42: What is GLP-1, What Does It Do, and Where Does It Come From with Dr. Ben Bikman

Good afternoon, everyone. Thank you so much for joining me today and for being a diligent student in today's episode of the Metabolic Classroom. I'm professor or Dr. Ben Bickman, and the topic for today is one that many people are interested in at the moment, which is GLP1. Now, just by way of introducing the topic, I wanted to expand it a little bit rather than exclusively discuss GLP1. Just as we're framing up the discussion for the day, I wanted to expand it to include other incretins and even define the incretins as a class of hormones so that you have a better understanding of, of GLP1 and its place within this broader, well, family of hormones. There have been, there has been tremendous interest in the incretins ever since they were first discovered. And just by way of a brief history lesson, they were discovered as a consequence of gastric bypass surgeries. What physicians and scientists found was that following gastric bypass procedures, people had much higher levels in the bloodstream of these particular hormones, as at the time undefined. And what they found in various experimental models is that they helped resolve diabetes. Now, remember, at the time, unless so now, gastric bypass was largely an intervention to correct diabetes, and it did and does so very quickly. Interestingly, it essentially uncouples. Gastric bypass does weight, body weight or fat mass from diabetes. Normally, the fatter or specifically the larger the fat cells are getting, the more diabetic or insulin resistant the person is. With gastric bypass, they found that the people, within a week, their diabetes was gone completely, and yet they were still very much overweight. They still had way too much fat mass or fat cells that were way too big that hadn't gone away. Now it was going away, but it hadn't gone away yet. And yet the diabetes was essentially completely resolved. Again, it was in that. It's with that perspective in mind that led the scientists at the time to start diving into some of the differences and again finding that these levels of what would later be called incretins was higher. Now, let's just dive right into the incretins then. The incretins are a class of hormone, a peptide hormone, that is produced from the small intestine. So these are. So this is another example of a tissue within the body, namely the small intestine, that is an endocrine organ. This is something that I've been long fascinated in as both a student and now a teacher or professor, specifically that we used to think of endocrine organs as just a small collection of glands within the body. That would secrete and release these molecules into the bloodstream, which would then flow through the blood and tell other cells in other places of the body what to do. You know, it's basically a way for one tissue or one cell type in one tissue in one place of the body to send a signal to a different cell in a different tissue in a different place of the body. That is essentially endocrinology. Now, in this case, as I noted, there used to be a very small number of tissues that were considered endocrine glands, like adrenal glands or thyroid glands, or the gonads, like the testes or the ov. Now we come to find out that really all tissues are endocrine organs and the intestines are no exception. The intestines secrete a massive array of hormones, but today we're talking about the incretins. Now, what all the incretins have in common is some effect, not only a response to nutrients that have been consumed, but then an effect on nutrient metabolism, influencing some of the hormone response, influencing satiety and hunger. And we'll get into that. Now, the four particular incretins I want to spend a little time discussing, of course, the first and foremost and most famous GLP1 or glucagon, like peptide 1, GLP1, and then gastric inhibitory polypeptide or GYP. Then another one called peptide YY or PYY, and then lastly cholecystokine and CKK. Each of these again are part of the incretin family. They respond to food when we eat them, and other stimuli as I'll get to at the end. And in some instances these have been leveraged, of course, with regards to drugs. Now, let's start with the first one, GLP1. If I were to just provide a very brief list of the effects of GLP1, the first one you will always see, and it is unfortunately the most unclear, would be its actions. GLP1's actions as to be technical, and then I'll define it as an insulin secretagogue. So GLP1's most well known or most trumped up effect is to stimulate the release of insulin in response to glucose. So in other words, if someone takes in a glucose load, they will see a certain insulin secretion. If they take in that glucose into the blood and have GLP1 go up, then insulin would go even higher. So it's boosting up insulin even higher. Now, this has been shown to be the case in cell culture models. So growing cells in little petri dishes and then stimulating them with GLP1. In other words, this insulin secretion effect. It's also been shown to happen in, in some animal models, but the evidence in humans isn't there that it does not appear to be the case in humans that GLP1 is inducing this insulin secretion. This is work that has been shown, in fact, by a scientist