Dr. Ben Bikman - 'GLP-1 Drugs: Consequences and Considerations'

Hello, my name is Professor Ben Bikman, and I am a biomedical scientist who focuses his lab on metabolic disorders. Because of this, I am very familiar with a topic that I think you might find interesting, and indeed a topic that I was invited to speak on. And by the way, Hey, Rod, thanks for the invitation. I wish I could be with you there in person, but the Low Carb Down Under meeting is a difficult one to get to when you're where I'm located. As you see here, the topic for my talk is the GLP-1 drugs, and I want you to have, at the end of this time, a better appreciation of the consequences and some considerations associated with these drugs. Now, to the drugs' credit, as we get started, there is a problem, uh, and it is metabolic in nature, um, and it spans the globe, where we know that the global population of people that are overweight and obese continues to increase. And this is matched very closely with the number of people who have insulin resistance, actually making insulin resistance the most common health disorder worldwide. Now, Even more relevant than its prevalence affecting over half of adults worldwide is insulin resistance relevance, which is really a function of the diseases that come from it. All of these, what I refer to as plagues of prosperity, despite their differences, do in fact have one thing in common, namely they share a common cause to a degree, insulin resistance. To varying degrees, insulin resistance contributes to each of these disorders that I have highlighted here, and indeed many, many more. Now, this confluence of fat gain worldwide and insulin resistance incidence worldwide is more than just a coincidence. There is in fact a causal relationship here. So let's move on to a question. I am a professor after all, so I like posing questions. Thanks for letting me be your guest professor for the next few minutes. How does insulin, um, how does insulin resistance get, uh, come or get elicited, or how does it rise in response to fat gains? Well, fat can be gained on the human body through two different processes. On one hand, a person can be gaining fat by the size of each fat cell just getting bigger. That's a process called hypertrophy. Alternatively, a person can be gaining fat mass, perhaps even the same mass of fat, but through— do it through an entirely different mechanism, namely hyperplasia, which is when the size of the fat cells remain somewhat unchanged, but the number of fat cells is increasing dramatically. So again, this is a difference of size versus number. Hypertrophy is the main way through which most people gain their fat. This is a problem for two reasons. First reason is that as fat cells get bigger and bigger, they essentially begin to run out of room. They have no vacancy. Normally, um, a fat cell that is insulin sensitive will be responding to insulin by growing. However, once the fat cell has grown to a maximal point, which is about 10 or 20 times volumetrically than what it used to be, it cannot grow any further. Of course, that's why it's the maximum point, and it must then stop listening to insulin lest it break apart, literally explode with fat. And so the fat cell that is hypertrophic becomes insulin resistant to prevent that catastrophic fat explosion. So that's one problem with hypertrophic fat cells— they become insulin resistant in order to prevent growth. At the second time— on the second reason here is that as the fat cells get bigger and bigger, they begin to suffocate. Now, a quirk of cell biology is that a cell must be within just a few dozen micrometers of a capillary. It must be so close to that capillary so that it can effectively move gases. It can get oxygen, it can expel its CO2, it can take in nutrients, it can expel metabolites. However, as the fat cell has grown to this maximal dimension, It is multiple times bigger than the distance a cell is supposed to be from a capillary. This can mean that any adjacent fat cells have been pushed simply too far from the life-giving blood of the capillary, and this creates this suffocation state, or at the level of the cell, hypoxia, we would say. One effort that the cell has in order to try to correct this is to become pro-inflammatory by secreting a, a large profile of pro-inflammatory cytokines. The hypertrophic fat cell can stimulate the growth of new capillaries, thereby attempting to correct the hypoxia. Now, unfortunately, with both of these ideas together, we end up really creating a perfect metabolic storm where the hypertrophic fat cells are becoming insulin resistant, and they're leaking free fatty acids, and at the same time the hypertrophic fat cells become, uh, hypoxic and must attempt to correct that by becoming pro-inflammatory. Well, these two things that ensure the survival of the hypertrophic fat cell end up coordinating in order to really drive insulin resistance throughout the body. All right, by now you know that big fat cells are problematic, that they are insulin resistant and pro-inflammatory. How can we shrink The fat cells, then, in order to improve their insulin sensitivity and by extension the insulin sensitivity of the body— that is the question. In fact, anytime someone is talking about losing weight to improve metabolic health, you should actually be thinking shrinking fat cells to, to improve metabolic health. To shrink a fat cell, there are generally two components to it: reducing energy and reducing insulin. Now let me just say as an aside, Although that's not the purpose of this talk, even if energy were still high