The Science of Metabolic Flexibility, Zone 2, and Reversing Diabetes | A Masterclass

0:08I tested once in the laboratory an 81-year-old gentleman who was world champion, cycling world champion of the 80 to 85-year-old bracket, which believe me, it exists, right? Which is great to see. So anyways, I was fascinated because his metabolism, his metabolic efficiency during the test that I do was that of someone in their 30s or 40s, healthy and active. It was unbelievable. I keep that test like a treasure because it's an absolute treasure to see those adaptations. right so anyways I right away I thought boy you've been doing sports all your life right so man you chose the right lifestyle right and he told me actually no actually until I was uh in the early 50s I was obese I was hypertensive I used to smoke uh I had a very poor lifestyle I didn't exercise at all and one day I started to ride and bike and think about life and things like that and ever since then so uh to your point like you said right this was an individual the early 50s uh sedentary very poor uh healthy lifestyle and then boom you know 30 years later at 81 years old his metabolic health was some of that of someone in their 30s who's healthy that's unbelievable hard to believe in and this is how that that person obviously 81 year old that's an example of what exercise can do for your longevity, right?

1:49That person was not on any medication.

1:57What is your definition of metabolic health and why should the listener care about this? Yeah, that's a good question. And I think this is something that we're understanding more and more, right? As you know, and many people know, right? The traditional definition of metabolic health is a compendium of the multiple parameters like your lipid profile, your blood pressure levels, your glucose levels, right? And your body max index or at least your waist ratio. So circumference, sorry. But as we know more about the adaptations or what happens at the cellular level, right? We are getting to an inflection point in the field of medicine where metabolism has gone from being the poor brother to being the crown prince.

2:56I mean, you look at the curriculum of medical schools, even still today, they barely have any courses or notions of metabolism at the cellular level. while at the research level, the advances have been immense that we can already use to help people as well as to understand diseases at a level that we have never been, right? So this is why metabolic health implies more mitochondrial function, implies also more fitness, implies longevity, right? So people nowadays are not happy just to have good cholesterol levels or good blood pressure or good A1C or glucose levels. People want to be fitter, want to live longer, not necessarily in the amounts of years, because we all want more, but to live better and want to be healthier.

4:02So all this, I would put it in the new basket, if you will, of metabolic health. A lot of your work seems to focus on how efficiently we can take the, I guess, potential energy in food, be it carbohydrates or fat, and turn that from a chemical energy into a mechanical energy, contract the muscle and move the skeleton. Do you also consider sort of fuel partitioning? I'm interested in some of Professor Roy Taylor's work. I'm not sure if you're familiar with him and his work looking at type 2 diabetes and this concept of personal fat threshold being sort of integral to metabolic health in that once we kind of spill over or store fat beyond our subcutaneous fat, capability.

5:00It starts to get in between and within organs. And that seems to also be a sort of key component of metabolic health. Yeah, absolutely. There's no doubt about it. That's a big component. Abdominal fat is highly associated with cardiometabolic disease. And also, there's more and more research. One of the leading researchers is my colleague here at University of Colorado, Dr. Brian Bergman, with his research in intramuscular fat, which is highly, and others, right? They have been doing extensive research on this, linking that intramuscular fat with insulin resistance and type 2 diabetes as well.

5:48So yeah, definitely fat. The connection between fat and metabolic diseases is there for sure.

6:00How much of the sort of cardiometabolic disease burden that we see today do you feel is explained by sedentary lifestyles and a lack of specific cardiovascular training versus other things like nutrition, which you just mentioned. Yeah, so I'm going to wear my cell physiology background, right, and try to see this from a decrease in mitochondrial function or a decay in the mitochondrial function. So mitochondria, you know, is, as we know, the powerhouse of the cells. And this is how we have been learning about that for decades, right? However, not until recently, relatively speaking, we've been very interested in mitochondrial function.

6:57And now what we see is like pretty much no matter which medical field you get into, and you talk to leading researchers in multiple medical fields, everybody's stumbled upon mitochondria, right? And mitochondrial function. Now, when it comes to cardiometabolic disease, there are two main events that happen when it comes to nutrition. One is the metabolization of carbohydrates and fats. So during postprandial conditions after a meal, about 80 % of all carbohydrates are burned or metabolized in skeletal muscle, right? And it's time to really call skeletal muscle an organ. It's probably the largest organ in the body.

7:47And it's very important to see this because within skeletal muscle at rest, carbohydrates, which are turning to glucose in the blood, no matter what type of carbohydrate you have, whether it's good or bad carbohydrates, they're all going to become glucose in the blood, like fructose. most of the fructose that you ingest is converted by the liver into glucose, right? So all that has to be metabolized and under resting conditions, about 80 % are done in skeletal muscle. And within skeletal muscle, this happens in mitochondria. So if you have a dysfunctional mitochondria or a mitochondrial that is impaired, you're going to have a metabolic challenge because you're going to have to burn that glucose.

8:41And if you don't do it correctly, eventually you're going to have a problem because that glucose is going to be building up in the blood, causing hyperglycemia, high glucose levels. And the pancreas reacts to that because it's dangerous to have high glucose levels. And the pancreas reacts by releasing insulin. And insulin triggers the transportation of glucose inside the cell. But it's not just about the transfer of glucose inside the cell, which is what we've been hearing for decades, right? The world of type 2 diabetes has been evolved more at peripheral level, if you will, at the level of hyperglycemia, insulinemia, or hyperinsulinemia, insulin resistance, even GLUT4, which are the transporters of glucose that are stimulated by insulin, right?

9:36But we need to start talking about pyruvate and about the fate of glucose inside the cell because this is absolutely key because one thing is to transport glucose inside the cell and the other thing is to metabolize glucose to ATP and energy in mitochondria inside the cell, right? So this is the key aspect. So there's two sort of critical things here we're talking about with regards to glucose and metabolic health. One is the ability to get glucose from circulation into the muscle cell. And you sort of alluded to the fact that that's been the story for a long time. And earlier you spoke about intramuscular fat.

10:23And so to my understanding, part of that story has been that as fat starts to accumulate in muscle tissue, it can make it harder to get glucose into the cell. But what you're adding and saying is that the story of metabolic health and glucose metabolism and the difference between someone with poor metabolic health and an elite athlete goes beyond that. And we need to begin thinking about once that glucose is within the cell, how it is being metabolized which i believe from from from your work and and it's something that we're going to discuss comes down to the function and health of the mitochondria exactly and and and then the problem is like if you don't metabolize that glucose in mitochondria inside the cell within mitochondria then you have a metabolic challenge right and eventually yeah you're going to increase or you're going to elicit a condition of hyperglycemia, hyperinsulinemia, eventually insulin resistance.

11:28But the same thing happens also, or the same metabolic problem happens with fats because fats can only be oxidized in mitochondria as well, right? So when fats cannot be oxidized in mitochondria, they build up, right? You cannot utilize them as energy, so you store them in adipose tissue, but you also store them just into mitochondria in the muscle. And that eventually increases their reservoir or the deposits of fat inside muscle, which is, again, as I said at the beginning, is highly related to insulin resistance. And that could be a connection between cardiovascular disease and type 2 diabetes.

12:13We know that about 80 % of, not 80%, I don't want to say a percentage yet because we still have to learn more, but a big number of people with type 2 diabetes, they also have cardiovascular disease and vice versa. And this is what's been now termed more like a cardiometabolic disease, right? Because it's the combination of both diseases, right? So this is what probably a big nexus for this is, it happens in mitochondria. If you've been listening to me or some of my guests talk about the gut microbiome, you'll know that it thrives on very specific types of fiber and polyphenols and resistant starch, many of which the average person falls short on, despite the very best of intentions.

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13:50Another term I want to define here, Inigo, at the outset that is thrown out a lot is metabolic flexibility. What does metabolic flexibility actually mean? Yeah, so the term metabolic flexibility, it's not a new term. We are starting to use it more, right? But it's a term that was coined over 25 years ago by Kelly and Mandarino, as well as Good Pastor. and even before that in the late 1700s it was thanks to the work of Lavoisier who started to look into aerobic metabolism and so he started everything related to cellular respiration but the term metabolic flexibility in a very simple way is the ability of humans to burn fat and carbohydrates and to switch back and forth.

14:55So when there is a carbohydrate availability, like elite athletes, for example, or fit individuals, they can use them very rapidly for energy purposes, and they metabolize it very rapidly. When there is not much carbohydrate availability, then you switch very well and very efficiently to utilize fatty acids for energy purposes. Or when you're fed fatty acids, you can metabolize them very well, right? And all that happens in mitochondria or most of that happens in mitochondria. At rest, everything happens in mitochondria. During exercise, it can happen in the cytosol. So it's inside the cell bedline mitochondria, right?

15:39Because you can use it through the aerobic glycolysis. But during rest, under resting conditions, yeah, everything happens in mitochondria. So that's, again, it's at the epicenter of metabolic flexibility. So people who are metabolically inflexible, there are people who cannot metabolize fatty acids or glucose properly, right? And therefore, yeah, as we mentioned earlier, it's going to pose a metabolic challenge because you can increase glucose levels on one hand has also increased the fat deposits in the muscles as well as then in the adipose tissue what does hepatic fat oxidation mean if someone's hearing that for the first time so the fancy it is the fancy way of saying the the the utilization of fat in the liver so that's actually something we we really should uh kind of highlight when fatty acids present to the liver there are typically two primary fates so to speak one is esterification and the other is known as beta-oxidation or oxidation.

17:01So explain essentially what both of those really entail. Esterification is the fancy term for the creation of new triglycerides, three fatty acids bound together with the glycerol backbone, the primary form of fat in the circulation other than free fatty acids. And of course, the primary form that we consume fat through our diets in. So esterification, listeners should think that's the process of creating new fat in the liver. Of course, that's going to be important to this retention and accumulation of fat in the liver. And then beta oxidation is essentially the pathway of producing energy from fats in our diet.

17:49what we would colloquially term as burning fat, so to speak. And so within that pathway, you're talking about the actual utilization, the processing of fatty acids down the pathway of oxidation is to say that those fatty acids are being utilized in the production of energy. And as a result, they're not being stored. So when we use the term hepatic fat oxidation, we're talking about the actual utilization of fatty acids for the production of energy in the liver, which means they're not as a corollary being stored in the liver. And we know from stabilized isotope tracer studies that there is a sex difference in the ability to oxidize, to utilize fatty acids um and that the liver's ability to do that is greater in women compared to men whereas men typically have a lower rate of utilization of fatty acids or oxidation of fatty acids um and potentially then obviously then have a a greater partitioning of fatty acids into the other pathway, which is esterification and storage within the liver, which leads to this increase in the production of triglycerides and triglycerides in VLDL.