who's at the company that makes the most famous GLP1 agonist, Arnie Ostrup in Denmark. Dr. Ostrup has shown that GLP1 does not induce an insulin secretion in humans and ness has been followed up with work published by David Ludwig at Harvard. So anyway, the degree to which GLP1 really is acting as an insulin secretague in humans is debatable. What is less debatable are the other effects of GLP1, most especially glucagon suppression. You've heard me talk about glucagon before. I take a particular, if perhaps modest amount of pride in helping glucagon become part of the conversation within the generally low carb sphere. But even on kind of pop culture interest, glucagon is insulin's opposite. Whereas insulin wants to reduce blood glucose, glucagon is constantly seeking to increase blood glucose. Now you can see why it's a problem in diabetes, in type 1 especially. But even type 2, these are disorders of too much glucagon. Glucagon is too high all the time. And as glucagon is too high, it's constantly telling the liver to release its stored glucose and release it into the blood. So glucagon wants to constantly increase glucose. So with that in mind, seeing how GLP1 suppresses glucagon, it becomes quite obvious that that's the mechanism whereby GLP1 can correct high glucose levels so quickly, or correct GL type 2 diabetes very quickly. Um, that is one of the main mechanisms of action whereby GLP1 activation, or GLP1 itself, can improve diabetes. Now, there are two other effects that are relevant here, very relevant, as we continue to Talk through how GLP1 has been leveraged in medications. Because remember, we're for now still just talking about the hormone itself. Another effect is delayed gastric emptying. In other words, it slows down the rate at which food is moving through the intestines. And so when you eat food, normally, food is lingering in the stomach for a handful of hours, mulching around, and then it will, as it's been thoroughly mixed, it will move from the stomach into the small intestine where it now formally begins to undergo, or more heavily undergo the process of digestion. Now, just as a point of definition, you digest foodstuff into its base molecules and then you can absorb them. Then you're moving them into the, from the intestine, into the body, into the blood. So you digest, then you absorb. And the digestion, of course, is starting in the stomach and then it really reaches its peak in the small intestine when it leaves. Now, sitting around in the stomach is essential. You want the food to stick around there for a little while in order to help it get digested. You want to be breaking it apart. In the case of GLP1 increase, the food is staying in the stomach longer than normal, so it's delaying. Now, that is, on its own, not a bad thing, and to a modest degree, not a bad thing at all, indeed even a good thing, because this would be a scenario in which a person feels fuller, longer. So in other words, their satiety is much better and their hunger is diminished or delayed. They may also find that it's easier for them to control cravings because they just don't feel their tummy rumbling. Again. That is the phenomenon known as delayed gastric or stomach emptying. Now, related to that, but still distinct, is a central nervous system effect of GLP1 stimulating satiety. So there's this direct effect of GLP1 telling the brain, you're not hungry, we don't need to eat. And then that becomes, of course, particularly powerful when combined with the delayed gastric emptying. So those two really do work in concert to help someone control their appetite. Now, we'll talk, we'll come back to that, because remember, we're talking about it just as a direct hormone effect. But that particular effect gets dialed up to an 11 on a scale of 1 to 10 when we start really bumping it up with drugs. Now let's get to that point. Let's get to. Now, speaking about drugs, how GLP1 as a hormone is leveraged in an effort to maximize its benefits. So there are a handful of drugs that have been developed over the years. What they have in common, as you'll notice as I just read them, and then you then just briefly describe their effects, is that they usually they will end with the suffix at the end of the word. A tide. A tide, whatever. A tide. That whenever you hear that name of a drug, then you can assume, ah, that's probably a GLP1 agonist. Now, as a point of just physiology and cell signaling, an agonist which is not the same as an antagonist, indeed, it's the opposite. An agonist is something that activates. And so these are molecules that act like GLP1. They're not GLP1, but they bind the same receptors that GLP1 does on cells throughout the body. So in other words, they're going to have the same effect as GLP1 just in these instances, much, much higher because we're putting a lot of this molecule in the body. Now what's common about most of these, but I'll mention later an exception is that they're all injectable because all of these are proteins. And if you orally, if you take in a protein, if it were a drug, the stomach would just rip it down into its pieces and then later enzymes just break it down into its amino acids or little peptides. Then the drug itself or the protein itself doesn't stay intact. So to circumvent that you have to just inject it direct. So first