Wouldn't be as good with it. Okay. Let me tell you, I have a 10 year old daughter and for the last two years now, she walks up to me and it still gets me and she goes, knock knock. I say, who's there? She goes, oh. I say, oh, oh. Oh, oh. Oh, oh. And I'm like, really? It's remarkable.

I'm like,

damn, you were watching too much TV, girl. I expected better for her as the daughter of a comedian. Just put it out there. All right. Yeah. Maybe I'm not that good of a comedian. What's the heart of my... So Nick, we've heard a lot about this. I knew it had some relevance to to diabetes, right? For diabetes patients. And then people started losing weight, losing their cravings. And I know people, it's an expensive drug and I know some rich people. And apparently this is just in their regimen, their weekly regimen. So it feels like a wonder drug, another quick fix. So how do we go from type two diabetes to a weight loss drug? How does that happen?

Well, I guess Osempic was FDA approved. So any drug that comes onto the market has to be approved by the Food and Drug Administration. So the FDA approved this in 2017 as a treatment for type two diabetes. So type two diabetes is when people produce insulin from the pancreas, but the insulin, they're insulin resistant. So the insulin that they're producing is not exerting its effects on the body. And of course, insulin's function is to extract glucose from the blood, to keep blood glucose levels within a very narrow homeostatic range. And glucose is synonymous in that example with energy

driving your body needs, correct? Right. Absolutely.

Glucose is just a simple carbohydrate. So any type of carbohydrate generally will cause your blood sugar levels to rise to some extent. So

it's just one of that family of Ose's, right? There's sucrose, fructose, glucose. So they're all sugars, right? Yeah.

They're all sugars. Glucose is the simplest form of sugar. There's a single molecule. Fructose is another one. It's a single molecule. Sucrose, what we call table sugar, is a disaccharide. So it's glucose and fructose bound together. But essentially, they all get absorbed through the intestine, enter the blood, and they're going to cause a rise in blood glucose. People with diabetes can't control the blood sugar because of the reason that I just mentioned that they're either not producing enough insulin.

That would be type

one. That's type one. Okay. Type two diabetes, they're producing it, but it's not potent enough. It's not exerting its effect. If blood sugar gets too high, it can cause systemic inflammation and all sorts of other problems. And if your blood sugar falls too low, it's difficult to stay conscious generally. So

your body will try. Your body will try to maintain. I don't mind knowing. If my glucose is too level, yeah, you won't. You don't know because you're unconscious, right? Yeah. Well, yeah. Whoever's

in the room with you will know because you'll be lying horizontal on the floor. Okay. So your body will do whatever it can to maintain your blood sugar levels within this kind of narrow normal, this homeostatic range. So this drug that we call it, the Zampic, it's called a GLP1 agonist. And GLP1 is glucagon-like peptide one as a very important role in the body, that when we take in some food, particularly if the food contains fats and sugars, will stimulate the release of GLP1, which acts on the pancreas, which then releases insulin. Is there another term for the drug? I mean, we're calling them GLP1s and they've got brand names. So what is semi-glutides? So the drug itself is called semagletide, and the brand name is Hozenpix. So that's what's actually branded, and then FDA approved to treat type 2 diabetes. But shortly after these drugs were being prescribed to people with type 2 diabetes, physicians and scientists found that one of the side, I mean, you can call it a side effect or an additional effect, was that people were losing weight as well, which is generally good because people with type 2 diabetes are often overweight, or if you're obese, if you're clinically obese, it predisposes you to type 2 diabetes. And so after a couple of years, the drug was prescribed by physicians off label, which I guess we're going to talk about in a little while, to help people with weight loss. And then in 2021, the FDA re-approved semagletide under a different brand name, WeGoV, specifically to help people to lose weight. But it works via the same kind of mechanism.

So what it seems to me, there's an interesting back door here that you're describing, because if FDA approves a drug for whatever reason, and you find another application for that drug, it doesn't have to be FDA-approved again. Is that correct?

That's correct.

As long as your doses are within the range of the originally intended dose, it doesn't have to be tested. That's why everybody loves the little blue pill.

