Why Your Brain Thinks You're Full (Even When You're Not)

How did the Gila monster, a desert lizard that eats just five times a year, help unlock the science behind Ozempic, Wegovy and Mounjaro? In this episode of The Rest Is Science, Professor Hannah Fry and Michael Stevens (Vsauce) trace the strange journey from a molecule found in lizard venom to medicines reshaping diabetes and weight-loss treatment, exploring how GLP-1 helps regulate blood sugar, appetite and the hum of ‘food noise’. Early evidence suggests their effects may extend far beyond food, quieting cravings for alcohol and cigarettes, and even the urge to gamble. What might this reveal about the biology of wanting itself, and how much control do any of us really have over what we crave?-------------------For more information about Cancer Research UK, their research, breakthroughs and how you can support them, visit https://www.cancerresearchuk.org/our-research/rest-is-scienceCancer Research UK is a registered charity in England and Wales (1089464), Scotland (SC041666), the Isle of Man (1103) and Jersey (247). A company limited by guarantee. Registered company in England and Wales (4325234) and the Isle of Man (5713F). Registered address: 2 Redman Place, London, E20 1JQ.-------------------Find The Rest Is Science all over the internet by ⁠⁠clicking here.⁠⁠-------------------Video Producer: Adam Thornton + Teo Ayodeji-Ansell + Jack MeekAnimator: Sam BensonVideo & Social: Bex TyrrellAssistant Producer: Lucy LipscombeProducer: Simona RataSenior Producer: Lauren Armstrong-CarterChief Digital Officer: Samuel OakleyExec Producer: Neil Fearn Learn more about your ad choices. Visit podcastchoices.com/adchoices

• 0:01Speaker 00

  Hello and welcome to The Rest Is Science. I am Michael Stevens.

• 0:04Speaker 01

  And I'm Hannah Fry. Michael, you know, if you ask somebody if they want sugar in their tea and they respond, no, thank you. I'm sweet enough. Here's my question for you. How sweet are you? I want to know, how much sugar do you think there is in your bloodstream right now?

• 0:19Speaker 00

  Did you know that I've actually calculated this before?

• 0:21Speaker 01

  Have you?

• 0:22Speaker 00

  Yes, I did. This entire series of videos for a diabetes medication company, forgiving to doctors, they were never public. And the scripts they wrote were so boring, I did a bunch of like, V saucing them up. And I calculated, like, if a diabetic person with really high blood sugar got bit by a vampire, would they be a dessert? Turns out, no. But I don't remember at all what I calculated. But yeah, I did calculate, like, how sweet is my blood? Is someone with low blood sugar, high blood sugar? I think that, like, diffused into my whole body, I'm not that sweet.

• 0:59Speaker 01

  Vampires have not got sweet tubes, you know, because even a diabetic person with, like, all this sugar running around in their blood, it's not going to taste that sweet. But you, on the other hand, Michael, I mean, I haven't done the exact calculations. I didn't, I didn't want to sort of email through in advance for your height and weight. But it's about four grams in your blood.

• 1:16Speaker 00

  That's it?

• 1:17Speaker 01

  That's it, like a teaspoon, basically.

• 1:19Speaker 00

  Wow, a little teaspoon?

• 1:21Speaker 01

  A little teaspoon in your blood at any moment in time. You can eat a massive dessert, and your body will be like, no, too much, thank you, need to put, lock some of that away. Or you can, like, do a starvation diet and have none there, and your body will be like, what? Not okay, thank you, need to put more in.

• 1:38Speaker 00

  Right.

• 1:38Speaker 01

  This is like, an incredibly narrow window that your body is continually fighting.

• 1:44Speaker 00

  High blood sugar doesn't mean 400 grams. It means a little bit more than four. And low blood sugar is a little bit below that, that narrow path, that narrow band where we are fine.

• 1:57Speaker 01

  Exactly. So what I want to talk about today is how your body manages this incredible dance of keeping your blood fine, whatever you throw at it. And then, in turn, how people are now hacking our own biology via fat traps, in order to disrupt this system to our advantage.

• 2:30Speaker 01

  This episode is brought to you by Cancer Research UK.

• 2:32Speaker 00

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• 3:28Speaker 01

  For more information about Cancer Research UK, their research and breakthroughs, and how you can support them, visit cancerresearchuk.org/restiscience.

• 3:38Speaker 02

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• 4:10Speaker 03

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• 4:40Speaker 01

  Okay, there's two main hormones that are in charge of keeping this incredibly fine balance. One of them is insulin, which of course is the one that's the problem when people have diabetes. Do you know how insulin actually works, though? It's kind of clever.

• 4:53Speaker 00

  Okay, I thought you said, do you know how internet works? And I was like, whoa, it's a bunch of tubes, is all I know. Insulin, I don't remember.

• 5:02Speaker 01

  At top level, insulin is produced by your pancreas when you have too much blood sugar. If you're kind of, if you're, if you're all fine and good, it will take away excess sugar from your blood and put it into storage. That's sort of like the top line level.

• 5:14Speaker 00

  When it stores it, it doesn't store it as sugar.