one, exenatide. Exenatide was one of the earliest versions of, of GLP1 agonists and it was a twice daily injection and they had different, slightly different versions of one version of it being twice daily and one version of it being a once weekly. That was a later development and pardon me if I get some of the drug, the, the actual trade names wrong. So exenatide is the name of the molecule and that would, that was sold as, under the drug names Byetta and Bidurion. Byetta was the daily injectable version of it and then there was a longer lasting version which was the Baidurion. So I may be mispronouncing some of the trade names but I won't be mispronouncing the drug name, which is how I learned it as a scientist and we study it in animals or cultures. Now liraglutide is an interesting one. There's a little more evidence on this. It goes by the trade name Victoza or Saxenda. And this was, and exenatide was used for diabetes treatment again because of the glucagon inhibition. And, and then they started to find with these later versions like liraglutide, which is a once daily injection, Liraglutide was the first one to really start being used at higher doses to really take advantage of the delayed gastric emptying, in other words, curbing appetite and in other words leading to weight loss. But remember, remember these were first leveraged to control diabetes. Then it happened that they noticed the weight loss and then they started to really dial up the dose by several multiples. So, you know, when you start looking at some of these, like when we get to semaglutide in a moment, it's quite a bit of a higher dose when it goes from the diabetes controlling dose to the weight loss controlling dose. One interesting thing about liraglutide that I'm aware of, but not with the others, is that liraglutide has been shown to activate adipogenesis, or in other words, the synthesis of new fat cells. Now, I know what you're thinking. You're thinking, ben, how can a drug be both stimulating the synthesis of new fat cells and stimulating weight loss? Remember, most of fat mass is a consequence of the size of our fat cells, not how many fat cells we have. And so these two things can in fact be happening at the same time. You can be increasing the fat cell number, which, as you'll recall from last month's discussions or earlier metabolic classrooms episodes, that if you increase your fat cell number, you will improve insulin sensitivity because it allows fat cells to be smaller, even if they are more abundant. But when you also couple this like liraglutide to an overall body that is eating a lot less, then they are losing weight, they're eating less, insulin's coming down, calories are coming down. And so even though they may have more fat cells, all of the fat cells are much smaller than they were before. Again, that is a phenomenon known that has been shown that's published with liraglutide. I'm unaware of that being shown with others. Now another version of this is dula glutide. This is trulicity. It's a once weekly injection and it has, it is used generally it's supposed to be used. If it's being used appropriately just for diabetes, there isn't this higher dose of dulaglutide for obesity. Now we come to the big one once again, which is semaglutide. This is sold in a couple different forms. Firstly, it is Ozempic and WeGovy, which are both injectable at a lower dose or a higher dose. Low dose being for ozempic, being just for type 2 diabetes because you just have the glucagon inhibition which corrects glucose levels. And then at the much higher dose now you're really, really taking advantage of the delayed gastric emptying and so you get a lot of weight loss. But there's also another version of semaglutide that has been designed and encapsulated to be able to handle the acidity of the stomach and digestion, and that is rybelsis. So rybelsis is an oral version. It's much less effective, but of course it's much more convenient because you just pop a pill rather than poke yourself with a needle. Now, the final one that I want to mention, although we're not going to be done talking about semaglutide yet, we're going to get into some of its effects and some of its side effects more before we move on to the other incretins. And the final one is Tirzepatide, sold with the trade name Manjaro. Sorry, you've heard of this one, too? Manjaro. This is a dual agonist where it is not only stimulating GLP1 receptors, but it's also stimulating the receptors for another incretin, the glucose dependent insulinotropic polypeptide, or GIP. GIP. And GIP. We're gonna talk about GIP more in just a moment. Remember, we're still just talking about GLP1, but Gyp is worth talking about. So tirzepatite is this combination or this dual agonist. So it's taken both of them and the results are pretty remarkable with regards to weight loss and resolution of type 2 diabetes. So just as a general overview, then, semaglutide is the most common version of the GLP1 agonists. It primarily works by inhibiting glucagon, which is what allows it to correct blood glucose levels so well and bring glucose levels down. And that's, of course, very effective for type two, may even be effective for type one. There's a little bit of evidence there. It'll be exciting to see where that goes with type one. But then, of course, the