chapter, we put forward some of the arguments for genetic explanations as an alternative to the thrifty phenotype hypothesis. We would accept that these two mechanisms are not exclusive and it is likely that the adult phenotype of diseases like type 2 diabetes is a reflection of the genotype and the intra-uterine and the post-natal environment with different factors having different predominance in different individuals.

View larger version (20K): [in this window] [in a new window]   Fig. 1 Genes or environment? The two explanations for the association between low birth size and type 2 diabetes, insulin resistance and ischaemic heart disease (adapted from Hattersley & Tooke4).

 

	Low birth weight and type 2 diabetes: genes can explain the association

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 
Genetic variation is a potential explanation of the association between birth weight and adult disorders such as type 2 diabetes. In the ‘fetal insulin hypothesis’⁴, we proposed that gene variants that result in differences in insulin resistance or secretion within the normal population may also affect birth weight and size through effects on insulin-mediated fetal growth. The crucial components of this proposal are that: (i) genetic susceptibility is important for both birth weight and diabetes; and (ii) genes that reduce insulin secretion or increase insulin resistance will predispose to small babies as well as to diabetes. Finally, it will be important to define the relative role of these genes compared to the impact of the intra-uterine environment. This is not just a sterile intellectual debate, but will give fundamental insights into the aetiology of adult disease and the most appropriate prevention strategies.

	The predisposition to type 2 diabetes is influenced by genes

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 
Type 2 diabetes results from the interaction of genetic susceptibility and a permissive environment. The prevalence of type 2 diabetes and the ‘metabolic syndrome’ is rapidly increasing due to environmental and behavioural changes such as the increasingly sedentary life-style and high-fat, high-refined carbohydrate diet. This does not exclude a role for genes as the risk of type 2 diabetes for a given individual is likely to reflect their genetic predisposition as well as their activity and obesity (factors which in turn may be partially genetic (reviewed by Vogler et al⁵). There is a large amount of evidence to suggest an individual's susceptibility to diabetes is, at least in part, genetically determined. Type 2 diabetes and insulin resistance clusters in families with siblings of patients having a 3–4-fold increased risk of developing the disease compared to members of the general population^6–8. Monozygotic twins have higher concordance rates than dizygotic twins⁹. Populations at high risk of diabetes remain at high risk when they migrate to countries associated with a low prevalence of type 2 diabetes¹⁰. Some of these observations can be put down to shared environment as well as, or instead of, shared genes. Stronger evidence comes from population admixture studies^11,12. For example, in the high prevalence native-American Pima Indian population, the risk of diabetes is altered by the degree of genetic admixture from low prevalence populations such as Caucasians despite apparently identical environments¹². Furthermore, recent successes in the mapping of type 2 diabetes genes demonstrates that genes are important in determining who develops type 2 diabetes. Variants in the Calpain 10 gene¹³ and the regulatory ‘VNTR’ region of the insulin gene¹⁴ are linked with type 2 diabetes risk.

	Birth weight is influenced by genetic factors – the importance of paternal as well as maternal factors

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 
There is considerable evidence that genetic factors are important in the determination of fetal birth weight. There is greater variation in birth size between non-identical twins than identical twins¹⁵ There are also clear paternal effects on fetal growth in utero. Mothers have two ways of influencing the growth and health of their unborn offspring – their DNA and the intra-uterine environment. Fathers can influence the unborn offspring solely through their DNA. There are, therefore, numerous strong correlations between maternal factors and fetal growth parameters (see Barker, this issue). There is much evidence, however, that indicates fathers also influence the growth and development of their unborn child. In a study of 538 infants born in Southampton, birth weight, length and placental weight were all highly significantly correlated with the father's own birth weight and height¹⁶. In a simultaneous regression analysis, birth weight showed the strongest independent association with paternal birth weight and height¹⁶.

Studies of agricultural animals, where body size and composition are important economic variables, also indicate that genes as well as maternal environment affect birth weight. Studies of cattle demonstrate that breed of sire influences birth weight as well as other important growth traits^17,18. There is evidence of a genetic effect on birth weight and growth from the classic study of Shetland pony/Shire horse crosses performed in the 1930s. These studies demonstrated that foals closely resembled in size the mare's size at birth, perhaps unsurprisingly given the vast differences between the two breeds. However, foals born to Shire mares and Shetland stallions tended to be smaller at birth and were significantly smaller than pure bred Shires after 4 months’ growth (see Barker, this issue, for further discussion)¹⁹.

