Good evening. The Association for Bariatric Endoscopy, a division of the American Society for Gastrointestinal Endoscopy, welcomes you to this evening's presentation titled In Vivo Metabolic Testing and Mechanisms of Actions of EBMTs. My name is Marty Roth, and I will be the facilitator for this program. Please note that this presentation is being recorded and will be posted in GILeap, ASGE's online learning management platform. You will have ongoing access to the recording in GILeap as part of your registration. Before we get started, please note a number of features in tonight's platform available to you during and after tonight's program. Currently, you are located in the auditorium. As you enter the lobby, you should note the Satellite Symposia section with a few recent Satellite Symposia recordings you can access. In the resource room, you will find a number of options, including Video GIE, Meet the Master Videos, History of Endoscopy section, a Gaming section, as well as access to ASGE's Guidelines and GILeap. In the networking lounge, you will find a link to complete an evaluation survey for tonight's webinar. We would appreciate you completing this. Finally, I would like to acknowledge Olympus Corporation of the Americas for sponsoring our Thursday Night Light webinars. There will be a question and answer session at the close of the presentation. Questions can be submitted at any time online by using the Q&A icon at the bottom of your screen. Please do not use the chat box for submitting questions. Our presenters for this evening are Dr. Picamal Girapigno and Dr. Shelby Sullivan. Dr. Picamal Girapigno is an interventional endoscopist at Brigham and Women's Hospital and Harvard Medical School, where she also serves as the Director of Bariatric Endoscopy Fellowship. In addition to performing therapeutic procedures, including EUS and ERCP, Dr. Girapigno routinely performs both primary endoscopic bariatric procedures and a range of endoscopic treatments of bariatric surgical complications, including weight regain. Additionally, she routinely prescribes lifestyle intervention and FDA approval weight loss medications for patients with obesity and metabolic diseases. Dr. Girapigno has published extensively in the areas of endoscopic management of obesity and metabolic disorders, including fatty liver and their mechanisms of action. And our next presenter, Dr. Shelby Sullivan, is Associate Professor of Medicine at the University of Colorado School of Medicine and is the Director of the Gastroenterology Metabolic and Bariatric Program. She graduated with a degree in nutrition from the University of Wisconsin in Madison, where she studied the effect of caloric restriction on intracellular insulin signaling in a primate model. She attended Washington University School of Medicine in St. Louis for medical school and stayed through residency and fellowship to continue her research in obesity and metabolism. She joined the faculty of Washington University in 2004 and then moved to the University of Colorado School of Medicine in 2016. I will now turn the presentation over to Dr. Shelby Sullivan. All right. So we're going to be talking about the first part of this talk is going to be really about in vivo metabolic testing. These are my disclosures. I've been involved in a number of the endoscopic bariatric therapy studies, and I also consult for multiple companies. So first, first off, we know bariatric surgery is the most effective treatment for diabetes. And this is one of the studies that kind of demonstrates that. This is a randomized controlled trial of 150 patients that were randomized to intensive lifestyle therapy alone, intensive lifestyle therapy plus gastric bypass or intensive lifestyle therapy plus sleep gastrectomy. And at five years, what you can clearly see is that there is a difference between the two bariatric surgery groups compared with the lifestyle therapy only group in terms of hemoglobin A1C levels. But one thing that's really important to note, we're going to talk about this again later in this talk, is that there was a difference in the amount of weight loss that was seen between these groups, which makes sense that bariatric surgery patients get more weight loss than patients who are undergoing lifestyle therapy. And in fact, the lifestyle therapy patients only lost 5.3 kilograms, and that's compared to 23 and 19 kilograms respectively for gastric bypass and sleep gastrectomy patients. And this is going to be an important point when we get through the rest of this talk to see what are the effects of the actual weight loss independent of the weight of the effects of the surgery. And we know that obesity, and the other reason why this is so important to talk about in terms of what happens with metabolic function with weight loss and with our procedures and with surgical procedures, is because of the impact of diabetes, prediabetes, non-alcoholic fatty liver disease, just to name a few in terms of the diseases that are caused by obesity. And we can see that we've got about 84 million Americans with NAFLD, 88 million with prediabetes, 34 with diabetes, and about 108 million Americans with obesity, and about 24 million Americans who would qualify for bariatric surgery. And we only have about 1% of patients that are actually treated with bariatric surgery per year. And this is important. This is one of the most effective therapies that we have for diabetes and reversing these metabolic and negative effects of obesity. And these have costs to them. So the cost of a new diagnosis of non-alcoholic fatty liver disease is about $7,800 versus about $2,300 for control patients in 2010 to 2014 dollars. The cost of prediabetes is about almost $7,000, and that's in 2010 to 2012 dollars, so significantly higher now. And the incremental cost of diabetes is $9,600 per person per year. That was adjusted to 2017. So these have really significant costs associated with them. So we're going to first give a brief overview of all of the organs that are involved in kind of glucose metabolism. This is a very, very basic overview. So we've got the gut, which is really important for controlling the rate of nutrient absorption. It produces hormones that are involved in gastric motility, glucose-stimulated insulin secretion, hunger, and satiety, namely ghrelin, glucagon-like peptide one, and glucose-dependent insulinotropic polypeptide, or GIP. Some of the other peptides as well as these will be discussed further in Dr. Giropinio's talk as well. And there's also theorized, there's possibly theorized to be anti-incretin that is produced by the small bowel as well, and we'll talk a little bit about that in a minute. For the pancreas, we know we have exercant function for nutrient breakdown and absorption. And then we have endocrine function, which produces insulin, glucagon, somatostatin. And of course, we know that insulin and glucagon are very integrally involved in glucose homeostasis. The liver is responsible for about 95% of endogenous glucose production. So that is from protein and from gluconeogenesis of the lactic acid. And then we have, it also controls, it also stores glycogen and also breaks down glycogen to again, have additional glucose that can be sent out to the periphery. It controls the