delayed gastric emptying and the increased appetite, the increased satiety signal, rather at the appetite center of the brain, facilitates weight loss. I already mentioned some of the drugs that particularly take advantage of semaglutide, and that is Ozempic at a lower dose for anti diabetes. And wegovy for the weight loss dose is much, much higher. That's the obesity dose, if you will, and that's multiples higher. That's about two to five times higher. Actually, it's more than two. It's four to five times higher, I believe, at the WeGovy dose. Now, what are the side effects? It is appropriate to consider side effects, and I don't want you to necessarily. I'm trying to, at least at the moment, come across as a bit of an impartial or objective observer. So that means I need to objectively present these side effects. It is very worth noting. First one is nausea. Nausea is in fact a more accurate name to describe how a person feels. Some of the advertising version of how a person feels in their guts when they're taking semaglutide or these other GLP1 agonists is that we will say they're not hungry and they're not craving. Their cravings gets better. That's a nice way of saying they feel nauseous or a little sick to their stomach. And that's largely because food sits in the stomach for a very long time, leading to constipation too. The intestines, I don't want to be dramatic here, but they experience a modest degree of paralysis. In some instances more than modest. Where the stom the intestines normally have this phenomenon referred to as paralysis. Sorry, peristalsis sounds like a little bit like paralysis, but it's not. Peristalsis is the process whereby the intestines are contracting and relaxing in the synchronized manner in order to slowly be moving foodstuff and then waste through the intestines, ultimately to be eliminated from the body. GLP1 agonists, which are super high levels of GLP1 activation, slow that down in some instances too much. There are reports of people who experience what's called an ilus, or basically a frozen or paralyzed intestinal tract. And then the food stops moving. That, of course, is very, very lethal and worthy of note. Appetite changes. I already mentioned this. That's not. That's neither. I mean, that can be a good thing if it's changing the way you eat. If it's food you need to be eating less of, which if you have diabetes and obesity, there are foods like that. There are foods you do need to be eating less of. But that of course, is a potential negative where a person finds much less enjoyment in things that they used to enjoy. There's a risk of pancreatitis. So an inflamed pancreas, not good. That would be manifested as some degree of abdominal pain. There's also growing concern of certain thyroid tumors, these thyroid C cell tumors. That's been shown to be higher in people who are taking GLP1 agonists and then the last one, the third and final. And these are all specific to semaglutide. So I should be clear here. And semaglutide is the most commonly used one. There's a lot of lean mass lost. Now it's debated exactly how much because of the methodology that is used to determine lean mass. In other words, some of this could be a lot of water weight. But there was a report published in a very good journal that doesn't mean it's an infallible paper that found that about 40% of the weight loss is from lean mass, that muscle and bone. The reason that matters is because let's imagine a day, let's imagine someone who's lost 100 pounds and this is, let's just say a 60 year old woman, she's lost 100 pounds by taking semaglutide but eventually she gets tired of feeling very sick to her stomach, the nausea gets very old and or she gets tired of paying the out of pocket expense for these, for the drug because it can be very expensive and so she gets off the drug. Now she has lost both fat mass and lean mass, indeed a significant amount of both. Well, guess which one of those fat, which one of those masses can return very, very easily. And again this is a 60 year old woman, we're not talking about a 25 year old male who can recover his lean mass very, very well. A 60 year old woman is going to have a very hard time regaining her muscle and bone mass, whereas it won't be difficult at all indeed as it is for most bodies to regain that fat mass and then regain it and go beyond where she had been originally. So I hope you can appreciate the consequence of the loss of the lean mass, that's mass that is very unlikely to return. All right, now with all of this discussion of drug methods to leverage the benefits of GLP1, what about natural methods? Because after all, GLP1 is a hormone that our intestines make, indeed make all the time. So what can we do to take advantage of GLP1 on our own without injecting? So first of all, food will induce GLP1 release, all of the macronutrients to varying degrees, carbohydrates, although there's some nuance there, will induce a GLP1 release. Fats will and protein will. From everything I've seen, every protein will increase GLP1 by about double over fasted conditions. I, I've not seen a study that has tested out specific types of protein yet, so I can't get any more specific than that. So I think it's a, it's a bit of an assumption but it's safe to say any protein is going to increase GLP1. Now what about