How GLP-1s Actually Work (in Plain English)

Your body already makes GLP-1 every time you eat. The problem? Natural GLP-1 lasts about two minutes before an enzyme destroys it. Semaglutide and tirzepatide are engineered to do the same job, just louder and longer.

Dr. Clete Barrick breaks down how these medications work at three job sites: your pancreas, your stomach, and (most importantly) your brain. He explains the difference between homeostatic hunger and hedonic hunger, why GLP-1s quiet "food noise" through the brain's reward circuit, and why the "you only lose weight because you feel sick" myth is flat wrong.

In this episode:

• GLP-1: the hormone you already make
• Three job sites: pancreas, stomach, brain
• Homeostatic vs. hedonic hunger (the car wash sign analogy)
• Why less than 1% of weight loss comes from nausea
• Semaglutide vs. tirzepatide: what's different
• What GLP-1s don't do
• The Straight Shot: you are not cheating

No biochemistry degree required. Just the science you need to understand what's happening when you take your shot.

New episodes weekly. Subscribe and visit barrickhealth.com for physician-led weight loss care.

Transcript

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Your body already makes GLP1 right now. Sitting wherever you are, you have the machinery to produce this hormone. It happens every time you eat. So specialized cells in your small intestine release a burst of GLP1 into your bloodstream. And it does three things. It tells your pancreas to release insulin, it signals your brain that food has arrived, and it slows your stomach so you stay full longer. The whole system fires in minutes, runs briefly, and shuts off. The medication does the exact same thing, just does it louder and longer. That's the entire concept. Today I'm going to explain exactly how these medications work in language that doesn't require a biochemistry degree. Because understanding what's happening in your body changes how you use the medication. Everything on this show is education, not medical advice for your specific situation. Talk to your provider before making changes to your treatment plan. Let's get into it. Today we're covering the single most important foundation for everything else on this show. So how GLP1 medications actually work inside your body. GLP1 stands for glucagon-like peptide 1. I know. Terrible name. Sounds like something a committee invented, but forget the name and focus on what it does. After you eat a meal, specialized cells called L cells. They line your small intestine, release GLP1 into your bloodstream. These cells are reading the contents of your meal and responding appropriately. It's a coordinated signal that fans out across your body, like a crew getting to work. The problem is natural GLP1 has a half-life of about two minutes. So all of two minutes. An enzyme called DPP4 chews it up almost as fast as your body makes it. So the signal's real, but it's brief. A quick pulse that says food's arrived, let's handle it, and then it's gone. What the medications do is simple in concept. So they're synthetic versions of GLP1. They've been engineered to resist the DPP4 enzyme. Semaglutide has a half-life of about seven days, terzepatite about five days. So instead of a two-minute pulse, you're getting a constant steady signal running around the clock for an entire week from a single injection. So same hormones, same receptors, same jobs, just amplified and extended. So that's really the whole trick. When GLP1 hits your system, whether natural or from a medication, it does three things simultaneously. So I think of these kind of as the three job sites. So job site one is your pancreas. GLP1 tells your pancreas to release insulin, but only when your blood sugar is elevated. So this is called glucose-dependent insulin secretion. And it's a critical safety feature. So unlike older diabetes drugs that would drive blood sugar dangerously low, GLP1 medications only boost insulin when there's sugar in the bloodstream to deal with. So when your blood sugar is normal, the signal doesn't fire. That's why hypoglycemia is actually quite rare with these medications when they're used alone. At the same time, GLP1 suppresses another hormone called glucagon. Glucagon tells your liver to dump stored sugar into your bloodstream. So when you're trying to manage blood sugar, you want less of that, of course. So GLP1 hits the accelerator on insulin, but the brakes on glucagon at the same time. So both systems working in the right direction. This is why these medications were originally developed for type 2 diabetes. The weight loss is actually a happy accident or a side effect that the pharmaceutical companies noticed and jumped all over and have developed specifically since then. The diabetes application came first. Onto job site two. So that would be your stomach. GLP1 slows gastric emptying, means food sits in your stomach longer. So you're gonna feel full sooner and stay full longer. The idea is you're more full from less food for a longer period of