Welcome, everybody, to today's webinar hosted by the Nutrition Science and Metabolism group, as well as the Exercise Physiology Interest Group. My name is Steve Mallon. I'm an associate professor at Rutgers University in the Department of Kinesiology and Health. And welcome, everyone. I'm Janice McLeod, a registered dietitian, certified diabetes care and education specialist, and currently chair-elect of the Nutrition Science and Metabolism Interest Group. Thank you for joining us. Here's a glance at today's agenda. We're going to provide a few announcements to get started, and we'll introduce our speakers in a moment. OK, and the presenters will, of course, be taking questions at the end of the event. We would ask that you not wait until the end, though, to submit your questions. And please use the Q&A box to submit those questions as we're going through the presentations. Please do not use the chat function. You're going to see that's being used right now as we're making these announcements to send some important links and so forth. And of course, you can use the chat for chatting with other attendees throughout the webinar. So another real benefit, just to share about ADA membership, is connecting with members within interest groups on the Diabetes Pro member form. To continue all these types of conversations about the topics in the webinar, you can see the link that's going to be provided in the chat. OK, and finally, I would like to introduce our speakers for today. We're very grateful to have three speakers with us today. First, I'll introduce Dr. Fleming DeLa, a professor at the University of Copenhagen, who specializes in human physiology, metabolism, and endocrinology. His research focuses on insulin action, glucose metabolism, and exercise effects, particularly in type 2 diabetes. And in today's webinar, he'll be discussing pancreatic beta cell function in relation to GLP-1 agonists and lifestyle changes, drawing from his recent study on aerobic training and semaglutide in diabetes management. We're also joined today by Dr. Danny Green, a Winthrop Professor in the School of Human Sciences in Sports and Exercise Science at the University of Western Australia. He's a cardiovascular exercise physiologist specializing in chronic disease prevention. His research spans all ages, from preventing atherosclerosis in obese youth to optimizing exercise and medication for heart disease, stroke, and diabetes. And he leads the university's cardiovascular research group, which develops early disease detection and personalized prevention strategies through transdisciplinary collaborations in science, engineering, and medicine. And we are also joined today by Laura Russell, who is a registered dietitian with 20 years of experience taking care of patients, 15 years of those as also a diabetes care and education specialist. Laura has worked in private practice, in research, inpatient care, telemedicine, and outpatient clinics, and specializes in diabetes medication management and diabetes-related technology. She is a frequent speaker, including at the Food and Nutrition Expo with the Academy of Nutrition and Dietetics. She's presented on continuous glucose monitoring, weight management, clinical inertia, and has held leadership roles with the Diabetes Practice Group of the Academy of Nutrition and Dietetics, the Association of Diabetes Care and Education Specialists, and also with the Minnesota Academy of Nutrition and Dietetics. And so with that, I invite Laura to get us started with today's presentations. And thanks so much to all of you for joining us. All right. Thank you so much for having me. I'm in Minneapolis, where we potentially are having a blizzard this morning. So looking forward to that today. I am here to talk about the role of nutrition on general health and muscle mass during incretion treatment. I'm really here as the clinical boots on the ground, working with patients day in and day out. My role has really evolved over the past couple of years from just being diabetes educator and a diabetes dietician to more weight management as we're treating more and more people for obesity and trying to prevent some progression to diabetes. So I'll be discussing some of the nutritional concerns related to these medications, including reduced food intake, altered body composition, side effects, and then long-term management. So reduced food intake, a hallmark of these medications is appetite suppressant. Going into therapy, we know 40% of adults are estimated to have inadequate intake of micronutrients. People living with obesity may have inadequate protein and micronutrients to begin with. And so this can be a concern. With medication, total caloric intake may be reduced 16 to 39%. That's anywhere from 350 to over 600 calories a day related to the slowed gastric emptying, reduced hunger, also working on those brain signals and reducing some of that food noise. Many patients report reduction in cravings, although I do have one lady who works at a local chocolate factory here, and I see her pretty often. And she says, you told me my cravings for sweets would be reduced, but they're not. But she is able to eat less and have them less frequently. Many people come into therapy with disordered eating patterns. And so there's great opportunity to talk about, you know, not going too long between meals. The goal here is not to have zero hunger. Hunger is good. That is a cue of our body that we need to listen to hunger and fullness. I've had a lady one day who told me, medication's going great. I can eat half an English muffin for breakfast and then I'm good all day. I said, no, that is not good. We want you to be getting adequate nutrition. So there is a concern about imbalance of caloric intake versus requirements and undernutrition. The ADA standards of care recommend whole food-based eating patterns, so really promoting good quality of those calories that they are taking in. Fluid intake, increase in therapy can reduce feelings of thirst. And so talking about, you know, importance of getting hydration, figuring out strategies of how to increase fluids does not necessarily have to be only water. There can be some flavor in there, you know, milk and yogurt drinks, things like that can also fit. Fiber is incredibly important, especially with some of the GI side effects we'll talk about later and can be really difficult with the reduction in appetite and that slowed gastric emptying. So this is from the Almondose article about nutrition considerations, a great resource. So fluids, two to three liters per day, calories about 1200 to 1500 calories for women, 15 to 1800 for men. And again, that whole food eating pattern, I do feel like, you know, a lot of times the medication makes it easier to follow that whole food