Glucagon-like peptide-1
Based on Wikipedia: Glucagon-like peptide-1
Your body has a two-minute window to use one of its most powerful metabolic signals before it's destroyed. That's the half-life of glucagon-like peptide-1, or GLP-1—a hormone so potent that pharmaceutical companies have spent billions trying to make synthetic versions that last longer. Those efforts produced Ozempic, Wegovy, and the other drugs now reshaping how we treat diabetes and obesity.
But before we get to the drugs, let's understand what GLP-1 actually does and why your body destroys it so quickly.
A Hormone Born from Food
When you eat, specialized cells in your intestines spring into action. These are called L-cells, and they're shaped like tiny triangles lining your gut. One end touches the food passing through; the other end connects to blood vessels and nerves. They're perfectly positioned to sense what you're eating and broadcast that information to the rest of your body.
The message they send is GLP-1.
Here's something curious: the release happens in two waves. The first wave comes just ten to fifteen minutes after you start eating—far too quickly for the food to have reached most of your L-cells, which cluster in the lower part of your small intestine and colon. Scientists believe this early signal comes from neural pathways or from the smaller number of L-cells in the upper intestine. The second, larger wave arrives thirty to sixty minutes later, when digested nutrients actually reach those distant L-cells.
The amount of GLP-1 released depends on what you eat. Fatty acids, essential amino acids, dietary fiber, and sugars all trigger its secretion. Your body essentially reads the composition of your meal and responds accordingly.
The Incretin Effect
GLP-1 belongs to a class of hormones called incretins. The name comes from a fascinating observation made decades ago: when you swallow glucose, your body releases far more insulin than when you inject the same amount of glucose directly into your bloodstream.
Why would that be? The answer is incretins—hormones released by your gut that prime your pancreas to handle incoming nutrients. GLP-1 is one of the two major incretins, alongside another hormone called glucose-dependent insulinotropic peptide, or GIP.
The "glucose-dependent" part is crucial. GLP-1 only stimulates insulin release when blood sugar is elevated. When blood sugar drops to normal levels, GLP-1 stops pushing for more insulin. This built-in safety mechanism means GLP-1-based drugs carry a much lower risk of hypoglycemia—dangerously low blood sugar—compared to older diabetes medications like insulin injections or drugs called sulfonylureas that force insulin release regardless of blood sugar levels.
The Two-Minute Problem
So why does the body destroy such a useful hormone so quickly?
The executioner is an enzyme called dipeptidyl peptidase-4, or DPP-4. It lurks on the surface of cells throughout your body, including the cells lining blood vessels right next to where L-cells release GLP-1. The enzyme snips off two amino acids from the GLP-1 molecule, rendering it inactive.
The numbers are striking. Less than twenty-five percent of GLP-1 makes it out of the gut intact. Of what survives, another forty to fifty percent gets destroyed passing through the liver, which is densely coated with DPP-4. By the time GLP-1 reaches general circulation, only ten to fifteen percent of what was originally released remains active.
Your kidneys also contain another enzyme, neutral endopeptidase 24.11, that can degrade GLP-1—though this matters less in practice because by the time GLP-1 reaches the kidneys, DPP-4 has already inactivated most of it.
The result: fasting levels of active GLP-1 in your blood hover between zero and fifteen picomoles per liter. After a meal, that rises only two to three times higher. These are vanishingly small concentrations.
One Gene, Different Scissors
Here's where the biochemistry gets elegant. GLP-1 comes from a gene called proglucagon—the same gene that produces glucagon, the hormone that raises blood sugar. How can one gene make two hormones with opposite effects?
The answer lies in tissue-specific processing. In your pancreas, enzymes cut the proglucagon protein one way, producing glucagon. In your gut and brain, different enzymes make different cuts, producing GLP-1 and its cousin, glucagon-like peptide-2.
Think of proglucagon as a long string of beads. Depending on where you cut, you get different functional pieces. The pancreas uses molecular scissors called prohormone convertase 2. The gut and brain use prohormone convertase 1/3. Same gene, same protein precursor, but radically different hormonal outputs depending on the tissue.
This helps explain why GLP-1 isn't just a gut hormone. Neurons in a region of your brainstem called the nucleus of the solitary tract also produce it. The brain's GLP-1 contributes to feelings of fullness after eating—part of the reason GLP-1-based drugs suppress appetite.
Beyond Insulin: A Whole-Body Hormone
GLP-1's effects extend far beyond insulin secretion.
In your stomach, it slows gastric emptying—the rate at which food leaves your stomach and enters your small intestine. This creates an interesting feedback loop: by slowing digestion, GLP-1 reduces how quickly nutrients reach the L-cells that produce it. The hormone essentially regulates its own secretion.
Slower gastric emptying also blunts the spike in blood sugar after meals. For people with diabetes, this is valuable. But it's also why some people taking GLP-1-based drugs experience nausea—their stomachs hold food longer than they're accustomed to.
In the pancreas, GLP-1 doesn't just make existing beta cells release more insulin. It helps those cells survive and multiply. Type 2 diabetes involves a progressive loss of functional beta cells, so a hormone that promotes beta cell health while stimulating insulin release is exactly what you'd want in a treatment.
GLP-1 also suppresses glucagon release from the pancreas's alpha cells—but only when blood sugar is elevated. When blood sugar drops too low, the glucagon response remains intact. This glucose-dependent dual action, boosting insulin while suppressing glucagon but only when appropriate, makes GLP-1 an unusually safe way to lower blood sugar.
In the brain, GLP-1 promotes satiety. People feel full sooner and stay satisfied longer. This contributes to the weight loss seen with GLP-1 receptor agonists—a striking contrast to older diabetes drugs that often cause weight gain.
