Late one night in 1984, Frances Ashcroft found a key link between the blood sugar level in your body and insulin secretion. That discovery helped transform the lives of those with a rare inherited form of diabetes. The Oxford-based Royal Society Research Professor is in New Zealand this month, speaking about electricity in our cells, the spark of life, which governs everything from hearing to the beating of the heart. She tells us here about the path from that eureka moment to a new therapy for people with neonatal diabetes, and challenges still to come.
What exactly did you find?
Insulin is the only hormone that can lower the blood glucose and if you don’t have enough you get diabetes. I was interested in understanding how a rise in blood sugar results in insulin release from beta-cells of the pancreas. Previous work suggested an ion channel might be involved. These tiny pores sit in the membrane of all of our cells and allow ions (salts like sodium and potassium) to flow through them, producing an electrical current. I found that glucose closed a specific ion channel, and this led to insulin release. I used a method recently invented by two German scientists (which won them the Nobel Prize) to measure the very tiny electrical current that flows through the channel when it is open.
What difference did your discovery make to patients’ lives?
Some people have a mutation in the gene that codes for the channel, which impairs the ability of glucose to close it – so no insulin is released. This means they are born with diabetes – their disease is known as neonatal diabetes and it is extremely rare. Originally it was thought that they had type 1 diabetes, so they were treated with insulin injections. However, our work with Professor Hattersley in Exeter showed they had a very different disease. Furthermore, a class of drugs known as sulphonylureas could close the open channels and so stimulate insulin release. More than 90 per cent of patients with neonatal diabetes have now transferred to tablet therapy and it has markedly improved their clinical condition and quality of life. However, it took over twenty years to go from showing glucose closed the channel to a new therapy for people with neonatal diabetes.
Why did it take so long?
It’s actually quite a short time! Most people are not fortunate enough to see their work translated into the clinic in their own lifetime. And the journey to get there involved many different labs throughout the world. Newton once said ‘If I have seen further it is because I have stood on the shoulder of giants.’ Today, we not only stand on their shoulders, we are lucky enough to walk side by side with them – present day science is a massive collaborative effort.
Back in 1984 we knew we needed to look for mutations in the DNA for people with diabetes. But to do so we first had to identify the DNA sequence that codes for the channel, and that took a long time. When we did so, we found no mutations in people with type 2 diabetes. We realised that we really should be looking at people who were born with diabetes but at that time we were told such people did not exist. But in fact they do exist – they are just very rare. It was Professor Hattersley who collected their DNA and discovered the first mutations. He asked us to collaborate and we were able to show the mutations prevented the channel from working properly. It was then obvious that a drug that closed the open channels might stimulate insulin secretion and provide a new therapy. Happily such a drug had been used to treat type 2 diabetes for over 50 years and could immediately be tested in patients with neonatal diabetes. So things then happened very quickly. It would have been a different story if we had had to find a new drug.
Do many drugs target ion channels?
Yes, lots of them do. They are good targets because they sit on the surface of the cell and are easily accessible from the bloodstream. The local anaesthetic you have when you go to the dentist works by blocking sodium channels in your pain nerve fibres and prevents them sending signals to the brain. Many poisons also work on ion channels. I’ll tell some of their fascinating stories in my lecture.
We are still trying to understand precisely how the channel works. We’d also like to know why some of the more severe mutations cause developmental problems as well as neonatal diabetes and why the developmental problems don’t respond as well to drug therapy. We’d also like to know what causes type 2 diabetes, which has reached epidemic levels worldwide. But that’s a far more difficult problem!
These interviews are supported by the Royal Society of New Zealand, which promotes, invests in and celebrates excellence in people and ideas, for the benefit of all New Zealanders.