The Life Scientific: Jens Juul Holst

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Hello, Azempic, Wigovi, Manjaro. Just a few years ago most of us had never heard these names. Now they're everywhere, hailed as miracle weight loss drugs that help people shed the pounds by replicating a gut hormone called GLP1, which tells the brain that you've eaten enough and nudges the pancreas to release insulin.

One of the leading researchers behind this breakthrough is Jens Jule Holst, professor of medical physiology and biomedical sciences at the University of Copenhagen, whose work in the nineteen eighties helped discover and decode GLP one. Over the decades since then, Jens has laid the groundwork for today's wonder drugs that are changing the lives of millions worldwide by treating obesity and diabetes.

This has earned Jens a slew of high profile accolades, including the Breakthrough Prize and the Tang Prize, and he was named among Time magazine's hundred most influential people in health for twenty twenty four. But with great power come great big questions. The rise of GLP one drugs is not only reshaping medicine, but also sparking debate about how they should be used and exactly what they mean for long term healthcare and healthy societies.

So hopefully we'll get some of those questions answered today. Jens Jul Holz, welcome to the Life Scientific. Thank you very much and thank you very much for y asking me to do this. Certainly a lot of people will have heard about weight loss jabs in recent years. How exactly do they work? The interesting new thing about them is that they inhibit appetite.

So that's the principle of the slimming. And that's quite a difference to many other approaches to weight loss. And if you think about it, it is one of the key ways of regulating the problem, which is the food intake. There is and always has been a lot of stigma around obesity and and and weight loss. Have you seen that attitude play out around these new drugs? Yes, of course, uh mostly I I know of it from my my own country, from Denmark.

where people think that it is kind of cheating, you know, you're not supposed to do this. This is this is not the right way. You must suffer to lose weight. And some people, you know, object to the idea that you should lose weight at all. You should be happy with your own size and From my angle it's it's a different question. The problem is the complications of obesity. I'm a doctor.

So this is my interest here and we know that there is a large number of complications to obesity and that's what you can do something about with these new medications and I think that's fantastic. Mm. Well we're certainly going to talk about a lot of these hugely positive results, but concerns have been raised, including by you.

You said a couple of years ago that the success of GLP one drugs has brought new scientific, clinical and ethical questions that the medical community needs to navigate with care. So which questions do you think should be prioritised? So these drugs were originally meant for diabetes therapy and they're now spreading out to uh obesity therapy also. And the problem with both of them is that you have a decreased life expectancy.

And not only that, but also uh you run a risk of having complications during your lifetime and that can be very cumbersome in invalidating. And this is something that the societies should do something about. Now these new drugs have been proven To reduce the mortality and been proven to improve these complications and the morbidities that are associated with diabetes and obesity. So now we know that you can do something about it.

So that's where I think that society somehow has to take over. And somebody should think about how we spread these possibilities to to the general benefit of the population rather than to the few that can afford.

But let's talk about you, Jens. You were born in nineteen forty five in Copenhagen. Yes. Tell me about your family. So my parents were were dentists, both of them. My father was a professor uh at the dental school and I think I'm pretty sure that that has influenced uh my way, my attitudes, my choices. Another thing is that my mother didn't become dentist of her own will because uh she had planned to become a doctor. But uh it turned out that my grandfather couldn't afford

her studies, so he asked her to y find a shorter training and so she became a dentist instead, but met the professor, which was good. I mean that's that's So so so that was the atmosphere. It it was an academic atmosphere. So this this kind of lifestyle was oozing through everything, I think. And in your early years at school, I gather you had a bit of a tough time.

That was because I you know, I was good in classes. I had red hair and I was not terribly good at sports, so you know, I was the victim of Yeah, yeah, of the bullying, exactly. Uh so so that lasted for the first five years of schooling, but then I moved to uh uh you know, uh the high school system. And uh things became a lot better and and eventually I went to the real high school the three years and uh that was one of the greatest times in my life. So so things changed wonderfully.