	The central role of insulin in both fetal growth and carbohydrate regulation: a possible common pathway for the influence of genes

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 
What are the potential mechanisms whereby genes could influence fetal growth and also the development of diabetes? Insulin secretion and insulin action are excellent candidate pathways as insulin plays a key role both in carbohydrate regulation and also in fetal growth (see Fowden & Hill, this issue). Impaired insulin action and secretion are the two features common to type 2 diabetes²⁰. Fetal insulin secretion is one of the key determinants of fetal growth acting mainly in the third trimester when the weight of the fetus increases markedly. The clearest clinical example of this is the macrosomic children born to mothers with diabetes in pregnancy. Pedersen proposed that this macrosomia did not result from a direct increase in the transfer of nutrients, but was mediated indirectly by increased fetal insulin secretion in response to fetal sensing of maternal hyperglycaemia²¹. In pregnant mothers with diabetes or glucose intolerance, the maintenance of maternal euglycaemia, particularly in the third trimester, reduces the risk of macrosomia²². The evidence for the important role of insulin comes not only from diabetic pregnancies. In normal pregnancies, there is a direct correlation between the maternal blood glucose levels in the third trimester of pregnancy and the birth weight of the child^23–26.

Fetal insulin mediated growth may not only reflect maternal glycaemia (altering the stimulus to fetal insulin secretion) but also fetal genetic factors which regulate the fetus’ insulin secretion and the sensitivity of fetal tissues to the effects of insulin. As the fetus produces insulin in response to the maternal glucose level, then a genetic defect in either the sensing of the maternal glucose by the fetal pancreas, or insulin secretion by the fetal pancreas, or the action of the insulin on the insulin-dependent tissues, would all result in reduced fetal growth (Fig. 2). There is now support for this ‘fetal insulin hypothesis’ which is outlined below.

View larger version (16K): [in this window] [in a new window]   Fig. 2 The fetal insulin hypothesis. A simplified diagram of how fetal genetics may alter birth weight through insulin mediated growth (adapted from Hattersley & Tooke4).

 

	Evidence for the role of genes in birth weight and type 2 diabetes: single gene disorders of insulin secretion and action alter fetal growth

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 
Observations of fetal development in single gene disorders that alter fetal insulin secretion or fetal insulin resistance strongly support the fetal insulin hypothesis (Table 1). These examples show how genetically determined alterations in pancreatic glucose sensing, insulin secretion or insulin resistance all have considerable effects on fetal growth. Insights have come from our new studies of mothers and neonates with mutations in the gene that codes for the glycolytic enzyme glucokinase, that acts as the ‘pancreatic glucose sensor’²⁷. Glucokinase gene mutation results in mild ß-cell dysfunction with fasting blood glucose levels typically between 5.5–8 mmol/l; this hyperglycaemia is present in early childhood and shows little deterioration with age²⁸. Figure 3 shows the effects of fetal and maternal mutations on mean birth weight centiles²⁹. A mutation in the glucokinase gene in the mother resulted in a 601 g increase in fetal size mediated through increased fetal insulin secretion in response to maternal hyperglycaemia, but the same mutation in the fetus resulted in a 533 g decrease in its weight by reducing fetal insulin secretion. When both mother and fetus had the glucokinase mutation, the two opposing effects cancelled out and the baby was of normal weight²⁹.

View this table: [in this window] [in a new window]   Table 1 Single gene disorders that alter fetal insulin secretion or fetal insulin resistance

 

View larger version (13K): [in this window] [in a new window]   Fig. 3 The effect of mutations in the glucokinase gene on centile birth weight. Data from 58 offspring of parents with glucokinase mutations29.

 
Further examples of genes affecting fetal growth include the insulin promoter factor-1 (IPF-1) gene. This gene is crucial for normal pancreatic development and ß-cell specific expression of the insulin gene^30,31. Homozygous mutations result in pancreatic agenesis and greatly reduced fetal growth (<1st centile)³². Mutations in the insulin receptor result in marked insulin resistance and also greatly reduce fetal growth (<1st centile)³³. Transient neonatal diabetes mellitus (TNDM) results from alterations to the imprinted pattern of a gene on chromosome 6³⁴. Paternal disomy (the inheritance of two paternal chromosomes and none from the mother) or paternal duplication of this region results in two copies of this gene being expressed instead of one and, in addition to the diabetic phenotype, infants show reduced birth weight (most <1st centile)³⁵.

