Maternal vitamin B12, folic acid and homocysteine as determinants of gestational diabetes, fetal growth and intergenerational programming of diabesity

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There is a rapidly escalating epidemic of obesity and type 2 diabetes across the world, with the fastest rise occurring in low- and middle-income countries. India not only has one of the highest rates in the world, but the disease starts at a younger age and lower levels of body weight than in UK white caucasians. Among city-dwelling Indians, approximately 8% of people aged 30-40 years already have diabetes. This is creating a heavy burden of disease and disability, and an intolerable economic burden through medical costs and lost earnings. Until now, efforts to prevent diabetes have mainly focussed on modifying the diet, lifestyle and activity of at-risk adults (for example those who are overweight, have a family history of diabetes or already have high blood sugar). However, recent research has indicated that factors acting in early life (during development in the womb) place an individual at risk of later diabetes. These include maternal malnutrition and low birthweight, and diabetes in the mother during pregnancy. Our research has shown that Indian mothers often have low vitamin B12 levels, which in turn causes high blood levels of a harmful metabolite (homocysteine). We have shown that these mothers get more diabetes in pregnancy. Their children are more likely to born with a low birth weight, and develop more body fat and higher plasma insulin levels during childhood, which are signs of higher diabetes risk in later life. The risk is increased further if the mother has normal or high status for another B vitamin, folate. Thus, we have shown, for the first time a link between a specific nutritional deficiency in the mother and diabetes risk in the next generation. One possible mechanism for the effect of maternal nutrition on risk of diabetes in her children is through epigenetic effects, whereby the nutritional environment during early development affects the switches that control gene expression. Since these switches are passed on via either parent, we think it is possible that paternal vitamin B12 status could also be important.Our proposed programme comprises 3 related projects in India and the UK: 1) A randomised controlled trial of vitamin B12 supplementation in a cohort of 700 rural Indian adolescents (Pune Maternal Nutrition Study) with the aim of improving their vitamin B12 status prior to marriage, conception and pregnancy.The objectives are to determine a) whether vitamin B12 supplementation of young Indian women improves the vitamin B12 status of their newborns.b) whether vitamin B12 supplementation of young Indian women and men improves birth weight, neonatal body composition, and (beyond the time span of this grant) body composition and insulin sensitivity in the children.2) A case-control study of mothers with gestational diabetes (N=700) and controls (N=1400) in a UK population with a high proportion of S Asians (Coventry, Nuneaton and Leicester).The objective is to determine:c) whether Indian and white caucasian women who develop GDM were more likely to have low vitamin B12 status, or an imbalance between B12 and folate (low B12, normal/high folate) in early pregnancy.3) Measurement of vitamin B12, folate and homocysteine in stored maternal plasma samples from 3000 pregnancies in a UK birth cohort (Southampton Women's Survey) which has subsequently collected data on body composition in the newborns and children.The objectives will be to determine:d) whether lower maternal B12 status and higher homocysteine concentrations are associated with lower birthweight in a UK population.e) whether B12-folate imbalance (low maternal B12 and normal/high folate status) are associated with a more adipose body composition at birth and during childhood.We expect this unique research to have a major impact on future strategies to prevent diabetes.