The Peter Attia Drive - Iñigo San Millán, Ph.D.： Zone 2 Training and Metabolic Health (Ep. #85 Rebroadcast)

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:15.500 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

00:00:19.840 into something accessible for everyone. Our goal is to provide the best content in health and

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00:00:41.760 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.800 here's today's episode. Welcome to another special episode of the drive podcast. For this week's

00:00:55.300 episode, we're going to rebroadcast my conversation with Inigo Sanmilan, which was originally aired two

00:01:01.420 years ago in December of 2019. Now, this was one of our most popular episodes and we're as such going

00:01:07.780 to invite Inigo back for round two shortly. Now, I got to be honest with you. I've always been amazed

00:01:12.360 at how popular this episode was because it was kind of a technical episode. We did not shy away

00:01:17.440 from the nuances of physiology. But one of the things that we talked about in great detail was the

00:01:23.120 importance of zone two training. And many of you have heard me talk about that since. This is really

00:01:28.820 the first episode in which it was discussed on the podcast. So I want to make sure that folks who

00:01:35.060 haven't had a chance to listen to this, take the time to go back and do it. And it's a deep podcast.

00:01:40.520 So I want to make sure that we don't overload you with another podcast this week. Secondly,

00:01:44.080 I want to make sure that even the people who have heard it go back and perhaps dig in a little bit

00:01:48.280 more and come back to us with some follow-up questions. When I have people back on the show,

00:01:52.000 I love giving the audience a chance to give us their feedback on where they'd like to see the

00:01:57.020 conversation go. So as a brief reminder, Inigo is an assistant professor at the University of

00:02:00.740 Colorado School of Medicine. His areas of research include exercise physiology, metabolism, nutrition,

00:02:06.600 sports performance, overtraining, type 2 diabetes, cancer, and critical care. He is also the cycling

00:02:12.240 coach for today, Pogaccia. And Pogaccia, if those of you don't follow cycling, is the guy who's won

00:02:18.380 the Tour de France the last two times. So in 2020, 2021, he's an absolute phenom. And I suspect that

00:02:26.740 we will do a little bit of discussing his training, at least what it is that Inigo is able to share

00:02:32.080 publicly. Of course, a lot of how these guys train is somewhat secretive. So in this episode that you're

00:02:37.260 going to listen to today, we talk about mitochondria, exercise, metabolic health. We also discuss all the

00:02:41.720 different energy systems and the fuels used during exercise. So we speak about the six training zones.

00:02:46.600 We focus extensively on zone two, why it matters, why lactate is an important fuel source, and why

00:02:52.000 measuring lactate provides great insight into mitochondrial function. So without further delay,

00:02:57.880 please enjoy, or potentially re-enjoy, my conversation with Inigo Sanmilan prior to round two.

00:03:08.620 Inigo, thank you so much for making time to sit down today in your new office here.

00:03:13.700 Thank you very much, Peter. It's my pleasure and honor that you're here with us at the University

00:03:17.760 of Colorado at the School of Medicine.

00:03:19.840 I emailed my team. I emailed Nick and Bob and a couple of the guys today when I was on the way

00:03:24.320 over here. I was on the plane and I was reviewing my notes and I thought, I am so excited to sit down

00:03:29.360 with you today and Rick tomorrow because we've had so many kind of off-the-cuff sidebar conversations

00:03:36.320 about mitochondria, mitochondrial function, health, efficiency, etc. And it's sort of like we never

00:03:42.700 have enough time. It's like 15 minutes here and 12 minutes there and an email here and an email

00:03:47.060 there. But it was in preparing for this, the team helped me really kind of put a lot of my thoughts

00:03:51.180 together. But I think before we kind of get into the really hardcore stuff around mitochondria,

00:03:56.000 which is something that I think anybody who's interested in health at any level, whether it's

00:04:00.700 really at the deep cellular level or just at the level of I want to live as long as I can,

00:04:05.460 as healthy as I can. Everybody sort of has a sense that all roads point to the mitochondria.

00:04:10.280 But your path to getting there to me is particularly interesting because it starts with looking at

00:04:16.620 athletes. And you yourself, even though you downplay it a lot, you were quite the athlete

00:04:20.280 growing up. So you grew up in Spain and what sports did you play? Yeah, I grew up in Spain and I

00:04:25.300 played for Real Madrid for the academy for six years. And I was always very passionate about

00:04:30.340 sport. Then I, when I turned 16, I discovered cycling and, and that's the way I changed sports.

00:04:35.460 So my dad still thinks that that was the dumbest decision of my life.

00:04:39.140 Is that true statistically? Would a child growing up in Spain, who's already in the feeder program for

00:04:44.860 Real Madrid, would they have a better chance of having a career as a professional football player

00:04:49.540 than a professional cyclist? That's hard to say, but when you're already at that age in Real

00:04:54.960 Madrid, you can be getting to the top team is very difficult, obviously, but definitely be a feeder

00:05:00.220 to other smaller teams. That's a higher possibility, but you never know, but you have to follow your

00:05:05.680 passion, I guess. And I followed it and I changed to cycling and I got to race professionally for two

00:05:11.700 years at a low level. So I always say that I admit it. I'm a truncated and frustrated professional

00:05:17.620 athlete because I never got to the top, but that said, I learned a lot and it's been a school of life

00:05:22.220 all my life. Since I was nine years old, I've been in the high level of competition up until today on

00:05:28.760 the other side of the table, working with athletes. And that's what I became very familiar with

00:05:34.340 everything related to the elite sport and that everything that involves.

00:05:39.060 I don't think most people who have not themselves been on a bicycle and trying to do something at a

00:05:44.920 reasonably high level can appreciate that even being a professional quote unquote, low level,

00:05:50.540 I guess what you're saying by that is you were not necessarily on a team that was even going to go

00:05:55.260 to the big grand tours and such, but I still think most people don't understand the level,

00:06:00.000 how much higher that is above a general fitness athlete type of thing. So when you were at that

00:06:06.460 level, what was your specialty? Were you a time trialist? Were you, uh, you look too tall to be a

00:06:11.140 climber, but who knows what you weighed back then?

00:06:13.140 Yeah, I was very skinny though.

00:06:14.620 You're taller than me.

00:06:15.840 I'm like 5'11".

00:06:17.140 Okay. So you're an inch taller.

00:06:18.360 But I used to be 143, 145 pounds, so I was very skinny. So I used to be a good climber. I was

00:06:24.920 good overall, but I'm better as a climber. But yeah, I, I, is that I appreciate it now when I see

00:06:32.060 people who are category ones or twos or threes as a cyclist or so that their fitness level is very

00:06:38.820 good. That definitely my fitness level was better. But at the same time, there is like a whole world

00:06:45.100 between my fitness level and what the Tour de France guys have.

00:06:48.820 It is unbelievable. When I was sort of going through category 5, 4, 3, 2, by some metrics,

00:06:54.300 I could maybe time trial at the level of a category 2, 3, but of course my climbing and

00:06:59.400 sprinting and everything else would have been like a category 4. And you realize that the guy who's

00:07:03.720 category 1, the guys I used to train with who are collegiate athletes who were exceptional at

00:07:08.420 category 1, they're still not even pro. There's still a step between them and a domestic pro.

00:07:13.520 And then the domestic pro to get from that level to a European pro. And then the European pro to get

00:07:19.520 to a major team. And then to be on a major team and the difference between the GC contender and

00:07:25.120 everybody else. We're talking about log orders of ability. It's not subtle.

00:07:30.300 No. And I have all the data from all these years collecting the data. And I know very well the

00:07:36.260 physiological parameters typical of a top junior athlete or category 3, category 2, 1, domestic pro.

00:07:43.300 So average pro tour cyclist and best of the best. And the difference is amazing. They're very

00:07:49.740 significant. You can really categorize people accordingly.

00:07:52.680 We're going to come back and start to talk about professional cycling and things. And there's so

00:07:56.060 many things I want to talk about because I think for also the person who's not immediately wed to the

00:08:00.340 sport might too easily want to dismiss the accolades of these athletes and the physiologic prowess

00:08:06.740 as simply, well, you know, those guys all use drugs. And while that's probably true at some level with

00:08:12.700 respect to some drugs and certainly a certain class of athletes, it in no way diminishes what their

00:08:18.840 physiology looks like completely off drugs. So we'll come back to all that, but going to you. So after

00:08:24.700 two years at a professional level, what made you decide, I am not going to continue doing this. I'm

00:08:30.220 going to pursue my education and the other things that you've gone on to do.

00:08:33.360 I realized that it's very difficult and you need to be in the right place at the right time at the

00:08:38.040 right moment and that different planets need to be aligned. It is not just the best always get up

00:08:43.860 there to call it destiny, call it whatever, but a lot of things have to happen to become a pro and

00:08:49.560 they were not on my side. But at the same time, I needed to make a decision either trying to get an

00:08:55.060 education that can not assure me, but at least give me some future professionally speaking outside the

00:09:01.700 sport or try to go for the sport where the planets were not aligned. I didn't know if I could even

00:09:07.340 make it and it would take that sacrifice. So that's what I decided. I think this is not good for me.

00:09:14.260 And then as I was studying also, I had a good possibility of doing a very good internship

00:09:19.700 at a top, if not the top sports medicine clinic in Spain. In fact, the famous PRP therapy was born

00:09:26.640 in that clinic. And that's where I said, Hmm, I had a good possibility to start internship and then

00:09:32.240 became a part-time job. And at that time I said, okay, I'm just going to stay here and continue.

00:09:37.540 And how long have you been here at the University of Colorado?

00:09:40.820 11 years.

00:09:41.840 Okay. Now you and I met through an interesting circumstance. It's a funny story. I don't

00:09:46.320 know if you remember the very first time, but I had just flown into Abu Dhabi and I think I came

00:09:51.100 straight from the airport to the training facility and it was like 11 o'clock at night or something.

00:09:55.780 And you put me right on the bike and we did a VO2 max test and which anybody who's done a VO2 max

00:10:00.860 test on a bike knows there's nothing very pleasant about it. You've got this mask that is incredibly

00:10:05.060 restrictive. I hadn't done one since I stopped cycling. So that was probably six, five years or

00:10:10.660 six years. And then I think you weren't happy with the air mixer because we were getting weird

00:10:14.580 numbers. And it was at some point, I think when I hit about 50 milliliters per milligram per

00:10:19.580 kilogram, we sort of said that's enough. And that was a good thing because I don't think I had much

00:10:22.940 more. It's amazing how much you lose when you stop training that zone. Yeah. I never thought there

00:10:29.600 could be a day when my VO2 max could be below 50. Like I thought it'll be 50 when I'm a hundred,

00:10:34.100 right? Yeah. That's not true. Yeah. It really falls away. Yeah. It falls apart. Yeah. So I would

00:10:38.700 be surprised if I could hit 55 today actually. But we connected immediately because it was a great

00:10:44.360 point in my life where I was almost, I was sort of looking for direction as a former, I don't even

00:10:50.800 want to use the word athlete to describe myself, but as a person who formerly took training very

00:10:55.260 seriously to now someone who was trying to think about reshaping my training around longevity.

00:11:00.520 It was a perfect collision of ideas because I was sort of in search of what to really focus on.

00:11:07.240 And what we immediately clicked over was your protocol for zone two training, which you were

00:11:12.560 instituting heavily with the UAE team and other folks that you were training there. And the rest

00:11:18.080 is history. I mean, it's really completely shaped the way I think about using this type of training

00:11:23.500 as a way to improve mitochondrial function and as a way to test it. I almost think at this point

00:11:29.540 for the listener, we should pause for a moment and explain these energy systems because so much

00:11:34.440 of what I want to ask you about and so much of what your research focuses on assumes a level

00:11:40.280 of understanding I don't want to take for granted. So maybe explain for people what aerobic metabolism

00:11:46.600 means.

