153: Why Amylin May Be the Most Important Weight Loss Hormone You've Never Heard Of

We all know that GLP-1 medications help control appetite. But what if I told you there's another hormone your body naturally makes that also helps regulate hunger and fullness? It's called amylin. Every time your body releases insulin, it also releases amylin. But unlike insulin, amylin helps you feel full. It slows digestion and helps reduce blood sugar spikes without forcing insulin higher. And that's exactly why researchers are so excited about combining amylin with GLP-1 medications. The two hormones work through different pathways in the brain, meaning they may work better together than either one alone. In fact, some of these next-generation medications are already showing weight loss results approaching what we once only saw with surgery. But here's the bigger point. The future of metabolic medicine may not be about forcing the body harder. It may be about restoring the body's natural signals of satiety. This is Lecture 153 of The Metabolic Classroom. Welcome back to The Metabolic Classroom. I'm Ben Bikman, metabolic scientist and professor of cell biology. Today we are turning our attention to a hormone that has spent almost its entire scientific life in the shadow of its far more famous sibling, insulin. However, it's quietly moved close to the center of the most active area in all of weight loss pharmacology. The hormone that I'm referring to is Amylin. By the end of this mini lecture today, I hope you'll understand exactly why drug companies are interested in what amylin can do. But before we get to that point, let's just review what it is. To appreciate why amylin matters, we need to discuss the pancreatic beta cell. Yes, you recognize that cell because it's the same one that produces insulin. When you eat and nutrients, especially glucose, begin to appear in the blood, the beta cell doesn't release insulin alone. It releases insulin together with amylin, a second, much smaller hormone packaged in the very same secretory granules and pushed out into the circulation at roughly 1 molecule of amylin for every 100 molecules of insulin. Although amylin travels out of the cell hand in hand with insulin, the job it performs is its own. Although, as you'll see, there's some complementary work here. Where insulin works mainly to move glucose into tissues and regulate nutrient metabolism in such a way to promote anabolism, or building up. Generally, amylin works mainly on the brain and on the pace of digestion. You can see the obvious complement to incretin hormones like GLP-1. Amylin's receptor is an unusual one. It's assembled from the calcitonin receptor, but joined to a small accessory protein. So it's kind of a modified receptor that normally would just bind calcitonin. Now it's sensing amylin, and the densest concentration of these receptors sits in a part of the brainstem that helps decide when a meal should end. In other words, a satiety center. When amylin reaches this region after eating, it contributes to the sensation of fullness. At the same time, there are amylin receptors throughout the intestines, and it slows the rate at which the stomach empties its contents into the small intestine so that the nutrients from a meal arrive more gradually rather than all at once. Now, amylin has a third effect, and this is the action that it has on the alpha cell of the pancreas, specifically to inhibit glucagon. Amylin suppresses the inappropriate release of glucagon. But especially in the period right after eating. So amylin will smooth the rise in blood sugar after a meal by slowing the delivery of nutrients and by making sure that glucagon is not getting activated, which means it can keep the glucose load in the bloodstream much easier to handle. So it kind of eases the burden on insulin by preventing glucagon from misfiring, if you will, from misbehaving. So with this in mind, amylin is rightly considered an insulin-sparing hormone, helping to control glucose without demanding that the pancreas pump out ever more insulin in order to do it. Now, I also know what you're wondering, given my prior focus. You're thinking, what about the fat cells? This is actually a little complicated. The receptor machinery does appear to be present in fat tissue. And in isolated or cell culture grown fat cells, Amylin does act on those fat cells. But largely what it does is just enhance the insulin signal. So that nevertheless is a bit odd given that I'm talking about Amylin in the context of weight loss drugs. So if anything, the direct effect of, of this on the fat cell would oppose weight loss, which tells us that the fat loss from Amylin is driven by the brain and the drop in food intake, with the fat cell following along rather than the leading effect. So this direct effect at the fat cell is really diminished in light of the fact that there is a substantial change in just what and how often and how much the person's eating. All right, so if Amylin does all of these things, why did it take so long to turn into a drug? This is another little bit of the biochemistry or the endocrinology of amylin, which I, of course, find endlessly interesting before we get into some of its application nowadays. The obstacle in turning amylin into a drug actually is revealed when we consider amylin's other name. Another group of scientists in another lab once upon a time called that same hormone— they called it the islet amylloid polypeptide. And that word amyloid is a warning. Pathologists studying the pancreas in type 2 diabetes had long noticed dense protein deposits building up inside the islets, uh, as the disease progressed. And the main protein in those deposits turned out to be amylin itself. Human amylin is prone to misfolding and sticking to itself, clumping into these, um, fibers that we call amyloid. Now, that is not the same amyloid as that, that is seen in the brain with Alzheimer's disease. Whether that amyloid beta is relevant or not, they're not the same thing, just so you know. But nevertheless, those little insoluble fibers that we call amyloid, they are a problem. Um, if you are hoping to leverage amylin as a medicine, the natural