9 April 2021

Danish diabetes researcher receives international top award: "There's hope to think that diabetes can be cured"


Having made several ground-breaking discoveries in his career, Jens Juul Holst from Department of Biomedical Sciences is one of the world’s leading diabetes researchers. He cements his position in the major league of science when he and two of his colleagues receive this year’s Canada Gairdner International Award.

Professor Jens Juul Holst in the lab looking at the camera
Jens Juul Holst discovered GLP-1. Photo: Simon Skipper.

More than a quarter of a million Danes suffering from type 2 diabetes depend on their daily medication to be able to lead a normal everyday life. The same is true for more than 450 million people worldwide. A Danish researcher, who has been a leading player in the international fight against diabetes, has helped develop some of the more recent drugs.

In 1986, Professor Jens Juul Holst discovered what is now one of the cornerstones of modern diabetes treatment. He identified the intestinal hormone GLP-1 (Glucagon-Like Peptide- 1), which plays a key role in drugs for treating diabetes and now also overweight, and throughout this career he has worked closely together with clinical practice on developing the drugs.

That is why he and two of his colleagues now receive the Canada Gairdner International Award, which is one of the most prestigious science awards. The award is often said to pave the way for a Nobel Prize in medicine, and around every third recipient of the award has subsequently won the Nobel Prize. The award comes with CAD 100,000.

"I am very happy to receive the award. It puts me in the company of some very talented people, and this year I will be sharing the award with two excellent researchers. Their research supports mine and vice versa, even though we have never worked together’, says Jens Juul Holst from the Department of Biomedical Sciences and the Novo Nordisk Center for Basic Metabolic Research at the University of Copenhagen.

The other two award winners are Dr Joel F. Habener from the Harvard Medical School in the US and Dr Daniel J. Drucker from the Mount Sinai Hospital in Toronto, Canada. The three researchers also received a joint award back in 2017, namely the prestigious Harrington Prize for Innovation in Medicine.

Together, the three scientists have shed light on diabetes from different perspectives. Dr Habener has focussed on genetic research, Dr Drucker on transgenic mice, whereas Jens Juul Holst has always had one leg planted firmly in clinical research.

A small, but amazing hormone

Jens Juul Holst began his career in the autumn of 1971 as a surgeon at Bispebjerg Hospital specialising in the intestinal tract. While continuing his work in the emergency room at Bispebjerg, he took up a position as associate professor at the University of Copenhagen in 1978. His focus on the intestines led to the discovery of the intestinal hormone GLP-1, which kicked off an impressive career, which currently counts around 1,900 publications and 75,000 citations in scientific journals.

‘Today, the GLP-1 hormone forms the basis of treatment for millions of people with diabetes worldwide. It is amazing to think of how the small hormone we discovered many years ago has now become one of the most widely used drugs in the world’, says Jens Juul Holst.

Patients with diabetes have elevated blood glucose levels, which can lead to many dangerous health complications. One of the reasons for this is increased amounts of fat in liver, muscles and heart which cause resistance to insulin and increases the concentration of glucagon, leading to increased glucose levels. When we eat, GLP-1 is released from the gut and at the same time stimulates the release of insulin and inhibits glucagon production, thereby lowering glucose levels in the blood.

‘When we discovered GLP-1 back in the 1980s, we also studied the way it is metabolised. But we soon found that it is broken down extremely fast and only remained in the body for a few minutes. We then came up with the idea that if we were able to increase its lifespan in the body, it would have a greater impact on the diabetes. So we began to study how GLP-1 is broken down and found that a particular enzyme, DPP4, is responsible for this process’, explains Jens Juul Holst.

The fact that DPP4 had already been discovered, though for a different purpose, lent Jens Juul Holst and his colleagues a helping hand.

’We soon launched experimental studies intended to inhibit the DPP4 enzyme. And it worked. It protected GLP-1, which then remained in the body for longer. We were able to utilise this to achieve a much greater effect on sugar metabolism than previously. It was amazing’.

’We tried everything. Nose powder, eating tablets. Everything’

In the early 1990s, Jens Juul Holst and his colleagues really began searching for an insulin drug.

