Commentary: Twins, low birthweight and type 2 diabetes

DIW Phillips

MRC Unit, Southampton General Hospital, Tremona Road, Southampton SO16 4YD, UK. E-mail: diwp{at}mrc.soton.ac.uk

One of the important issues raised by the fetal origins hypothesis is the extent to which the associations between birthweight and adult health outcomes, such as type 2 diabetes, are explained by common genetic factors, or are a result of fetal programming by the early environment. Indeed, a genetic explanation has been specifically proposed for the association between birthweight and type 2 diabetes.1 In pathophysiological terms this is logical. Since insulin has a central role in controlling fetal growth, genetic factors which impair insulin secretion or decrease insulin action, both features of type 2 diabetes, would be expected to reduce fetal growth. This has been demonstrated experimentally in transgenic mice lacking key intermediates of the insulin signalling pathway,2 in human infants with rare inherited defects such as insulin receptor mutations,3 and in patients with mutations which reduce insulin secretion.4 Distinguishing between the effects of the early environment and genes is not merely of academic interest, but has considerable public health importance as it points the direction for future research and possible interventions.

Twin studies may provide one way of distinguishing between these competing hypotheses. Differences in birthweight between genetically identical, monozygous twins must be due to differences in the fetal environment. Thus associations between these within-pair differences in birthweight and subsequent diabetes cannot be explained by genetic factors. Studying twins also has the advantage in achieving perfect matching for maternal factors which influence outcomes, for example maternal size, body composition, and socio-economic status. Although a number of studies have now been carried out in twins, to date they have been hampered by small size and as a consequence, low statistical power. The paper by Iliadou et al. in the current issue of the International Journal of Epidemiology, which is based on over 11 000 Swedish twins born between 1906 and 1958,5 is therefore an important and welcome contribution to the literature. As with most studies of this size, the ascertainment of both birthweight and the occurrence of diabetes is by self-report; while this will introduce some random error, it does not invalidate their conclusions. When an unpaired analysis (i.e. considering twins as singletons) was carried out, it showed a doubling of diabetes risk for every kilogram decline in birthweight. This effect size is similar to that described in studies of singleton births. However, when the authors carried out a within-pair analysis in monozygous twins, a similar doubling of diabetes risk in the smaller twin was observed for each kilogram decrement in birthweight. The authors are understandably cautious about their conclusion, as the CI marginally overlapped zero. But given the results of other studies, for example an analysis based on the Danish Twin register which showed that among 14 monozygous twin pairs discordant for diabetes the diabetic twin had significantly lower birthweight than the normal co-twin,6 together with a similar Italian study,7 these data suggest the existence of the effect of the fetal environment on diabetes risk which is not mediated by genetic factors.

These findings further our knowledge about the long-term health of twins by adding to evidence that the smaller twin in a twin pair is not only disadvantaged in stature and intelligence but also in terms of adult disease risk.8 But what do they tell us about the fetal origins hypothesis and in particular about the mechanisms involved? Although obesity as indicated by the body mass index (BMI) had an important effect on the prevalence of diabetes, the findings with respect to birthweight were independent of the BMI. Both defects in insulin secretion and insulin resistance are involved in the pathogenesis of diabetes. Current evidence from the Danish twin study suggests that the smaller twin in monozygous pairs has evidence of both abnormalities but clearly more work is needed.9 These twin studies are important as they offer the possibility of further studies of discordant pairs and insights into the mechanisms of fetal programming.

However, there are clearly a number of issues, which limit the utility of twins as a model for investigating the fetal origins hypothesis. Studies of within-pair differences in monozygous twins are sensitive to feto-placental influences on twin growth and physiology but not maternal factors, which will be shared by both twins. The influence of maternal factors such as diet and body composition, increasingly suspected to play an important role in fetal programming, needs to be evaluated in other ways. Consideration of the biology of twinning also suggests that intrauterine growth in twins is different from intrauterine growth in singletons and is subject to different constraints.10 For example, birthweight discordance in monozygous twins is likely to be a result of differences in nutrient partitioning and blood supply between twins. An extreme example of this is the so-called Twin–Twin Transfusion syndrome, which occurs as a result of arteriovenous anastomoses in the placenta allowing the slow leakage of blood from one twin to the other. Discordance may also reflect adaptive responses by twins in response to limitations in the fetal environment.11 Hence, although the findings in these Swedish twins are an important proof of concept and may lead to helpful mechanistic insights, there is a need to be cautious about generalizing from twin studies.


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