19:31I want to go back a little bit to before your ultra-processed food study. If I recall correctly, I mean, the earlier part of your career, you're very well known for conducting these studies that that kind of pitted carbohydrates up against fat. And I guess there was all sorts of hypotheses at the time around, is a calorie, a carbohydrate's uniquely fattening, is fat uniquely fattening? And you ran all these experiments and neither turned out to be a clear driver. Would you say that it's case closed today on the idea that carbohydrates or fat are uniquely fattening, uniquely a problem? No, I don't think the case is ever closed, really.

20:22But I also think that, you know, the different studies had different contexts, which I think are important to kind of unpack, right? So again, I came into this field from a very different place, right? I was trying to build computer simulation models of how the body adapted to different fuels, and in the diet and within the body and where we kind of get our fuels from when we're not eating and how that changes when we are eating and those types of things. And I heard about this kind of phrase of a calorie is a calorie. And I didn't really know where it came from at the time. It's like, what do you mean by that?

20:55Number one, of course, I mean, you just repeated the same word and put an is in the middle. It's like, how is this insightful? Right. And the challenge that I was having was, you know, I'm trying to build this computer simulation model where you have this input of nutrients, carbohydrate, fat, and protein. Your body's built of those nutrients, along with some water and minerals. And how is it that when we change the proportion of the nutrients coming into the body that the thing just doesn't break apart, right? I mean, I can't just, I can't kind of pull up my diesel automobile to a fuel station and put regular gasoline in the fuel tank and expect it to work properly, right?

21:36But for whatever reason, we seem to have this remarkable ability to fuel ourselves on a wide array of mixtures of carbohydrate, fat, and protein. And what's the underlying physiology that allows that to happen? So the idea that the body treated all calories in terms of carbs, fat, and protein as equivalent was, it's patently false, right? It's just not true, right? I mean, there are internal responses to carbs are very different than they are for fat and they're very different than they are for protein. And we walk through some of that physiology in our book, but it's classic physiology that goes back to the beginning of the 20th century.

22:15But prior to that, I found out where this concept of a calorie is a calorie came from. And it was this really brilliant scientist named Max Rubner from Germany who noticed something very interesting in a kind of a mystery that his mentors had, which was they were doing these experiments in dogs where they would take a dog and they would try to measure how the rate of fat, body fat loss of a dog when it was starving. You're not giving it any food at all and you can measure how much fat it's losing. And they asked the question, okay, well, what happens when you feed the dog different kinds of nutrients?

22:53Like what happens if you feed a dog sugar? And lo and behold, you feed a dog different amounts of sugar and the rate of fat loss will change. It'll be slowed down as compared to feeding it nothing at all. And you can do the same thing with fat, right? So lard. You can give the dog different amounts of lard and you can slow down fat. And the conundrum was that you had to give twice as much sugar as lard to slow the body fat loss to the same amount, a little bit more than twice as much. And so why? Why is it so much different per gram of sugar than per gram of fat to keep the dog's fat mass from going down at the same rate?

23:33And what Rubner did was something really interesting. He took the sugar and took the fat and tried to figure out how many calories, how much heat energy are in these two things. And what he found was that it precisely matched the ratio per gram as the amount of sugar and fat that would prevent the body fat loss to the same extent in the dog. And so he was the one who came up with what he called his isodynamic law, that it wasn't the mass of the sugar and the mass of the fat that mattered for slowing body fat loss. It was the calories of sugar and the calories of fat that mattered when it came to body fat loss.

24:13Now, he had no idea what was going on inside the body to make that seeming equivalency of calories for body fat changes. We learned about insulin only after it was discovered in 1920s in Toronto by Banting and Best and McLeod. And we started to understand and unpack the remarkable hormonal changes that take place inside the body that shuttle these nutrients from different organs in their storage form. And in such a way, they do it in a remarkable way so that the fuels that are being selected to burn are such that what's left over ends up either as fat inside fat tissue or being removed as fat from inside fat tissue, almost independent of how much of that came from carbs or fat or protein.

25:02And that's amazing to me, right? So that was like, okay, now can I model that in a computer? And is it perfect? Like, is this a, did evolution devise this so that it's a perfect system? And what we, what I kind of came to the conclusion was that, you know, you could actually engineer a diet where there could be really tiny differences and maybe a calorie isn't exactly a calorie. And that led me to the first study that, that we ever did, which was based on a computer simulation model prediction, which was that if I cut the same number of calories from a diet that was weight maintenance sort of diet to keep people's body fat constant, if I cut 30 % of calories from carbs versus cutting 30 % of calories just from fat, the prediction of the model was that the reduction in fat would lead to just a tiny bit more body fat loss than the same number of calories coming from carbs.

25:57And the only way we would be able to measure this is if we put people in these respiratory chambers and measured on a daily basis how much fat they were burning and how much fat they were taking in. And so that was the first study that we published. And it was happening at a time when there was this resurgence in low-carb diets that were getting to be extremely popular. Gary Taubes had published his book, Good Calories, Bad Calories. And it was a New York Times best seller. And everybody was talking about restricting carbs. And so here we came along and we had this computer simulation and this result, which showed actually, you know what, over this really small period of time, all these major hormonal changes are going on inside the body.

26:40And a calorie is almost a calorie, but at least in this particular circumstance, a little bit more body fat was lost in the reduced fat period as compared to the reduced carb period. And the same people eating the same number of calories in different occasions. And so, yes, that was my first sort of step into this world. I didn't know I was doing a, because it wasn't a weight loss study, right? It's a meaninglessly small difference in body fat over a very short period of time, but it got a huge amount of pushback from the low-carb community. It was my first introduction to some of the nastiness that can occur when people receive a result that doesn't match their way of thinking about things.

27:23So we've done several studies since then that basically, I think, show that this system isn't perfect, that a calorie isn't exactly a calorie when it comes to body fat loss. but the differences are incredibly tiny and certainly they're tiny even when it comes to how many calories are being burned by the body so the sort of efficiency the metabolic efficiency on these different diets yeah you can detect small effects but they're you know 100 calories maybe if you believe some people's data 200 calories a day differently but compare that to what happens when you put people in two different food environments that vary in energy density and hyperpalatable foods it's a very small effect size

28:06metabolic health or metabolic disease and dysfunction i should say is it's more of a spectrum would you agree so it's not as though you go from being metabolically healthy to the next moment being diagnosed with type 2 diabetes so if someone's listening today and is thinking, well, I live a pretty sedentary lifestyle, but I don't have type 2 diabetes. What you're saying is, despite the fact that you haven't been diagnosed with a metabolic condition, if we were to take out the microscope, we took a biopsy of your muscle tissue, we would be able to identify that there is decay, deterioration occurring, mitochondrial dysfunction and you are on the path to metabolic disease despite not currently having it yes without a doubt and and and yeah and uh exactly and and this is why yeah it's just uh sedentary individuals even though they're healthy now they're they're the majority are going to encounter cardiometabolic disease in the forms of type 2 diabetes cardiovascular disease both They're going to have a higher chances of developing cancers.

29:23There's more and more data around cancer. At this point, there's a lot of epidemiological data, more than scientific cellular data, of what being sedentary does to you or obese, right? So being obese or being sedentary, it can increase about 50 % chances of many cancers, right? So that's absolutely astronomical. But we're still trying to find out that more. But yes, we know that also Alzheimer's, people who are sedentary, they have higher risk for Alzheimer's and all-time disease. And this is also, you and I were, you sent me yesterday an article about cardiorespiratory fitness. And cardiorespiratory fitness is highly associated to a high risk of full-cause mortality more than any other disease.

30:28Our last conversation, we spoke about the importance of zone 2 training or moderate intensity cardiovascular training as some people may know it as. and really central to that and to your research is this molecule lactate which as you know and as you speak about is often quite misunderstood so i wanted to come back to to lactate as as the kind of on-ramp for our discussion today and maybe we can start at a a really high level here inigo should the average person a a non-athlete should they care about lactate and if so why yes i think they should care about lactate or try to understand what lactate is and i think that it's been as you said a big uh you know like it hasn't been understood and it's going to be a a major biomarker in the in the next years and uh going forward but yeah it is a major biomarker of mitochondrial function.

31:34And it's probably right now the best biomarker that we have to see what's your mitochondrial function in a non-invasive way without the need of doing a muscle biopsy or a tissue biopsy. And it's everywhere. It's ubiquitous to every, pretty much every single reaction in the body. And it's presence across the body is as ubiquitous as the presence of oxygen or CO2. And so tying that together, so it's a biomarker of mitochondrial health, essentially a window into your mitochondrial health. Why should people care about that? How do you connect that to health? And I should have rephrased that a little bit better because it's more than biomarker.

32:20And thanks to the work that Dr. George Brooks has done for the last 54 years at UC Berkeley, We know that it's a signaling molecule that it's responsible for many different functions and homeostasis in the body. It has, as Dr. Brooks coined it, a lact hormone, right? It has hormone-like properties because it has tremendous amounts of signaling properties for health and also for disease. So not only biomarker, but it's also a major player in the homeostasis of human metabolism and health, as well as a major player in disease. And from our last conversation, if I recall correctly, it can also be used as a fuel source for producing energy.

33:08Absolutely. I forgot to mention that as well. So many functions. But yeah, it's probably the preferred fuel source for the body. It's mainly because it's the most direct fuel. It enters mitochondria directly through its transporter. It doesn't have to be broken down like carbohydrates or fatty acids. It enters directly in the mitochondria for fuel purposes. So right at the top here, this might challenge the way that people have thought about lactate previously, perhaps what they had learned during university or afterwards. And what I'm hearing and what I want to underscore here and just throw back at you to confirm is that we should be thinking of lactate as a signaling molecule as a fuel source rather than some some form of of waste kind of byproduct or metabolic byproduct that the body produces during exercise that is harmful or toxic and we need to get rid of yeah absolutely and we've been always thought that uh it's been a or it's been always thought right there's been a waste product as a result of anaerobic metabolism and came back from the beginning of 1900s where Otto Meyerhoff, Nobel Prize, discovered that he placed a frog into like a flask and somehow he was studying how glycogen was converted to lactate under anaerobic conditions.

