GLP 1 Deep Dive with Dr. Jeff Bland

Hi everybody. Hey. I'm so pleased to be with you this afternoon and a chance to share a really important topic that I'm quite passionate about, this whole GLP one extraordinary experience that we're all going through here globally. And I love to know, are you all set? If you, if you hear me okay, go to chat and just give me a thumbs up if you can record and hear. Okay. And secondly, love to know where you are. We've got people from all over the world that have signed up and I'd, I'd love to get some information as to the various places that you're responding from. We got people from South Africa, we've got people from Australia, we got people from Copenhagen. Oh, gee whiz. Cincinnati, Virginia. Wow, what fun. Look at, look at this. This is the, the beauty of this media that we're working on these days. A chance to see a, a global, a global audience sitting here in Bainbridge Island, Washington this, this afternoon. So, so thanks so much and a thumbs up to all of you. I hope I can share with you some, some news to use. I think I can over the course of the next hour on this important topic of GLP1 and its relationship to the future of healthcare. So thank you again for being part of the, of the series and let me, if I can, I'm going to share my screen and, and we're going to have at it here. So get your five position harness in place and away we go. So, GLP1 in focus. Bridging the gap between nature and innovation. And the reason I put nature in there is that this is a natural molecule, glucagon, like peptide 1. So we want to put it in the right context as we're discussing it. Let me just say a couple of quick words before we get into the material at hand. So this turns out, I just thought about this today, that this is my 50th anniversary year of being involved in the nutritional field as a professional. 50 years ago I was a professor of chemistry and environmental science and we published our first papers on vitamin E with my graduate student at the time and that kind of birthed me in this whole field. It's hard to believe a half a century has passed, but a lot of things happen. One of the things that we know that's happened, obviously, is that we as a global community have got better, particularly in the Western world. Obesity has become a major pandemic of its own and it begs the question why? And we often think, well, it's because we eat a lot more food. We have ultra processed diets and all of that then creates this obesity epidemic. And it is true that certainly the composition and the quantity of our diet, the calories that we're consuming, does contribute to this obesity problem. However, and this is an important fact, the increase in the average weight in our population per person does not track with the increase in calories. In fact, the weight has gone up faster than the calories. So what's going on? There's got to be something beyond calories. And that's going to be really the focus of this discussion I've been speaking for now over 30 years about food is information. It's not just calories, it's not just vitamins and minerals. It brings information from which our genes then express themselves into what becomes our phenotype, how we look, act and feel. And therefore, if we really want to understand the obesity epidemic, we have to understand more than just calories. We have to understand the composition of calories as it relates to the information those calories are bringing to our body and how that as a signal or signals is translated into our function and how we look, act and feel. And our body composition is part of that. So I want to emphasize that this story about GLP1 is a very symbolic and enigmatic way of thinking about food as information because this family of intro endocrine hormones is a response to information that our body is getting from our diet. Okay, with that in mind, let's move ahead and see what we can, we can find about the, the connection. So for me, you probably know I'm been around in this, as I said, for half a century. Hard to believe. This information I'm presenting is in part related to my five decades of experience, but also related to my more recent experience as a founder and president of Big Bold Health, which I'm very proud to be part of this, this organization that's really focused on personal immune health. And we've made, I think some really significant progress the last few years in starting to interrogate and decipher the signals of the immune system and how we optimize its function. So it's with that then, I continue on the program. So let's talk about GLP1 Agonist, a new recipe for Success. That's the title of this JAMA March 26, 2024 article. The author of this article is the celebrity, well known opinion leader in the field, Dr. Darius Musafarian, who is in charge of the Food is Medicine program at Tufts University in, in Boston. And he was discussing this new recipe for success And I think that the little breakout that I chose from the article is sim symbolic of what we're learning about GLP1 based drugs, he says. Yet clinical and public confusion ex around worldwide costs and tolerability and access to the drugs. 1/2 of US adults are interested in taking a prescription weight loss drug. That's one half. 50% of the population and 93 million people meet the GLP1 weight loss criteria eligible to take that drug. The GLP1 agonist drug. US list prices presently for these drugs is between $12,000 and $16,000 per year. Even with maximum negotiated discounts, cost will widely come down to no less than $6,500 per year. So if all the people that were eligible that are interested in taking this weight loss family of drugs were to receive a GLP1 agonist at discounts, the annual cost would be $600 billion in the United States alone, equal to all other US prescription drug spending combined. Wow. Okay, so what is he suggesting? What is he suggesting is this can't be the long term solution to the problem. There's got to be some other way of getting to the answer to our obesity epidemic and its connection to a variety of chronic age related diseases that are associated with excess body weight. And so he's suggesting this combined stage GLP1, I guess you would call food as medicine approach, in which the healthcare practitioner, allied health sciences, dietitians, health coaches and so forth, were involved in delivering a