The video delves into the complex mechanisms and historical background of GLP1-based treatments, primarily used to manage diabetes and aid weight loss. It outlines the creation of these drugs based on a peptide found in the Gila monster, leading to revolutionary treatments like Ozempic and Mounjaro. Explaining how GLP1 works, the speaker highlights its role in amplifying insulin response and how its drug variants evolved to manage blood glucose levels effectively.

These treatments, which initially focused on diabetes, were shown to have potential in weight loss due to their appetite suppression capabilities. By elaborating on the fascinating history of these drugs, from initial glucose ingestion studies to the modern pharmaceutical engineering tactics, the video draws a clear line from their medical origins to their current applications in weight management. It also discusses the related side effects, such as nausea, and how patients adapt over time.

Main takeaways from the video:

Please remember to turn on the CC button to view the subtitles.

Key Vocabularies and Common Phrases:

1. homolog [ˈhɑːməˌlɔɡ] - (noun) - A gene related to a second gene by descent from a common ancestral DNA sequence. - Synonyms: (equivalent, counterpart, parallel)

It has an analog homolog. You know, we don't know.

2. incretin [ˈɪŋkrɪtɪn] - (noun) - A group of metabolic hormones that stimulate a decrease in blood glucose levels. - Synonyms: (peptide, hormone, insulin-stimulator)

incretin? incretin. Not the cretin effect, not the creatine effect.

3. hypoglycemic [ˌhaɪpoʊˌɡlaɪˈsiːmɪk] - (adjective) - Relating to, or suffering from an abnormally low level of glucose in the blood. - Synonyms: (low-blood sugar, glucose-deficient, sugar-depleted)

Because if you inject too much insulin, you can kill yourself by making yourself hypoglycemic.

4. opposing [əˈpoʊzɪŋ] - (adjective) - Acting in opposition or contrary; adverse contrasted forces. - Synonyms: (contradictory, conflicting, rival)

So glucagon and insulin are these two opposing hormones.

5. differentially [ˌdɪfəˈrɛnʃəli] - (adverb) - In a way that causes or represents a difference; varied. - Synonyms: (distinctly, diversely, variably)

It's differentially processed to produce different hormones.

6. degrades [dɪˈɡreɪdz] - (verb) - Breaks down or deteriorates chemically or biologically. - Synonyms: (deteriorates, disintegrates, decomposes)

And the reason it's degraded is because there's an enzyme, DPP4 is what it's called, that degrades GLP1

7. stabilized [ˈsteɪbəˌlaɪzd] - (adjective) - Made stable; rendered less likely to change or break down. - Synonyms: (secured, fixed, anchored)

It produces a stabilized form of GLP1 and it's Venom.

8. pharmaceutical [ˌfɑːrməˈsuːtɪkl] - (adjective) - Relating to medicinal drugs, or their preparation, use, or sale. - Synonyms: (medicinal, therapeutic, drug)

So then pharmaceutical industry said, can we basically improve this even further?

9. side effect [saɪd əˈfɛkt] - (noun) - An unexpected or unwanted physical or mental effect caused by a drug. - Synonyms: (adverse reaction, secondary effect, bad reaction)

A known side effect of these GLP1 drugs.

10. hypothalamus [ˌhaɪpəˈθæləməs] - (noun) - A region of the forebrain below the thalamus, coordinating both the autonomic nervous system and activity of the pituitary. - Synonyms: (brain region, neural center, diencephalon part)

They're going to talk to the hypothalamus and all these other brain regions.

How Do Ozempic, Mounjaro & Other GPL-1 Agonists Work? - Dr. Zachary Knight & Dr. Andrew Huberman

The increased hunger seems to be the main reason people find it so difficult to keep weight off. That seems the perfect segue to talk about GLP1 glucagon, like Peptide 1, Ozempic, Mounjaro and similar drugs. My understanding of the back history on these is that a biologist obsessed with Gila monsters, a reptile that doesn't need to eat very often, discovered a peptide within their bloodstream called extendin. Yeah. That allowed them to eat very seldom curbed appetite in the Gila monster of all things. And it has an analog homolog. You know, we don't know. I don't know the sequence homology exactly, but there's a similar peptide made in mice and in humans that suppresses appetite.

If you would, could you tell us what is known about how GLP1 works to suppress appetite? Where in the body and or brain? Sure. And your sort of read of these drugs and what's happening there. Good, bad, exciting, ugly. Sure. Be happy to anything else. So the story of GLP1. So the Gila monster is an important turn and I'll talk about that. It actually goes back before that quite a ways. So I should take a step back and say these were developed as drugs for diabetes. Diabetes is a condition where basically I've elevated blood glucose either because you don't produce enough insulin or because your insulin is not effective. Back in the 1920s, right around the time insulin was discovered, there was this phenomenon discovered known as the incretin effect.

incretin? incretin. Not the cretin effect, not the creatine effect. You can observe the cretin effect in numerous places in daily life and online. Just kidding. So it's called the incretin effect. You can think of it as increase insulin because that's what the effect is. And the idea was that if you take glucose by mouth, if you consume glucose orally versus if you have the same amount of glucose injected intravenously, more insulin is produced when you take the glucose orally versus if it's delivered intravenously. Suggesting something about the process of ingesting the glucose causes more insulin to be released and causes you to lower your body's sugar more, more accurately, more strongly.

