Timing of inter‐generational prevention of adiposity and type 2 diabetes

Abstract

Increasing evidence from animal studies, as well as from human epidemiological and physiological studies, supports the idea of adiposity and type 2 diabetes (T2D) to be programmed at the earliest stages of life. This paradigm shift in our understanding of the origin of adiposity and T2D has been further substantiated by our recognition of the multiple known susceptibility genes to explain only a small proportion of the primary origin of these diseases. To this end, even intensified prevention programmes targeting adult life style factors have not been shown sufficiently effective to stop the global propagation of adiposity and T2D. Studies of twins showed that the fetal environment associated with low birth weight (LBW) and zygosity status influence the risk of adiposity, insulin resistance, as well as glucose tolerance in adults in a non-genetic and age-dependent manner (Vaag & Poulsen, 2007). The consistent associations between LBW and markers of adiposity and T2D has intuitively been suspected to occur as a result of factors limiting growth per se during critical windows of fetal development. As fetal growth rates are highest during late pregnancy, much focus has been on factors operating during the second and third trimesters of pregnancy. Twins are born with lower birth weights than singletons, and recent evidence from sheep as well as from human studies have shown that twin status in itself may influence risk of adiposity and glucose intolerance with age (Poulsen et al. 2009). At the opposite end of the birth weight spectrum, studies have shown that a high birth weight associated with diabetes during pregnancy, including women with gestational diabetes (GDM) defined as incident (new) cases with diabetes being unmasked by insulin resistance during late pregnancy, seems also to be associated with increased adiposity and risk of T2D in the offspring. Accordingly, reduced fetal growth per se may not be the only answer to the question of the association between factors operating in pregnancy and risk of developing adiposity and T2D. More recently, attention has been on a potential role of maternal diet influencing risk of adiposity and T2D at the time of conception in sheep (Rumball et al. 2008). The issue is further complicated by the report of the fathers diet at the time of conception influencing insulin secretion and, thus, potentially risk of T2D in the offspring (Ng et al. 2010). The extent to which factors operating early as opposed to late in pregnancy may play a role for a lower fetal growth rate, as well as for an increased adiposity risk in twin sheep, is unknown. The study by Hancock et al. (2012) published in this issue of The Journal of Physiology randomized pregnant sheep with twin fetuses to either reduction of fetuses at day 42 of pregnancy, or a sham intervention mimicking the technical reduction procedure. A control group of singleton pregnancies was included too. The normal length of pregnancy in sheep is 148 days, and the study set-up was therefore well suited to examine the extent to which adverse nutritional exposures, or other factors operating during late pregnancy, might influence the outcome at birth according to weight or adiposity at age 2 years. Clearly, the study results pointed towards a key role of factors operating during the first 42 days of pregnancy. Thus, both birth weights as well as degree of adiposity at age 2 years was very similar to – or identical – among the reduction compared with the twin offspring. A slightly increased birth weight in the twin reductions compared with singleton lambs suggested that factors operating between day 42 and 148 in pregnancy may play some minor additional role for the impaired rate of fetal growth in sheep twin pregnancies. Although the results from human and sheep twin studies add to the increasing awareness of the fetal environment playing a very important role for the risk of adiposity and T2D many decades later in life, it is important to note that the results simultaneously question the extent to which metabolic results from twin studies can explain mechanisms involved in the development of metabolic diseases in humans and animals born as singletons, including the mechanisms linking LBW with increased risk of T2D. For instance, the risk of T2D in twins is much lower than what would be expected if extrapolating the quantitative impact of LBW among singletons to twins (Vaag & Poulsen, 2007), why LBW in twins is not the same as LBW in singletons. Factors such as survival of the fittest during fetal life according to genetic constitution may also influence the extent to which results from twin studies may be extrapolated to singletons. Regardless, a major question of importance for understanding – and potentially in the future to prevent – metabolic diseases with a fetal developmental origin relates to the critical time window during development sensitive to adverse events influencing risk of adiposity and T2D later in life. Therefore, the paper by Hancock et al. is important as it, with an original and not previously seen approach, provides further proof-of-concept that unknown factors operating at the earliest periods of pregnancy influence both birth weight and risk of adiposity. With the widespread acceptance of a fetal and developmental origin of adiposity and T2D in humans, possibly contributing significantly to the propagation of cardiometabolic diseases in developing countries transitioning over the last decades from being challenged by under-nutrition to being challenged by over-nutrition and physical inactivity, the crucial question arises of how and during which period of– or even before – pregnancy to implement prevention of adiposity and T2D for the generations to come. Failure to understand the importance of the timing of the physiological mechanisms underlying developmental programming of adiposity and T2D could result in massive losses of resources, if for instance, focusing inter-generational prevention initiatives on improving life style conditions in pregnant women during their last periods of pregnancy, when in fact the adverse developmental programming events had taken place during earlier periods of gestation, and perhaps already at the time of conception. It may sound trivial, and to some eager public health-oriented professionals even disappointing, but there is no easy way to by-pass investments in further research addressing the basic physiology and molecular mechanisms, including the timing of events during pregnancy, underlying developmental programming of adiposity and T2D.