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

肥胖症和2型糖尿病在世界各地的流行迅速升级，最快的上升发生在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，而且与英国白人高加索人相比，印度人的发病年龄更早，体重水平也更低。在居住在城市的印度人中，大约8%的30-40岁的人已经患有糖尿病。这造成了沉重的疾病和残疾负担，以及因医疗费用和收入损失而无法忍受的经济负担。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的饮食、生活方式和活动上(例如，那些超重、有糖尿病家族史或已经有高血糖的人)。然而，最近的研究表明，在生命早期(在子宫内发育期间)起作用的因素会使个人面临日后患糖尿病的风险。这些问题包括产妇营养不良和低出生体重，以及母亲怀孕期间的糖尿病。我们的研究表明，印度母亲的维生素B12水平通常较低，这反过来会导致血液中有害代谢物(同型半胱氨酸)水平升高。我们已经证明，这些母亲在怀孕期间患糖尿病的几率更大。他们的孩子出生时更有可能出生时体重较低，在童年时期发展出更多的体脂和更高的血浆胰岛素水平，这是以后生活中糖尿病风险更高的迹象。如果母亲的另一种维生素B叶酸处于正常或高水平，风险会进一步增加。因此，我们首次展示了母亲的特定营养缺乏与下一代糖尿病风险之间的联系。母亲营养对孩子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。由于这些转换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状态也可能是重要的。我们提议的计划包括在印度和英国的3个相关项目：1)在700名印度农村青少年中进行一项补充维生素B12的随机对照试验(浦那母亲营养研究)，目的是改善他们婚前、受孕和怀孕前的维生素B12状态。目的是确定a)印度年轻女性补充维生素B12是否改善了她们新生儿的维生素B12状态。b)印度年轻女性和男性补充维生素B12是否改善了出生体重、新生儿身体组成、2)在S亚裔(考文垂、纽顿和莱斯特)比例较高的英国人群中，对患有妊娠期糖尿病的母亲(N=700)和对照组(N=1 400)进行的病例对照研究。目的是确定：c)患有妊娠期糖尿病的印度和白人高加索女性更有可能患有低维生素B12状态，或者怀孕早期B12和叶酸(低B12，正常/高叶酸)之间的失衡。3)维生素B12的测量，来自英国出生队列(南安普顿妇女调查)的3000名孕妇的储存血浆样本中的叶酸和同型半胱氨酸，随后收集了新生儿和儿童的身体成分数据。目标是确定：d)较低的母体B12水平和较高的同型半胱氨酸浓度是否与英国人口中较低的出生体重相关。e)B12-叶酸失衡(母体B12较低和叶酸水平正常/较高)是否与出生时和儿童时期脂肪较多的身体成分有关。我们期待这项独特的研究对未来的糖尿病预防策略产生重大影响。

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.