recipe to support a patient's long term weight management to get them off of the GLP1 agonist drugs after maybe using them for a short period of time as a booster rocket. Now the reason I bring that up is that recently Mark Wolf Schneider, the previous CEO of arguably one of the largest food companies in the world, and that is Nestle, made a statement to the public and his board that he is not worried about these GLP1 agonist drugs as a, as a food company, because we should be designing foods that are supportive of GLP1 and helping then for people to have success by utilizing available science to construct the composition of foods that would ultimately lead to proper weight management by regulation of GLP1 and other the enteroendocrine hormones. And I think that's a very thoughtful and visionary approach that really syncs up with what Dr. Muzaffarian is talking about in this recent JAMA paper about this combined stage GLP1 food is medicine approach. So with that, let's go on to ask, what do we know about GLP1? Well, we started to Recognize that this, this hormone that is produced by the body has many, many benefits. It's not just solely on reducing appetite or solely on brown fat activation, mitochondrial influences, but it influences across the range of many, many organs, positive health benefits. And in fact, this recent paper in Maturitis talks about the GLP1 agonist drugs as a key to turn back the aging clock biological age. And it helps in things like neurodegenerative disorders, it helps in cardiovascular disease, it helps in type 2 diabetes, it helps in areas of cancer prevention. So there may be many, many beneficial effects for GLP1 agonists beyond that, just solely for weight control. And if we look at the multiple clinical benefits, this was discussed in a recent issue of Science magazine, in the July 19 issue of 2024, we can see that there are many powerful effects of GLP1 agonists that tie themselves together with reduction in whole body inflammation. And I think that's an interesting process. This chronic, what's called sometimes inflamma aging that's associated with relative risk to many different disorders. Myocardial infarction, atherosclerosis, chronic kidney disease, kidney failure, metabolic liver disorders related to mash, and neurodegenerative disorders associated with early stage dementia. So these GLP1 agonists have a wide range of potential. But I want to emphasize this hormone is produced naturally and it's been with us for some period of time. And so you might ask the question, you know, why do we suddenly have all these obesity related problems that are associated with all these age related disorders which didn't plague the human population until recently? Well, part of it is maybe because we're living longer, but also we're living longer, less helpfully because of the signals that have changed these neuroendocrine and neur, I mean intro endocrine hormone activities. And it's those that we'll be talking about the signals. I said food is information that play a role in this whole pandemic that we're starting to see as it relates to these conditions. So glucagon, like peptide one, what does this name mean? Let's take it apart just for a second. So glucagon, what is glucagon? Glucagon is the counter regulatory hormone produced by the endocrine pancreas to that of insulin. We all know about insulin and its ability to stimulate glucose transport across cell membranes. And we also know that the balancing effect for insulin so that you don't end up with lowering your blood sugar too much, is glucagon so they have this counter balancing crosstalk between glucagon and insulin. Now, both glucagon and insulin are, are hormones made up of amino acids because they're peptide protein hormones. And so peptides are small strings of amino acids that have specific activities. And so specific activity in this case with glucagon like peptide 1, is that this hormone that's produced by the body is a small kind of a cognate or a similar signaling kind of substance to that of glucagon, but it regulates different functions and it is produced then in response to when and how and what we eat. So glucagon, like peptide 1, natural hormone, has to do with this whole insulin signaling, glucoregulatory capacity. So if we look at glucagon like peptide 1, we find out it's built out of a variety of amino acids that are unique to its composition. It is stored in cells that happen to be in the intestinal mucosa, waiting to be released into the blood when it is signaled to do so from the signals that come from our diet. And so our foods and specific constituents within our foods then are capable of stimulating the release from the specific cell types in the, in the intestinal mucosa into the blood of this, this hormone, which is called an enteroendocrine hormone, entero E N T E R o, meaning it's produced inside the endocrine system of the intestinal tract, which is something probably new to many of you, that these drugs or these hormones can be produced in that capacity. So here's a summary as to what we say. GLP1 is a hormone that plays a crucial role in managing blood sugar, and it has effect across many different organs. Several organs play role in the synthesis, but one that is most important is the small intestine. And there are cells within the distal region of the ilium that are called L cells that are specific to the release of GLP1 when the information from the diet specific information triggers the release. You also find GLP1 being released from the pancreas, the endocrine pancreas, from the liver, from the brain and the stomach. So there are many different sites of release, but the most important one in terms of magnitude comes from the GI mucosa, the L cells. So it's a member of a family of hormones. It's not working all by itself. It is a part of the, what I call the intra endocrine hormone family, which, by the way, we've known about for some time, but only kind of recently has it received the this family of hormones the attention that it deserves. So GLP1 Gastrointestinal Intestinal Peptide or GIP, Vasoactive Intestinal Peptide, VAP, Cholecystokinin, CCK, PYY, Ghrelin. These are all examples of intro endocrine hormones that are produced by specific cells within the gastrointestinal tract in response from our diet that then regulates our function postprandially, meaning after eating. So what