The Chemist Who Gave GLP-1 a Week

At the start of 1996, Nature published a short paper from Stephen Bloom's group at Hammersmith Hospital in London. The researchers had injected glucagon-like peptide-1 directly into the brains of fasted rats, and the animals, which should have been ravenous, largely stopped eating 6. Nobody recorded where Lotte Bjerre Knudsen was when she read it. The Lasker Foundation's account of her career says only that in 1996 a paper caught her attention, and names this one 1. What is documented is what she did next. She was by then at the helm of Novo Nordisk's effort to make GLP-1 into a diabetes medicine, and she began arguing that the same molecule could be an obesity medicine too.

Knudsen is the scientist most closely tied to the GLP-1 drugs that now dominate metabolic medicine. She started at Novo Nordisk while still a chemical engineering student at the Technical University of Denmark 2, and stayed for thirty-six years 8. Her decisive contribution was not a new hormone but a way of keeping an old one alive: attach a fatty acid to the human GLP-1 sequence so that it clings to albumin, the most abundant protein in blood, and travels shielded from the enzymes and the kidney filtration that otherwise clear it within minutes 13. That gave the hormone a day. Its successor, built by her colleagues on the same principle, gave it a week. In 2024 she shared the Lasker–DeBakey Clinical Medical Research Award with Joel Habener and Svetlana Mojsov, whose work in Boston had identified the active hormone in the first place 1. This is not the venom story: the route to a durable GLP-1 drug that ran through a desert lizard produced exenatide, and it is told elsewhere on this site. Knudsen's route ran the other way — back to the human sequence, and into the chemistry of fat.

A hormone with a two-minute life

By the time Knudsen reached the problem, its shape was well understood. GLP-1 is released from the gut after a meal and tells the pancreas to release insulin, but only when blood glucose is already raised — the property that made it so attractive as a treatment for diabetes. It is also destroyed almost as soon as it appears. An enzyme called dipeptidyl peptidase-4 clips the front of the molecule, and what survives is filtered out by the kidney. A hormone that lasts a couple of minutes can be infused in a clinical laboratory. It cannot be prescribed 5.

There were two broad ways out. One was to find or build a peptide the enzyme could not cut, which is the path the venom peptide exendin-4 opened. The other was to keep the human sequence, with its native fit at the human receptor, and change how it moved through the body. Novo Nordisk chose the second, and started from human GLP-1 rather than from the lizard molecule 5. The choice has a logic that is easy to miss. A sequence close to the body's own gives every modification a known baseline to be measured against, and gives the immune system less that looks foreign.

The trick borrowed from insulin

The means of changing how it moved came from inside the company. Novo Nordisk was an insulin maker, and its chemists had already done something unusual with insulin: attached a fatty-acid chain to it. Insulin detemir was the first clinically approved protein modified in this way, and the fatty acid lengthened its action by letting it bind albumin 5.

Albumin is the obvious carrier once somebody thinks of it. It is abundant, it circulates for weeks, and carrying fatty acids is one of its ordinary jobs. A peptide that holds on to albumin loosely — attaching, letting go, attaching again — spends most of its time as part of something too large for the kidney to filter, and partly hidden from the enzymes that would otherwise degrade it. The Lasker Foundation's account puts the logic in one sentence: albumin would ferry its GLP-1 cargo through the bloodstream while protecting it from enzymatic destruction and renal filtration 1.

The difficulty was that GLP-1 is not insulin. It is a thirty-amino-acid peptide whose activity depends on a precise fit at its receptor, and a fatty chain hung from the wrong residue could ruin that fit entirely. The question was chemical before it was pharmacological. Where on the chain could the fat go? How long could it be? And would the result still switch the receptor on?

The paper that answered the chemistry

The answer appeared in the Journal of Medicinal Chemistry in 2000, with Knudsen as first author. Her group had made a series of GLP-1 derivatives carrying fatty acids of different lengths at different positions. Many were as potent at the cloned human receptor as the native hormone, or more so, despite the size of what had been attached. A fatty acid could go almost anywhere in the back half of the molecule without a large loss of potency, and every compound carrying a chain of twelve carbons or more was markedly protracted — slow enough, the authors concluded, to suit once-daily administration in type 2 diabetes 3.

One compound from that work, carried under the code NN2211, became liraglutide. The company's later account describes it as chosen after comprehensive characterisation because it had the best overall properties — not simply the longest life 5. The European Medicines Agency approved it for type 2 diabetes in 2009, and the US Food and Drug Administration followed the next year 1.

