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

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.

There is an escalating global epidemic of type 2 diabetes, with developing countries experiencing the most rapid increase. Current strategies for preventing the disease rely mainly on altering adult lifestyles. Recent research suggests that factors acting during early development, including fetal growth restriction, and exposure to gestational diabetes (GDM) in the mother, increase diabetes and obesity risk in later life. Our research in India has shown that maternal vitamin B12 deficiency and hyper-homocysteinaemia, in combination with normal/high folate status, is associated with an increased risk of GDM in the mother, growth restriction in her fetus, and adiposity and insulin resistance in her children. These effects could act through epigenetic mechanisms and occur in paternal as well as maternal B12 deficiency. Improving the B12 status of women and men preparing for pregnancy could be a scalable and affordable intervention to prevent diabetes in future generations. Our proposed programme includes an RCT of B12 supplementation in rural Indian adolescents who will marry and conceive within the next 4 years, aiming to improve newborn B12 status and body composition and reduce diabetes risk in their children. We will also carry out 2 observational studies in the UK, to replicate the earlier Indian findings and study their wider relevance. We will measure B12, folate and homocysteine in stored maternal samples from a UK birth cohort which has measured body composition in the children, and carry out a case-control study of mothers with and without GDM in a UK population at high risk and with a high S Asian population (W Midlands) to determine whether UK women who develop GDM have low B12 status, or B12/folate imbalance, in early pregnancy. Samples taken in all studies will be used for genetic studies, and future epigenetic research, relevant to our objectives. We expect this unique research to have a major impact on future strategies to prevent type 2 diabetes.

This comprehensive programme will assess the impact of 2 B vitamins (B12 and folic acid) on metabolic risk of pregnant mothers, fetal growth and inter-generational programming of common chronic metabolic disorders (obesity and diabetes). We will assess impact in India, as well as in white Caucasians and South Asians living in the UK. We expect the work to have an influence on future strategies to prevent these disorders. This is important given the high burden of disease potentially caused by vitamin B12 deficiency and the scalable and affordable nature of widespread B12 supplementation. It is anticipated 15-20% of all pregnant mothers will develop GDM in the UK if the new International Association of Diabetes and Pregnancy Study Group (IADPSG) guidelines are adopted. Despite best efforts, childhood obesity is increasing along with the epidemic of metabolic disorders in adult life.

Apart from patients who develop GDM, the beneficiaries from this research will be: pregnant mothers of all ethnicities living in India, UK and elsewhere; diabetologists in the NHS and world-wide (if B12 deficiency predicts the risk of GDM); public health experts (involved in strategies to reduce childhood obesity); and policy makers (huge potential to reduce the burden of obesity and metabolic diseases of the next generation).