concentration of insulin seen by the body through first pass metabolism, produces fatty acids from excess carbohydrates, and intrabiotic triglyceride content directly correlates with skeletal muscle insulin sensitivity. So it's a more sensitive marker of insulin, skeletal muscle insulin resistance than visceral adipose tissue is. The muscle, in this simplistic view, it takes up glucose. And we know that muscle uses glucose for energy. And in terms of the nervous system, this stimulates both liver and pancreas in response to hypo or hyperglycemia, controls nutrient partitioning. So that's the use of fat versus glucose for energy use and contributes to control of eating, you know, centrally, and is also involved in neuroendocrine signaling. So let's talk about the small bowel. And we're really going to talk first about incretin hormones and their role in health and disease. And so the first thing to note is that the incretin hormones that we're going to talk about on this part of the talk, which is GIP and GLP-1 are produced in K cells and L cells throughout the small bowel, L cells being a little bit more distributed farther down and more distally, both proximal and distally in the small bowel, but increasing in number as you go distally. And what their effects are on insulin secretion. And so in the top graph, what you can see is a graph of glucose excursion. And this is in two different scenarios, one with oral glucose, where a patient is actually drinking the glucose, and then with IV glucose, where the investigators are trying to match the glucose concentration with a glucose infusion to match the time course of glucose during the oral glucose administration. And in these two tests, they also measure, are measuring insulin and glucagon. And what you can see is that in the solid circles is the oral glucose. And so in the case of the oral glucose, we have significantly more insulin that is secreted compared to the IV matched IV glucose concentration. And that's the incretin effect. That's the effect of it coming into the small bowel and small bowel signals being sent to the pancreas to increase insulin concentration. Likewise, glucagon is also less suppressed with oral administration of glucose compared to IV administration of glucose. And again, that is the incretin effect, where you see that we have more of a balance with glucagon, less of a suppression than if it's just coming in with IV glucose alone. So how does that play into glucose tolerance? And this study really did the same thing with giving oral glucose and IV glucose to match the oral glucose concentration curve in three different groups of patients, a group of patients that had normal glucose tolerance, a group of patients with impaired glucose tolerance, and a group of patients with type 2 diabetes. And what we can see in the top row, row A, are the glucose excursions. And you can see again, or you can see here very clearly that as you go from normal glucose tolerance to impaired to diabetes, that you have significantly higher glucose concentrations, which with oral and again, with the match with IV glucose infusion, because they have worsening impaired glucose tolerance as we go from impaired glucose tolerance to diabetes. In row B, what we can see is that there is this difference between the insulin that is secreted with IV, which is the bottom row or bottom curve, and the top curve, which is the oral glucose, an oral glucose ingestion. And again, the grayed area between these two is the incretin effect. It's the effect of the small bowel increasing the insulin secretion in response to an oral glucose load, which doesn't happen with an IV load. And we see that there is increasing insulin secretion when we get to the impaired glucose tolerance, again, because these patients have decreased insulin sensitivity in the periphery and need more insulin in order to, you know, to try to control the glucose concentration. And when we get to the diabetic patients, you can see that there's that that that incretin effect is almost gone, that there's very little difference between the insulin secretion or the insulin concentration, I'm sorry, between the the oral glucose administration and the IV glucose administration, suggesting that, again, in the diabetic setting, that we see a really almost abolishment of this incretin effect. The other thing that was seen in this study, they also looked at GLP1 concentrations, GIP1, and also glucagon. And in the top graph, you can see the GLP1 excursions. And you can see the top two lines are the normal glucose tolerance and impaired glucose tolerance. And they're pretty similar in how they were secreting GLP1, which makes sense because we think that GLP1 is really stimulating that insulin secretion. And they had significant increases in their insulin, insulin concentration in the oral glucose versus the IV glucose administration. But the diabetes patients had almost no increase, very little increase in GLP1. And again, they had almost no increase in insulin concentration in the oral glucose versus the IV glucose scenario or administration. However, GIP was increased in the diabetic patients compared to the insulin, the impaired glucose tolerance or the normal glucose tolerance patients. And going along with that, there was increasing glucagon. Remember, glucagon increases glucose concentration. So it's glucagon is there to really prevent hypoglycemia, and it increases glucose. And GIP is actually known to stimulate glucagon secretion. So you have this double whammy. You have the loss of the Incretin effect. And then you also have increased glucagon secretion, which significantly increases the glucose concentration in those patients with diabetes. Now the anti-Incretin theory, and this is one of the papers that really kind of is the basis for this theory. So I will tell you that it's not widely accepted, and there is no anti-Incretin hormone or peptide that's actually been discovered. In this study, they took normal controls and patients with obesity that were undergoing biliopancreatic diversion. They did the same kind of thing with the oral glucose and the graded IV glucose tolerance test one day apart, same study, same kind of scenario that you were seeing in the last two slides so that we can see what the insulin does in response to the oral versus the IV infusion of glucose. What they saw, and what I want you to look at is panel E compared to panel D. So these panel D, panel E, and panel F. And what they noted was that there was less insulin needed for the same glucose concentration in the IV versus the oral glucose in patients who had undergone intestinal bypass. And so what this group thinks is that this supports the hypothesis of an anti-Incretin that is secreted in the small bowel causing insulin resistance in the periphery. And when you bypass the small bowel, you bypass that anti-Incretin and therefore no longer have the insulin resistance in the peripheral tissue, in the skeletal muscle. And they think that in normal controls, the anti-Incretin effect may prevent hypoglycemia. But again, no anti-Incretin molecule has been identified, and not everyone agrees that this actually exists or actually occurs. All right, so putting all of this together, let's kind of walk through kind of normal metabolism