00:11:47.260 Okay. So there are different energy systems and those energy systems, they're also used by different

00:11:53.400 muscle fibers in the muscle. There are different conditions like the aerobic condition and anaerobic

00:11:58.380 condition. We tend to believe that the immense majority of activity that we do is aerobic. We tend

00:12:04.420 to believe that any hard effort is anaerobic and therefore the concept of anaerobic threshold. But

00:12:10.820 actually, even what we call the anaerobic threshold is an aerobic activity. So the majority of the efforts

00:12:16.400 that we do are in an anaerobic environment, except for when you do a sprint or when you do maybe like a

00:12:24.500 one minute maximum. Outside that, the majority of the activities that we do are in the aerobic state.

00:12:31.580 Then what changes is the fuels that you use to produce energy. So at the end of the day, what we want to do is

00:12:41.020 to contract the muscles and not only to contract them as fast and as forceful as possible, but what we want also

00:12:48.500 is to do this as efficiently as possible. So for example, for a marathon race or for a 1500 meter race, you need

00:12:56.980 to calculate when you pull the trigger and go for it. And then when you have to deploy all the maximum

00:13:04.540 efficiency that you have. So you need to be very efficient metabolically speaking. So the fuels are very

00:13:10.700 important for that. So the main fuels that we use for exercise are the fatty acids and glucose. And

00:13:18.260 those are oxidized or burned in the different skeletal muscle fibers that we have. So we have the slow

00:13:25.520 twitch muscle fibers and the fast twitch muscle fibers. The fast twitch muscle fibers are divided

00:13:30.940 in two. The type 1A and type 2B, if you will. Some people call it type 2X as well, but there are two

00:13:39.400 kinds of muscle fibers. And I just want to interject for a moment because I know a lot of people listening

00:13:44.060 to this have heard the term fast twitch and slow twitch. And the assumption is that they twitch at

00:13:49.140 different speeds, but really it's that they twitch with a different force. And the speed is referring

00:13:53.920 to how quickly they fatigue, not the speed with which they fire. So when you're talking about a type 1

00:13:59.840 or a slow twitch muscle fiber, it's just a less forceful fiber. Whereas a type 2 fiber, and as you said,

00:14:06.160 they're divided into A's and B's. With each firing of, with each time that the muscle fiber fires,

00:14:11.880 there are more motor end plates and therefore it's generating more force. But the trade-off is

00:14:15.660 it's going to be more quick to fatigue. And why is that? Why does it fatigue faster? Because it comes

00:14:20.720 down to what you're talking about. Yeah, it's because metabolically they're more stressed. The way we

00:14:25.380 recruit muscle fibers or base a sequential pattern that is very similar to the stick gears of a manual

00:14:32.000 car. So you first start and you go in first gear. And as the RPMs go up, then you get to a point,

00:14:39.260 you get to the red zone. So that car cannot keep up with that first gear. You need to shift to second

00:14:44.600 gear and you speed up and the RPMs go higher. And then eventually you need to shift to third gear.

00:14:49.720 This is very similar to what happens at the skeletal muscle. The type 1 muscle fibers, slow twitch,

00:14:56.140 they can produce ATP, which is the energy coin, the classic that we always hear about,

00:15:01.900 which is what elicits that muscle contraction. So at low exercise intensities, we don't need to

00:15:08.380 contract the muscles nearly as forceful nor as fast as when we do high intensity.

00:15:14.160 Meaning we don't need to go back and keep firing and keep firing and keep firing.

00:15:18.400 Exactly. And for that, we don't need to generate ATP as fast as we do at higher intensities.

00:15:24.260 And it's about ATP generation. That's exercise intensity. So at low exercise intensities,

00:15:31.320 those slow twitch muscle fibers or type 1 muscle fibers, they are very well designed to use an

00:15:38.420 energy that is good enough to provide ATP. And yet you can do this for a very long time. And that's

00:15:45.140 the diesel gasoline. And that is the fatty acids. However, as exercise intensity increases,

00:15:51.480 the necessity to produce ATP at a higher rate increases as well. And it gets to a point where

00:15:58.880 fatty acids alone are not enough to produce ATP. And therefore you need another energy system.

00:16:06.120 And that energy system is the glucose, which is a faster energy system, which going back to the

00:16:11.500 analogy of the car is like if we had, imagine a car with two tanks, one is gasoline and the other

00:16:18.580 one are regular gasoline and the other one is diesel gasoline. So if you were to go from here to Denver

00:16:24.760 to Kansas where everything is flat and you don't need to accelerate or go fast, you would try to be more

00:16:30.040 efficient and would try to use then the diesel gasoline. It's more economical. You get more

00:16:34.780 miles per gallon. But if you want to go to the mountains and you need to accelerate fast, that diesel

00:16:40.940 might not do the trick. You need extra acceleration. So that's where you utilize the glucose.

00:16:46.720 And that's a very, I mean, the regular gasoline, which is like the glucose for the muscles. And

00:16:51.020 that's kind of how the bioenergetics of the muscles kind of principles start.

00:16:55.320 I like the way you've explained it. And I did a much worse job. I think probably seven years ago,

00:16:59.920 I wrote a blog post on this. The insight I was trying to get across, I don't know if I did,

00:17:04.460 was that we should not think of aerobic and anaerobic as with or without oxygen, which is sort of the way

00:17:10.060 people are taught in high school biology. Aerobic means in the presence of oxygen. Anaerobic means not in the

00:17:15.480 presence of oxygen. No, it's always in the presence of oxygen. It comes down to the speed with which the

00:17:19.780 muscle is demanding ATP. Aerobic means you're generating ATP at a rate that is slow enough that

00:17:27.400 all of the metabolic demands can be met through mitochondrial oxidation of hopefully mostly fatty

00:17:35.180 acids, but even glucose. Anaerobic just means exactly as you said, the demand for ATP has now exceeded

00:17:42.840 the capacity of the mitochondria. Do you agree with that? Yeah. And even the cytosol. So the

00:17:47.360 cytosol, which is a part of the cell, that's where you can oxidize glucose there into pyruvate. And that

00:17:54.580 pyruvate doesn't enter the mitochondria, but you produce lactate, but you produce energy and ATP

00:18:00.820 there. And that can perfectly be still aerobic capacity. And my colleague, George Brooks from Berkeley,

00:18:06.580 he's been studying lactate since the eighties. And he's the one who proved it, that you can produce

00:18:11.920 lactate under fully aerobic conditions, not necessarily in the mitochondria, but in the

00:18:16.280 cytosol. However, when the ATP demands even exceed the cytosolic production of ATP, that's where you

00:18:23.860 need to use the ATP that is already stored in the muscles. You just don't have time to synthesize it.

00:18:29.060 You need just to use it. And that's why the body stores very, very minimal amounts of ATP. And that's

00:18:35.260 what you develop in the sprint, where you use in the sprint, but you need to resynthesize it very fast.

00:18:40.200 That's the pure anaerobic. You don't need any energy systems. And that goes also that of the

00:18:45.820 confusion that is out there too. And are you saying this is distinct from the creatine phosphate

00:18:49.600 system? Yeah, you can use the creatine phosphate as well. So you can have ATP and you can use the

00:18:54.900 creatine phosphate systems. Those two, they don't need oxygen necessarily. Anything else can be under

00:19:01.160 fully aerobic conditions, like even cytosolic production of ATP in the cytosol without mitochondria

00:19:07.740 or oxidation necessarily can happen under fully aerobic conditions. And in fact, that's what

00:19:13.220 we also call aerobic glycolysis. And in other areas of biomedical research or medicine, it's called

00:19:19.600 the Warburg effect, which is now a lot of people are into cancer talk about it. The Warburg effect is

00:19:25.280 that, is the production of lactate or the utilization of glucose in the cytosol, not in the mitochondria,

00:19:32.480 but in the cytosol outside the mitochondria for production of energy.

00:19:35.260 Well, I want to come back to the Warburg effect, but you brought up Brooks and there's a paper that

00:19:39.460 the two of you wrote together somewhat recently. I think it was maybe 2018, if not this year, but

00:19:45.380 it's actually, I'm in the process of writing a book, as you may recall. And in the exercise

00:19:49.900 chapter, I actually really explore that paper that you guys wrote, which looked at the zone two

00:19:54.860 efficiency of world-class cyclists, recreational athletes, and people with diabetes. That's an

00:20:02.040 unbelievable paper. And that's an unbelievable example of, I think the clinical applicability

00:20:08.560 of what we're talking about. So to put it in context, when we got talking back in Abu Dhabi

00:20:13.500 last year about this, I remember you saying, and I'm paraphrasing, so you should clarify if I'm not

00:20:18.880 saying it correctly, that your interest in athletes is in large part due to your interest in diabetes,

00:20:26.420 diabetes. Because if you want to understand how to fix an example of arguably the most

00:20:33.120 defective mitochondria, why not at least study what the perfect mitochondria look like? Is that

00:20:38.740 a fair statement?

00:20:39.620 Exactly. Yes. And that's kind of what I'm trying to bring to the table. The elite athletes have the

00:20:45.060 perfect metabolism. And mitochondria is at the epicenter of metabolism and health, as you said

00:20:50.780 earlier. There are no other population in the planet with the mitochondria of elite endurance

00:20:55.680 athletes.

00:20:56.000 I was about to say, yeah, you said elite athletes. I would go even sharper. It really, in my mind,

00:21:00.260 comes down to cyclists and runners.

00:21:02.100 Yes. And triathletes.

00:21:03.800 Even more than swimmers because of just the duration of it. It's these people who can go out

00:21:08.680 and function at their anaerobic threshold for hours. And that's only really found in two sports.

00:21:16.440 Oh, yes. And that's what we see that even with an elite athlete. And I work with many elite

00:21:21.180 athletes. Yeah. You compare them and there'll be huge differences.

00:21:24.420 I guess I should add one. I think cross-country skiers are probably at that level as well.

00:21:28.060 Yeah. So this population is the population in the planet with the healthiest mitochondria.

00:21:32.400 So that's what I call perfection. And that's what I try to bring to the table that in order to study

00:21:38.740 other diseases where mitochondrial dysfunction is at the epicenter as well, we need to understand

00:21:44.240 what perfection is in order to understand imperfection. And what we see in people with

00:21:48.800 type 2 diabetes, for example, they are on the opposite metabolic pole of what a world-class

00:21:54.220 cyclist or runner is. So by knowing the mechanisms of why that metabolism in this world-class

00:22:01.260 athlete works, we can get to understand the imperfection or the imperfect metabolic pathways

00:22:07.400 and potentially develop diagnostic tools and even therapeutics for them as well as prevention programs.

00:22:14.280 Yeah. And really cancer and type 2 diabetes or insulin resistance as part of a spectrum

00:22:19.460 do represent two very common findings in the population. So if you look at what percentage

00:22:25.760 of the United States population either has cancer or is insulin resistant or has metabolic syndrome

00:22:30.540 and or type 2 diabetes or fatty liver disease, all of these things which are part of a continuum,

00:22:34.540 you're talking about half the country basically that has some form of dysfunction in the mitochondria.

00:22:39.580 In the case of cancer, we can debate how much of that is a genetic insult versus other things.

00:22:44.040 But because I want to talk so much about that, I want to go back and understand perfection a bit more.

