41: Weight Loss Drugs with Dr. Ben Bikman

Good morning, everyone, all of you wonderful and curious students who are joining me for this week's version or this week's episode of the Metabolic Classroom. This is going to be one that you will find very interesting because we are all interested in weight loss. We all want to shrink our fat cells and have less fat mass. And that's the purpose of today, namely to explore the drugs that are marketed as weight loss drugs. Now, I say marketed because some of them weren't originally used for weight loss. They weren't designed for weight loss, but weight loss was found to be a consequence, and so it became part of the marketing and now part of their use. So again, the topic for the day is weight loss drugs. And we're going to go over some of the most common ones, how they act, the good things you want, or the way they act to help you lose weight. And then also, as is the case with all drugs, there are side effects and I'll take a little time to highlight those as well. And of course, I'll always be inserting a lot of my opinion. But what we're going to talk about is based on publications and then where I insert my opinion, it'll. It'll be obvious or I'll make sure I mention it. Now, before I get into the specific topic, you guys know that I like to just highlight a random scientific fact that may be on my mind. The one today is a follow up from some dialogue I'd had on social media last week, specifically with regards to lactate. Now, as a reminder, the human body does not make lactic acid. We make lactate. There is no lactic acid in our bodies and it doesn't. Lactate does in no way contribute to muscle soreness or muscle ache. Now, when you work out a muscle hard, you will make lactate as the muscle cells are burning glucose for energy. But. But that's not causing any pain. It's a, if you will, associated it's being produced in the same environment that is causing the muscle aches. Now, what about lactate? Why am I mentioning it? Well, we're talking about drug mechanisms of weight loss today. Lactate does have a potential role here. Not that it is used in any sort of drug, but lactate has been shown to act directly on the fat cells. Not only can fat cells use the lactate as an energy source, but lactate has been shown to increase adipose tissue. Beijing, now, you've heard me talk about white and brown fat. In fact, next month's metabolic classrooms are all going to be about fat tissue. And so we're going to talk much more about this. But Beijing is this weird verb that refers to converting white fat with its very low metabolic rate and having it behave a little more like brown fat, and it's much higher maybe metabolic rates. So lactate that's coming from a working muscle has been shown to increase the metabolic rate of fat tissue by making it behave a little more like brown fat. All right, anyway, an interesting little tidbit. So those of you who want to take advantage of adipocyte Beijing or brown fat, you don't need to just be immersing yourself in a really cold bath. So there might be some comfort, perhaps you find in the fact that the lactate that's coming from your exercising muscles has some similar effect, if not to the same degree. Okay, now let's get right into the weight loss drugs. Of course, we have been battling obesity for decades now. This really started to climb in the latter part of the 1900s, 1960s, 70s. That's when things really started to tick up. It is known, noteworthy that that was the same time, around that same time that we first had the dietary guidelines. That might be a correlation, it might be causal, but it is a heck of a coincidence. Nevertheless. We've been struggling with finding ways to help with weight loss. And because so many people struggle with weight loss and because excess fat mass is such a problem, it is indeed, it does contribute to disease, including insulin resistance, very specifically, like we talked about last month's classroom episodes. So we want to be mindful of obesity. We want to reduce it if we have it, or we want to keep it at bay. So how can we best do it? Of course, lifestyle is best, but some people just want to pop a pill. So let's talk about that because it is such a hot topic. Now, I'm just going to go through. There are myriad, nearly countless drugs that can and have been used for weight loss. I'm of course, this is not going to be an exhaustive episode. We're going to go over just the most prominent, like the highest five or six that are used clinically prescribed specifically for weight loss. And so in the time we have together today, I want to talk about the main mechanism of action, in other words, how they promote weight loss, as well as some of the side effects associated with their use. Now, some of these drugs, it gets a little complicated because they will have multiple trade names, there will be multiple terms or names for a drug that's sort of packaged it at different doses or is using a slightly different version of it. All right, so the first drug that I want to discuss that's very common is Orlistat. This comes in a drug like Ali or Alli. It's Alli, A L L I or Xenical. Now, of course, I'm not giving any