Homozygous mutations of the ß-cell potassium channel sulphonylurea or Kir6 genes result in marked over-secretion of insulin for given glucose levels and cause persistent hypoglycaemia and hyperinsulinaemia in infants^36,37. In keeping with the key role of insulin in fetal growth, these individuals are born at greatly increased birth size (>90th centile)³⁸.

X-chromosome abnormalities also result in low birth weight – a study of 14 females with either partial X chromosome deletions or X/autosome translocations demonstrated that those with a chromosome breakpoint proximal of Xq22 had low birth weight (<3 kg) and adult height (<155 cm)³⁹. Interestingly, this region of the X-chromosome harbours the insulin receptor substrate-4 (IRS-4) gene (http://www.ncbi.nlm.nih.gov/ genemap99/) an important component of the insulin-signalling pathway. IRS genes are crucial for normal growth and glucose homeostasis in mice⁴⁰. Whether the reduced birth weight in X-chromosome deleted females is due to the loss of IRS-4 is not yet known.

	Imprinted genes and growth

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 
Genes that are imprinted play a critical role in growth. For the vast majority of human genes, two copies are required – one from the maternal and one from the paternal chromosome. The exceptions are imprinted genes in which either the maternal or paternal copy is inactivated in the parental gametes. Over 40 imprinted genes have been localised⁴¹, and often this discovery has been facilitated by defects in imprinted genes resulting in a clinical syndrome. Notably, many of these syndromes result in abnormal patterns of growth, including alterations to birth size. Table 2 shows some of the defects involving imprinted genes and their effects on growth. The best characterised of these is Beckwith-Weidemann syndrome. This disorder is the result of paternal duplication or paternal uniparental disomy of a region of chromosome 11. The disease is thought to arise as a result of the expression of two rather than one paternal copy of IGF-II. IGF-II is imprinted with only the paternal copy being expressed in most tissues and has growth and metabolic effects mediated by the IGF-I receptor and insulin receptor^42,43.

View this table: [in this window] [in a new window]   Table 2 Defects in imprinted genes resulting in alterations in growth

 

	Paternal diabetes reduces birth weight and predisposes to type 2 diabetes

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 
Genetic defects in the glucokinase and Beckwith-Weidemann genes resulting in the syndromes described are very rare and cannot explain the association between birth weight and type 2 diabetes seen in the normal population. However, recent elegant studies in the Pima Indians strongly support the hypothesis that more common gene variants can explain the association between type 2 diabetes and reduced birth weight.

Lindsay et al hypothesised that if genes were important in the link between birth size and type 2 diabetes, then low birth weight would be associated with paternal diabetes. If, however, intra-uterine environmental factors predominated, birth weight should be independent of paternal diabetes⁴⁴. This study was possible because the Pima Indians of Arizona have one of the highest prevalences of type 2 diabetes in the world⁴⁵; of 1608 subjects with birth weight data available 41% of fathers and 50% of mothers were diabetic⁴⁴. The results strongly supported a role for genes; infants born to couples in which the father alone had diabetes were significantly lighter at birth than if mother, both, or neither of the parents had diabetes (Fig. 4). The most obvious explanation for this is that diabetes susceptibility genes inherited from the father are also affecting insulin-mediated growth. In support of this, the children with a diabetic father who were in the lowest tertile of birth weight were significantly more likely to be diabetic than those in the middle and highest tertiles⁴⁴.

View larger version (11K): [in this window] [in a new window]   Fig. 4 Birth weight and parental diabetes in Arizona Pima-Indians. Values are expressed as means ± SE. General effect of parental diagnosis of diabetes on birth weight (P <0.001). Independent effect of maternal diabetes (P <0.001) and independent effect of paternal diabetes (P <0.001)44. [Reproduced with permission of Diabetes.]