34:35And therefore, his deduction was that glycogen was used by the muscle and the waste product was lactate. And then he got the Nobel Prize for that. So it became Dogma and other researchers and two other Nobel Prizes. They also were very into glycolytic metabolism and lactate was always there as a waste product. So that was embedded in textbooks for forever and thought that people thought that also was like crystals. They would become crystallized and they would cause dumps, delayed onset of muscle soreness, and all kinds of different things. But then, yeah, in the 1980s, mid-80s, George Brooks from the University of Berkeley, California, Berkeley, he started to swim upstream against the thought that lactate was a waste product.

35:23He's been debunking every single thought that was written about lactate, and now we have a whole kind of understanding of what lactate does and what lactate is. Speaking of dogma or perhaps misunderstandings, and firstly here actually, is lactic acid synonymous with lactate? No. So lactic acid never sees the light of the day, if you will, right? So the final product, I mean, the only product that you see is lactate. It's been used back and forth, lactic acid or lactate. but uh the real compound that we see that the real metabolite is lactate

36:07so what do you think about this idea that you know after you do sprints that real fatigue and burn that you you might feel in your legs that's that's often been attributed to lactic acid you know people might say yeah you know that's a kind of lactic acid burn post-exercise is that a myth Absolutely. It's a myth. And the thing is that what really causes that burning sensations that we all have felt is muscle acidosis, right? Where the pH in the muscle goes from 7.2, 7.4, goes all the way down to, it depends, 6.5, 6.8, 6.2, depends on the person. So it becomes quite acidic, but that's not due to lactate, it's due to ATP hydrolysis.

36:56Because when there's a high exercise intensity, or in the case of a spring, a high necessity to replenish ATP at a very fast rate, the ATP hydrolysis is very, very high, and therefore the protons are building up in the muscles, and that's what causes acidosis, but not lactate. Lactate, in fact, it's a mild buffer during glycolysis. So lactate is always, always the end product of glucose metabolism. So glucose enters the muscle and through its transporters, mainly it depends on the tissue, but let's say muscle is the GLUT4. And then through that, it enters the cytosol, the cell, and it's broken down through different steps called glycolysis.

37:42It's broken down to pyruvate. And then pyruvate enters mitochondria, right, for oxidation, for final destination, and is converted to acetyl-CoA, which enters mitochondria for ATP production. Then there's always, always some lactate production. So there's always some lactate production from pyruvate to lactate. So lactate is always present. However, when there's a very high rate of glucose utilization, which is called glycolysis, there is a depletion of NAD +, that famous compound that is very popular now. So in the step from glycerol dehyde-3-phosphate to 1 ,3-biphosphoglycerate, which is one of the steps of glycolysis, NAD +, is consumed and is converted to NADH+.

38:35age. So that NAD plus is essential for the continuation of glycolysis and homeostasis of the redox status in the cell. So that is the normal homeostasis of the cell so it can keep functioning. Otherwise, glycolysis will stop. So whether you're exercising or whether it's a proliferating tissue or whether it is a tumor tissue, glycolysis will stop, right? So the only way to rescue NAD plus is the conversion or the reduction of pyruvate into lactate. That's the only way. So in that step, pyruvate or lactate, it's the result of taking those NADH plus H. So two protons there, they are given to lactate in a way.

39:25So our lactate is a result of uptaking those protons from pyruvate to lactate and lactate is formed. So in a way, lactate is a mild buffer because it takes those protons. So it has nothing to do with hydrolysis from ATP at the muscle. But in that process, what lactate does is like it regenerates NAD plus from pyruvate to NAD to lactate. It regenerates NAD plus and therefore that's the only way for the continuation of glycolysis. The more I've learned about the supplement industry, the more selective I've become about the supplements that I put into my body. This category has a real trust problem.

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42:49and if we were to come back to lactate as a biomarker of mitochondrial function or dysfunction and we were to think about the difference between a diseased person with poor metabolic health and a healthy person or even an athlete my understanding of this is that the healthy person and the athlete are better at sort of quote-unquote recycling lactate and sort of putting it to good use and that stops at a given intensity that stops the blood lactate levels going up as much as you may see in someone who has poor metabolic health and less capacity to sort of recycle lactate is that kind of high level accurate accurate yes so there are two events here one is that if you have a good mitochondrial function you're going to use glucose at a faster rate and you're going to oxidize it or burn it in mitochondria so what's called the full oxidation of glucose into ATP through oxphos oxidative phosphorylation in mitochondria is going to give you around 34 to 36 ETPs, right?

44:00That's on one hand. If you don't have enough mitochondrial function, you're not going to be able to tolerate that higher glycolytic flux and you're going to be producing more lactate, right? So that alone is going to give you a biomarker of a poorer mitochondrial function when you stress it, the lactate production. The second point is that well-trained athletes that lactate instead of accumulating what it does it oxidized in mitochondria so that pyruvate mainly goes from the fast twitch muscle fibers which are the glucose users and lactate producers it goes to the adjacent slow twitch muscle fibers which are richer in mitochondria and that's where it's oxidized to energy so as you said very well it doesn't show up in the blood.

44:50So when you see in the blood lactate at the same exercise intensity relatively to another person, you are going to see that, yeah, the person who has more lactate is because cannot, that person cannot oxidize or recycle lactic correctly and builds up in the bloodstream because it has nowhere to go. And once it's in the bloodstream, it's oxidized by every cell in the body, whether it's the brain, the kidneys, the heart, right, at the lungs, it's very well oxidized everywhere and is is lactate increasing in the blood is that a problem or are we still saying that lactate itself is not a sort of toxic byproduct but this is just more of a a window into that person's metabolic health which is the real problem exactly that's where you see lactate traveling in the blood it reflects on one hand that there's a metabolic stress somewhere right When we exercise, we know that there's a metabolic stress there.

45:46So that's why it's a biomarker. That being said, it's not toxic per se because that lactate is going to be oxidized everywhere. So it's fuel. You're in a way, you're recycling it somewhere, so you're giving it fuel. But when you see lactate under non-exercise conditions, like for example, ICU patients, lactate becomes, along with cortisol, the top predictor of mortality. when you see someone with lactate, very high lactate levels. I think it's above 5 millimoles or 4.8 millimoles. I forgot exactly what it is in the ICU, but there are very low chances of survival. And historically, that has been thought to be like lactate acidosis.

46:28And it was treated as a lactate acidosis or thought that, oh boy, there's a lot of lactate. That patient is in acidosis state, right? when what it's telling you is that that patient is in a very high metabolic stress, which is very typical of ICU patients. And the two characteristics of ICU patients are very high rate of glycolysis because they're fighting for survival. And it's not one hour or two hours or three, like when you go outside and exercise or high intensity. It's 24-7, right? And second, what you have in people with the acute phase of ICU is glucose intolerance. So they have insulin resistance and mitochondrial dysfunction, which is going to push even more towards the production of lactate.

47:16This building up of lactate in a person with poor metabolic health is coming from increased production of lactate. So glycolysis is kind of happening in overdrive, presumably because the mitochondria is not as healthy and good at oxidizing fats. Is that what's happening on that side of the equation? Yes. And then on the other side, they're not as good at clearing. So if we think about the machinery within a cell that's responsible here for the building up of lactate, what I'm hearing is that mitochondria not being as functional and healthy and also those mct1 and mct4 transporters which are really important in the muscle fibers for for kind of pushing out lactate from the fast switch fibers and then receiving it in the slow twitch fibers exactly so there's a whole and this is what dr george bruce discovered what's called the mitochondrial lactate oxidation complex or m lock that not many people talk about but it's very important to understand also lactate behavior and uh as you said very well yeah it's just you need especially high levels of mct once to be able to accept lactate because lactate cannot penetrate cells by the diffusion it has to be through active transport and it's taken by the mct once and then uh into mitochondria So if you have poor mitochondrial function normally, everything kind of builds up around that mitochondria at the end of the day.

48:45You're going to have lower different elements that we can talk later about mitochondria. But also you have lower M-Loc or mitochondrial lactate activation complex, which is the MCT1 and LDH and also MPC1, which is the mitochondrial pyruvic carrier. It's a different thing. And we're going to come to some of the interventions later in this conversation, I'm sure. But just in short, this machinery that we're talking about here, whether it's the mitochondria or these transporters for shuttling lactate, these are not sort of 100 % determined by genes. These are affected by lifestyle and something that we can kind of modulate.

49:25Yes, we can modulate for the good and for the bad. So exercise has been known to be the best form or probably the only form that we know of really inducing not just the expression of mitochondria or enzymes responsible for mitochondrial biogenesis, but it is really the form of increasing mitochondrial function. And being sedentary, for example, it's going to start a decay process of mitochondrial function. We have a study that we published as a preprint. I just have to finalize the graphs. I haven't had the time to wrap it up, to send it to a peer review. But we just wanted to publish it to say, hey, we have done this before others were true.

50:05But it is an interesting study. We had sedentary individuals versus moderately active individuals. And so we did both exercise, maximal intensity test with the, like CPET, right, with the gas exchange through the metabolic cart. And also we did muscle biopsies to study the components of the M-Log, right? and how lactate behaved. We also did metabolomics, but we looked at the protein expression. We did a transporter expression as well and the fluxes. So we saw how well mitochondria from sedentary and moderately active individuals, 150 minutes or more per week, would use fatty acids, we use glucose, we use amino acids.

50:47And it's very clear that sedentary individuals have a significant can decrease in mitochondrial function already. And we can see that also without the need of doing muscle biopsy by looking at lactate during incremental tests. So this is what we wanted to also correlate. What we see in the muscle biopsy versus what we see in the metabolic heart, right, during the test. And we saw very clearly that they have a problem already with glucose metabolism.

51:22The way we have been understanding and studying glucose and approaching it clinically is by what happens at the peripheral level. More like, right, we're talking about hyperglycemia, hyperinsulinemia, insulin resistance, right, even GLUT4 resistance, right? But that's the first part of the trip. The trip for glucose to be fully oxidized, it's a longer trip than just getting glucose into the cell. And this is what we wanted to see, right? So glucose, the first step is to be taken by the cell through that transporter. That's what we know. But then glucose, as I mentioned earlier, has to be broken down into the cytosol inside the cell, into pyruvate.

52:07That's the second part of the trip. The third part of the trip is that pyruvate has to enter mitochondria through a transporter. In the same way glucose enters the surface of the cell for transporter, pyruvate, does the same thing at the surface of mitochondria, right? And that's called the MPC or mitochondrial pyruvate carrier. And then a fourth part of the trip, that pyruvate has to be converted to acetyl-CoA and then enter the Krebs cycle, right? And then finally enter the electron transport chain for ATP production. So it's a long series of events. However, we've been only focusing on what happens at the peripheral level.