recommendations that you go buy these at all, but Orlistat is a very commonly used drug. Its mechanism of action is to inhibit this enzyme in your guts called lipase. Most of the lipase comes from the pancreas, a part of the pancreas that we commonly call the exocrine pancreas. Because in contrast to releasing hormones and molecules into the blood, which would be the endocrine pancreas, the exocrine pancreas is releasing things out of the body, specifically into the guts. And this is where almost all of the digestive enzymes come from, including a bunch of enzymes called lipases. Now, lipases work by taking a triglyceride molecule and splitting them apart, because it. The triglyceride is the kind of functional unit of fat that we eat. When we eat fat, we're eating triglycerides. We can't absorb those triglycerides. We can't get them into the bloodstream. And so the lipases will come and snip it apart into smaller pieces of just fatty acids. And now we can absorb those into the bloodstream. So Orlistat works primarily by inhibiting our body's ability to digest fat. And if you can't digest fat, then you can't absorb the fat. And now you have fat that hasn't gotten into your body. Now, this view is primarily justified, just keeping calories in mind, that it is purely a matter of if you are focusing on eating low calorie, low fat foods, well, here's a way to help you do it. Here's a way to, or rather to have your body do it for you in a way where no matter what you eat, you're going to be getting less fat. Now, the fact, so that's the main mechanism of action, is that you absorb less fat. So there's less fat and less calories coming into your. Coming into your body. Now, it doesn't block fat digestion completely. It'll get up to about a third of the fat you eat at the normal doses of orlistat. So about a third of the fat you eat won't get digested. It'll stay in your intestines. But therein is the problem, because if you can't move that fat into your bloodstream, that fat is left in your guts, and it moves through as a lot of fat. And typically all that fat has been absorbed and you get it out of your intestines. As it stays in your intestines, it becomes a substantial part of your fecal matter. In other words, the person's going to have very runny and oily poop. This is a problem that is sometimes referred to as steatorrhea or fatty diarrhea, but it is just as pleasant as you might expect. The person will have a lot of gas, a lot of flatulence and some nausea and very urgent bowel movements. Because the bowel movement itself will have so little physical substance to it, it's harder to kind of keep it clenched up into the. Into the rectum, and it'll be a little more urgent. So if the person feels like they need to have a bowel movement, they better get to the toilet quickly for fear of having an accident. So it's a pretty unpleasant series of consequences or consequences or side effects here. Of course, the more fat a person eats, the more they're going to experience this. So it becomes a pretty relevant side effect. All right, let's move on to another one that's a classic and common and popular one over the years called phentermine. You've probably heard of this. This comes. This can come in drugs like Adipex P or Lamyra. So phentermine is an. Sometimes called an anorectic. It, in other words, it makes you less hungry. So it tells the brain that you just don't need to eat as much. And it primarily does this by increasing brain levels of a. Of a signal, a neuron signal, but also it's in the blood sometimes, so we can call it a hormone. So we'll say a neuroendocrine signal called norepinephrine. Now, a part of that might sound familia. Epinephrine. You've probably heard of epinephrine. If you haven't heard of norepinephrine, it is in fact very related. Norepinephrine is in much lower levels in the blood, but it's more relevant when it comes to signals between cells, or specifically between neurons and cells. Phentermine will increase the amount of norepinephrine that's being signaled to the brain. Now, norepinephrine itself will have several direct effects, including promoting satiety, so reducing hunger. That that is a direct effect of the norepinephrine. But also it increases norepinephrine increases leptin and leptin is an appetite suppressant. So there's a little bit of this redundancy here, ultimately leading to this reduced appetite. Now, at the same time, norepinephrine is a component of the sympathetic nervous system. That is the so called fight or flight nervous system. That's the part of our brain that is getting us amped up. It's increasing our heart rate, it's increasing our body temperature, our sweat production rate. It's getting the body ready for some physical action, for some kind of activity like running, sprinting, jumping, whatever the sympathetic nervous system is, that is the body, the part of the nervous system that primes us for that kind of thing. And so that gets turned on a bit with phentermine. And so it does in fact also result in an increase in epinephrine. So we have those systemic effects now with regards to weight loss. That is a further mechanism because epinephrine will activate lipolysis, breaking