 
This study also confirmed a key role for the intra-uterine environment. The offspring of mothers who were diagnosed as having diabetes, were heavier and had an increased risk of diabetes in latter life⁴⁴. This is in keeping with previous studies in this population suggesting that exposure to hyperglycaemia in utero predisposes to diabetes. The ‘U’-shaped curve seen with risk of diabetes in the Pima Indians⁴⁵ can now be explained by the increased risk of developing diabetes of small babies who have diabetic fathers and large babies who have diabetic mothers.

	Genes influencing normal variation in birth weight

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 
The recent data from the Pima Indian study strongly indicate that paternal, and therefore genetic, effects are important in normal variation in birth weight and that at least some of these genes may predispose to diabetes. But which genes are important? Several gene variants have recently been associated with alterations in birth size. Dunger et al demonstrated that the insulin VNTR is associated with altered birth weight, but only in infants that remained on the same post-natal growth rank from 0–2 years old⁴⁶. Conversely, Casteels et al demonstrated an associated between birth size and a mitochondrial DNA variant, but only in infants that changed post-natal growth rank⁴⁷. In addition, two recent studies have demonstrated associations between features of fetal and maternal metabolism, including birth size, and a DNA variant in the gene encoding a member of the important G-protein family of signal-transducing proteins^48,49. Of these gene associations, the insulin VNTR is perhaps the most convincing. The insulin VNTR is also linked with type 2 diabetes but in a paternally specific manner¹⁴. This suggests the imprinted IGF-II gene, expression of which is partly controlled by the insulin VNTR⁵⁰, may influence both type 2 diabetes and birth weight, most obviously through its effects on growth and metabolism mediated by IGF-1 and insulin receptors. Further studies are required to investigate this.

	Dissecting the genetics of birth weight and type 2 diabetes

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 
If a common gene variant was found to influence both susceptibility to type 2 diabetes and birth weight, it would lend substantial weight to the argument that genes may explain the association between birth weight and adult disorders of metabolism. However, a number of hurdles lie in the way of this seemingly straightforward experiment. The first is that finding type 2 diabetes gene variants is very difficult due to the highly heterogeneous nature of the disease and poor understanding of the primary physiological defects. There are likely to be many genes all having subtle effects on diabetes risk and, therefore, very large and well characterised patient cohorts are needed. When we have a diabetes gene variant, how will it influence fetal growth? We know that maternal glucose levels influence fetal size as increased levels are correlated with increased fetal growth. However, a mother's blood glucose level is likely to be influenced by a number of factors including a conglomerate of genes that affect insulin secretion and action. Half of these genes she will pass to her fetus. As previously pointed out, therefore, a baby with a high future genetic risk of diabetes may be born large if inheriting most diabetes-risk genes from the mother or small if inheriting most diabetes-risk genes from the father⁵¹. This point is illustrated by the findings in Pima Indians that low birth weight is associated with an increased risk of paternal diabetes and high birth weight is associated with an increased risk of maternal diabetes (Fig. 5)⁴⁴ .

View larger version (12K): [in this window] [in a new window]   Fig. 5 Hazard rate ratio (mean and 95% CI) for later diabetes in parents who did not have diabetes at the time of birth of their children. Rates are compared to middle quintile of child birth weight which is set to 1. Birth weight quintile acted as a significant predictor of later paternal diabetes (P <0.005)44. [Reproduced with permission of Diabetes.]

 
Studies of putative diabetes genes on the effects of birth weight will, therefore, require careful characterisation of maternal glucose levels in addition to controlling for well known influences on birth weight such as gestational age, sex and maternal smoking. Only then are the effects of any single genetic factor likely to be detected.

	Acknowledgements

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 
We thank all our colleagues in Exeter and Professor Mark McCarthy for helpful discussion. Dr Tim Frayling is supported by the NHS South and West Research and Development Directorate. Figures 4 and 5 were reproduced with kind permission from Diabetes.

	Footnotes

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 
Correspondence to: Dr Tim M Frayling, Department of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Barrack Road, Exeter EX2 5AX, UK T.M.Frayling{at}exeter.ac.uk

	References

Top Footnotes Abstract Introduction Low birth weight and... The predisposition to type... Birth weight is influenced... The central role of... Evidence for the role... Imprinted genes and growth Paternal diabetes reduces birth... Genes influencing normal... Dissecting the genetics of... Acknowledgements References

 

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