fat? Fat comes in three main forms. Saturated fats, monounsaturated fats, and polyunsaturated fats. Well, there was a fascinating human study that quantified the GLP1 response to all three of those types of fats. Saturated fat spiked GLP1 considerably about two to three times. Monounsaturated fat spiked GLP1 considerably. I believe it was a little less than the saturated and then polyunsaturated fat. That fat that comes largely from refined seed oils. In fact, didn't it not have a significant or sustained effect on GLP1 release? So a very interesting fat specific response with regards to GLP1. Now what about the last macronutrient, namely carbohydrates? I can't give you a hard rule here like I could with say fats. There are two distinct studies I'm aware of in humans that one looked at potato consumption and found the potato alone had no effect on GLP1. Pure glucose did have an effect on GLP1 increasing it to about the same level that protein did. So about double, albeit at a slightly different timeline. Rather than an earlier spike, it was more of a delayed one. So glucose did it but a potato didn't. Now this happens for reasons I don't know unfortunately. Now what about none caloric methods or non nutrient methods? There are two that I'm aware of. Very likely there are more. First one is the rare sugar allulose. Many of you have heard me talk about this before. Allulose has been shown to increase GLP1 substantially by multiples over fasting conditions and that's nice because it comes without a caloric load. This is essentially a version of fructose that isn't metabolizable by the body and thus there's no energy that needs to be accounted. In other words no calories that we need to to count. Allulose comes from again it's a rare sugar that occurs naturally in figs and corn for example, but that's been taken advantage of by companies like RX sugar in in their supplements. Another way to increase GLP1. And indeed my final point on GLP1 is yerba mate. Yerba mate as that that South American little brew is this it is coming from the yerba mate leaves but there are a number of chemicals or molecules to say it a little more fairly, like saponins and polyphenols that have also been shown to activate GLP1 secretion. In fact we just. Conduct finished conduct finished conducting a study looking at yerba mate consumption in in rodents and we found that GLP1 in a even in a fasted State in the yerba mate consuming animals was about 80% higher, so almost double compared to the control group. So yerba mate is another thing that is personally something I enjoy sipping on throughout the day and may take a sip of in just a moment to clear my sore throat. So I get it from a concentrated source called Unimate from a company called Unicity. That's the best one I found and I've tried a lot. All right, now with that all having been said, let's leave GLP1 behind and take a little breath because we're not done. And I know this is going a little longer. I usually like to go to around 30 minutes, but let's just go through the other three incretins and discuss them briefly because they're all important and in fact they are all released in response to food and even yerba mate has been shown to increase all of them too. So let's go to the ME next most relevant which is gastric inhibitory polypeptide or gyp. It is once again classified as an insulin secretag so enabling or increasing the beta cell's ability to secrete insulin in response to a glucose load. That last part was italicized. If you couldn't hear the italics in my voice in response to a glucose load, you didn't. You wouldn't just inject GYP and then see a big insulin release. It would be that there was already a high glucose load coming through the blood. GYP basically bumps the beta cells response up and that would, that would. The good thing there is that it would correct glucose better. Now I cannot say whether or not this is something that has been confirmed in humans like GLP1 has been challenged in humans. Another effect of GYP is a potential role in fat metabolism which is a little unclear still for the moment. So it's okay to just really consider it through the lens of glucose and insulin reg with a possible role in fat metabolism. But it is that insulin glucose specific effect and glucagon inhibition effect, another emphasis that is why it's used in Manjaro. Now Peptide YY is not leveraged in a medic in a drug that I'm aware of, it will slow, it will reduce appetite and activate satiety signaling in the brain helping contribute to satiety. Like the others, it will slow gastric emptying so keeping food in the stomach longer, prolonging a sense of fullness and thus so Those are the two main mechanisms. So PyY is another potential not leveraged yet in a drug but Relevant still when we look at the incretins and their effects on metabolism. Now, the last one, cholecystokinin, is involved in satiety and digestion. So digestion is a unique one. None of the others we've talked about help with digestion. It does help with satiety, similar with the central nervous system effect that we've mentioned already of helping a person eat a little less. But cholecystokinin will also facilitate the contraction of the gallbladder. And we haven't talked about the gallbladder recently. We have long ago in some metabolic classroom episodes. But