pattern. I think of one woman who coming in never ate a vegetable, didn't like them, wasn't part of her plan. Now a year and a half later, she tells me she craves vegetables. So they really can help promote some of those healthier eating patterns. And then fiber, 21 to 25 grams a day for women, 30 to 38 grams a day for men. That's a lot that can be really hard with this. And so a lot of times I am recommending a fiber supplement, especially to help with some of the GI side effects. As far as macronutrient considerations, carbohydrates, we want to promote complex sources. This is not a time for a keto diet. I feel like many people I work with when they're working towards weight loss, that's the first thing they do is cut out the carbs and you really do not need to do that. I don't recommend that with this, especially with diabetes and medications, there could be more of a risk of hypoglycemia if people are doing that. With fat, I'm discussing what a high fat meal looks like and the potential impact that can have on any GI side effects. I've seen more vomiting related to higher fat meal choices than anything. And so explaining what that might look like to someone. And then protein, which is kind of our star child right now. If you are on any social media, you hear about protein and then probably get fed at least 10 cottage cheese recipes. So protein has really come to the forefront. The ADA standards of care recommend about 15 to 20% of calories from protein. So for a 1200 calorie eating plan, that's about 60 grams, 0.8 to 1.5 grams per kilogram. And I've seen it based on body weight or ideal body weight is also part of the recommendation. So that could be 50 to 80 grams for someone's ideal body weight of 120 pounds. So I see a lot more than that recommended by some of these influencers. Protein supplements, I do recommend very often just because they can help when appetite's decreased, not to mention they're a quick and easy meal replacement as you're running out the door. That's an easy thing to bring for breakfast. Or sometimes I see people's appetite decreases throughout the day. So it might be something they have later on in the day. I kind of keep a running list of what people like because I feel like palatability is a big issue there, but looking for something that's at least 20 grams of protein. And then back to the nutrition recommendation. So just the same thing of the protein, carbohydrate, and fat recommendations. I use the ADA plate method a lot just to discuss balance, portion control. With these people maybe are not able to eat that much starchy vegetable, maybe more of a quarter, but at least showing what a plate should look like, what that balanced meal looks like. I also go through specific, what is a specific portion of protein? I had a woman last week who was just shocked when she saw seven grams of protein in one egg. She was like, I thought eggs were way higher in protein. I feel tricked. So really going through, showing them what are the amounts of protein in foods that they may be consuming or maybe some new foods to be including. Micronutrient concerns. I think lab work here is important to be checked. It makes sense that a multivitamin would fit with reduced caloric intake. Looking at bariatric patients, bariatric surgery patients, vitamin B12, iron, vitamin D, and calcium are some common deficiencies with reduced caloric intake. Another good resource is this paper from the Academy of Nutrition and Dietetics discussing increment in therapy and the role of the dietitian. I can't emphasize enough the importance I think that a dietitian can play with these medications as we can assess what is that dietary intake? What are those disordered eating patterns? Screening for eating disorder, maybe they're not appropriate for this therapy and need to have some behavioral intervention first. Talk about expectations for therapy and really dive into the lifestyle that they're experiencing, food intolerances, GI concerns, and none of these things disqualify them from therapy but can really help make a personalized plan. And I think ongoing assessment is really key. And I check in on all of these things, you know, initially once a month, and then we kind of spread it out from there over time, but really diving into what the lifestyle modification piece looks like. Altered body composition, this is not my area of expertise. I will not spend long on this. I will let the other doctors dive more into this, but obesity does lead to an increase in both fat mass and fat-free mass. Weight loss, really of any kind, you're going to experience some fat-free mass. That's normal. There's really no guidelines on what is okay. There's a 2014 guideline that estimates about 25% of total weight loss from fat-free mass. This study on trazepatide versus placebo, I think is really interesting. In both of the groups, there was weight loss, much more in trazepatide. Of that weight that was lost in trazepatide, 74% was fat, 26% was lean. In the placebo group, of the weight that they lost, 75% was fat, 25% was lean. Definitely an area where there needs to be more research and guidelines. What are we looking for? What exactly are the concerns? What should we be monitoring and looking for? If you have ability to do body composition assessment, I think that's great and helpful to track over time. I do not have that ability where I work, so I'm asking more of those questions on energy and how they feel, maybe doing some grip strength, looking at squeezing a ball or getting up and down out of a chair, but definitely an area where more guidance and research is needed. As far as the side effects, GI side effects, very common. I know 72% is a high number, but that could include one day of nausea or one day of a headache. Most common during dose escalation really contribute very little to overall weight loss and less than 10% of discontinuation rates. People are not losing weight because they're vomiting all the time with these medications. That's really not the case. Many side effects can be managed with dietary modifications. This is from the Academy of Nutrition and Dietetics paper, again, that goes through some of those common GI. I really see constipation the most common. That's really what we're talking about the most and navigating. It's really important to build that relationship in talking about these. Many people fear they'll lose the medication if they tell us about their symptoms. A couple years ago, a lady came to see me for training on her continuous glucose monitor. As we're leaving the visit, she says, oh, by the way, yesterday at the ER, I had four days of stool removed. Do you think that's related to my medication? I thought, oh my gosh. I definitely bring it up. I talk about it. I make it normal as part of the