down fat from fat cells, and it also contributes to satiety and appetite suppression. But the main side effects then become obvious where the person can feel very anxious and agitated because they have this sympathetic nervous system that just won't turn off. You know, you need to have a balance between sympathetic nervous system when it's time to do something, and the parasympathetic nervous system when it's time to not do something. If the sympathetic nervous system has the prototypical fight or flight response, the parasympathetic nervous system could be best defined as rest and digest. So we need to have times where we need to rest and calm down, settle down. So no surprise, the person has a much higher heart rate. The person will have insomnia, they'll have a higher blood pressure, may even develop some kind of cardiac palpations, palpitations. So it is this sort of incessant stimulant aspect of phentermine that is a substantial side effect. But again, that is also part of what is promoting weight loss, which is the primary purpose of the topic today. Now, the next drug is actually a combination of phentermine and another drug called topiramate. And topiramate is used in conjunction with phentermine often, and it will have an additive effect at promoting weight loss. Classically, topiramate was used as an anticonvulsant. So this is an instance when it was realized to have another effect, weight loss in this case, and began to be marketed. Now, topiramate's main mechanism of action is once again, generally appetite suppression and promoting satiety. But primarily, or in addition to just what phentermine is doing, topiramate is going to alter taste. So it actually changes someone's palatable enjoyment of. Of foods that would be promoting weight gain. So it's just changing overall taste sensation to make eating less enjoyable. So, you know, that might be. That sounds kind of brutal, right? You want to enjoy eating, but at the same time, if you're addicted to certain foods, if you can reduce that enjoyment, then that's going to be a good thing. Well, theoretically, it would also make life a little more miserable. But also topiramate has an effect at increasing energy expenditure. And. And so in that sense, so increasing metabolic rate a little. And. And in that sense, it does complement the sympathetic nervous system activation of phentermine through norepinephrine and epinephrine. So this combination, which is marketed in a drug that I think is pronounced cassemia or cassimia. So those two drugs together will have, as I mentioned, an additive or greater weight loss effect than just phentermine alone. The common side effects are a bit odd here, but it includes, it's very diverse, like dry mouth, for example, and constipation, numbness and tingling, tingling and numbness of the hands and feet. And then also pretty substantial warnings with regards to pregnancy and the potential for birth defects. So absolutely not to be used. None of these should ever be used with pregnancy, of course, but especially this one, apparently. All right, now let's get into some that are a little more familiar as we're kind of halfway through of the six. So number four is a drug called liraglutide, and this is found in drugs like Saxenda. Now, lira glutide. Hearing the glutide may make you think of another drug which we're going to get to next called semaglutide. And it's not a surprise that they sound the same because they are cousins. They're within the same drug family. Anytime you hear that suffix glutide, you know you're talking about some GLP1 agonists. And so that is back to liraglutide. That is the main mechanism of action with weight loss when it comes to liraglutide is that it is a GLP1 receptor agonist. So it will mimic the action of the incretin, GLP1. Now, incretin hormones and how they're used in drugs including liraglutide and semaglutide are going to be the topic for next week's Metabolic Classroom that's going to be totally devoted to incretins and their use in weight loss drugs. So we're going to have it much more focused on drugs like wegovia and Ozempic and I'll talk a little bit more about them in just a second. But nevertheless. So it's this, it's mimicking the actions of this GLP1 hormone, which is an incretin, because it's a class of hormone that comes from the guts and the, the gut. Hormones are sometimes referred to as incretin hormones. So one of its, its main mechanism of action for promoting weight loss is in one simple phrase, reduced or slowed gastric emptying. Normally when you eat, the food will mash around in the stomach for a handful of hours and then it will move on into the duodenum to be further digested and then absorbed. And then we get the nutrition, including all the dreaded calories, as people are so afraid of calories. Now if you make the food stay in the stomach longer by slowing the movement of the intestines, a process called peristalsis, if you slow peristalsis or delay the emptying of the stomach, the, the food will stay in the stomach longer and then you will feel fuller for longer and you will simply want to eat less. So by slowing gastric emptying, you will have a greater feeling of