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

肥胖症和2型糖尿病在世界范围内迅速蔓延，其中增长最快的是低收入和中等收入国家。印度不仅是世界上发病率最高的国家之一，而且这种疾病的发病年龄和体重水平都低于英国的白色高加索人。在印度城市居民中，大约8%的30-40岁的人已经患有糖尿病。这造成了疾病和残疾的沉重负担，以及医疗费用和收入损失造成的无法承受的经济负担。到目前为止，预防糖尿病的努力主要集中在改变高危成年人（例如超重，有糖尿病家族史或已经有高血糖的人）的饮食，生活方式和活动。然而，最近的研究表明，在生命早期（在子宫内发育期间）起作用的因素使个体处于后期糖尿病的风险中。这些问题包括产妇营养不良和出生体重不足，以及母亲在怀孕期间患糖尿病。我们的研究表明，印度母亲的维生素B12水平通常较低，这反过来又会导致有害代谢物（同型半胱氨酸）的血液水平较高。我们已经证明，这些母亲在怀孕期间患糖尿病的几率更大。他们的孩子更有可能出生时体重较轻，在儿童时期发展更多的体脂和更高的血浆胰岛素水平，这是晚年糖尿病风险较高的迹象。如果母亲的另一种B族维生素叶酸水平正常或高，则风险进一步增加。因此，我们首次证明了母亲特定营养缺乏与下一代糖尿病风险之间的联系。母亲营养对其子女患糖尿病风险的影响的一个可能机制是通过表观遗传效应，即早期发育期间的营养环境影响控制基因表达的开关。由于这些开关是通过父母中的任何一方传递的，我们认为父亲的维生素B12状态也可能很重要。我们提出的计划包括在印度和英国的3个相关项目：1）一项在700名印度农村青少年中补充维生素B12的随机对照试验（浦那产妇营养研究），目的是改善她们婚前的维生素B12状况，目的是确定a）补充印度年轻妇女的维生素B12是否能改善其新生儿的维生素B12状况。B）补充印度年轻妇女和男子的维生素B12是否能改善出生体重，新生儿身体组成，和（超出本资助的时间范围）儿童的身体成分和胰岛素敏感性。2）在南亚人比例较高的英国人群中，对妊娠期糖尿病母亲（N=700）和对照组（N=1400）进行的病例对照研究（考文垂、纽尼顿和莱斯特），目的是确定：c）是否印度和白色高加索妇女谁发展GDM更可能有低维生素B12的状态，或B12和叶酸之间的不平衡（低B12，正常/高叶酸）。3）测量来自英国出生队列的3000名孕妇的储存母体血浆样品中的维生素B12、叶酸和同型半胱氨酸（南安普顿妇女调查），随后收集了有关新生儿和儿童身体成分的数据，目的是确定：d）在英国人群中，较低的母亲B12状态和较高的同型半胱氨酸浓度是否与较低的出生体重相关。（低母体B12和正常/高叶酸状态）与出生时和儿童时期的脂肪体组成有关。我们希望这项独特的研究对未来预防糖尿病的策略产生重大影响。

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.