is an agonist? Because we, we say These drugs are GLP1 agonist. An agonist is a substance that stimulates the release or activity of that particular substance. So in this case it's an agonist drug is stimulating the release and activity of that specific intro endocrine hormone GLP1. And the drug names that you're familiar with that are in this class include oic, wovi, Tricity, Victoza, Rusis and and more recently Munaro. Munaro is interesting because it's a dual intro endocrine hormone stimulant. It's called a TIRS of peptide. So it's a dual GLP1 and GIP stimulator. And it has also been associated with weight loss and effects on body composition. So this can transform obesity by these multi receptor drugs. Because you can imagine well if one receptor activity is good, what about two, three or four. So you're going to see drugs that are being produced and released into our marketplace that will add together many different endocrine hor intro endocrine hormone stimulants. And so the Tyra peptide that I just mentioned with Mounjaro has just got two. But one can consider that there are drugs in kind of work right now that have three stimulants of these enteroendocrine hormones. So this is going to be a horsepower race here to see who can get the biggest part of market share and the most activity of these compounds. So we know the names like semaglutide. I talked about Tirzapeptide. So these are one receptor agonist, GLP1 with ozemic and MOGOVI2 receptor agonists with Mounjaro and Zephound. And now there's a new drug that's being explored that has three. So just keep your, keep your eyes on the news because we're going to see more and more drug intervention into this family of intra endocrine hormones. Now where do they come from? It's a very interesting history and those of you not familiar with how this was discovered, let me just quickly review and there's a lot more to this story than we have time to go through, but I'll give you some top line. So in the early 1930s, a Belgian researcher, Jean Leviar Barre, identified that there was a hormone in the gastrointestinal tract that was responsible for stimulating insulin secretion. And he called this an incretin, that's the English translation. And it was a blending of ingestion and secretion, this incretin. In the 1960s then researchers showed the incretin effect was responsible for about two thirds of people's insulin response. And so this would be like an insulin booster or an insulin activity sensitizer. And one of those was found out to be gip, glucose dependent insulotrophic polypeptide. And then later another member of that family, the so called intra endocrine hormone family, was found to be glucagon, like peptide 1 or GLP1. Now this, it turns out that if you start to say, okay, now we have a mechanism of action, but how can the drug world take advantage of these discoveries? Well, believe it or not, we go to the Gila Monster because it turns out that the Gila Monster in their saliva was found to be a inhibitor of the enzyme that breaks down GLP1 in the blood. That enzyme is called DPP4, dipeptidial peptidase 4. And this agent that was found in Gila Monster saliva could then block the breakdown of GLP1 when it goes in the blood and extend its lifetime. And that became then the basis of the first drug that was focused on the intra endocrine hormones, this incretin effect using the DPP4 inhibitor. Now we recognize that the intestinal cells make these GLP1 agonists and they rapidly, when put into the blood, are broken down by the DPP4. And so the body has a natural process upon the information that comes from certain foods. It stimulates the release of hormones into the blood. But it doesn't stick around for a long time, only a few, less than an hour. And then the, the enzyme DPP4 breaks it down. Now that begs the question, why would that happen? Why would it produce it and then break it down? And there's regulatory effects for that because you do not want that hormone sticking around indefinitely because it could have untoward effects in terms of the resiliency and network biology associated with the, the regulation of glucose and the other functions that occur from the enteroendocrine compounds. Now let's go to the GLP1 agonist drugs. What do they do they produce supraphysiological levels of these hormones in the blood? And they're designed to stick around for a long time. They don't just go away in a few minutes, they stick around. Now do we know what that impact is over the long term? Not yet. We're doing this study right now in the human volunteers that are taking these drugs for a long period of time. What that effect might be? We don't really know the answer to that question yet because it's not the natural way that the GLP1 works in the body, which is produced after meals and then broken down rather rapidly. So there are multiple organs then, as I said, that have functions associated with the GLP1. And you know, we talked about the brain and obviously the stomach, the endocrine pancreas. It has effects on muscle physiology, on adipose tissue. The adipocyte is also influenced by the intra endocrine hormones, liver, so called mash, the metabolic associated steatosis and cardiovascular function. All of these have signals from these inter intro endocrine hormones that are influencing in the function of these organs. And so we would consider the clinical effects that have been seen from that include body weight, blood pressure, plasma glucose, plasma lipids, all of those, as well as electrolyte exchange of the nephron in the kidney, sodium excretion. All of these are related then to the activity of GLP1. This is kind of a partial list. So it lowers inflammatory potential in the adiposide, it lowers liver fat. It has an improvement on insulin signaling by reducing insulin resistance. It lowers appetite and increases satiety. It has a positive effect on endothelial nitric oxide synthase. So it improves contractability of the blood vessels to regulate blood pressure. A lot of good things here that are associated with the regulation of these enteroendocrine hormones. Now what are the problems that one might then suggest could come from long term use of GLP1 agonist drugs? Interesting question. Well, first of all, we already talked about the expense. They are not cheap and they're not reimbursed at present. They do have a side effect that is seen in