fullness and thus reduced appetite. And that is the main mechanism of action by reduce, by slowing the rate at which food is moving through the intestines. Now, at the same time, a sort of secondary action here is inhibiting the hormone glucagon. And if you inhibit glucagon, you help blood glucose levels come down. And if blood glucose levels come down, so too does insulin. And if insulin is down, metabolic rate will go up and overall fat burning will go up, thereby helping with further weight loss. Now some of the side effects with liraglutide are not too surprising, just given that the main mechanism of action is slowing the stomach or slowing the intestines. In delaying peristalsis, the person will just feel a little sick to their stomach. So they may feel a little nausea, they have may have a greater risk of vomiting as the food is just sticking around in the stomach for too long. They just got to get it up and out somehow. If it's not going down, then it'll come up diarrhea or even constipation. So kind of the opposite ends, the opposite ends when it comes to gastrointestinal distress, again, diarrhea or constipation. Now with all of these GLP1 agonists there is a hint of human evidence to suggest that it may increase the risk of certain thyroid cancers. And that goes the same with semaglutide, which we can transition to now. Now, semaglutide is most famously included in two drugs, wegovy and Ozempic. Ozempic is the lower dose, so I'm not talking about that here because that's specifically used for diabetes, because at that lower dose, it has a very mild effect on delaying gastric emptying. And the more substantial effect is inhibiting glucagon, thereby inhibiting lowering glucose levels, thereby improving type 2 diabetes especially. And even some evidence to suggest they may be useful on type 1 diabetes because of that same inhibition of glucagon. And so again, at this, at the higher dose with semaglutide, it is marketed as a drug called WeGovy. It's funny, isn't it, that there's different levels of drug that get patented and then used, not that the molecule itself is different, but that the dose is different enough that they can get a separate patent and market it as a separate drug. And again, that's what WeGovy is. But I just remembered another side effect of liraglutide, so pardon me for backing up. Let's just talk about liraglutide for one more moment because this is a pretty interesting aspect, one of liraglutide's totally overlooked effects, although there is a publication to support this. Otherwise I wouldn't say it is that it has the ability to activate the growth of new fat cells. This has not been shown, to my knowledge, to occur with semaglutide, which was the drug we'd gotten to speaking on. Just a moment. That's Wegovian Ozempic. But it may happen. But. But there's no evidence that I'm aware of. But with liraglutide, there is evidence that it increases the hyperplasia or the multiplication of fat cells. Now you're thinking, Ben, how can the multiplication of fat cells coincide or coexist with weight loss? If this is a weight loss drug, how is it helping lose weight if it's making new fat cells? Well, if you're basically starving because you're not eating anymore, because your guts aren't moving food through your intestines anymore, then you are going to be shrinking fat cells. The overall amount of energy in the body is just so low and you're eating so little that insulin's also down that you're going to be burning a lot of fat. The fact that you're making new fat cells doesn't mean that you have more fat, but you just simply have more fat cells than you did before, even though they're all much smaller. And so the overall mass of fat has gone down. So that is how we can reconcile that apparent metabolic paradox when it comes to liraglutide. Now, let's get back to semaglutide. Although there is some redundancy with how I just got done describing liraglutide, its main mechanism of action is as a GLP1 receptor agonist. So it's mimicking what GLP1 would be doing. GLP1, the incretin that's always getting released from the guts, particularly when we eat. And so it promotes the sense of satiety and reduces appetite. Again, primarily because it slows gastric emptying. In fact, at this high, at this high dose, it slows gastric emptying so much that there are now some instances talking about side effects of what's called an ileus, which is basically when the intestines are paralyzed. They're not moving at all anymore. It's no surprise that that is a catastrophic side effect and can become very lethal very quickly. But it is one that is becoming more commonly reported, appropriately so, because it is a concern when you just are stimulating these GLP1 receptors so high, there's so much stimulus, you're basically activating GLP1 receptors to a point that you could never activate them to in a normal physiological state. You know, there's nothing you could eat that would increase GLP1 enough to mimic what the stimulation is when you're injecting these GLP1 agonists. And just as a term of physiology and agonist or cell biology, agonist is an activator, not an antagonist, which is of course going to be an inhibitor. Now, once