Well, after those difficult early years things, as you say, did improve. Um you were a good student academically, but initially you wanted to focus on something other than science. You were very keen on music. Yeah, yeah, yeah. For a while in school I thought that maybe I should end up doing something with music. Today I'm quite happy that I didn't. I think that uh that would have been a tough life. Fun, but but uh

Uh so so no that that had to go away and and it was substituted with the hard work of being a medical student. But um music is still a wonderful thing for me on. I was going to ask you, you know, you still play piano? play and uh always have music in my ears when I can get away with it. So yes, music is a is a big part of my life. My wife fortunately is also uh musically gifted and is playing the clarinet so we can we can do duets. Oh very nice.

Yeah. Well Jens, as you say, you went to study medicine at the University of Copenhagen and you really threw yourself into student life. I qualified in medicine in nineteen seventy, which means that the last two years was nineteen sixty eight, sixty nine, right? Yeah. Where we had all the revolutions and and and student revolutions in all over Europe and all over the world really.

And of course I was part of that, you know. I was a young enthusiastic socialist and I was taking very much part in the in the different student activities we had and even some of the more, you know, yeah, yeah. uh w which we shouldn't talk too much about today. But it was a great time and you know, I think it cemented my attitude to health and society and things like that. Uh so I think it was very, very, very useful.

So after your studies you started working at Bisperbjerg Hospital, which then became affiliated with the University of Copenhagen. And that meant you were encouraged to do research alongside your clinical work. Yeah yeah, I think I was interested in research already, but the possibilities were improving as we were transgrading to to uh university status. And so the boss, the head of the department, became professor and he was then entitled to have a scientific assistant.

And I became his assistant, so that meant that I was even obliged to do research, I mean. Right, right. Apart from the surgery. So so that really facilitated things.

And that's when you first began studying gut hormones in earnest. Yes, I was introduced to this very new field of the gut hormone. Because my real mentor who's called uh Jens Reifeld, he had been to the United States uh to work with the hormone gastrin in Florida and came home with some hints about uh technology and and the field as a such.

And he said, Okay, let's join forces and and see what we can make out of it because then we were able to create a laboratory and that laboratory was devoted to Gott Hormon. And for this the big thing was the new technology of radioimmunoassay, which had more or less recently been discovered or developed by two Nobel laureates.

And um we adopted that technology as quickly as we could because that was necessary to study these gut hormones because they circulate in very, very low concentrations. So you must have a a a method of sufficient sensitivity, and this new method had that. There were no other methods that would be able to And at that point you were looking at a group of metabolic hormones called incratin.

Yeah, our main interest became the regulation and the gut of insulin secretion. And for me that was logical because I came from this department that had specialized in peptic ulcer disease, you know. And we had some peptic ulcer patients with too low blood glucose levels after we have been operating on them. And uh we wanted to find out why that was. We thought it would be a a a gut hormone, right? Uh so it was absolutely natural for us to find out how the gut regulated

insulin secretion and glucose levels in the body. So that became one of the key questions. We put that up as a target for us, try to find out what are the increasin hormones. Mm and and that's what actually Well you say eventually'cause this is this is like a decades worth of research to to get the answers. Ultimately you were successful in isolating and characterizing this all important GLP one hormone. Talk me through that process.

I was chasing this hormone that was responsible for the hypoglycemia in our patients. And then a new peptide came up. It came from Stockholm. It was called GIP. Peptides, I mean these are basically molecular chains of amino acids. Sh short chains and there was one coming up from Stockholm which was demonstrated to be able to stimulate insulin secretion in people. But for various reasons we could show that this was not

The substance that was responsible for our hypoglycemia patients. So there had to be another one. This was clear. And we found some cells in the gut. that were illuminating with antibodies against glucagon. And glucagon is a hormone from the pancreas that is normally irregulating blood glucose and it was ridiculous that glucagon should be found in the gut all of a sudden.

But uh we eventually isolated the peptides from those cells and found out what it was. And it was a peptide that contained glucagon in the middle. Right. So we found out that this was actually the precursor of glucagon, because we could also find it in the pancreas and all the bits and pieces there. So uh the interesting thing was of course to find out what was the in the rest of the molecule.