Interesting. Which is a little bit counterintuitive because in the pancreas, so insulin is released from the pancreas, from the beta cell, the pancreas senses the glucose concentration in the blood directly. And so it suggests that insulin is being released not just in response to changes in blood glucose, but in response to a second factor. And so they Call that an incretin. And through various experiments, it was shown that this incretin effect comes from the intestine, that there's some substance being produced by the intestine, that when you eat a meal, sugar goes through your intestine that boosts this insulin response to glucose in the blood. And people immediately realize this could potentially be very valuable.

And the reason is that you can treat diabetes with insulin injections. But insulin is dangerous because if you inject too much insulin, you can kill yourself by making yourself hypoglycemic. So you have to be very careful. But the thing about the incretin effect is it's not causing insulin release directly, but it's rather boosting the natural insulin release that comes when your glucose is higher in your blood. So it's sort of an amplifier on the natural insulin release. So basically, in the years that followed, whenever someone would find a new hormone, they would test it. Is it this incretin? And there's lots of failures. They weren't the incretin. But then.

So there's this other hormone that comes from the pancreas called glucagon. And so glucagon was also discovered in the 1920s. Glucagon is kind of the anti insulin. So when blood sugar goes low, glucagon is released in order to cause your liver to release glucose into the blood. So glucagon and insulin are these two opposing hormones. Glucagon was known for a long time, but people discovered in the 1980s that the glucagon gene is expressed in other tissues other than the pancreas, and it's differentially processed. The protein is differentially processed to produce different hormones, hormones other than glucagon. And they discovered there was one in the intestine.

And so they called it glucagon, like peptide, because it came from the same gene, but it's just slightly different. It's cut up slightly differently. And this hormone wasn't incretin. So basically, if you put it on beta cells, you get this increased response of insulin in response to glucose. And so there was the idea, okay, this could be a great diabetes drug, right? And I should say there was one other incretin that's been found. It's called gyp gip. And that will be important, talking about some of these other drugs, also a hormone that comes from the intestine.

And so the challenge with making GLP1 into a drug is that it has an extremely short half life. So it has a half life about two minutes in the blood. And so even if you inject people with GLP1, it won't really be useful for anything. You don't decrease appetite, you don't affect blood sugar because it's just degraded too fast. And the reason it's degraded is because there's an enzyme, DPP4 is what it's called, that degrades GLP1. So the first thing people tried was let's make inhibitors of that enzyme so we can boost this natural GLP1 signal. And those are approved diabetes drugs, are called gliptins. You've probably heard about them. Januvia is the most common one. And those boost the level of GLP1, the natural GLP1, produced from the intestine, by about threefold, and they're effective in treating diabetes. People lose weight. People do not lose weight. Interesting. And that's one of the key reasons that we know the natural function of GLP1 is not really to control body weight, because you can boost the level three fold with these DPP4 drugs. Millions of people have taken them. They do not lose weight. That's a great question.

But a threefold is great. But you'd like to increase it even more. And to do that, you can't block this enzyme. You have to actually produce a GLP one that is more stable in the blood. And that's where this lizard that you mentioned comes into play. It produces a stabilized form of GLP1 and it's Venom. No one knows why. One hypothesis is that it's something to do with the lizard, as you said, basically having this long time period between meals, and it needs to regulate its blood glucose. Who knows if that is true? But it turned out to be fortuitous because then this GLP one from this lizard, it has a half life of like two hours. And so the first GLP1 drug that was approved was just this molecule from this lizard, basically, and it's called exenatide, and it's approved in 2005.

Works well for diabetes. Has a half life of two hours. You inject it and doesn't cause a ton of weight loss. But two hours is good, but it's not so great. So then pharmaceutical industry said, can we basically improve this even further? And so they start engineering this hormone, making mutations, attaching lipid tails to make it bind to proteins in the blood that would stabilize it. Chemistry jockey stuff. Yeah, exactly. And I think the next big advance was this compound, liraglutide. And liraglutide was approved for diabetes in 2010. And then for weight loss in 2014. And so liraglutide has a half life of about 13 hours in the blood, nose. Now you're getting up to something serious. We've gone from 2 minutes, 2 hours, 13 hours. And you get better effects on aspects of blood glucose and diabetes control.

And they started to see that some people were losing weight, very variable responses. Not everyone loses weight on liraglutide. And one of the things they noticed that I think is just fascinating, just sort of example of how drug discovery works in the real world. A lot of these people who take liraglutide, now, it has this longer half life, they start to get nauseous and that would limit how much of the liraglutide they could take. And it's a known side effect of these GLP1 drugs. It causes nausea and sort of this gastrointestinal distress. But they noticed that over time the nausea would just sort of go away. And so they would start dose escalating, sort of raising the dose that the person would take. So you would go a month at this dose and then a month at a slightly higher dose, and then a month at a slightly higher dose and you could work your way up and these side effects would reappear, but then they go away.