about a quarter of the of the people that take them. Nausea, vomiting and diarrhea. They can lead to hypoglycemia, especially if they're combined with other drugs that lower blood sugar. So that has to be concerning. There is a small percentage of people have taken these drugs that end up with pancreatitis, bowel obstruction, gastroparesis and other kinds of gastrointestinal complaints. It's not common, but it has occurred. And as more people take these drugs, obviously you're going to get more people that have these complaints. And then maybe most interestingly for us is something a lot of people have thought, have not thought about. But Dr. Mark Schneider was, was talking about when he talked about Nestle's response to this and that is the creation of dietary insufficiencies. Now what do we, why would we create dietary insufficiencies? Because if you create then a appetite suppressing effect, so you're eating less calories, you're also eating less calories from the foods that you were eating which were probably marginally nutrient adequate to begin with, maybe even not adequate. And now you've made that problem even worse. So now you've exacerbated the potential for nutrient insufficiencies and the problems of metabolically that occur downstream from that. And so now you get into the potential for metabolic dysfunction. So that means we need high density, nutrient density foods in order to go along with the GLP agonists so that we don't end up inducing nutritional insufficiencies in individuals. We'll come back to talk about that more. But I think it is an important part of the story that's emerging around these GLP agonist drugs. Now how does GLP1 connect to the metabolism of sugar? This mechanism is being explored extensively because of the use of these medications. So I'm just giving you a little cartoon here that kind of summarizes a part of what we've Learned about how GLP1 connects to the metabolism sugar. So you know that blood sugar is transported across the cellular membrane by a glucose transporter, glutform, and that that then transports glucose ultimately into the mitochondria where it can be broken down into, into energy through the glycolytic pathway. GLP1 then stimulates through its receptor a whole signaling process that travels through the mammalian target of rapamycin or mtor. And you've, you've heard about a lot MTOR and the hypoxic induced factor 2 alpha. These are associated with longevity. They're associated with positive influences on cellular metabolism. And so we get this complex signaling effect that occurs as a consequence of improving glucose metabolism, improved MTOR and AMPI cake kindness, adenosine monophosphate kinase activity and how that influences then the, the proper regulation of insulin and, and cellular metabolism. And as I mentioned, that connects then to the metabolism in many organs and one of those tissues that is really important in this story. Is the immune system. Because the immune system is a sugar hungry cell type, it, it needs a lot of energy in order to do its function. Just like the, in, in the nervous system, the, the brain requires a lot of energy through proper glucose management. And so the immune system is really dependent also on the activity of GLP1 and how that translates its message out through many different immune cell types and ultimately influences this process of cellular balance in many organs. So I think again we tie immune system function to GLP1 signaling. And again I want to go back to say historically the way this worked was by eating the right foods with the right dietary information that created the proper regulation of these enteroendocrine hormones. Now what about diet? It's a relationship to GLP1 and this problem of DPP4. Well, we know that when eating a, a diet that's really supportive of proper intro endocrine function, meaning the signals or the messages from that diet. Remember food is information to keep coming back to that concept that the, the digestive system, the, the enzymes that are present will ultimately stimulate the, the release from the receptors on the small intestine, the so called L cell receptors that will release GLP1 that will go out of the blood and it will have its activity in improving all those functions that I just mentioned. But we'll then have a only a certain length of time that that message is retained in the blood and then it is broken down by the enzyme DPP4. So these are these, this relationship is a very important relationship that is a natural part of the process of regulating these functions over time in imbalanced diet which we have as a culture been consuming for some time. We all know that some people call that the standard American diet or the SAD diet or SAD diet. It has a significant connection to this imbalance then of the enter endocrine hormone signaling, particularly GLP1 signaling. And so it also induces another thing and that is that that altered diet, that ultra processed diet, that SAD diet also induces alterations in our gut microbiome and alterations in the gut microbiome have been found to produce dysbiosis. Dysbiosis then does what? It sends different signals to the receptor sites on our GI mucosa that regulate GLP1 secretion. So dysbiosis then induces alterations in GLP1 secretion. So you'll notice we're getting multiple mechanisms by which we have reduced by the way we eat and the way we live and the toxins we're exposed to on the alteration of intro endocrine hormone regulation, blood sugar and the relationship that has to our immune system. All of those things then have downstream adverse effects. So if we want to talk about upstream or root cause, we've got to go up to the signals that the diet then sends downstream that regulates these processes such as the incretin mechanisms associated with GLP1. This also connects to the nervous system through the vagus nerve, this long winding pathway from the central nervous system of cranial nerve that innervates the GI tract and goes down through the length of our body and sends signals out back to the brain. So both efferent and afferent. And that we now know that GLP1 and its relationship with, with the diet of reading the messages we're getting. The diet influences a vagal nerve signaling and has an effect on the hypothalamus of the brain. So in part this also talks about regulation of appetite because we know the