What Is GLP-1? The Science Behind GLP-1 Drugs

The discovery of GLP-1 and its role in regulating blood glucose was a major scientific breakthrough in diabetes research, yet turning this peptide hormone into an effective medication was no easy task. After decades of research and development, scientists have created next-generation GLP-1 drugs with applications that extend far beyond the treatment of type 2 diabetes. In this article, we delve into the science of GLP-1: what it is, how it works, the development of GLP-1 drugs like semaglutide, their side effects, and the applications of these drugs in the treatment of diabetes, obesity, and more.

What is GLP-1, and What Does it Do?

Glucagon-like peptide 1 (GLP-1) is a peptide incretin hormone that is naturally released by the cells of the intestine when people consume food, reducing blood glucose levels.¹ It is derived from a precursor protein called preproglucagon; this precursor also produces the hormones glucagon, which raises blood glucose, and glucagon-like peptide 2 (GLP-2), which appears to promote cell growth in the intestines.^2,3 Under normal physiological conditions, this hormone is broken down within minutes by an enzyme called dipeptidyl peptidase IV (DPP-4).²

Svetlana Mojsov, a chemist at Rockefeller University and pioneer in the field of GLP-1 research, had been studying glucagon for years when she first identified the cleavage sites in preproglucagon that give rise to biologically active GLP-1.⁴ “By the time I finished my studies with glucagon, I really knew its sequence by heart, backwards and forwards,” said Mojsov in a previous interview with The Scientist. “It was that knowledge of glucagon sequence, and its biology…which actually was very critical for my discovery of GLP-1.”

Originally thought to be simply responsible for triggering insulin secretion by the pancreas, scientists soon discovered that the hormone also inhibits glucagon secretion by the pancreas and delays gastric emptying.¹ These findings led researchers to develop GLP-1 drugs to lower blood glucose levels in patients with type 2 diabetes (T2D), triggering a paradigm shift in the management of the disease.

After the success of these first-generation GLP-1 medications in T2D, scientists continued to discover the wide-reaching effects and applications of this remarkable hormone. GLP-1 drugs, such as the blockbuster medication Ozempic (semaglutide) are now widely used in the treatment of obesity as well as T2D, offering reduced cardiovascular and renal morbidity to these patients.⁵ Scientists are currently researching the possibility of using next-generation GLP-1 drugs to treat disorders of the central nervous system, such as Alzheimer’s disease, Parkinson’s disease, and stroke, neuropsychiatric conditions, and cardiovascular disease.⁶

How Does GLP-1 Work?

Natural GLP-1 and GLP-1 drugs are highly pleiotropic, meaning they act on several molecular pathways and have a range of effects in the body. GLP-1 drugs work by promoting satiety, reducing food intake, and thus decreasing body weight and blood pressure.⁷ To understand the GLP-1 mechanism of action, it’s crucial to understand how it interacts with the GLP-1 receptor and how GLP-1 agonists differ from natural GLP-1.

GLP-1 receptor

The GLP-1 receptor, often referred to as GLP-1R, is a G protein-coupled receptor (GPCR) that binds to GLP-1. The GLP-1 receptor is expressed on the surface of cells across many different tissues, including the pancreas, intestines, liver, central and autonomic nervous systems, immune system, heart, and muscle.⁸ This extensive expression of the GLP-1 receptor explains the wide-ranging effects of GLP-1 drugs.

GLP-1 agonists

Glucagon-like peptide 1 receptor agonists, otherwise known as GLP-1 agonists or GLP-1Ras, are drugs that imitate the natural hormone.⁸ These medications are synthetic forms of the peptide, or GLP-1 mimics, which bind to the GLP-1 receptor and act on the same pathways. Unlike natural GLP-1, which has a very short lifespan in the body, GLP-1 agonists are designed to resist degradation by DPP-4, giving them a longer half-life.

GLP-1 mechanism of action

When the natural hormone or GLP-1 drugs bind to the GLP-1 receptor, they trigger an intracellular signaling cascade; the ligand activates its GPCR, which in turn activates intracellular G proteins.² These G proteins subsequently increase the cyclic adenosine monophosphate secondary messenger, which then activates protein kinase A. This cascade results in the production of insulin, prevents the release of glucagon, and delays gastric emptying.²

The hormone also works via the phosphoinositide 3-kinase/protein kinase B pathway, which is responsible for maintaining the beta cells of the pancreas.² Researchers are still studying the mechanism and effects of GLP-1 drugs in other tissues where the GLP-1 receptor is expressed, including the brain, heart, and immune system.

Development of GLP-1 Drugs

Decades after the discovery of the natural hormone, there are now several available GLP-1 drugs—or GLP-1 receptor agonists—that can be used to treat diabetes, obesity, and other conditions. Not long after her original discovery in the 1980s, Mojsov was looking at the results of supplemental GLP-1 testing in humans with a lab technician when she realized she was onto something big. “I remember both of us looking at the data, and we looked at each other and said, ‘Well, this is going to be a drug,’” she said.

