"We were walking in the streets, chanting 'research for the people, not for profit'"

You originally trained as a doctor and surgeon and spent the first part of your career in the 1970s as a surgeon at Bispebjerg Hospital – so how did your research career get started?

I was absolutely fascinated and absorbed by surgery and very quickly rose within the ranks of the department, and I got to do an incredible number of operations. There's no doubt that I should be a surgeon. I stayed until 1988 in the hospital’s emergency department and witnessed everything: car crashes,  patching people up, psychiatric events, cardiac arrests, anything, everything. But we didn’t get a raise in 16 years.

I entered research in 1972 when my supervisor, Francis Zachariae, was promoted to Professor when Bispebjerg Hospital became a University Hospital. He was more interested in organizational matters, but now that he had to start a research department and was entitled to a research assistant, I got that position. And then the question was, what should I do?

I was already engaged in pancreas research at the department. They were doing mainly peptic ulcer research, and they were a leading department in that field in the country. But one of the heads of the department, Paul Martin Christiansen, had been to a conference in Aalborg, where he had met Jens Rehfeld and had heard about gut hormones and the new possibility of measuring them with new technologies. And Jens Rehfeld had a research position at the department of clinical chemistry  at Bispebjerg Hospital, so I was sent over to him to try to see if we could think of something together. And that's what we did.

You went on to discover and describe the hormone GLP-1 in 1986, which you are most well known for. That discovery really paved the way to GLP-1 as a foundation of new diabetes medications like liraglutide, since you showed that GLP-1 could stimulate insulin secretion. Was this a surprise?

Initially, nobody believed gut hormones could treat diabetes. The thinking was that diabetic patients had diseased pancreases that couldn't respond to glucose, so why would they respond to a gut peptide? GIP didn't work, and since GLP-1 was so closely related, expectations were low. What changed our perspective was discovering GLP-1's inhibition of glucagon secretion, which no other peptide did, and glucagon was increasingly recognized as a problem in diabetes. Combined with other findings like slowed gastric emptying, we finally felt it was time to test GLP-1 in diabetic patients.

When we started human studies, we quickly discovered GLP-1 had a ridiculously short half-life, just two minutes. We identified the culprit: the enzyme DPP-4. This finding opened two paths forward. First, we could make GLP-1 resistant to the enzyme by exchanging a single amino acid, though this created a new substance requiring fresh approvals. Even then, the modified version only lasted five minutes because the kidneys cleared it. That's when Novo Nordisk came in with their solution: attaching a fatty acid chain to the molecule, a technique they'd already used on insulin. This simple modification extended the half-life from two minutes to twelve hours, and that became liraglutide. The second path was inhibiting the enzyme itself, which led to the DPP-4 inhibitors that have been used by millions of patients worldwide since 2006.

You continue to study bariatric surgery in patients and  using perfusion models. Do you still see a role for bariatric surgery alongside these new medications, and how do you view the relationship between the two approaches?

Bariatric surgery remains a constant source of inspiration for us. We continue to hold it up as a benchmark, trying to understand exactly what happens physiologically so we can reproduce those effects if we fully grasp the underlying mechanisms. One of the main mechanisms is that by bypassing the stomach and getting food to the small intestine faster, you generate much higher levels of GLP-1. In a sense, surgery represents what the body can achieve naturally, and with drugs, we're trying to mimic that as effectively as possible.

I often cite a study of 200,000 people who had bariatric surgery, which found that those who had diabetes at the time of their operation lived an additional nine years longer compared to controls. The mechanisms are essentially the same as what we're targeting with the drugs. Surgery does have some problems; there are several complications to surgery and a slightly elevated suicide risk that we fortunately don't see with GLP-1 therapies. And of course, surgery is irreversible, with surgical complications and occasional fatalities, though not many. Today, everybody who is going to have bariatric surgery is receiving GLP-1  drugs first to facilitate the operations and to enhance the results.

The current therapies are incredibly effective, but up to 40% of patients discontinue them. Shouldn’t we do more about the food environment that could be a root cause of these cardiometabolic diseases?

The high discontinuation rates need some qualification, but there is a risk that some people may perceive these therapies as simply not fun. That's really the right word for it, not having fun with meals anymore. So, some patients start wondering whether it's all worth it.

As for the food environment, that's not my table, as we say. Someone else will have to take care of that. My focus is on the complications that arise from lifestyle factors, where people develop cardiovascular disease and start dying from these disturbances. The remarkable thing about these therapies is that it's now proven beyond doubt that you can actually do something about it. That's really amazing.

Were you ever tempted to move over to the private sector and continue your research closer to drug development?

In those days, I was a young socialist, and I simply wasn't interested in industry. We were walking in the streets, chanting "research for the people, not for profit". We didn't even think about patents, and the university leadership didn't require it. We were interested in papers and getting famous for our science. That was our motive. Though when we discovered GLP-1's effect on food intake, we tried to patent it together with Novo Nordisk, but unsuccessfully.

There's been a tremendous shift since the 80s and 90s, partly because commercialization is now demanded of us. But I haven't really changed my opinion. I still think scientists should stay in their laboratories doing science, while intensifying communication with people who know how to create companies.

You’ve published more than 2000 articles and made an incredible impact. What do you attribute your success to?

I think we made a lot of our discoveries because of our tenacity and detective work. We were staying on it and not giving up. And always remembering that this is about understanding metabolic disease. So having that at the back of your head at all times to find the mechanism, to find how it works. The research question was overshadowing everything else. “Here is something we don't understand. Why is that? Let's go and try to find out.” This was always the driving force.

What’s changed most about research is that it has become extremely expensive and multiomics data and I am not attracted at all. No, I still go for the old detective way of following a single path and trying to see where it takes us.

What’s also kept me going all these years has been the young people who have surrounded me. They are a great source of inspiration and joy. There are no two identical individuals.

So I have had fun for 50 years in research. And that I think is fantastic. Of course, there have been days when we did not get that grant or did not have that article accepted. But, on average, it has been successful, and I've had fun.