appetite control center resides in the brain. So we, we, we break, we see this mechanism of this crosstalk, this network among the immune system, gut microbiome, nervous system and the intro endocrine system all communicating together. They magically and beautifully do that when they given the right information from the appropriate information that comes from our diet. The problem is we haven't getting the right information from our diet. We've been getting disinformation from the diet produces disharmony well relative to this process and produces dis ease in the person who is consuming that diet for a long period of time. So GLP1 and other intracrine endocrine hormones which are released by the intestinal mucosal cells are an important part of this story. So if we really look at these hormones again, there are many in this family and I want again just remind you that this is a family, it's not just GLP1 by itself. So we have serotonin. Over half of the body serotonin is produced almost 2/3 actually in the GI mucosa, gastrin, secretin, intro, glucagon and we already talked about VIP, chistokinin, CCK, motilin, somatostatin, GLP1. All of these are gut hormones as part of the inter integrin system. And here is the aha. It turns out that the hormones that we're talking about are released into the blood after eating as a consequence of, of activities that have come through receptors on the GI mucosa that have the same functional construction as do the bitter taste receptors on our tongue, meaning our digestive system is tasting food. And it's tasting bitter. Bitter receptors in the gut mucosa control the release of glucagon like peptide 1. Is that an aha or what? As we've cut bitter out of our diet, we have cut then down the level of intranicron GLP1 that's produced. Now where does bitter come from? Bitter J basically comes from vegetables. So as we've removed vegetables from our diet, which is standard operating procedure, we have lowered the signals that come from the diet information that then triggers the release of these intra endocrine hormones. So we look at the five main tastes. Salty, sour, umami, bitter, sweet. We know that you get different intro endocrine hormone reactions from each of these particular sensations of these foods. And that the receptors the the task one, which are sweet receptors, or the task two, which are bitter receptors, have different constituents in different foods that activate the release of these intran hormones into the blood. So if we then look at the particular site of these receptors along our digestive tract, this is kind of a diagram that shows where the fat receptors are, where the umami and protein receptors are, where the bitter taste receptors are, and where the sweet and carbohydrate receptors are. And you'll note that the bitter receptors reside principally in the small intestine. And so we then get the release of the intro endocrine hormones from activation of these bitter receptors. And does that mean that every bitter substance activates the same bitter receptors? Well, no. There are 35 different mammalian bitter taste receptors. Some are more active in releasing glucagon like peptide one than others. And within foods, not all bitterness induces glucagon like peptide 1. So certain foods are much more capable of activating these receptors and others. So it's eating the right foods, sending the right information to our digestive system that then activates and regulates the release of these enteroendocrine hormones. So there's a direct connection between this bitter receptors that sit on the tip of our tongue and those receptors that sit on the GI mucosa, particularly in this case on the L cells of the distal ilium. And how that then secretes upon stimulation of the right bitter agent. That would be a chemical communication. Something in the food is a substance that binds to that receptor. On the bitter taste receptor on a gut mucosa sets through the cell a signaling process that then ultimately causes the release into the blood of GLP1. Again, this is the classic example of food is information. So let's look at some examples here. We know that various toxins, alkaloids, Drugs and bitter agents in foods all influence then through this mechanism the release of these enteroendocrine cell activated taste receptors, releasing then whole series of different things depending upon the bitter agent and the bitter receptor that it activates. Remember I said there are 35 different bitter receptors that have been found in human physiology. And so you get different effects on regulating ultimately these enteroendocrine hormone orchestrated processes. This network biology that speaks across the body to all these organs and tissues that I've been describing previously. This is a really fascinating advancing in our knowledge of the role that diet plays in how it regulates all these functions across these mini organs based upon the foods we eat and the specific families of foods, and within those foods, specific molecules that participate in these processes. So let's just review the different types of cells in the gastrointestinal tract and the release of different intracran hormones, the intra endocrine hormones. So you have the A cells in the stomach with gilinin and Nef satin, you have the D cells found in the stomach and intestine with somatostatin, you have the 5 hydroxytryptamine with the intraochromophen cells and serotonin and that's where it's principally produced. Go down to L cells. If you would look at L cells in the terminal ilium, colon and rectum, you've got GLP1, GLP2, P, Y, Y, Oxonomodulin. So all of these are specific places within our digestive system in which there is an activity that releases specific intra intro endocrine hormones that regulate specific function in the body that is activated by specific principles within our foods. Specific foods with specific principles within those foods. Wow, this is pretty exciting stuff, isn't it? Because it teaches us a little bit about what we should be including in our diet. It also tells us to some extent why we've had such obesity problems as we've cut out a lot of these signals out of our food by ultra processing and those signals are not there to regulate these processes any longer. So the intestinal microbiome as I also mentioned, plays an important part because it's producing its own secondary metabolites