molecule is prone to aggregating or clumping together. The fix for this, when researchers were trying to apply the benefits of amylin without those downsides, came from a clever, a clever piece of engineering, if you will, at the level of the protein. Amylin from rodents, unlike the human version, doesn't form these amyloid fibers. And the difference comes down to a handful of amino acids in one single little stretch of the molecule. By swapping 3 of those amino acids into the human amylin form, researchers built a peptide that still switches on the amylin receptor and still thus delivers the, the satiety benefits and the glucose-insulin-sparing effects that we care about, but no longer clumps into the fibers. That molecule became the first amylin-based drug and the proof that this pathway could indeed be harnessed. All right. Now let's talk about how that pathway has been harnessed. The first drug that was ever produced was called Pramlintide. And it has been available for about, uh, 20 years. It was initially approved as an add-on to mealtime insulin for people with type 1 and people with type 2 who are treated with insulin. In that setting, it does exactly what the biology would predict. It slows gastric emptying. By slowing gastric emptying and by restraining glucagon after the meal, it helps blunt the sharp rise in blood sugar. That follows a meal, and it does so while modestly reducing body weight rather than adding to it, which sets it apart from insulin itself. But the more telling experiments came when pramlintide was tested specifically as a weight loss agent in people with obesity who were not using insulin at all. In a carefully controlled trial, people given pramlintide before meals reduced their food intake and lost a meaningful amount of weight compared with those given just a placebo, with roughly a third of the treated patients losing at least 5% of their body weight over the recorded months. And of course, revealing the mechanism of all of this magic, many were reporting that their appetite and their cravings were much easier to manage. This was the crucial demonstration. It showed that activating the amylin pathway in humans does what it does in the laboratory. It reduces how much people crave and thus eat, and it brings their weight down. Pramlintide, however, carries two practical burdens that have always limited its reach. The first is it has a very short duration of action, which means it has to be injected before every single meal, three times a day, on top of whatever else a person is already taking. The second is tolerability, because pushing the amylin signal too hard too quickly tends to produce a pretty significant bout of nausea. Pramlintide proved the concept in a good way, but it was never going to be the molecule that brought Amylin to the masses. For that, two things had to happen. The drug had to last much longer and ideally combined with something that did the job even a little better. That something is GLP-1, the hormone behind the medications you are now very familiar with. GLP-1 and Amylin both reduce appetite, but they do it through largely separate circuits. They engage different receptors in overlapping but distinct regions of the brainstem and the hypothalamus, the areas that govern both the, um, the homeostatic drive to eat— or that is to just say that when you're hungry, you're eating, when you're full, you're not— but also the more emotional, reward-driven pull toward food. So both of those regions are affected with both amylin and GLP-1. But because these two signals enter the system through different doors, if you will, their effects tend to add to one another rather than simply overlap. And that complementary action is the core rationale for pairing them. But there is a second reason to combine Amylin with another agent, and it involves the hormone leptin. This is pretty interesting and elegant. Leptin is the long-term signal of how much fat you're carrying, and in a lean, healthy state, It tells the brain that energy stores are full and appetite can ease off. This is a way for the fat cell to send a signal to the brain saying, hey, we're full, stop eating. Now, the cruel irony of obesity is that the brain becomes resistant to leptin so that even with abundant fat stores and high leptin, the satiety message no longer gets through. For years, researchers tried to overcome this resistance by giving more leptin. And it simply didn't work. Then came a striking discovery. Amylin appears to restore the brain's sensitivity to leptin. In animals made obese by diet, treatment with amylin resensitized the brain leptin signaling— that signaling that had gone quiet, that the brain had become resistant to. And when amylin and leptin were given together, they produced a fat-specific weight loss far greater than either one of those proteins were capable of doing alone. The same, uh, synergy was then seen in an early human study where combining an amylin analog with leptin produced substantially more weight loss than either treatment by itself. Amylin, in other words, isn't just another appetite signal. It seems to act as a kind of key that unlocks the brain's responsiveness to the body's own satiety hormones. And throughout all of this, the way amylin and GLP-1 improve blood sugar remains insulin sparing. GLP-1 can enhance the body's own insulin response only when blood sugar is actually spiked, but amylin works by restraining glucagon and slowing nutrient delivery. Neither one achieves its effect by flogging the pancreas to release more insulin around the clock, which is precisely why this, this combination is so attractive from a metabolic standpoint. Again, It's hard to lose weight if a drug is increasing insulin, and neither of these do, as I've described previously and just recently. They're both insulin sparing in their own way. All right, let's move on then from these first attempts at leveraging amylin signaling. The first serious attempt to build on this rationale of combining amylin with other signals came with a long-acting amylin analog called cagrilintide. Where Pramlintide lasts only minutes and must be injected with every meal, Cagrilintide was engineered to last