That was an American who found out that, a guy called Graeme Bell, who in nineteen eighty three was able to pull out a gene sequence. And we found in that DNA sequence there was coding for something that looked like glucagon. Actually there were two stretches that looked like glucagon, both of them. And they were of course designated glucagon like peptides one and glucagon like. Which is the G L P And that's the GLP one and GLP two. Yeah. So that opened the field, I must say.

And it's a lot of technical detail there, but I think it's important because as we come to talking about these weight loss drugs, they all rely on this glucagon like peptide GLP one. Yes. Now in nineteen ninety three your team provided the first clinical evidence that GLP one could help patients with diabetes. Now yeah you told us about GLP one itself, but how exactly was that translated into a treatment for diabetes? How did it work?

So first of all, um we pulled out the natural peptide from tissues and found out that it stimulated insulin secretion directly. And the question was then, is is this really interesting? And the prediction was, no, no, it's not interesting because People with type two diabetes, you know, they have uh lousy beta cells, they don't react to anything and they don't even react to glucose. And it didn't react to to this first

Incretin hormone GIP, it didn't react to those either. So the probability that this would make any change was very, very small. But again, we had put it on our pancreas and found out I mean I had a pancreas in the laboratory, you know, and living as one is isolated living w as a tool was really fun.

And it also inhibited glucagon secretion. Now there's a problem in people with diabetes that they have too much glucagon at the wrong times. And here we had something that could inhibit glucagon secretion. And this was news. Right. So so now we had two features of this hormone that could be interesting in diabetes. So I was working very closely together with Michael Nauk from Germany and um he was a working in a diabetes hospital and with the

the big increasing expert in these days, Werner Kreutzfeld, important professor from Germany. And um together we arranged to have infusions made in his diabetes hospital. Uh people came in with really bad glucose regulation. And gave them infusions of this new peptide for four hours and were able to completely normalize their blood glucose. And that was really a breakthrough. That was really a breakthrough. But as you say, this is for people with type two diabetes, not type one.

Yeah, yeah, this is true. But it didn't take long before we tried on type one also. And it actually worked to some extent, not as well as in those with type two, because it partly acts on the insulin. And since people with type one diabetes do not have insulin, that part of the activity cannot be put into practice. But but they do have the Grugacum problem and and also there are many other things that are improved with GLP one. So it actually works to some extent.

on people with type one diabetes. And it's very interesting today because the uh cardiovascular improvements that you get with GLP one and the anti obesity effect Both of those are relevant for people with type one diabetes also today. So that's why it's come back into the picture, you know, as something that really is of interest.

Right, right. Of course, as we've mentioned, all of this was the culmination of years of research and and not just a single uh eureka moment. But in the diabetes world this breakthrough was huge. Do you remember how you felt about it at the time? So this demonstration of the complete normalization of the glucose levels really meant that we convinced not only ourselves.

that this was a future therapy for diabetes but also some of the pharmaceutical industries. And that's how Novonoidisk, for instance, became interested. And of course we also demonstrated uh in in ninety six and ninety seven, eight That it also inhibited food intake in people who are

And that of course was also very, very interesting. So we started doing studies and and tried to see what happened and sure enough we could inhibit appetite and we could inhibit food intake with infusions of GLP one in people.

So things are looking very promising then. But when it came to making GLP one suitable for obesity therapy, there were some issues. Can you explain what these issues were? Can easily explain that. So what we found immediately was that if we gave them intravenous infusions into the bloodstream, that worked. But if we gave them just a single injection, it didn't work. Why not? Because the peptide was eliminated from the body immediately almost. So it has what we call a half life.

It means that h half half of what you have in the body is is eliminated within two minutes. So it disappears during very, very few minutes, it completely disappears. And you can't treat people with a peptide that is eliminated so quickly. We found the reason for it and that was an enzyme. But we also found out that if you could inhibit that enzyme, you could actually make the the hormone GLP one survive for a longer time. But that was one of the problems, the the very short survival.

Survival. And I gathered, you know, you couldn't give people a higher dose because it would lead to nausea. We tried that of course. Right. And it turned out no, no, we couldn't because the higher the doses we gave them. the more side effects there would be, there would be nausea and eventually vomiting. But we found out that you could stabilize the molecule by exchanging a really a single amino acid in the chain and that could make it resistant towards this enzyme.