in somebody who has normal glucose tolerance. So we've got food coming into the stomach and into the small bowel where we have K cells and L cells. Again, the K cells mostly producing GIP and the L cells mostly producing GLP-1, although there is some cross between those two. We have GIP and GLP-1 that are acting on the pancreas to increase insulin and really in normal settings don't have much effect on glucagon. So we're not really significantly increasing glucagon or we're not increasing glucagon during the normal glucose tolerance patient. Then GLP-1, and this has an effect on the liver to suppress hepatic glucose production, so that reduces the amount of glucose that the liver is producing. GLP also likely has direct effects on the liver as well to help with hepatic glucose production suppression and also acting centrally in terms of satiety, and Dr. Girapina is going to talk a little bit more about this as well. And then with skeletal muscle, we see that there's an increase in glucose uptake in response to insulin, and all of these things result in controlled blood glucose. And again, there may be this anti-Incretin effect, but that is definitely not proven at this point. So small bowel control of glucose in diabetes is a little bit different. So we, first of all, have hyperplasia of the endothelial and enteroendocrine cells, and even though there's hyperplasia of these cells, they're not really working very well. And so in the presence of high-fat, high-sugar foods, we see that secretion of GLP-1 is potentially a little bit higher than GLP-1, and again, we saw that in that previous study. And what this leads to is we have insulin secretion, but it's not as much as it was before, and then we also have glucagon secretion, which is affecting glucose concentrations. We also have ineffective suppression of hepatic glucose production and decreased glucose uptake in muscle, and all of this leads to uncontrolled blood glucose and those much higher glucose concentrations that we saw a couple of slides earlier. So how does bariatric surgery help this? Because we know that bariatric surgery is the most effective therapy for diabetes. So this was a study that looked at gastric bypass versus lap band, where there is no rearrangement of the GI tract. You're just restricting how much somebody can eat because of a band being in the cardia of the stomach. And this was a study that was done in non-diabetic subjects that were tested before surgery and after 19 to 20 percent total body weight loss, and there was 10 subjects in each group. There was no difference in changes in body composition or liver fat. And in gastric bypass versus lap band, what we can see with glucose is that there is an increase in glucose concentration after surgery, and it's an increase, and it's not an increase in area under the curve concentration, but it's an increase in the peak of that concentration. So it's a very brisk peak increase in glucose, and then it comes back down. And that's really driven by ingested glucose, and that's what you can see in the bottom of this graph, that the ingested glucose in the gastric bypass patients are really driving that glucose coming up. It's being absorbed very quickly. And this doesn't happen in the patients with laparoscopic adjustable gastric banding. And in terms of GLP-1, we see that there isn't really a change in GLP-1 in the lap band group, but there is an increase in GLP-1 concentrations after bariatric surgery. And going along with this, there's also an increase in insulin concentration peak. So there's no increase in the area under the curve of insulin, but there is an increase in the peak of insulin, again, matching that peak of glucose and augmented by the increase in GLP-1. So there is definitely an effect of bariatric surgery on these hormones to handle that immediate glucose that's coming into the small bowel very quickly after it enters the gastric pouch. However, it's important to note that in this study, there was no difference in insulin sensitivity or beta cell function. So these patients all got to 19% to 20% total body weight loss, and the rest of their parameters were really essentially the same. So one of the problems with studying groups after weight loss is that rapid changes occur even before significant weight loss or weight gain. So the previous study that we just showed you, they had significant weight gain, 20%. But the same thing is actually true for smaller, shorter time intervals. And how do we measure these? So there's multiple different ways that we can measure them. And this talk is not going to make you an expert on how to measure insulin sensitivity or beta cell function. But what I really want you to get out of this is that there's multiple ways that you can measure it. And I also want you to understand why the gold standard approaches are really gold standard. So we have insulin sensitivity methods that are static, that are steady state or require steady state. And HOMA-IR is an example of that. It's very easy to do, and we're going to talk about this in a minute, hepatic insulin sensitivity in index implants. So we're going to, again, talk a little bit more about this on our next slide. We have semi-dynamic where patients are ingesting oral glucose, and you're able to do calculations based off of the glucose time course and insulin time course with this. And then we have the dynamic or definitely not steady state, and that's IV glucose tolerance tests and some OGTTs with or without tracers. Beta cell function methods, you can get insulin secretion rates, insulin secretion rates as a function of glucose. There's minimal models of glucose, insulin, and C-peptide. C-peptide is what's cleaved off of insulin, pro-insulin before secretion. And so C-peptide is a good marker for the actual insulin secretion because it does not have go through first path, it doesn't have the first aid first pass metabolism as insulin does through the liver. And then we have mixed meal tolerance tests. And when you use these with tracers, you can not only get the beta cell function, the insulin secretion rates and insulin secretion as a function of glucose, but you can also get whole body insulin sensitivity, glucose production, glucose absorption. And those were some of the methods that were used in that study that looked at LATVAN versus gastric bypass. So when we look at insulin sensitivity, so separating out the insulin sensitivity versus the beta cell function, these are just some of the tests and what are the benefits and disadvantages of these tests. So with the homeostatic model of insulin resistance, the HOMA-IR, it uses fasting glucose and fasting insulin or fasting C-peptide concentrations. And there are models that you can actually import this into. So there are computer programs that you can use this as a model, but the simple calculation doesn't do that. It's an estimate of insulin sensitivity and beta cell function, but it's just an estimate, but it's easy to measure. And it's very easy to do across a large study. Disadvantages is that there's no distinction between hepatic and peripheral insulin sensitivity, although there are some people that say this really is more of a marker of hepatic insulin sensitivity than peripheral insulin sensitivity. It has a