again, in addition to that side effect, the side effects are the nausea and the vomiting. It's interesting that with the use of these drugs, and again, that we're going to talk much more about these drugs in next week's episode, we're going to go across all of the incretins and look at how they're used as drugs for weight loss and just overall metabolic health, because the, the, the theme for the month is just drug use for cardiometabolic disorders. And today we were starting with weight loss, and we'll do a little more weight loss and general metabolism in next week's episode before getting onto other cardio metabolically related drugs. Now, again, another risk here is thyroid Tumors. So thyroid cancer is also noted here, which is just appears to common concern with all of these GLP1 agonists. All right, now if you want more information on GLP1 agonists, including Wegovian Ozempic, tune in next week, that's going to be the explicit focus. All right, last one to mention is Metformin. Metformin is not classically designated as a weight loss drug even though it is heavily known to be used. So the fda, it's not not officially FDA approved for weight loss, but its ability to affect weight loss is so obvious to clinicians that they'll often prescribe it, if you will, off label or off intended use. And now how does it work? It's an interesting thing about metformin is that we don't fully understand how it works and this is not uncommon. Interestingly we will know what a drug does, but then filling in the gap between putting something in your mouth or injecting it into your bloodstream and its effect, there's a lot of unknown there with a lot of drugs, metformin included as even though metformin is the most widely used anti diabetic drug on the planet, we still are learning new things about it all the time. Now one thing we do know is that it increases, it activates an enzyme called ampk. Now that's relevant because it activates the enzyme by actually inhibiting the mitochondria's ability to make ATP. Now that sounds like I'm getting into the side effects which I don't intend to do yet, but it is a relevant feature here. By inhibiting ATP, we end up activating an enzyme called ampk. And AMPK is this master regulator of catabolism. It wants to break things down, it wants to burn things, wants to burn energy, it'll increase glucose use. So it wants to break glucose down, it wants to break fats down, it doesn't want to build things up. And thus in that little brief description, you can start to see how it could contribute to weight loss. Now specifically, metformin does improve insulin sensitivity. It improves for example, how muscles respond to insulin. And if muscles respond to insulin better, they will clear glucose faster. And if we can clear glucose more easily, then insulin can come down and be lower. And if insulin is low, we'll have an overall more fat burning metabolic milieu within the body, thereby helping promote weight loss. Also, metformin reduces the liver's production of glucose, so the liver's releasing less glucose into the bloodstream. So similar to how a GLP1 agonist will inhibit glucagon and thus reduce glucose and thus reduce insulin. We have a somewhat similar effect, albeit through different mechanisms when it comes to metformin. Also, metformin has been shown, although less data, to promote some degree of satiety. Now, that might be through some nausea, because metformin does promote nausea, you know, so this person just feeling a little sick to their stomach, very much like how they might feel with GLP1 agonists. But there is some evidence to also suggest that it could be a specific brain effect promoting satiety and thus suppressing appetite. Now, the weight loss associated with metformin is not substantial, nothing like what you see with the GLP1 agonists. It's usually on the order of just a few pounds over several months. Now, the side effects I'll get into the ATP and mitochondrial effect second, but the main side effects are just promoting nausea and diarrhea. So it just can upset the intestines. It also, there's a little bit of evidence to suggest metformin can lead to a vitamin B12 deficiency, which is very important. You need B12 for normal, just normal health and cells dividing and growing. And that is something that's particularly relevant in pregnancy and the growth of the baby in the, in the uterus. Now, what else? The last one with metformin is the ATP inhibition. Like I said. Now, it's not too hard to see that if you prevent or you reduce a mitochondria's ability, the mitochondria's ability to produce ATP. ATP is the currency with which a cell purchases work, and this is no more obvious than it is in the muscle. If you want a muscle to be dynamically contracting and relaxing, like, say, during exercise, you need to be producing a of ATP. ATP is directly relevant and directly connected and, and functional to the process of contracting and relaxing a muscle. With that in mind, it might not surprise you to learn that there is work, particularly out of Colorado State University, finding that metformin has the ability to offset or undo the mitochondrial benefits of exercise. Let me just rephrase