00:22:48.600 So there are lots of different ways people codify energy systems. When I was cycling,

00:22:53.140 we used seven zones because that was Andy Coggins FTP based energy system. You write about six zones and

00:23:01.000 others have talked about five, but I want to talk about your six zones because one, I think they're a

00:23:06.360 little easier to explain than the FTP based ones, which if you don't know, if a functional threshold

00:23:11.100 power number doesn't mean something to someone, then seven energy systems based on it is harder to

00:23:16.380 understand. How would you walk us through zones one through six? What do they mean? Because when

00:23:21.240 we start to talk about zone two, I want people to understand the difference between the normal

00:23:26.140 person and the super person and the sick person. So what is zone one? What does that mean?

00:23:31.280 So that's from 25 years working with athletes and also my experience from being a former athlete and

00:23:36.580 being obsessed with training and, and all these things, that's kind of, it led me to develop this.

00:23:42.640 I'm not saying that they're the right things. And maybe in 10 years, I changed my mind or someone

00:23:47.520 else comes with different things are better, but that's what I have right now, at least.

00:23:51.660 So I do this along with the muscle fiber recruitment pattern and the energy systems. So the type one

00:23:58.600 muscle fibers, we know also that because they're the ones who oxidize fat, burn the fat very well,

00:24:06.320 they have the highest mitochondrial density and content because fat can only be burned in the

00:24:11.680 mitochondria. Type two muscle fibers, especially the first type of muscle fibers, type two, the type

00:24:17.180 two A's, they have lower mitochondrial function because...

00:24:20.700 Lower mitochondrial function or density?

00:24:22.420 Density. I'm sorry. Because they don't necessarily need to oxidize glucose in the mitochondria. They can

00:24:27.200 do it in the cytosol of the cell and therefore produce lactate, but they can produce ATP fast.

00:24:33.400 So those muscle fibers, they don't contain as much mitochondria. And then the second type of muscle,

00:24:39.580 slow fast twitch muscle fiber, the type two B or two X, that is the one that is the pure

00:24:45.140 anaerobic, if you will. And that is the one that barely has mitochondria, has very minimal mitochondria.

00:24:50.700 So starting with that, that's where I start breaking down the zones. So the zone one would represent

00:24:57.480 the minimum stimulation the muscle fibers receive. It's just pure contraction. That's what would you

00:25:04.100 do on a recovery day or recovery mode. You have very low exercise intensity and you burn a little

00:25:09.860 bit of fat mainly. And that's what we see also. We look at also fat and carbohydrate utilization.

00:25:17.320 Scientifically, we call it fat and carbohydrate oxidation rates, how many grams per minute of

00:25:22.080 carbohydrate and fat you burn. So we know that at this intensity is you burn mostly fat, although

00:25:27.880 you also burn a little bit of carbohydrates, which we can go through that. Yeah. I want to come back

00:25:32.540 to it because there's such an interesting clinical observation that I've seen over the past five or

00:25:38.020 six years. And your paper, your recent paper with Brooks just hammered it home in a much more rigorous

00:25:44.240 way. So yeah, we are going to come back to our cue at rest as a harbinger of these other things

00:25:50.760 that follow under distress. Yeah. So that's the zone one. So just to put that in energy terms for

00:25:56.060 people, you and I walking up the stairs, we were coming from the lobby, we're in zone one. Yeah.

00:26:01.600 Walking down the street. Walking down the street or if you are very fit and you go for a jog,

00:26:07.560 very easy recovery day, that's your zone one. And then for the elite, give us an example. So if you

00:26:12.700 took Meb or someone who's going to run a sub 210 marathon, you have a sense of how fast they could run

00:26:19.060 and still be in zone one. Someone who's used to running 445 to 450 miles, could their zone one be

00:26:25.360 as fast as like a seven minute mile? Yeah. Yeah, absolutely. You can see world-class athletes

00:26:30.640 that their zone one, it's my sprinting, for example. It's kind of what we see also in cyclists.

00:26:36.360 The recovery day is 200 watts average. And for most merimorals, 200 watts, they can do that for

00:26:43.560 15 minutes. Yeah. I just wrote a post about this recently using as an example. For people who ride

00:26:49.560 a bike, 200 watts is about how fast it would take you to go 30 kilometers an hour without wind or

00:26:58.020 without elevation. And that's certainly not all out, but that's pretty fast. And if you can imagine

00:27:04.900 being able to ride at that level indefinitely without any metabolic consequence, that's what an

00:27:11.640 elite athlete is doing. And that says nothing, by the way, about their weight. They're doing that at

00:27:16.440 a body weight that is a fraction of most people. Yeah. That's what they call the coffee ride. Yeah.

00:27:22.200 They go for a coffee or ice cream ride and they chit chat and they're like, it's unbelievable.

00:27:27.400 So zone one, does lactate get produced? It should not get produced. Well, we start from the base that

00:27:34.460 there's always lactate produced in the body. So if you were to poke my finger right now or poke your

00:27:39.960 finger right now, we measure lactate in millimolar, what would you expect to measure in me or you?

00:27:45.400 You would be about one millimole. Okay. 0.7 to one millimole. That's kind of like a standard

00:27:51.200 resting levels in a health individual. And in a normal person, so not an elite athlete,

00:27:56.560 but sort of a recreational athlete, what's the highest lactate you'll typically measure in that

00:28:01.740 person if you put them in a treadmill test or a... It depends on the protocol that you do.

00:28:06.320 If it's a very violent protocol or it's a longer protocol, violent protocols, they produce more

00:28:11.400 lactate. You might see 10, 12 millimoles, whether that protocol, let's say a six minutes maximal effort

00:28:19.580 on a rowing machine, right? And the concept, for example, I've seen world-class rowers. It's a

00:28:26.040 maximal effort with 20 millimoles of lactate. It's very rare. You see very easily 15, 16, 17.

00:28:32.740 That's because, and we can talk about that later, their glycolytic capacity, it's off the charts.

00:28:38.260 Whereas people who they're not elite athletes, it's for them that's in protocol, it's more difficult

00:28:44.500 to go over 12 millimoles, 10 millimoles, because their glycolytic capacity is not so good as the

00:28:51.560 one that the elite athletes have. And sometimes elite athletes have the opposite issue, which is

00:28:56.720 they don't make much lactate at all. They're so efficient. I've actually discussed this with Lance

00:29:01.560 Armstrong after I erroneously had been on a podcast and made the case that he had a very high lactate

00:29:07.580 tolerance. He was talking about it one day informally and he said, no, it's actually the opposite. I would

00:29:12.100 barely produce any lactate. He was usually producing less lactate than others. And again, this was when

00:29:16.960 everybody's on the same drug or everybody's off the same drug. I mean, just genetically, there are

00:29:20.640 some people who probably have more MCT, which we'll come back and talk to and they become more efficient

00:29:25.280 at it. But okay. So that gives us a sense that lactate will go from maybe one to 10. If you're

00:29:30.600 a normal person, maybe one to 20, I actually measured. 20 is difficult. I measured a lactate of

00:29:35.920 24 in a friend of mine once. Wow. The highest I've ever measured in myself was 19.7. Wow. And that was

00:29:42.140 only a four minute protocol. Wow. Pretty impressive. But also I almost wonder like maybe it's, I wasn't

00:29:47.580 even in particularly great shape at the time, but I wonder if that same exertion under better fitness

00:29:53.920 would have produced less lactate potentially, right? It depends on the protocol, right? If

00:29:57.900 the protocol stops there and what you intend is to produce, mobilize the glycolytic system

00:30:03.280 to the maximum, yeah, you will produce a lot of lactate. If you want to continue and do a longer

00:30:08.080 protocol, eventually you just cannot mobilize as much lactate. I mean, as much glycolytic system,

00:30:14.460 because you have a little bit more of fatigue. I think the difference between the really good

00:30:17.880 people, I mean, when I hit, if I hit, and I've been above 18 and maybe a dozen times, I'm done

00:30:23.200 for half an hour. Like I can barely get up off the floor to go and take a shower. Whereas this

00:30:30.080 friend of mine who was at 24, I saw him go from 24 to 14 in a span of about seven minutes and then

00:30:39.460 jump in the pool and swim another race. And he's world-class. So that's sort of the difference. I

00:30:43.660 think the world-class athlete can also clear the lactate much quicker than I can. For sure. And that's

00:30:48.500 what happens in the mitochondria and any other part of the body. Because one thing with lactate,

00:30:53.600 we believe that it's a waste product. However, lactate is the most important, if not the most

00:30:59.600 important fuel for the body. That's a profound statement. Yes. Yes. I completely agree with you

00:31:05.480 that lactate is not a waste product, but say more about that point. So one of the things, the brain

00:31:11.280 prefers to use lactate. So I have heard this. Talk to me about the data on this front. So my colleague,

00:31:16.880 George Brooks, who is lactate man. So yeah, he started doing research with TBI, traumatic brain

00:31:23.480 injury patients at UCLA. It's typical to give them glucose. And then when there's like a brain injury,

00:31:30.620 the brain in the first place has evolved to use glucose as the main fuel. So when the brain is

00:31:36.780 injured, they use more glucose. However, when it's injured, different metabolic pathways might be

00:31:41.800 dysregulated. So what my colleague George Brooks suggested was to give them lactate. And he showed,

00:31:48.300 and he published, they do better. Better than beta-hydroxybutyrate, which also seems to be

00:31:53.120 really beneficial in TBI patients for maybe a different reason than lactate, although it could

00:31:57.300 be all similar, which is if you buy the argument, which I find favorable, that part of the insult of TBI

00:32:06.200 is pyruvate dehydrogenase becomes resistant to insulin. That would explain why glucose becomes

00:32:12.420 ineffective in those patients. And it would explain why beta-hydroxybutyrate can bypass it. And the

00:32:17.660 same could be true of lactate. Yes, absolutely. It's an alternative substrate that doesn't get

00:32:22.220 limited through pyruvate dehydrogenase. Is that what you think is happening? Yes, because it has its own

00:32:26.980 transporter in the mitochondria and doesn't need PTH for that. It can enter the mitochondria directly for

00:32:33.140 energy systems like hydroxybutyrate as well. But the thing is like lactate is a faster fuel.

00:32:38.400 So the thing is like also... Yeah, BHB is not a fast fuel. Exactly. Whereas lactate is as fast,

00:32:44.780 if not faster as glucose, because it doesn't have to be processed, if you will. Now the listener might

00:32:49.740 say, wait a minute, what are you guys talking about? Anyone who's ever done a lactate test knows how

00:32:54.100 much pain you're in when your lactate level goes up. So one of the other, I think, misunderstandings is

00:32:59.880 what's actually causing that pain. Because that's, I think, why so many of us have a negative

00:33:04.520 association with lactate. It's not actually the lactate that's causing the physical discomfort

00:33:09.380 that you feel when you're vomiting on the floor after a maximal lactate test. It's the hydrogen.

00:33:14.220 So explain why that's the case and why we tend to confound the two.

