Diabetes and Genomics by Mark McCarthy

Q: People in Britain love to draw and research their family trees. Can this help us to understand complicated diseases like diabetes?

MM: Yes, having a good family history and medical records is a very important part of what we do as doctors. In the context of diabetes it can tell us quite a lot about an individual's risk of getting diabetes in the future, tell us something about the complications they might get if they get the disease; it can tell us something about the type of diabetes they might get as well and in particular in some rarer types of diabetes, it can be very informative in terms of understanding whether they have one of these rarer or more familiar forms of diabetes or obesity for example. Having said that it doesn't tell us everything. Diabetes and obesity are diseases that involve both genes and environment and also if you think about type 2 diabetes it's a disease that comes on late in life. It's often not diagnosed very well so an absence of a family history of diabetes doesn't necessarily mean that you're immune it could just be that the diagnosis was not made in a parent before they became ill with something else.

Q: Can you tell us about the genetic basis of diabetes and obesity?

MM: Both these diseases have a very strong tendency to cluster in families and that's clearly a clue that genes are important. In fact if you do rather sophisticated measures to try and tease apart genes and environment, or nature and nurture, you'll find that a very high proportion of the risk of either of these conditions is actually in our genes. That may come as something of a surprise of course for diseases that we know are also heavily influenced by lifestyle and other exposures in the environment. I think it just goes to show that for both diabetes and obesity one's risk of disease is really a very complex mix of both nature and nurture. Over the last few years we've really been able to pin down a lot more details about the basis of these diseases. For example we know that in common forms of type 2 diabetes there are over 70 positions in the genome, in the DNA sequence, that seemed to be playing a role in risk of type 2 diabetes and the individual and we are starting to use that information to understand the disease a little better.

Q: Can this research helps us treat patients with type 2 diabetes?

MM: Yes I think in two main ways. One is that through genetics we can gain a much clearer understanding of disease; how it comes about; what the mechanisms are, that normally regulate blood glucose in the individual and what happens when those go wrong. That really provides a rational basis for thinking about new ways of treating and preventing disease. We can try and identify what the processes are that go wrong and then think about ways in which we can intervene to make them better. The second hope is that we might be able to use knowledge of an individual's genetic make-up, so-called 'personalised medicine', to understand the type of disease that particularly affects them and what medication they might particularly benefit from, in order to be able to target the available ways of treating or preventing disease to an individual in a much more effective way than at present where it's essentially trial and error.

Q: What are the most important lines of research that have developed over the past 5 or 10 years?

MM: There have been many but in my field, thinking about the genetics of these diseases what we've really been able to do over the last 5 or 10 years is instead of just focusing on one or two points in the DNA sequence to really look at the whole sequence from top to toe and chart the differences between individuals that alter their risk of diabetes and obesity. We've also been able to tie that into a much better understanding of the inner workings of some of the organs and cells that are relevant to these diseases; in the case of diabetes for example the pancreatic islet, fat, liver and muscle. I really think that over the next decade we stand poised to make major advances to bring that genetics and that biology together in a way that really charts the basis of this disease and gives us a solid platform for finding better ways of treating and preventing it.

Q: Why does your research matter? Why should we put money into it?

MM: There's no doubt that diabetes and obesity are major challenges for global healthcare. More than 1 in 10 people on the planet at the moment either has diabetes or will develop it during their lifetime. If you count up the health, social, economic costs of diabetes projected over the next 40 or 50 years you get some astronomical figures in the trillions and tens of trillions of dollars. Those are going to fall disproportionately on societies that are least able to cope. It may come as something of a surprise then that despite all of that importance we still don't understand this disease well. We are still not very good at preventing or treating it and probably genetics is one of our more important tools to be able to deliver a systematic understanding of this disease: what causes it, how does it come about, how can we intervene to prevent it and to treat it.

Q: How does your research fit into translational medicine within the department?

MM: I've talked a lot about the ways in which we are using these new tools to discover more about diabetes but that's really a prelude to being able to translate it, to find ways to mitigate the impact of these diseases and we're already working with Pharma and other partners to find ways to take these discoveries, to use them to identify new drugs, to target drugs in a more effective way. Another approach that we think has a lot of promise is to use genetics as a clue to identify biomarkers, not necessarily genetic differences but things we can measure in the blood, proteins and so on that can be measured on a simple blood test that provide markers of disease sub-type, progression and so on, that can be very clinically useful in helping to identify which individuals would benefit from which treatment. To give you an example, we used some very basic genetic discoveries to get a clue that individuals with a particular rare sub-type of diabetes called MODY might have relatively low levels of a protein circulating in the blood called C-reactive protein. We were then able to demonstrate that this was indeed the case, that our hypothesis was confirmed looking at patients with this disease and this test is now something that is going to be very useful in the clinic when we see someone with early onset diabetes to identify those who are very likely to have this sub-type to make sure they get the right tests to confirm whether they do or do not have this sub-type of diabetes and then to ensure that they are put on the right treatment which is actually a different set of treatment to what we might place someone with early onset diabetes on. So I think that's one nice example of how we can take genetic findings and move them through to translation into the clinic in a fairly short order.