time. This is why patients describe eating half a plate and feeling done. So your stomach is sending a still full signal that it wouldn't normally send yet. It's also why eating too fast or eating too much at once on these medicines can cause nausea. So your stomach is running at a different speed, and you need to learn to match that pace. The delayed gastric emptying also explains a few practical things that I'm going to cover in some future episodes. So why some oral medications may absorb differently when you're on a GLP1, why you need to stop the medication before surgery, and why eating greasy food on injection day is generally asking for trouble. So job site three is the brain. This is, in my opinion, the most important job site, and the one that people don't really hear about until they experience it on the medication. GLP1 receptors, they're scattered throughout your brain. They're in the hypothalamus, which regulates hunger and satiety. They're in the brainstem in an area called the area prostrema, and they're in the nucleus accumbens, which is the core of your brain's reward circuit. When the medication activates receptors in the hypothalamus, it enhances satiety signaling. Your brain gets a much louder, clearer. Hey, you've had enough message. When it activates areas in the or receptors in the area post-strama, that's actually what's causing the nausea that some patients experience. Because part of that part of the brainstem, it's actually your body's toxin detector. And when it activates receptors in the reward circuit, it is uh dampening the craving signal, the I want that feeling. It gets quieter. And that last piece is what patients call food noise, going silent. And it's the piece that really distinguishes GLP1 medications from everything that came before. I do want to spend a minute on the brain piece because it matters for how you think about these medications. So every previous generation of weight loss drugs, they worked primarily on hunger. So they suppressed appetite through various mechanisms, mostly stimulant-based. So, like fentramine, for instance, cranks up norepinephrine. So you're going to feel less hungry. But what fentramine doesn't do is it doesn't make the pizza commercial less interesting. It doesn't stop the 10 p.m. pantry rating, which, full disclosure, that is one of the things that I have traditionally, personally struggled with the most. And it doesn't quiet the part of your brain that lights up when someone brings, heaven forbid, donuts to the office. That's because hunger is not one thing, it's really two things. So there's homeostatic hunker, which is need-based eating. So you're burning calories, your energy stores dip, gorillin rises, and your hypothalamus says, okay, it's time to refuel. That's the low fuel light on your dashboard. When you eat and energy is then restored, fuel light turns off. Then there's hedonic hunger, which is reward-based eating. So you just finished a full meal, your stomach is physically satisfied, and then the dessert menu arrives, and something in your brain says yes. So that's not your stomach, that's your reward system. It's eating driven by pleasure, craving, and anticipation, not actual thermodynamic energy needs. Critical to understand that both are real, both are biological, both can be measured in a lab. Hedonic hunger is a neuroscience term for a specific pattern of brain activation that's driven by the mesolimic dopamine system. Here's why this matters. So older weight loss drugs, they worked primarily on the homeostatic side. So fendramine suppressed the low fuel signal. You feel less physically hungry. But for many patients, myself included, the real problem was never really the low fuel light. It was that reward system running at 11. The constant pull towards the pantry after a full dinner. So the inability to drive past a freaking fast food restaurant without going through a full hostage negotiation in your head. The fentramine did nothing for that. GLP1s work on both systems simultaneously. So that's why patients describe the experience as fundamentally different from anything they've tried before. And here's how I explain it to patients. So homeostatic hunger, it's like your cars, like I said, low fuel light. It turns on when you need gas, whereas hedonic hunger, it's like driving past a gas station, but they have a sign out there that says, hey, free car wash with fill-up. You don't need the gas, but boy, that that reward is appealing. You pull in, anyways. Older medications dimmed that fuel light. GLP1 medications also make that car wash signal much less appealing. So if you're listening to all of this and thinking, I wish my doctor explained things like this. That's exactly why I started Beric Health. Beric Health is my concierge telehealth practice. Real appointments, real time with a physician who understands these medications from the prescribing side and the patient side. I take pictures of appetite myself. I've lost over 80 pounds on it. When I talk about the three job sides, or