visit that we're going to talk about these side effects. There might be other options or some adjustments we can make to get through this. Do talk about specific tips when starting a medication. I wanted to highlight this from the Diabetes Dietetic Practice Group that goes through those common side effects. You can find this for free on our website under patient education handouts. Long-term management, this is a chronic condition. I think we need to have a plan as far as navigating medication breaks or needing to discontinue therapy. Insurance coverage is very sketchy and super frustrating right now. We really need to support those healthful eating patterns with all of the stressors and obstacles that people are facing. This is really where the dietician can shine. We can help participate in that shared decision-making process before starting therapy. Do the nutrition assessment. Provide education and counseling to minimize adverse effects as they're going through treatment and then assist with long-term management of obesity as a chronic condition. In conclusion, Incretin medication is very effective for weight loss and glycemic management. It can be life-changing. The ways I have seen people's life changed has just been really exciting and motivating. Assessment, education, follow-up, client-centered care are really key for preventing nutritional deficiencies and promoting lifestyle change. Just wanted to do a quick shout-out to Dr. Nina Crowley who helped with some of the content development for this presentation. Okay, Stephen, can you just give a sign of life that you can see and see the slide and hear me okay? We all good to proceed? You're good to go, Dan. Yep. Thank you, Stephen. Good evening, everyone. It's 9pm where I am in Perth, Western Australia. Hope you're having a nice day. I thought I'd start with something controversial. I should start by saying thanks to Stephen and to Janice for pulling this together and it's a pleasure to be able to give a talk and thanks to Laura for the introduction. I'm looking forward to Fleming's excellent talk to follow. I thought I'd start with this headline. Lots of headlines around these drugs, but it's bad news, Laura. Looks like diet and exercise are both finished. Doctors might be slow to admit it, but Ozempic and other GLP ones are making dieting and exercise obsolete apparently. So I'm going to put forward some data today. I think it's honestly the truth to say that there's more known unknowns at this point than there are known knowns, but let's have a look. Here's the outline of what I'm going to do in the next 10-15 minutes, which reminds me to start my timer. We'll talk a little bit about increasing therapies and body composition, a little bit more detail than Laura just gave so that's dovetailing nicely. I'll talk about exercise training effects on body composition and in particular a study performed in our lab, which is called the Struth study, which compared different types of exercise training for their impact on body composition and particularly lean mass. I probably won't get to touch on pleiotropic effects of the incretins and of exercise today, but I'm happy to deal with that in questions. I'm going to introduce the idea that we may need a box warning on incretins in future. So here's a logical place to start. Here's the semaglutide study, the step one study from now almost four years ago, and the tazepatide study from about a year later looking at Ozempic and Maljaro respectively. You can see the weeks from randomisation on the x-axis changes from baseline. This is body weight change and you can see that with semaglutide there's about a 17% body weight change, 2.4% in placebo, and with tazepatide at the higher doses of 10 and 15 milligrams, 22.5%, so even more weight loss. Both studies concluded that there was substantial and sustained weight loss as a result of these interventions, which were 68 to 72 weeks long, but you can see that a lot of the impact happens fairly early. What we've learned now that we've done a few studies with tazepatide, it's quite surprising to me that the CEMOUT1 study randomised patients to go on 15 milligrams of tazepatide from the start. This was not dose escalation, this was straight into it, and in our hands at least we've had a decent number of gastrointestinal side effects as you dose escalate, so maybe we'll talk about that in the question time as well. This is really important because not only do these drugs affect body weight, but they also affect hard cardiovascular endpoints and the select trial combined cardiovascular death with non-fatal MI and stroke and showed on top of pretty good patient management and clinical management, medical management of these patients they already had, already pretty well medically managed, there was a 20% survival benefit at 40 years for semaglutide. So there's real benefit of these drugs and in terms of important cardiovascular endpoints. So we summarised this in a review recently. We've got a series of studies here with the early phase increase in GLP1 agonists through semaglutide, more recently dual agonism with tazepatide where GIP was added to GLP1 and now of course we've got the triple agonists coming through and you can see that as time goes by and as these drugs develop you get larger effect sizes, more percentage change in body weight. So pretty spectacular body weight changes from these drugs, but many years ago I learnt as an exercise physiologist that body weight is a problematic outcome measure for interventional studies. So 20 years ago we did some studies in obese adolescents, these kids were 14 years old, their body weight was about 100 kilos, their BMIs were all above 35 and we exposed them to circuit weight training, this was centre-based supervised circuit weight training, just eight weeks long to see what we could do with these patients. We combined aerobic and resistance training in these groups in an intervention which pretty much follows the ACSM guidelines for the type of exercise interventions that we use these days and we were very pleased with the results that we saw anecdotally in the patients who came along. It was really hard to get obese adolescents to exercise at school, but if you put them all together in a gym and they all look alike, they exercise like demons, they were fantastic. Our compliance or adherence with this study was well over 95% for the sessions attended. But we analysed the data and we were very disappointed because in body weight change and in BMI there was obviously no change in the adolescents. That's because when we did the DEXAs we discovered there was substantial change in central abdominal obesity, trunk fat and abdominal fat by DEXA and a corresponding and countervailing increase in lean mass. So of course exercise