52:48So our study wanted to see like an inside out model. What if the problem behind the pathogenesis of type 2 diabetes or glucose intolerance would not be at the surface of the cell, but at the mitochondrial level, right? And this is what we saw. We saw that moderately active individuals, they have somewhere between 30 to 50 % reduced in the mitochondrial pyrovate carrier, the transporter of pyrovate into mitochondria, electron transport chain, the complexes, especially complex one and complex two that we studied. We also saw that the flux, the oxidation of pyruvate, which is the end product of glucose, was significantly decreased by about 35-40%.

53:34We also saw that the transporters for fatty acids are decreased as well, CPT1 and CPT2. And also we saw that the oxidation of body acids were highly decreased, right? However, and this was to us was the big finding, the GLUT4 expression was the same in both groups. So these are healthy, sedentary individuals. They have no clinical issues at all. They have normal glucose levels and they have, in fact, Yeah, their glucose transport is normal because the transporters are normal. However, the last part of the trip, when that pyruvate, the entrance mitochondria for being utilized and being produced ATP, it's already dysregulated compared to more reactive individuals.

54:25And a biomarker through exercise was lactate, right, without the need of muscle biopsy. So what you're seeing there is you can have an individual who may have normal blood glucose and insulin levels and is sort of quote unquote insulin sensitive or doesn't have type 2 diabetes because the first part of that trip's okay. But they still are having some form of metabolic dysfunction, but it's lowered down in that journey of getting glucose into the mitochondria to produce energy. Exactly. And this is what's already dysregulated. And it's regulated maybe 10, 15, 20 years before someone develops type 2 diabetes.

55:11And this is why it's a great chance that we have to diagnose it and intervene through lifestyle interventions, mainly exercise and proper nutrition, or develop some therapeutics to target what happens at a mitochondrial level. But yes, absolutely, we can see that there's a dysfunction already in those individuals.

55:35so how would we use that on a on an individual or population level because where my mind's going is what i'm hearing is that maybe lactate in the blood is a better way to see someone's risk of developing you know pre-diabetes or type 2 diabetes way in advance but then at an individual level to use lactate. I would presume that you need to have baseline levels and then be monitoring how that's changing over time for a given intensity. Exactly. So for that, I use the same approach as exercise stress test that cardiologists do. At rest, if you're laying down the traditional EKG or ECG, the reliability or accuracy of those tests is about 50%, right?

56:21Right. So from when we were kids, right, people would just lay down EKG or HG for whatever the physical. People don't do that anymore in general. Right. What you want to do is you want to stress the heart. And that's what's called a stress test. So you put that person on the treadmill and you are increasing exercise intensity. So the heart starts pumping harder and harder until the point that you're going to see some pathology because the heart starts suffering. Right. Because it has to work harder. That accuracy of that stress test is about 90 to 95%. So I'm using the same approach for mitochondrial function.

57:01So in a non-invasive way, right? So at resting levels, blood lactate levels, sure, and many people are going to be slightly above. Let's say normal levels are around one millimole. Many people with some metabolic syndrome might be around one millimole or might be slightly above one millimole. people with type 2 diabetes, full-blown type 2 diabetes, chances are that lactase will be two to three millimoles already. So that alone can be for more diseased population, can be a biomarker. But for pre-diabetics or people like in the study that we saw, like healthy sedentary individuals, we might see one millimole.

57:40But if we put those people to the test in the same manner as we did, as cardiologists do with their patients, that's when we tell mitochondria hey speak up so we're in this case we're not stressing the heart we're stressing the muscles and therefore the muscles get more stressed they need to use more oxygen from the heart so therefore the heart gets stressed as well but especially that glucose starts kicking in you need more glucose more glucose that you're not oxidizing properly in mitochondria so you're producing more lactate and since you don't have the slow twitch muscle fibers to oxidize it then it builds up in the blood so it's a very good test to indirectly measure mitochondrial function indirectly in a non-invasive way can be done in an ambulatory manner right and it's also a good way to since you're there in the same manner that we do with elite athletes for for many years so i have done at least for 30 years we can establish training zones for that patient or that person so we can already intervene with exercise in an individualized manner and when when you're measuring someone's lactate levels at various intensities what are you benchmarking that against do we have data that says okay for this gentleman who's 45 years old you know at this intensity on the bike this is what their lactate levels should look like if they're healthy or or are you just looking at someone's baseline and then how it changes how are we actually doing this in real life in the lab at an individual level yeah that's a great That's a question.

59:11And yeah, honestly, I'm not aware of many people who do this kind of testing, right? In fact, George Brooks and I, we introduced this test as a potential way to indirectly look into or assess mitochondrial function. I've been doing it for a long time. I have my own database from all kinds of populations, from elite populations through the France level all the way to people with chronic diseases like type 2 diabetes, metabolic syndrome, cancer, long COVID patients, COPDs, and this is our normal people of all levels. So this is why I have my own database.

59:54Let's step through this as intensity is increasing so the listener can appreciate what changes are happening with regards to the substrates that are being used to produce energy, where that energy is being produced. And Inigo, it may make sense here to start introducing zones. I think people have heard zone one, zone two, zone three, zone four, zone five. So if you think it's a good idea, perhaps as we're talking about the changes that are occurring with regards to how energy is being produced and where it's being produced, we can kind of pair that with the zone slash intensity. Yeah. So, yeah, I mean, again, the way I see zones is from, you know, like a cellular metabolism glasses, right?

1:00:50So, I see, for example, this is also based on the muscle fiber recruitment pattern, which is going to also elicit different fuel utilizations and fuel partitioning, right? So when we start exercising very easily, like a very easy walk, for example, or a very easy bike ride for those ones who are fit on the bike, the body prefers to use fat for energy purposes. Now, that doesn't mean that we don't use glucose, right? Because we also use glucose. There is a misconception that at low intensities, we do not use glucose. We do use glucose. And this is, I've been for almost two decades measuring in the laboratory fat and carbohydrate oxidation rates at the wide range of exercise intensities.

1:01:42All the exercise intensities and seeing in grams per minute, how many carbohydrates and fatty acids you burn, or oxidized at different intensities, right? Which has helped me tremendously to understand the bioenergetics and metabolic map, as I call, of what are the series of events of different intensities. So again, at slow intensity, we deploy a lot of the fat and then we use a little bit of glucose, right? It's very low intensity and we deploy, we recruit the slow twitch muscle fibers. That's what I called zone one, right? And again, when it comes to zones, the multiple zones, people have different terminologies and interpretations.

1:02:32I'm just giving you mine, right? So then as exercise intensity increases, then the muscle contraction gets faster, right? And stronger. So it needs a higher metabolic demand to produce ATP. So that's what you start burning even more fat, right? But you also start burning more glucose also, but not as much fluctuation in glucose utilization as it is in fat, right? And this glucose at this stage is being used to produce energy within the mitochondria. All of this is still occurring in the mitochondria. Normally, yes, because it's the glycolytic flux, as we call it, allows the velocity of the glucose to be used through pyruvate in mitochondria.

1:03:24Yes. Although some is reduced or transformed to lactate in the cytosol of the cell, and therefore there's a little bit of lactate production, which also coincides with this intensity. Little bit, which is about baseline levels or a little bit about baseline levels, right? But this is where, at this intensity that I call zone two, this is where you reach a point where you oxidize the highest amount of fat, right? And this is a key point because fat is oxidized exclusively in mitochondria, right? So when you reach a point where you achieve the maximum fat oxidation is that, yeah, you're putting those mitochondria to work at that bioenergetic system, which is the fatty acid oxidation and oxidative phosphorylation to the max.

1:04:22So this is what I use this zone to prescribe exercise as this is what I see that this is where you oxidize the most amount of fat. So we can see in many people when we do this test in the laboratory, we can see that we can translate this into heart rate, for example, or into pace or into power. So that is the exercise intensity that releases the highest fat oxidation. then we start we continue increasing the exercise intensity and the metabolic demand becomes even larger right so you need to produce atp faster and this is where there's an inflection point where fat cannot continue producing atp at the same rate as before so this is where glucose is called in at a higher rate because ATP from glucose is produced significantly faster than from fat, right?

1:05:33So that's when glucose starts to be recruited. And then you see in the laboratory at this intensity, you see that fat starts to drop significantly. There's a significant drop in fat oxidation and there's a significant increase in glucose oxidation or utilization. And at the same time, you see also an inflection point also for lactate because lactate and glucose go together. As I was saying earlier, it's about glucose flux. The higher the glucose flux into the cell, the higher the lactate accumulation, right? So this is what's starting to happen in this zone three that I call. which is a transition zone before we enter a whole different bioenergetic terrain, which is glycolysis, right?

1:06:26Or, yeah, the glycolytic system. So this is when exercise intensity is now so hard that fat can no longer provide ATP or, you know, like, or be a substrate for ATP production, right? And this is when you need to start deploying carbohydrates and glucose. And this is what we see that at this intensity, fat oxidation completely disappears. It's gone. At the same time, you see a big increase in glucose oxidation and a sharp increase in lactate because of the glucose flux. And this is also what lactate also has the endocrine, paracrine, and autocrine functions. So the endocrine function of lactate is that when accumulates in the cell and cannot be metabolized in mitochondria, it goes to the blood.

1:07:24And it goes to the blood, it inhibits lipolysis, which is the breakdown of fatty acids from adipose tissue. So when it inhibits lipolysis, you're not going to be able in the first place to bring the fatty acids to the muscles to be burned, right? And then secondly, and we have published this recently two years ago, that we saw and we demonstrated that lactate as an autocrine function, it also inhibits the fatty acid transporter. So in the muscles, fatty acids, they have a door, which are the CPT1 and CPT2. In mitochondria, outside and inside mitochondria, they transport fatty acids, right? So lactate inhibits both doors.

1:08:10So when you have a high glycolytic flux and you use a lot of glucose, the fat disappears for several reasons. First, because of necessity to produce ATP, right, at a faster rate. And second, because the actions of lactate on both adipose tissue and also on the transporters for fat. So it's a way to fit for a mechanism, right? To kind of get fat out of the way and say, hey, fat, you're done. Your job is done. Now we go into glucose. And this is what I call zone four, right? Or people call it a lactate threshold. although there are many interpretations of lactate threshold also of our ftp functional threshold power etc right and then but all this is aerobic all this is 100 % aerobic metabolism right although this is what i was mentioning earlier the misconception is like we're already in an anaerobic state and that's why people call it anaerobic threshold right we're still aerobic Then we move on into the next phase, which is it's an intensity that is where you reach your V2 max.