from the the various microbes that live in our intestinal tract. They're eating and they're producing their waste products and they're dying and their cell walls are being released. All of which then can influence in these receptors of the various parts of the intro endocrine system. And so dysbiosis has been associated with alterations of intraendocrine hormone Release and then alteration in blood sugar, alteration in the immune system. So this all ties back again to our bitter taste receptor story that we've been advancing. And so we know there are certain food principles again that help in establishing the proper integrity of our microbiome. So we talk about prebiotics as being specific types of non digestible carbohydrate or other members of the flavonoid family that stimulate specific types of bacteria to flourish in the gut friendly bacteria, symbiotic bacteria, which then helps in the agonism of GLP1 and the other endocrine intro endocrine hormones. And so this is like you would say a natural GLP1 agonist. When we have an appropriate microbiome as a consequence of feeding the microbiome, the food it needs for the symbiotic friendly bacteria to produce the right signals that stimulate the the right receptors, in this case the bitter receptors to release GLP1 and other intra endocrine hormones. So bitter foods have surprising health benefits. That's what we're learning. So we have to learn how to eat bitter. You know, it's interesting to note that the major source of bitter presently in the standard American dietary intake is coffee. Coffee does stimulate actually some of these bitter taste receptors. So that is one contribution. Tea is also does that. These are your major things that the standard American gets their bitter receptor stimulated by. But there are many, many other foods that we're not eating in our diet that are even better for regulating the intravenicine hormone release. And so you know, you might look at grapefruit, radicio, artichoke, dill, lemons, rocket or as you know, one of the kind of bitter tasting lettuce alternatives, radish, ginger, olives, all of these are known to contain specific substances that are bitter that activate favorably these enteroendocrine hormones. Wow, isn't that fascinating? Dill seed, celery seed, golden Crest black tea. I, I think this is really a fascinating chapter in how we design diets to help support proper GLP1 release. And so bitter taste receptors are a key target to understanding the effects of how nutrients play roles and the family of nutrients that relate to the bittering activities that activate the release of GLP1 have been found within the polyphenol family, the flavonoid family, that then infect blood sugar levels, affect body weight homeostasis and have these very important roles to play in the regulation of ghrelin, GLP1, cholecystokinin. Through these receptors that I've been Mentioning wow, isn't that powerful. So think of flavonoid polyphenol rich foods. The, the more the better maybe if they' attach them, if they're attaching to the right receptors. Well, one of those foods that we've been studying extensively which happens to have a very, very high level of these polyphenols and flavonoids that are associated with activity of GLP1 agonist. As a GLP1 agonist is the 4000 year old food Himalayan Chartery Buckwheat and I, I happened onto this and recognized that in the American diet we kind of lost this food over 200 years ago. It wasn't even available in the United States. So we're back to growing it again and we recognize the history of this is quite powerful. It's associated with the longevity kind of a blue zone food. High levels of immune active polyphenols, it's gluten free, it's not a grain but a fruit seed. It's very high in unique prebiotics that are very useful for supporting proper microbiome integrity. It is known to stimulate GLP1. It has favorable effects on blood sugar. There are over a hundred phytochemicals that operate synergistically and it's known to activate the GLP1 receptor in the small intestine. And it is a member of the bitter family of high protein vegetables. So it, this is one of those kind of superfoods that fits into this category of contributions to improving GLP1 influence. We, we know that dietary supplementation with Himalayan tartary buckwheat polyphenols has been proven to increase endogenous glucagon like peptide 1 release and it facilitates glycemic control. It has a favorable effect on immune system function. And so we're starting to recognize when you start studying these things in detail, this is kind of food chemistry applied to food is medicine that there is something we can learn about the history that's back to the future that these foods really participate in the regulation of the natural processes of weight control, sending the right message from our food to regulate the intra endocrine system. So we know that there are other foods that do this. Mimordica or wild gourd bitter gourd bitter melon as it's sometimes called also is a GLP1 agonist. And it probably accounts for why it has been historically known to be a, a food that is associated with proper blood sugar control and insulin regulation. We know that cacao, which is a polyphenol rich chocolate ingredient is known to have a GLP1 agonist effect and influence postprandial glycemia, insulin and incretin secretion in healthy participants. So this is another member of this family of food, is information that signals through the intra endocrine system. We know that hops, you know, those of you that love hoppy beers, it also also has a positive Effect on the GLP1 secretion and maintenance of healthy weight. This is a randomized controlled crossover trial looking at a concentrate of the hops derived flavonoids that influence then these processes. And we now know that even the organs of the body, like the reproductive organs, are speaking through the bitter receptors. This is a study that we were involved with a number of years ago looking at pcos, polycystic ovary syndrome, showing that the ovaries actually have bitter receptors that stimulated release then enteroendocrine functions that regulate hormone, androgen, estrogen balance and can help in promoting proper balance, at least in this animal model of pcos. So you notice this story cuts across so many different clinical conditions. And when we've eaten the wrong things that