00:33:17.720 I mean, there are many causes for pain or fatigue that in different hypotheses from the central fatigue

00:33:23.120 to the peripheral fatigue. And it's very possible that both are interconnected at some point,

00:33:28.840 and we don't know the exact mechanisms. At some point, the central fatigue calls for the brain to

00:33:34.060 be the ruler, where the peripheral fatigue is what happens at the cellular level. So it is possible

00:33:39.580 that there's like a crosstalk among both of them, and either the chicken or the egg, right? Either one

00:33:45.000 of them says stop. But what we know is that, yeah, it's not lactate itself, but the hydrogen ions

00:33:50.340 associated to lactate, they build up. One of the things that, and it's been researched,

00:33:55.460 they can decrease both the contracted capacity of the muscle fibers, as well as the force by up to

00:34:02.240 50% or more. So that's one of the things that what we see is like the muscles, they cannot contract

00:34:08.680 as fast or as forceful as before. And this is an important point for people to understand,

00:34:13.220 because if you haven't taken a physiology course, why would most people do so? It's also not obvious

00:34:19.380 why you even need ATP to make your muscles contract. It's actually to unleash or unlock

00:34:26.040 the actin myosin contact. It's the relaxation phase of the muscle that requires energy.

00:34:31.780 Exactly.

00:34:31.920 So now, if you imagine anybody who's done that, sit on the rowing machine for four minutes and

00:34:36.960 go as hard as you can, well, at the end of that, anyone who's done it will acknowledge it feels like

00:34:42.020 you can't actually contract your muscle. You've lost the voluntary ability to make them do what you

00:34:47.420 want to do. And it's really two things going on. It's this hydrogen poison. And then on top of that,

00:34:53.700 you're not generating enough ATP to hit all of those fibers that need to be uncoupled from their

00:34:59.700 actin and myosin. So anyone who's been there knows, like you think I'm going crazy. Why can I not make

00:35:05.240 myself do this?

00:35:06.200 Yeah. And that's where maybe the central fatigue component, the brain might be-

00:35:10.260 Must be factoring in as well.

00:35:10.960 You're kicking in and say, hey, dude, you know, you're getting to a point that this is not

00:35:15.820 physiological. So I'm going to protect your muscles. And they're telling me through different

00:35:20.520 signals, one might be the hydrogen ions, which also are produced from the hydrolysis or the

00:35:26.200 breakdown or ATP. They produce also hydrogen. So you have the lactate on one hand and the ATP

00:35:31.620 or the fast rate of ATP hydrolysis also produces hydrogen ions. But yeah, as you said very well,

00:35:37.160 like your conscious wants, but there's something at the neuromuscular level also that impedes

00:35:43.800 that. Could be at the local level specifically, but could also perfectly be that the brain says,

00:35:50.340 hey, let's stop it. And one of the things that we know when people are fatigued is that there's a

00:35:55.840 decrease in adrenaline secretion to protect yourself because adrenaline or epinephrine, we call it here

00:36:03.320 in the US epinephrine in Europe is called adrenaline is the major or one of the major

00:36:08.220 elements involved in the breakdown of glycogen into glucose. We can talk about that later as part of

00:36:13.920 the overtraining, but the adrenergic activity, it's also decreased as well when someone is in a

00:36:19.720 fatigued state. So by the way, Alex Hutchinson's written a great book on this. Have you,

00:36:24.120 have you read his book Endure? I heard about it, but I haven't read it yet. Again, it's good for

00:36:28.740 someone like me who comes into this without world-class knowledge. And I found that a very

00:36:32.920 interesting survey. In fact, I hope to have him on the podcast at some point to go into some real

00:36:36.640 depth on that. So now we've talked about the two ends of the spectrum, the most extreme end and the

00:36:41.280 first end. Let's now get into zone two. What's happening physiologically as that athlete or that

00:36:46.300 person enters zone two? So the zone two is that now, then when you start stimulating those

00:36:52.280 slow twitch muscle fibers to the fullest, let's imagine that you're in that first gear that I mentioned

00:36:58.200 earlier in the manual stick car, and then you're in that red zone. And that's where the car is asking

00:37:04.440 you, hey, shift to second gear. And that's where like you're forcing physiologically because the

00:37:10.020 body adapts to say, no, you get stronger at this gear. That's kind of that zone two is like when you

00:37:16.680 stimulate those muscle fibers before you start changing to a whole different environment where

00:37:22.960 you start then recruiting fully the type two or fast twitch muscle fibers, and therefore the

00:37:29.580 different energy system, which is the glucose. So the zone two coincides also with what we call the

00:37:36.760 fat max, which is exercise intensity at the one you oxidize the highest amount of fat. And then we can

00:37:43.580 see that clearly in the laboratory, as we saw in the graph that we can show. Yeah, we're going to include

00:37:48.400 a lot of great pictures here. So if you're looking at the show notes, there's something called the

00:37:51.920 metabolic map, which is a great slide that we'll walk through this. And I think what's very interesting

00:37:56.700 here, this occurs so often in physiology, it's a bit counterintuitive. As you go from zone one to two

00:38:02.840 to three to four, five, and six, you're generating more and more ATP as you go up that chain. So that part

00:38:09.920 is monotonic. It's increasing without stopping, but there's a local maximum that's occurring in zone two,

00:38:16.160 which is your highest amount of fat oxidation. So as you go from zone two to three to four,

00:38:23.240 you will still produce more energy. You will consume even more oxygen. Your VO2 max has not

00:38:29.960 been achieved, which is your maximal uptake of oxygen, but you will now become less efficient and

00:38:35.840 you're moving to a less efficient fuel. You're moving away from this diesel example or the fat. So

00:38:40.480 again, I think for a lot of people, the semantics get confusing here because you just said that zone

00:38:45.880 two is your maximum. I mean, maybe a better way to explain it for me is zone two is the place at

00:38:52.240 which your mitochondria are producing the maximum amount under purely aerobic conditions of ATP. Is that

00:38:58.740 fair? I would say that too. And that's where you still recruiting those type one muscle fibers. That's

00:39:04.360 the exercise intensity where you're creating the most and they had the highest stimulus. Without tipping

00:39:10.320 into the twos. That's basically it. And since that type one muscle fibers have the highest mitochondria

00:39:15.900 density, you're really stimulating them a lot. As you said before, you need to tap into the fast

00:39:22.540 twitch muscle fibers. And in the moment you tap into the fast twitch muscle fibers is because the ATP demand

00:39:29.400 that you need cannot be covered by fat and you need to switch to a different fuel. And that's where we

00:39:37.320 see a big drop in fat oxidation and we see an increase also in glucose oxidation. And that's when we start

00:39:45.560 seeing also an increase in lactate as well. Because lactate is always, and I forgot to mention that earlier,

00:39:53.400 lactate is the mandatory by-product, not waste product, by-product of glucose utilization. Mandatory.

00:40:01.560 Every time you use glucose, you use lactate. And at higher intensity, you produce more.

00:40:06.920 Let's talk about that because again, I think that's more nuanced than most of us would come to this

00:40:11.580 discussion with. We learned in physiology class that a molecule of glucose in the cytosol is turned into

00:40:19.520 two molecules of pyruvate. Under conditions of sufficient cellular oxygen to meet the ATP demand,

00:40:26.880 the pyruvate enters the mitochondria where it undergoes oxidative phosphorylation to make ATP

00:40:32.460 and no lactate is generated. If that ATP demand exceeds the capacity that you just described in zone two,

00:40:41.060 we now have to start turning some of that pyruvate into lactate to generate additional ATP that's faster

00:40:48.260 to generate. In the first case that I described, is there still by necessity, some lactate production?

00:40:54.700 Yes, there's some lactate production. And we can see that even at rest, we have always a little bit

00:40:59.980 of lactate in our bloodstream. Which is what you said at the outside. You said, if you checked my finger

00:41:04.360 or your finger now, we would probably still have somewhere between 0.7 and one millimole of lactate.

00:41:09.180 Why is that? That's where we're trying to understand. And we believe, my colleague George Brooks

00:41:13.940 and I, that lactate is a major signaling molecule that when it's regulated, it can signal and maintain

00:41:21.520 homeostasis of different metabolic pathways. It's kind of like a visa for the body, as my colleague

00:41:27.800 George Brooks calls it. When it's dysregulated, as we're starting to see in cancer, for example,

00:41:33.280 or we can see in type 2 diabetes, it can dysregulate different pathways. Every cell in the body produces

00:41:39.900 lactate. And pretty much every cell in the body consumes lactate.

00:41:43.700 Including red blood cells, I'm guessing?

00:41:45.680 Yes. They produce a lot of lactate, red blood cells, because they don't have mitochondria.

00:41:49.940 Yeah, I wonder if-

00:41:50.560 It's glycolytic mechanism.

00:41:52.000 Yeah. Do the red blood cells account for most of the lactate production we see at baseline?

00:41:56.520 Not necessarily, because there's not so much hemolysis and there's not so much

00:42:00.820 activity in the red blood cells. But there's always some metabolic lactate produced from glucose

00:42:06.580 utilization, because we always use a little bit of glucose, of course, the brain. But that lactate

00:42:12.940 escapes to the blood, to the circulation. And for us, it's significant that it's always so steady

00:42:18.440 also. And every cell in the body produces lactate, and almost every cell in the body utilizes lactate.

00:42:24.120 So it's got to be a why. And we believe, and that's what we're trying to scratch the surface,

00:42:29.860 that it's a very important signaling molecule that goes beyond being a byproduct or metabolite.

00:42:37.500 And that's something that we've already seen in cancer, where we have seen that lactate

00:42:41.580 stimulates the expression of the major oncogenes, transcription factors, and cell cycle genes

00:42:49.320 in breast cancer. So it's acts, and we have the paper on the review now, it acts as a signaling

00:42:54.980 molecule.

00:42:56.300 So this is interesting, because again, in physiology class, you sort of learn that all of that waste

00:43:00.700 lactate goes back to the liver, and the Cori cycle converts it into glucose, and it becomes now stored

00:43:07.040 glucose. But what you're saying is it's much broader than that. I mean, obviously, the Cori cycle still

00:43:11.800 exists, but it's not even clear how much of the lactate that we're measuring is undergoing that pathway to be

00:43:18.260 converted back to glucose versus itself being consumed as a fuel, correct?

00:43:22.320 Yes. And thanks to the great work that my colleague Brooks did starting in the 80s, what he saw is

00:43:27.320 that the majority of that lactate is oxidized by the slow-twitch muscle fibers, by the mitochondria of

00:43:34.980 the slow-twitch muscle fibers.

00:43:36.780 And each mole of lactate gives how many moles of ATP under those conditions?

00:43:41.580 I don't have it on top of my mind right now.

00:43:42.880 Is it a small number or a big number?

00:43:44.000 Yeah, it'll be a smaller number as well.

00:43:46.340 But it's not like the 16 or whatever you get per acetyl-CoA.

00:43:49.780 No, no, no, no. I don't think so. I don't have it on top of my head. But the thing is a constant

00:43:54.020 flux of lactate from the fast-twitch muscle fibers to the slow-twitch muscle fibers. That's when you

00:44:00.260 start entering that zone three. You start mobilizing more of the glycolytic system, and that's kind of

00:44:05.380 a transition state where you still mix fuels, fatty acids, and carbohydrates, but you start using more

00:44:12.820 carbohydrates, and therefore you start producing lactate. That's said that lactate is transported

00:44:18.820 from mainly from the fast-twitch muscle fibers into the mitochondria of the slow-twitch muscle fibers,

00:44:25.300 where it's used for energy. It enters directly the mitochondria for energy purposes. And that is the

00:44:31.460 ability that elite athletes have. They can be recruiting fast-twitch muscle fibers. They can be

00:44:38.180 utilizing a lot of glucose and producing a lot of lactate. But since they have a very

00:44:44.020 well-developed mitochondria in the slow-twitch muscle fibers, they don't need to export it to the

00:44:49.940 blood, and it doesn't accumulate. Yeah, this to me is the grail. This is the stuff that sets apart

00:44:55.700 the best from the rest. Going back to zone two, tell me where you typically see a lactate level there.