Right, well, and that's an interesting one, actually, because... Big green dump truck. Well, when that was originally discovered, I've written down some of the drug names here, so Denefels citrate, because I can't remember the drug name, but Cetanaphyl citrate was discovered because researchers were looking at ways to lower blood pressure. They found that this blood pressure lowering drug had this unintended side effect that it increased blood flow to the male genitalia. So they rebranded it as Viagra. And the weird thing is, they now prescribed Viagra off label to treat high blood pressure. That's right. That's right. It's gone full circle. It's gone full circle. Okay,

so what is it about carrying extra weight, specifically subcutaneous belly fat, that leads to diabetes? What is that association body that's even happening? I never knew the amplitude that happened. That myself. So, yeah, what is going on there?

Right, so belly fat is more metabolically active, and it's closer to your viscera, to the internal organs. So if you have a large amount of belly fat, it's more likely to penetrate deep into the viscera, and surround your pancreas, and your liver, and so forth. So because this fat is more metabolically active, it has a much closer association with disrupted blood sugar control and signaling. So, and this is a problem for men especially, because I don't know if you've noticed this, but men tend to store more of their body fat around the midsection. Yeah. Women in general tend to store more of their body fat around their hips and bumps. Wow,

they get, they're so lucky.

And in effect, they are, because it's the fat, it's the visceral fat, the central adiposity, which predisposes, as you say, to type 2 diabetes. So that means men are more prone to type 2 diabetes than

women, based on this analysis.

Men who have greater waist to hit ratios, yeah. Right, right. Right.

So, Chuck, we need a Sir Mix-A-Lot to do a song about men's belly fat. That's right. I like big guts in the cannot man.

All right. So, Nick, when patients being

treated for type 2

diabetes with the, I call it semaglutide, but semaglutide, it's a tomato, it's a tomato, whatever. That's because you're English. I know, sorry.

But I'm apologize today. The thing is- You just did. Yeah. I

take it back. This is not the apology you're looking for. So, looking at that and saying to you, is there

enough clinical evidence to back up this downstream off labeling of

this drug as another

use? Or was it enough of what Dr. Lasway, fabulous? Great. Or has it just got to go cleanly? How do you process this for this drug to come again in another way? Yeah.

So, the only similarities between the two approval processes is that semaglutide, semaglutide has already gone through the phase 1 and 2 trials, which are essentially about making sure that administering the thing is not going to cause toxic downstream effects. So, the safety profile is already sort of in place, but they'll study independently for the independent effects. And there are dozens and dozens of very, very good randomized controlled trials that have looked at this independently in terms of treating type 2 diabetes because it helps control blood glucose, and independently using semaglutide for weight loss. Because it is a slightly, I guess you could say it's a slightly different mechanism. So, you have GLP1, it has a bunch of different effects on the body. Wherever there's a concentration of GLP1 receptors, then GLP1 is going to exert its effects. So, the first place that we have receptors is obviously in the pancreas that we've just discussed. So, GLP1 helps to up-regulate the secretion of insulin, and it helps the beta cells of the pancreas, which actually does the secreting of insulin to proliferate, and it sort of they increase in number. So, it can actually help to treat type 2 diabetes in that way. But we know that GLP1 also acts on the stomach, and it does so in a way that suppresses the amount of gastric acid that's being secreted into the stomach. So, obviously, when you when you take in food, you swallow the food down into the stomach, it comes into contact with these different lipases and different enzymes to break down the food and hydrochloric acid, and it turns the food into a mushy sludge and empties into the small intestine.

And GLP1 actually- Ever since then, just look at anyone's throw up. Yes. Right.

Exactly. It turns it into that stuff. But it does so in a way that it suppresses the amount of gastric acid that's secreted. So, it takes longer to break down the food, and it slows the rate of gastric emptying. So, you essentially stay fuller for longer. Mechanically, you keep more food in your stomach. So, it's helped to suppress appetite in that way. But there's one other mechanism that's really important that we have to mention, and that GLP1 also acts on receptors in the brain. So, hypothalamus is the body's kind of appetite control center. Right. And by stimulating GLP1 receptors in our hypothalamus, then we can actually reduce appetite, increase feelings of satiety, and people want to eat less.

So, is it true, or is this correlation rather than causation? That it not only reduces appetite for food, it reduces the other cravings and appetites, including alcohol, and, you know, like sugar cravings. And suppressing urges. Urges. Urges. Very good. Thank you. Is that where the brain part of this comes in? Is that true?