homeostatic versus hedonic hunker, or why your dose might need adjusting, I'm not just reading from a chart. I've lived it. If you're on a GLP1 and feel like your care has been, here's your prescription, see ya in a month or two or three. Or if you want a doctor who actually sits with you and builds a plan around your body, not a one-size-fits-all algorithm, barrichealth.com. Link is in the show notes. Alright, back to the science. Now, there's an important distinction within the GLP1 medication class that I want to introduce today. Semaglutide, brand names Ozempic and Wagovi, activates one receptor in the body, the GLP1 receptor, so a single agonist, whereas terzepitide, which is Monjaro and Z-bound, activates two receptors, GLP1 receptor and the GIP receptor. So it's a dual agonist. GIP stands for glucose-dependent insulinotropic polypeptide, another wonderful committee name. But what matters is that GIP so adds a second channel of metabolic signaling. So it enhances the insulin response. It may have a direct effect on adipose or fat tissue, and it appears to contribute to the overall appetite suppression through mechanisms that we're still parsing out. Now in the head-to-head surmount five trial, trzepatide produced about 6.5% points more weight loss than semiglutide at their maximum doses, respectively over 72 weeks. So trzepatide also tends to be better tolerated on the GI side for most patients, though not universal, but I would generally put it, in my experience, at about 99% of patients tend to have fewer GI side effects on trzepatide. We'll do a deep dive on semaglutide versus trzepatide next episode. For now, the key concept is these medications use your body's own signaling system. So they're not adding something foreign, they're just amplifying something that already exists. Same hormones, same receptors, just turned up to 11. GLP1s do not make food taste bad. Patients sometimes ref report subtle taste changes, but the core experience is not aversion, so it's indifference. You still enjoy food when you eat. You just don't think about it constantly between meals. They don't work by making you sick. I know nausea gets all the headlines, but uh mediation analysis from the STEP trial trials found that less than 1% point of semaglutide's weight loss was actually attributable to the GI side effects. Patients who had nausea and patients who didn't lost essentially this same amount of weight. The mechanism is appetite and metabolic signaling, not suffering. This is a very important concept to understand. If you are experiencing food aversion and having significant nausea, that is not normal. That is not ideal with these medications. I do see that a lot on patients I may inherit who are on too high of a dose and having food aversion, it's pretty simple to solve. Pull back the dose to one that they're tolerating well and not having aversion with, and then gently work it into the weight loss zone. So again, there's absolutely a sweet spot, and if you're having food aversion, you're not in the sweet spot. Continuing on, so they are not stimulants, they do not make you jittery, they don't generally increase your heart rate significantly, and they don't cause the kind of crashes that you can get, like with fentramine. Some patients actually report feeling calmer on these medications because the constant mental noise about food is subsiding. You think about it, you're not fighting 10% of your it's a much more unified mind state, and a lot of patients notice that, and they feel mentally quite a bit better on these medicines. And they're not permanent changes to your body's wiring. When you stop the medicine, the natural GLP1 system bounces back and gets back to its baseline. So hunger returns, that set point is going to reassert itself. So that's not a flaw. That's what happens when you stop treating any chronic disease. We'll talk about what that means for the long game in later episodes. So here's what I actually tell my patients about how these medications work. You are not cheating, you are not taking a shortcut. You are correcting a biological system that was working against you. Your body's GLP1 signaling was not strong enough or long-lasting enough to counteract the genetic, hormonal, and environmental forces that have been driving your weight up. The medication fixes that specific problem. So if you needed glasses, nobody would tell you that using lenses is the easy way out of seeing clearly. This is honestly, in my view, the same thing. A biological tool for a biological problem. Next episode, we're getting specific. Semaglutide versus terceptide, the ultimate showdown. Which one is better? Who does better on which? I'll walk you through the trial data and what I see in my own practice with thousands of patients. Subscribe so you don't miss it. If someone in your life is curious about GLP1s and wants the science without the jargon, send up this episode. If you want a physician who takes the time to explain this stuff, perrichealth.com. I'm Dr. Cleek Berrick. See you next week.