Metabolic programming of offspring by vitamin B12/folate imbalance during pregnancy

Abstract

With two reports in the current issue of Diabetologia, C. S. Yajnik and his international cast of collaborators have created conceptual bridges between some of the most important global public health challenges of our time: obesity (or is it adiposity?), fetal or early life origins of adult disease, and prevalent and persisting micronutrient malnutrition [1, 2]. One study from the cohort within the Pune Maternal Nutrition Study allows analysis of the relationship between maternal nutritional status and midand late pregnancy and childhood outcomes at 6 years of age [1]. A striking finding was that two-thirds of the mothers had low circulating levels of vitamin B12; their offspring were short and thin, but had more body fat. This was associated with a high prevalence of insulin resistance, presumably presaging later entry into the epidemic of type 2 diabetes among adults in India. From this novel focus comes the observation that the combination or interaction of vitamin B12 deficiency and high erythrocyte folate in mothers is associated with the highest prevalence of insulin resistance according to homeostatic model assessment of insulin resistance. This provides confirmation of a previous study reporting childhood insulin resistance in association with higher adiposity and thinness (presumably with low lean mass) [3]. The observation of low vitamin B12 status in mothers [1] was not surprising, given the high prevalence of vegetarian dietary habits, but the relationship to later insulin resistance and adiposity in the offspring provides a powerful challenge for further work to explain this relationship and its persistence in the offspring. While the evidence presented by Yajnik et al. [1] does not distinguish between the positive relationship between adiposity and insulin resistance, as opposed to an inverse relationship between low lean or muscle mass and insulin resistance, these data call out for a mechanistic explanation of the relationship between micronutrient changes in the mother in late pregnancy and persisting metabolic/functional abnormalities in the offspring. Some suggestions are offered by the authors, although with no supporting data as yet. The concept of fetal or early infancy programming of later metabolic and disease outcomes is well described [4, 5], even though the mechanism by which programming in fetal life or infancy might be sustained remains unexplained. We know that the two micronutrients in this report are related metabolically, and that both folate and vitamin B12 are involved in DNA synthesis and methylation— actions at the core of what has been called epigenetics. Folate in particular is related to the efficiency of DNA methylation, which in turn has lasting effects on selected metabolic processes through the ability of strategic DNA methylation to promote or silence gene expression. One of the two known functions of vitamin B12 as a cofactor in the methionine synthase reaction (Fig. 1), which converts homocysteine into methionine, depends on methylfolate to provide the methyl group, and methionine is converted into S-adenosyl methionine, which is subsequently utilised in dozens of methylation reactions, including methylation of Diabetologia (2008) 51:6–7 DOI 10.1007/s00125-007-0869-8