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

0:00Hannah Fry:Hello and welcome to The Rest is Science. I am Michael Stevens. 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? Did you know that I've actually calculated this before? Have you? Yes, I did this entire series of videos for a diabetes medication company. for giving to doctors. They were never public. And the scripts they wrote were so boring. I did a bunch of like V-saucing them up.

0:37And 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.

0:59Hannah Fry:Vampires have not got sweet tooths, 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. That's it. That's it. Like a teaspoon, basically. Wow. A little teaspoon. A little teaspoon in your blood at any moment in time. You can eat a massive dessert and your body will be like, nope, too much. Thank you. You need to lock some of that away.

1:30Hannah Fry:Or you can do a starvation diet and have none there and your body will be like, what? Not okay. Thank you. You need to put more in. This is like an incredibly narrow window that your body is continually fighting. 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 narrow path, that narrow band where we are fine. 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.

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4:37Hannah Fry: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. 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. At top level, insulin is produced by your pancreas. When you have too much blood sugar, 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.

5:11When it stores it, it doesn't store it as sugar.

5:14Hannah Fry:Correct. the way that it works is all of your muscle and fat cells, they have, I mean, simplifying slightly here, but they essentially have like little doors in their walls that glucose can pass through. These are like very specific little protein gates. But normally those doors are locked close, 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 one So if you do not have insulin in your body, if you have 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.

5:55Hannah Fry:And it just can't get in, right? If the insulin 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, this 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 insane abundance of fuel right next door. 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.

6:39But we need to have glucose for the cells to have the energy they need.

6:43Hannah Fry:Exactly. I mean, that's the whole thing about energy is it's glucose plus oxygen equals water plus carbon dioxide plus energy. That's literally the thing that your cells are running on. So I use the energy to move. I breathe out the carbon dioxide. Thank you, glucose. 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.

7:24Hannah Fry: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 sort of like the body's pantry. It can break through stored glucose, stored as glycogen, can break it back down into 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. By the way, glucagon would be a great name for a child. Glucagon, put down your sister's toys. Wait, are we saying glucagon is male or female?

8:01It could be either. It's just a great name for a child that makes everything sweeter.

8:06Hannah Fry:Well, that's true. Adds in sugar. Adds in sugar when required. What about insulin as a child's name? Yeah, obviously insulin would be their sibling. Yeah, necessary, but robs the sweetness. That's right. Okay, so here's this puzzle, right? So obviously people with type 1 diabetes have existed for probably as long as people. but here is a real puzzle that bothered doctors and scientists for a really long time. If you take some glucose and you drink it, right, let's just say you take some leucosate 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 sort of deal with it, to kind of clean it up and make sure it doesn't get too much.

8:47Hannah Fry:Fine, expect it. Now, if you take exactly the same amount of glucose, not as Lucas said this time, but as the same amount of glucose, and instead you just inject it directly into a vein, you're bypassing the 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 something like, that is very strange, right?

9:24Hannah Fry:That like the only difference that's going on here is the root 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 ingesting something that is telling your pancreas to produce more insulin. You can't bypass the gut or the pancreas acts differently. Right. There's something going on here. And so in the 1980s, stomach ulcers used to be a really, really big thing. Do you remember like when I was a kid, you would hear about, oh, it's got a stomach ulcer, like a stress, stomach ulcer.

10:04Hannah Fry:It's really awful. 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. Yeah, but you don't see them anymore at all. It's like the Bermuda Triangle, like the 90s were full of all these things that 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. Not completely, but they sort of have because it turns out that they were caused by bacteria.

10:36Hannah Fry:There's a great story about how they proved that it was a 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. Right. So drinking someone's ulcer, bad idea. It's contagious. Don't lick the inside of someone's stomach if they're infected with ulcers. Let me just write this down because actually, no, I need to cross it off. It's on my list of to-dos today. But yeah, ulcers weren't caused by a stressful job. I mean, I think it probably exacerbated it.

11:13Hannah Fry: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 lop 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 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 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 were 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.

12:12Hannah Fry:So it was like depleting all of the sugar that was in their blood really quickly. The balance was off, essentially. 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. Correct. If you cut part of the stomach away and you eat the sugar, then too much insulin is made. 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 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.

13:01Hannah Fry: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 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 the signal is around about there somewhere because as all this food is like getting dumped in the signal is going like what 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 high glycemic 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 Or daughter.