but insulin were low, fat cells would still shrink. A perfect case study for this would be the untreated Type 1 diabetic. If you simply eliminate insulin, even though all other kinds of, of variables are still there, indeed including perhaps an abundance of energy, the person could be eating thousands of calories in excess a day, and yet they cannot keep a single scrap of fat on their bodies. But for the most part, these two variables are going to go together, and sure enough, they will shrink the fat cell. Now, there are two ways to do this very effectively with nutritional changes, namely control carbs and frequently fasting. This is going to be a perfect way to address both of these aspects, reducing energy and controlling insulin, most importantly. And thus, again, as I stated, how we eat is the most relevant variable here in shrinking fat cells. However, this is in many instances easier said than done. It is in fact a simple principle: control carbs, frequently fast with structured fasting, and yet most people don't do it. Let me show you why. This is the group of all professionals. They will ardently claim with their clarion call that we just should— that someone who needs to shrink their fat cells just eat less and exercise More. It's that easy. Even easier than what I just showed you, perhaps they would say. Let me show you why that's a problem briefly. Let's imagine that Rod is hosting a beautiful dinner and he has invited every one of us, even flown me down from the US to come and join this beaut and participate in this amazing buffet. And he's invited the world's best chefs. And what we have been invited to do is come and eat as much as we can because we're going to want to try everything. So come hungry is the invitation. Think for just a moment, what would you do to ensure that you came to Rod's dinner as hungry as possible? I bet you would do two things. First, you'd eat a little less in the day or so before the event. Another thing, I bet you'd exercise a little harder, and it would work. It would work very well. As we were preparing to go to Rod's buffet and we would want to sample a little bit of everything. And so to help us do that, we'd want to come as hungry as possible. This would work. But the problem is, eat less, exercise more— if we go back to that original set of advice, eat less, exercise more to lose weight— it also is a perfect recipe to cause hunger. And hunger always wins. And so we need to have a way of controlling carbs and frequently fasting that doesn't pit an individual against hunger. And that is where drugs come in, injectables or oral medications. Now, to move the conversation forward, allow me to step outside of this particular trend for a moment and introduce you to the fact that the gut is one of the busiest endocrine organs in the body. The gut makes more hormones than most of the classic endocrine organs. When you think about the hormone-secreting glands of the body, you may think of the thyroid gland. You may think the gonads, you may think of the adrenal glands, and yet the gut produces dozens of more hormones than any of them— any of, any of those tissues produce. Uh, so there are dozens of hormones, and a family or a class of these said hormones from the gut are the incretins. Now, this is a fair— an area of research that I have actually been quite familiar with since its inception. When I did my PhD work, as I'll show you in a moment, it was actually based on people who had undergone gastric bypass. Surgeries, or so-called metabolic surgeries. And that's some of the origin of this, as I'm going to show you in a moment. Now, the incretins as a family of hormones are lumped together because among this small group of hormones, what they have in common is the— to affect blood glucose levels. Now, as I'd mentioned, some of the origin of the interest and even the discovery of the incretins was looking at humans post-gastric bypass. When they come in and chop the stomach up to a teeny little remnant knees, and then they bypass the duodenum, which is the main site of digestion. So basically forcing people to eat less and not digest even the modest amount they are eating very well. Well, interestingly, and bringing us right back to the story, it has been known for decades that someone who is very insulin resistant, as measured by the HOMA score, um, they can come and get a gastric bypass procedure, and their, um, glucose— their insulin sensitivity improves to a level of normal almost within a week. So look at what's happened here in the diabetic population having undergone gastric bypass. Their insulin sensitivity, their HOMA score, goes from about a 12 down to about a 3 or so, which by my standards is still a little high. But even still, their type 2 diabetes is gone in just 1 week. That begs the question, how, how did this— how did the diabetes improve so quickly? They're still very overweight after all. It's not like they've lost their 100 kilos of excess fat mass in just 6 days, but the diabetes is gone in a week. They get off their medications. How did it improve so quickly? This is part of what led to the discovery of the incretins, and in particular, the most famous of all of them, namely GLP-1. Now, GLP-1 is the most famous of the incretins for good reason, because its effects to improve metabolic health are so substantial. And here are just some of the effects of GLP-1, the hormone glucagon-like peptide 1. And the glucagon-like aspect of it is something we're going to talk about more in just a moment. But GLP-1 has an effect to slow the intestines down. That means that someone