It's probably not just correlation. It probably is causation. The reason that I say probably is because this all started because patients who have prescribed some appetite for one reason or another were coming back to their doctors saying, you know, it's not just that I want to eat less food, but my cravings and my typical addictions, like alcohol or even cigarette smoking, have also been suppressed. So, then we started to look at this under controlled conditions. There are a bit of bunch of studies now mostly in rodent models, so in rats and mice, and a couple of studies in non-human primates. And what we think is happening, the mechanism hasn't been fully unpacked, but what we think is happening is that that GLP1 acts to down regulate dopamine transmission in the brain.

And dopamine, as we know, has a recent- Whether we have an entire episode on dopamine, so people want to look

into our archives. It's there. Absolutely. And when we eat some kind of food, particularly if it's tasty food, it contains lots of fat and sugar, the stuff that tastes really good, right? We get a dopamine spike in the brain that makes us, it gives us kind of a nice sensation in reinforces, food-related, urgent and reward-seeking mechanisms. And by down-regulating that pathway, then GLP1 can in theory help to improve impulse control and decrease reward-seeking behavior. And that would be for whatever stimulates dopamine.

So Nick, I have some friends who are foodies, but like high-level, high-profile foodies, seeking out the finest chefs in the finest restaurants, those who went on ozempic, they noticed not only did they eat less, but they were deriving less enjoyment from the food. This isn't a same-beared wordy. It was a double effect. It's like, not only am I not really hungry, I don't even want it. And so some of them were worried that it was subtracting away from them, this big part of their social life, going out enjoying fine food-y type things prepared by high-profile chefs. You call this a miscellaneous star meal? This is one of those... We have a passion for eating. We have a passion for eating. ...of the meals. Right. It's

one of those repercussions that you don't even think about. But yeah, I guess we have to frame this in the context that there are... There are two types of feedings. There's what we call homeostatic feeding, and then there's hedonic or hedonic feeding. And they're self-explanatory. But homeostatic feeding is when we eat, because we haven't had enough calories. That has survived. You've got to survive. Eat to live, not living to eat. If you go out and do a hard training session, or you haven't eaten for a number of hours, then you're going to have a negative calorie deficit. So your body's going to tell you to go and eat more. That's the homeostatic feeding. Homeostatic feeding. Exactly. Just in an effort to maintain normal

dynamic equilibrium. By the way, the way you were, it sounds like we're zoo animals. It's your feeding. In a way. In a way. That's not

tugging at that thread. Okay. And so hedonic feeding is literally... is chasing that reward, seeking behavior. The food that makes us feel good. And that explains how we can go and have a huge Thanksgiving meal, have a big full stomach, and still find ourselves going back to get a second helping. Second helping. The dessert. Yeah. We don't need the calories, but we like the feeling. Right.

So if the feeling doesn't drive the dopamine, you're not even going to have the thought. Right.

Exactly. And that's how this... That's how GOP won in theory by down regulating that process. And that's why, you know, if we were only... If we only obeyed the homeostatic feeding triggers, where most people would probably be normal weight. Because we would eat to make some. We're calling everybody in the 1970s.

And I know you want to get in here, but... Sure. ...on this right here. Just right here. I want to stay right here for one second. Wouldn't it make sense then, that neurochemically, if we were to just deprive ourselves these kind of pleasure triggers that our brain would naturally kind of go into a state where it doesn't care? Like we wouldn't be seeking the rewards. So you cut out sugar for like two weeks, right? And just stay off of it. Like your body will say, all right, eff it. I don't want sugar anymore. You know?

Are you asking for a question? Are you declaring it? I'm asking. I think it was... I think it was... Impressing up my body. But

that's asking the question.

Well, I think it's intuitive. But if you ask anybody who's ever followed a fat diet, they can probably cut out all kinds of junk food and confectionery and alcohol for six weeks, two months. They can go for a long time without them. And eventually they fall off the wagon, right? This kind of characterizes most people's experiences with dieting, which is why dieting never works. Because as soon as you conceive the idea of a wagon, you're going to fall off it, right? So... The trouble is, the answer is no. Yeah. Probably no. There might be some kind of neurochemical mechanism that I'm not very, you know, that I don't fully understand. But experience tells me that that's not the case.