13:56Hannah Fry:Or daughter. Any kind of child should be called glucagon. That's the official policy of me. Okay. Anyway, they were like, right, we want to know what gene is creating this. And they were particularly interested in the anglerfish because the anglerfish has this entire organ, which is called the Brockman body, for making glucagon. Okay. So normally you've got 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 really difficult but in the angler fish it's really simple so what they did is they managed to find the gene for glucagon via this fish and then they were really surprised to discover that this this gene also makes two other little peptides peptide by the way anyone who has like ever experienced a skincare advert will think that it's something that you put on your face peptide is It's just a cute little chain of amino acids.

14:54Hannah Fry:Okay, that's all it is. It's like a little cute, cute little, cute little peptide. A cute word for a cute thing. Peptide is another great child's name. Hey, peptide. We've got triplets now. I think peptide should be the pet. Should be like a little mini chihuahua, you know? It's the little dog. It's the little dog. I love this little family that we're creating, Hannah. We've got to decide what the mum and dad are called at some point. Yeah, we will. but one of them surely is called ulcer. 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.

15:36Hannah Fry:I think you'll feel right. Okay, so this gene that makes glucagon turns out also makes these two little peptides and they're looking at them and they're like, well, I 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 1 and glucagon-like peptide 2. GLP-1 and GLP-2. There they are. You may have heard of GLP-1. Yeah. Because this is the hormone that fat jabs aim to mimic. Things like azempic, wagovi, 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, hello, we're going to get some insulin out there because otherwise our blood sugar is going to end up being a bit too high.

16:29Okay, so that's what GLP-1 does. It's a messenger to the pancreas to make insulin?

16:37Hannah Fry: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 charts instead. Yeah. 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.

17:17Hannah Fry:Yeah. 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, your eyes in particular are really, really susceptible to going blind if there's too much sugar in your blood for a long period of time. The thing about this GLP-1 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, better than nothing, but still not great. But GLP-1 will only signal the pancreas to produce more insulin if you have high blood sugar.

17:59Hannah Fry:So if you've got GLP-1 floating around and your blood sugar is low, your pancreas will not go crazy. 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 pancreas overreacted. So in 1993, this Danish scientist, he's called Jens Juhlholst, he was like, okay, well, let's try this, shall we? Should we just whack a load of this peptide, this cute little peptide, GLP-1, into people's bodies, see what happens?

18:37Hannah Fry: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 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. That's the scientific term, puke all over the place.

19:12Hannah Fry:This is essentially where this is going. Did this 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 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 because essentially your body, in order to keep that incredibly fine balance, that four grams of sugar, You can't let the GLP-1 like float around for too long, you know, because then you'd be like carrying on putting out insulin long after the blood sugar had been dealt with.

19:51Hannah Fry:So you also have this little enzyme in your blood, which is called DPP-4. I don't know if that's going to be the mother's name. That's the mom. That's the mom. We met her. She's here. Yeah, maybe we shouldn't call the mom that because it sounds like a very awkward question. What's DPP-4?

20:13Hannah Fry:She's here. She's snippy though, the mum. I mean, that's essentially her job is to go along and cut GLP-1 in half. And destroy it. I don't think she's, I mean, she's good. She's keeping everything balancing, but she's sort of, she's doing it by cutting the play in half, you know? Yeah. Yeah, everyone was like, you know, it feels like we're onto something, but everyone's puking and it doesn't work. So it's not looking so good. And then enter into the frame the unusual family pet, the Gila monster. So this is a lizard, right? Because the Gila monster solves everything, my friend. The Gila monster is the root source of this miracle that happened with diabetes.

20:58Hannah Fry:Tell us about the animal. It's a venomous lizard, lives in America. It's quite fat. It's quite chunky. 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 managed to catch and eat a meal about five times a year. No kidding. Yeah. Have you eaten this quarter? Okay. I can see how this is related. But when they do, when they do, they eat like half their body weight all at once. Right. Okay. But scientists were like, right, well, this guy over here, this Gila monster is like, He's going very long periods without eating.

21:36Hannah Fry: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 Guillain-Monts-Date is that they bite humans. Oh, 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. Really? I mean, you're absolutely seeing where this is going, right? Yeah. A team of scientists, they decided 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?

22:20Hannah Fry: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 the pancreas. That's like so weird. He found in this venom, this chain of 39 amino acids, acutelylt peptide, and he called it Xendin4. You really need to get better names for these things. Xendin4. Is that the mum?

23:03Hannah Fry:Xendin4. That's the second wife, maybe. I think that might be the car number plate. Okay, fair enough. Yeah, I like that. Anyway, the thing is, it turns out that this little peptide is almost the same as GLP-1. like they're really, really similar, 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 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-1 does, can last for ages and ages and ages.