00:45:03.460 You and I have talked about a bunch of these numbers. When I try to explain this to my patients,

00:45:07.140 because I have many of my patients on a zone two protocol, for a lot of the time, we just use

00:45:11.860 voice. We use ability to talk. I sort of say, look, if you don't want to go through the protocol of

00:45:16.180 poking your finger, zone two is about the highest level of exertion at which you're still able to

00:45:20.980 carry out a conversation. But let's talk more technically. We're really seeing what, lactate

00:45:26.340 levels of about 1.7 to 1.9 millimole? Yeah, 1.5 to 2. That's something what we see,

00:45:32.900 and that's kind of what corresponds also to that fat max. So today, my data that I showed

00:45:37.700 you from my ride this morning, I was 1.3 and 1.2 on my two meters. So I always do two separate meters.

00:45:44.340 So I average 1.25 millimole. That was clearly not zone two. That was a zone one. It depends the

00:45:49.700 feeder that you get. Like for example, a world-class athlete at zone two is really high. Yeah. Well,

00:45:54.820 I'm not world-class, but just by lactate levels, that's probably not quite there.

00:45:59.620 Yeah. It might not be quite there because it's slightly above resting levels. So there's no

00:46:04.020 accumulation. And it's this accumulation. There's a homeostasis or a steady state

00:46:10.020 below two. So call it 1.7, 1.8, 1.9, where you're right at the limit of not accumulating at a net level.

00:46:17.620 Correct? Yes. Yes. So you're pretty much, that lactate comes, you obviously see it in the blood

00:46:22.980 and it comes from the muscles. So that means that the muscles overall are good. First,

00:46:28.340 they're not very metabolically stressed. So therefore they're not utilizing a lot of glucose.

00:46:34.500 And even if they're stressed, they're clearing the lactate very well, because you see in blood

00:46:39.620 1.5, 1.7, 2 millimoles, slightly above resting levels. However, when you start seeing higher lactate

00:46:46.580 levels in the blood, that means that your muscle clearance capacity cannot meet.

00:46:53.220 No, I think what you're saying, if I understand, is once you hit 2, 3, 4, 5 millimolar,

00:46:58.660 you're saying that the muscle's ability to recirculate and utilize the lactate is going down.

00:47:03.940 It has to export it into the circulation? Exactly.

00:47:05.940 Exactly. And that's where it goes to every cell in the body. It goes to the brain,

00:47:09.780 it goes to the kidney, it goes to the heart. The heart is a great utilizer of lactate. And obviously,

00:47:14.260 as you said earlier, it goes to the Cori cycle to be resynthesized back to glucose or to a certain

00:47:19.460 length for form of glycogen. But yeah, that's when we see that in blood, that means that that athlete

00:47:23.940 cannot clear the lactate efficiently. And therefore that's why it shows up in the blood. And that's where we

00:47:29.540 can see that, for example, one professional athlete at 300 watts, a world-class athlete might,

00:47:36.740 well, let's say, yeah, 300 watts might have three millimoles of lactate, let's say, or two and a

00:47:41.140 half. And a memorial might have 12. That means that the power output is the same, but how do you get

00:47:47.540 there? It's different. In the first place, the elite athlete might not need to use so much glucose.

00:47:53.780 And if they do, they produce lactate, but they clear out so efficiently

00:47:58.500 in the slow-twitch muscle fibers that it doesn't have to go to the blood. Whereas the person who

00:48:05.140 doesn't have a very good mitochondrial function cannot oxidize lactate very efficiently locally

00:48:11.860 in the skeletal muscle, and they have to export it to the circulation. And that's a way to see the

00:48:17.460 metabolic stress. And indirectly, as we published, a way to look at what is the mitochondrial function.

00:48:24.340 So let's talk about that now. I do want to come back and talk about zones three and up,

00:48:28.340 but because this is the perfect point to go back to the paper you and Brooks recently wrote,

00:48:32.740 what you showed that I just thought was so elegant was, as you said, you can either cap the output or

00:48:39.540 clamp the power required or clamp the lactate production and look at the power required. And you

00:48:44.820 did the latter. You basically said, we're going to find everybody's zone two, meaning we're going to

00:48:49.540 find everybody's tipping point at which point their mitochondria are no longer high enough in function

00:48:56.820 to meet the requirement. And what you showed was world-class cyclists were able to get to an average

00:49:04.660 of something like 300 watts before they would finally flip that switch and have to start recruiting the

00:49:12.260 fast twitch muscle fibers, which was measured indirectly by lactate production. Conversely,

00:49:19.060 the weekend warrior reasonably fit people, guys like me could get to 200 watts before that switch got

00:49:27.540 flipped. But most interesting was the people with type two diabetes. I think we're like 120 watts.

00:49:34.340 Is that about right? Yeah. We've been knowing for years now that a typical characteristic that we

00:49:39.540 know of people with pre-type two or type two diabetes is that they have a poor metabolic flexibility

00:49:45.780 that is called also a poor capacity to oxidize fuels. One of them is fat. We know that fat can only be

00:49:52.500 oxidized in the mitochondria. Therefore, by measuring the fat oxidation of these patients, we can indirectly

00:50:00.980 see the mitochondria function, especially when we put them in context or in comparison with those ones who

00:50:07.620 are healthy individuals that could be moderately active individuals who don't have diabetes or pre-diabetes or

00:50:14.500 don't have any medications or elite athletes. So that's what we see that their fat capacity is very, very low.

00:50:21.060 And that's kind of what we can see directly. But it's not often you see in biology, such a difference

00:50:26.580 because if the numbers 300 versus 200 versus 100 sound extreme, that's nothing compared to when you

00:50:34.020 normalize by weight. So really the answer is in watts per kilo, what's the difference? And 300 watts to

00:50:41.140 a professional cyclist who only weighs 60 to 65 kilos is just below five watts per kilogram. Whereas the

00:50:48.580 person with diabetes almost assuredly weighs more. So their 120 watts is probably 1.5 watts per kilo.

00:50:57.940 There are not a lot of examples of things in physiology where you see that much of a difference.

00:51:02.820 You rarely even see that much of a difference in average glucose level between someone with diabetes

00:51:07.540 and not. So this functional definition that you guys have proposed is to me very important,

00:51:16.100 just as a clinician, just as someone who's trying to gather more data about a patient to understand

00:51:24.260 their health. It's sort of like in a magic scenario, in a magic world, you would have these data on every

00:51:30.100 single person. You would want to know what is your zone two threshold. And that becomes a way to assess

00:51:36.020 mitochondrial function. Now the story I was going to tell earlier, this is as good a time as any to tell

00:51:40.020 it. About five years ago, in some of the most insulin resistant patients that I was taking care of,

00:51:45.220 I began looking at baseline resting respiratory quotient, which you alluded to earlier. This is

00:51:51.380 the ratio of produced carbon dioxide to consumed oxygen. Say a little bit about that number and how

00:51:59.060 to interpret it. And then I'll finish the story. So that's kind of, we can see through expired gases.

00:52:04.500 We can see the amount of CO2 that you produce and the amount of oxygen that you utilize.

00:52:11.220 So under resting conditions, and that's what's called the respiratory coefficient or the respiratory

00:52:17.300 exchange ratio. The respiratory exchange ratio is purely at the respiratory level, at the lung level,

00:52:23.860 with the respiratory quotient, it's at the muscle level. They're quite similar, but not academically.

00:52:29.540 You know, that might not the same, but we can call it RQ or RER2. So under normal conditions,

00:52:35.460 you don't produce much CO2. So the ratio, it's always below one, could be 0.7, something like that,

00:52:42.660 for example. That means that it's CO2 divided by oxygen. So that's where you don't produce a lot of

00:52:50.180 CO2. You use more oxygen and therefore the ratio is 0.7. As exercise intensity increases.

00:52:56.980 And so that ratio of 0.7, we can impute from that, that a person is virtually all dependent

00:53:03.940 on fat oxidation at that moment. Probably. Yes. And that's what we can use

00:53:07.940 through what's called a stoichiometric equation. You can deduct the amount of fat it is oxidized,

00:53:13.700 because to oxidize one mole of fat, you need X amount of oxygen and you produce X amount of CO2.

00:53:21.060 So by measuring both, you can see what kind of fuel you're burning. And that's what we're doing

00:53:25.780 in our paper. So as exercise intensity increases, or if the person is not metabolically flexible,

00:53:32.260 they cannot oxidize fat very efficiently. So normally these people, they tend to defend,

00:53:36.980 to depend more on glucose or any other extra source of fuel. And that's why you see use already people

00:53:43.380 at rest, they have a higher RQs or RERs, which could be in the eighties. Then as exercise,

00:53:50.820 if you were to do exercises, exercise intensity increases, you still produce more CO2 and therefore

00:53:56.660 the ratio starts getting closer and closer to one. And that's where we see that you start

00:54:03.220 oxidizing more glucose than fat. When the ratio gets to one, yeah, it's just a hundred percent of the

00:54:10.020 fuel that you use is glucose and you don't see any fat, which is kind of what we also call kind of that

00:54:16.980 end of the zone four. Yeah. So this was the observation. I was noticing a subset of patients,

00:54:23.060 again, very hyperinsulinemic, insulin resistant by whatever metric you would use to explain it,

00:54:29.220 that had resting RER or RQ of 0.9 to 1, easily 0.95. So what does it mean when someone who is laying down

00:54:41.380 to do this test under no physiologic distress has an RQ of 0.95? What does that mean? Obviously,

00:54:50.580 based on what you said, it means they are almost exclusively relying on glucose and not oxidizing

00:54:56.100 any fatty acid. But what is that telling you at a molecular level about the illness or the function

00:55:02.580 of that person's mitochondria? It's a red flag for mitochondrial dysfunction right there,

00:55:07.460 because that's not normal. Obviously after eating a meal of carbohydrates, yeah, for a while you're

00:55:12.260 going to have a higher RQ, but at rest in the fasting state when someone is in the 90s.

00:55:17.940 This is a morning fasted resting test. It's a red flag that is already telling you

00:55:22.660 that there's something going probably at the mitochondrial level. And this is what we wanted

00:55:27.140 to do this paper that we wrote. We want to see the same thing that is done usually at the EKG

00:55:34.100 level. So when a cardiologist wants to study the heart, if there's any abnormality,

00:55:39.060 resting EKG has a reliability of about 50%. So you could see some red flags already,

00:55:45.940 but you don't see everything. You have to stress the heart to see something.

00:55:48.820 Exactly. And you stress the heart and similar protocol than what we did here. And that's what

00:55:54.660 you do when you do EKG in stress situations. Derailability is about 95, 97%. So you see a lot of things.

00:56:02.420 So I decided to take the same approach and say, okay, now at rest, as you very well said,

00:56:08.420 you see people in the nineties with RQ and that's a red flag. Now, okay, let's stress those

00:56:14.260 mitochondria. Right. So in other words, the analogy is sometimes you'll do an EKG on somebody at rest and

00:56:19.380 you'll see changes in the ST segment that tell you immediately there's a problem. But there are many

00:56:24.020 people who have a normal resting EKG, but only when you put them on the treadmill and make them run,

00:56:28.340 do you see that change in the electrical signal that tells you there's a problem? And so similarly,

00:56:32.580 maybe somebody walks around with a resting RQ of 0.8 and you think, oh, they're perfectly fine.

00:56:37.940 But you see that their zone two level, the level at which they tap out at their fat

00:56:43.460 oxidation maximum or their maximum aerobic output is much lower than predicted. And now you have a

00:56:49.860 functional assay. Exactly. You can categorize people by looking at the fat and also looking at the

00:56:56.820 lactate. If you burn very little fat, that means that you don't have a good mitochondrial function.