just as a very, very brief primer, the gallbladder is storing bile that's been produced from the liver. And the role of bile is to release, to be dumped into the small intestine to emulsify the fats, to pull all of the fats apart to make them more easily digested and then absorbed. So we need to break them down into kind of manageable bite sized pieces, if you will. And that's all coming from bile, which is coming from the gallbladder, which is in part being induced to contract because of CCK or cholecystokinin. So it has. So this one again is unique, just to wrap it up, it is involved in digestion, particularly with fats and with satiety. Now, one other moment on digestion. You heard my pause there, my pregnant pause for a moment. Just as a reminder, something that we've discussed a little bit in the past, which is that bile has a greater influence than just digesting fats by emulsifying them. Bile also facilitates proteolytic enzymes. Proteolytic enzymes are involved in protein digestion. This has been shown in humans and animal models to be very relevant, where if a person just eats a straight load of protein, they will get a certain amount of amino acids that hit the bloodstream. If they eat that same amount of protein with a bolus of fat, they will have a much higher amount of amino acids that hit the bloodstream from that same bolus of protein. So there's something about bile in particular that is enhancing the, but the intestines ability to digest protein. And again, you're only getting the bile release if you're lean, if you're eating some degree of fat. And this is why I'm such an advocate of not fearing fat, that as much as I am an advocate also of prioritizing protein in the diet, we should not fear the fat that comes with that protein. I'm getting a little off topic but still in context in nature, there's no exception to the two of them coming together. None. Every protein in nature comes with a fat source. I believe that the human body has been designed to eat those proteins as they come in nature, namely with fat. And that may be why the human body appears to digest the protein better. When the protein comes with fat again, it is very likely a consequence of more bile and CCK to bring it back to the topic. Cholecystokinin released from the small intestine is a hormone that will facilitate the contraction of the gallbladder, thereby moving the bile in its stored site, the gallbladder, into the intestines to actually be put to work. All right, thank you for listening. That is the classroom part. Now, with all of that having been said, let me just thank you again for joining the Metabolic Classroom today to talk about incretins and GLP1. As a reminder, if you want to participate in the live chat which we're going to do now, getting to the live Q and A, you need to be here live. That of course, this I'm not. I can't answer your questions if you aren't joining me live. All right, let's get into the questions. First one by Antonella can semaglutide reduce liver fibrosis? Liver fibrosis? So fib fibrosis is scarring. And I am unaware of any evidence that suggests semaglutide can help with liver fibrosis. There is some evidence to show that semaglutide will increase liver glycogen and thereby increase the mass of the liver a little bit. But that does not appear to be harmful at all. It literally is just increasing the glycogen in the liver, the stored glucose. But I've not seen any evidence that suggests it can improve hepatic or liver fibrosis or liver scarring. Just as a reminder, of course, I'm not a physician, just your friendly neighborhood scientist. Okay, Jackie, what prescription medications can negatively impact insulin? Raise it. Thanks, Jackie. We are going to talk all about. I'll answer your question, but be sure to join me next week. Next week's Metabolic Classroom. The upcoming Metabolic Classroom is all about anti diabetic medications. So we're going to talk all about that exclusively. So it's a deep dive into the diabetes side of medications. The first episode was weight loss medications. Today was the GLP1s and incretins. In specific, just because of interest in them, next week is the diabetic medication. So Jackie, make sure you tune in next week and listen to the next episode. There are a number of medications that fall into that class of insulin secretagogues. The degree to which GLP1 or semaglutide should be one of them is debated, but the human evidence suggests that that shouldn't be part of that. But the sulfonylureas are a class of drug that do. And again, we'll talk about them more next week. Jerry, does the effect of delayed gastric emptying include slower peristalsis in the small intestine, large intestine, or just stomach? That's a great question, and I need to speculate a little bit. Jerry, I hate to hate to say that, but I believe it's all of it, at least through the small intestine. But this is not an inconsequential phenomenon. Normally, just as a point of interest, if a person goes in for a surgery, they will usually tell the person to fast for 24 hours because that will have been enough time to clear out the intestines or certainly clear out the stomach. And then if the stomach is empty, then there's just less. Less risk of the person vomiting in response to the anesthetics that may make them a little sick, less