Nova: Imagine a hormone that lives in your gut, quietly sending signals to your brain that you've had enough to eat, nudging your pancreas to release insulin, and even talking to your immune system. Now imagine that this hormone was hiding in plain sight for millions of years, and it took a Danish physiologist named Jens Juul Holst and a global network of scientists over three decades to unlock its secrets. Welcome to Aibrary. I'm Nova.

Nova: : And I'm your co-host. So this hormone you're describing, this is GLP-1, right? The thing behind Ozempic, Wegovy, all those drugs that are suddenly everywhere?

Nova: Exactly. And today we're diving into a remarkable book called The Story of GLP-1: A Historical Journey in the Treatment of Diabetes and Obesity, written by Professor Jens Juul Holst himself, alongside co-authors Sten Madsbad, Jens Meldgaard Bruun, and Mads Krogsgaard Thomsen. Published by Elsevier, this book is essentially the definitive insider account of one of the most consequential medical discoveries of our time.

Nova: : What makes this book different from just reading news articles about weight-loss drugs?

Nova: Because Holst was there. He co-discovered GLP-1 in the 1980s. He has written roughly 900 scientific articles on this hormone. He's won the Banting Medal, the Gairdner Award, the Tang Prize, the Princess of Asturias Award, and the 2025 Breakthrough Prize in Life Sciences. This isn't a journalist reconstructing history. This is the scientist who lived it, telling us exactly how a gut hormone went from a curiosity in a Copenhagen laboratory to a drug class that's reshaping global health.

Nova: : Alright, I'm sold. Let's get into it. Where does this story actually begin?

Nova: It begins, surprisingly, not with GLP-1 at all, but with a much older idea called the incretin effect. And that's where chapter one of the book takes us.

Nova: So picture this. It's the early 1900s. Two physiologists named Bayliss and Starling have just discovered the first hormone, secretin, and they're starting to realize the gut is not just a passive digestive tube. It's an endocrine organ. Then, in the 1960s, researchers notice something strange. If you give someone glucose through an IV, their insulin goes up a certain amount. But if you give them the exact same amount of glucose by mouth, their insulin spikes much higher. Same blood sugar level, completely different insulin response.

Nova: : Wait, that is weird. Why would the route of glucose delivery matter?

Nova: That's exactly the question that launched a thousand experiments. The phenomenon was named the incretin effect. The idea was that the gut must be releasing some hormone, or hormones, that tell the pancreas to amp up insulin production when food is coming. And by the 1970s, the first incretin hormone was discovered: GIP, glucose-dependent insulinotropic polypeptide, isolated by John Brown.

Nova: : So GIP was the first incretin. Where does GLP-1 come in?

Nova: This is where the story gets really interesting. In the early 1980s, recombinant DNA technology was brand new. Joel Habener's lab at Massachusetts General Hospital used it to decode the gene for glucagon, a hormone made in the pancreas. And what they found was stunning. The glucagon gene didn't just code for glucagon. It also coded for two other related peptides that nobody had seen before. They named them glucagon-like peptide-1 and glucagon-like peptide-2, or GLP-1 and GLP-2.

Nova: : So GLP-1 was discovered almost by accident, hiding inside the glucagon gene?

Nova: Exactly. And here's the kicker. The amino acid sequence of GLP-1 was identical across hamsters, cows, and humans. In biology, when a sequence is perfectly conserved across species, it usually means it's doing something critically important. Nature doesn't waste energy preserving things that don't matter.

Nova: : But knowing the sequence is one thing. Figuring out what it actually does is another.

Nova: Right. And that's where Holst enters the picture. While Habener's lab was decoding the gene in Boston, Holst at the University of Copenhagen was developing a reliable radioimmunoassay for GLP-1, which let him measure it in the body. He showed that GLP-1 was secreted from the gut after eating. And then, in 1987, a flurry of papers came out. Daniel Drucker in the Habener lab showed that the truncated form, GLP-1, stimulated insulin secretion from pancreatic beta cells. Holst independently showed the same thing in the perfused pig pancreas. And by December 1987, a group in London had confirmed it worked in humans.

Nova: : So 1987 was the breakthrough year.