• 5:16Speaker 01

  Correct. The way that it works is all of your, your muscle and fat cells, they have, I mean, simplifying slightly here, but they, they essentially have like little doors in their walls that glucose can pass through, these like very specific little protein gates. But normally, those doors are locked closed, right? The glucose can't get in. So that any glucose that's within the cell stays within the cell, it's not sort of floating in and out. And then what happens is that insulin is essentially like the lock for this door. So as insulin comes past, it opens up the door, the glucose can wander in. So if you do not have insulin in your body, if you're like a deprivation of insulin in your body, then you can have glucose literally standing right outside of a cell being like, hello, please let me in. And it just can't get in, right? If, if the insulin

• 6:00Speaker 01

  doesn't dock into its receptor to open the door, there's like, sort of nothing going on. So this is what's happening when people, especially with type 1 diabetes, is exactly what happens. Your blood can be completely full of sugar, way, way, way above the four grams that's sort of normal. But because the doors are not unlocking, your cells can't get any. So your body is like starving to death, despite there being this, this insane abundance of fuel right next door.

• 6:28Speaker 00

  Wow, wow. And by the way, glucose is the type of sugar that our body uses. If I eat a bunch of fructose, or lactose, or some other kind of sugar, the body goes, okay, cool. But we need to have glucose for the cells to

• 6:45Speaker 01

  Yeah.

• 6:45Speaker 00

  have the energy they need.

• 6:46Speaker 01

  Exactly. I mean, that's the whole, the whole thing about energy is it's glucose plus oxygen equals water plus carbon dioxide plus energy. Like, that's literally the thing that your cells are running on.

• 6:57Speaker 00

  So I use the energy to move. I breathe out the carbon dioxide. Thank you, glucose.

• 7:03Speaker 01

  Thank you very much, glucose. Appreciate it. But without insulin, you're in trouble, right? You're really in trouble. Anyway, at the other end of the spectrum, so that's what happens if you have too much sugar in your blood, that's what's supposed to happen is that all these doors open, and then it goes in and it gets stored. At the other end of the spectrum, you have something called glucagon, which is actually also, I think, created very close by in the pancreas. And this gets released when the blood sugar is low instead. So like, if you're fasting or overnight, or whatever it is. And that goes to the liver, and then the liver is, I mean, it's sort of like the body's pantry. It can break through stored glucose, stored as glycogen, can break it back down into

• 7:43Speaker 01

  glucose, it can pour it into the blood, and it can even manufacture sort of brand new glucose from scratch out of amino acids and other spare parts, right? If you really need to.

• 7:54Speaker 00

  By the way, glucagon would be a great name for a child.

• 7:58Speaker 01

  Glucagon, put down your sister's toys. Wait, are we saying glucagon is male or female?

• 8:04Speaker 00

  Oh, it could be either. It's just a great name for a child that makes everything sweeter.

• 8:09Speaker 01

  Well, that's true. Adds in sugar, adds in sugar when required. What about insulin as a child's name?

• 8:14Speaker 00

  Yeah, obviously insulin would be their sibling.

• 8:16Speaker 01

  Yeah, necessary, but, but robs the sweetness.

• 8:20Speaker 00

  That's right.

• 8:21Speaker 01

  Okay, so here's this puzzle, right? So, so obviously, people with type 1 diabetes have existed for, I mean, probably as long as people. But here is a real puzzle that bothered doctors and scientists for, for a really long time. If you take some glucose and you drink it, right? Let's just say you take some, some Lucozade or something, right? Something really, really sugary and you drink it. Your blood sugar rises, as expected, and your pancreas will dump out loads of insulin to, to sort of deal with it, to kind of clean it up and make sure it doesn't get too much. Fine, expected. Now, if you take exactly the same amount of glucose, not as Lucozade this time, but the same amount of glucose, and instead you just inject it directly into a vein, you're bypassing the

• 9:03Speaker 01

  gut, but it's the same sugar, same blood concentration, you would expect that your pancreas should react in the same way. It should be like, okay, loads of sugar here, dumps out loads of insulin. But it doesn't. What actually happens is your pancreas does produce insulin, but way, way less, like half as much as it does if you actually ingest it. People notice this, like, that is very strange, right? That, like, the only difference that's going on here is, is the route that it gets into your bloodstream, but still it's about being in your bloodstream. So this was, I think, one of the first clues that people were like, okay. It looks like something is happening in your gut or in your mouth as you're literally

• 9:43Speaker 01

  ingesting something that is telling your pancreas to produce more insulin.

• 9:49Speaker 00

  You can't bypass the gut or the pancreas acts differently.

• 9:53Speaker 01

  Right, there's something going on here. And so in the nineteen eighties, stomach ulcers used to be a really, really big thing. Do you remember like when, when I was a kid, you would hear about, ah, it's got a stomach ulcer, like a stress stomach ulcer is really awful.

• 10:08Speaker 00

  Yeah. And you heard about this in movies and the media all the time. Like every dad had an ulcer that was getting worse because the kids were loud. I thought that would be a much bigger part of my life today.

• 10:18Speaker 01

  Yeah, but you don't see them anymore at all.

• 10:20Speaker 00

  It's like the Bermuda Triangle, like the nineties was full of all these things that I, I learned to be very, very aware of and fear. And then now I'm just like, hey, what happened to the Bermuda Triangle? What happened to ulcers? Not that they've gone away, but yeah, yeah, you're right.

• 10:35Speaker 01

  Not completely, but they sort of had because it turns out that they were caused by bacteria.