will feel more full for longer, so hunger will be somewhat abated because is just sticking around in their guts for longer. At the same time, however, complementing this effect is a central stimulus to the brain from GLP-1 telling the brain that it does not need to eat, and thus once again we are driving down hunger. At the same time, GLP-1 does have a direct effect at fat cells to stimulate lipolysis, which increases free fatty acids, which can increase ketogenesis, which can further fuel the brain and reduce hunger. Now back to the gastric bypass procedures. I simply at this point have shown you that the diabetes, the type 2 diabetes, is resolved in a week. Now back to the GLP-1 story. This is what happens to these individuals when they eat a, a mixed macronutrient meal. And then before their bypass, if you looked at their GLP-1 levels, it's a modest increase. Over these handful of hours. That's the light blue line. But then post-bypass, look at that difference. This really is the data— are the data that put the focus on GLP-1 as a potential therapeutic that should be leveraged or exploited. And indeed it has been. This is what gave rise to the so-called glutides. Whenever you hear a drug, if it ends with the suffix -glutide, then you know it's a GLP-1-based drug. It's mimicking GLP-1. Now, the name of this is glucagon-like peptide 1, and these drugs, these glutes, are meant to act like GLP-1. Well, in its original discovery and why this was marketed, these GLP-1-like drugs, why it was marketed as an anti-diabetic medication is because of its effect on glucagon. GLP-1 was found to inhibit glucagon very, very well. And you may recall that glucagon's effect is the opposite of insulin's effect. These are two battling siblings. Whereas insulin wants to lower blood glucose, glucagon seeks to increase blood glucose. And indeed, in someone with type 2 diabetes or even type 1, they always have too much glucagon because insulin isn't working well enough to shut it off. So if you can take a drug like a GLP-1 drug and inhibit glucagon, you can now lower blood glucose very effectively. And indeed it is effective. And this is the original intention and use of the GLP-1-based drugs. Now, even at this original lower dose of these GLP-1 agonists or mimics, they found that yes, it would improve blood glucose levels, but it also helped people lose a little weight, even at this relatively lower dose. And this was primarily an effect of the reduced gastric emptying, where food was just sticking around a little longer in the guts, and hunger would go down, they would eat less, and they would lose weight. So that was just thought of as a beneficial side effect in what was originally an anti-diabetic drug. Again, just to state this clearly, these GLP-1 mimics or copy drugs were not originally used for weight loss. The weight loss was a modest effect, and it was just considered a beneficial side effect of what was primarily viewed as a glucose-lowering medication, which itself was an effect of the reduction in glucagon. Now, however, with this finding of delayed gastric emptying and weight loss, that of course gave birth to increasing the dose which is the only difference between the anti-diabetic version of the drug and the weight loss version of the drug. It's just how many times have we multiplied the dose. Now the intestines are really slowed down. That can create a problem that is worth knowing. This is a consideration and a consequence that some people who are on these drugs can experience a paralysis of the intestines, which is an acutely lethal situation. The person can die, and it does require immediate intervention, but it has happened. You can slow the intestines down too much. At the same time, if you slow the intestines down and the person is eating a lot less, it's no surprise that among the weight that they are losing is potentially a significant amount of lean mass. As much as these drugs are marketed for their ability to make the body lose fat mass, which it does, this study published in the New England Journal found that up to 40% of the weight that is being lost is coming from lean mass, which, which does include more than just muscle. It does include bone, which is also problematic, but also water. Let me just admit that upfront, that I'm not claiming that 40% of the weight they're losing is just coming from the muscle. There is some water mass that would be included in that as well. But even still, a pretty meaningful amount of the weight that is being lost is coming from weight that we don't want to lose. particularly in an older person. This matters so much because of what happens when a person gets off the medication. You can look at the dramatic degree of weight regain here as you see the weight loss with the GLP-1 agonist, and then the moment the drug is stopped, the weight regaining. Now look at the trend. Now you could say, well, Ben, there's still a 5-kilogram difference here. 2 things. One, what would happen if they would have continued to go? It absolutely would have gone right back to where they started. But also, mind the gap. What is this weight loss? What have they regained? What will they not regain? Remembering as we go back that 40% of what they lost was not fat mass. So if you look at lean mass and fat mass, one of those masses will return, will, will return very readily. One of them will not. And so it's not outside the realm of likely possibility that even though they're still 5 kilograms less than they were in total mass, as a percent of body fat, they're probably fatter than before they ever started. Now, why