is an intervention that doesn't do much for body weight but what does body weight matter? Perhaps body composition matters more than body weight. So that brings us back to the increment drugs and to take the example of Tazepatidia from the Surmount study, in our review we tried to back calculate from the data available, there was a supplement available that showed DEXA results in about 160 individuals from this study of about 4,000 people I think it was, and so we were able to sort of do a rough calculation based on that data and some data that they put in the paper itself and the data in the paper was interesting because it showed or reported the ratio of fat mass to in this case lean mass at the beginning of the study and at the end of the study and it was great news because fat mass went down and lean mass went up. So if you're looking at relative changes in those individuals pre and post the intervention it's all good news but we got thinking about it a little more and thought well there's probably a bit more to this so if we look at the absolute changes that we saw in each of those things of course there was a big change 23 kilo drop in body weight on average across those four doses, three, three doses, four doses I think. The change in fat mass was really spectacular in those 160 but there was also a six kilo drop in lean body mass. Now lean body mass is not all muscle, appendicular lean mass might be 70% muscle, total body lean mass might be about 50 or more percent muscle but this is a steak that I use and put on my barbecue in Australia once in a while. This is a 500 gram steak, six kilos of lean mass looks something like that. Does it matter that we're losing even half this much if it's muscle or does it not matter? That is an open question, there's different perspectives on it. Our perspective was to go and look at other interventions where we could detect changes in lean mass and this is the semaglutide impact from step one, this is the semalt one impact on lean mass as a percentage and here's the impact of non-metastatic nasopharyngeal carcinoma, esophageal cancer, rheumatoid arthritis and some other cancers. So certainly it's a large change in lean mass and in other conditions a highly clinically relevant one but others have presented an alternative perspective and for balance I think that's to contemplate. This is a really excellent viewpoint published in Charlotte a little while ago now but it really taught me some lessons and I think it's an excellent thing that you should read. It's a couple of pages long, it's a really good read. It starts out by saying well there may be actually a difference between these classes of drugs or same class really but the monocretins versus the dualcretins in this case in the proportion of fat-free mass versus fat mass that is lost and again if you know your dexers, the dexer machine measures bone mass and fat mass and everything else is lean tissue. So in this case we've got a dichotomy between fat mass and everything else. Dexer will also report fat-free mass subtracted when you subtract bone and that's what they call lean mass. So neither of those things are skeletal muscle mass because that's not detectable via dexer directly but it can be interpreted or inferred or intuited from the changes, particularly in lean mass, particularly if you focus on the appendicular lean mass which I think is something we should do more of. In this study they summarise weight loss interventions and the impact of weight loss intervention on fat mass as a proportion pre and post and again just as we saw with the reportage from the Tazepatide-Sanat-1 study, when you do it this way interventions such as diets that have a large and significant effect on weight loss and increase in interventions both decrease fat mass and relatively speaking increase skeletal muscle mass and their argument which was well made was that obese individuals may start with relatively preserved lean mass and the exception there is psychopenic obesity which is relatively rare. There's a greater relative decrease in fat than muscle which I don't think there's any argument about that. The interventions diet and the creatins decrease harmful intramuscular fat depots and the quality of muscle improves and that's a beneficial and virtuous thing. And the argument is if function and mobility are measured and they improve because of the relatively large change in fat mass even if you've lost some muscle maybe it doesn't matter that much. And so I do think this is still an open question and we're not really sure and it may depend on the characteristics of the individual patients. I think what we can agree on is the optimal midlife preventative health intervention is one that probably decreases fat mass if possible maintains or increases lean mass if that's possible and enhances physical and cardiovascular function. So let's look at different exercise interventions and their impacts and their potential impact. We've had an interest for a long time in comparing dichotomized forms of exercise. We come from a cardiac physiology background where resistance and endurance training have very distinct and different loading impacts on the ventricle and have different impacts on left ventricular muscle mass. So we know that different forms and exposures to different types of stress in terms of exercise triggers a whole different set of gene adaptations and upregulation of different protein groups. So they're different interventions and all exercise is not the same. In a study that we designed to have a look at this we recruited monozygotic and diazygotic twin pairs. We were interested in the heritability of change in body composition and other things. We called this study the STRESS study that stands for Study of Twin Responses to Understand Exercise as a Therapy. It was undertaken by two terrific PhD students, Hannah and Thomas and Shannon Marsh. The design was three months of intervention. The twins were randomized together as a pair and exercised at the same intensity of exercise. Randomized to endurance training or resistance training. So this was, there was no control group here, it was a comparator study. Three months, repeated measurements, wash out for three months, come back, another set of measurements and crossover. So everyone has their own control in this experiment. We got within subjects comparisons of the effects of endurance and resistance training. So that's quite rare. And we were also able to tell whether the adaptations were very similar in monozygotic twins or more similar in monozygotic twins and diazygotic twins. I won't get time to talk about that much today. Here's the results. This is the fat mass change. These are individual data points plotted in the waterfalls on the right. Here's the mean