Is type 2 diabetes really a “lifestyle disease”? Why do some people develop diabetes even though they’re eating healthily while many obese people escape the disease? How can your environment shape your diabetes risk before you’re even born? Dr Inês Cebola, Dr Shivani Misra and Dr Lorna Smith are on a myth-busting mission tackling the misconceptions around type 2 diabetes.
Sally: Hello and welcome to Hormones: The Inside Story, the podcast from the Society for Endocrinology. I'm Dr Sally Le Page, an evolutionary biologist and science presenter, and I'll be chatting with a whole bunch of hormones scientists - or endocrinologists - to bring you surprising stories and cutting edge research.
Sally: Today, we're on a myth-busting mission, meandering into all of the misconceptions around type 2 diabetes - such as that it's all down to our lifestyle...
Lorna: Hopefully, after this podcast, people won't consider type 2 diabetes to be exclusively a lifestyle disease. There's a lot of genetic factors that can lead you to get type 2 diabetes.
Sally: - or that you will get diabetes if you're obese
Inês: Definitely not, definitely not. Unfortunately, there's this huge misconception that, "Oh, you're obese, therefore you're going to have diabetes."
Sally: - or even that if you develop diabetes, well it's just because you eat too much sugar and don't exercise enough
Shivani: You often hear people that aren't experts in obesity and type 2 diabetes suggest that people developing type 2 diabetes, you know, need to eat less and move more, which I really despise as a narrative.
Sally: So join me as we untangle the complexities of diabetes, separating the facts from the fiction and ask, "Is my diabetes my fault?"
Sally: Diabetes is very common. Roughly 1 person in every 20 in the UK is living with diabetes. In the US, that figure is 1 in 10, and the number of people living with diabetes around the world is increasing every year. It's a disease that causes high levels of sugar in your blood, and unless it's properly managed, those high sugar levels can damage the heart, kidneys, blood vessels, eyes and nerves.
Sally: Diabetes comes in a few different flavours. You're probably already familiar with the two big ones, type 1 diabetes and type 2 diabetes, but there are also other types, such as gestational diabetes, which you might get during pregnancy.
Sally: Type 1 diabetes makes up about 10% of diabetes cases and often starts to show up during childhood or adolescence. It's an autoimmune condition where your immune system starts attacking and destroying the cells in your pancreas, called beta cells. Beta cells are responsible for making insulin, a hormone that tells your liver, fat and muscles to pull sugar out of the bloodstream and into your tissues. Without enough beta cells to make enough insulin, people living with type 1 diabetes have to manually inject themselves with artificial insulin to control their blood sugar levels.
Sally: Type 2 diabetes, on the other hand, is much more common than type 1 and makes up almost 90% of all diabetes cases. With type 2 diabetes, the beta cells in the pancreas still produce insulin but the other cells in the body stop responding to it - just like when you move to a noisy city, after a while you stop noticing the sound of the traffic. A lot of people living with type 2 diabetes manage their blood sugar levels by taking drugs that help the insulin work better and by controlling their diet.
Sally: We tend to think of type 1 diabetes as a genetic disease, whereas type 2 diabetes is said to be a - quote unquote - "lifestyle disease". You'll often hear in the media that type 2 is caused by obesity, unhealthy diets and physical inactivity. There is a nugget of truth to that: research consistently shows that people with a higher BMI - or Body Mass Index - are at a much greater risk of developing type 2 diabetes. But is it really that simple? Just get your act together, eat salads, go for a jog, it'll fix your hormones and you'll be fine? Well... I'm not so sure about that.
Inês: It's not just about any one thing. It's not just about your diet. It's not just about how much you exercise and it's not just about your genes. It's this melting pot of different contributing factors that altogether increase your risk of developing diabetes during your life.
Sally: That's Dr Inês Cebola, a research fellow at Imperial College London who studies the genetics of diabetes and liver disease. It turns out that not all people with type 2 diabetes are overweight or obese.
Inês: There's about 10% of all people in the world who have type 2 diabetes who are lean, so they're not overweight, they're not obese. And you may tell me, "Okay, so 10% is not that much, right?" But let me give it to you again in numbers.