And then once you got up to the highest doses, then people really started losing weight. And so there's a couple of things that pharmaceutical industry realized, wow, these are potentially really effective weight loss drugs. And also this nausea, which we thought was a killer, people are able to just get used to it and then it just goes away. It undergoes. The word is tachyphylaxis. The idea is that the receptor in the gut that's causing these effects, it undergoes some sort of downregulation with chronic, chronic exposure.

So liraglutide, it's been on the market for 14 years now, was used, but still you're only getting sort of like 7 to 10% weight loss, which is good, but not amazing, impressive. But then semaglutide came along and that was approved for diabetes in 2017. And semaglutide is Ozempic or also also marketed as Wegovy for weight loss. And semaglutide now has a half life of seven days. So now we've gone from 2 minutes, 2 hours, 13 hours, 7 days. And you can really jack up the concentration with a seven day half life. And then they saw people start really losing weight. And so in some of those trials, people lost 16% of their body weight, which previously had been unattainable in what timeframe? Typically takes about a year.

Okay. And most of the loss in body weight is from body fat or from other compartments. The typical number is that if you lose weight either through dieting or through taking one of these drugs and you don't do anything like eat a high protein diet or do resistance training, somewhere between 25 and 33% of what you lose is going to be muscle. The rest is going to be fat. But as you said, some of that could be offset by resistance training and. Or consuming a higher protein diet. Yeah. You can almost completely eliminate that if you eat enough protein and do serious weightlifting. Obviously not the whole population is interested in doing that. And there's been a lot of discussion of how serious a side effect this is among elderly people. You don't want to be losing muscle mass because you're already losing so much muscle mass.

On the other hand, the counterargument that has been made, which I think is also kind of convincing, is that true, you're losing some muscle, but you're also losing all this fat, and you no longer need as much muscle when you're not carrying around as much body fat. So people who are heavier naturally have more muscle because they need to. To move their body. Right. And so, yeah, the calves on very obese people are often enormous. Exactly. And then they lose weight and. Exactly. And I mentioned the calves in particular because they're carrying a lot of the body load. Exactly, exactly. So it's still an open question as to whether. As to how serious a problem this must lean muscle mass loss is. Although the pharmaceutical industry is all in now on making drugs that basically are going to prevent that. So that's something that will be happening probably in the future.

Sorry to interrupt, but is the weight loss on these drugs the consequence of reduced appetite or some other aspect of metabolism? And if it's the consequence of reduced appetite, is that occurring at the level of the brain and gut or combination? So it's almost entirely reduced appetite and it's almost entirely incurring at the level of the brain, which neurons. It's thought that the key targets of these drugs are neurons in these two regions. One's called the nucleus of the solitary tract and the other one's called the area postrema.

So we're back in the brainstem. Back in the brainstem. So these are actually the neurons in that decerebrate rat story I was telling earlier. These are the brain regions that are preserved in the decerebrate rat. The decerebrate rat still has these very caudal brainstem structures. They're two very special brain regions because they get direct input from the vagus nerve. So the vagus nerve is the nerve that innervates your stomach and intestines and heart and lungs, and is sort of the major pathway from gut to brain and provides most of the sensor of the neural input from gut to brain, telling you about things like your stomach, distension, how many nutrients are in your intestine, breathing, all that stuff. And almost all of those vagal nerves terminate on these two structures in the brainstem.

When I hear postrema, I think about nausea because I was taught that postrema contains neurons that can stimulate vomiting. And this seems to link up, well, at least in the logical sense, with the idea that stimulating activating receptors in these neurons within postrema might explain part of the transient nausea side effect of ozempic and related drugs. Yeah, so the current thought is that a lot of the nausea is coming from activating the neurons of the area postrema, and that a lot of the sort of physiologic satiety is coming from activating the neurons in the nucleus of the solitary tract.

Now, the whole brain is connected to each other. And so if you really turn on these neurons in the NTs and the AP, they're going to talk to the hypothalamus and all these other brain regions, it's going to change the whole brain. So it's not just those regions, but these drugs don't have great access to the brain. They can penetrate a little bit into the brain, but they don't penetrate into the whole brain. And it's thought that if you take fluorescently labeled versions of these drugs and see where, so you can visualize where do they actually go? They're enriched in these structures in the brain stem.

So that's why people think that this is probably where they're acting. And is that because they're. There's an abundance of the receptors for these compounds in postrema and nts. Or is it because the blood brain barrier is somehow weaker at that location? It's because the blood brain barrier is weaker. So basically it's a region, what's known as a circumventricular organ, meaning it's one of these rare places in the brain where the blood brain barrier is weakened. And so substances can come from the outside into the brain. And that's important for these big peptides, because these are not small molecules. These are big peptides with lipid chains.

On them and other things and so they can really get only get into areas of the brain where the blood brain barrier is weakened.

Science, Technology, Innovation, Glp1, Diabetes, Weightloss, Huberman Lab Clips