Nova: It was. But here's the problem they immediately faced. Native GLP-1 has a half-life of about two minutes in the bloodstream. It's rapidly chopped up by an enzyme called DPP-4. So you have this incredibly powerful hormone that can stimulate insulin, suppress glucagon, slow gastric emptying, and signal satiety to the brain, but it vanishes almost instantly. Making it into a drug seemed nearly impossible.

Nova: So now we're in the 1990s, and the challenge is clear. How do you make GLP-1 last long enough in the body to be useful as a medicine? And this is where one of the most delightful twists in the history of pharmacology enters the story. A researcher named John Eng at the VA Medical Center in the Bronx was studying the venom of the Gila monster, a slow-moving lizard native to the American Southwest.

Nova: : The Gila monster? The poisonous lizard?

Nova: The very same. Gila monsters eat only a few times a year, and Eng was curious about how their metabolism worked. He discovered that their venom contained a peptide that looked remarkably like human GLP-1, but with one crucial difference. It was resistant to DPP-4 degradation. It lasted for hours instead of minutes. He called it exendin-4.

Nova: : So a lizard's spit basically solved the half-life problem?

Nova: In a sense, yes. Exendin-4 became exenatide, marketed as Byetta, and in 2005 it became the first GLP-1 receptor agonist approved for type 2 diabetes. But the story doesn't end there, because at the same time, a young scientist at Novo Nordisk named Lotte Bjerre Knudsen was taking a completely different approach.

Nova: : What was her strategy?

Nova: Knudsen's insight was elegant. Instead of finding a GLP-1 lookalike in nature, she would engineer a human GLP-1 molecule that could bind to albumin, the most abundant protein in blood. Albumin has a half-life of several weeks. If you could attach GLP-1 to albumin, you could dramatically extend its duration of action. She achieved this by adding a fatty acid chain to the GLP-1 molecule, which would reversibly bind to albumin in the bloodstream.

Nova: : And that became liraglutide?

Nova: Exactly. Liraglutide, sold as Victoza for diabetes, was approved in 2010. But here's what Holst describes as a pivotal moment. Even with liraglutide, the weight loss was modest, maybe three to five kilograms. Not enough to change the world. Not enough to convince anyone that obesity could be treated pharmacologically.

Nova: : So what changed?

Nova: Two things. First, Novo Nordisk developed semaglutide, an even better molecule that could be given once weekly instead of daily. Second, and this is crucial, they did something brave. They did dose-escalation studies, slowly titrating patients up to higher and higher doses. And at the higher doses, something remarkable happened. Weight loss jumped from six or eight percent to fourteen, fifteen, and eventually, in the STEP trials with 2.4 milligrams of semaglutide weekly, an average of nearly eighteen percent body weight reduction.

Nova: : Eighteen percent. That's not a diet. That's approaching what you'd see with bariatric surgery.

Nova: You've hit on something Holst explores deeply in the book. He and his colleagues studied bariatric surgery and discovered that after gastric bypass, GLP-1 secretion can increase up to thirty-fold. The food rushes past the stomach directly into the lower small intestine where the L-cells that produce GLP-1 live, and they go into overdrive. The surgery works, in large part, by supercharging the body's own GLP-1 system. The drugs essentially mimic that effect pharmacologically.

Nova: One of the most striking passages in Holst's book is about the sheer resistance the scientific and medical establishment had to the idea of treating obesity with medication. He writes that nobody in the beginning believed it was possible to create an obesity treatment with this kind of drug. Nobody would pay for it. Everybody would say, oh, it's their own fault, they can just eat a little bit less.

Nova: : That framing of obesity as a moral failing rather than a biological condition, that's been around forever.

Nova: Exactly. And Holst is quite candid about this. He describes how no government would help, no reimbursement was available, and no company would dare pursue obesity as an indication, except for what he calls the stupid Novo Nordisk company, who felt it was actually possible. With the launch of Saxenda, the 3-milligram liraglutide dose for obesity in 2014, Novo Nordisk also launched a worldwide campaign lobbying for the recognition of obesity as a disease deserving pharmacological treatment.

Nova: : And Saxenda wasn't even that effective, right? You mentioned seven to eight percent weight loss?