long enough for a single weekly injection, the same convenient schedule as the modern GLP-1 drugs. On its own, in a dose-finding study in people with overweight and obesity, Cagrilintide produced clear dose-dependent weight loss, with the highest dose bringing about a reduction of roughly 11% of body weight about over 6 months. Months. That was a result that definitely exceeded the placebo, and it did confirm that a long-acting amylin analog could stand on its own as a weight loss agent. But of course, the real ambition was always the combination. Cagrilintide was paired with semaglutide in a weekly— a single weekly injection that came to be called Cagra-Sema. Early studies established that the two could be safely given together and hinted at some additive effects. And a mid-stage trial in people with Type 2 diabetes confirmed meaningful weight loss and glucose improvement from the pairing. But the results that truly captured the field's attention came from a large Phase 3 program. In the first of these trials, conducted in adults with obesity or overweight who did not have diabetes, the combination was tested head-to-head against each of its components and against placebo over a fairly long period of 68 weeks. Participants on Kagrasema lost about 20% of their body weight on average, and among those who stayed on the full intended dose, the figure was closer to 23%, with roughly 4 in 10 of them losing at least a quarter of their starting weight. Crucially, the combination outperformed semaglutide alone or cagrilintide alone. This is exactly what you'd hope to see if the two hormones really are working through complementary pathways. The whole was meaningfully greater than either part. A companion trial in people who did have type 2 diabetes told a similar story, with the combination producing close to 14% weight loss against about 3% on placebo, a substantial result in a population that typically loses weight slowly and ultimately just less readily. The combination is not without its costs, though. The most common side effects are, of course, gastrointestinal the same nausea and related complaints that follow any drug that slows the gut and dampens appetite. And these effects are part of why the trials show— allowed some flexibility in how high the dose was pushed. But as a demonstration that adding amylin to a GLP-1 backbone pushes weight loss into territory once reachable only through surgery, Kagrasema made the case for such a perspective, and it did so decisively. All right, now let's move on. If two separate signals or hormones given together produce this kind of synergy, an obvious next question follows: why use two molecules at all? Why not design a single molecule that activates both the GLP-1 receptor and the amylin receptor at once? Well, that is precisely the idea behind a compound called amicretin. The first drug to fold both of these biologies into one peptide. Amicretin has been tested in two forms, and both are frankly striking. As a daily tablet, an unusual achievement for a peptide drug since peptides are normally destroyed in the gut, it proved very tolerable in its first human trial and produced clinically meaningful weight loss over 12 weeks. As a once-weekly injection, the results, of course, were even more dramatic, with the highest doses producing weight loss approaching 22 percent over roughly 8 to 9 months. And this is in an early-stage trial rather than a large definitive one. Numbers like these achieved by a single molecule doing the work of two hormones are part of why this drug has moved rapidly toward large-scale testing. Whether the convenience of a single agent, potentially even a pill, can match the efficacy of the two-drug combinations is frankly one of the most closely watched questions in this field of weight loss drugs right now. Okay, so what about the next wave? In the open questions, amicretin is not alone at the frontier. A growing number of companies have concluded that amylin may be one of the most important targets in metabolic medicine, and several other long-acting amylin analogs are now advancing through testing across several companies. The recurring theme is that amylin-based drugs deliver weight loss comparable to the GLP-1 medications while being a little gentler on the gastrointestinal system. And that gentler profile could matter enormously for people who cannot tolerate the GLP-1 drugs as they are currently used. Now let's bring it all together and wrap it up. Let's step back. Um, amylin is the long-overlooked partner of insulin. It's a satiety hormone that quiets appetite through the brainstem. It slows the emptying of the stomach.. It also keeps glucagon restrained or in check after a meal and helps control blood sugar without demanding more insulin. For years, the therapeutic promise of Amylin was locked behind its tendency to form these amyloids, those fibers, uh, those insoluble fibers within cells. However, with some protein engineering, it's been set free. Now, first set free as a mealtime drug. Um, but then there were the long-acting analogs that could be given once a week. And the reason amylin has become so central is that it does not merely echo what GLP-1 does, it complements it, reaching the brain through different routes and even restoring the brain's lost sensitivity to its own satiety signals. As kind of a related thought there, I'm— as much as I mentioned the evidence showing that amylin can help restore leptin sensitivity in the brain, I also can't help but speculate, so I'm purely wondering, the degree to which amylin may also improve GLP-1 sensitivity. There is some evidence, albeit limited, that the brain can become GLP-1 resistant. Maybe amylin helps with that as well. Now, whether it's delivered as two separate molecules in one injection or as a single molecule engineered to do both jobs, the pairing of amylin with GLP-1 does represent a very powerful approach to weight loss that pharmacology Uh, it's one of the strongest ones pharmacology has given us, and it's arrived not by pushing insulin higher, very importantly, but by working with the body's own satiety signals. Class dismissed. Until next time, more knowledge, better health.