• 10:39Speaker 00

  Yeah.

• 10:39Speaker 01

  Um, there's a great story about how they proved that it was bacteria because the person who came up with the discovery decided to swallow, to drink the bacteria, deliberately give himself a stomach ulcer in order to then demonstrate that that was the thing that caused it. Anyway, that's by the by.

• 10:53Speaker 00

  Right. So drinking someone's ulcer, bad idea. It's contagious.

• 10:59Speaker 01

  Don't lick the inside of someone's stomach if they're infected with ulcers.

• 11:04Speaker 00

  Let me just write this down because actually no, I need to cross it off. It's on my list of to do's today. But yeah, ulcers weren't caused by a stressful job.

• 11:14Speaker 01

  I mean, I think it probably exacerbated it. Your immune system would be more liable to be unable to fight something and so on. Okay. Here's the thing, what they used to do, which actually seems brutal now, I think, when you think about it, is if people had stomach ulcers, they would be like, well, I don't know, should we just cut out that bit of the stomach? Like, should we just go in there and like loft it out maybe? I think they would only do it if someone had a particularly nasty ulcer. They'd go in, they would like cut out the bottom of your stomach. Okay. And the way your stomach is sort of like this, it's, it's kind of almost like a U-bend shape, right? Sort of like dips below and then comes back up. What then happened was some of these patients started having these

• 11:56Speaker 01

  really bad low blood sugar attacks. They'd be like really shaky. They'd be really sweaty. They'd be like faint and hypoglycemic. They're like, what on earth is going on with these people? Like, why, why is this happening? And they worked out that it was because their bodies were pumping out more insulin than it should have been. So it was like depleting all of the sugar that was in their blood really quickly. The balance was off essentially.

• 12:22Speaker 00

  Let me get this straight. So if you eat the glucose, then normally everything's fine. If you inject it and bypass the gut, not enough insulin is made.

• 12:32Speaker 01

  Correct.

• 12:33Speaker 00

  If you cut part of the stomach away and you eat the sugar, then too much insulin is made.

• 12:42Speaker 01

  Exactly. So there's some sort of messaging signal that's going on. When you ingest food all the way through, some messaging system is going on, um, that is telling the pancreas to release the correct amount of insulin. And they worked out essentially that what was happening, that down there in the bottom of the stomach is this little muscular valve. And what it's doing is it is, its whole job is to be really stingy, right? Is to like hold back everything in the stomach and then squirt it through really carefully, like drip, drip, drip, drip, drip. Now, if you take that valve out, the food doesn't

• 13:21Speaker 01

  drip, it like dumps the whole meal kind of comes crashing through into the lower gut all at once, right? And so they were like, okay, well, this signal, maybe this signal is around about there somewhere because as all this food is like getting dumped in, the signal is going like, whoa, like crazy. We need insulin now. We need loads of insulin way, way, way faster than the body needs it or can handle it. And that's what's making people be hypoglycemic. All of this is going on. These couple of scientists in Boston and Harvard, they were like, okay, this whole thing about glucagon, which isn't their son, unfortunately.

• 13:58Speaker 00

  Or daughter.

• 13:59Speaker 01

  Or daughter.

• 13:59Speaker 00

  Any kind of child should be called glucagon. That's the official policy of me.

• 14:05Speaker 01

  Okay. Anyway, they were like, right, we want to know what, what gene is, is creating this. And they were particularly interested in the angler fish because the angler fish has this entire organ, which is called the Brokman body for making glucagon. Okay. So, so like normally you've got like a pancreas in a human or in other animals. And if you want to go in and you want to work out where the glucagon is being made, you've got like kind of pick out tiny little bits of glucagon and it's all mixed in with other bits. It's really difficult. But in the angler fish, it's really simple. So what they did is they managed to find the gene for glucan via this fish. And then they were really surprised to discover that this, this gene also makes two other little peptides. Peptide, by the

• 14:48Speaker 01

  way, anyone who has like ever experienced a skincare advert will think that it's something that you put on your face. Peptide is just a, it's a cute little chain of amino acids. Okay. That's all it is. It's like a little cute, cute little, cute little peptide.

• 15:01Speaker 00

  A cute word for a cute thing. Peptide is another great child's name.

• 15:07Speaker 01

  Hey peptide. We've got triplets now. I think peptide should be the pet. Should be like a little mini chihuahua, you know?

• 15:13Speaker 00

  It's the little dog.

• 15:14Speaker 01

  It's the little dog.

• 15:15Speaker 00

  I love this little family that we're creating, Hannah.

• 15:19Speaker 01

  We've got to decide what the mom and dad are called at some point.

• 15:22Speaker 00

  Yeah, we will.

• 15:23Speaker 01

  But one of them surely is called ulcer.

• 15:26Speaker 00

  Ulcer, that's the dad and the mom TBH, TBD. TBH, what is TBH? To be honest. Oh, gosh. The kids are gonna blast me for misusing an acronym.

• 15:39Speaker 01

  I think you'll feel all right. Okay. So this gene that makes glucan turns out also makes these two little peptides. And they're looking at them like, well, I don't know what this is, don't know what this one is, don't know what this is. Oh, it's sort of a bit like a glucagon. It's glucagon like, a glucagon like peptide? Let's call them glucagon like peptide one and glucagon like peptide two, GLP one and GLP two.