does that even matter? Why not just stay on the drug? People get— they feel so sick and nauseous on the drug that this study published in the US in Another study in the UK found that it's just right at that same level, actually, that 70% of people willingly stop taking the drug at 24 months. So this is not the clinician telling them to stop it. They are so sick of feeling sick. That's the ultimate effect of slowing the intestines down, that the person just always feels a little nauseous, which we say— the nice way of saying that is they control their cravings. The, the realistic way is to say— the realistic version of that is just to say they feel sick and they don't want to eat anything. Well, people get sick of feeling sick, so they want to stop taking the drug of their own volition. That has consequences, including weight regain. All right, now one of the earliest, um, weaponized misconceptions with the GLP-1 receptor agonists was the effect on insulin. So I wanted to take a moment to talk about this because the idea has been, um, among the uninformed that GLP-1 agonists are able to lower glucose because they increase insulin. That's not an irrational perspective because if you do increase insulin, you will lower glucose. But then how could a person be losing weight? After all, I showed you at the outset of this lecture that You must have reduced insulin in order to shrink a fat cell. There's no getting around that. And this created, um, this was weaponized by people who believe insulin has very little relevance or, or none in the case of weight balance or body fat regulation. So this was a sentiment that was even published in papers saying this disproves the use of GLP-1 agonists, disproves the insulin theory, the— or the endocrine theory of obesity. Um, and yet these people have, um, egg on their face because that does not happen, as indicated here in this study. And I'm quoting it: GLP-1 is believed to increase insulin secretion according to its isolated actions on islet cells. So in isolated cell cultures, this was shown to have an insulin effect, the GLP-1 agonist. However, when you actually look at whole animal or whole body human studies, insulin secretion is actually down. Now, one of the earliest studies that have explored this really showed the effect powerfully. This is work by Arne Astrup's group, and Arne is one of the godfathers of incretin research and now works with the Novo Nordisk Foundation. A wonderful man. And his— this is decades ago now, 20 years ago or so. They gave humans, uh, a mixed macronutrient meal and then looked at insulin secretion, whether they just got a vehicle, the sodium chloride infusion, or whether they got a GLP-1 infusion. And look at what GLP-1 did. It actually halved— it halved the amount of insulin that is secreted. So the idea that, that GLP-1 agonists somehow induce insulin secretion is laughably false. Very easy to disprove with just even a modest amount of searching that goes beyond the isolated cell culture work. Let that be a lesson to you budding scientists: the model matters when it comes to making conclusions about experimental design and, and conclusions. All right, now I want to just mention a tangent here. Um, I showed you at the outset of this lecture that small and more abundant fat cells help improve insulin sensitivity. So is it possible that GLP-1 receptor agonists could improve insulin resistance by increasing the number of fat cells. Now, this is not as crazy as it may seem. After all, let's do one more tangent within this tangent. How do thiazolidinediones improve insulin resistance in the body? So TZDs— thiazolidinediones— are recognized generally as one of the few medications that actually directly improve insulin sensitivity. Most anti- diabetic drugs do not. They just lower the glucose without actually improving the insulin resistance. Metformin does though, to a degree. But thiazolidinediones are sometimes credited as being the only actual insulin sensitizing drugs. How do they work? TZDs actually will take big fat, hypertrophic fat cells and stimulate the proliferation of new fat cells. So it basically converts the hypertrophic fat cells, which are very insulin resistant, into smaller yet more abundant hyperplastic fat cells, which in turn indeed are insulin sensitive. But paradoxically, of course, the reason people don't like taking TZDs is that while they are improving their type 2 diabetes, they're getting fatter with every week that goes by. Now you're thinking to yourself, Ben, what on earth does this have to do with GLP-1 receptor agonist drugs? Well, even here it might be relevant. One of the early versions of the GLP-1 drugs, which can still be used, is liraglutide, and that's indicated by LG in this quote. Liraglutide increased the expression of differentiation marker genes and lipid accumulation during pre-adipocyte differentiation. In other words, GLP-1 agonists may be stimulating fat cell hyperplasia. Mm-hmm. Now you're thinking, but Ben, how do we square that off? Because we know people lose weight. This is not an irreconcilable feature. You could both be making new fat cells, but because the person has low insulin and is eating less, the fat cells are all smaller. That would result in a net loss of fat mass, even though it may be increasing the number of fat cells. But that becomes very relevant should the person ever, and likely will, stop taking the medication. Now they have more fat cells than they did before, and they have a greater material capability or potential of gaining more fat mass than they did before they were ever on the drug