00:57:02.580 And that confirms it, that test. If you produce a lot of lactate, that means that you don't have

00:57:08.020 a good mitochondrial function either because lactate is metabolized in the mitochondria. So if it's in the

00:57:14.020 blood, that means that the mitochondria cannot metabolize it. So what we did with the three

00:57:18.340 populations from world-class athletes to moderately active individuals with people with metabolic

00:57:23.540 syndrome, which is a companion of type 2 diabetes, pre-type 2 cardiovascular disease as well, or what

00:57:29.620 we call now cardiometabolic disease, because 80% of people with diabetes has cardiovascular disease

00:57:34.900 and vice versa. So these people, what we did then with these three groups is then we paired both

00:57:40.580 the fat curve, burning curve in the test, as well as the lactate. And the correlations were

00:57:47.700 in the nineties. So we see that it's a valid indirect test to see the mitochondrial function.

00:57:53.460 Now, as we speak, and in this office right now, we have all the supplies. We're going to do this now

00:57:59.860 with muscle biopsies, and we're going to try to prove not just this, but what are the metabolic

00:58:06.100 pathways? Wait, do you have the IRB approved already?

00:58:08.100 Yes. We're going to start next week. We already have-

00:58:10.020 Can I do it tomorrow?

00:58:10.980 We don't have the laboratory set yet. We're in the recruiting patients phase now.

00:58:15.620 I might have to come back and do this. I would love to get a muscle biopsy.

00:58:19.060 Yeah, we can do that because we're going to be looking in the muscle biopsy, mitochondrial density,

00:58:23.860 respiration. We have two different machines, the oraboros and seahorse where you can-

00:58:27.940 How many subjects are you looking to recruit?

00:58:29.620 Well, so far we want to have about 50. We're going to be recruiting people who

00:58:34.580 are well-trained. It's difficult to-

00:58:37.060 How will you define well-trained?

00:58:38.340 Well, yes. So well-trained are people who are usually competing. Like for example,

00:58:42.500 in cycling would be like a category three, two, and one.

00:58:45.460 Okay. So pretty serious cyclists.

00:58:46.980 Yeah, pretty serious cyclists. I'm going to try to see if I can fool

00:58:50.340 a professional athlete to get a muscle biopsy, which might be difficult, but I'm trying to.

00:58:54.580 Then we're going to have also moderately active individuals who are healthy. Then we're going

00:58:59.540 to have another group that is masters athletes. Those masters who are 50, 60, 70 years who don't

00:59:06.500 develop type 2 diabetes and they're very healthy. They don't take any medication

00:59:09.940 to match for the age of diabetes. And then we're going to be looking at pre-diabetics

00:59:15.380 and type 2 diabetes. And we're going to be looking at mitochondrial function,

00:59:19.380 mitochondrial respiration, genomics, proteomics, metabolomics as well,

00:59:23.940 and try to find the exact mechanisms that go wrong. Something that we see in this paper indirectly,

00:59:29.140 we know that's something wrong, but we don't know the exact. This is PDH enzyme,

00:59:33.860 or it is something that an LDH in the mitochondria that is not working or is faulty or is both of

00:59:39.460 them. And that's where we're going to try to target the mechanism so that it can give us maybe better

00:59:44.340 diagnosis or open the doors for maybe potential therapeutics to target those mechanisms that we

00:59:50.100 have seen that they're dysregulated.

00:59:51.300 Well, my guess is people listening to this, if they're interested, will be able to

00:59:55.540 very easily come and find where the enrollment is. And I might have to come back. And even if I

01:00:00.100 don't fit into one of the nice, neat buckets, I'll just, I'd love to do the muscle biopsy.

01:00:04.100 Now, of course you talk about the need for a treatment here, but you already know,

01:00:09.140 you've already discovered arguably the single best treatment imaginable for this, which is more zone two.

01:00:14.340 How do you increase mitochondrial function? You train at the maximum level of mitochondrial output,

01:00:19.380 correct? That's my hypothesis. And that's what I have been seeing for 25 years working with elite

01:00:25.140 athletes, that this is the exercise intensity where I see the biggest improvement in fat burning and

01:00:31.300 the biggest improvement in lactate clearance capacity. Therefore, that means that the mitochondria

01:00:36.740 is where you see the biggest improvement. We see also the biggest improvement in performance.

01:00:41.700 Pause there for a moment. You're coaching professional cyclists in the Tour de France. So

01:00:45.780 do they need to exercise at that low level of intensity? It's not that low level. Well,

01:00:51.380 for them, for them, it's low, but for us, it would be excruciating. But even for them,

01:00:55.860 because for them, their mitochondrial density infection is so incredible. And the way they

01:01:01.140 recruit the type one muscle fibers, it's so big that you need to push it. So it's having a much

01:01:07.220 bigger gear range. Exactly. Exactly. It's like in the first gear that we say, when you get to the

01:01:12.740 seven, 8,000 RPM, you're in the red zone. Okay. You push it there. These guys first gear is in the

01:01:19.700 15,000 RPM. So you still need to push into the 15,000, which could be, uh, they really go very fast,

01:01:27.540 but then you see their lactate and the lactate is not more than 1.8. So it's telling you that they're

01:01:33.940 just so efficient. They're incredibly efficient. Reusing that lactate and keeping it confined to the

01:01:39.780 muscle as another fuel for the adjacent fiber. Exactly. And if you see that in the blood,

01:01:45.060 there's such a low levels of lactate, that means that they're have a very good mitochondrial function

01:01:51.060 and they're stimulating that system there. When you see that any athlete or any person is in the

01:01:56.260 three, four, five millimoles, then you see that that system has given up already. It has to be

01:02:01.140 exported in the, to the circulation. Is the biopsy that you're going to do in this subsequent study

01:02:05.700 going to allow you to differentiate between two plausible hypotheses to explain this observation?

01:02:10.580 One being that they actually make less lactate. The other being their muscles actually utilize

01:02:16.740 more of it before it gets back into circulation. Both of those could explain the observation because

01:02:21.700 you're only sampling in the blood. So you're only looking at how much lactate is making it to the

01:02:26.580 blood. You don't know if it's just that they make less or they make the same amount, but use

01:02:31.220 it much more efficiently. Do you have a sense of that? We know that because my colleague,

01:02:34.740 George Brooks will be also a coauthor in this paper. He already has described that, that a

01:02:40.180 well-trained individuals, they can get to produce more lactate and at the same time they utilize it

01:02:45.700 better. So their gift, I'm using air quotes, the gift of the gifted athlete is not the production of

01:02:52.020 less lactate. It's the ability to re-utilize it more. Exactly. Yes. And we choose the skeletal muscle.

01:02:58.100 And this is a very important point in my opinion, because it's the, probably the first tissue where

01:03:03.540 diabetes starts, skeletal muscle. About 80% of all the glucose or carbohydrates that we oxidize in

01:03:11.060 the body after a meal, they're oxidizing the skeletal muscle. And within the skeletal muscle is in the

01:03:16.980 mitochondria. So that's why looking at the mitochondria of the skeletal muscle, it gives us a very good

01:03:22.180 ability to describe this in a more precise way. So again, if you could sort of as a thought experiment,

01:03:29.620 if you're looking at the muscle of someone who's going to get diabetes in two years versus the muscle

01:03:37.060 of someone who is not, what do you think they look like in terms of differences? So there'll be many,

01:03:43.220 but I just want to hear you talk through them, right? In terms of, so not talking functional at

01:03:46.660 this point, I'm just talking purely visible. Will there be differences in glycogen capacity of the

01:03:50.820 muscle? Will there be differences in the actual density of mitochondria? Will you see differences

01:03:55.540 in the types of fibers? I mean, again, just playing that game of, you know, this person's going to get

01:03:59.700 diabetes, this person's not. What looks different? So you would see very clearly, for example, that

01:04:04.820 well-trained athlete has at least three to four times the amount of mitochondria and the size of the

01:04:10.660 mitochondria. That's very visible that you would see it right away. And this is Toledo from the

01:04:16.900 University of Pittsburgh. He did a great paper where we can show it in the slides as well where

01:04:22.660 he can show that very well. So three to four times the number plus larger. Yeah. And that's the number

01:04:29.300 and the density of the mitochondria. Then we delve in the function of the mitochondria, how well they

01:04:36.020 function. That's the zone two that you've been talking about. Yeah. That's one of the things that we

01:04:39.940 believe it might stimulate different pathways for mitochondrial biogenesis, as well as different

01:04:46.100 pathways for the improvement of the efficiency of the mitochondria itself. Are there other functional

01:04:52.020 tests used besides the amount of basically ATP to lactate, which is what you're doing in a zone two

01:04:58.340 test? Non-invasively, to my knowledge, there are no other ways to look at mitochondrial function. You

01:05:04.660 would need to look at the muscle biopsy. And when they do a muscle biopsy, what functional assay are

01:05:09.620 they doing in vitro? When you look at muscle biopsy, this is kind of what we're going to be

01:05:14.820 doing. You can expose the tissue of the muscle to glucose, pyruvate, or fatty acids and see what is

01:05:22.660 their metabolism. You label them and you see what goes where. I see. So you will use metabolomics to

01:05:30.180 get a signature of the preference for different circulating fuels. Exactly. So we would be seeing

01:05:35.780 like this type 2 diabetics, for example, they barely use fat when they're exposed to fat. We trace that

01:05:42.740 fatty acid, but they have a much higher capacity or willingness to use glucose for energy. And that

01:05:50.180 energy might not be happening in the mitochondria either. It happens in the cytosol. That's one of the

01:05:54.660 things that there's what's called a metabolic reprogramming that happens in these patients, happens in type 2

01:06:01.620 diabetics, happens in cancer patients as well and in other diseases. There's like a local metabolic

01:06:07.140 reprogramming, but there's also a whole body metabolic reprogramming where you just cannot

01:06:12.580 synthesize fatty acids. I mean, you cannot utilize fatty acids for energy purposes very efficiently

01:06:17.780 because you don't have the mitochondria and you need to rely more on glucose. And at rest, glucose

01:06:25.140 is mainly oxidizing the mitochondria, as you said earlier. It goes to pyruvate, pyruvate enters the

01:06:29.860 mitochondria. But when your mitochondria at rest are not functioning very well, you need to rely on

01:06:35.220 the cytosolic production of ATP through pyruvate and then lactate. So this is why we believe these

01:06:42.980 patients rely on the most, the cytosolic and glucose utilization, which is what we see in higher

01:06:50.020 exercise intensities in athletes. And that's what we see higher lactate levels as a biomarker

01:06:55.060 for mitochondrial function. Do you see other differences between the very, very fit and

01:07:00.580 someone, again, who's going to go on to get diabetes just to make the experiment such that

01:07:04.500 you're not looking at someone with diabetes in terms of glycogen storage capacity?

01:07:08.260 Yes. We see that too. We see that. So I developed with a colleague here, John Hill,

01:07:13.060 from the School of Medicine, we developed a methodology to indirectly look for glycogen

01:07:17.380 content in a non-invasive way using ultrasound, high-frequency ultrasound. And we validated with

01:07:22.660 the muscle biopsy as well. And another researcher, David Neiman, also validated the system. And we saw

01:07:29.380 very good correlations with the scale that we use.

01:07:32.100 So just doing a high-frequency ultrasound of the quadricep, you can get to within what degree

01:07:37.780 of accuracy of a muscle biopsy?