are devoid of the right messenger molecules and the message that we're getting is one of inflammation and alarm, not the inflammation of regulation, then we start getting these downstream effects that we see as the pandemic of obesity in our culture. So we recognize that these bitter receptors are really important for the function of many, many cell types. This is another recent paper showing that they influence the function of one of the types of cells in the ovaries, the granulosa cells, kind of confirming what we published from our research a few years ago. So many organs are tasting, if I can put that in air quotes, and the information provided by these bitter foods that are the specific polyphenols that we now know activate these receptors produce regulatory effects that cut across all organs. Well, how about the Mediterranean diet? This. Well, the Mediterranean diet is a good exemplar of a diet that activates GLP1 and has a bitter taste component to it because of the nature of the foods that are within the Mediterranean diet. There's a recent paper looking at the Mediterranean diet, increasing glucagon like peptide and octonomodulin, compared with a normal vegetarian diet in patients who have blood sugar, insulin resistance. And this is a randomized, controlled crossover trial in which they showed that the people that the Mediterranean diet with virgin olive oil and more vegetables, and particularly the bitter family, that they were capable of having enhanced regulation, glucoregulation, insulin sensitivity and body weight control than people just on a kind of a garden variety. I use that euphemistically vegetarian diet. So activation of bitter receptors by olive oil phenolics is part of the benefit of. Because these olive oil bittering agents in virgin olive oil activate GLP1 receptors. And through this various task receptor family, the TAS2R8 which is one of the 35 different bitter receptors that activates then the release of these enteroendocrine hormones. Can you see what I've been saying here in terms of food is information? I hope so. This keeps coming back, coming back to reinforce the story that we've been eating disinformation in our diet. It's been devoid of this information. We need to regulate this class of intra endocrine regulating hormones that help insulin, help control immune function, help multiple organ activities as a part of of then seeing the pandemic of obesity develop. All of this is part of a new ahaism that we're developing mechanistically from this research. So what's the effect of a short term Mediterranean intervention in neurodegenerative disease? So this is an interesting again example of this Mediterranean impact on hunger hormones. This whole family of intra endocrine hormones showing that hunger and metabolism and the immune system are all positively influenced and therefore it influences brain function, brain activity in middle aged, overweight and obese women. So it really starts talking about wow, even way up there in the brain, way away from the GI tract, we're starting to see the signaling effects from eating the right information and its downstream effects to these intra endocrine hormones. So bitter is better, says this article. Wild greens are used in the blue zone. Remember the Ikeria Greece longevity population, 100 year old individuals, very common, not taking medications, being out of doors, being active. And part of the components of that blue zone is that in fact these people are eating these high flavonoid diets that are rich in these agonists of natural production of the intra endocrine hormones. It is a component of every one of the blue zone diets. Even in Loma Linda, California, one of the blue zones. If you would look at the dietary survey data from people who live in Loma Linda county or the area of Loman in in LA county, you'll find that they are consuming diets that are very much higher in these polyphenols and flavonoids than our individuals who live in LA county out of Loma Linda. Now why is Loma Linda so unique? Because it's a seventh Day Adventist community, a lot more emphasis on vegetarian diets, a lot more fruits and vegetable intake, a lot more whole grain intake. So we're really dealing here with signaling, eating the right information. It's a classic example of a city that sits right in the middle of la, drinking the same water, breathing the same air, but having a very different longevity profile and profile of chronic illnesses as a consequence of getting the right signals from their diet that regulate their function. By the way, also lowered incidence of obesity. It's not because they're all dieting, it's because they're eating the foods that signal properly to regulate body composition. I want to emphasize that again, it's not dieting, it's eating the right foods to send the right signals for regulation of those things that control adipocyte function, fat storage and metabolism. It's not just eating too many calories. That's what I've been talking about. So if we look at genetic poly polymorphisms at the bitter taste receptor, we find that those individuals who are bitter taste receptors, we call these individuals that have super tasters for bitter, that they're individuals that have different relationships to the amount of bitter they consume in their diet. And it influences then downstream the signaling that influences ultimately the intro endocrine hormone release. So there are differences among us based upon our genetic polymorphisms of the bitter taste receptors that modulates then our appetite habits, our taste habits and ultimately how our diet is composed and how it influences our intra endocrine hormone levels. So healthy diets and lifestyles in the world, the Mediterranean and blue zone people live longer. Yes, and there's special emphasis in on the diet connected to the gut microbiome, connected to the intro endocrine system. This is an emerging mechanistic explanation of for how this blue zone connection to longevity emerges. And by the way, it's interesting to note the two oldest foods in the world, both over 4,000 years old, are millet in the Indian continent and tartery buckwheat in the Asian China continent. They are associated with these favorable effects that we see that regulate weight, regulate body signaling, regulate energy economy, regulate immune system function. We are relearning back to the