Researchers have also found GLP-1 receptors in the heart, kidneys, liver, lungs, muscles, bones, and fat tissue. Early studies suggest protective effects in many of these organs, though the clinical significance is still being worked out. Some of the most intriguing research involves the brain: GLP-1 receptor activation appears to protect neurons and even promote the growth of new ones. Studies in animal models suggest potential benefits in Parkinson's disease, Alzheimer's disease, stroke, and traumatic brain injury.
From Discovery to Drug
The story of GLP-1's discovery begins with anglerfish.
In the early 1980s, two researchers named Richard Goodman and P. Kay Lund were working in Joel Habener's laboratory at Massachusetts General Hospital. Goodman was hunting for the gene that codes for somatostatin, a hormone that regulates various body functions. He was using DNA from the pancreatic cells of American anglerfish—deep-sea fish with bioluminescent lures dangling from their heads, but more importantly for science, unusually large insulin-producing cells that made gene hunting easier.
When Lund used Goodman's techniques to find the glucagon gene, they discovered something unexpected. The gene didn't just code for glucagon. It coded for a longer protein that, when cut up by the body's enzymes, produced glucagon plus two additional peptides nobody had seen before.
Other researchers eventually isolated and characterized these mystery peptides. They became glucagon-like peptide-1 and glucagon-like peptide-2.
The critical insight that GLP-1 was an incretin came from Svetlana Mojsov, who ran a peptide synthesis facility at Massachusetts General Hospital. To test whether a particular fragment of the GLP-1 protein could stimulate insulin release, she synthesized it in the lab and created an antibody to track it. She identified that a stretch of thirty-one amino acids was the active incretin.
Working with Daniel Drucker and Joel Habener, Mojsov showed that tiny amounts of laboratory-made GLP-1 could trigger insulin secretion. The potential for diabetes treatment was obvious.
But there was a problem: that two-minute half-life.
Engineering Persistence
You can't make a useful drug from something the body destroys in two minutes. Patients would need continuous infusions. So researchers took a different approach: instead of giving people natural GLP-1, they engineered molecules that activate the GLP-1 receptor but resist degradation by DPP-4.
These GLP-1 receptor agonists have transformed diabetes and obesity treatment. The list includes exenatide, derived from a compound found in Gila monster saliva. Liraglutide, dulaglutide, and semaglutide are modified versions of human GLP-1 with chemical changes that extend their half-lives from minutes to days or even weeks.
Semaglutide, marketed as Ozempic for diabetes and Wegovy for obesity, has become one of the most discussed drugs in recent memory. Tirzepatide goes further, activating both the GLP-1 receptor and the GIP receptor for enhanced effects.
A parallel approach involves DPP-4 inhibitors—drugs that block the enzyme that destroys natural GLP-1, allowing your own hormone to work longer. These are less potent than the receptor agonists but simpler to take as pills.
Why GLP-1 Works When Others Fail
Here's something that puzzled researchers for years. People with type 2 diabetes have a reduced incretin effect—their gut hormones don't stimulate as much insulin release as in healthy people. Scientists initially assumed this meant diabetics produced less GLP-1.
But when they measured GLP-1 levels, they found something surprising: people with type 2 diabetes secrete essentially normal amounts of GLP-1. The problem isn't production; it's response. Their pancreatic beta cells don't react to GLP-1 as strongly as healthy cells do.
Yet GLP-1 receptor agonists still work in these patients. The explanation seems to be that pharmacological doses—much higher than what the body produces naturally—can overcome the reduced sensitivity. Flood the receptors with enough agonist, and you get a response.
This differs from the other major incretin, glucose-dependent insulinotropic peptide or GIP. In type 2 diabetes, the response to GIP is severely blunted, and simply giving more GIP doesn't help much. GLP-1's preserved effectiveness in diabetic patients is one reason it became the focus of drug development.
The Patent Dispute
Scientific discovery rarely follows clean lines, and credit can be contested. Svetlana Mojsov had to fight to have her name included on patents related to GLP-1. Massachusetts General Hospital eventually agreed to amend four patents to list her as an inventor. She received her one-third share of drug royalties—but only for one year.
The pharmaceutical industry built on these discoveries generates billions of dollars annually. The contrast between the messy, collaborative nature of basic research and the precise, adversarial world of patent law creates tensions that most patients taking these drugs never see.
A Hormone Finding Its Moment
GLP-1 sat in relative obscurity for years after its discovery. The two-minute half-life seemed like an insurmountable barrier to drug development. Researchers focused on understanding its biology while engineers worked on making it last longer in the body.
Those engineering efforts succeeded beyond early expectations. The drugs that emerged don't just treat diabetes—they produce substantial weight loss, and emerging evidence suggests benefits for heart disease, kidney disease, and possibly neurodegenerative conditions.
All from a hormone your body produces in tiny amounts and destroys almost immediately.
The story of GLP-1 illustrates something important about drug development. Sometimes the body's own signaling molecules point toward powerful therapeutic approaches, but those molecules themselves can't be drugs. The real work lies in understanding the biology deeply enough to engineer something that captures the benefits while avoiding the limitations.
In GLP-1's case, that meant understanding why the body destroys it so quickly, which enzymes are responsible, and how to modify the molecule or its receptor to preserve the therapeutic effects. Decades of basic research preceded the blockbuster drugs now in pharmacies.
And the story isn't over. Researchers continue to explore GLP-1's effects beyond metabolism—its neuroprotective properties, its role in addiction, its potential in conditions far removed from diabetes. That two-minute hormone, it turns out, has much longer reach than anyone initially imagined.