1:09:20This is an intensity where you max your aerobic capacity. Your lactate, it's off the chart. Your glucose utilization and the glucose flux in the cells is off the chart. There's no fat oxidation either, but you're at the intensity where you have the highest aerobic capacity. And this is the VO2 max. And I call that the zone five, right? And then lastly, I call the zone six, which is pure anaerobic. This is where we're talking about sprinting or about efforts that last two or three minutes, right? where that oxygen that you were referring to earlier is not enough, or even glucose is not enough to maintain, I mean, to synthesize ATP and then the muscles they need, the ATP that's stored in the muscles already without the need of oxygen.

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1:13:14there's a a really nice review paper i'm sure you've come across this is it was in nature metabolism by mark hargraves and i'll put figure two up on the screen for those that are watching on youtube but it speaks to the potential energy that's available in the form of fat in adipose tissue and glycogen in the liver and muscle and it sort of makes it very clear that there is this order of magnitude more potential energy in the form of fat stored in adipose tissue as you just kind of walked us through the next question i have is you you stress the importance of the point of maximum fat oxidation quite a lot and my understanding of where you're coming from there is that during specific exercise namely zone two at this point of maximum fat oxidation we're providing a very specific direct stimulus to the mitochondria which then causes it to upgrade or adapt or grow stronger which we can we can get into in a little bit as to exactly what happens but my question is why that is the best intensity to stimulate the mitochondria because you just made it clear as well that when we go into zone three and zone four this is still aerobic so even though the the contribution of fat to the production of ATP may be declining glucose is ramping up and that glucose is being used to produce ATP within the mitochondria.

1:14:59So why is it that we're chasing a stimulus to directly target the production of ATP from fat within the mitochondria as opposed to just the total amount of ATP that's produced within the mitochondria regardless of whether it's coming from fat or glucose? I'm not sure if I articulated that well. Yeah, that's a great question. And, yeah, it's complicated and we're still trying to really answer it, I guess, you know, in a more articulated way, right, and in a more scientific way, if you will, right? So what I have seen from 30 years of work with athletes, with patients and research is that that's the intensity when I started using it.

1:15:48And by no means, I'm saying I invented Zone 2 because who knows who started it. I just say that my Zone 2, the way I see it, I started using it 30 years ago. And this is what I first saw looking at lactate clearance capacity. that that intensity was the one that improved the most lactate clearance capacity and performance. So lactate, it's a mitochondrial substrate because lactate can only be oxidized in mitochondria or be converted back to pyruvate to be oxidized in mitochondria. So lactate is a great proxy or surrogate for mitochondrial function. Then about 18 years ago, I started to add fat and carbohydrate oxidation rates in the laboratory to measure, as I mentioned earlier, fat oxidation.

1:16:47And I could see also that that intensity was the one that improved fat oxidation the most, right? So that's what I developed, this indirect methodology to look at or to assess mitochondrial function in a non-invasive way without doing muscle biopsy. So by looking at lactate and looking at fat oxidation, both are mitochondrial surrogates and mitochondrial substrates, right? So we can indirectly measure that. And my colleague, George Brooks, and I, we published in 2017 a study looking at the correlations between fat oxidation and lactate, blood lactate levels, denoting lactic clearance capacity.

1:17:35And the correlations, whether you were like an elite athlete, a moderately active individual, or a person with a metabolic disease, a metabolic syndrome, the correlation was incredibly high. So that's why we know that they both can be very good surrogates for mitochondrial function. Now, that being said, again, this is why at first it was a trial and error, right? I was saying, okay, which intensity of the ones I define in my dictionary, which intensities improve mitochondrial function the most? Is it so one, so two, three, four, five, right? So with thousands of tests that I've done, this is what I saw constantly, that this was the intensity that improved mitochondrial function the most.

1:18:22And also I saw that this was the intensity that improved performance the most. So this is what I saw with my athletes. It was very successful to see this with results. and now this is what I from the beginning I was saying from lessons learned from athletes can we use this to prescribe exercise to populations with chronic diseases to stimulate mitochondrial function so again this is a way and I'm sorry if I didn't do that the best way but this is my way to explain why zone 2 is an important to stimulate mitochondrial function Not saying that the other ones are not going to do that, right? But what I've seen is this is the most efficient and I've seen over 30 years.

1:19:13I think many of the listeners will be thinking, how do I know that I'm in zone two? And there are a lot of different calculations online. There are running tests, there are lab tests, etc. How do you encourage people to think about this? Yeah, that's a great point. So I think that as we're starting to look at exercise prescription for the mass market and for many people, as opposed to just to elite athletes, right? We're going to see more and more exercise physiology or metabolic laboratories around the world, right? And in fact, it's happening, right? Until recently, there were very few laboratories around the world.

1:19:59who did this test to specifically find out your training intensities, right, based on heart rate or power output, right? And they were only for the elite athletes, right? And then now more and more are popping up around the world. And people are not so scared to go to a laboratory because I remember when I started doing this in the U.S. for health purposes with patients 15 years ago, people were scared because they say, oh, I'm not an elite athlete, right? Or they would see a cycling jersey or a runner's jersey on the wall and say, I'm not one of those, right? No, but this is not about that, right?

1:20:40This is about you. And so anyways, those laboratories and those testing, they're becoming more sophisticated. And people running those tests, they're more and more professionals. Before, there are not that many professionals working in this area. and that people would go to their local university. And with all the respects to graduating undergrad students, they were seen and tested by them, right? Now you see a lot of professionals who they were undergrad or graduate students and become into this field, right? So that's on one hand, but there are people out there that they cannot find a place, right?

1:21:19There's no laboratory in their town, or maybe it's too expensive and they cannot afford it, right? So for those, and from my experience, right, I think that the breathing and talk test, it's a great way. And I'll explain it. So like when you and I talk like this now, when you can maintain a conversation like this, you're in your zone one. You're recovering. You're not stimulating much, right? Right. Zone two, it would be like a hard conversation to maintain. Right. If you imagine yourself exercising with someone else, you could maintain a conversation, but it would be costly. Right. You will be talking with some difficulty, but you could maintain it.

1:22:09Right. Not for a long time, not for one hour, because it would be too fastidious. Right. But you could maintain it. That would be kind of what we see the results in the laboratory. And it kind of corresponds to that, right? And then zone three would be an exercise intensity where it's very difficult to maintain a conversation. Very difficult. Just exchange a few phrases or a few words, right? Then zone four, no conversation. That's it, you know? Maybe one word you can say, you know? And then some five and some six, yeah, there's no possibility, right? But I think that, and I honestly, and I know it might sound old school, but we have now watches and all these algorithms, you know, that gives us zones, you know, that the immense majority are far away from giving you the right intensities.

1:23:09Because those algorithms are not individualized yet. It'll happen at some point, right? But at this point, I really think that the talk and test is much more accurate than the immense algorithms that you find out there in all these brands telling you the training zones. And it's easy to do. And again, from my experience in the data, the hardcore data from laboratory, it's not that matches perfectly, but it corresponds quite well. Yeah, and I think it's just worth us remembering that there are so many people living a sedentary lifestyle. So trying to remove barriers to just get people moving is a great thing.

1:23:56And what you've just described there is really accessible to people. Are you a little bit puffy? Perhaps you have a little bit of sweat happening, but you can carry that conversation. If you were on the phone to someone, they would know you're exercising, but they could still have a bit of a conversation with you without it being sort of too interruptive. And the good thing with that too is that as you get fitter, you can be displacing that intensity, right? So now maybe someone is sedentary and obese or overweight and maybe just walking around the block, right? It might be tiring, right? But that might be the zone two, for example.

1:24:38but maybe in one year that person can do like a breeze walk, right? And be at that same intensity, right? So that's what you can guide yourself through this simple test, right? Which at the same time, these zone two intensities, it's something that's sustainable for life, you know? And again, I also say that any intensity will help and you need, as we discussed, higher intensity to maintain your fitness and your glycolytic capacity. and obviously we haven't talked about resistance exercise, which is very important, right? And you know more than I do. But the thing is like, yeah, when it comes to both exercise and diets, I always ask people who do these extremes, extreme exercise routines and extreme diets and they have great results.

1:25:30The immense majority are just temporary because the immense majority go back to where they were. And when you ask them, can you do this for the rest of your life? The answer is no. So if you cannot do a diet or an exercise for the rest of your life, it's not going to work. So you need to have some sustainability both in your nutrition and both in your exercise. And when it comes to exercise, a zone two is something that anybody can do for the rest of their lives.

1:26:02so dose-wise across a week we've mentioned 150 minutes a few times in this conversation is 150 minutes of zone 2 per week is that the minimum dose that would be required to build healthy mitochondria i don't know i i personally question those numbers right i mean I think that we, as humans and our health, we got in so low, right, that the recombinations of 150 minutes, you know, that's my opinion. You know, they're probably not enough. I would do more. And I think that more research is coming out, right, that if you do more minutes, you know, your health is going to be better and your longevity is going to be better.

1:26:54beyond X amount of minutes, which I forgot how many now, you're not going to see much benefit. But I think that 150 is kind of borderline, especially for people who want to delay many diseases and for longevity, 150 minutes, like at the end of the day. Yeah, it's just, if you do, I mean, yeah, I don't think it's enough. I think that somewhere more than 300 to 400 minutes a week, it's ideal, which is twice. Yeah, I think I've seen some research suggesting that there's continued benefits up to 10 hours a week, and maybe it's diminishing returns after that. Maybe there's just not enough subjects doing more than 10 hours to get a good amount of data.

1:27:44You mentioned 60 minutes in a session being perhaps ideal. I know a number of people will be thinking, okay, let's say I do 300 minutes per week. Can I split that up into 10, 30-minute sessions? Or does each session really need to be at least 60 minutes in duration? Yeah. Yeah, I think that it comes to your schedule, right? If you can do that, boom, and get out of the way, in my opinion, doing it continuously, it's better than to break it apart. But sometimes people, yeah, and I have clients and patients all the time, right? They ask me, hey, I just don't have, I can do 30 minutes walking to work or bridge walking or before work and then 30 minutes afterwards or something like that, right?

1:28:37If that's the case, it is what it is, right? But I just want to go back to what you were saying real quick about the benefits because it just came up to my mind. I see people who are in the late 50s, early 60s, who've been for years doing 150 minutes, 200, struggling with time, right? But maintaining, being fit, right? Because they're moderately active, right? But being fit, but always struggling with work, family, et cetera. And then they retire earlier. if they're like those who are lucky, right? Or pre-retire or they work, you know, like 20 hours a week or part-time or something like that. And then they start exercising and training in a more serious way, doing 10 hours a week, for example, right?