limited use in patients who are on insulin and it's an index. It's not a true measurement. It's an index that's based off of a calculation from just two fasting measurements. The Matsuda index of insulin sensitivity uses measurements during an oral glucose tolerance test and it's put into a model. There's some good correlation between rates of insulin mediated glucose uptake during a clamp, which is the gold standard. We're going to talk about that in just a second on this slide. And the oral glucose tolerance part can also be used for beta cell function. However, there's variability in gastric emptying and it's more of a measure of whole body insulin sensitivity. You can't necessarily tease out hepatic versus skeletal muscle insulin sensitivity. The minimal model of frequently sampled IV glucose tolerance test uses measurements before and after a bolus of glucose given over two minutes, which is modeled to generate an index of insulin sensitivity. And sometimes you can give insulin with this as well. It's easier to do than a clamp. It can derive insulin sensitivity, glucose effectiveness, and beta cell function. But again, estimates of insulin sensitivity are less reliable in patients with impaired insulin secretion. Whole body insulin sensitivity, for the most part, it really can't necessarily differentiate between tissues. And then we come to the hyperinsulinemic euglycemic clamp. And especially when we do this with tracers, insulin is infused at a constant rate and glucose is infused to reach a steady state. So that glucose concentration changes, you adjust it as the study goes so that you can reach a steady state. And we're really trying to get right to 100 milligrams per deciliter and really plus or minus three on either side of that to get to that steady state to be able to measure things. It is considered the gold standard for insulin sensitivity. It directly measures glucose disposal or the uptake of glucose into skeletal muscle, as well as the appearance of glucose into the system from the liver or endogenous glucose production when you're using isotopes. And it can differentiate insulin sensitivity of different tissues. The disadvantages is it's time consuming. It's labor intensive. It's difficult for patients. They essentially, for the entire clamp, which may be hours long, they have to lay still but not fall asleep. It's really tough to do. And if they move at all or if they have to go to the bathroom, that can then bring you back to square one and you've got to readjust your glucose concentration so you get back to steady state. And you have to reach steady state in order for this to really be a good test. And you don't get beta cell function out of this. You need a mixed meal test or some other test in order to get that. So using these tests, and in particular the clamp test, what we can look at are changes over a short period of time. And so what I really want to demonstrate here is that there are changes due to long-term weight loss, but there are also changes related just to short-term, very short-term changes. This was a study that looked at 72 hours of overfeeding. And this was done in nine healthy young men that were tested at baseline and 72 hours after high-fat or high-carbohydrate feeding. And they were doing a hyper-insulinemic e-glycemic clamp. Again, that gold standard for clamping. And what they saw in this, this is in A panel and B panel, is that there was a decrease in glucose infusion rate that was needed after patients were on 72 hours of a high-fat diet. So that means that there was a reduction in insulin sensitivity in skeletal muscle. And it went up in the carbohydrate feeding. However, the opposite happened with the liver sensitivity. So glucose rate of appearance, and that's endogenous glucose production. So the liver producing glucose and sending it out to the periphery, that decreased slightly in the basal state after eating the high-fat diet and increased in the basal state on the high-carbohydrate diet. And the hepatic insulin resistant index increased on the high-carbohydrate diet. So high-carbohydrate diet caused insulin resistance in the liver, but insulin improvement in skeletal muscle. Opposite occurred with the fat and fat diet. But the important thing to remember here is that these changes occurred after just 72 hours of this alternate diet. So it really is, these are short-term changes that can have significant effects on metabolic outcomes. This study looked, this second study is looked at hepatic insulin sensitivity, which also changed very quickly with calorie restriction. So this was a study that looked at two different diets, but in this slide, we've combined both of those diets, high-carb and low-carb diets. We've combined them together into kind of one group for this slide for the purposes of looking at the effects of overall calorie restriction. So these patients were only under calorie restrictions for 48 hours and were tested, and then were tested again after 7% total body weight loss. The first thing to note is that enteropatic triglyceride content or liver fat decreased by almost 25% in just 48 hours of calorie restriction, and then improved, increased again to almost 50% reduction after 7% total body weight loss. Hepatic insulin sensitivity determined during a clamp test completely improved in 48 hours, and there was no additional improvement with 7% total body weight loss. Skeletal muscle was a little bit different. There was no significant improvement at 48 hours, but significant improvement in skeletal muscle insulin sensitivity at 7% total body weight loss. So different tissues respond to nutrients and to calorie restriction in different ways, and they can respond very quickly. So the metabolic summary so far here is that multiple organs are involved in the control of insulin and blood glucose concentrations. Oral ingestion of nutrients increases insulin secretion in people with normal glucose tolerance through the action of incretins, and this is impaired in patients with diabetes. So the small bowel really is important for insulin secretion. There is a hypothesis of an anti-incretin produced in the small bowel that causes peripheral insulin resistance, but no molecule has been identified, and there's no consensus on this actually occurring. Multiple different tests for measurements of insulin sensitivity and beta cell function exist, but hyperinsulinemic elicinic clamp is the gold standard and can differentiate insulin sensitivity of different tissues. The mixed meal test with tracers is also ideal for beta cell function. And tissues can respond very quickly, within 48 to 72 hours, to changes in diet and calorie intake. And so in the presence of calorie reduction, metabolic change can't be assumed to be due to device or procedure. It may be due to calorie reduction before weight loss is seen. So we're going to go back to this slide, this issue of weight loss, and a controversial finding that was published in the New England Journal in August of 2020. And this study looked at the effect of diet versus gastric bypass on metabolic outcomes. And essentially, there was no difference in metabolic outcomes when weight loss was equivalent, regardless of whether it was lifestyle therapy alone, or Roon-Y gastric bypass. And we're going to