Inês: So if you think about worldwide, everyone who's got type 2 diabetes, it's almost now at a figure of 500 million people. 10% of that is 50 million. That's the population of Spain. I would say that's a sizable proportion of the world's population. It's not just a small exception. It's something that we should acknowledge when we think about it.
Sally: And the reverse is also true: not all people with obesity go on to develop type 2 diabetes.
Inês: About half of the people who are obese do not have diabetes.
Sally: Now it is true that a poor diet and sedentary lifestyle does increase your risk of developing diabetes. And we consistently see that wherever obesity becomes more prevalent, rates of type 2 diabetes also go up. But clearly, it's not as simple as obesity equals diabetes.
Sally: So why is it that some people with obesity escape type 2 diabetes while there are 50 million people in the world today who are lean and yet live with the disease?
Inês: In very short answer, I would say that one of the things that justifies this diversity is genetics.
Sally: We often think of type 1 diabetes - that's the autoimmune one - as a genetic disease. If you've got family members with type 1 diabetes, you have a much higher risk than the general population of developing the condition yourself.
Sally: Well it turns out, the same is true for type 2 diabetes.
Inês: If you have a twin and they have type 2 diabetes, your likelihood or your chances of getting diabetes as well are in the order of 70 to 90%.
Inês: It's also known that having a parent who's got type 2 diabetes, that's something else that increases your risk. So there is definitely that same pattern arising there.
Inês: But what's interesting is that even within the family, they might develop diabetes but at a different age, for example. I think that's also something that we should acknowledge; that we don't know it all.
Sally: So although genetics might not explain all of why someone develops type 2 diabetes, it's certainly an important contributing factor. But don't be fooled into thinking that this means there's only one or two genes that control your chance of getting diabetes.
Inês: We tend to explain genetics from the perspective of genes, but actually, what we are looking at when we are looking at the risk of developing a disease versus not developing it, it's more about DNA variants.
Inês: So if you think about your whole genome as this book that has letters. It's actually a very boring book because we write it just with four letters instead of writing it with a whole alphabet.
Inês: And what we have found out over the years is that in some positions in the genome, let's call it some pages, sometimes just changing one of those letters can change very slightly your risk of developing type 2 diabetes.
Inês: But in the case of type 2 diabetes, you're talking about maybe thousands of those small changes in these huge encyclopaedia that is your genome that all contribute, but very, very small, very small changes in your risk profile and all together they can increase or they can decrease your risk of developing diabetes.
Sally: You inherit most of these DNA variants from your mum and dad, and a handful of them are unique to you; typos that were written into your genome when you were conceived. These small changes can impact a wide range of processes in the body, some related to insulin, some not. We know for instance that type 2 diabetes occurs when your cells stop responding to insulin, so it's not surprising that some of these genetic variations also affect how well your body is able to detect this hormone in the first place.
Sally: But not all of those thousands of genetic alterations are to do with insulin sensing - that would make Inês's job far too easy! These variations can crop up in a huge number of different processes around the body, from controlling how much insulin your beta cells produce, to seemingly unrelated processes like how much of an appetite you have.
Inês: Then you're going to have other people who have DNA variants, where actually what they have is a very strong risk of becoming obese despite having maybe a normal diet with sometimes, okay, they have a few burgers, but nothing excessive. And they still have this huge susceptibility to just become obese and accumulate weight, right? So there are different, we call it, disease trajectories where you can end up at the same endpoint, which is to have diabetes, but the path you take to develop diabetes can be very different.
Sally: There are many diseases where multiple genetic factors are involved, such as heart diseases and some cancers. And all of these bring up the same question: how can we account for all these minute variations in a way that is manageable and helpful for doctors and patients?
Sally: Rather than having to grapple with hundreds or even thousands of these small changes, scientists have come up with a way of combining them all into a single number for each person. This is called a "polygenic risk score".
Inês: Polygenic risk score is taking those DNA variants , so for all of them, we can calculate what's the small proportion of increased risk you have from having that DNA variant.
Inês: So you use information from, sometimes it's 10, sometimes it's hundreds, other times it's thousands of DNA positions in the genome, and you try to use that information to position people from the very low risk up to the very high risk of, in this case, developing type 2 diabetes but you could think about it for developing certain types of cancer, cardiovascular disease, so on and so forth.