1:29:26Or eight hours a week, right? We're talking about 500 minutes, 600 minutes. And in one year, within one year, their metabolic fitness increases dramatically, right? Their mitochondrial function, their fat burning capacity, lactic genes capacity. And then you see data in people in their 60s that it resembles the metabolic data of people in their 30s. So this is kind of not as extreme as the example of the 81-year-old person that I told you, but I see this all the time. And it's incredibly inspiring to see that you can get a metabolic fitness of someone in their 30s when you're 65. Right. It's attainable for for those ones who can afford the time.

1:30:12But also, I think it speaks a lot in the in the about that probably we need more minutes than 150 to be better, you know, for longevity, for metabolic health than 150 minutes. We can do better. That's maybe the right way to put it.

1:30:33so if we come back to the individual who has metabolic disease and let's say they're listening to this now and they're they're understanding the mechanisms here and it's obvious to me that the mitochondria is very important here in terms of being able to oxidize fats and be very functional But then also the other part of this equation, if you look at it end-to-end that influences lactate levels, is your ability to shuttle lactate out of fast twitch and then into slow twitch and get that kind of lactate shuttling, recycling happening. And I think the zone two piece for stressing the mitochondria and improving fat oxidation capacity, that makes a lot of sense.

1:31:19And I think as someone prescribing exercise to this person, I think, and this is what I want your thoughts on, if we were trying to specifically stress like the MCT4 transporter that's kind of effluxing or pushing lactate out of fast twitch muscle fibers, would high intensity exercise up into zone 3, 4, 5 be better at that because you're recruiting more fast twitch muscle fibers? For sure, 100%. I agree with you. And this is in fact one of the many reasons why high-intensity exercise is absolutely crucial because you need to stress those mechanisms, right? Lactate is there and how do you get it out?

1:32:03You get it out through MCT force. Therefore, how do you stimulate that the muscles, they synthesize more of those transporters and they work better through high-intensity exercise. It's one of the very important benefits of that, along as they increase in the activity of glycolytic enzymes, right? Glycolysis, the faster it happens, the faster it's going to produce ATP, right? So that machinery, that turbo that I call, right, you only stimulate that through high-intensity training and this is why it's through different you know training zones that's that's how i came up with that a way to to try to stimulate some bioenergetics that are specific to that zone and in this case would be like zone four or zone five where you isolate that exercise intensity where it's full-blown carbohydrate oxidation forget about the fat forget about mitochondria it's about lactate production and glycolytic improvement, right?

1:33:03And that's very important. And with the athletes that I train, I look at their files, right? And all their best 5, 10, 20, 15 minutes, their top 10, about 30 to 40 % are during training, not competition, right? So that's telling you that competition, they go 100%, that's maximum. But you can see that also in training. And in fact, This is why we stimulate those training, those energy systems, right? And it's way more than just Zone 2, obviously, right? And it would be naive to think that the best athletes in the world, they just do Zone 2 training and then boom, voila, you know, they go through the mountains deploying that turbo and the high glycolytic capacity just because they train Zone 2.

1:33:45No, that's one part of that equation, right? But for health purposes, it's important to touch Zone 3 and Zone 4 in glycolytic capacity, but it's not so crucial, right? Because you're not going to be competing or deploying that turbo nearly as much.

1:34:07Over your extensive career, Dr. Eichel, what belief about obesity or metabolism have you changed your mind or evolved your thinking on the most? Well, obesity is really a complex topic. And the whole etiology of obesity is really debated in terms of what the importance of genes in terms of genetic predisposition to excess body fat is, how to define obesity. In fact, I'm involved in the Lancet Commission, which was released a year ago, that's redefined obesity. and then ultimately the role of the individual subject and the environment that he or she lives in in terms of the impact that they have on the origin of excess body fat.

1:35:01We're living in a world now where it's not only, you know, urban populations but growing urban populations in underdeveloped areas of the world where obesity is a major problem. And I've seen some recent data in China that I'm really part of, reviewing, and ready to publish that ultimately in China, the increasing prevalence of obesity has been dramatic over the last decade. So we're looking at a real global problem. And in terms of the metabolic aspects, which relates to your question, I think that's really a very complicated question and not simply answered in a one-liner. I certainly believe that the condition called clinical obesity, which is when obesity causes illnesses or diseases related to it, is probably not the majority of people that have excess body fat, but certainly when it becomes a clinically apparent obesity that needs attention therapeutically.

1:36:00In that particular setting, I think that most of the complications of excess body fat, which include metabolic disturbances such as type 2 diabetes, the metabolic syndrome, ultimately hypertension, inflammation, cardiovascular disease, liver disease, kidney disease, and even perhaps neurocognitive impairment relate to a concept called insulin resistance. Now, insulin resistance does not cause obesity, but insulin resistance, I believe strongly the evidence suggests, is a consequence of excess body fat. And that relates not to necessarily only total body fat, but body fat distribution. In other words, a more central distribution of body fat relates to more insulin resistance than if, in fact, you put excess body fat in your legs and your arms.

1:36:57Now, that redistribution of body fat is male-only, basically, but it's also women after the menopause. And we see an increase in many of the so-called comorbidities or illnesses we call clinical obesity in women after the menopause. So that's a long answer to your very clear question, which is not simply answered with a one-liner.

1:37:27Professor Roy Taylor, let's dive straight into the deep end here. And then maybe if need be along the way, I can ask you to clarify a few things. What is the twin cycle hypothesis? The twin cycle hypothesis was my attempt to put together all the observations on how the body actually worked, how the body dealt with food and metabolism, and what went wrong in type 2 diabetes. So over the years, we'd learned, firstly, that muscle was very resistant to insulin, and using MRI techniques, advanced MRI techniques, we could measure the glycogen in muscle. and, in fact, used this to show that people who had normal insulin sensitivity in muscle stored a lot of their food as muscle glycogen within the first five hours after eating.

1:38:36One third, really quite a lot. Whereas people who had low sensitivity to insulin in muscle, so-called insulin resistance, Those people stored almost none. And from other work, we knew that the only way that that glucose would be handled, it's not being stored properly, the only way it could be handled would be for the body to turn it into fat. Now, that sounds like magic, but that's exactly what the liver does. And so that excess glucose would be shunted into fat, and people will be more likely to build up fat in the liver. Now, we've shown fat in the liver causes the liver not to respond to insulin.

1:39:24Now, I put all this together and the twin-sital hypothesis runs like this. Basically, a little too much food over a long period of time will cause fat to start building up in the liver. And when the liver starts getting resistant to insulin, it will start putting out too much glucose, because insulin usually dampens down the constant production of the liver, of glucose. So there we have glucose rising a bit, but what happens next is that the pancreas kicks in and insulin levels rise a bit to just bring things under control. Now, that's fine temporarily, but unfortunately insulin speeds up the process of turning glucose into fat, and so we've got a vicious cycle that started running.

1:40:19That will run on, and glucose levels will gradually peg up. But it's not just the glucose that the liver puts out. The liver also puts out fat for the rest of the body. The liver really supplies you with the energy you need to live every day. Overnight, it's the glucose coming out from the body that keeps your brain alive and the fat coming out from your liver that keeps the rest of the body alive. That's what they use to burn for energy, second by second. It's an astonishing process. but if there's too much fat in the liver then that one livercital will have a knock-on effect because it will leave too much fat in the blood the liver puts out too much fat it will be delivered to all tissues now any excess fat would usually be stored under the skin and metabolically that's safe, it doesn't cause any metabolic damage however However, in the situation of excess and with a relatively full subcutaneous under the skin compartment, then fat's going to build up elsewhere.

1:41:36And that's the problem. And it's when fat starts building up inside the pancreas that really the action starts. So we have a second vicious cycle in the pancreas. The fat stops the insulin-producing cells from working properly. Lo and behold, that means glucose levels are higher after every meal. And lo and behold, that means more glucose is going to be turned into fat. And so we have these twin vicious cycles interacting. The importance of this twin cycle, Simon, was that it explained type 2 diabetes as a simple chain of events. Yes, interacting cycles, but a single cause. Now, that is simple.

1:42:25And what we see in populations is when they're overfed, diabetes erupts. If they're relatively starved, diabetes goes away. So all of a sudden, we had a handle on this, and it was a complete revelation and a move away from what all the experts were saying up to 2011, that type 2 diabetes was a complex heterogeneous disorder caused by multiple different factors. Well, that's nonsense. Basically, you inherit your genes, but if you put on a bit too much weight, heavier than you can bear, then these twin vicious cycles will start turning. And being a hypothesis, it could be tested and shown to be right or wrong.

1:43:19Just to kind of double-click on your concept, the personal fat threshold, I guess a phrase that I believe that you coined that, the personal fat threshold speaks to how much fat you can store subcutaneously. Is that right? Yes, that is the essence of it. Although there is also a lever component. So some people can be very large and obviously have fat under the skin, excess fat under the skin, but be metabolically normal. Relatively small percentage, but this is entirely recognised. At the other end of the scale, there are some severe genetic conditions with absence of subcutaneous fat. And guess what?

1:44:12They have high levels of liver fat, high levels of fat delivered to the pancreas, and a proportion of people get type 2 diabetes. Now, a very high proportion compared to other thin people. But even so, it's not 100 % because some people have the problem with storing fat and the good kind of beta cell that doesn't bother about fat being on their doorstep. So, yes, the personal fat threshold is largely a matter of being able to hold fat in the tissues under the skin and remain metabolically safe. If you exceed your personal fat threshold, you're likely to have diabetes if you're susceptible to it.

1:45:01And so in our recent study, the retuned study, we found that getting people in the normal or near normal body mass index range to lose an average of 6.5 % of the body weight, they became non-diabetic. 70 % became non-diabetic. So we need to set in context this unfortunate idea that doctors and nurses tend to cling to, that if you have a normal body mass index, you mustn't lose weight. Well, that's absurd, because the concept of normal is rooted in a population, and the advice is being given to one person in the consultation. We're all individuals, and I know for my patients that everyone likes being treated as an individual.

1:45:52That person there, which I think is about one out of six people with type 2 diabetes, is that right, who have normal BMI? What you're saying is that despite the normal BMI and from the outside, looking at this person, you may believe that they don't have any weight to lose. that person has exceeded their individual personal fat threshold and has excessive fat in the liver and pancreas to the point where things like fasting blood glucose and their HbA1c are putting them into pre-diabetes or type 2 diabetes kind of territory. That's correct.