talk about this just a little bit. So in this method, there were 11 patients in both groups, and they got to about 18% total body weight loss. They used multiple different studies to look at these patients. Mixed meal test and a 24-hour metabolic study, three-stage hyperinsulinemic elysemic pancreatic clamp. This means that they suppressed all pancreatic secretion, and then gave things back. And this was able to look at hepatic insulin sensitivity, muscle insulin sensitivity, and adipose tissue insulin sensitivity. And I just want to show you the slide, just so that you can see. These studies are really difficult, and they're hard to do, which is why you don't have a lot of patients in each group. They're long studies as well, and you can see that there's a lot of things being infused, and a lot of things that are being measured. And in both of these studies, they were using things that were isotopically labeled. So we really are able to get rates. We're able to understand the rate of appearance and the rate of disappearance with glucose in the presence of these isotopic tracers that we're able to measure. So what did we find in this study? Well, first of all, we found that there was equal weight loss, essentially, between the two groups, that the intrapathic triglyceride content decreased between the two groups pretty consistently, that there was insulin therapy that was required in some patients in both groups. There's no difference between the two. Hemoglobin A1c decreased in both groups. Basal glucose decreased in both groups. Basal insulin decreased in both groups. And there was four patients in the low-calorie diet that were able to come off of diabetes medications and have a hemoglobin A1c of less than six, and two patients in the gastric bypass group. So really, when we look at these outcomes, they're pretty similar between the two. So what did the other studies show? Well, first of all, when we look at glucose kinetics, and this is from the mixed meal test, we saw that there was the same thing that we saw before, where gastric bypass patients, you see a spike in glucose concentration, and then coming down, and this is driven by the glucose that they're drinking. And going along with that, there's suppression of endogenous glucose production by the liver. But in overall, the area under the curve of both the glucose and the endogenous glucose production, they were decreased pretty equally between the two groups. Even though the curves look different, the area under the curve was pretty similar. The other thing is that there was the same improvement in glucose production, suppression of endogenous glucose production, and increase in skeletal muscle glucose uptake in the clamp study, regardless of what diet you got, regardless of how you got the weight loss. So it didn't matter if you were on the diet alone or if you had gastric bypass, your improvements were the same. The other thing that they looked at, again, was beta cell function. And this looked at kind of a measure of beta cell function versus the insulin sensitivity that they saw during the clamp. And when they plotted this against the horizontal and vertical axis, what you see is that there's the same improvement in beta cell function, regardless of whether you lost weight with the diet or you lost weight with gastric bypass. So does this mean that Roux-en-Y gastric bypass has no weight loss independent effects? Well, no. This study really demonstrated that at some level of weight loss, weight loss is the driving factor for metabolic improvement. But it doesn't mean that small bowel therapies don't have an effect or that you wouldn't have an effect if you didn't have this weight loss. The other thing is that this study did not investigate the mechanisms by which gastric bypass causes weight loss, which are weight loss independent and is driving the weight loss. So we know that it's way easier to lose weight with gastric bypass than it is with lifestyle therapy alone. This study does demonstrate, however, the importance of weight loss at a level achieved by many patients undergoing the gastric endoscopic bariatric therapies so that even though they might not have weight loss independent effects on metabolism, the weight loss that they get is sufficient to get significant improvements in metabolic function because of the weight loss that they achieve. And with that, we're going to go on to mechanisms of action of endoscopic bariatric and metabolic therapies with Dr. Giropinio. I'd like to thank the ABE and the ASHE for the invitation. I'm honored and excited to talk about one of my favorite topics, which is mechanisms of action of endoscopic bariatric and metabolic therapies. Now that you've learned about in vivo metabolic testing from Dr. Sullivan, we'll spend the second half of the webinar applying some of these concepts to clinical practice. Here are my disclosures. You may wonder why it is important to understand mechanisms of action of EBMTs. Here's the current situation. You learn about the field and are excited to dive into bariatric endoscopy. You start learning the cognitive and technical aspects of bariatric endoscopic procedures, spending time perfecting your suturing skills. Now your practice starts to grow and you start doing a high volume and offering a variety of bariatric procedures. The challenges you may be facing are, number one, not every patient will be happy. For example, in my bariatric clinic this past Monday, I saw about 10 patients. Three were news and seven were follow-ups after either a primary or revision procedures that I previously performed. Out of those seven follow-up patients, two were extremely happy with almost 30% total weight loss. Three to four patients were satisfied, happy, as there were somewhere between 10 to 20% total weight loss. And one patient was frustrated because she's lost less than 5% of her baseline weight. So if you look at the data, this is pretty consistent in the literature, where you're always going to have that 15 to 20% of the patients who were non-responders. And if you're like me, you always wonder why. Additionally, once you start offering a variety of cases, one of the most common questions from the patients is, which procedure do you think is best for me? And to answer these questions, we need to understand mechanisms of action of each procedure. Here's an outline of the talk today. We're going to start with a brief overview of EBMTs. We'll then spend more time discussing the mechanisms of action of gastric followed by small bowel interventions. Here's a quick pictorial summary of EBMTs. The left side is gastric interventions. We have intragastric balloons, transpyloric shuttle, endoscopic sleeve, which can be broken down to ESG and POS and aspiration therapy. For small bowel interventions, we have duodenal jejunal bypass liner, also known as endobarrier, and duodenal mucosal resurfacing, or RAVITA. Both of these small bowel devices are undergoing US pivotal trials. When you see patients with obesity, you care not only about helping them lose weight, but also improve their comorbidities that they have, such as diabetes or fatty liver. So in general, for gastric interventions, they have a primary effect on weight loss, which leads to improvement in metabolic outcomes. In