One key area of your research is how beta cells in the pancreas release insulin to control blood sugar levels, and what goes wrong with this mechanism in people with type 2 diabetes. What have you discovered about the role of ion channels in this process?
Many years ago, we discovered that there is an ion channel in the beta cells of the pancreas that plays an important role in regulating insulin secretion. When blood sugar levels are low, this ion channel is open, and that prevents the release of insulin. But when your blood sugar rises, more of it enters the beta cell where it is metabolised, or broken down, to generate an intracellular compound known as ATP. This binds to the channel and shuts it. For this reason the channel is known as the ATP-sensitive potassium channel, or KATP channel.
Channel closure triggers a whole chain of events that finally culminates in the release of insulin. Briefly, channel closure causes the electrical potential of the membrane to become more positive, which makes calcium channels open. Calcium ions then flood into the cell and interact with the secretory vesicles, causing them to fuse with the cell membrane and release insulin into the bloodstream.
Your research has discovered that the KATP ion channel is mutated and doesn't work properly in infants with neonatal diabetes. What are the clinical implications of this finding for patients with this disease?
This work, which was done in collaboration with Professor Andrew Hattersely, showed that mutations which prevent the channel from closing when blood sugar levels rise inhibit insulin secretion and cause diabetes very early in life, meaning within the first six months. We thought that if we had a drug that closed the channel, we might be able to use it to treat patients who had diabetes caused by mutant KATP channels.
Fortunately, just such a drug was already available. It had been used for many years to treat type 2 diabetes but it had never been used in neonatal diabetes. Even more wonderfully, it worked! So now people who have neonatal diabetes can take a drug instead of having to have insulin injections, which makes their lives a lot easier. I should make it clear that neonatal diabetes is an extremely rare inherited form of diabetes, and quite different from either type 1 or type 2 diabetes.
You started out your career studying zoology at undergraduate level and then did a PhD in the same subject, both at the University of Cambridge. Why did you make the switch to human physiology?
I started out looking at ion movements and electrical activity in stick insect muscle fibres. That was very interesting from a scientific point of view, but not so easy to explain to my mother or other people why it might be important. But in those days it was not possible to study electrical signal in small cells like beta cells. That required a specialised technique and tissue culture methods that did not become available until some years later. When these were invented, I realised it was possible to work on different cells. So I picked the beta cell because it had interesting electrical activity and a disease – diabetes - associated with it.
You're honorary visiting professor in the medical school at Exeter University, and have previously held tutor positions in medicine at Oxford. How does being involved in medicine support and enhance your lab research?
I'm not really involved in clinical medicine. I am a basic scientist and my research is driven by curiosity. I am fascinated to know how things work. But I've been extraordinarily fortunate that our findings – together with those of many colleagues around the world - have actually led to a better therapy for some patients.
If you're a scientist, you never really expect that your work is going to be translated into clinical practice. It's rather wonderful when it does. What is even more extraordinary in a way is that I have been able to meet some of the people affected. But I'd like to emphasise that this has been a huge collaborative effort, involving many people, and it has been a joy working with them.
In 2012 you were the European Laureate for the l'Oreal-UNESCO Women in Science Award, which recognises exceptional female scientists from around the world. How did you feel when you won this award?
I was delighted – and honoured – it's a truly fantastic award. And I had a wonderful unforgettable week in Paris where the ceremony was held.
Dear Prof. Ashcroft, thank you very much for this interesting interview!
Interview: Helen Jaques