Sally: So in principle, we could sequence your whole genome, look at all of your variants, and calculate your polygenic risk score for type 2 diabetes. But what about in practice? It seems some direct-to-consumer genetic testing companies are already offering this service; is this something they can do?
Inês: They may tell you they can do that. I strongly suspect they cannot. And there are multiple reasons for that.
Inês: So one, the vast majority of those services, they're not actually sequencing or looking at your whole genome, they're looking at the DNA variants of a sizable but still small proportion of the genome. And then they infer, so they guess with a statistical method, but it's still a guess, what are the other DNA variants you have in the rest of your genome.
Inês: The other point that is very important to acknowledge is that, to be fair, I don't think we still understand what are all the DNA variants that contribute to type 2 diabetes.
Inês: So how can you put a figure and tell someone, "Oh, you have a 25% chance of developing diabetes in your life," if you still don't understand all the parts of the puzzle.
Inês: Currently the clinical utility of polygenic risk scores, I think it's still very far from a reality. And for someone to not even sequence their full genome, to just sequence a very small proportion of it and then come up with a big claim that they have a very high risk of this or that; it's debatable at best.
Sally: Right now, we simply don't know enough about these DNA variants to make accurate and useful risk predictions just based on someone's genome.
Sally: But there is another reason why polygenic risk scores for type 2 diabetes - and many other diseases - are still way off the mark. And it goes to a core issue in scientific research as a whole:
Inês: Something that unfortunately I think people outside the genetics world might not grasp very well, is that there's still a very poor representation of non-white populations within genetic studies.
Inês: So one major issue right now with polygenic risk scores is that we don't really understand how well they can be transposed from white populations to the other populations in the globe.
Inês: And there's actually very interesting work being done. Shivani Misra at Imperial, she's actually trying to tackle these and to do tailored studies to understand the genetic risk of South Asians.
Shivani: Hi, my name's Shivani Misra and I'm a consultant in metabolic medicine and a diabetes researcher at Imperial College in London.
Sally: So far, we've been finding out how our genes influence our chances of developing diabetes.
Sally: But of course, your genetic make-up is a reflection of your ancestry; who you're related to and who you are descended from, and that ancestry is in part reflected in your ethnicity.
Sally: Now before we go any further, let's be very clear: you can't determine someone's ethnicity just by looking at their genome. Ethnicity is a much broader concept. It's a social identity, not a genetic identity, and while it does take into account shared ancestry, it also encompasses societal factors like religion, language and culture.
Sally: That said, people from the same ethnic group are more likely to share certain genetic variations. And the risk of developing certain diseases, including diabetes, varies between ethnic groups.
Shivani: We know that certain ethnic groups, so for example, South Asian people originating from the Indian subcontinent, but also African Caribbean people and even East Asian people are far more likely to develop type 2 diabetes than the white European population.
Shivani: South Asian and African Caribbean people have at least double the risk of developing type 2 diabetes, and in certain subgroups, so if you look for example within the South Asian ethnicity, Bangladeshi people in particular have a very high risk with some studies suggesting up to six times the risk of type 2 diabetes.
Sally: In her role as a clinician, Shivani sees patients of all ethnicities and witnesses first hand just how much the disease can vary across the population.
Shivani: When I was a registrar just practising in London, this is what I found so interesting; how can people all be labelled with type 2 diabetes and be presenting completely differently?
Shivani: So to give you a flavour, we know that type 2 diabetes tends to occur at younger age in Asian, both South and East Asian ethnicity, and also at a leaner body mass index in those ethnic groups.
Shivani: And so actually when you see these people in the clinic, they may not be in an obese weight category and sometimes not even in an overweight category.
Shivani: And that really turns the paradigm of type 2 diabetes on its head because what we're all taught when we're at medical school or doing our degrees, is that type 2 diabetes is driven by insulin resistance, and insulin resistance is associated with obesity. But then you have relatively lean people developing type 2 diabetes, and so we know that it cannot just be insulin resistance. There must also be something else going on.
Sally: So someone from a South or East Asian ethnic group with a lower BMI, who has a healthy weight, may nevertheless have the same risk of developing type 2 diabetes as someone with a higher BMI but has white European background.
Sally: Are there any other differences in what diabetes looks like between these ethnic groups?
Shivani: The other thing that manifests is earlier age of onset. So in white Europeans, the average age of developing type 2 is around 60 to 65, whereas Asian people are around 55.
