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Periconceptional nutrition, twinning and how this impacts on current understanding of the aetiology and pathophysiology of the metabolic syndrome

In this issue of The Journal of Physiology, Rumball et al. publish an important article on the impact of periconceptional undernutrition on maternal and fetal metabolism with special emphasis on the glucose–insulin axis function and fetal growth in twin versus singleton ovine pregnancies (Rumball et al. 2008). The authors previously showed that periconceptional undernutrition leads to altered maternal metabolism and fetal growth in sheep with singleton pregnancies during late gestation, and they therefore hypothesized that the periconceptional circumstances associated with twinning might affect late pregnancy metabolism and fetal growth in a similar way as that of periconceptional undernutrition. This was, however, not the case. Thus, twins were characterized by a more severe growth retardation as opposed to singleton fetuses during late gestation when exposed to both normal feeding as well as in particular to fasting of the mothers (ewes). Whereas twin fetuses displayed an exaggerated plasma insulin response to a glucose challenge in late gestation, singleton fetuses of periconceptional undernourished ewes showed reduced glucose excursions in response to the glucose challenges at the same time point of gestation, indicating increased glucose effectiveness, metabolism or perhaps even insulin sensitivity. 
 
Taken together, these data add to mounting evidence of twins being exposed to a unique and different intrauterine environment from conception to birth as compared with singletons, and given the fact that this period in early life may play a (or the) key role for the risk of developing the metabolic syndrome including type 2 diabetes, hypertension, dyslipidaemia and abdominal obesity many decades later, known as the ‘thrifty phenotype hypothesis’ (Hales & Barker, 2001), it does give rise to many layers of reflection regarding twins and how they may be used – or not used – in studies on the aetiology and pathophysiology of diseases and states inherent in the metabolic syndrome. 
 
The authors conclude that the data indicate that twins and singletons must be examined separately in any study of fetal and postnatal physiology. Indeed, these findings along with others warrant caution extrapolating data obtained in twins to singletons and vice versa, but they do not indicate that twins cannot be used to study the early (periconceptional and fetal) origin of the metabolic syndrome. In that respect, studies using identical twins discordant for both type 2 diabetes (Poulsen et al. 1997) as well as hypertension (Bergvall et al. 2007) provided conclusive evidence that these key components of the metabolic syndrome are associated with low birth weight and an adverse intrauterine environment in a non-genetic manner. 
 
Interestingly, as also discussed in the article by Rumball et al., intra-pair differences of birth weights in twins are much more predictive of later metabolic health as compared with absolute birth weights, and the reason for that may be explained by the very special early life conditions and intrauterine growth trajectories associated with twinning (Rumball et al. 2008). As for the absolute birth weights, an argument used against the ‘thrifty phenotype hypothesis’ has been that low birth weight in twins does not predict an excess risk of premature death from especially cardiovascular disease (Christensen et al. 1995), the unfortunate ultimate risk or consequence of having the metabolic syndrome. Although we need to know more about the specific disease patterns and causes of mortality in twins versus singletons, the data from Rumball et al. provide some of the first physiological evidence for altered and distinct intrauterine programming mechanisms and intrauterine growth trajectories in twins compared with singletons, supporting the notion that birth weight in twins may not necessarily predict later metabolic health in the same way – and to the same extent – as birth weight in singletons. 
 
The findings by Rumball et al. may also provide additional concerns about the validity of heritability estimates, disease concordance rates and thus genetic contributions to various states of disease obtained from studies of monozygotic and dizygotic twins, as discussed recently (Vaag & Poulsen, 2007). 
 
An additional lesson that can be learned from the study by Rumball et al., as well as from previous studies from the same group (Oliver et al. 2005), is that periconceptional undernutrition may influence maternal and fetal metabolism during late gestation without influencing weight at birth per se after correction for gestational age. Indeed, this finding supports the view that birth weight represents only a (although surprisingly predictive) proxy of risk of later metabolic disease, and that we need to find other and even more precise markers of factors linking an adverse intrauterine environment with later risk of disease. 
 
Another very recent study documented that periconceptional dietary restriction of vitamin B12 and folate within the physiological range of mature female sheep led to adult offspring that were both fatter, more insulin resistant and had higher blood pressures, but without any significant alterations of birth weights, as compared with control animals (Sinclair et al. 2007). Interestingly, the offspring displayed widespread alterations of the methylation pattern of a number of DNA CpG islands in liver cells, providing the first evidence of epigenetic mechanisms linking physiologically relevant periconceptional micronutrient manipulations to distinct adult features of the metabolic syndrome in the offspring. 
 
Altogether, the scene has been set to a new area of understanding the molecular mechanisms linking periconceptional and intrauterine nutrition – as well as fetal growth – to relevant outcomes of metabolic health in late gestation, after birth and throughout the entire life course from detailed physiological studies of twins and singletons, separately or in comparisons when appropriate.