• 16:02Speaker 00

  There they are.

• 16:03Speaker 01

  You may have heard of GLP one.

• 16:06Speaker 00

  Yeah.

• 16:06Speaker 01

  Because this is the hormone that fat jabs aim to mimic. Um, things like Ozempic, Wegovy, Manjaro, all of those. It turns out that you have these little factories, they are essentially this messenger system directly to your pancreas to say, uh, hello, we're just gonna get some insulin out there because otherwise our blood sugar is gonna get, get, end up being a bit too high.

• 16:32Speaker 00

  Okay. So that's what GLP one does. It's a messenger to the pancreas to make insulin?

• 16:40Speaker 01

  Well, yes, but only if the blood sugar is high. The reason why people were so excited about this is because if you have somebody with diabetes, right? And you just whack a load of insulin into their bodies, well then, great. You know, you've dealt with that particular sugar high, but you need to assess it really carefully because you could accidentally put too much in and then have their sugar levels dropping off the, the charts instead.

• 17:08Speaker 00

  Yeah.

• 17:08Speaker 01

  It's unbelievably difficult to get that balance, that incredibly fine balance, right at all times. Because also, if you have blood sugar that's too low, I mean, your brain literally starves.

• 17:20Speaker 00

  Yeah.

• 17:20Speaker 01

  It cannot function. I mean, it's really, really dangerous. But if you have too high a sugar in your blood, then you sort of candy all of your, all of your internal organs, you know? Uh, your eyes in particular are really, really susceptible to going blind if there's too much sugar in your blood for a prolonged period of time. The thing about this GLP one that everyone was excited about was like, okay, so insulin is like, it's kind of, it's kind of fixing the problem with a sledgehammer, you know, which is like, whoa, that's better than nothing, but still not great. But GLP one will only signal the pancreas to produce more insulin if you have high blood sugar. So if you've got GLP one floating

• 18:04Speaker 01

  around and your blood sugar is low, your pancreas will not go crazy.

• 18:09Speaker 00

  Right.

• 18:09Speaker 01

  Right. It's only because, the reason why you've got such big spikes in the people who'd had those stomach ulcers removed was because this great big dump of food coming through the stomach coincided with there being a lot of sugar in the blood and therefore the, the pancreas overreacted. So in nineteen ninety-three, this Danish scientist, he's called Jens Jørg Holst, he was like, okay, well, let's, let's try this, shall we? Should we just, should we just whack a load of this, this peptide, this cute little peptide, GLP one into people's bodies, see what happens? And he did it with people who had diabetes in particular, right? So this is all about a diabetes medication. So for starters, having GLP in the body did normalize people's blood glucose levels, right? So it worked. But

• 18:53Speaker 01

  he says, the first problem was that we realized that injecting people with simple subcutaneous injections of this peptide ultimately didn't really work. The reason was that the peptide was destroyed in the body within minutes. So it couldn't be done that way. And you couldn't give them a higher dose because they just start to puke all over the place. So that didn't work either.

• 19:13Speaker 00

  That's the scientific term, puke all over the place.

• 19:15Speaker 01

  This is essentially why this is going. Did the scientific study, injected people, they just all started puking all over the place, which is, I mean, tells you that like flooding your body with this stuff is not, is not good. But the other point about how it gets broken down by the body really quickly, like this made it sort of, okay, maybe there's this miracle drug somewhere, but it's not going to work. Cause

• 19:39Speaker 00

  Right.

• 19:39Speaker 01

  Because essentially your body, in order to keep that incredibly fine balance, that four grams of sugar, it can't let the GLP one like float around for too long, you know? Cause then you'd be, you'd be like carrying on putting out insulin long after it had been, the blood sugar had been dealt with. So you also have this little enzyme in your blood, which is called DPP four. I don't know if that's going to be the mother's name.

• 20:01Speaker 00

  That's the mom. That's the mom. We met her.

• 20:04Speaker 01

  She's here.

• 20:05Speaker 00

  Yeah. Maybe we shouldn't call the mom that because it sounds like a, a very awkward question. What's DPP for?

• 20:16Speaker 01

  She's here. She's snippy though, the mum. I mean, that's essentially her job is to go along and cut GLP one in half.

• 20:22Speaker 00

  And destroy it.

• 20:23Speaker 01

  I don't think she's, I mean, she's good. She's keeping balance, everything balancing, but she's sort of, um, she's doing it by cutting the play in half, you know?

• 20:31Speaker 00

  Yeah.

• 20:32Speaker 01

  Yeah. Everyone was like, you know, it feels like we're on to something, but everyone's puking and it doesn't work. So this is not looking so good. And then enter into the frame, the unusual family pet, the Gila monster. So this is a lizard, right?

• 20:51Speaker 00

  Yes.

• 20:51Speaker 01

  Cause the Gila monster solves everything, my friend. The Gila monster is the root source of this miracle that happened with diabetes.

• 21:01Speaker 00

  Tell us about the animal.

• 21:02Speaker 01

  It's a venomous lizard, lives in America. It's quite fat. It's quite like chunky. Um, it's got like this orange, black skin kind of mottled. They live in the desert. They're like, they're quite lazy. They don't move very fast. So they only actually manage to catch and eat a meal about five times a year.

• 21:21Speaker 00

  No kidding.