Shivani: But separate to that is this group of individuals who develop type 2 diabetes much earlier in life, let's say under the age of 40. And that group is disproportionately overrepresented in Asian, Black and mixed ethnic groups in the UK and also globally.
Sally: Clearly, ethnicity does affect your chances of developing type 2 diabetes, both at what age you're likely to get it and what weight. But why is that the case? Is it all down to underlying biological differences, such as specific DNA variants being more common in certain ethnic groups? Or is there more to the story than just genetics?
Sally: As I've already mentioned, ethnicity isn't just your genes, it's also defined by social and cultural factors. This includes diet and lifestyle habits, both of which play a part in your risk of developing type 2 diabetes.
Shivani: So you know, we cannot ignore sociocultural contributors. So we know that the Asian ethnicity, for example, is more sedentary than other ethnic groups. And we know that there's huge variation in the carbohydrate content of different ethnic group diets and also within ethnic group diets.
Sally: Plus, in the UK where Shivani's research is based, people from ethnic minorities are more likely to live in poverty and have limited access to healthcare.
Shivani: Type 2 diabetes occurs more in people who are socioeconomically deprived. We're in a massive period of austerity at the moment where people are queuing up for food banks or they're working all hours of the day, zero contract hour jobs and coming home late. You just want to get food on the plate. You're not thinking about what is healthy, what's gonna lower my risk of type 2 diabetes.
Sally: So are the differences we see in diabetes between ethnic groups more because of genetic differences or social differences?
Shivani: It's always quite difficult to say that it's more one thing than the other thing, because in reality in science, it's always a combination of lots of things. And I think genetics has a much bigger contribution to the development of type 2 diabetes than we realise.
Sally: If genetics plays such an important role, why do so many more people have diabetes today compared to a hundred years ago? I mean sure, the human genome continues to change with every passing generation. But evolution would need several million years to make this big of a difference, not a hundred years.
Sally: So if our genetics are the same now as they were back then, wouldn't that suggest that it's the major lifestyle changes we've seen over the last hundred years that are to blame? Well yes...but also, no.
Shivani: If we have a spectrum of genetic risk, that increases your risk of developing type 2 diabetes, then a hundred years ago when nutrition was sparse and everybody was doing a lot of physical labour there was no environmental process that was unmasking this genetic risk. And then if you fast-forward 100-150 years where food is in surplus with energy dense foods, the level of sedentary behaviour is through the roof, then suddenly you start to unmask the people who are at higher genetic risk. So there is a lifestyle issue for sure, but it is unmasking an intrinsically higher genetic risk.
Sally: In other words, those genetic variations were already in our genomes a hundred years ago, but they didn't make a big difference to your risk of developing diabetes until the environment changed.
Sally: You can think of it as a loaded gun:
Shivani: Someone's genetic makeup is loading the gun, but it's the environmental factors that lead to the trigger being pulled. And when the trigger is pulled, that manifests as type 2 diabetes. And so using that analogy, it's likely that people from certain backgrounds are more likely to have the gun loaded and they need less of an environmental trigger to shoot that gun.
Sally: If the same environmental trigger might cause one person's loaded gun to go off but not another person's, what does that mean for how we help someone keep their diabetes under control?
Shivani: It's very easy to just bucket everyone in the same bucket and say, "You know, well you need to lose weight."
Shivani: But that is not what we see in the clinic. We see a complete spread of BMIs. We see a complete spread of physical activity, complete spread of diet, and this really gives birth to the concept of precision medicine, which a lot of my research focuses on, which is with people labelled with the same disease, how can we be more precise in the treatment that we give them.
Sally: It's clear from talking to Shivani that both our genes and our environment play a role in our risk of getting type 2 diabetes. You may be thinking, "Well, I can't control my genetics, but at least I can control my environment."
Sally: We know that a healthy diet and regular exercise can reverse diabetes or lower your risk of developing the condition. But how easily a person can control their environment for their health isn’t the same for everyone.
Sally: Depending on who you are there are environmental factors that might be incredibly difficult to control. What types of food are both affordable and available at your local supermarket. How much time you have to prepare your own meals while holding down multiple jobs. The amount of sleep you can get while caring for small children.
Sally: On top of all of this, there are some environmental factors that are simply impossible to control. And that's because they happened before you were even born.