But uh it will still be eliminated quickly from the kidneys. And that would be a problem. So something special had to be done to circumvent that problem. And that's what they did at Novan What is where they attached a fatty acid chain to the molecule. And what happens is that when you inject that, it will bind to one of the proteins in the plasma in the blood.

And it has a long half life of twenty days or something like that. So all of a sudden uh this peptide GLP one can now survive in the body. And it turned out that the half life of this fatty acid substituted GLP one was now twelve hours. uh rather than uh two minutes. So that was quite a different, right? So that is the new Ratwood site that was developed at the Nobu Nordis Company.

So the first version of a weight loss drug launched in the UK in twenty fifteen, longer ago than people might think. So the people at Novodor has created some dose response studies and could demonstrate that if they they were very careful with the increasing dosing in the beginning, you could actually get to higher doses, which would give a weight loss of some seven to eight percent.

And this was the procedure that eventually led to Saxenta, which was the first of these uh drugs to be approved for obesity therapy. Well as you say, you know, this eight percent is significant, but your team and indeed others around the world were working to develop more effective versions. This is how you arrived at semaglutide, uh this drug that's the basis of Azempic and Wagovie.

What happened was that several pharmaceutical companies were now interested in this and tried to um extend the half life by changing a few other details of the molecule, not very much by the way, and managed to produce a molecule that could last for a week. requiring only weekly injections. So that was of course very nice. And this was sematide. I was part of that process myself, so I really enjoyed it. It also was improved in terms of insulin secretion and food intake.

But again it was felt that perhaps with higher doses you could obtain even more. And again, you know, a very meticulous careful study was carried out and it was found that indeed you could increase the dose and it was possible now to create weight losses of up to eighteen percent. And that started the whole craze. And that wasn't the only positive outcome, was it? There was more good news from the cardiovascular trials which you have to do with with a w any new drug.

Yeah, and it turned out to reduce the risk of cardiovascular adverse events quite significantly. It was a wonderful surprise.

That's incredible. Absolutely. I want to come back to that a little later on, but in the meantime, Jens, the GLP one therapies developed by you and others translated into those medications that we're seeing today. And within a comparatively short space of time have had a remarkable impact helping people with diabetes and obesity. Have you had any feedback from people you know about how it's changed things for them?

Oh yes. I get a lot of emails from people who are thanking for and describing how this has changed their lives and how happy they are. One thing is that people are happy, another thing is that it can be documented in hard data that it really helps. There's been a lot of discussion around other possible benefits of GLP one therapy. We mentioned the surprising positive results from the cardiovascular trials earlier. What possible applications are you exploring now?

So there are a whole set of things uh some of them are related to the weight loss I guess in itself. For instance, something like sleep apnea. And there is wonderful data now that this really helps a lot. But in addition to that, we need to understand why these compounds have this effect on the cardiovascular problems. And the focus is really on inflammation and the immune system these days.

And uh there are a a lot of observations on interactions with GLP one with receptors in the immune system. And uh there is typically in obesity and diabetes what we call a low grade inflammation, systemic inflammation. And this is thought to contribute very much to the problems, the complications. So that is in the heart.

هذا هو في المنزل، هذا هو في المنزل، هذا هو في المنزل، هذا هو في المنزل، هذا هو في المنزل، وفي المنزل، وفي المنزل، So one of the theories and it's actually more than a theory these days because it's quite evident, is that one of the ways GLP ones improve all these conditions because they do, is by interfering with the inflammation.

reducing the inflammation that causes these problems in the various organs. So, you know, it's not even m miraculous any longer. It's it's a fact. There is a mechanism behind this. So that's really fantastic, I think. That's incredible. So v various positive and unexpected uh impacts.

But as with almost any new medication, there are of course also concerns. And one that's been covered quite recently in the media is possible swift weight regain after stopping treatment. What what's your reaction to that? So first of all, it was predicted and it also turns out to be true. Because what happens when you're in therapy is that you inhibit your appetite and because of that you eat less and then eventually will lose some weight.