in the first place. Now, one other consideration is, could GLP-1 receptor agonists be too much of a good thing? GLP-1 is good, there's no doubt. It has myriad metabolic benefits. Let me just pose you a couple questions to put this question in context and why I would even consider asking it. What happens to insulin resistance with insulin insulin therapy in someone with type 2 diabetes? If you've ever heard me speak about that, and perhaps many of you haven't, you'd know it's catastrophic. Type 2 diabetes is a disease of too much insulin. Giving them even more insulin in a naive effort to just control their glucose actually makes them more insulin resistant. Now, a slightly different question: what happens to testosterone production in the testes of a man who goes on testosterone therapy? Um, Well, it goes down as you begin to put in this, uh, this drug, the molecule itself. The testes, whose primary job in this context is to produce testosterone, it basically says, oh, okay, I don't need to anymore. There's so much testosterone already here, so I'm just going to stop producing it. Well, this is not too crazy to put in the context of GLP-1 drugs. This study found that chronic exposure to GLP-1 receptor agonists actually desensitizes the receptors. So by putting it— by overstimulating the GLP-1 receptors with the drugs, we might be reducing their sensitivity. Similarly, or along this same line but moving over one lane, so going in the same direction, this study finds that this GLP-1 receptor agonist actually reduces people's endogenous GLP-1 production. So there is some evidence, potentially, although the, the real ramifications of this have to be determined, that GLP-1 receptor agonists could be too much of a good thing. That at these really high doses that are commonly used, you may be reducing the sensitivity to GLP-1, and you may be compromising your own ability to produce GLP-1. Now, another consideration here is the future of the weight loss drugs. At this point, The main mechanism of action for GLP-1 is to basically make people eat less. Now, there are other molecules, other hormone signals that do the same thing. In particular, a hormone called amylin— very overlooked. It's a product of the beta cells that gets released when the beta cells make insulin. Well, amylin has the same effects. Amylin delays gastric emptying. Amylin promotes satiety. These two drugs together— and amylin analog and a GLP-1 analog actually can result in double the weight loss of the GLP-1 drug alone. This early test is what ultimately led to Novo Nordisk actually getting a valuation that made it the— among the most valuable companies on the planet. So this is the immediate future, potentially, where we start to couple the GLP-1 with other drugs, or in this case hormone analogs or hormone mimics, that really exaggerate this effect. But you, um, there is still the consideration of, say, the lean mass loss. And this was a result of a paper published, or an abstract published at a conference. There was no corresponding peer-reviewed paper, so please appreciate that this was just a conference abstract. They're looking at now the use of GLP-1 with drugs that will attempt to maintain muscle mass, namely these myostatin inhibitors. I'm actually quite, um, skeptical about that. There has been a search for effective myostatin inhibitors for decades, and it never works. Maybe they'll overcome that, but myostatin is a signal, a biochemical signal in the muscle that inhibits muscle growth, and if you can block that, you promote muscle growth. So the idea is basically give them an anabolic signal while they— while you're giving them the GLP-1 drug. All right. Now, at this point, I hope you appreciate the benefits of GLP-1. It is absolutely a hormone that works in our metabolic favor, so we do want it. How can we get it on our own? How can we increase our own production of GLP-1? That's how I wanted to end my talk here. So can you get some of the benefits? Yes, indeed you can. Namely, soluble fiber. Can increase GLP-1 production. Yerba mate, the South American tea, has been shown to increase your GLP-1 production. The rare sugar allulose, um, is maybe the single most powerful, um, GLP-1 release molecule inducer, um, in the human diet. And then also just natural foods like proteins and natural fats. Now, why do I emphasize natural fats? If you'll indulge me for just a moment, Um, if we look at the classification, common methods of classifying fats, we would look at it based on its level of saturation. We have saturated fats, monounsaturated fats, and then polyunsaturated fats. The saturated and monounsaturated fats, I commonly say, are ancestral fats. These are fats that we as humans have been eating for, well, since time immemorial. Animal fats fall into this category, and so too do fruit fats, the fats coming from things like coconuts, avocados, and olives, where our ancestors simply would have needed to press it and we would get the oil. However, the polyunsaturated fats, while yes, they exist in nature, including animal fats, they do exist in those instances in very low levels. We now eat more fat from polyunsaturated fats than any other single, than any other single fat, because it's these so-called vegetable oils, which are more or accurately known as refined seed oils that have come to predominate all food we eat. Basically, if you're eating food that comes from a bag or a box with a barcode, it's likely enriched with some form of a refined seed oil. Now, this is not a lecture about the consequences of linoleic acid, the primary polyunsaturated fat. It