• 21:22Speaker 01

  Yeah. Have you eaten this quarter?

• 21:25Speaker 00

  Okay, I can see how this is related.

• 21:27Speaker 01

  But when they do, when they do, they eat like half their body weight all at once.

• 21:30Speaker 00

  Right, okay.

• 21:31Speaker 01

  But scientists were like, right, well, this guy over here, this Gila monster is like, he's going very long periods without eating. They've got to have some way to keep this balanced, you know, their metabolism running really smoothly throughout that time. The thing is, one of the reasons why you might know the Gila monster is that they bite humans, or they can bite humans. The bite is venomous. It causes this incredible pain. Something else kind of separately that scientists had noticed in the 1970s and 80s, when people had been bitten, was that the victim's pancreas would start secreting all kinds of hormones.

• 22:05Speaker 00

  Really?

• 22:06Speaker 01

  I mean, you're absolutely seeing where this is going, right?

• 22:09Speaker 00

  Yeah.

• 22:10Speaker 01

  A team of scientists, they decided they would, they would get the venom of this Gila monster and they would test it on pancreas cells to see if any of them did anything, which is really difficult because it's like this kind of tangled web of molecules, right? But there's one venom in particular that makes a pancreas start secreting. And they wrote this paper about it. They just left it. It was untouched for like 10 years. No one touched it. No one went anywhere near it. And then in the early 1990s, this different doctor, Dr. John Eng, read this paper and was like, oh, I wonder what, I wonder what venom spit from the Gila monster is doing to a pancreas? That's like so weird. He found

• 22:52Speaker 01

  in this venom, this chain of 39 amino acids, cute not peptide, and he called it Xendin four. They really need to get better names for these things. Xendin four. Is that the mum?

• 23:05Speaker 00

  Xendin four. That's the second wife, maybe.

• 23:11Speaker 01

  I think that might be the, the car number plate.

• 23:13Speaker 00

  Okay, fair enough. Yeah, I like that.

• 23:15Speaker 01

  Anyway, the thing is, is it turns out that this little peptide is almost the same as GLP one. Like they're really, really similar. Um, but it is different in one important way, which is that venom has to be stable, right? Like the animal makes the chemicals and the venom and it sort of sits inside the animal's body. So it has to last way longer, uh, without breaking down. And the crucial thing is that the peptide in this Gila monster's spit, instead of like disappearing in a few minutes like GLP one does, can last for ages and ages and ages. And the reason why is that the enzyme can't cut it.

• 23:58Speaker 00

  DPP four can't cut it up.

• 24:00Speaker 01

  Is blocked. It's blocked. I mean, this is like an unbelievable revelation. I think just really demonstrates the way that science sort of inches forwards towards progress because over here, someone's looking at venom bites in lizards. Over here, somebody's looking at patients with diabetes. Over here, somebody's looking at stomach ulcers. And then it ends up all coming together and this lizard that eats four times a year, turns out is carrying in its spit is an almost perfect human version of the like satiety hormone that sort of makes you feel full. Right? It's like they're absolutely crazy that this is the case.

• 24:42Speaker 00

  Is that what GLP one does? It makes you feel full?

• 24:45Speaker 01

  Yes. Well, I'll get to that in a second about, because we don't know totally how it completely works. We know a bit about how it works, but one of the things is it makes you feel full.

• 24:53Speaker 00

  So Xendin four lasts longer than GLP one.

• 24:57Speaker 01

  Cause it can't be cut.

• 24:58Speaker 00

  If you inject someone with a bunch of it, does it make them puke all over the place?

• 25:03Speaker 01

  Well, you still have to be quite careful about that. But, but okay, for starters, they didn't just, they didn't like harvest the venom of a monster, the spit of a monster to do it. They like manufactured synthetic versions of the same thing. The very first class of these drugs were just copying the lizard's protein. But the modern ones, what they've done is they've like tweaked it a tiny bit. So they've, they've tweaked the spot where the enzyme, um, where DPP four can latch on to, so that it can't really get a grip anymore. So there's no risk of it sort of breaking down. And then they've also added on, I just find this crazy about modern microbiology is obviously astonishing. They've like added on this little tail, this little like fatty tail off it, which can

• 25:47Speaker 01

  hook onto the albumin, which is this really big carrier protein that kind of floats around your blood, is hitching a ride essentially on like the main train so that it can move around your body. And, and because it's hitched a ride, it can't get filtered out by your kidneys. So it's like it stays in your body for longer as well. So, so you've moved from GLP one, which is a molecule that you make yourself that lasts about 90 seconds before it gets cut up by the wife. And now you've got semaglutide, which lasts for a week in your body. That's the whole thing. You haven't invented anything new. You've just taken like a body's own process. And then you've made that process instead of lasting for 90

• 26:30Speaker 01

  seconds after you've eaten a biscuit, instead lasts for, you know, a whole seven days.

• 26:35Speaker 00

  Wow. That really is incredible. Who was the dad again?

• 26:39Speaker 01

  The dad, dad was ulcer.

• 26:41Speaker 00

  The dad was ulcer.

• 26:42Speaker 01

  He's got a bit part in the story. Let's be honest.

• 26:45Speaker 00

  Yeah, this is the dad who like went out for cigarettes and never came back. GLP one came around, but it still wasn't quite perfect. But then the dad put in the work and he grew as a person and became this manufactured semaglutide that sticks around, hitches a ride, does the work. That's just incredible.