‘Around 1990, we discovered that GLP-1 affects the appetite. It occurred to me that this was the most ground-breaking opportunity I would ever have. And in the following years, I decided to focus all my attention to it. Everyone worked on it. And in 1991 I received a research council professorship, which enabled me to focus on it for the next five years. At the same time, we chose to support researchers from all over the world who wanted to work on GLP-1 or DPP4 inhibitors’, Jens Juul Holst says.

The following years’ research sowed the seeds of the drugs currently used by millions of people all over the world. Together with researchers Michael Nauck in Germany and Sten Madsbad at Hvidovre Hospital, in particular, Jens Juul Holst set out to examine diabetes patients to get a complete picture of the physiology of the GLP-1 hormone.

‘We tried everything. We created a GLP-1 nose powder, GLP-1 eating tablets, all kinds of things. It was at this point that we saw the first indications that it worked extremely well in practice. Through continuous, intravenous infusions of GLP-1, we were actually able to normalise blood sugar levels. This was what we had predicted and hoped would happen, so it was amazing’, he says.

‘But because the hormone was eliminated soon after emerging in the body, we were unable to use if offhand. This led us to the realisation that DPP4 inhibitors could help us out’, he explains.

The process really picked up speed when the researchers added GLP-1 instead of insulin to the insulin pumps people were carrying around. However, they feared the effect would stop after a while.

‘The fear was that the effect of the hormone would decrease when the body received continuous amounts of it. Fortunately, that did not happen. Instead the patients lost weight, their beta-cells improved, and their blood sugar level became almost normal. We published these studies in 2003 in continuation of the studies we had launched in the early 1990s’, says Jens Juul Holst.

In 2006, the first DPP4 inhibitor, sitagliptin, entered the market, and in 2009 Novo Nordisk introduced liraglutide, which is now the most widely used GLP-1 analogue. In both cases, Jens Juul Holst’s research and knowledge have played a key role in enabling the companies to introduce the drugs in the market.

‘Liraglutide was the turning point for diabetes treatment. Today, it is being taken over by the next generation of the drug, though, called semaglutid, which my research has also helped develop. It is more potent and effective, and patients only have to take it once a week, unlike liraglutide, which has to be taken once a day’, says Jens Juul Holst.

Can diabetes be cured?

If you ask the researchers what the future of diabetes treatment will be like, the answer is undeniably linked to overweight. Because type 2 diabetes is inextricably linked with overweight, and at least 80 percent of all cases of diabetes are believed to be a result of overweight, Jens Juul Holst explains.

‘When researchers ask patients about the drugs, many say that they have experienced a loss of appetite. And that is also the point, because overweight is directly linked with diabetes. But it is a sad side effect, because it can simply make patients not want to eat. And this can severely affect their quality of life’, says Jens Juul Holst and refers to the fact that 10-20 percent of patients experience a loss of appetite.

But appetite may hold the key to the next big breakthrough in diabetes research, Jens Juul Holst explains. Over the past 15 years, he has been working on a so-called ’gastric bypass operation without surgery’.

‘Not only do people lose a lot of weight after a normal gastric bypass operation, but if they have diabetes, the condition actually disappears. This is extremely interesting. In our studies, we have found that the release of GLP-1 had increased as much as 10 to 30 times after the operation. So now we are trying to determine whether it is possible to stimulate the body’s own release of GLP-1 in order to avoid surgery’, he says.

And these findings are supported by a large number of studies showing that if patients can get rid of fat – especially the fat that affects the metabolism in the liver, muscles and heart – they can become completely or almost symptom free.

‘So it is natural to think that diabetes can be cured. Using the latest GLP-1 drugs, patients achieve a 15 to 20 percent weight loss. This is enough to trigger this apparent cure. So there is hope in the immediate future’, he says.

Researcher for life

Last year, Jens Juul Holst turned 75. At this age, many people will have long ago stopped working, but Jens Juul Holst lives and breathes for his field and refuses to stop.

‘Doing research is a lot of fun, and we are doing well. The young researchers also play a main role, and I enjoy following them. It would not be much fun to sit by myself and wonder what to add to the cup next’, he says.

‘You see, we are doing all kinds of projects here, and there are a lot of talented people working on projects that are very different from mine. I draw inspirations from them, and I love it’.

Jens Juul Holst should have received the award along with Joel F. Habener and Daniel J. Drucker at a ceremony on 7 April 2021. Instead the ceremony will take place online.