and standard deviation data on the left. Both groups we saw decreases in fat mass, significant decreases. There was a slightly larger impact of endurance training and more endurance. These are the same individuals in both waterfalls. More of them responded to endurance training than resistance training, but both interventions could be said to be having some beneficial effect on total fat mass. Here's the lean mass data. It was about a threefold larger impact on total body lean mass of the resistance training intervention relative to the endurance training intervention. And a lot more individuals responded positively in terms of change in lean mass to the resistance training intervention. When we looked at muscle strength, this is maximal muscle strength in this case of the leg press, but this is pretty typical of a range of strength measures that we took. There was 100% of individuals increased their strength. So there's actually some people who didn't increase their lean mass. There's no sign of hypertrophy or signal for that, but strength improved. So there's neuromuscular adaptations that find a strength benefit as well as hypertrophy benefits in muscle. That's worth keeping in mind in the context of ageing and frailty. When we tried to work out what the moderators were, and this is a narrative review, it wasn't a structured meta-analysis, but to our reading of the literature that's out there at the moment, resistance training has larger impacts on lean mass, this is total body lean mass change, than combined aerobic and resistance training. And both of those things, including any resistance training, has a bigger impact than just doing endurance exercise. There's a differential effect in the literature between males with age. The older you get, it seems that the harder it is to modify this. We've done some work with testosterone supplementation in older men with some positive findings there that may modify that upwards a little bit. And there's data in the literature that suggests that there's a sex difference, which may relate to testosterone or, if I'm being honest, may relate to the fact that there's a lot of data in the literature focused on males and far less focused on female effects of resistance training. That's a problem in the literature and exercise science generally. What about deprescribing? This is data from a more recent experiment. This is SEMAD4 data where treatment went out to 36 weeks and then half of the individuals were put back on a placebo and half were maintained onto Zepatide. You can see from 36 weeks onwards, there was a little bit more weight loss, a spectacular drop in body weight here. But the placebo group who went off the drug rebounded by about two thirds. So there's some interesting takeouts from this. One is that about two thirds of weight is regained if you come off a drug and that shouldn't surprise anyone who's been doing diet studies over the years. This was the conclusion from the study. Results emphasised the need to continue pharmacotherapy to prevent regain. Obesity is a chronic condition similar to type 2 diabetes and requires long-term therapy. I think that's an interesting conclusion. A lot of people who are taking these drugs, I think, are looking for a midlife, sharp, short-term reset and not necessarily looking at these drugs as lifelong therapy. So there's some implications to this. I'm just going to, probably because of time, move on to a study that we've designed and that we're undertaking in birth at the moment, which is called the T-REX study. It's a Zepatide and resistance training where we're randomising individuals to either the drug, dose escalated over a 40-week period, or the drug plus resistance exercise training. Our major takeouts are body composition, outcomes from DEXA with strength, vascular, ultrasound measures for vascular health, echocardiography measures of heart, three-dimensional and cardiac mechanics, cardiovascular fitness, metabolic function, blood pressure, and lipid levels. So this is an ongoing study. It's an investigator-initiated trial. We're grateful to Lilly for providing the drug, which they were good enough to support us with. Here's the design of the study. We're doing DXA scans every eight weeks or so during the dose-ranging period. You can see that the dose goes up every four weeks by 2.5 milligrams until you get to the dose of 15. Not everyone escalates all the way, it should be said. Not everyone makes it. You have to make it to at least 5 milligrams to stay in the study. We have strength measures, blood pressure measures, urine, vascular, echocardiography, VO2 max, and physical activity and diet monitoring studies underway. So to summarize, I'd say the optimal midlife preventative intervention to help benefit would decrease fat loss, maintaining or increasing lean mass, and cardiovascular function. Increases have profound impacts on fat mass, but also decrease lean and muscle mass. They may decrease those things by different amounts if the drugs don't seem to have the same effect. Resistance training has larger impacts than other exercise modalities on lean mass and strength, and similar impacts on fat mass. Resistance training may increase fat loss, reduce fat regain, and assist with deprescribing. That's something we can discuss in the question time, if you like. And I'd like to say that I think maybe we're heading towards a new paradigm, far from throwing exercise and diet in the bin around these drugs. I think there's a new rationale for the importance of those things as concurrent therapy. A new paradigm might be that we should be focusing on muscle gain a lot more than we think about even fat loss. My take out is that I think these drugs may in the future should come perhaps with a box warning, which says must be prescribed with resistance exercise. And I think I'll leave it there. Thank you, Stephen. Thank you for the invitation. I'll share my slide here. I hope you can see it. And my name is Flemming Dela. I'm speaking from University of Copenhagen, which is in Denmark, the kingdom of Denmark, which currently includes Greenland, by the way, but this is not the topic here. I will be talking about the interaction of combining exercise with the somatolocyte on the glucose homeostasis, and particularly the glucose-induced insulin secretion. And I'll talk a little bit as a follow-up on Danny's talk on the importance of adding exercise when you prescribe these drugs. So first of all, the key message is that I will focus on the importance of physical training during the treatment with these drugs. I will show that we have an enhanced secretory capacity of insulin when you combine GLP-1 receptor agonist and training, and you also have an improved insulin sensitivity. So for a start here, I'll use this old