Europe's elite prepare to understand diabetes

A collaborative project bringing together Europe’s leading researchers on Type 1 diabetes aims to understand how the chronic condition develops in young children. Ezio Bonifacio, Professor for preclinical approaches to stem cell therapy and diabetes at Dresden Technical University, explains how DIAPREPP is battling a lifelong disease that has no cure.

Most people have heard of diabetes and understand that it has something to do with a deficiency in insulin within the body. The most common form is Type 2 diabetes, where cells produce insulin but fail to use it properly. But just as significant for the future health of our population is Type 1 diabetes – a condition that often sows its seeds within two years of birth and means a lifetime of injecting with insulin just to stay alive.

Because with Type 1 diabetes, the body’s insulin production is dangerously low in the first place, before it even starts to use it properly. In order to survive, the body then feeds off its own fat reserves. The result is a high blood sugar level, dehydration, dangerously low energy levels, and the ever-present risk of a diabetic coma. To survive this, a sufferer of type 1 diabetes must inject insulin several times a day. Alarming is that the number of Type 1 sufferers is steadily increasing across Europe, particularly in the childhood population.

DIAPREPP (Diabetes type 1 Prediction Early Pathogenesis and Prevention) is a network of 13 partners (11 research groups and two SMEs) across the EU – about 100 researchers in total. The project began in March 2008, completing in summer this year. Crucially, the network draws on special resources from the three major IDDM studies in Europe – in Germany (Munich) Sweden (Malmö) and Finland (Turku). “These are studies that began in the 1980s and 1990s,” explains Professor Bonifacio, “so we are harnessing three decades of knowledge, resources and research techniques.”

Though insulin injections have been available since 1921, it was more than 50 years later that we had an idea of the cause of insulin deficiency in the body. “Insulin is naturally created by beta cells in the pancreas,” explains Professor Bonifacio. “In type 1 diabetes patients, the body’s immune system which normally has sentinels that prevent it from turning against itself, creates cells and antibodies that attack its own insulin-producing beta cells – a process known as autoimmunity. Obviously this is a counter-productive thing for the body to do, and we don’t know why it does it – is it a mutation of the immune system or has it been ‘tricked’ into doing it by a foreign virus, for example? That’s part of what this project hopes to find out.”

Whatever the cause, it appears that susceptibility to type 1 diabetes is genetic. “That doesn’t mean that you have to have a member in your family with type 1 diabetes to get the disease, although it certainly increases your risk about 10 fold” says Professor Bonifacio. “That inheritance means you have a set of genes that increase the chances that you will get type 1 diabetes. Only some people with these genes will develop disease and why some do and some don’t is what we need to find out.”

Since autoimmunity is the condition that enables type 1 diabetes to develop, the research teams have been looking for these early signs in children as young as one or two years old. “We’re looking for antibodies in their blood that are signs that the immune system is attacking beta cells in the pancreas,” says Professor Bonifacio. “That’s an early sign that the child will go on to develop type 1 diabetes at some stage. But it’s quite possible that the body has been establishing the complex pattern of genetic signals that create these rogue antibodies, even before we see them. So the body could be determining its fate even before the age of one.”

Just when a person will develop full type 1 diabetes from this early stage, is still unclear. “It’s very hard to predict,” says Professor Bonifacio. “It depends on the individual’s situation. It could be months, years or even decades but it will happen sometime. Finding out what makes a child develop diabetes quickly and another be spared for more than a decade is something else we’re looking at in the project.”

With funding for the project due to draw to a close in the summer, what successes has Professor Bonifacio seen over the last three years? “Firstly, we understand the autoimmune response in children better. Our partners in Germany, France and Sweden have learnt that different children make different antibodies and we have learnt much more about how to identify the immune T cells that actually kill the beta cells. Combining these two findings will help us predict how quickly a child will develop type 1 diabetes and hopefully how to see if we have stopped the autoimmunity in some children. And our partners in the UK are using some of this knowledge to develop commercial tests for type 1 diabetes prediction.”

“Second, our partners in Finland have made progress in the area of metabalomics – looking for relevant profiles or patterns in people’s metabolism, by comparing one person’s with another. This has helped us identify the signals for autoimmunity before the antibodies are even made. They also plan to develop this into a commercial test.

‘We’re also gaining knowledge of which viruses may trick the immune system into attacking its own cells. By infecting healthy beta cells in a pancreas with a virus we’ve been able to observe the changes – for example, does this kill the cells or mutate them in some way?

“And we’ve also progressed by simply gaining access to more pancreases, to study. Obviously you can’t take away a living patient’s pancreas and go and study it, so we only have those of deceased patients which makes it hard to study early processes. Through DIAPREPP, partners in Sweden have set up a programme of screening organ donors for the antibodies in type 1 diabetes. These donors are likely to be on their way to diabetes and therefore it is probably a good idea not to use their pancreas for transplant.

That’s also good for us as we can look for viruses inside these pancreases and also learn what changes are going on in the beta cell at an early stage of the disease. This has been a great achievement and we are happy that this should be continued beyond DIAPREPP’s existence through the Npod initiative (www.jdrfnpod.org).”

Professor Bonifacio hopes the significant progress that DIAPREPP has made will encourage an extension of the project. “It would be good to keep it going,’ he agrees. “With networking of this kind, you’re 18 months into the project before that collaborative process is working smoothly so that’s half the time gone already. I hope that the momentum we now have will continue for some time.”

With the incidence of Type 1 diabetes steadily increasing across Europe, finding a cure is becoming increasingly important. “Part of DIAPREPP’s remit is to raise awareness of just how serious Type I diabetes is,” says Professor Bonifacio.

“We’ve got this life-threatening, incurable disease that starts in childhood and leaves people with the unpleasant and inconvenient necessity of injecting themselves for the rest of their lives knowing full well that they are likely to get one or more of the many serious complications of diabetes at some stage. It often wrongly gets lumped in with other types of diabetes and therefore unjustly suffers from the stigma of obesity, poor diet and so on, also when it comes to funding. With the kind of research that will find causes and cure, we don’t just need funding, but long-term continuity of funding.”

Despite the progress DIAPREPP has made, Professor Bonifacio says further funding would work towards tackling the many unanswered questions that remain. “We still don’t know why the body acts in this way,” he says.

And we don’t know why the number of children getting type 1 diabetes is increasing – if it was purely for genetic reasons, that wouldn’t be happening. And why does Finland have the highest incidence of Type 1 in Europe while its neighbours, with genetically similar inhabitants, enjoy a far lower level?

Could it be that there is something in our environment today – or something missing from that environment – that is making us more susceptible? I hope research projects like DIAPREPP can continue to find the answers.”

Click here to access the project website.

Published: Friday, 7th October 2011