contrast, small bowel interventions have a direct impact on metabolic improvement, like what Dr. Sullivan discussed earlier, with or without weight loss, suggesting that they work through different mechanisms. Here's a summary table of pivotal trials and landmark studies in bariatric endoscopy. Overall, gastric balloons and transpyloric shuttle give you about 10% total weight loss, while endoscopic sleeve and aspiration therapy give you somewhere between 15% and 20% total weight loss. For small bowel devices, the US trials are ongoing, but international data look promising with 19% total weight loss and 3% total weight loss at one year for patients with obesity and concomitant diabetes. When you look at metabolic outcomes, studies show significant improvements in hemoglobin A1c, HOMA-IR, which is a surrogate of insulin resistance, and ALT. We also noted two interesting observations. Number one, in Dr. Shariah's recent study, she found that HOMA-IR improved as early as one week following ESG, even before patients experienced significant weight loss. Secondly, for Revita, patients experienced minimal weight loss of about 2% to 3%, but had significant improvement in hemoglobin A1c, insulin resistance, and possible fatty liver. Therefore, they suggest that there may be a weight loss independent mechanism following certain endoscopic procedures. Let's start with gastric devices. A lot of you are familiar or have seen this diagram, which represents the gut-brain axis. It basically shows that there are several ways that the GI tract communicates with the brain to tell the brain when you're full or when you're hungry. Similar to how weight loss medications work by affecting some of the neuronal pathways, our endoscopic procedures work by intervening with this gut-brain axis. For gastric interventions, they appear to alter gastric emptying and gut hormones. The relationship between gastric emptying and obesity has been described since 1983. In this study by Dr. Wright, he looked at gastric emptying of 77 subjects. 46 had obesity and 31 were normal weight. On the graph here, the y-axis represents the amount of food remaining in the stomach at each time point after eating. You see that for patients with obesity, represented by the white dots, they had less food at each time point compared to patients with normal weight because they empty faster. So, they suggested that maybe slowing down gastric emptying may be beneficial for weight loss. Why is that? It's because the rate of gastric emptying controls how much food remains in the stomach after eating. This then affects the extent and duration of gastric distention. For example, if you have slow emptying, this prolongs gastric distention, which triggers stress and tension mechanoreceptors, which then tell the brain that you're full. Additionally, the rate of gastric emptying also affects the amount of gut hormone secretion. However, data on this are conflicting, so we're not going to go over this in more detail. Moving on to gut hormones, these are the major gut hormones, and they'll keep coming back throughout the talk. So, I like to summarize them here. Ghrelin, which is secreted in the fundus of the stomach, is the only hunger hormone. CCK and GIP are secreted in the proximal small bowel, with CCK stimulating gallbladder contraction and pancreatic enzyme secretion, and GIP causing an increase in insulin secretion. GLP-1, PYY, and oxytomodulin are secreted in the distal small bowel and proximal colon and help induce satiation and satiety, with GLP-1 also stimulating insulin secretion. All right, so now we're ready to talk about each device. We're going to start off with the most common procedure worldwide, which is an intragastric balloon. Currently, we have three balloons that are approved in the U.S., Obero, Oblon, and the most recent one being Spaz, which is a fluid-filled adjustable balloon. We also have Ellipse, which is currently being reviewed by the FDA. Of these, Obalon is the only gas-filled balloon while the rest are fluid-filled. Here's a patient of mine. She's 48 with class 1 obesity and underwent 500cc Spaz balloon placement two months prior. She came in complaining of PO intolerance, requesting balloon removal. During the endoscopy, we found large food bezoar, so this is not uncommon when we scope balloon patients, which suggests that there's a relationship between an intragastric balloon and gastric emptying rate. What's the association between a balloon and bezoars? Here's an early study on mechanisms of balloons, which was published in 2005. In the study, 17 patients received an early version of Obero balloon, BIB. They found that the time required for the stomach to empty half of the ingested meal or gastric emptying halftime increased with a balloon being in place. Specifically, the emptying halftime went from 92 minutes before the balloon to 116 minutes at one month and 157 minutes at four months. The balloon was then removed at six months, and the emptying halftime went down to 118 minutes. So this suggested that a balloon was associated with delayed gastric emptying. Additionally, the study showed that fasting ghrelin decreased. And remember, ghrelin makes you hungry, so lowering ghrelin level is a good thing. They also showed a positive correlation between the amount of ghrelin reduction and the amount of weight loss, as shown in the right upper corner. However, if you pump ghrelin and intragastric balloon, you'll get various results. For example, the study showed no changes in ghrelin in both the balloon and sham groups, despite weight loss in both groups. However, we know that when people lose weight, ghrelin goes up. So this suggested that there were flaws with either the study design or the way ghrelin was measured. The study showed no changes in fasting or meal-suppressed ghrelin. However, it measured total and not isolated ghrelin. So most of these studies were likely flawed and misleading. So how does a balloon affect gastric emptying and ghrelin? For gastric emptying, because a fluid-filled balloon can sit either in the fundus or gastric body, it weakens tonic contractions, which is generated in the fundus, or phasic peristaltic contractions, which is generated in the gastric body. This then leads to inefficient gastric contractions and delay in gastric emptying, which causes food to sit in the stomach for a longer period of time, resulting in ghrelin suppression. Currently, there has been no study on mechanisms of gas-filled balloons. We think they may work differently and may have a direct effect on ghrelin because they tend to sit up in the fundus, as shown on the fluoroscopy image from Dr. Sullivan. Now, you may wonder what the practical implication is from what we discussed so far. First, we may be able to apply mechanisms of action for personalized therapy. Specifically, here's a study from Dr. Abudaye and the team at Mayo. The study included 32 patients who underwent balloon therapy. All patients underwent gastric emptying before and at two to three months after the balloon. On the left, they found that patients with more gastric retention, i.e., slower emptying, were more likely to have balloon intolerance and early balloon removal. Additionally, when they looked at gastric emptying rate at two to three months