figure, which is still valid, I would believe, from DeFranco many years ago. If you look at the bottom, you'll see when you go from a healthy condition to type 2 diabetes, what you see in the blood is that during an OGTT, the mean glucose levels would increase as you progress in the disease here. At the same time, actually, what you see is a decrease in insulin sensitivity as you go from healthy towards slightly unhealthy, towards overt type 2 diabetes. You will also see an increase, a compensatory increase in the insulin secretion. This is quite normal. These two balance each other, so you will maintain a normal glycemic level. But as insulin sensitivity decreases, and there are many reasons for that, you'll see a progressive increase in the insulin secretion capacity and the response to an old glucose load, for example. And if you further progress into the diabetes, you will have a low insulin sensitivity, more or less as low as it can get. But at some point, you'll see a decrease in the capacity to produce insulin, which will result in a continuous increase in the glycemic level. This is a little bit simplified version, but it's good for understanding the interaction between insulin secretion and insulin sensitivity. So, on the other hand, when you go from type 2 diabetes, which is, I think could be debated, a chronic disease or not, you will actually see the opposite thing. When you improve your diabetes, and you may even go into pre-diabetes or healthy condition, the glycemic level will decrease as a result of a continuous increase in the insulin sensitivity. And you will probably also see a regain of the insulin secretory response. And this has been shown in several studies. And in type 2 diabetes with obesity, you'll see that we have an increase in insulin secretory response. When you actually do aerobic training, improving your diabetes condition, so you will move upwards this way. Some of these studies included dietary interventions, which makes it a little bit difficult to talk about what is the effect of training and what's the effect of diet. But when you look at the healthy ones over here, there's actually no doubt that when you go from here and you increase your daily physical activity, you will move this way, which will mean that your insulin sensitivity will go up and your insulin secretion will go down, which is shown many, many times over the years. This is in the healthy ones shown here. The insulin secretion capacity goes down in the healthy ones and obese. But once you are diabetic with obesity, you have the opposite response. Your insulin secretion will actually increase. Now, when you combine training with GLP-1 receptor agonists, you will see that, I'll just show a few studies. They work in a synergistic way to improve glucose homeostasis. And in this study, they only focused or primarily focused on long-term glycemic level. And it, of course, induces a weight loss in obese people as shown before. And it is further enhanced if you add training to that. But the effects on the beta cell secretory function are actually unknown. So what happens when you combine training, which is supposedly will mean that you increase your insulin secretion if you're a diabetic. If you combine that with GLP-1 receptor agonist treatment, which will also have the same effect, do they work in concert or will they actually nullify each other or what will happen? This was what we studied in this study published a few years ago. We had about 30 people entering into the study. They were randomized into either semaglutide and training or training alone. And the patients who were randomized this way started out with clamps, a hyperglycemic clamp at a 20 and a 30 millimolar level. That's quite high. And we'd also did some exercise testing and OGGTs shown by one and two here. Then they started escalating on the treatment until they reached the therapeutic level. And that was for 20 weeks. And then we did it again. So we had a measurement point for semaglutide alone. The training guys, they did not receive anything. They were primarily on metformin, but started directly on training, first with the clamps and other experiments, training for 12 weeks, and then the experiments again. The semaglutide patients, then when they finished the 20 weeks, then they started training at the same relative intensity as the training group. And so we had after 12 weeks, the combined effect of semaglutide and training. And again, measurements of here, I will focus on the insulin secretory capacity and a little bit on the insulin sensitivity. Now, just a few basic characteristics in the two groups, the training group and the group that started with semaglutide and then continued with training. You see that they were in the late 50s. They had diabetes for four to five years. They weighed about 112 kilos. They were obese, no doubt. We had a lean mass, which was similar in the two. Visceral fat was also similar, body fat percentage similar, more or less the same glycemic level. And they had a capacity to produce insulin shown here with this value, which is the C-peptide concentration six minutes after one milligram of glucagon. If they do not have an insulin secretory capacity left, it will be difficult to see an improvement. So it should be patients who are at a diabetes duration of around four, five, six years or so, but probably not eight to 10 years because then the insulin secretion capacity is probably too low, but that hasn't been tested. And finally, they were definitely not well-trained as you can see on the VO2 maxes. Now, this is the body composition. First of all, in panel A, you look at the body weight and this is changed in kilograms. It was a little more than six, about seven kilos they lost with the semaglutide alone. And when they continued with training, they in addition lost two kilos of body weight. And the training people who trained alone only lost about one kilo. But as we learned just recently in the previous talk, it's important to look at the fat mass and the lean mass. If you look at the fat mass again, around five kilos were lost and in addition, two kilos were lost when they added training and training alone gave more or less the same two to three kilos. But the important part here is the lean mass. And you'll see that they lost not a lot, but still significantly a lot, two kilos of lean mass, which is predominantly muscle. And when they then continued in the training program, the blue one, you'll see that the loss was reverted to a slight increase actually, and the training, a slight increase again. So this underlines the talk from just previously by Danny. It is important to combine exercise training. It could be, in this case, it was aerobic training. Had we used resistance trainings, it would probably have