Sally: As a foetus, you were still being subjected to the influences of an environment, only in this case, the environment was your mother's womb. It turns out, your mother's blood sugar levels in the nine or so months before you were born can affect your chances of getting type 2 diabetes long after birth.
Sally: For some, pregnancy itself can cause the mother to develop a type of diabetes called gestational diabetes
Lorna: Gestational diabetes itself actually occurs in roughly one in 20 pregnancies, so around 4- 5% of pregnancies.
Sally: That's Dr Lorna Smith, a diabetes researcher at King's College London.
Sally: Now pregnancy is a natural process we, and many other animals, have been adapting to for hundreds of millions of years. It doesn't make sense for evolution to make us bad at having kids and passing on our genes. So why would being pregnant make you diabetic?
Lorna: Being pregnant doesn't make you diabetic. But insulin resistance, which is a key aspect that's needed to develop diabetes, is something that actually just occurs in all pregnancies including healthy pregnancies. You'll see a reduction in the mother's sensitivity to insulin by about 45 to 70%, compared to normal. And this is occurring mid to late pregnancy, so not in the first trimester.
Lorna: And it's actually a really important mechanism to help to divert nutrients from the mother's tissues and the mother's organs to the growing foetus, because as the mother, you want to allow your foetus to absorb some of that increase in blood glucose that we get after we eat dinner. And so the best way to do that is to become slightly resistant to insulin so that the glucose cannot be absorbed by the body. And instead it sticks around in the blood a bit longer and gives the time for the foetus to absorb and build up stores of glycogen and fat itself.
Sally: The body taking longer to lower blood sugar levels after a meal is actually a good thing for the foetus.
Sally: But what about the mother? For the foetus to successfully develop, presumably the mother needs to stay healthy too.
Lorna: Yes it's also really important that the mother is still able to maintain normal blood glucose levels most of the time. And to do this in most pregnant women, you'll actually see insulin secretion double by the third trimester to help combat that increased resistance to insulin.
Sally: It's a balancing act. On the one hand, the body will allow high levels of sugar in the blood after a meal in order to feed the developing foetus. To compensate, the body will also produce more insulin so that these high sugar levels don't stick around for too long. It's a tricky compromise to reach, and sometimes the body doesn't get it quite right.
Lorna: So in people with gestational diabetes for whatever reason, that mechanism, that adaptation fails to occur either at all or sufficiently.
Sally: And gestational diabetes can lead to serious complications for the mother.
Lorna: So some of the most important complications that you can get from gestational diabetes is that the baby can grow larger than normal and this can create difficulty in labour.
Lorna: You might have a premature birth and the mother herself can get something called pre-eclampsia, which is a very dangerous condition in women.
Sally: Mothers who have gestational diabetes are more likely to develop type 2 diabetes in the 5-10 years after having their baby, and it also impacts the baby well beyond pregnancy too!
Lorna: There's around an eight times higher risk of developing type 2 diabetes in the children of mothers who had gestational diabetes compared to the background population.
Lorna: And we also know from a study of children whose mothers had diabetes during pregnancy, 20% of adolescents had impaired glucose tolerance, if not overt diabetes.
Lorna: That just goes to show how massive an effect that environment in the womb is.
Sally: So you might have eight times the risk of developing type 2 diabetes just because your mother had gestational diabetes when she was pregnant with you, all because of changes in your environment before you were even born. Talk about it being out of your control.
Sally: But hang on a minute: the pregnancy environment isn't the only thing that is shared between the mother and the foetus. They also share genes; half of all your genes come from your mum, the other half from your dad. And we already know certain genetic factors increase your risk of type 2 diabetes.
Sally: So how do we know that this difference is to do with the maternal environment, and not just caused by genetic variations you inherited from your mother? Well, if it was just genetics, you'd expect your dad's genes to play just as important a role as your mum's genes, but in fact...
Lorna: We found that about twice as many people with type 2 diabetes had a mother that had a history of type 2 diabetes versus those that had a father with a history of type 2 diabetes.
Lorna: So that suggests that it's not just going to be genetic factors at play here but potentially also the maternal environment during pregnancy as well.
Sally: Clearly, the amount of blood sugar you're exposed to in the womb makes a big difference not just during the pregnancy but also in later life.