that this is in humans even. This is human work. When we work out, we can, in, in a academic laboratory setting, we can detect an improvement in mitochondrial function. We increase the number of mitochondria and they're all working a little better in response to the exercise challenge. Metformin takes that favorable response and undoes it. So that's a pretty, I would argue, relevant, negative consequence. Ironically, and much to my personal frustration, a lot of these, what I call longevity gurus, these people who claim that they've unlocked the secrets to aging, which is all laughable because there is not, there's nothing to supporting their claims in humans. It's all based on insects or rodents. And then they're extrapolating to humans. But nevertheless, a lot of these longevity gurus, while in one breath promoting the use of Metformin, in the next breath will be promoting the benefits of exercise. I agree with one of those things. When it comes to longevity, the more muscle mass you have, the more likely you are to survive. So there's a strong correlation between the amount of muscle you have in your overall longevity. But if you're trying to stimulate, challenge and grow your muscles, but at the same time you're taking a drug that is directly offsetting the benefits of the exercise, and that's. It sounds like it's a kind of a zero sum game to me. So that is a side effect that the same person who may be taking Metformin to improve their metabolic profile and lose weight would also be exercising, I would imagine. And indeed, every one of these drugs are recommended to be used with proper diet and exercise. That's the common line with all of them. But in the case of metformin, as effective as this drug is, it does directly challenge what you're trying to do when you're exercising. All right, so that's a pretty interesting takeaway and we'll end with that as we are halfway through the hour. So that's the concluding part of the metabolic classroom. And let's just see those of you who have joined, thank you so much for joining live. It is wonderful to always be able to connect with you. And remember, if you want to submit questions, you have to be live. And then when you are part of the live group, you can just put your questions in the chat like some of you have here. And I'll get to those now, but thanks again for tuning in. I love these diligent students. Okay, first one, Jackie. Are there any dangers to someone taking something like allulose to activate or stimulate GLP1 or any medical conditions where it's not advised, specifically heart failure? That's a good question, Jackie. I am unaware. Now remember, of course, I'm never giving medical advice. I've been looking into allulose a great deal, Jackie, as you know, for reasons that you mention here, including GLP1 activation, that this is a unique, rare sugar because of what it does to hormones like GLP1, unlike other sweeteners or sweet tasting things. So does Allulose have any effect. So it's important to note that allulose will increase GLP1, but at normal to normal levels, like for example, if you were to eat fat or protein, you'll get a significant increase. Your GLP1 may go up by double. Allulose is going to do something similar, although albeit additive. You know, if you're eating it, eating protein and you had allulose, it's going to be bigger, but it's still a physiological level. You're making it with a, in the, in the context of a normal stimulus. So it's never reaching the level of activation that you get from those injectables. But I'm unaware of any time it would be ill advised. In fact, more and more, it appears that allulose is very therapeutic, including in not only instances like diabetes, but also in these rare genetic disorders of fructose metabolism. Allulose appears may have some benefit there, although that's all forthcoming. But heart failure specifically, Jackie, as you noted, no, I'm unaware of anything with heart failure. Amanda, UA semiglutide is documented. Hypoglycemia side effects. Can natural GLP1 agonist like unimate cause hypoglycemia leading to tachycardia? Okay, so Amanda, you, you've introduced a couple interesting and nuanced aspects here. So like the hypoglycemia leading to tachycardia, you have filled in a lot of gaps there, but I'll fill them in for the audience. As hypoglycemia occurs and blood glucose levels drop too low, that activates a sympathetic nervous response, just like we were talking about earlier. So it's no surprise that epinephrine skyrockets because one of its effects is to increase blood glucose dramatically and quickly. But also now you have this cardiovascular effect where it starts to ramp up heart rate and try to increase blood pressure, which it is able to do in this case because there's no change in blood volume. Now back to the question Amanda mentions, Unimate, which is a Yerba mate based supplement. You've heard me within the insulin IQ community mention it, partly because we published a paper on its effects a few months ago. But this is a specific, very concentrated Yerba Mate produced by a company called Unicity. So that's what Amanda is referring to here. Now, Yerba Mate is a Natural activator of