• 27:05Speaker 01

  Isn't it? I tell you what, let's go for a break and then when we come back, I'll answer your question because you, you have asked about four times, what is it actually doing? And I have got an answer for you ish.

• 27:29Speaker 00

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• 29:30Speaker 01

  Okay, we're back. You've asked, what do they actually do?

• 29:33Speaker 00

  Yeah.

• 29:34Speaker 01

  And the answer is, there's four things with varying degrees of us understanding them.

• 29:42Speaker 00

  Yeah, hold on, we're talking about GLP-1?

• 29:44Speaker 01

  GLP-1, yeah.

• 29:46Speaker 00

  Okay.

• 29:46Speaker 01

  Because, because semaglutide is doing the same thing. It's like, it's the same shape as GLP-1, it's doing the same thing. It's just got these additions to stop it being chopped apart.

• 29:56Speaker 00

  Yeah.

• 29:56Speaker 01

  We know GLP-1 goes to the pancreas, tells it to make insulin when the blood sugar is also high.

• 30:03Speaker 00

  Right.

• 30:03Speaker 01

  That is what makes it an amazing medication for diabetics. It's also why your, you know, your blood sugar doesn't crash to the floor. It sort of, it keeps you regulated in a really good way. It also, so as well as increasing your insulin, it also calms down your glucagon.

• 30:22Speaker 00

  Okay.

• 30:23Speaker 01

  This is the one, of course, that's telling your liver to sort of pour stored sugar into the blood. So it's just on both ends of the, on both ends of that spectrum, it's just saying, guys, calm down. All right?

• 30:34Speaker 00

  Yeah.

• 30:35Speaker 01

  No big deal. Just like a good dad, you know?

• 30:37Speaker 00

  Yeah, it kind of keeps the peace, lets everyone talk. I love it. Okay.

• 30:43Speaker 01

  It also, we know that it slows down how fast your stomach empties into your intestines. That means essentially that, that food is going to sit in your stomach for longer. It's gonna, sugar will trickle in much slower instead of arriving in a flood, uh, which, I mean, if you, I don't know, like, you sort of know to do this anyway. I think, like, I think people broadly know that having something like porridge for breakfast is better, especially with like rolled oats or whatever, is better than having pancakes with maple syrup. And it's because the sugar is being released more slowly, so.

• 31:18Speaker 00

  Well, better, better depends on what your goal is. If your goal is to get really sugared up, then just drink the syrup. But yeah, if you want that long release of energy, you have the porridge.

• 31:29Speaker 01

  I mean, this is true, but I think the effect of that is that it also just makes you feel physically fuller for a longer time.

• 31:36Speaker 00

  Ah, and there's the rub.

• 31:37Speaker 01

  There is the rub, but here is the ultimate, ultimate rub, because GLP-1 manages to talk to your brain. There are receptors for GLP-1 in the hypothalamus. There is a, a little patch in your brain stem. And when GLP-1 lands there, it basically turns down the volume on hunger. It's not like, oh, I'm being disciplined and I'm not gonna eat, I'm gonna push myself through. It's like, you just, it just doesn't even occur to you. It doesn't even occur to you.

• 32:07Speaker 00

  The desire is, is not there.

• 32:10Speaker 01

  The desire is not there. This is the, the thing that really makes it this amazing, amazing intervention for obesity. Because, you know, it's not like, it's not feeding, it's feeding up your metabolism. It's not blocking fat. It's not a stimulant. It's not like, you know, um, dissecting sections of your stomach like gastric bands used to. It's just changing the demand. Like, that's it. It's just, just turning down the dial on how you think about it.

• 32:38Speaker 00

  I'm a little surprised because I thought that the big innovation we would see would be that we would find a way to allow people to continue to desire and consume a lot of food without any problems health-wise. Because that's what made more sense for companies. Like, they need to sell all this food to us. And the more food we buy, the, the, the more their profits go up and the happier their boards are. But a medication that causes a decrease in demand sounded too anti-capitalism to ever take off. And yet, here we are.

• 33:13Speaker 01

  Except that there's the other capitalism of it on the other side.

• 33:16Speaker 00

  That, that's right. That's right.

• 33:17Speaker 01

  In the sense of like the capitalism of selling the drug.

• 33:20Speaker 00

  Right.

• 33:21Speaker 01

  I think you make a really important point here, which is that when companies have been making foods, whether it's like breakfast cereals or, you know, like crisps that you might snack on over and over again, especially if those, that food has existed for, for a really long time, the thing that the company is trying to optimize for is volume, you know? You go in and you have like a sit-down, a consumer panel where they all try the stuff. And of course, they're asking them, how delicious is it? Did you enjoy it? Was it really tasty? But the thing they care about most was how much did you eat?

• 33:53Speaker 00

  Right.

• 33:53Speaker 01

  What volume did you consume? And, I mean, I'm not just saying this is like a hunch, right? Like, there is so much evidence that this has been the metric that these companies have optimized for over and over again.

• 34:05Speaker 00

  And it should have been, because if I'm investing in these companies, I need them to have customers that want to consume, consume, consume. Otherwise, they don't grow.