However, the race to develop effective GLP-1 drugs took researchers down challenging paths. Because natural GLP-1 is rapidly broken down by DPP-4 in one to two minutes, it would need to be either administered continuously, or researchers would need to produce a mimic with improved stability that would last longer in the bloodstream. This task fell to Lotte Bjerre Knudsen, a pharmaceutical scientist at Novo Nordisk. “I just thought, ‘Okay, I’m going to convince them,’” she told The Scientist. “And it kind of became fun that way.”

The first GLP-1-based drug has an unusual origin story. Discovered in the saliva of the Gila monster, a venomous reptile, the peptide exendin-4 is a structural analog of the human hormone with a longer half-life of approximately 2.4 hours. Researchers developed a synthetic version of exendin-4 called exenatide and showed that it could lower blood glucose in T2D patients.⁹ Approved in 2005, exenatide was the first GLP-1 drug to be made available, and later modifications allowed for its extended release. Other first-generation GLP-1 medications include liraglutide, a synthetic form of the peptide with fatty acids attached for increased stability. Developed by Knudsen, liraglutide could be administered just once a day.

After several setbacks and challenges, researchers, including Knudsen, developed improved, next-generation GLP-1 drugs. These medications have significantly improved pharmacokinetic profiles and are long-acting, requiring only weekly administration. This includes the blockbuster drugs semaglutide—better known by its brand names Ozempic or Wegovy—and tirzepatide (Mounjaro). The FDA approved semaglutide for the treatment of diabetes and obesity in 2021, and the drug has since generated billions of dollars for its developers.

Knudsen acknowledges that she was one of many researchers who contributed to GLP-1 drugs becoming the juggernauts they are today. “[It’s been] an interesting journey,” said Knudsen. “When you see a success story like GLP-1, there are multiple inventors.”

GLP-1 Side Effects: Is GLP-1 Safe?

GLP-1 drugs have been approved for the treatment of diabetes and obesity, meaning that the FDA has determined that for people with these disorders, the benefits of taking the drug outweigh the potential risks. But is GLP-1 safe? Let’s take a look at GLP-1 side effects, if there really is a natural GLP-1 alternative, and the effects of these drugs on the brain.

GLP-1 long-term side effects

The use of semaglutide and similar drugs carries the risk of significant and common side effects. GLP-1 side effects include gastrointestinal complications, such as nausea, vomiting, diarrhea, constipation, and diverticulitis.¹⁰ People who take these drugs also have a higher risk of developing GLP-1 long-term side effects such as eye diseases, gallbladder disorders, acute pancreatitis, and cancers.¹¹ Research is continuing to assess the potential for GLP-1 drugs to cause psychiatric issues, such as suicidal ideation.¹¹ Additionally, a significant amount of the weight loss induced by GLP-1 drugs is derived from lean muscle tissue, which is crucial for health and longevity.¹¹

Is there really a ‘natural’ GLP-1?

Natural GLP-1 is produced by the body, however, as we discussed earlier, it has a very short lifespan, and patients with T2D and other metabolic disorders can experience reduced secretion of the hormone or reduced sensitivity to it. Because GLP-1 drugs are expensive, can be difficult to access, and have significant side effects, many people have sought to increase their production of the natural hormone via nutritional modifications. Increasing the production of natural GLP-1 does not have the same effects as GLP-1 drugs, as it is still rapidly degraded by the DPP-4 enzyme.

GLP-1 effects on the brain

The GLP-1 receptor is expressed in the hypothalamus, brainstem, and other parts of the central nervous system, helping GLP-1 drugs to reduce body weight by decreasing hunger and increasing feelings of satiety.¹ However, scientists are still investigating the other effects of GLP-1 on the brain. Research in rodents has shown that mimics like semaglutide alter the reward pathways in the brain, potentially reducing addictions to food, drugs, and tobacco.¹² Other studies have demonstrated that semaglutide can reduce the sensitivity of mice to pain.¹³

GLP-1 drugs have also shown potential in the treatment of neurodegenerative disorders. Animal models of Parkinson’s disease have shown that treatment with semaglutide can restore dopamine levels and alleviate symptoms.¹⁴ In models of Alzheimer’s disease, researchers demonstrated that semaglutide can mitigate the deficits in memory and cognition and prevent the death of neurons.¹⁵

Scientists continue to explore the effects and applications of GLP-1 beyond diabetes and obesity, and to improve GLP-1 drugs to avoid side effects and increase longevity. Recent research suggests that GLP-1 drugs may have promise in the treatment of cardiovascular disease, neurodegenerative disorders, and drug and alcohol addiction, among others.^12,16,17 Mojsov said that the synergy between basic and clinical GLP-1 research offers the perfect environment for collaborations between industry and academia. “We can lead each other,” Mojsov remarked. “There are a lot of very interesting questions ahead of us.”