future what people have known for 4,000 years as it relates to the the benefits of the of these foods. So let me just close by have giving you some questions to consider. Obviously these are questions that kind of arise out of the concepts that I've shared with you over this last hour. So number one, why does the body produce TLP1 and other enteroendocrine hormones and why are they naturally degraded by enzymes such as DPP4? And the answer is that's all part of the regulatory network, the symphony of our metabolism that has been evolved or the largest study ever done called natural selection over millions of years to give us the proper relationship with our food so that we regulate naturally our body weight, our body metabolism, our body energy. All those things occur by sending the right signals. I hope that concept is properly articulated by me that you can understand. It's important. Number two, what are the potential effects of overriding this, the regulatory control of the integrine hormones by taking these GLP1 agonist drugs that result in supra physiological exposures over a long duration in the body's bloodstream? I would say right now we don't know the answer to that question. We don't know because we're the first group of people now that have had ability to take these drugs for a long period of time. And you probably know if we look at ozemic versus the drug wegovi, it's interesting, isn't it? It's the same drug is semi glutide in both those medications. What's the difference? The difference is that oic which was approved for diabetes is the same drug molecule semiglutide that's in the drug wobi this that's approved for obesity. The difference is that the dose in WeGovy for obesity is twice the dose that is in ozemic for diabetes. So we're pushing even harder on these regulatory pathways or networks when we start sending higher and high degrees of signals through these drugs to this system that's evolved naturally to regulate itself. And I don't think we know what the long term implications of this pharmacological override is. Stay tuned. We're going to learn number three, why should we eat in order to promote natural regulation of the intra endocrine hormones and regulate weight and blood sugar? Well that's a pretty duh question, right? The answer is that's what natural physiology is built around. That's our system that we have evolved over millennia, that we have in our inherit in our genes that gives respons to our diets in certain ways, how that information is processed. And therefore rather than just control calories and be in weight loss diets, maybe we should be eating the right information. Foods like tartery, buckwheat and, and, and foods that regulate then these processes naturally that actually induce these favorable outcomes. Next, what have we learned about the role of specific bitter taste receptors and Their bitter phytochemicals in plant foods in the regulation of GLP1. This is a huge new advancing understanding of the role of certain members of the polyphenol flavonoid family and how they connect into the agonism of bitter receptors that then regulate the release of the enterprine hormones that then have these multiple organ effects across the body. This is new stuff where we're seeing this information become available and now we're seeing it become available associated with longevity that actually people who eat these kinds of diets and get these signals and they're in regulation are attributes that are associated with long and healthy life longevity. This may be part of the longevity secret that we have only started to learn or relearn. The blue zones maybe were an observation of that, but now we're mechanistically starting to understand that. So stay tuned. As we're seeing more and more research going on as it relates to longevity, you're going to see many more I think studies talking about the connection between these bitter receptors, agonists in our diet and how they connect into the release of these hormones that associate themselves with longevity. So how do we establish a healthy intestinal microbiome that contributes to the production of regulation of GLP1 and other intra endocrine hormones? The answer is you have to have the right kind of prebiotics, you have to have the right kind of GI mlu, you have to have absence of exposure to toxins. All of those things become part of the comprehensive approach towards managing your hormones that then regulate naturally your body weight, your appetite, your metabolism. And lastly of course, how does a Mediterranean or Mediterranean diet improve the regulation of the endocrine intra endocrine hormones? I think you know the answer to that. We've gone through it at some length now. Weed information. Culturally we've learned from certain cultures that they're associated with longer life, lower chronic disease, lower obesity. Those are happen to be diets and lifestyles that are associated with the proper regulation of intra endocrine hormones. And now we know their classes of nutrients that are specifically capable of signaling those processes naturally. That should be part of what Dr. Moussa and talked about in my initial article that I shared with you in jama of this graded approach away from the GLP1 agonist drugs into a lifestyle management utilizing the diet and nutrients that are now found to create the right kind of signals for the right kind of harmonization of our intran intro intro endocrine hormones. So in close I really want to thank you for the opportunity to share this with you. I hope this gave you some interesting and useful take away information. I can tell you for me, without question, having been in this field for five decades, this is one of those. Aha. Just moments of great excitement and opportunity. We at Big Bold Health are doing all we can to try to continue to know more on how to translate this into consumers and make it available and and really have it stand up so people can employ these concepts simply in their daily lives. But we're on the threshold of moving away from drug dependency for weight loss into how we construct healthy lifestyles in ways that will really lead to long term positive health outcomes, improved immune function, resilience and long lives and healthy lives. Thanks so much on behalf of Dupold Health. I really appreciate the opportunity to share this information with you. Be well.