1:46:39do you think uh it sounds like it's not really an even playing field like some people are dealing with heightened hunger relative to the next person is it is it that you you put on weight and then as a result of that you become leptin tolerant or is it that be it genetics or other reasons certain people are just more leptin tolerant or have less jlp1 sensitivity from birth yes well this is a very good question um and we tend to uh to believe these days that And this is our culture out there, right? That there should be no differences, everybody is equal, and we are equal. But in terms of our genetics, we are so similar, but also so different.

1:47:39Some of us have a predisposition to be more obese or to be less obese, or predisposition to develop diabetes. even if you have obesity, I mean let's go deeper if I may, right? Not each and every, and we have realized that not each and every obesity is also the same. So some of us have more or less storage space in their adipose tissue. All of us have the subcutaneous adipose tissue. I've heard people describe that as a personal fat threshold. There is a threshold, right? So some of us have a small storage space. Think about your apartment, your house, and you have your storage room. Some people have little storage space.

1:48:27Others have plenty of it. So for those of us who are fortunate to have a lot of storage space, potentially, in our subcutaneous adipose tissue, you can store their fat. Your body weight can increase. and to the extent that fat remains where it is supposed to be in the subcutaneous antipose tissue, you have no medical problems. So if it stays in the storage room, not a problem. Not a problem. But if it's overflowing into the living room and the kitchen... That's when you start creating problems. So about 20-22 % of people, especially women, may be slightly more obese. if fat is not spilling over in other organs, we call them metabolically healthy obese.

1:49:19Could be chubby or obese. There is no problem. No need to treat them. But if the fat goes where it should not be, liver can cause fatty liver disease, can cause cirrhosis and liver failure, death over a period of decades, right? Not over a period of months. If it goes to muscle, it causes insulin resistance for people who are predisposed to develop insulin resistance. And the longer and the higher the degree of insulin resistance, the higher the risk to develop diabetes. If it goes to our vasculature, it's the same process. Atherosclerosis. It goes to our brain and causes inflammation, neurocognitive decline, Alzheimer's.

1:50:09So you've got to keep fat out of the muscle, fat out of the arteries, fat out of the liver, fat out of the brain. And the very first and most indicative marker is the belly fat, intra-abdominal fat. right? So if you see intra-abdominal fat, you know that most probably you have fat in muscle, you have fat in the liver, you have ectopic fat.

1:50:45On the questions related to kind of how long someone has perhaps had excessive adiposity, was it something that they kind of had early in life? Was it something that came after pregnancy? What's the significance of that? So as a clinician, I understand you're asking that for obviously an important reason. Is understanding when the excessive adiposity sort of came on relevant and important to the treatment? Yes, and I think one thing I really didn't mention is part of the history, which is an important answer to your question, is have you tried to lose weight? And how many times have you lost more than 5 % or 10 % of your body weight?

1:51:26And were you able to maintain your weight loss? And often they can't, and why? So this gets more directly to your question. You know, the brain really probably has a fat stat. That means there's a place in the brain that knows your body composition. And, you know, there's tremendous evidence of overfeeding studies over finite periods of time, months to six months, where people lose all their weight after they've been overfed. And so we know we don't force feed people to excess body weight. But over years and perhaps five to 10 year intervals, if excess body weight continues to occur and ultimately then plateaus, I think in the environment that we live in, which is one of basically energy dense foods that are cheaper and more available and also not much physical activity, we settle into a body weight that reflects starvation benefit.

1:52:23I think this is very helpful and perhaps we bring it back and make it super practical for the listener here to kind of underscore why this is an important conversation. So why the fuss and the research on looking at different types of obesity and who has obesity and is suffering metabolic or other consequences from that excessive fat versus not. If someone was to just sort of ask a very simple question here. You know, why not encourage every single person that has a BMI over a certain amount to lose weight either through lifestyle plus or minus pharmaceuticals? Well, important question. And I think it relates to data that we're evaluating in four cohorts from around the world in China, in Spain, in the UK, and also in the US, the All of us study in the United States.

1:53:17We have data from all those four cohorts from around the world. And in a sense, we can answer your question directly with data that has not been submitted yet, but is close to being submitted for publication. I can't give you the numbers, but we have the data for the transition over 10 years for three of those cohorts from preclinical to clinical obesity. And over time, there is a transition from a subset of people that have preclinical obesity to obesity. So we have that kind of information. And again, I can't share that data now because it's not published and peer-reviewed. But we know that there is this transition.

1:53:56Now, ultimately, I think that transition would demand us to look back at what factors may have been present in people who transition from preclinical obesity to clinical obesity. And there, a more aggressive approach to weight reduction would be entirely appropriate in those people that have preclinical obesity. Now, your point has been one of the criticisms of the Lancet Commission. Why not have everybody who has excess body fat lose weight? Well, what we found is a lot of people with excess body fat do not have clinical obesity. I mean, many of them are overdiagnosed or underdiagnosed based on the BMI as a criterion.

1:54:36So I think, Simon, we have to dismiss BMI is the only way to assess accurately how much body fat is present. Now, by the way, if somebody has a BMI of 40 and above, the Lancet Commission says we don't need these other measures. And, you know, Mike Tyson had a BMI of 32 when he was in prime shape in the boxing arena. And the BMI of 32, his percent body fat was like under 5%. So, I mean, the BMI is sometimes inaccurate in assessing excess body fat. For the most part, I think above 30 is too much body fat. That's been used historically, but we find that people above 30 can have normal body fat content and normal body composition.

1:55:23So again, I don't know whether the audience, I think they'll know a little bit about when your doctor orders a SED rate, that SED rate, if it's elevated, It may indicate some inflammation that's going on in your body, but it's not specific. And we're saying the BMI is like a set rate for obesity. It's a good tool to say something's going on here. And here specifically, body composition, excess body fat is likely. But we think we need more than that to determine the accuracy of the BMI in detecting excess body fat.

1:56:01I think this will shock some people. Online, there are a lot of comments, both on social media, I get them on YouTube, where people are adamant that carbohydrates are responsible for fatty liver disease, for the accumulation of fat in the liver. But what you're saying, and I'm going to throw this back to you, is that if I'm consuming a eucaloric diet, so I'm consuming the exact number of calories that I'm expending per day, but I'm drinking a couple of cans of Coca-Cola, that the simple sugars that are added to those Coca-Cola drinks are not going to be driving up hepatic fat in my liver. I'm not going to be accumulating fat in my liver because I'm not consuming an excess of energy over the day.

1:57:02It could depend on the actual level of added sugars, but based on the available evidence that we have from isocaloric studies, one in particular, Parry and colleagues from Leanne Hodson's group at Oxford looked at two diets. One was a high sugar, high simple sugar diet, 20 % of energy from sugars. And the other was a high saturated fat diet, 20 % of energy from saturated fat. And diets consumed for four weeks. And this is a crossover study. So all participants ate one diet, then had a seven week break, washout period, then consumed the other diet. and what was particularly interesting was that liver fat increased by about 40 percent in the saturated fat group but there was no change in an increase in liver fat in the 20 percent added sugar group that's eucaloric so that was at they were consuming the perfect amount of energy the exact amount of energy that they were expending such that they wouldn't be gaining weight so so that was the intent that the diets were consumed free living the sugar group didn't actually gain weight so they you know they had a 0.2 kilogram change in weight so that would indicate yes they were an energy balance the saturated fat group did in fact gain 1.5 kilos over that four weeks so people might look at that and say well that that explains the increase But they did do a regression analysis to look at the association between weight gain and liver fat, to what extent that correlated.

1:58:55And the increase in body weight explained only 17 % of the change in liver fat. So the majority of the increase in liver fat was attributable to the diet. And again, we can tie in multiple other studies looking at effects of saturated fat in the context of eucaloric or isocaloric intakes. So there are other effects of sugars. So high dietary sugar intake can influence this process of de novo lipogenesis. that itself is mediated by the metabolic status of of the individual so in otherwise healthy individuals the contribution of de novo lipogenesis to fatty acids in the liver is is relatively low like less than five percent but in individuals who already have high levels of central adiposity the contribution of de novo lipogenesis can be up to about 24 percent but but but what's particularly interesting is that In energy balance studies, we can see an independent effect of saturated fat and we can see the inverse effect of polyunsaturated fat enrichment, which can actually lower hepatic fat independent of kind of much change in body weight.

2:00:31But in terms of sugar, then we typically don't see independent effects of added sugars without the context of energy surplus. So if we're not talking about energy excess, then the composition of fats in the diet may be more relevant than, you know, the presence of sugar. And, you know, average population sugar intakes of 12 % in the UK, at least. I'm not familiar with Australian data, but the numbers of people that would even be consuming the levels of sugar used in that study is 20%, for example. and there was also a paper published by the group at surrey margot umpelby and colleagues that looked at the extremes of uk levels of habitual sugar intake so either you know 24 would represent the upper 95th percentile of intake versus 2.5 in both individuals with naffles and non-naffles lean controls and you see this modifying effect of response to high sugar intake relative to someone's you know existing metabolic health so it's more deleterious than individuals that have you know high levels of of liver fat

2:01:59coming back to the direct trial which you mentioned before which i guess is one of the more prominent trials of yours that's tested the twin cycle hypothesis. It was 15 kilograms, I think you mentioned, that seemed to be an important kind of number, 15 kilograms of weight loss. So that was the typical weight loss that was required for people within that study to get enough fat out of the liver and pancreas to enter remission. the average weight loss immediately after the low calorie phase which indirect was a 12-week phase the average weight loss was just over 15 kilograms so yes that was an average but some people needed all of that 15 kilogram weight loss to get rid of their diabetes because putting on even a small amount of weight allowed the diabetes to come back when we tested subsequently.

2:03:04Other people could manage to put on quite a bit and still be free of the diabetes, so that at two years down the line, because DIRECT was a two-year randomized control trial, Well, two years down the line, in the weight loss group, the average weight loss had dropped to 8.8 kilograms. And even so, one third of the entire group was still in remission from the diabetes. So you see, that's how it works. we need to aim for the 15 kilograms weight loss that will take most people into the range where the chances are they'll be free of diabetes that has the important effect of demonstrating to everyone concerned the possibilities so if at say 15 kilograms a person is in remission but then life kicks in and they're distracted with other problems and the weight increases by say three kilograms they're going into 12 kilograms if there's still free of diabetes well life goes on but the chances are that they will just continue to put on a bit of weight especially if they discover they can put on weight without getting their diabetes pack suddenly say at 10 and a half kilograms.