Sally: In the case of gestational diabetes, the foetus is exposed to blood sugar levels that are too high. What happens if it is exposed to blood sugar levels that are too low instead?
Lorna: There are multiple occurrences throughout history that scientists have been able to research into periods of severe famine. And they've looked at the pregnant mothers during these periods of time. And what they found is repeatedly that the children have higher rates of type 2 diabetes.
Lorna: One key example of this is the Dutch Hunger Winter, which was a period of a very rapid onset of famine due to a Nazi blockade at the end of the Second World War where all the citizens of the Netherlands were struggling to get enough food to eat.
Lorna: There's a lot of incidences of this happening throughout history. So we see it during famInês in the Ukraine, in Austria, in Nigeria. It's almost like if there is a deficit of food available, the body could be programming itself to maximise the amount of resources it can take from any food that it gets. So it increases the efficiency of that person's ability to store fat, to store glycogen, to store energy.
Lorna: Low birth weight and high birth weight, due to either overnutrition or undernutrition during pregnancy have both been associated with obesity and type 2 diabetes.
Sally: So is my diabetes my fault? Well, perhaps we shouldn't be asking that question at all.
Sally: Clearly, lifestyle is not the only thing affecting your chance of developing this condition. Your genetics play a role, your ethnicity plays a role, what happens in the womb plays a role...
Sally: Of course, we can all benefit from having a healthier lifestyle, and that does reduce our risk of developing type 2 diabetes.
Inês: All of us, regardless of our polygenic risk score, we should aim to have an okay lifestyle.
Lorna: You can do things now that might change that potential future.
Sally: But we should also be aware that some people might have conventionally healthy lifestyles and still develop type 2 diabetes, partly due to factors outside their control.
Lorna: You know, a lot of it is determined before you are even born, so you've got the genetics, which is determined from the moment of conception, and then you've got what we call foetal programming, and all that stuff is happening before you are born. It's all happening in the womb and it's not really in your control at all.
Sally: For some people, being - quote unquote - "healthy" is just biologically harder to achieve.
Inês: Our genes even change our preference for sweet versus salty. I mean, how crazy is that? So when we say something is easy, I would really put it with a pinch of salt, if I may. Because for some people, yes, it's going to be easy to change their diet and to, for example, exercise more. But for others, their brains are just, we think of it as wired in a different way, where their brains are just not able to cope with that in the same way as other people are.
Sally: And for some people, the option of making certain food choices or changing their lifestyle simply isn't there in the first place.
Shivani: If you are socioeconomically deprived, these sort of eating behaviours or lifestyle behaviours are the kind of default.
Sally: So let's end the blame game. Not only does it not reflect the science and what we know about type 2 diabetes, it's also damaging and unhelpful for people who are just trying to do the best with what they've got.
Shivani: Medical professionals, we never blame anyone, but society I think and the media, for example, do blame people. And I think that's really, really negative. And as someone who looks after a lot of people who are obese, overweight, lean, and they've all got type 2, they're all trying to do things in their own way, and they're trying to make inroads into their management. And we are here to help them.
Sally: That's all for now. Thank you to all our guests; Dr Inês Cebola, Dr Shivani Misra and Dr Lorna Smith
Sally: Next time, we'll be asking "Do I have a thyroid problem?" Does Dr Google say you have an underactive thyroid?
Peter: I feel tired, sluggish, and I've gained weight. Lots of people in the last two, three years have had an absolutely miserable time. And it does lead to lots of thyroid function testing.
Sally: Should you trust the thyroid tests you buy off the Internet?
Annice: They may start you on treatment that you don't need because those thyroid function tests were not abnormal because of a thyroid problem. They were abnormal because of other things going on.
Sally: And what happens if your thyroid goes into overdrive?
Kristien: Often they come in and say, I'm eating like a horse and I’m losing weight, and I don't know why that is. Essentially what you get is a speeding up of virtually every physiological system in your body.
Sally: Hormones: The Inside Story is a podcast from the Society for Endocrinology. Explore more about the world of hormones at yourhormones.info and follow them on twitter @your_hormones
Sally: The show is a First Create the Media production. It was researched, written and produced by me, Sally Le Page and Emma Werner. Our executive producer is Kat Arney. Thank you for listening and we'll see you again soon.