Nova: Right. It was better than anything else available, but not transformative. The real earthquake came with the STEP trials for semaglutide 2.4 milligrams, which reported results in 2021. Suddenly you had a drug producing fifteen to eighteen percent weight loss, with cardiovascular benefits on top. That changed everything. Holst describes it as the moment the whole picture changed.

Nova: : What does Holst say about the mechanism? How does GLP-1 actually cause weight loss?

Nova: This is one of the most fascinating parts of the book. Holst explains that GLP-1 is fundamentally an ileal brake hormone. The L-cells that produce it sit in the distal small intestine. When food reaches them, which normally shouldn't happen in large quantities, they release GLP-1 as a signal saying, enough is enough, stop eating. That signal travels via the vagus nerve to the brain. GLP-1 also slows gastric emptying, so food stays in your stomach longer, and it reduces glucagon secretion from the pancreas.

Nova: : So it's not just appetite suppression. It's a whole-body stop signal.

Nova: Precisely. And Holst makes a fascinating point about the colon. There are enormous numbers of L-cells in the colon producing GLP-1, and honestly, he writes, nobody understands what they are doing there. But one hypothesis is that GLP-1, along with its sister hormone GLP-2, may be part of a gut defense and repair system, maintaining the integrity of the intestinal lining.

Nova: : So the hormone we're using for weight loss might actually have evolved primarily as a gut protection mechanism?

Nova: That's the emerging picture. And it gets even more interesting. Holst describes how GLP-1 receptors are expressed on intraepithelial lymphocytes in the gut, providing a direct link to the immune system. This may explain some of the anti-inflammatory effects now being observed with GLP-1 drugs.

Nova: Chapter nine of the book deals with GLP-1 and society, but before we get there, we need to talk about one of the most surprising chapters in the GLP-1 story: the discovery of cardiovascular benefits. Holst recounts this with the suspense of a detective novel.

Nova: : Set the scene for us.

Nova: In 2008, the FDA started requiring cardiovascular outcome trials for all new diabetes drugs. The first results came from a class of drugs called DPP-4 inhibitors, which work by preventing the breakdown of natural GLP-1. The SAVOR-TIMI trial with saxagliptin showed no cardiovascular benefit. In fact, there was a signal for increased heart failure risk. Then TECOS, the trial with sitagliptin, came out completely flat. No benefit, no harm. Then the first GLP-1 agonist trial, ELIXA with lixisenatide, also showed no cardiovascular benefit.

Nova: : So at this point, everyone assumed GLP-1 drugs didn't help the heart.

Nova: Exactly. Holst says the expectation going into the LEADER trial with liraglutide in 2015 was that nothing would happen. But the result was almost the same as with the SGLT2 inhibitors, which had just shown formidable cardiovascular benefits. There was a very significant reduction in cardiovascular events. It completely changed the game.

Nova: : What explains the difference? Why did liraglutide work when the earlier drugs didn't?

Nova: Holst is refreshingly honest about this. He says it's still quite difficult to understand. The mediation analyses didn't point to any single factor. It wasn't just the improved blood sugar. It wasn't just the weight loss. It wasn't just the lower blood pressure or improved lipids. Eventually, researchers started looking at C-reactive protein, a marker of inflammation, and things started pointing toward the immune system and anti-inflammatory actions.

Nova: : So GLP-1 drugs might be working partly as anti-inflammatory agents?

Nova: That's the emerging hypothesis. And it would explain why we're now seeing potential benefits in conditions as diverse as fatty liver disease, kidney disease, Alzheimer's, Parkinson's, and even addiction. Holst's book captures this moment of scientific excitement, where a hormone originally studied for insulin secretion turns out to have effects throughout the body that nobody predicted.

Nova: : What about the addiction angle? That's been in the news a lot.

Nova: Holst touches on this in the context of GLP-1 receptors in the brain. The receptors are expressed in areas involved in reward and craving. Patients taking these drugs for diabetes or obesity started reporting reduced desire for alcohol, reduced cravings for nicotine. Clinical trials are now underway for alcohol use disorder. As Holst notes, the story is far from over. He's written 900 articles on GLP-1 and says there's still so much to learn.