• 34:15Speaker 01

  Right, except that the way to get people to consume more and more food isn't to make it more and more delicious. It is instead to make the food so easy to disintegrate that it never reaches the part of your stomach which releases these hormones to tell your body that it's full. That whole idea of Pringles being, once you pop, you can't stop, it is literally true. It is literally true. They are so predigested in laboratories, macerated to death, that when it enters your mouth, it just evaporates into thin air and the evolutionary system that your body has spent millions of years perfecting

• 34:58Speaker 01

  is no longer capable of telling you you need to stop.

• 35:03Speaker 00

  That's incredible, because I would never eat like three baked potatoes all at once. But if you predigest them for me by mashing them up into a, a powder and reconstituting it into a fun shape and adding a lot of fun flavors, I will blow through that and I'll still be hungry. So I will keep buying and buying and buying, and the Pringles company can make a lot more money than the potato farmer.

• 35:30Speaker 01

  But you're not hungry because the calories haven't been consumed. You're not hungry because your body doesn't have the same glucose input. You're hungry because you have overridden the systems that your body has in place to tell you when to stop eating.

• 35:45Speaker 00

  Right.

• 35:46Speaker 01

  Right? Which is wild. So what GLP-1 is doing in a world where all of these products exist, all of these super-processed, ultra-processed foods, it's basically like there is this little sort of arms race going on within your own body. So it's like, it's extra capitalism rather than less capitalism. It's like, you had the capitalism of the food companies, kind of like make people eat more, more, more, more, more. And now you've got the capitalism of the pharmaceutical companies being like, hey, here's the war against it.

• 36:22Speaker 00

  So then the solution, if I'm like trying to sell a lot of food, is that in order to keep hitting my benchmarks for profits, I need to make the food probably just more expensive. I need to find a way to say, look, you're gonna buy half as much, but now it's like so organic or it's got just the right trendy thing in it that it's worth paying twice as much for, phew, we're not losing money.

• 36:47Speaker 01

  Or you could do the other thing, which is what apparently some companies are doing, which is to start researching anti-GLP-1 foods.

• 36:56Speaker 00

  Whoa, that's it, isn't it? The, the, the third option is to just buy the GLP company and then you're like, you know, you're.

• 37:04Speaker 01

  Keep it going around and around and around.

• 37:06Speaker 00

  You sell the food and the toilet paper. You're just there for the whole cycle. So wow, so anti-GLP food additives.

• 37:15Speaker 01

  Yeah.

• 37:16Speaker 00

  Spark a desire that these GLP-1, I mean, that's not really what they are. They're, they're modified versions of the GLP-1 hormone.

• 37:25Speaker 01

  Yeah, you can think of them as GLP-1s.

• 37:27Speaker 00

  Got it. So yeah, finding some additive that makes, that sparks a desire for more that GLP-1, like medicines, cannot touch would be a goldmine.

• 37:40Speaker 01

  The thing I think that's really interesting about the GLP-1 stuff, like, that is actually sort of aside from the food industry, is that, um, the effect that it has on the brain does appear to go beyond just not wanting to eat.

• 37:54Speaker 00

  That's what I've heard.

• 37:55Speaker 01

  I've tried them, right? I've, I've like had them in the past. And you hear people describe food noise, okay? So like, and, and I think, actually, I think Oprah Winfrey said something about this when she started on, on semaglutide. She was saying that it just hadn't occurred to her that people who were thin, it just, they didn't think about it. It's not, it's not that they were like so capable and strict and like able to resist. It's just that they didn't have to fight the battle in the first place.

• 38:23Speaker 00

  That's right. They weren't resisting anything. It wasn't there in the first place. Yeah.

• 38:27Speaker 01

  Exactly. And so I've definitely had that experience of, of this food noise being turned down, that, that dial of food noise being turned down. Absolutely have had that, um, had that experience. But there is this evidence that actually it turns down the dial on all kinds of other over-consumption behaviors. So alcohol, for example.

• 38:44Speaker 00

  Yep.

• 38:45Speaker 01

  Smoking, even gambling.

• 38:47Speaker 00

  Yep.

• 38:47Speaker 01

  Which is incredibly fascinating that actually you could potentially satiate that with a GLP-1 mimicker.

• 38:56Speaker 00

  Yeah, and like we've said, satiate almost isn't the word, because you're actually cutting away the desire at the root. It's not there to be sated. There just isn't, you're just, you exist without the desire and the need and the drive to consume, whether it be food or even experiences like gambling. That is part of human experience, though. So I have heard people complain about how like, yeah, I'm not like desiring a bunch of sweet pies, but at the same time, my love for my grandmother's pies was a big part of our relationship and now it's gone.

• 39:37Speaker 01

  Yeah, I mean, I would say when when I have been on it, it's not that food tastes less delicious. It's not that you can't plan and enjoy the planning of a really amazing meal, you know, it's not like that. It's just that you, you know, I I remember the first week when I had taken it and I was in a hotel in New York, so I was really jet lagged. And like normally in that situation, I will order room service and I will like have a massive burger and I'll sit on the bed and I watch a stupid film and I just eat the entire thing, right? And I wanted to do exactly the same thing. I was in a bathrobe, you know, whatever. I was there, I was ready and I had this massive burger and I had two or three bites and it was great. And then I was done.

• 40:19Speaker 00

  Right, right.

• 40:20Speaker 01

  It just stopped.

