Patrik Rorsman: Diabetes and Insulin Secretion

Q: How do pancreatic cells control insulin secretion?

PR: It is the beta cells which secrete insulin. The beta cells sit in tiny organs which are called the pancreatic islets. The interesting things about beta cells is that they use electrical signals to couple changes in the blood glucose concentration to variations in insulin secretion. They have an ingenious way of sensing changes in plasma glucose concentration by using a protein which can sense the metabolic state of the cells. When we have more glucose we can produce more energy within the beta cells, and these changes in the metabolic energy state are picked up by this protein which leads to the electrical signal that triggers insulin secretion.

Q: What happens to people affected with type-2 diabetes?

PR: The problem is that we do not really know what is going on in type-2 diabetes. We know the consequences; we know that these patients secrete too little insulin, and we think that there is something wrong with the way that the cells produce this electrical signal. We also think there may be something wrong with metabolism. The reason we believe this is the cast is because there are medicines which we have been using for 60 years which actually target this protein or mechanism that can sense the energy. These medicines are called sulfonylureas and many people have been using them. They bypass the effect of metabolism and act directly on the beta cells to initiate the electrical signal.

Impaired insulin secretion is one aspect of diabetes. The second aspect is that we have too much of another hormone: glucagon. Glucagon is a hormone which increases glucose levels whereas insulin, of course, should lower it. If you combine these two defects, too much glucagon and too little insulin, then you get the increased plasma glucose production which is a hallmark of type-2 diabetes.

Q: Will your research help to develop new diabetes therapies?

PR: We certainly hope so. It won't be easy but we already have access to the sulfonylurea medicines. They provide us with a proof of concept so we know it is at least theoretically possible. The problem is producing something which is better than the available drugs. For this we would need new targets or new mechanisms that we can exploit to make the beta cells release more insulin. I should perhaps add that although there is too little insulin in the blood when you have type-2 diabetes, there is still a lot of insulin within the beta cells. If we can persuade the beta cells to secrete a bit of that insulin it would be more than enough to cure diabetes.

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

PR: There are two things. Firstly, our friends the geneticists have had a breakthrough and have been able to identify some 50 new genes which lead to increased risk of developing diabetes. Although most people hadn't heard about any of these 50 genes or proteins a few years ago it is clear that they are important. The hope now is that if we can understand how these proteins increase diabetes risk, we can then identify new mechanisms which are important for controlling insulin secretion. Perhaps these new mechanisms can be used as target for new diabetes medicines.

The second major development during the last five or ten years is that for the first time we have been able to study the properties of human beta cells. In the past we have mostly been using cells from rodents, which we have discovered are quite different to human beta cells. We are different from mice and as my clinical friends often remind me, rodent diabetes is not a major clinical problem! So if we want to understand human diabetes we should work on human beta cells and that is the only way of moving forward.

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

PR: Many people have diabetes. It has been estimated that 10% of the population have the disease and half of them have not even been diagnosed yet. If we take 10% of the population of a big country like the UK that is 6 million people -the equivalent of two Birminghams. Diabetes affects society in many ways; of course it affects the lives of those affected, but it also has huge financial implications. If we can provide better diabetes medicines that can make people work better and live healthy lives for longer it would be a benefit to all tax payers and society.

Q: How does your research fit into Translation Medicine within the department?

PR: We are trying to develop new medicines but that is a long term goal and, although it won't happen tomorrow, that is certainly what we hope to accomplish. The second thing is our work on the human beta cells. They are prepared by our friends in the islet transplantation centre where they are used for curing people with type 1-diabetes. Some of these islets can't be used for transplantations, in which case we can use them for our work. Our studies can inform us and them of the factors which influence the viability or the performance of these cells. This can maybe have an effect that will lead to better beta cells becoming available for transplantation in the short term.