GLP-1 therapies have revolutionised the management of type 2 diabetes and obesity. Their unique mechanism of action, targeting both blood sugar and appetite, offers significant therapeutic benefits to millions of patients in need. Animal models were essential in the discovery, development, and testing of these GLP-1 receptor agonists.
The story of GLP-1 medicines is that of ground-breaking research that began with studies on anglerfish, continued with Gila monster venom extraction, and culminated in preclinical trials in rodents and nonhuman primates. These crucial animal experiments have enabled GLP-1 drugs to help millions of people with obesity and type 2 diabetes with many more – benefits still emerging. Beyond their well-characterised effects on lowering blood glucose and body weight, GLP-1 medicines have been shown to improve outcomes in people with cardiovascular, kidney, liver, arthritis, and sleep apnea disorders.
A fishing expedition for an insulin regulator
In the 1960s, scientists hypothesised that the gut was capable of producing hormones that regulate insulin levels. Insulin is a hormone produced by the pancreas that regulates blood glucose (sugar) levels, allowing sugar to move from the bloodstream into cells to produce energy. As diabetic patients often become resistant to insulin, such a gut hormone offered hope for a novel treatment.
In the search for this prophesised molecule, Dr Joel Habener and his team at Massachusetts General Hospital decided in the late 1970s to study glucagon, another hormone produced by the pancreas that has an opposite action to insulin and increases blood glucose levels. Instead of studying the mammalian system, the researchers focused their attention on fish, more specifically the anglerfish. In contrast to mammals, the glucagon and insulin producing cells are not embedded in the pancreas, but rather in separate organs known as Brockmann bodies which provide an easily accessible and enriched source of glucagon-producing cells. At the time there were strict guidelines limiting the use of recombinant DNA technology – a form of genetic engineering – in warm-blooded animals. Habener and his team had to switch from a rat model to a cold-blooded animal model for their genetic research.
Using the anglerfish model, Habener’s team identified a precursor to glucagon capable of also encoding a new – and much sought after – hormone: the glucagon-like peptide 1, better known as GLP-1. Switching back to mammalian models (hamster, rats, pigs), researchers found that GLP-1 could stimulate insulin secretion and inhibit glucagon release, which could vastly benefit diabetic patients.
From venom to drug
Once the hormone was identified and understood, it was just a matter of time before researchers turned the biological pathway into an actionable drug approach.
Mojsov et al. showed that only a small portion of the GLP-1 hormone was physiologically active and sufficient to stimulate insulin secretion in rats. Similar findings were also published in early 1987 by Holst et al., who confirmed that the condensed version could be found in pig small intestines and that both the natural (isolated from pig intestine) and the synthetic version stimulated a two-fold increase in insulin secretion in isolated pig pancreas.
After exploring the mechanism of action in diabetic fatty rats and obese mice, researchers rapidly moved on to show the same effect in humans. In 1987 a study of seven human volunteers, showed that an infusion of the short version of GLP-1 increased insulin and reduced glucose in the blood of patients that had received a glucose load. However, it was still unclear whether the hormone would provide a clinical benefit in diabetic patients. It was only at the beginning of the 1990s that several reports confirmed a clinical response in diabetic patients. These results established the potential of this new hormone as a therapy for diabetes, but a key problem persisted.
The miracle molecule only remained in the blood for a few minutes, necessitating the use of continuous intravenous infusion to deliver it in sufficient amounts. To be market-worthy, the drug needed to remain active 24 hours a day, remain physically stable for long periods of time and be as – or more – potent than native GLP-1. Researchers rose to the challenge thanks to an unlikely source, the Gila monster’s saliva.
In the mid 1980s, John Eng was studying bioactive molecules in the venom of the Gila monster (Heloderma suspectum), a lizard native to the southwestern United States and Mexico. He identified a novel compound named Exendin-4 which looked a lot like short GLP-1 but performed better. Exendin-4 bound to same receptors as GLP-1, stimulated insulin secretion in rodents, and lasted longer in the body thanks to a mutation that protects it from being cut up by enzymes. In type 2 diabetic mice, Exendin-4 rapidly normalised blood glucose levels. This success led to the development of exenatide, the first GLP-1 receptor agonist approved by the FDA for the treatment of diabetes (in 2004).
Critical preclinical studies in animals
Building on this foundation, many drugs were developed targeting this pathway, such as liraglutide and semaglutide (including Ozempic and Wegovy) helping millions of people manage diabetes and achieve healthy weight loss.
Animal research played an important role in understanding, developing, and bringing to market these drugs. Not only did different animal models such as rats, mice, rabbits and hamsters, help in the discovery and understanding of the therapeutic pathway of GLP-1 drugs, but they also provided crucial data on drug safety, pharmacokinetics and organ-specific effects, all of which were necessary for achieving regulatory approval and the successful translation to human use.
Non-human primates, in particular Cynomolgus macaques (long-tailed macaques), were critical in determining how long-acting GLP-1 receptor agonist drugs are metabolised and cleared by the body, helping define proper dosing and delivery methods. Rhesus macaques were also used to study GLP-1’s effects on pancreatic function and glucose metabolism, further validating the drug’s mechanism and safety before human trials.
Monkey studies were also critical in determining the safety profiles of GLP-1 therapies both in the short term and over longer periods of time. They were especially important in identifying cardiovascular effects such as increased heart rate, and assessing gastrointestinal tolerability. Dogs and pigs were also used in pharmacology studies to assess cardiovascular and gastrointestinal effects. This data was vital for regulatory approval and understanding the broader physiological effects of GLP-1 receptor agonist drugs.
A highly effective treatment for obesity and more
The story doesn’t stop there. GLP-1 therapies revealed surprising beneficial effects. Diabetic patients treated with semaglutide (Ozempic) showed substantial weight loss with some patients losing more than 10% of their weight. Similar effects had already been observed in animals. Several studies from Ole Madsen (University of Copenhagen) had shown that transplantation of glucagon producing tumours caused profound anorexia in animals. Consistent with this, Bloom et al. had shown that injecting the short version of GLP-1 into rats profoundly reduced food intake. GLP-1 therapies slow down the process of food digestion and increase feelings of fullness, leading to a reduction in food intake.
Following these observations, clinical trials using GLP-1 therapies for the treatment of obesity showed stunning results, with treated patients losing an average of 12.4% of their initial body weight. The health implications of these changes run deep. In diabetic patients, semaglutide significantly reduced the incidence of cardiovascular events by 26%. Similar effects could be observed in overweight and obese patients with pre-existing cardiovascular disease. Additional unanticipated health benefits could soon be identified as the GLP-1 receptor is found throughout the body, including in the brain. Recent studies have claimed clinical benefits in patients with heart and kidney failure, arthritis, and sleep apnea disorders, mediated in part through anti-inflammatory and metabolic pathways, with some benefits partly independent of the degree of weight loss achieved.
The impact has been vast and further preclinical studies are still necessary to explore and understand the potential of the drugs that have already revolutionised the lives of millions of people with obesity and type 2 diabetes. To mark the importance of the discovery of these GLP-1–based drugs, Dr. Joel Habener, Dr. Svetlana Mojsov and Dr. Lotte Bjerre Knudsen received the prestigious Lasker-DeBakey Clinical Medical Research Award in 2024 for their pivotal roles.
Last edited: 12 May 2026 09:32
