The Science Behind GLP-1 Diabetes and Weight Loss Drugs

GLP-1 Drugs: A Medical Breakthrough by Animal Research

Animal models were essential in the discovery, development and testing of GLP-1 receptor agonists — a class of drugs now revolutionizing treatment for type 2 diabetes and obesity. These therapies are based on a hormone that helps regulate blood sugar, insulin secretion and appetite. Here’s a look at the role of animal research at each stage.

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From Discovery to Life-Changing Therapies

How GLP-1 Drugs Were Born: A Journey in Animal Research

Explore the groundbreaking research that began with anglerfish studies and advanced through preclinical trials with nonhuman primates, ultimately leading to GLP-1–based therapies that revolutionize diabetes and obesity treatment.

Discovery Phase: A Fishing Expedition Leads to a Breakthrough

In the late 1970s, Dr. Joel Habener and his team at Massachusetts General Hospital sought to identify precursor molecules for pancreatic endocrine hormones such as glucagon and somatostatin, which regulate blood sugar, insulin secretion and appetite.
These were the very early days of recombinant DNA technology — a form of genetic engineering — and the National Institutes of Health (NIH), which supported Habener’s work, had issued strict guidelines limiting its use in warm-blooded animals. Habener and his team had to switch from a rat model to a cold-blooded animal model exempt from the restrictions to continue their research. They turned to the anglerfish.
In anglerfish, unlike in mammals, endocrine cells of the pancreas are concentrated in a distinct organ called the Brockmann body, making it easier to isolate and study hormone precursors.
With the anglerfish model, Habener’s team identified proglucagon — the precursor to glucagon — and discovered it also encoded a new hormone, glucagon-like peptide-1 (GLP-1). They found GLP-1 stimulates insulin secretion and inhibits glucagon release, laying the biochemical foundation for the GLP-1–based therapies now used to treat diabetes and obesity.

Drug Design and Mechanism Testing

Zucker diabetic fatty rats, a model for type 2 diabetes, helped researchers understand on a molecular level how the GLP-1 hormone signals to endocrine cells to regulate blood glucose levels and appetite. This basic science knowledge was necessary to develop drugs that mimic the GLP-1 function in the endocrine cells, called receptor agonist drugs.
Obese mice provided insights into how GLP-1 affects weight loss, satiety and metabolism.
A key discovery came from an unlikely source: the Gila monster. In the 1990s, scientists found a compound in its saliva called exendin-4, a naturally occurring GLP-1 receptor agonist. This led to the development of exenatide, the first GLP-1 receptor agonist the FDA approved.

Nonhuman Primate Preclinical Studies

Nonhuman primates (NHPs) were critical in determining how long-acting GLP-1 receptor agonist drugs are metabolized and cleared by the body, helping define proper dosing and delivery methods (e.g., daily vs. weekly injections).
NHPs were also critical in determining the safety profiles of GLP-1 receptor agonist drugs: how they affected the body’s organs and complex interconnected systems, both in the short term and over longer periods of time.
These studies confirmed the safety and efficacy of longer-acting versions of GLP-1 receptor agonist drugs like semaglutide.
Cynomolgus macaques (long-tailed macaques) were the primary NHP model for GLP-1 receptor agonist drug studies.
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.
NHP models were especially important in identifying cardiovascular effects (such as increased heart rate), assessing gastrointestinal tolerability (e.g., nausea and slowed gastric emptying) and supporting FDA safety requirements for human clinical trials.

Additional Preclinical Studies

Dogs and pigs were part of additional safety pharmacology studies to assess cardiovascular and gastrointestinal effects.
These data were vital for regulatory approval and understanding the broader physiological effects of GLP-1 receptor agonist drugs.
In addition to other animal models mentioned, rabbits and hamsters were also used in preclinical studies. Animal models provided crucial data on drug safety, pharmacokinetics and organ-specific effects, all of which supported regulatory approvals and the successful translation to human use.
The FDA approved the first GLP-1 drug, exenatide, in 2005, followed by newer agents like liraglutide and semaglutide (such as Ozempic and Wegovy). These drugs now help millions of people manage diabetes and achieve healthy weight loss.

2024 Lasker Award Recognizes GLP-1 Breakthrough

In 2024, Dr. Joel Habener, Dr. Svetlana Mojsov and Dr. Lotte Bjerre Knudsen received the prestigious Lasker-DeBakey Clinical Medical Research Award for their pivotal roles in the discovery and development of GLP-1–based therapies.
This achievement was built on decades of research involving animal models — from anglerfish and rodents to nonhuman primates — which made it possible to understand GLP-1’s role in blood sugar regulation and to develop safe, effective therapies.

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