01:07:39.460 With the muscle biopsy, we saw in the 90s, the R, the correlation, pre and post-exercise,

01:07:44.660 using the scale that we use. There are a couple of authors that have done a replication of the study,

01:07:49.860 but they have used a completely different scale. We know that the skeletal muscle glycogen is stored

01:07:55.780 in different parts of the body. I mean, in different pockets of the muscle and in different muscles.

01:08:01.460 So what we do is we look at the entire image of the rectus femoris, for example,

01:08:06.820 but in the validation, we did not validate the score of the rectus femoris with the high-frequency

01:08:13.940 ultrasound with the one square centimeter biopsy sample. We validated the image, the one square

01:08:21.380 centimeter image sample from the muscle biopsy with the muscle biopsy. And that's where you have the

01:08:27.940 same size in image. And therefore you have the correlation. A couple of authors,

01:08:33.380 they have correlated the entire muscle with different pockets of glycogen everywhere

01:08:39.460 with only the specific size.

01:08:40.580 I got it. But you did apples to apples.

01:08:42.660 Yes.

01:08:43.060 And you have an R squared of 0.9.

01:08:45.140 The R is, yeah, it's in the 90s, 93, 94, pre and post.

01:08:49.860 Wow.

01:08:50.260 Without the need of doing this.

01:08:51.700 And if you had to guess, two individuals

01:08:56.020 could differ how much between a person who's fit and someone who's insulin resistant.

01:08:59.940 So this is exactly to your question. So we see it very well. Others have done it before with muscle

01:09:04.420 biopsies where they have shown that feeder individuals, they can store more glycogen

01:09:09.700 than other individuals. And that's what we see. So on a scale from zero to a hundred that we have,

01:09:14.660 you see the world-class athletes, they can go to 85, 90, 100. Whereas someone like myself,

01:09:21.300 I'm considered now like a weekend warrior, right? I just, you know, try to exercise.

01:09:25.700 Oh, hang on, hang on, hang on. What's your FTP right now? I'll be the determinant of whether

01:09:29.940 you're a weekend warrior.

01:09:30.980 You know, to be honest.

01:09:32.340 If you had to guess, what is your FTP?

01:09:33.940 I don't even know.

01:09:35.140 Above 300 or below 300?

01:09:36.500 No, no. I, uh, I don't know.

01:09:39.140 275.

01:09:40.180 Yeah. I would say something like that.

01:09:41.780 Okay. It's still, you're not a weekend warrior.

01:09:43.700 No.

01:09:43.940 275 is still respectable.

01:09:45.860 I exercise four or five times a week, but to be honest, and I don't use a power meter. I

01:09:50.740 don't use a heart rate monitor. I just go to enjoy the ride.

01:09:53.540 How long does it take you to climb Mount Evans?

01:09:56.660 Oh, poof. I've only done it once. And it took me a long time. Since years ago, when I've been

01:10:02.900 playing with numbers all my life and be my own guinea pig, I got to know myself quite well. So I

01:10:07.860 should not say that, but I'm reading numbers all day. And the last thing that I want to do is like,

01:10:12.420 just read my own numbers. You know, when I go there.

01:10:14.660 I haven't got there yet. I've thought about it a lot, but I still obsessively look at all my

01:10:19.860 numbers and I still use a power meter when I'm doing all of the zone two training. Like I could

01:10:25.460 at this point probably just put it away and ride based on feel, but I don't know why I still love

01:10:31.140 the numbers, even though it depresses me a little bit because the numbers are so bad. But it's

01:10:36.740 interesting that you've been able to sort of separate yourself from that and say, look, I eat,

01:10:40.420 sleep and breathe the numbers in the lab and with my athletes. But when I'm riding it by myself,

01:10:46.020 you know what? I'm going to just enjoy myself.

01:10:47.780 Yeah. I mean, the laboratory reading all these numbers all day and working with athletes and

01:10:52.260 patients, I just go riding. And I know that I'm stimulating my mitochondria. And here and there,

01:10:58.500 that's right too. I bring my portable analyzer with you here and there. And I just double check

01:11:03.300 and like, okay, this is the zone two.

01:11:05.220 So I sort of interrupted you, but you were about to guess what your glycogen storage capacity would be

01:11:09.540 relative to the, so the world-class would be say 85 to a hundred.

01:11:12.740 Yeah. So I might be maybe 60 to 70, whereas people with like maybe type two diabetes might

01:11:18.660 be 30 to 40 or 50. They might have a normal glycogen storage capacity or on the low side,

01:11:24.900 but the well-trained athlete, they really increase it as well.

01:11:28.100 It's an irony because the fitter you are and the more glycogen you store, the less you are

01:11:32.740 dependent on it.

01:11:33.620 Yes.

01:11:34.260 Isn't that interesting?

01:11:34.980 Yeah, exactly. But at the same time, it's that energy that you need to

01:11:38.900 move quickly for energy purposes. This is a very interesting thing on the other side,

01:11:43.620 looking at the fat oxidation, the fat droplet. If you heard about that, the intramuscular

01:11:48.500 triglycerides, they are highly related to cardiovascular disease and type two diabetes

01:11:53.860 and insulin resistance. And this is the athlete's paradox. What's the name of the researcher?

01:11:58.420 Sorry, I blanked right now. But what he did is like the same approach of looking at,

01:12:02.740 they had been seeing that people with type two diabetes, they have this fat droplet. It's like a

01:12:08.740 a little deposit of fat right outside the mitochondria and it was a characteristic.

01:12:13.380 So what he did is like, okay, I'm going to look at, and then that was in comparison with people

01:12:18.740 without type two diabetes. They didn't have this fat droplet. So what he did is like, okay,

01:12:23.220 I'm going to see if elite athletes or well-trained athletes, what histologically characteristic they

01:12:28.180 have. And he found a big fat droplet as well, adjusting to the mitochondria. So that's the paradox.

01:12:34.500 It's like, wow, why in the world they have that fat stored by the mitochondria?

01:12:38.820 So what it was found that in the people with type two diabetes, that fat is not active. And in fact,

01:12:46.420 it can produce ceramides and other pre-inflammatory mediators that are not only involved with the

01:12:52.900 insulin resistance, but maybe with cardiovascular disease or atherosclerosis,

01:12:57.060 they cannot be oxidizing in the mitochondria. So they build up outside. Whereas in the

01:13:03.140 well-trained athletes, it's a reservoir there. The fat that we burn in the mitochondria, it comes

01:13:09.460 mainly from the subcutaneous fat and it has to travel. It's a long trip all the way to the muscle.

01:13:17.060 So why not from an evolutionary perspective, why not having a reservoir right there by the mitochondria

01:13:22.980 and effectively about 25 to 35% of all the fat oxidation that elite athletes do during exercise,

01:13:29.780 it comes from fat droplet. It's very active.

01:13:32.100 So do you suspect that in the study you're about to embark on, the biopsies will also show this,

01:13:37.620 that in your fittest and your least fit, you'll see the droplets?

01:13:41.060 Yes, we're going to look at that as well.

01:13:42.420 Why do you think that the average people don't have droplets? Does that mean you and I probably

01:13:46.740 don't have too many fat droplets in our muscle?

01:13:48.660 Probably not.

01:13:49.460 I would understand that if everybody had it sort of like structurally, but then there's a functional

01:13:56.500 difference where there's a gradation from the person with diabetes to the world-class athlete,

01:14:01.620 the gradation is in the utilization and activity of it. But why do you think people in the middle

01:14:06.740 of the road like us have actually lost the capacity for that reservoir?

01:14:10.660 Well, I think because we're not elite athletes.

01:14:13.620 But why do the people with diabetes still retain it, but in a static, non-utilizable fashion?

01:14:18.100 That's what we're trying to find out why. And in my opinion, is the hypothesis one that

01:14:22.820 went to test is that their mitochondrial function is not good. So therefore,

01:14:26.980 fatty acids cannot be transported into the mitochondria and they're sort of building

01:14:31.140 up outside the mitochondria. We can.

01:14:33.540 I see. But we haven't completely built our capacity to use it at high amounts

01:14:37.540 so we don't have the reservoir.

01:14:38.900 It's like the glycogen thing. We don't store 80 or 90 or 100 because we don't need it. And at

01:14:44.900 the end of the day, the body is very wise and it's based on a lot of evolutionary mechanisms.

01:14:50.500 And this is one of them, glycogen storage capacity, as well as the fat right outside the mitochondria.

01:14:57.060 I've always thought of that paradox through the lens of fat flux, which is when you take a snapshot

01:15:02.100 in time, which is what you're doing when you do a blood test or a biopsy, you're looking at something

01:15:07.620 in a moment. It tells you nothing about the velocity. And what I think your example illustrates

01:15:15.620 is that there's such a high turnover of things in the really, really fit person that even if it's

01:15:22.020 elevated, it's not problematic. Another place you see this, by the way, in the blood is free

01:15:25.780 fatty acid concentration. So when you're doing a blood test to screen for diabetes, if you're doing

01:15:32.260 very advanced testing, you're looking at lots of things, not just something as sort of banal as the

01:15:37.300 hemoglobin A1C, but you'll, you'll look at insulin and you'll look at insulin under sort of provocation

01:15:43.460 and you'll look at free fatty acids under provocation. And amazingly under the most metabolically

01:15:49.220 flexible and least metabolically flexible conditions, you see the same pattern, which is

01:15:53.380 higher free fatty acids. But again, it comes down to flux. Exactly. I suspect that in the person with

01:15:59.060 diabetes, it's just an accumulation of free fatty acid in the plasma. Whereas in the

01:16:04.260 very metabolically flexible person, if you were putting a tracer on that FFA, you'd see rapid

01:16:09.860 turnover. Exactly. Exactly. And exactly. And this blood analysis, they don't use a tracer. So you

01:16:15.940 just see, whoa, there's a lot of free fatty acids going around there. And like, what are they doing?

01:16:19.780 Where are they being metabolized for energy purposes in the metabolically flexible? And you see it very

01:16:24.660 well, kind of they're accumulating the other ones. This is kind of what we probably see at the cellular

01:16:30.260 level. So I want to kind of finish energy zones. Obviously at zone three, you're getting into,

01:16:36.020 you're exceeding the capacity to maintain a stable level of lactate, which tells you you're now

01:16:41.940 exceeding the mitochondria's capacity to be the sole provider of ATP. You are now becoming obligately

01:16:50.020 dependent on glycolysis in the cytosol. By definition, the percentage of fat oxidation

01:16:57.380 is now going down as the percentage contribution from glycolysis is going up.

01:17:02.420 Is this where the lactate threshold now occurs? Because I'm sure that people listening to this

01:17:06.980 who are going to say, wait a minute, wait a minute. I always thought lactate threshold was

01:17:10.100 around four millimolar. So how does that concept fit in?

01:17:13.380 I would put the zone three as a transition zone where your glycolytic system starts kicking in at

01:17:19.460 a very high rate because the ATP demand and your fat oxidation says, okay, I think I'm starting to

01:17:26.580 be done here. Now you take over. And that's where you start seeing a decrease in fat. Yet you use fat.

01:17:33.300 So it's not a completely glycolytic state. It's a transition phase. That is when we move into the zone

01:17:38.660 four. In the zone four, that's where we see very, very well that the lactate also you see an inflection

01:17:45.380 point. That kind of where we could see the lactate threshold where like all of a sudden the lactate

01:17:50.420 accumulation is not steady. It jumps and you see the inflection point. And at the same time,

01:17:54.980 that's where you usually start seeing the R of 1.0, the RQ, and there's zero fat oxidation.