is in fact focused on GLP-1. So what happens? when a human eats these fats? Well, thankfully we have an answer because some sharp scientists have asked this question previously. So if you measure the area under the curve eating these fats, if someone eats saturated fats in the form of lard, the overall area under the curve is 15 times greater than a control state. If they eat monounsaturated fat in the form of olive oil, it's even a little higher. It's 20 times higher with the total area under the curve. When a person eats the refined seed oil, it's a fraction of this. It's only roughly a 7 times area under the curve over the fasted state. So a significantly greater GLP-1 response when a human consumes the natural fats from animals and fruits. Now, just so that you don't feel like I'm not giving you the most current cutting-edge research, this was a paper that was just published a couple weeks ago at the time of me recording this that looked at the the increase in GLP-1 secretion when someone ate a low-fat meal versus a low-carb meal. When someone ate a low-fat meal, their actual units of GLP-1 was 2.4 picograms per mL. I'm so sorry, given the audience, I should have changed this into picomoles, but pardon the lack of metric units here, and this even coming from a Canadian. So from one fellow Commonwealth citizen to a bunch of others, I apologize for my Americanization of science here. So we have the 2.4 picograms per mil. You'd say to yourself, well, that must be pretty fine unless you can triple it or so by eating a low-carb meal. No surprise. Um, it is primarily fats and proteins. It's not to say carbohydrates don't have an effect. Some do, but it is obviously not equal to the effect of a meal and a diet by extension that is based more heavily on fats and proteins. Now, at the end of it all, as a scientist who has almost from day one of my PhD been familiar and kept my finger on the pulse of these incretin drugs, what would I say about them? I used to look at these drugs more favorably than I do now, and that's all because of the dose. The dose makes the poison. Oh, that's a dramatic statement, I know, because this isn't poison. But when GLP-1 drugs was used at its original lower doses, I was generally quite favorable to them, um, that the overall net effect I thought was worth it. After all, every drug is a mal— is about— is a matter of balancing the consequences you want against the consequences you don't want. I considered them at the time to have generally consequences that were favorable enough to balance out positively. So my idea would be then to use the lowest effective dose, or if someone is on a currently a high dose, working with your clinician, do what you can to lower that dose. This may be particularly helpful in someone who manifests with significant food addictions. Um, as much as I am not a fan of weight loss drugs, in this case included, I'm not— perhaps that would be a reason I could look at it more favorably. If a person is trying to get to that next point of just controlling their carbohydrates, maybe this can help. Um, and I— that is a point worth elaborating, because if you look at the 3 macronutrients in the human diet— fats, proteins, carbs— people like to, to say that humans have an addiction to fats, but that's based on rodent work. This has been directly challenged and even dispelled in, in explicit research that has said we cannot apply the dietary habits of the rodent because rodents do appear to have a, a love for dietary fat that humans do not appear to have. Humans eat dietary fat and it actually makes them want to eat less of it, that there's this kind of growing aversion. Rodents do not have that same effect. So humans— Mm-hmm. There is no instance of— no publication of fat addiction alone, no evidence of protein addiction. There is abundant evidence of carbohydrate addiction. So as simple as the idea is, control carbs and you'll lower your insulin and you'll shrink your fat cell and reverse your metabolic, um, disturbances, it is easier said than done, as I've now stated a couple times. So perhaps at this lowest dose— that's effective, a person can find that they get a little help controlling their addictions. Um, but as they use these drugs to any dose, it must be offset by a pretty well-structured resistance exercise program to help maintain or even increase muscle mass as much as possible. And given that the person is eating less, all the more reason to emphasize the foods that a human needs. After all, there are such things as essential amino acids. Thankfully, you get them from any source from animals. There are such things as essential fats. Thankfully, again, you get them from any animal source. What are the essential carbohydrates? There are none. None. Now, I'm not saying we shouldn't eat them at all. I'm not saying that, but it is, I believe, noteworthy that if you have limited space to eat or limited interest in eating, focus on the things you need. That they happen to also be the things that have the least impact on insulin, even better. Focus on fats, prioritize protein. I hope that this has been insightful and that you feel like you know much more about the considerations and the consequences of these GLP-1-based weight loss drugs. And I wish I were there to answer questions. Perhaps Rod will find a way of passing them to me. In addition to my academic appointment, I invite you to find me on my insuliniq.com website or any of my social media channels where I just seek to be a professor teaching ideas. Thanks again for listening, and I hope the conference goes wonderfully well.