after balloon placement, those who had a delay in gastric emptying compared to baseline tend to lose more weight compared to those who had no changes in gastric emptying rate. They then proposed this algorithm incorporating gastric emptying to personalize a therapy for our patients. Start with getting a gastric emptying at baseline. If they have slow emptying, they may not be able to tolerate a balloon, and therefore, a different bariatric endoscopic procedure should be considered. For those who already got a balloon, they recommend getting a repeat gastric emptying at about two to three months. If there's no change in emptying rate compared to baseline, they will likely be a non-responder, and therefore, we should consider adding a medication or another procedure early. Very interesting and practical concept. Next device is transpyloric shutter or TPS. The device consists of a large bulb and a small bulb connected by a tether. When the stomach contracts, the TPS moves to block the pylorus, preventing food from passing down to the duodenum. When the stomach releases, the TPS moves back proximally to allow food to pass by. Therefore, we think that the TPS works by delaying gastric emptying. This is supported by this endoscopic image from Dr. Sullivan and Kushner showing very similar findings of food B-sore to those of balloon patients. Now we're going to move on to endoscopic sleeve gastroplasty. When you think about endoscopic sleeve, we usually compare it to a surgical analogs, which are surgical sleeve or sleeve gastrectomy and gastric placation. For endoscopic sleeve, we have ESG, which refers to when we use the Apollo suturing device to create a sleeve, and POSE, which is when we use the USGI placation device to create a sleeve. Let's start with how a surgical sleeve works. We conducted a meta-analysis looking at mechanisms of action of a surgical sleeve, which demonstrated that ghrelin decreased, so you're less hungry, and GOP1 and PYY increased, so you feel full sooner and longer. Also, gastric emptying was faster after a surgical sleeve. Now what about endoscopic sleeve? Here's another patient of mine. She's 36 with class III obesity who came into clinic looking for an endoscopic weight loss options since she's not interested in surgery. She also had prediabetes and NASH with F3 fibrosis on FibroScan. After discussing all the options, we decided on POSE, which I performed earlier this year. At three months, she complained of hunger pain. Workup revealed ash pylori. She was treated, and then at six months, I repeated her EGD for ash pylori biopsies. On entering her stomach, I saw this large amount of food residues, so this suggested some changes in gastric emptying following endoscopic sleeve procedure. The first study on mechanisms of action of endoscopic sleeve came out from the Technon Group in Spain in 2016. They looked at 18 patients who underwent POSE using the traditional pattern where they use the IOP placation system to reduce the fundus size. At two months, patients had a delay in gastric emptying. Shortly after, Dr. Agudaye showed similar results for ESG using the overstitch suturing device. In the study, four patients experienced a delay in gastric emptying at three months. In the graph on the right, the blue line represented the baseline emptying rate, and the red line was after ESG. You see that there's more food remaining in the stomach after a meal following an ESG procedure. What about gut hormones after endoscopic sleeve? In the same study from Technon in Spain, they showed an increase in fasting ghrelin, likely due to significant weight loss. However, postprandial ghrelin inhibition was significantly enhanced. This means that after you eat, ghrelin drops much more significantly, which then suppresses your hunger more dramatically. Additionally, postprandial PYY stimulation increased following POSE, which means that as soon as you eat, PYY increases more dramatically, causing you to feel full sooner. What about ESG and gut hormones? Currently, we have a 12-patient study from Dr. Lopez-Nava from Madrid, which showed no changes in ghrelin, GLP-1, and PYY. More studies on this procedure are needed. You may wonder why endoscopic sleeve works differently than surgical sleeve. For example, surgical sleeve accelerates emptying while endoscopic sleeve delays it. Or, ghrelin decreases after surgical sleeve but increases after hour and endoscopic approach. The answer is that the fundus. On the top row is a patient with sleeve gastrectomy, whom I did an endoscopy on in preparation for an endoscopic revision. You see the sleeve is quite dilated, and just like normal sleeve when you retroflex, you do not see the fundus because it's respected and removed. On the bottom row is another patient of mine whom I did a distal POSE on. She came back for abdominal pain, which prompted this endoscopy. You see the intact placations in the gastric body, and on retroflexion, the fundus remains intact. So, after a surgical sleeve, when you don't have the fundus, there's no accommodation. So, food passed into the gastric body and antrum immediately. Therefore, they have faster emptying. Additionally, since the fundus has been removed, surgical sleeve patients have fewer G-cells, and that's why they had a decrease in ghrelin. In contrast, when you have the fundus, like our endoscopic sleeve patients, food, especially solids, will reside in the fundus during the lax phase before getting ground by the gastric body, making emptying slower. From a practical standpoint, knowing that endoscopic sleeve delays gastric emptying rate may be beneficial. For example, this is a study from Brazil, which included 52 patients, 26 of whom underwent an ESG alone, and the other 26 underwent ESG, and at five months, liraglutide was added for a combination therapy. Liraglutide is one of the FDA-approved weight loss medications. It's a GLP-1 agonist. As you heard from Dr. Sullivan's talk earlier, GLP-1 has many beneficial roles, one of which is delaying gastric emptying. Therefore, by adding liraglutide to a procedure that works via delaying gastric emptying, like endoscopic sleeve, you augment the effect of the procedure even more. And this study showed just that. On the right, they showed that by combining a GLP-1 agonist to endoscopic sleeve, patients experienced greater weight loss of 25% total weight loss at one year compared to 21% for those with endoscopic sleeve alone. So what do I do in my clinical practice? For my patients, I usually assess them between three to six months after endoscopic sleeve if their BMI is still greater than 30 or if their rate of weight loss starts to slow down and consider adding a weight loss medication, ideally a form of GLP-1 agonist, especially if they have prediabetes or diabetes. Last but not least for the gastric category is aspiration therapy. We now know that reduction in calories from aspirating alone explains only 80% of the weight loss. So we believe that the other 20% of weight loss is explained by a reduction in total daily caloric intake, likely from behavioral changes. For example, many of our patients reported eating more healthily and chew more in order to prevent the A-tube from clocking. Furthermore, gut hormones may play a role. Specifically, the gastric portion of the