been a little bit more pronounced effects on the lean mass. But you have to prescribe both the drug and the exercise. Glucose homeostasis alone, just briefly, massive effect on Hb1c, continuously a drop when you add training. And when you just do exercise training in aerobic fashion, you also see a decrease. This is more or less well-known. Now, the next slide here is quite busy. It's divided in A and B, and let me start with B here. These are the patients measured before training and after training, so no semaglutide. Here we have the glucose level. It increased up to 20 millimolar for 120 minutes. We kept them there, and then we added more glucose, and we brought them up to something like 30 millimolar. Notice that the glycemic level are similar in the two groups. What is shown here is the glucose infusion rate. It's shown on the right axis here. It was very high in the beginning because you have to bring them up to 20 millimolar, and then this stabilizes, and you'll see actually that the red after training was a little bit higher here and even more pronounced at the 30 millimolar glycemic level, higher after training than before training, indicating an increased insulin sensitivity. This is not the proper way to measure insulin sensitivity because this is a hyperglycemic clamp, and it also includes the glucose-mediated glucose uptake, but nevertheless, it is definitely an indication of increased insulin sensitivity. The panel A is a little bit more busy. We have baseline, then only semaglutide, and then semaglutide and training. Again, glycemic level around 20 and 30, and now you see huge differences in the glucose infusion rate. Some of the differences, of course, also due to the differences in the prevailing insulin, but still you'll see an indication of increased insulin action due to this training. Now, the major point here and the major outcome is this graph. If you look at, we start again with the effect of training alone, we have 20 millimolars of glucose followed by 30 millimolars of glucose for 120 minutes and 120 minutes again, and here we measure insulin. The glucose is the same, but insulin response to the same glucose is much higher after training than before, and it's more pronounced at the highest level of 30 millimolar. A lot more insulin is produced after training than before. Now, if you compare this one with this one, please note the difference in scale here between the two. It's because the effect of semaglutide is enormous, I would say. Before at baseline, before anything you have around this increase in insulin when you increase the glucose level to 20 and 30, but if you do it in the green one where they've been treated for 20 weeks with semaglutide, you see a massive increase in the capacity to produce insulin, and even more here. And the major point here is actually that the blue one, which is the combined training and semaglutide, is significantly higher than the green one. So we have actually a synergistic effect. One potentiates the other. So there is definitely a massive effect on the beta cell. If we just compare and compare the training alone with the semaglutide and training alone, here we show it as the delta value of the increment of the area under the curve in the 20 millimolar and in the 30 and in the total. And if you just take total for the course of time, you'll see a massive effect of semaglutide alone on the insulin secretion capacity. So there is the following conclusions. Aerobic training increases insulin secretory capacity in type 2 diabetes with those patients who have a moderately preserved beta cell function. The combination have a synergistic effect in improving the glucose-stimulated insulin secretion. And training along with GLP-1 receptor agonist prevents the loss of lean mass. So this is the basic and the most important findings from this study. And the major question in my mind here is how does the beta cell know that it sits in a trained body? That we still need to figure out how to resolve. Thank you. Thank you, everyone, for those wonderful talks. Really appreciate the insights you all have given. We have a few minutes left. And there are a few questions in the Q&A box that I thought we might be able to tackle a bit. One of them relates back, Laura, I think a little bit to your talk regarding dietary protein and recommendations. Do you have any other practical pieces that you can provide instead of more the classic 0.8 grams per kilo? Is there something else that patients could be provided? Or as the question's asking, do you simply do the math with them and tell them that number? I honestly usually say try to get 20 to 30 grams per meal. And then say, palm of my hand is about 20 grams of protein of the piece of chicken, and kind of give them that guidance. I don't normally give a specific number unless they really ask for it. That's really nice, a simpler model of just really hitting sort of a set number. In that regard, perhaps, Fleming, something you had brought up is somewhat the controversy around diabetes being a chronic disease versus maybe not. I know that's a big kind of can of worms, so to speak. But maybe could you just elaborate briefly on what are you thinking with that kind of comment? My thinking is that it's reversible. And given the right therapy, and which in my mind, at least in the beginning of the disease, when you diagnose the patient, and in the first few years, you can actually reverse it. If they lose weight, and particularly if they increase their daily physical activity, they don't necessarily have to have the diagnosis of diabetes, i.e. an HB1C above a certain level. I think it's reversible. Maybe not if they've had it for 10 to 15 years. Sure, appreciate that comment about reversibility and sort of tying in then lifestyle as perhaps a modulator versus the disease itself. Thanks for that clarification. Danny, you had mentioned the T-Rex program. So this is a little bit of a two-part question where I'm combining some thoughts here from the audience. But on some levels, what would the recommended resistance training and say aerobic training prescription be in your mind? And does that parallel maybe some of the American College of Sports Medicine recommendations? With then the thought being in the T-Rex, do you fear that that training dose you provide is too hard for people? And do you think some other considerations should be had? Thanks, thanks, Stephen. And thanks, Michael, I think for the question. So two questions, two answers. The first answer is that I think in our review, you'll find data where we had a look at the three different, we characterized interventions in the three, broadly three types. Aerobic interventions like the one Fleming used, combined interventions, which are a bit like the ACSM guideline where