But if you regain your appetite, then you will start eating again and you will increase in body weight. So if you stop the therapy, of course your body weight will return. But fortunately there is something you can do, engage in a change of lifestyle. And that should consist of two components. One is the change of diet. And the good news is that you can do this.

Because now, for the first time maybe in a in a very long time, you have regained your power of will here. So uh that's one important thing. The other thing is that you must exercise. You must enhance your physical activity levels.

And as you lose weight, you can do it. You can actually master some increases in in physical activity levels and and that's extremely important because then you can maintain your muscle mass. And we've shown that if you can maintain those good new habits Then you don't need the medication after the termination of, let's say, treatment for a a year or two, uh where you have reached the nice plateau of new body weight.

Mm. Well it's the it's the good habits that I think is is the important thing here, isn't it? Using these drugs as part of a properly prescribed weight loss plan with, you know, your your GP support around, as you say, diet and exercise. But that actually speaks to another concern, which is about people getting these drugs from unofficial sources without any medical advice.

Yeah, and I think that's probably a little bit of a risky business because you need that medical advice. I mean otherwise you will be in a situation where you've lost the right. your lean body mass and you come out as a weaker person uh after the weight loss uh than you were. And that is not good. So it is really the advice here that is the essential. Uh just like after bariatric surgery where you have similar weight losses.

and you must obey the same kind of precautions not to come out with a bad result afterwards. Mm-hmm. Another problem right now is cost. Uh there was a BBC investigation last year reporting that out of an estimated one and a half million people using these drugs in the UK, nine in ten are believed to pay privately. Uh and although prices vary with doses, generally you're you're looking at several hundred pounds a month.

Which is particularly tough when you consider that diabetes and obesity rates are both higher in patients from lower income backgrounds. What what could help bring down costs? There are of course many, many important aspects of this question, and I cannot help to say that uh I think that there are some societal obligations again that should be considered at some stage. But fortunately uh there are other things happening. So

The first GLP one to be approved of this has gone off patent and there's now a buyer similar available. So you can buy it and it's cheaper. Now that is the daily injection, so that's not the most super popular, but it still works. And there's no doubt that the competition because there are many, many, many

pharmaceutical companies now producing GLP one uh redated uh agents and uh there some of them will be good and and approved and all that. So there will be competition and the prices will come down. There's no doubt about that. There's another development that is really interesting and that is But it's also possible to make GLP one agonists that are small uh small molecules as we call them, small chemical entities. And um they're much easier to produce and much cheaper to produce.

They haven't really been approved yet, but we will have these I m I I don't doubt that we will have these uh small molecules now coming up and they will be cheaper and they will uh put the prices further down. But I must say in the meantime I think that the societies will need to think about how how this should be dealt with and some support, some reimbursement for health reasons I think would be reasonable. That's what I think.

Uh I I guess that's something you'd have had a pretty strong opinion about back in your socialist student days. How how do you think the young Yens would have felt about all this? Uh you know, as a young person I marched around in the streets of Copenhagen with a sign saying, Research for the people, not for the profit, research for the people, not for the profit. You know, that kind of thinking.

So it was much more fun to to make something, to b make good progress, to get some development going than to just, you know, lock yourself up and try to collect money. And I still feel that way, I must say. Mm-hmm. But I mean it is one quarter of the adult population in our societies that that will benefit from these therapies and at least one quarter. And uh we have to find out how to do this. And do you think governments are listening sufficiently to the scientists?

So they were not listening, but now they will be listening. I I I think things have to go hand in hand. You have to be able to provide sufficient medication to a a reasonable price, but then I think you can engage the the soci because they will win. They will reduce the morpharises, they will avoid some of the sick leaves, they will get the benefit eventually. Well let's hope so. Jens Jul Holst, thank you very much for sharing your life scientific. Thank you very much.

Snälla, snälla, sluta! Jag kommer inte köpa ut någonting! Det blir i alla fall inte värre så här. Ibland är det ett nej det finaste du kan ge. Under miljontals år har djur utvecklat sofistikerade parningsritualer. Fåglar dansar, vargar gular och åskar går in på Amazon för att. Date night lasagne take care. På Amazon hittar han levande ljus, lyxiga vinglas till fyrer.