vomiting and less likely for them to inhale that vomit and hurt their lungs. But what they've found in people who are taking GLP1 agonists like semaglutide is that the food is staying longer. Now, that still is only relevant to the stomach, but they have to fast them like two or three days just to really make sure the stomach has had time to empty or have them not take the medication for the week. So, Jerry, I'm speculating. I believe it is largely all the way through. All right, Carly, from Connie. Thank you, Carly, for conveying Connie's question. Do you have any information on the insulin index rather than the glucose index? Is it important to understand? Yes. So there is. So the glucose index or the glycemic index is pretty well established. Although one problem with it, and this problem is amplified with an insulin index, is that not everyone responds the same way to glucose. There was a study done out of a group in Israel that found that people, by looking at their continuous glucose monitors, they were. And even their microbiome, their microbiome appeared to heavily influence this. You could have two people who would eat the same food and have very different, even though they're the same muscle mass, same body type, have very different glucose responses or glycemic responses to the consumed starches and sugars. And this problem is further amplified in an insulin index. Simply, not everyone responds the same way to the same foods. But there is an insulin index. I don't love it. I think it is. I think there are some concerns with it. For example, showing that a steak has the same insulin secretion as bread. That to me is ridiculous. And I say that with some authority. Having done multiple tests now, including another one starting up soon, where we draw blood from humans for hours and look at their insulin, it is interesting to see how different people respond. So there is an insulin index. You can find it out there, but you need to take it with a grain of salt. Carol, my endo says that she does not prescribe GLP1 for type 1 diabetes to suppress glucagon if they are low carb because the risk of DKA goes up if insulin drops. If insulin doses drop too much. Could that happen? That. That could certainly happen. Carol. I. I'm aware of one study in type 1 diabetics that has looked at the use of GLP1, and I don't believe there were any reports of diabetic ketoacidosis. But I respect the endocrinologist's view here, where if you have a type 1 diabetic who's adopted a low carb diet, that that reduces the need for insulin, it doesn't correct the high glucagon, which is going to still be trying to have the liver make new glucose all the time, which is going to be providing the type 1 diabetic, even in the midst of a low carb diet with a insulin requirement. It is theoretical. It is possible, rather I should say that if a type 1 diabetic were on a GLP1 agonist, which is inhibiting glucagon, which is reducing the amount of glucose coming from the liver, if that were coupled with a low carb diet, you. Your insulin demand may now be so low that it would enable the rapid production of ketones to the point of ketoacidosis. It is. It is totally possible, Carol. Indeed, kudos to your endocrinologist for really thinking through that. Now I am speculating. So is the endocrinologist, but I could see her point. Yvette, glad you could join us. Antonella. Some days ago, some medical Italian researchers based in Puglia. I probably mispronounced it. And Tanella, sorry, in Italy, discovered that semaglutide has benefits for liver fibrosis. Yeah, I can. I mean, I'm happy to look into that. I'm very interested in keeping my finger on the pulse of this area of research. So yeah, I'm happy to consider to see. Okay. In fact, let's just do a quick little search. Antonella, everyone. Pardon me for just looking quickly at PubMed. I don't like not knowing something. So here was a study and they found histological and biochemical assessment of hepatic fibrosis showed no significant effects. Semaglutide. So that's one report from the nih. Let's look at one more. Patients with NASH and compensated cirrhosis which would fit in with fibrosis. Semaglutide did not significantly improve it. Yeah, so here's two reports. Antonella. Right. That I found immediately that don't find any effect. So I'm going to lean into that so far now if you, if this is a study you did find we do have to balance that one Italian group's findings with this other groups. Now I'm unaware of any evidence suggesting it's hurting the liver and perhaps these dose these studies just haven't gone long enough. After all, fibrosis is. It's not easy to correct scarring. But the liver is one of the only tissues that is capable of doing it because of its ability to rejuvenate itself. There's evidence to suggest that it reduces liver inflammation, which would be referred to as a hepatitis. And the liver can be inflamed for any number of reasons. Viral infection like hepatitis C or the other ones or through drug use which in a non viral or non infection hepatitis. So there's evidence to show that it can reduce inflammation. But I'm unaware still here even. Here's another study I just pulled up published in the New England Journal that it did not improve fibrosis stage. So Antonella, I'll conclude that. I don't think that's. I don't think