The argument about obesity

Liraglutide's other property turned out to be the one that mattered most. People treated with GLP-1 drugs ate less and lost weight, which physiologists could explain and a diabetes programme could file as a secondary finding. Knudsen had been interested in obesity before the Hammersmith paper, because of hints from earlier animal work 1. The demonstration that GLP-1 acting in the brain could shut down feeding in rats gave that interest a mechanism 6.

What it did not give her was agreement. The Lasker Foundation records that the notion of a molecule pegged for one disease also combating another broke convention, and that as Knudsen championed it she faced resistance 1. In hindsight the resistance is not hard to understand. Obesity drugs had a long record of disappointment and withdrawal, and a company with a promising diabetes candidate had every reason not to tie it to the most discredited indication in pharmacology. The published accounts do not say who resisted, or how, and it would be invention to fill that in.

The argument was settled by trials rather than by persuasion. Liraglutide was developed separately for obesity, and in 2014 in the United States and 2015 in Europe it became the first GLP-1-based drug approved for the treatment of obesity 1.

From a day to a week

A once-daily injection was a triumph over a two-minute hormone, and still a daily injection. The next target was a week, and the team that pursued it was led by the chemists Jesper Lau and Thomas Kruse 1. Their stated aim was to raise albumin affinity further while making the peptide fully stable against metabolic degradation 4.

The search was long. The investigators went through around four thousand compounds before settling on one whose half-life had grown to about 165 hours 1. That compound, semaglutide, differs from human GLP-1 at two positions — aminoisobutyric acid, an amino acid the body does not make, at position 8, where the degrading enzyme would otherwise cut, and arginine at position 34 — and carries its fatty-acid side chain on the lysine at position 26. The fatty acid and the linker joining it to the peptide were the features that secured high albumin affinity while keeping potency at the receptor 4.

There is a trade inside that design worth noticing. Semaglutide binds the GLP-1 receptor about three times less tightly than liraglutide does, and binds albumin more tightly 4. The team gave up some grip at the target to gain time in the circulation, and the time was worth far more than the grip. Semaglutide was approved for type 2 diabetes in 2017 and for obesity in 2021 15.

What the rodents' thyroids said

Engineering durability into a hormone has consequences beyond the chemistry, and one of them shaped the safety file of the whole class. Rodents carry GLP-1 receptors in large numbers on the calcitonin-producing C-cells of the thyroid, and long-acting GLP-1 drugs stimulate those cells in rats and mice. Knudsen's own later account sets out why that finding was not taken to transfer straightforwardly to people: non-human primates have fewer C-cells and showed no measurable activation, and humans have little if any GLP-1 receptor expression in the thyroid 5.

The point here is less the verdict than the kind of work it represents. A molecule designed to linger will linger at every receptor it can reach. The career behind these drugs was spent as much on questions of that sort — which species, which tissue, whether the signal matters in a human — as on the elegant chemistry of the fatty acid.

Three names on one award

When the Lasker Foundation made its 2024 clinical award for the discovery and development of GLP-1-based drugs that have transformed the treatment of obesity, it divided the credit three ways 1. Habener, an endocrinologist at Massachusetts General Hospital, had reported in 1982 that the glucagon gene of the anglerfish encodes a precursor carrying a second, glucagon-like peptide 7. Mojsov, a peptide chemist, showed that a shortened form, GLP-1(7-37), is the physiologically active hormone 12. Knudsen turned it into a medicine.

Pairing a discovery with a development is unusual for a prize of that standing, and it says something about where the jury located the achievement. Hormones had been found before and left on the shelf because nobody could make them last. The award treated making them last as science in its own right. Habener died at the age of eighty-eight, and the Foundation published its memorial in January 2026 7. How long it took for Mojsov's part of the story to be told is a separate account, and a less comfortable one.

A career in one family of molecules

In April 2026 Knudsen left Novo Nordisk. The Nordic trade press marked it as the departure of the company's best-known GLP-1 scientist, and quoted her: "I grew up at Novo Nordisk and have spent my professional life here until now" 8.

Thirty-six years is a long time to spend on one family of molecules, and the arc is worth tracing once more. It begins with a hormone everyone admired and nobody could use. It runs through an idea borrowed from the insulin laboratories, a paper on where a fatty chain can hang from a peptide, an unpopular argument about which disease the molecule was for, and a four-thousand-compound search for a week of half-life. None of those steps was a discovery in the sense textbooks usually mean. Together they are the reason the discovery mattered.

The questions this story leaves open are technical ones. Why a chain of a particular length binds albumin at the right strength. Why tighter binding to albumin can be traded against weaker binding at the receptor without losing the effect. How the short linker between peptide and fat changes both. Those belong to the pharmacology of lipidation and half-life extension — and that is where a technical account of these molecules has to begin.