GLP1. It will increase GLP1 release just like allulose does, actually. But there's no evidence to find that this is such a substantial Effect that, that to take Amanda's comments and put them into a sequential set of steps, that there's no evidence that the following would happen, that a person drinks unimate a concentrated yerba mate that they get, then a GLP1 increase which then inhibits glucagon, which then results in substantial hypoglycemia, resulting in this sympathetic response, you know, this, this weird sort of set of steps here that, that Amanda's put together as a potential concern. No, I'm unaware of anything. In fact, I would strongly speculate there's no way you can increase your own amount of GLP1 to the degree that this would happen. It has to be a super physiological activation of GLP1 receptors for that to happen. And even then it would be. It's very uncommon. Okay, Carol, more GLP1. I love all this focus on GLP1. Remember next week is all incretins. It's GLP1, it's GYP, it's DPP4 inhibitors. It is C. Coli cystokinin, peptide YY. We're going to dive into the incretins and then describe how they're leveraged as medications, including GLP1 agonists. All right, so GLP1 receptors are in all kinds of tissues? Yes, they are. GLP1 receptors are prevalent throughout the body. Do we know yet how heart, lungs, brain, kidneys respond to the high doses? That is a great question, Carol. I. I don't know. Now, I know some of these. I don't know anything about the lungs or heart. I do know a little bit about the brain and kidneys, so I'll speak to those. And I regret the professor in me is weeping that I can't answer every part of that question, especially given the topic. And so it's something I'll try to correct in my own. I'll try to correct this gap in my own knowledge here. So within the brain there are GLP1 receptors. And when they're activated with these injectables, it has a direct effect of promoting satiety and a direct kind of neural connection to brown adipose tissue, where the brain is activating brown adipose tissue to increase its metabolic rate. Because brown adipose tissue is not always revving its engine, it has the potential to rev its engine. And again, the magic of brown adipose tissue. And we'll talk more again about adipose tissue next month. So I'm going to come back to this metaphor, but it's like the engine where the car is in neutral or it's parked and you're revving the gas where you're, you're using fuel but you're not getting any work done. You're not actually moving the car. So again, that's the relevance of brown adipose tissue and GLP1. Stimulation at the brain will stimulate brown adipose tissue. Now in the kidneys there is an effect at telling the kidneys to increase their glycogen. Now there's a little lesson for for you all where when we think of glycogen we typically just think of tissues like the liver and maybe even the muscle. These are tissues that have their own reservoir of glucose, the muscle to be used for their its own interest. Because once the muscle takes in energy and stores it, it never gives it back, it always keeps it. It's a selfish tissue. Unlike the liver where if the liver has glycogen in it, it's keeping it in order to break it down and share it with the rest of the body. That's why I joke that the liver is the ultimate kind of metabolic or nutrient soccer mom that the rest of the body needs a snack. Well, the liver's got one muscles crying, demanding and whining for some nutrients. All right, all right, fine muscle. The liver says let me give you this little pack of gummies from my stored glycogen or whatever it may be. So the liver is the ultimate giver metabolically within the body and GLP1 sorry, but I've lost the topic here. I was talking about the kidneys. Just like the the liver has glycogen, so too to do the kidneys. And this may be partly as an interesting aside and I just got done a tangent a moment ago, so pardon another one. The kidneys have the highest metabolic rate in the body and it's not even close. They destroy like multiples higher metabolic rate than any other tissue. So it might just be in their best interest to have some energy on hand including glycogen. Well, GLP1 similar to increasing glycogen in the liver, which is neither good nor bad. Maybe it's good actually if you're an athlete and you want to increase your. Oh, you know, you've heard of this glycogen Loading. Perhaps GLP1 has an has a role in promoting glycogen loading but it also appears to have a similar effect at the kidney that it'll slightly increase kidney glycogen. Okay, all right, Carol. I hope that helps. Lisa. Berberine and apple cider vinegar when to take in best times of day. So I Don't know if there is a best time of day in the absence of any eating. My suggestion is you take it before you eat your starchiest meals of the day. So importantly, if you are eating meals of just protein and fat, then I would say you don't need to worry about those at all. Although I am just such an advocate of apple cider vinegar in general, just I'm an advocate of us getting the full profile of fatty acids, that our diet nowadays is only long chain fats. As we incorporate other types of