it happens. Okay, question from Andrea or Andrea. So do type 1 diabetes always have higher glucagon or is that based on insulin dose? Yeah, it is. They always do. Just as a very brief answer here to a much, much longer and complicated principle. Within the pancreas we have these little communities or neighborhoods of cells and neighbors are in part beta cells that produce insulin right next to alpha cells that produce glucagon. In a non type 1 diabetic, insulin is being produced right here at a very, very high amount and it overwhelms the alpha cell's ability to produce. It tells the alpha cell, cell don't make glucagon. But when you take away that insulin, now the only insulin in the bloodstream is what the person's injecting. That is much too low of a signal. The alpha cell is used to getting or is expecting a really high amount of insulin because again, it's literally living right next door to the cells that should be producing insulin. So no amount of injected insulin is capable of turning off the alpha cells production of glucagon. Thus the alpha cell is constantly secreting glucagon. This was work really pioneered by a legendary scientist named Roger Unger who passed away just a few years ago. He found in type 1 diabetic models that even if you didn't give them insulin and you just inhibited the glucagon, their diabetes control, their glucose control was perfect. All right, the insulin IQ team prompts me with a question, a comment from George. In your opinion, Dr. Bickman, do you see huge repercussions coming in the near future from the current weight loss drug craze? I do, actually. In all the money being made. Well, there's not going to be a negative consequence to all the money being made. That's just the motive, which I appreciate. I appreciate capitalism as a mechanism of getting people up out of poverty, but I regret that there is a market for these. I will confess my view of them has evolved at their original lower doses. I looked at them somewhat warmly where they really did appear to simply have where the benefits really did appear to outweigh the negative consequences. Now that they are used at really higher doses and used in a way to just slow down the guts and promote weight loss, I worry about them more. And I do. When it comes to metabolism, you guys, there really is no shortcut Now I will say my most favorable comment then is that if someone were on these or really needed help to lose weight, I would just say use the lowest possible dose you can. Again, I'm not your clinician. I'm not giving medical advice. Use the lowest possible dose and couple it with a low carb diet. That's my view on how to really maximize the efficacy of the drug. Okay, last question by Tanya. Any evidence that the delayed gastric emptying with GLP1s O oh, not quite the last one. Amanda. UA Snuck one in. Any evidence that the delayed gastric emptying with GLP1S alters the microbiome leading to things like SIBO? That that is interesting. Insofar as semaglutide is injected, it's hard to imagine how an injectable is influencing the microbiome. However, everything affects the microbiome. Everything. And it's no surprise that there's some evidence to suggest that GLP1 agonists can influence the microbiome. There was a paper just published looking at statins and how they inhibit GLP1, and part of it was thought to be through the microbiome. Now again, that's statins inhibiting endogenous GLP1 production. But the degree to which the microbiome changes and it's an actual benefit, I'm unaware of anything there. And I also just think it would be all nonsense. I think we put a little too much stock in the microbiome. Everything changes the microbiome. You start drinking different water, microbiome changes. You fast for 24 hours, your microbiome changes. You adopt a vegetarian diet changes. You sneeze too hard, it changes everything. Changes the microbiome. Okay, Amanda, can you talk about semaglutide effect on autoimmune in elderly population? I'm unaware of any effect there, Amanda. I'm, I'm sorry to say, Carol, are GLP1s a hormone that affects brown fat? They do, actually. GLP1 agonists have been shown to stimulate brown adipose tissue. This is still a very modest effect as far as I'm aware. And the degree to which it's happening in humans is unclear. But suffice to say, if it is a real effect, it would just be one more mechanism whereby GLP1 is facilitating weight loss. All right, now you can tell by my voice that I'm done and we've reached the end. You guys, thank you so much for tuning in. My sentiment is always education is key, that the more you know, the more you can control your metabolic health. And I hope that you feel like you've learned some good ideas, some good. You've learned some good lessons today and that you can use this knowledge to help improve your own metabolic health. Tune in, join me next week and we'll talk all about the anti diabetic hormones and the problem with the conventional view of diabetes, which is a glucose centric paradigm. We're going to challenge that paradigm, but see how that paradigm gets us into trouble not only with diagnosing, but also with drug treatment. All right, thank you guys, see you next time. Paradigm gets us into trouble not only with diagnosing, but also with drug treatment. All right, thank you guys, see you next time.