Nova: The final chapters of Holst's book tackle what he calls the uncomfortable questions raised by mass consumer use of a therapy designed for disease. And these are questions that don't have easy answers.

Nova: : Let's start with access. These drugs are expensive.

Nova: Very. And Holst doesn't shy away from this. The book critically examines the challenges of accessibility and affordability. When a drug costs over a thousand dollars a month out of pocket and potentially needs to be taken for life, who gets access? In wealthy countries, it's often those with good insurance. In lower-income countries, it's almost nobody. Meanwhile, the global prevalence of obesity and type 2 diabetes continues to rise.

Nova: : There's also the question of what happens when you stop taking the drug.

Nova: Right. The weight comes back. The appetite returns. This isn't a cure. It's a treatment that requires ongoing use. Holst frames this as a fundamental challenge. Are we prepared as societies to fund lifelong pharmacological treatment for a substantial portion of the population?

Nova: : And what about side effects? We hear about nausea, vomiting, the so-called Ozempic face.

Nova: Holst is candid about the side effect profile. Nausea and gastrointestinal distress are common, especially during dose escalation. That's why the slow up-titration was so crucial. But he also notes that the side effects are dose-dependent. The higher the dose, the more weight loss, but also the more side effects. Finding the right balance for each patient is an ongoing clinical challenge.

Nova: : Does he address the concern about muscle loss?

Nova: Yes, and this connects to one of the most active areas of current research. When people lose weight rapidly on GLP-1 drugs, some of that weight loss is lean body mass, including muscle. The next generation of drugs is being designed to preserve muscle while still reducing fat. Holst describes this as part of the natural evolution of the drug class.

Nova: : What about the cultural dimension? These drugs have changed how we talk about obesity.

Nova: This is perhaps the most profound point Holst makes. For most of medical history, he says, obesity was treated as a failure of character, a moral problem dressed in physiological language. GLP-1 drugs dismantle that framing. They demonstrate that appetite and body weight are biologically regulated in ways that willpower alone cannot override. The book argues that this is a paradigm shift not just in medicine, but in how we understand human biology and behavior.

Nova: : So the book isn't just a scientific history. It's also a social commentary.

Nova: Exactly. Holst and his co-authors are making the case that GLP-1 therapies represent one of the most significant advances in metabolic medicine since the discovery of insulin. But they're also asking us to think critically about what it means when a drug class becomes a cultural phenomenon.

Nova: So here's what I take away from The Story of GLP-1. First, this is a story about the power of basic science. GLP-1 wasn't discovered because someone was looking for a weight-loss drug. It was discovered because scientists were curious about how the glucagon gene worked. The practical applications came decades later, and they came from places nobody could have predicted, including the venom of a Gila monster.

Nova: : Second, it's a story about persistence. Holst has been working on GLP-1 for over thirty years. There were long periods when nobody believed in the therapeutic potential, when the side effects seemed insurmountable, when the weight loss seemed too modest to matter. The breakthrough came because scientists and a pharmaceutical company kept pushing.

Nova: Third, it's a story about serendipity and collaboration. The discovery involved labs in Boston, Copenhagen, London, and the Bronx. It involved molecular biologists, physiologists, chemists, and clinicians. No single person could have done this alone.

Nova: : And fourth, it's a story that's still being written. As Holst says, we're just beginning to understand the full range of GLP-1's effects on the body. The applications in cardiovascular disease, kidney disease, liver disease, neurodegenerative conditions, and addiction are still emerging.

Nova: The book leaves us with a provocative question. If a single gut hormone can have such profound effects on metabolism, appetite, inflammation, and even behavior, what else might be hiding in the complex signaling systems of the human body, waiting to be discovered?

Nova: : That's both exciting and humbling. It reminds us that even in an age of artificial intelligence and gene editing, there are fundamental things about human biology we're only beginning to understand.

Nova: The Story of GLP-1 by Jens Juul Holst and colleagues is available from Elsevier's Academic Press. It's a book that will appeal to anyone interested in the history of medicine, the science of metabolism, or the story behind one of the most transformative drug classes of our time.

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