Rachel Freathy: Birthweight and diabetes risk

Image courtesy of Rachel Freathy

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Kat: Recent figures show that around one in ten people over the age of 40 in the UK are living with type 2 diabetes, adding up to millions of cases. But according to Rachel Freathy, Associate Professor and Wellcome Trust Senior Research Fellow at the University of Exeter Medical School, for at least some of these people the seeds of their disease may have been sown back in the very earliest stages of life. 

Rachel and her team have been looking at the correlation between birthweight and the risk of developing diabetes later in life - and I will say now, drinks receptions at conferences aren’t the best environment for recording, so apologies in advance for the background noise in this one.

Rachel: So our main interest is why there is this relationship between being a smaller baby and then having a greater risk of type two diabetes later in life. We have been looking in our studies to see whether that might be explained at least partly by genetics. What that means is genetic variants which predispose you to type two diabetes, but also those same genetic variants early in life might have a role in birthweight.

Rachel: We suspect that might be the case because foetal insulin, so insulin produced by the foetus, is a really important growth factor. But insulin when you are an adult or a child is the hormone that controls your blood sugar. So we think those genetic variants might be responsible for linking those two characteristics early and late in life.

Kat: That is fascinating. I'd never really thought about that because I've known about insulin and insulin-related growth factors and I’m like, "yeah, they make you grow" and now "Oh no, that is the same thing, right?"

Rachel: Yeah, it is. You mentioned maternal diabetes and so in our studies, although we're interested in what goes on in the genetics of the baby, the genetics of the mother is really important as well. Mothers who have diabetes in pregnancy generally have higher levels of glucose and that is responsible for making their babies grow. If the baby grows really large, then that can cause problems. So when we look at our genetic studies, we have to really be careful to try and distinguish between the effects of the mother's genetics and the baby's genetics. Sometimes they can pull in opposite directions.

Kat: And of course, a baby is half the mother anyway, genetically speaking.

Rachel: Yeah, that's right.

Kat: How do you start to tease this apart? What genetic studies are you doing? Who are you looking at? How do you find them?

Rachel: So we have a range of different approaches. We use these really large genome-wide associated studies and our collaborators who we work with have developed these really clever statistical techniques where you can take the information on an individual's genetics and their birth weight association, and then the mother's genetics and the birth weight association, and put them together and actually estimate what are the independent effects.

Rachel: Even better, although what we need is larger samples and they're coming online but they're not as available just yet, are large studies of fathers, mothers, and children where you have the genetics of all of them and you can put them together and really try and work out what's going on.

Kat: Have you found any interesting clues so far?

Rachel: We have. We found quite a lot of genetic variants that predisposed to type two diabetes are also associated with having a lower birth weight. So we know that at least some of that relationship between birth weight and diabetes is linked by foetal genes.

Rachel: What we've also been able to do is say, well, actually it's not all type two diabetes genes. Some of them are important earlier on. Some of them come into play a bit later on. And actually, the genetic variants that we found, the genes that are nearby, are leading us to understand a little bit more about the mechanisms involved.

Rachel: So we know that the genetic variants that tend to associate with birth weight are the ones that influence how much you produce insulin. They're not so much the variants that make you more likely to become obese and get diabetes that way, or they're not the ones that influence your liver function, which can lead to diabetes. So the genetics is helping us to tease apart these different mechanisms.

Kat: One of the things I have to ask is, you say that the foetus makes insulin and it's getting glucose from its mum. Well, why isn't it getting insulin from its mum? Doesn't this all go through the placenta?

Rachel: The mother's glucose does cross the placenta and that's available to the baby, the mother's insulin doesn't. It's the baby's insulin produced by the baby's pancreas that is the thing that responds to the mother's glucose and then makes the baby grow. So the baby's absolutely dependent on the mother's glucose for food, but it's the baby's insulin that's causing the growth.

Kat: So what does this information tell us? Where do we take this kind of information next? What can you do now you're finding these genes?

Rachel: So one thing is to actually combine the genetic variants that we've found with other studies: studies of other pregnancy characteristics, studies that might lead us a little bit more to the actual genes involved to try and understand the biology of foetal growth and pregnancy even more.

Rachel: The second thing we can do is, using those maternal genetic variants that influence birth weight by the intrauterine environment, we can actually ask questions about what maternal factors are important. Things like glucose or blood pressure and other things that might circulate in the mother.

Rachel: Then finally, we are interested to see if we add up a genetic score for birth weight in the mother and in the father, can that add to other information that could be obtained in pregnancy to improve the prediction of whether a baby's going to be large or small.

Kat: Then presumably if this information could be useful for the baby as they grow up and they're thinking about their own health.

Rachel: Yeah, that's true. It's definitely worth pointing out that it's not very predictive. We are only really explaining a small amount of the risk of type two diabetes by the genetics. But it's one thing in combination with a whole lot of others.

Kat: What do you want to find out next? What do you think is still really the big unknown?

Rachel: A lot of our genetic studies have been limited so far by the data that's available, limited to populations of Northern European ancestry.

Rachel: There's a whole lot more work to be done to look at diversity in human populations and to make sure we are understanding genetics in all humans. That is a real priority for our studies, to get studies together which are more representative of the human population.

Rachel: I guess the other thing is that we want to combine our studies where we look at birth weight with people with other expertise who are looking at pregnancy outcomes such as preeclampsia, or things that can go wrong in pregnancy, and see whether there's any crossover there. And whether any of our studies can inform those adverse pregnancy outcomes, which are really important for us to understand.