2:04:38The doctor says, I'm sorry, you've got your diabetes back again. What do you want to do about it? Are you going to lose more weight again? Or I can give you these drugs? Well, you see, the target of 15 kilograms is fairly secure and a good target for most people. And it's also a wake-up call along the lines of get real. You know, how much extra fat do you think you're carrying around, because most people in our studies have put on more than 15 kilograms than they were when they were in early adult life. So 15 kilograms is not a complete return to a state of youth. It's a return most of the way and will be sufficient to achieve the metabolic goal.

2:05:33in your interventions there didn't seem to be a focus on exercise and i guess given the importance of skeletal muscle in glucose homeostasis i wondered if you'd ever considered um the inevitable kind of muscle loss that that comes with losing a significant amount of body weight, particularly if you're not doing resistance training concurrently. Sure. Focusing for a moment on the loss of muscle mass, this is something we measured. It was a 4 % decrease in fat-free mass of the body in the counterpoint study. So we measured everything in that first study. Now, if I persuaded you to walk around every day wearing a weights vest that contained 15 kilograms of weight, guess what?

2:06:31Your muscle mass would increase by a few percent over eight weeks. If people lose 15 kilograms, the muscle mass has to decrease because every day they're carting around less body. And the muscles we're talking about are the muscles you never think about very much that the huge muscles maintaining the posture of the lower back and keeping the hips in the right position. Those are the real energy consumers during moving ourselves around our curious race of bipeds. We rely on those muscles and a lot of energy there. So when people are 15 kilograms lighter, there's a physiological reason for them to have less muscle mass.

2:07:18This has been completely misinterpreted as, oh dear, the weight loss causes loss of useful muscle. Well, no, it's not useful muscle. The body decides how much muscle is useful by how much work it has to do every day. You can prevent this using resistance exercise, and that's absolutely right. And I would add that in the Newcastle Magnetic Residence Centre, We've not just been researching food and diabetes. We also do exercise studies on ordinary people, couch potatoes, and athletes. So this is an area that we're really very tuned into. So our studies of resistance exercise show very precisely that that is a very good way of building muscle.

2:08:07Why didn't we use it in Counterpoint? Well, the reason relates to one of our exercise studies, which took a group of inactive people and got them to train up. And we made measurements on them throughout this period so that they could do a half marathon. They all completed the Great North Run. I have to say they didn't all run it. There was a lot of walking, but they all did it. And moving from their totally sedentary behavior to doing this was remarkable. what happened to the level of fitness it went up remarkably what happened to their weight it did not change now they had burnt huge amounts of energy in the training in during the race why hadn't it changed after every research project we invite back our participants to hear the results We explain the results for them, what they've gone through all these tools of measurements for, as well as finding out how it was for them.

2:09:16Because that's how we learn how people can perhaps have studies done in a more tolerable fashion. We learn how, for instance, a diet was affecting people. But in this case, I wanted to hear how it was from these people after all their training. And I said, one of the funny things is, the average weight stayed exactly the same, even though you were burning so much energy, and I'd expected it to drop. And this lady put up her hand and said, You don't understand, Doctor. When you're coming back from your half-hour walk, you've only got one thought in your mind. I deserve that pie. And suddenly, I had a completely different perspective.

2:10:05on ordinary people doing much more exercise than usual and the thoughts and behaviour that elucidated. So I went to the literature and found out if there was any basis for this. Yes, compensatory eating after starting an exercise programme is well recognised. This explains why your friends might say to you, hey, I joined that gym. I've slowed my guts out for three months. My weight hasn't changed. It's just not working. I don't know what's going on. Compensatory eating. And so this is why we asked people not to undertake additional exercise during the counterpoint study. And that's gone all the way through.

2:10:51And so in the NHS National Remission Programme, people are not asked to undertake more exercise during the weight loss phase. But let me emphasize a really important point. During the weight maintenance phase, we actively encourage people to increase what they do. If people want to make their neck a bit broader because they might have lost weight there, well, they can do upper body weights. That's very popular with men. So the exercise message is not that you mustn't do it. It's that we must separate in time the matter of weight loss from increased physical activity. That's a very important practical point.

2:11:35And it's one that is so often missed out by exercise enthusiasts who are quite rightly enthusiastic about exercise. But these young trainers think that everybody would respond to exercises they do as a ritual activity and not actually look at literature and realize that people who haven't done it before will increase what they eat when they start an exercise program.

2:12:08Other than just observing someone, is that something that you would become aware of through doing a blood test and looking at biomarkers or is it a scan? Yes, that's a beautiful question. So this is a work in progress, right? So we started several years ago with a crude indicator, BMI, Body Mass Index. And this was started by insurance companies, Simon, because they had an interest and they still have an interest, right? so bmi is a simple crude index correcting weight for height but we realized that this is not as as we realize what is happening but it is not reflecting a topping fat or right so then we started looking into waist circumference which is a little bit more specific to like body fat distribution.

2:13:06Exactly. A little bit more specific, right? But again, different races have different numbers and they tend to have, say, Southeast Asians, they tend to have lower BMI's, but for a lower BMI, they don't have a lot of subcutaneous tissue. They accumulate fat in the stomach, but still is not the best, right? We need to refine it. So now, inexpensive markers, we correct waist circumference for height. We have to correct it, right? Because the waist circumference depends also on height, right? But if one wanted to be even more specific, we now know which are the hormones that are secreted from overall fat, and this is leptin.

2:13:52You gave it the hormone leptin from the Greek word leptos, meaning thin. We are talking about obesity, but I can explain to you about what happens in anorexia nervosa or thin people, right? Because these are mirror images. And there is another hormone that we have done a lot of work on. It's called adiponectin. And adiponectin reflects the intra-abdominal fat. And this is a hormone and an inflammatory marker, anti-inflammatory marker. And the more the intra-abdominal fat, the lower the levels of this hormone. the higher the risk for diabetes and fatty liver disease and cardiovascular disease. So you can measure it.

2:14:34So the more intra-abdominal fat... The lower the levels of this beneficial protective hormone. A diponectin. Yes. And you can request that on a standard blood test? Most laboratories should have it. The big laboratories have both of them. It's not yet standard biomedical practice, but we are getting there. It's research that is becoming practice. But if you go to LabCorp, or I don't want to advertise any, the big national laboratories, they can measure it. Now, you mentioned about scans, right? MRIs or CAT scans. Yes, we can measure it. with CAT scans or MRIs, we can measure not only how much fat you have, but also whether the fat is in muscle or in the liver.

2:15:26And they're pretty accurate. The problem is that they are expensive. So you cannot do it many times. You cannot follow people with that. You can break the bank. What do you think about a DEXA scan or liver ultrasound? Yes. So the liver ultrasound, and there are several companies that are making ultrasounds for the liver, is very specific, but not sensitive enough. So if you have more than... Let me start by saying that a normal person should have no more than 5 % fat in the liver. So the ultrasound is very specific if the amount of fat in the liver is more than 30%. between 5 and 30 percent is a gray zone that is not pretty good in picking it up so if you have a lot of fat the ultrasound will find it but if you have between 5 and 30 percent is not as good as an MRI or measuring it so that's that makes it not a great option for kind of the great option for a lot of people who might be on the fence no no we are not using ultrasounds these days for fat liver disease.

2:16:40And DEXA? DEXA scan is pretty good in terms of overall fat. We don't have it. It's not available like everywhere. It's not as expensive as an MRI, but more expensive than running a hormone.

2:16:59It cannot tell us a lot about which organ has fat or not, but it can tell us the overall fat mass. Yes. So if someone's kind of listening and they're just thinking, I'd like to generally know where my metabolic health is at. Weight circumference to height ratio. Yes, for sure. And any particular blood biomarkers that you would also want them to look at? Yes. If a laboratory has adiponectin, I would run adiponectin. Another very simple measurement is triglycerides over HDL ratio. So if you start having ectopic fat and insulin resistance, your triglycerides keep going up. And the good cholesterol, HDL, starts going down.

2:17:49So this is a red flag. okay so triglyceride hdl ratio waist circumference to height ratio this is how i would be starting and then if you see that these are abnormal if you if you see your primary care doctor you see these are abnormal i would run a panel right uh the full cholesterol profile glucose goes, right? One by one, right? The diseases that we know of, right? There is non-invasive tests like FIB4 for fatty liver disease, uric acid for arthritis, right? And you name it.

2:18:35Last question, Inigo. I do think that some people may look to long-living populations like blue zones or other parts of the world where there are examples of people who seem to avoid metabolic disease or be at low risk of metabolic disease and live quite long healthy lives and they're not necessarily doing dedicated cycling or zone 2 training or lifting weights or sprinting. Is your view that these populations could be even healthier with more prescriptive exercise and a greater exercise stress? It's a great question and I don't think I have the answers, right? But I think that these people, they never stopped moving, right?

2:19:24If you look at a toddler, their ability to produce energy is amazing, right? They can't stop moving. They must have an ability to produce ATP that is from out of this world, right? And then we grow and we start playing on the streets and doing all kinds of errands and we never stopped moving. That's normally not anymore, but when we were kids or our parents or our grandparents, that was the lifestyle. And these people in these blue zones, our high longevity areas, a typical characteristic, they never stopped moving. They never became sedentary in the first place. And in light of our study that we're showing is that, yeah, sedentary individuals, Even if they're healthy, their mitochondrial function has decayed significantly.

2:20:10Now these people's mitochondrial function, I would love to poke their muscles and then take a sample. For sure, I have no doubt that their mitochondrial function is excellent because it never stopped decaying. Which happens also to those ones in many other societies that they've been fit forever. When you've been fit forever and you've never stopped moving, any exercise is going to work for you because you're always fit, right? That being said, as you said very well, can you improve it? I think so. You know, I really think that if you're a super fit athlete and you have never stopped and you're 35 years old, can you improve your PRs, your personal best?

2:20:52For sure. If you do like a more specific training using this, stimulating these training systems that we have. So I think that can be applied to these populations in the blue zones or high longevity. but I think the key thing is that they never stopped moving and this is the problem that we have in our society that people became sedentary or lose their fitness because they only exercised 50 100 minutes a week and they stopped decay and that that muscle plasticity and the mitochondrial plasticity is enormous and you can get back to to a very high level through the exercise and this is what I think is a wonderful, wonderful drug.

2:21:30I've seen multiple people over the years that have been very inspiring. There you have it, friends. I hope you enjoyed this episode. If you did and want to stay up to date with future episodes, be sure to hit that subscribe button on YouTube and follow on Apple or Spotify. Finally, thank you for showing up and the effort that you're making to take control of your health. I look forward to hanging out with you again in the next episode.

2:21:58Thank you.