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

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.

Babies born to mothers with Type 1 Diabetes Mellitus (T1DM) are at increased risk of stillbirth, especially babies born too big or too small. 57% of babies in T1DM pregnancy are born large for gestational age (LGA). LGA babies are also at increased risk of developing obesity, diabetes and cardiovascular disease in later life. Maternal glucose is a major determinant of fetal growth, however, recently we and others have shown that even when there are only very subtle changes in maternal glucose (<1mM), women with T1DM are still at very high risk of LGA. It is unclear how these subtle changes in glucose impact so significantly on fetal growth therefore the mechanisms underpinning the relationship between maternal glucose levels, abnormal fetal growth and long-term health of the offspring need further investigation.

We have generated data that shows that i) miRNAs, contained within extracellular vesicles (EVs) in maternal blood, are altered before the development of LGA, in women with T1DM ii) that EV/miRNAs can influence how the placenta and fetus develop, iii) that very small changes in glucose can cause changes to the miRNA content of EVs.

We propose that in women with T1DM that deliver LGA babies, subtle changes in glucose profiles impact on EV cargo release from maternal organs, and that these EVs/cargo impact on placental development, fetal growth and offspring cardio-metabolic health. We will address this using blood samples already obtained from women with T1DM, and state-of-the-art technologies in human placenta and in pregnant mice. The incidence of pregnancy complicated by diabetes is increasing. By establishing the link between maternal glucose profiles, EVs, fetal growth and long-term health, we will identify novel therapeutic targets that can be developed in future studies to aid in prevention of the short and long-term complications associated with T1DM in pregnancy, thereby halting transmission of the disease to the next generation.