you've got some aerobic sessions a week and some resistance training sessions a week. Complicated there because some people do combined sessions versus some people do different types of sessions on different days. And that may make a difference. And then the third group was resistance training, which is a pure focus on driving skeletal muscle hypertrophy. So the answer to the question was, in terms of lean mass, resistance training wins. Combined aerobic and resistance training comes second. And then a fair way behind that for lean mass is aerobic training. We still don't know a lot about males and females in that context. And we know even less about premenopausal and postmenopausal things. So there's a lot that we don't know. These studies are hard to do. They're labor intensive and expensive and they don't get funded by pharma very often. T-Rex was an attempt to really just drive the skeletal muscle side of things. And so we made a deliberate decision just to focus on resistance training. In terms of the toleration of that, we've now had three quarters of the subjects have been randomized. We've had three dropouts out of 90 individuals that they were all for gastrointestinal symptoms. And they all evolved at the moderate to high dose of Tazepatide, which has been escalated. No one's dropped out from an exercise training problem. It's center-based and supervised training. So we know exactly the dose that we're administering in terms of the training. And we're driving hypertrophy type training. So it's heavy resistance training. After a period of time, it's periodized. But exercise physiologists get into a lot of detail here. But that was the idea behind the trial. And the answer to your question is, these are 50 to 70 year old, overweight, mostly obese males and females who have a long history of no exercise. They had to be essentially sedentary to make it into the trial. And we've followed them up for 40 weeks of the intervention with no real, well, we haven't had a single dropout or sign of it from the training itself. People like the training. People don't, people love Tazepatide. I would say until about 36 weeks. And then they don't like it so much. I'm probably a bit concerned. We've had individuals lose 38 kilos body weight to 40 kilos. In someone who starts at 100 kilos, that's a very substantial change in body weight. We'll know what that fat and lean proportion are because no one's really done a DEXA study like this repeatedly. And we'll know when they lose the weight because we're doing it every eight weeks. So what's rapidly lost, what's lost later. And we're doing a follow-up after the Tazepatide stops and the training stops to see what happens for remount. A very important question here to whether resistance training can help people de-prescribing on the drug, which is what people want actually. No, that's really insightful. And what I appreciate about your answer is we don't really know the right recommendations right now in the context of the drugs and further studies are needed. But likely, as I'm getting a lot of your training was rooted in these ideas of the American College of Sports Medicine. And even the higher the intensity that was provided, it's personalized. So for each individual, they're getting an aspect of training relative to their own bodies versus what might be perceived as being too hard or high intensity for this person. It's all relative to them. So that's really impactful. Just because of time, I appreciate we're on the hour, but in consideration of our audience, there was two other questions, which maybe some brief thought would be related to anybody here, but maybe Laura, if you wanted to kickstart this, is carb reduction, the topic of reducing carbohydrate intake. Is that necessarily bad for patients trying to lose weight even on these GLP-1 agonists? Do you have any thoughts on that? Or is this something that should be considered in the lean protein intake context, anything related to GI upset? So any thoughts, Laura, on that? Yeah, and I definitely encourage them to eat the protein and the vegetables first and save the carbs last. So not promoting a carb-heavy eating pattern by any means, definitely focusing on the protein and the fiber, but it's just not necessary to do like a keto type of diet. They don't need to cut out all carbohydrates. And yes, sometimes carbohydrate can help with some of those GI side effects and calm some of those. Thank you. And just the last question here, we didn't get too much into this, but from the general knowledge of the group here, and maybe Fleming, I might pick on you a bit given you're our licensed MD, but the thought here is related to the cardiovascular benefits of Inkerton therapy. Is it dose-dependent to your knowledge? I don't know whether it's dose-dependent and I don't know whether it's independent of the weight loss, which I actually think is the most interesting question, but maybe Danny knows more about this. I do take an interest in this because we're looking at some subtle other measures like direct effects on vascular function in our study and also cardiac mechanics. And there's quite a lot of anecdotal or supportive evidence that there may be pleiotropic effects of those drugs. In a select trial, the benefits for a cardiovascular endpoint started to emerge very early in that trial before the dose was really escalated to a point where there was a very large change in body weight and there's been quite a lot of speculation around that a lot of the effects of these drugs are on other organ systems or on subtle other mechanisms that are not related directly to the weight loss per se. And I mean, Fleming's terrific talk gives us an insight into that for one organ, but there's already data out there on PEF, heart failure with preserved ejection fraction where cardiac mass is changed in those patients. There's some animal study on vascular function in the field cell function. The receptors for GLP-1 are very broadly dispersed. And I think we know everything about what they do yet, but there's certainly a lot of things. Thank you for that insight. Appreciating everyone's time. I again, like to thank all of our speakers for these insightful talks. As mentioned to everybody, these recordings will be released in the upcoming days. So stay tuned for that. But again, thank you everybody for a wonderful time and I wish you all well in your respective time zones. So sleep for some, a long day of work for others and take care. Appreciate it very much. Thank you. Thank you, sir. Yeah. Bye-bye. Bye, see you, Fleming. Bye, Danny.

GLP-1 agonists

lifestyle modifications

diabetes management

obesity management

insulin secretion

exercise physiology

semaglutide

body composition

resistance training

nutrition

incretin therapy