• 40:22Speaker 00

  So does it have an effect on our desire to keep scrolling on social media? Like, that's another one that goes like, I can't get enough and I just, I need to check my phone. But you're not seeing the same effect there.

• 40:36Speaker 01

  I haven't seen any evidence on that. There was one really big hope, actually, about how it might end up having an impact on the development of Alzheimer's in the brain.

• 40:49Speaker 00

  Really?

• 40:50Speaker 01

  There was this hope that actually having GLP-1 and these receptors in the brain might end up having this really positive impact on dementia and specifically Alzheimer's. But they did this really big trial with people, early stage dementia, early stage Alzheimer's, I should say. And although some of the things sort of around it were improved, actually, really, there was no difference to placebo, which is kind of, I think people were kind of, were pretty disappointed that this might be this panacea that actually, you know, cures sort of, sort of solves all kinds of of human ills.

• 41:23Speaker 00

  That would have been huge. Imagine that. If we, if we had medications for dementia, for cognitive decline, and then, then what comes after that? That's always been my question. Like, it used to be the heart. We can, people can survive heart issues better now, but then you live long enough to hit dementia. After that, you live long enough for what? What's the next thing?

• 41:52Speaker 01

  Yeah, I totally agree. I totally agree. And I think that actually, I mean, this, this, this thing that I've mentioned a couple of times in this, in this program about how scientists are taking an existing protein or existing peptide, and then they're redesigning it and they're like adding a bit here and adding a bit there. There's this explosion of research in this type of biology, and in a really, really, really exciting way, accelerated bluntly by the amazing use of AI, very domain specific, very focused, but a sort of AI assisted way to understand how these molecules and proteins interact with one another.

• 42:27Speaker 00

  What does the AI do here?

• 42:29Speaker 01

  There's one in particular, which is called AlphaFold. All of the stuff that I'm describing, all of the things about proteins, when you get down to that level, it's all about the physical structure of these chains of amino acids, that these long, long, long ribbons of amino acids that fold in this predefined way. But getting from what the ribbon was doing, the kind of chain of molecules, to what the folded pattern was, was incredibly difficult. The first person who managed to, to work out the folded pattern of a protein won a Nobel Prize, right? You could, you know, even very recently, an entire PhD would be like, can you work out the folding of this one protein? And then this Demis Sarbas, a friend of mine, who's the founder of DeepMind, him and his colleagues, particularly

• 43:13Speaker 01

  John Jumper, they won a Nobel Prize for this. They created an AI with the sole focus of working out how to go from the ribbon of amino acids to a folded protein, and then essentially folded all the proteins that humans know about, and then released it for free to the entire world.

• 43:33Speaker 00

  Which proteins has artificial intelligence discovered for us? Because the Hila monster, that discovery was, was prior to artificial intelligence.

• 43:44Speaker 01

  So it's not that artificial intelligence has necessarily discovered proteins, but it has given us this mechanistic understanding and ability to predict what the proteins are going to look like, how they're going to interact with molecules that might be from drugs or parts of the body, that has just completely shortened in this unbelievable way, the like, the work process that you need to go through when it comes to designing medicines, understanding diseases. I mean, this is like, for me, I think this whole thing about Alzheimer's that we were talking about a moment ago, I don't know, if I was a betting woman, I would put money on, on the fact that, that we will come up with some miracle,

• 44:27Speaker 01

  what feels like a miracle to us now, that there, I think that there is going to be some, some miracle intervention for Alzheimer's within the next 10 years or so, purely because of how these AI techniques have just completely accelerated our ability to understand these, these domains.

• 44:44Speaker 00

  Right.

• 44:45Speaker 01

  Also, my dad had Alzheimer's, right? So I'm on the list, okay?

• 44:48Speaker 00

  Yeah, my, my grandfather did too. So, and it's been a big cause for the curiosity box for the work I do there, is, is just brain health in general, whether it be cognitive decline or otherwise. Man, just, but like a lot of other innovations, it's one of those, like there's two doors, and you can use it to find these medicines, you can also use it to find their antidotes, right? Okay, so we figured out a way to quell the desire, but we could also create desires that slip through. And you've got this arms race, which is the story of human technology.

• 45:23Speaker 01

  It absolutely is. And there's definitely some quite serious downsides to the potential of biological weapons, biological warfare, all kinds of potential things on the horizon.

• 45:36Speaker 00

  Well, sure. And, and these ups and downs were always there in, in the human story, but the, now we can get to them faster, which can be even greater or even worse. It's just accelerated.

• 45:50Speaker 01

  Absolutely. Lots more on the horizon, I think, with all of this stuff. Yeah, that's my little tour, the history and wonder of GLP-1s and the little family.

• 45:59Speaker 00

  And the little family we created. Yeah, I love that. But I found this fascinating because I had, I actually had not learned any of this. It was about time that I understood this, this phenomenon and what's driving it.

• 46:14Speaker 01

  All right. Well, good stuff, as ever. If you would like to send us your questions, your ideas, anything you like, you can email us, [email protected]. Leave us a comment on our YouTube, on Spotify, or send us a little message on Reddit, we read them all.

• 46:29Speaker 00

  Or just yell really loud out your window. We might hear you. But at the very least, please subscribe to us on YouTube or follow us wherever you listen to podcasts and we will see you next time.

• 46:39Speaker 01

  Bye bye.

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