dairy, like goat dairy or coconut fat, then coconut oil, then we get more of the medium chain fats. But because we don't eat fermented foods very often, we get no short chain fats. And short chain fats just really punch above their metabolic weight. Their, their, their, their chemical weight that they're very small molecules, but they really carry a substantial metabolic impact. But nevertheless, usually you want to take it right before you eat or while you're eating or right after sometime right around your window of eating. Andrea, slightly different topic. Is there any risk of using exogenous ketones for people who aren't yet into ketosis? That's a good question. I don't believe there are any risks. There are none that I'm aware of. Exogenous ketones can come in different forms, including ketone salts and ketone esters. And now there's even newer ones than that. But the benefit of the newer ones is you aren't loading your body with all of those minerals where when you're getting the ketone salts, it's just an awful lot of calcium, sodium, potassium, magnesium that your body needs to deal with. And while none of those are harmful, it does. You do have to get rid of them. And so the person may have an increased risk of kidney stones. They most certainly will have an increased deposition of mineral plaque on their teeth. I get that when I am taking too much of these ketone salts or just too much electrolytes in general, where I actually will have to go in and scrape it off every, you know, month or so. I'm not, I mean, it's not that bad. It just bothers me, but it's something that I feel a little more. Anyway. So back to the question, though. Exogenous ketones. No, there's no risk. Indeed, the more evidence that continues to come out of the benefit of ketones. I, I hate to sound like I'm advocating it, but I could see how a person would justify, I'll say it that way, actually getting exogenous ketones. Now, I have no vested interest in saying that at all, but ketones are very favorable metabolic signaling molecules. And so if someone's having trouble getting into ketosis on their own, I do not think there's any harm. Indeed, I think there's a benefit to getting them through a supplement. Lisa, from your book, why We Get Sick, you give some vitamins and supplements to take. Some are fat soluble. So can Omega 3 be enough while fasting? Lisa, I'm not totally sure what you mean by that. A fat soluble vitamin just means that it is going to be absorbed with fat and then be stored with fat in the body, which is why it can have some degree of toxicity because we can't just eliminate it like we can water soluble vitamins. But yeah, I mean, take, I, I confess that. I mean usually a fat soluble vitamin will come with some kind of fat in it. It'll come as some kind of gel pack and there will always be a lipid that is carrying it. That's actually something you could pay attention to if you are a rabid seed oil avoider. A lot of those come with soybean oil as the carrier. So you might want to try to find some that are coconut oil or some other type of fat. And omega 3 fats. I, I'm an advocate of, in part because they improve muscle recovery if you're working out and they increase HDL and potentially offset the peroxidation of omega 6 fatty acids like linoleic acid from soybean oil. Lindsay, Lindsay Van, our resident physician assistant clinician mentions maybe a risk of ketones with SGLT2 inhibitors. Yeah, so I think what Lindsay's referring to is be evidence that if people are on an SGLT2 inhibitor, that drug itself has a capacity, a potential to increase ketogenesis. So if you're taking it in the midst of a low carb diet, you could take your mild ketosis and bump it up a notch too far into outright ketoacidosis, which is generally a realm reserved for the untreated type 1 diabetic. Carol, thanks for appreciating my analogy of the liver being the metabolic soccer moment. Andrea, do I have any recommended products for ketones? Of course. Remember, I have no vested interest here. I will maybe partly informed by my experience with them. There was a group that I met, oddly enough, given its name in Switzerland, called, I think it's called American Ketones. And they make these, what's called bioidentical ketones. And the nice thing about it was it tasted great. They let me try some and sent me a few bottles but it really increased my ketones. It worked like a ketone ester but it's not technically an ester. I don't recall it being but anyway it's I think it was called American ketones. They they just really seem like great people too. So I'm a little biased so pardon my bias. All right you guys, thank you so much for tuning in. Remember next week, join me next week we're going to be really diving into the incretin hormones, these gut based hormones in reviewing their impacts on metabolism but then again focusing on how it is leveraged, how that is leveraged within the context of overall metabolic drugs promoting weight loss and diabetes correction or resolution. So that'll be next week. Thanks again for joining me. Remember, the more you know, the more you can control your metabolic health. Thank you guys for tuning in. I'll see you next week.