A-tube tends to reside in the fundus as shown here. And there's a mice work showing that stroking the cardia caused a spike in CCK, which is one of the satiety hormones. I know you care about not only helping your patients lose weight, but also improving their comorbidities like diabetes and fatty liver, which are very prevalent in outpatients. So the next section is going to be very exciting. These small bowel therapies are under trials in the U.S. and not yet available, but I expect that we'll continue to hear more about them in the near future. For small bowel interventions, there appear to be several other players that link the GI tract to the brain, and we'll go over most of them during the second half of the webinar. First and foremost, the increase in effect. We heard a wonderful summary on this concept from Dr. Sullivan earlier, so I won't go into it in detail. But basically, the increase in effect refers to when you ingest glucose orally, there's a higher spike in insulin compared to when you get glucose intravenously. This is thought to be due to increase in hormones. However, for patients with type 2 diabetes, their increase in effect is blunted. There are two major increase in hormones, GIP, which is secreted in the duodenum, and GLP-1, which is secreted in the ileum. They both promote insulin secretion and satiety and also delay gastric emptying. What about foregut-hindgut hypothesis? This has been around for a while, but still remains controversial. This basically refers to the two theories of how bariatric surgery improves metabolic outcomes. Some say it's due to the proximal, and some say it's due to the distal small bowel. On the left is a picture of normal anatomy. White dots represent good cells that produce ingredients that are distributed throughout the small bowel. Black dots, on the other hand, are bad cells that are located only in the proximal small bowel, and they have an anti-ingredient effect. Following Roux-en-Y gastric bypass, the foregut people say you remove the proximal small bowel, so you remove those bad anti-ingredient cells. Therefore, you have an enhanced effect of ingredient hormones. On the other hand, just by rerouting the small bowel, the food limb becomes shorter, so the hindgut people believe that because nutrients can get into the distal small bowel faster, you stimulate more GLP-1 secretion. So, how does endobarrier or duodenal jejunal bypass liner work? It basically is a 60-centimeter liner that fits in the duodenum and proximal jejunum, so food can pass from the stomach into the liner directly into the jejunum. So, on one hand, it may work on the foregut theory because the liner excludes the contact between food and the proximal small bowel. On the other hand, food does move faster within the liner, so it reaches the distal small bowel sooner, potentially causing a spike in GLP-1. So, let's look at the data. Here's our meta-analysis. We found seven studies that looked at gut hormones following endobarrier. Our studies show that GIP decreased while GLP-1 and PYY increased, supporting the hindgut hypothesis. On the other hand, ghrelin increased, which was likely due to weight loss. Now, what about bioacids? This abstract looked at the effect of endobarrier on bioacids. It showed that FGF19 increased after 10 months of endobarrier. As you can see in the picture on the right, FGF19 is stimulated by bioacids and acts as a hormone to inhibit gluconeogenesis and stimulate glycogenesis in the liver. So, very similar function as insulin. So, it's one of the key facilitators between the small bowel and the liver. Last but not least, duodenal mucosal resurfacing or fractal. This is an endoscopic procedure where we left the submucosal space and then ablate the duodenal mucosa. So, we're fortunate to be a site for clinical trials for both endobarrier and fractal, and my patients sometimes ask about the difference between the two procedures. I usually respond and say that you can think of endobarrier as a facial mask where you cover the duodenal mucosa, while fractal is like an exfoliating cream where you devitalize the duodenal cells. So, you can see that for fractal, it likely works through the foregut hypothesis alone. In RAVITA1 study, which was a single-arm open-label study conducted on 46 subjects, patients lost about 2 to 3 percent of their initial weight during the first four weeks, then stabilized. However, their metabolic outcomes continued to improve throughout the whole 12 months, including hemoglobin A1c and HOMA-IR, which is a surrogate of insulin resistance. Additionally, they also found a significant decrease in ALT, suggesting a possible benefit on fatty liver. This was then confirmed on their follow-up RAVITA2 study, which was a randomized sham control study conducted in nine countries in Europe and two centers in Brazil. In addition to hemoglobin A1c, another primary outcome was liver fat content assessed using MRI-PDFF at three months. At six weeks, there was a greater reduction in A1c in the DMR group compared to sham for the European cohort. Additionally, liver fat significantly reduced in the DMR group compared to sham in the same population. These significant improvements in metabolic outcomes occurred despite minimal weight loss, suggestive of weight-independent mechanisms. So just to bring you back to the very first question we asked at the beginning of the talk, why is it important to understand mechanisms of action of EBMTs? I think there are a few reasons. First, there will always be those 15% to 20% of patients who do not respond to therapy. Second, we have seen these efficacy numbers of 10% total weight loss following intragastric balloons and 15% to 18% total weight loss following endoscopic sleeve and aspiration therapy for a while now. You may wonder if we can do better. Would there be a better endoscopic procedure that would give your patients even more weight loss? In order to decrease the non-responder rate and increase the amount of weight loss, we need to understand mechanisms of action. Additionally, I hope that you see that by now there's still positive data on this topic and therefore more work in this field is needed. In conclusion, EBMTs work via several mechanisms. Certain EBMTs have weight loss dependent while others have weight loss independent effects on metabolic conditions. Lastly, more mechanistic studies on EBMTs are needed to help guide personalized therapy and combination therapy. Thank you very much. Well, I want to thank you, Dr. Girapino and Dr. Sullivan for that very insightful and informative presentation and for sharing all of your knowledge and experience. Unfortunately, we don't have time for questions, but if any of the attendees have questions, please send them to me at mroff at asge.org. I would be happy to share your questions with Dr. Sullivan and Dr. Girapino. This concludes our presentation. We hope this information is useful to you and your practice. As a reminder, you can access a recording of this webinar by logging onto GILeap by going to the asge.org backslash learn. Thank you again for your participation and have a good evening.

EBMTs

gastric interventions

small bowel interventions

gut hormones

weight loss

insulin secretion

satiety

glucose metabolism

diabetes

metabolic diseases