Maternal extracellular vesicles as key mediators of fetal growth and offspring cardiometabolic health in pregnancies complicated by type-1 diabetes.

糖尿病影响1-2%的怀孕，并增加母亲和婴儿怀孕的风险。患有糖尿病的女性死产的可能性是女性的五倍。糖尿病会影响婴儿的生长发育--过大或过小都会增加他们死产的风险。国家审计署的数据显示，患有1型糖尿病(T1 DM)的母亲所生的婴儿中，57%的婴儿比正常体型大，被称为胎龄过大(LGA；出生体重&>90%百分位数)。大婴儿在出生时更容易受伤，在以后的生活中更有可能患上肥胖症、糖尿病或心脏病。直到最近，人们还认为婴儿长得更大了，因为母亲血液中的高血糖水平正在穿过胎盘，导致婴儿生长得更快。然而，最近的研究表明，即使在接受非常严格的血糖控制的母亲中，患有T1 DM的妇女仍然有很高的风险怀孕和LGA婴儿。NHS长期计划与皇家妇产科医学院(RCOG)和詹姆斯·林德联盟优先制定伙伴关系一起确定了改善妊娠护理和糖尿病预防和管理的重要性。鉴于越来越多的孕妇受到糖尿病的影响，以及它对婴儿终身健康的影响，迫切需要了解妊娠期糖尿病如何影响婴儿的生长和胎盘功能，以便我们能够确定潜在的新治疗方法。最近，我们的研究团队参与了一项大型国际临床试验，该试验使用最先进的技术(CGM)来监测患有1型糖尿病的孕妇的血糖(CONCEPTT)。这项研究表明，一天中母亲血糖的微小差异(其他方法无法检测到)与患有T1 DM的妇女的大婴儿有关。然而，这些微小的葡萄糖差异如何影响婴儿的生长和胎盘功能的机制尚不清楚。我们在实验室中已经证明，葡萄糖的这些非常小的变化会导致胎盘的一些变化，但它们不能解释为什么婴儿会长得这么大。使用CGM测量全天/夜间的血糖水平表明，患有T1 DM的妇女一天中母亲血糖的微小差异与大婴儿有关。我们的团队最近有数据表明，在妊娠期糖尿病(GDM)婴儿长大之前，母亲血液中称为细胞外小泡(EVS)的小泡状颗粒中包含的被称为microRNAs(MiRNAs)的分子会增加。我们已经证明，其中一些EV-miRNAs起源于母体器官，与血糖水平有关。这些EVS/miRNAs可以进入胎盘，影响胎盘的生长和功能。我们认为，这可能与患有T1 DM的女性更相关，她们更有可能生下大孩子。我们的团队可以访问从CONCEPTT试验中获得的母亲血液的数据和存储样本，我们将使用这些样本来查看EVS中包含的不同信息。然后我们将研究EVS的含量是如何与葡萄糖和LGA联系在一起的，我们将使用人类胎盘来确定EVS是否导致胎盘异常发育。然后，我们将在怀孕小鼠身上进行研究，测试EV和其中包含的信息是否有可能导致婴儿变得更大，以及它们是否会影响心脏和胰腺等不同器官在婴儿体内的发育，以及是否会影响他们在以后的生活中患糖尿病、肥胖症或心脏病的风险。如果像我们怀疑的那样，电动汽车确实会改变胎盘和婴儿的发育方式，将有助于我们设计治疗方案，以减少妊娠期糖尿病的短期和长期影响，并降低婴儿成年后患肥胖症、心血管疾病或糖尿病的机会。

Diabetes affects 1-2% of pregnancies and increases the risks of pregnancies for mothers and babies. Women with diabetes are five times more likely to have stillbirths. Diabetes can affect babies' growth- being too big or too small increases their risks of stillbirths. National Audit data shows that 57% of babies born to mothers with Type 1 diabetes mellitus (T1DM) are bigger than normal, known as large for gestational age (LGA; birth weight >90% centile). Big babies are more likely to experience injury during birth and are more likely to develop obesity, diabetes or heart disease in later life. Until recently, it was thought that babies were growing bigger because the high levels of glucose in mothers blood were crossing the placenta to cause babies to growth more. However, recently it has been shown that even in mothers who are treated to achieve very tight glucose control, women with T1DM are still at very high risk of having and LGA baby. The NHS Long Term Plan, alongside with the Royal College of Obstetricians and Gynaecologists (RCOG) and James Lind Alliance Priority Setting Partnership have identified the importance of improving pregnancy care and diabetes prevention and management. Given the increasing number of pregnancies affected by diabetes and the impact that it has on the life-long-health of babies, there is a crucial need to understand how diabetes in pregnancy affects baby's growth and function of placenta, so we can identify potential new treatments.Recently, our research team was part of a large international clinical trial,which was undertaken using state-of-the-art technology (CGM), to monitor glucose in pregnant women with type 1 diabetes (CONCEPTT). This study showed that that very small differences in maternal glucose throughout the day (undetectable by other methods) are linked to large babies in women with T1DM. However, the mechanisms through which these small differences in glucose affect baby's growth and function of placenta are unclear. We have shown in the lab, that these very small changes in glucose can cause some changes to the placenta, but they don't explain why babies grow so big. Using CGM to measure glucose levels over the whole day/night has shown that small differences in maternal glucose throughout the day are linked to large babies in women with T1DM. Our team has recent data that molecules known as microRNAs (miRNAs) contained in small bubble-like particles, called extracellular vesicles (EVs) in mother's blood are increased in pregnant women before babies become big in gestational diabetes mellitus (GDM). We have shown that some of these EV-miRNAs originate from maternal organs in relation to glucose levels. These EVs/miRNAs can travel to the placenta and affect how placenta grows and functions. We think this may be even more relevant in women with T1DM who are more likely to have big babies. Our team has access to data and stored samples of mother's blood obtained from the CONCEPTT trial and we will use these samples to look at the different messages contained within EVs. We will then look at how the content of EVs is linked to glucose and LGA, and we will use human placentas to determine if EVs are causing placentas to develop abnormally. We will then do studies in pregnant mice test whether EVs and the messages contained within them, can potentially cause babies to become bigger, and if they affect how different organs such as heart and pancreas develop in the baby, and if it affect their risk of getting diabetes, obesity or heart disease in later life. If as we suspect, EVs do cause changes to the way the placenta and baby develop, will help us to design treatments to decrease the short and long term effects of GDM and to reduce the chance of babies developing obesity, cardiovascular disease or diabetes in adulthood.