01:18:03.220 So we know very well, it's like if there's a lot of lactate and there's no fat oxidation,

01:18:09.460 that's another metabolic transition point that is indicating that you don't burn fat anymore.

01:18:15.940 It just depends on glucose. Yet you can breathe and it's probably done in the cytosol. So you're

01:18:23.460 aerobic and that's the zone four. We'll be calling the lactate threshold, if you will.

01:18:29.060 And what's the clinical significance of that or even the athletic significance of that? I mean,

01:18:33.300 once an athlete goes above their lactate threshold, how long can they sustain that pace?

01:18:39.620 There are many lactate thresholds. So we might believe that lactate threshold could be

01:18:44.820 maximum effort you can sustain for 50 minutes or 20 minutes or the FTP. The FTP could be a way

01:18:49.940 also of lactate threshold for a fatal 40K.

01:18:52.020 So for the person listening to this, who's not familiar with that, FTP is defined as functional

01:18:55.940 threshold power in cycling. We use it as the maximum power that can be sustained for 60 minutes,

01:19:01.140 or sometimes we do a 20 minute test and discounted by about 10%. But I mean, an FTP test for me has

01:19:08.420 never felt linear. You know what I mean? Like if your FTP is 300 watts, the pain at minutes 10, 20,

01:19:16.420 30, 40, 50, 60 is not linear. Like the last 10 minutes hurt more than the first 50. But now that I

01:19:24.340 think about it, whenever I did FTP tests, I was usually doing them on the road, not on a stationary

01:19:30.340 bike. I never had lactate levels throughout, but my intuition is my lactate was increasing

01:19:35.940 non-linearly. I would always FTP test on a hill because it was easiest to maintain a fixed power

01:19:41.780 output. But what do you think is happening to a person's lactate when they're at that threshold?

01:19:46.500 I have seen that. And I presented at American College of Sports Medicine, poof, like about 10

01:19:51.380 years ago. And I have to publish it. It's one of the things that you have so much things going on

01:19:55.700 that sometimes you don't have the time. You need to get some med students working for you.

01:19:59.060 Yeah, I know.

01:20:00.580 I'm looking at the poster you're bringing up, but you haven't even published yet from 10 years ago.

01:20:04.500 Yeah. This is 2009 or something like that. But this is where back in the days, a lot of people

01:20:10.100 talked about power. Everybody would just train by power and what's our what's. I started to see

01:20:16.340 at the pro level, a lot of people using just power output and car rate like as an old school.

01:20:22.420 I was one of those people actually, you know, five years ago where it was,

01:20:25.780 I really didn't pay attention to heart rate at all, except to notice that there were some days

01:20:32.340 when at the same power, my heart rate was much higher and I felt and performed much worse. That

01:20:37.060 was about the extent of my observation. Yeah. I wanted to kind of show that with numbers. And

01:20:41.700 that's what I say, like, okay, power is power and speed is speed. The ability of humans to perform

01:20:49.540 relies on the ability to convert chemical energy into mechanical energy. The mechanical energy,

01:20:55.140 that's your power output. The chemical energy is like all the metabolic adaptations that get you

01:21:01.060 there. So this is what I saw and we can put it. This is a poster you presented about 10 years ago.

01:21:06.020 And by the way, this is, I hope there's a med student out there at the university of Colorado,

01:21:10.420 who's listening to this, who's, uh, figured out what their next summer's task is going to be,

01:21:14.820 which has helped turning this into a manuscript. But tell us a little bit about this experiment and

01:21:19.380 what it showed, because it's, as I look at the figure, I see it is answering, it is answering the

01:21:24.580 exact question I just asked actually. So yes, one of the things is that a lot of people start to talk

01:21:29.540 about watts are watts, right? They ditched the heart rate monitor because watts are watts, therefore

01:21:35.860 metabolically speaking is the same thing. But as I said earlier, the ability of humans to exercise

01:21:40.820 depends on the ability to convert chemical energy or biochemical energy into mechanical energy.

01:21:45.780 The mechanical energy is the end product, watts, but how do you get there? So I wanted to see and put

01:21:50.740 it to the test. So I had both a group of elite cyclists, professionals, and a group of recreational

01:21:56.740 cyclists, but well-trained as well. And I did a maximal test where I could get that peak power

01:22:03.060 output at the end of the maximal test. One group, the elite cyclists, the next test, I put them at 80%

01:22:10.900 the peak power output from the first test and the second group at 75%. And then I just let them stay

01:22:18.180 there for 20 minutes. So if the elite cyclist hit a peak power of 400 watts,

01:22:26.740 on the previous test, 80% of that. So now you put him at 320 watts and say, you're going to spend 20

01:22:35.220 minutes here. And it's like similar calculation for the recreational athlete though at a lower level.

01:22:39.460 Exactly. Okay.

01:22:40.740 So the whole thing was like, if watts are watts, it was like the whole battle back in the days.

01:22:45.380 It's like, okay, then metabolically speaking, we're not going to see changes.

01:22:48.900 In other words, five minutes into this test, whatever's happening in you physiologically,

01:22:54.100 since you're not changing the output or the demand for ATP, there should be no change in anything else.

01:23:00.660 Exactly.

01:23:01.140 So what happened?

01:23:01.940 So what we saw is that after five minutes, both groups, they had about four millimoles of lactate.

01:23:08.100 Okay. In the elite athletes, five minutes later, which is minute 10, they had about seven millimoles of

01:23:15.300 lactate. And five minutes later, which is minute 15, they had nine millimoles of lactate.

01:23:20.740 So right there, we see that watts are not watts at the metabolic level. It was very stressful for them

01:23:27.380 and they could not keep it. And this is kind of to what you alluded that you notice that towards the

01:23:32.100 end of some of this FTP, it feels worse. And this is exactly what I was observing with many professional

01:23:39.220 athletes and elite athletes as well. I mean, cyclists that they would get over trained more. And they said,

01:23:44.900 hey, I had to do, let's say, my coach told me I had to do five hours or four hours at 200 watts.

01:23:51.540 And I do the job and you can see in training picture. So yeah, you do 200 watts, but what's the price?

01:23:57.460 I used to be obsessed with training peaks. And what was the other program called? There's another

01:24:02.500 program we used to use, but where does the TSS show up, the training stress score? Is that also

01:24:07.980 training peaks?

01:24:08.560 Yes.

01:24:09.280 And I remember I used to mostly just keep track of kilojoules. In the end of the day, it was

01:24:15.040 how many kilojoules today? What's my TSS and my training score balance and things like that. But

01:24:21.740 I think what this, and by the way, I'm looking at the graph, the recreational athletes

01:24:26.260 basically had the exact same pattern just at lower levels, meaning they fatigued quicker at a lower

01:24:32.700 level, but the pattern is identical. So heart rate, lactate, and-

01:24:36.900 And percentage of VO2 max.

01:24:38.840 And percentage of VO2 max.

01:24:39.280 As well as VO2 max in liters per minute. They all show statistical significance. So we see that

01:24:46.040 watts are not watts. That's when it's starting to throw because I've been always like a big believer

01:24:51.480 of heart rate. And when I was 15, I saved all the money that I had and I bought the sports tester

01:24:57.820 that back in the days was like $200. No, it was, sorry. It was like back in the day, it was about

01:25:04.000 $500. So I'm talking about 84, 83, no, 86. Sorry. I was my own sports tester.

01:25:11.840 The year Greg LeMond won his first tour.

01:25:13.940 Exactly. Yeah. And that's what I, since then, I've been looking at heart rate a lot because we

01:25:19.380 forget that heart rate is a physiological parameter. Watts is a mechanical parameter, but heart rate is

01:25:25.160 a physiological parameter and response to the physiological metabolic stress. So if you look

01:25:30.780 in that graph that the audience can see later, when we look at the graph of the lactate and the

01:25:36.340 heart rate, they go side by side. When heart rate goes up, lactate goes up.

01:25:41.540 Well, I've noticed this and I'll show you more of my data over dinner tonight, but for the past year,

01:25:47.040 I've been recording four times a week, my lactate levels on both devices, plus heart rate, plus power

01:25:54.740 at the end of, I always like, I'll do a minimum 20 minute steady power in a zone two. So anywhere from

01:26:03.260 basically 20 to 45 minutes where the power is clamped, I'm on a bike on an ERG. So there's

01:26:08.480 no deviation of power. And there's a very interesting correlation between. So even if you do the same

01:26:14.940 power for four consecutive workouts, you can have different heart rates and you can have different

01:26:20.340 lactates. Now we're going to come back to this because I want to talk about it later. There's

01:26:23.500 another confounder here, which is metformin, which will back burner even with or without metformin.

01:26:28.720 There's a coupling between heart rate. So for example, if you don't sleep well and your heart rate's

01:26:34.220 higher, you're not recovered, your heart rate's higher, you're under more stress for some other

01:26:37.820 reason. And heart rate is higher. Lactate tends to follow it even at the exact same power output.

01:26:43.640 Yes. Yes. And that's what we've shown. And that's where like then Joe Friel started to talk about the

01:26:48.940 coupling where you should maintain the power output and the heart rate as well. So among a bunch of us,

01:26:55.200 we kept pushing for heart rate because it was getting to a point that it was going to be erased.

01:27:00.220 And now everybody trains with both power output and the heart rate. In fact, now the whole HRV,

01:27:06.780 the heart rate variability, it's a big, big deal. And a lot of people look at and listen to their

01:27:11.720 hearts. And I always tell the athletes, the heart rate is going to tell you a lot. This is one of the

01:27:16.300 things also why I decided to try to develop a way to look at glycogen, because I would see that in

01:27:22.340 in maximal physiological states, many athletes who were fatigued or restricting carbohydrates,

01:27:29.300 they had a very low maximum lactate levels, very low maximum heart rate. Let's say that athlete that

01:27:36.620 I have tested multiple times, let's say a lactate of 12 and a heart rate of 190. When that athlete is

01:27:44.580 fatigued or tired or restricting severely carbohydrates, that lactate could be maybe four.

01:27:51.180 And the heart rate could be maybe 162.

01:27:54.320 And how much adaptation do they have? Because I know you and I have spoken about this before,

01:27:57.900 and I don't know if we're going to get into it on this podcast, because there's so many of the

01:28:01.300 things I want to talk about. But your view has always been that the fat oxidation data that we

01:28:06.980 sometimes see in heavily, heavily carbohydrate restricted or ketogenic athletes may actually be

01:28:12.340 an artifact. We might not actually be seeing fat oxidation of 1.7 to 2 grams per minute.

01:28:18.820 But you're saying in a GC contender, in the best cyclists on the planet, what is their maximum

01:28:24.800 fat oxidation in grams per minute?

01:28:26.600 Well, what we're seeing here is normally in the 0.7, 0.8 grams per minute under normal. And we have

01:28:34.600 done these experiments, although we haven't published them, but we have done a normal athlete,

01:28:40.540 like category two or three. They do under normal diet, not super high in carbohydrates, not super low,

01:28:46.760 normal diet. And their fat oxidation, the fat max, it's, let's say, 0.4. Then they do one week of

01:28:54.000 carbohydrate restriction or two weeks of carbohydrate restriction. And their fat max, yeah, it's 0.8.

01:28:59.940 But at the same time, we see that the power output decreases at least 0.5 watts per kilogram. So about

01:29:07.420 30 to 40 watts. And also we see that the maximum heart rate decreases and the maximum lactic decreases.

01:29:14.340 That said, this is more in a, if you will, a more acute situation.

01:29:19.280 I'll tell you this from my experience, Inigo. When I began carbohydrate restriction, which was,

01:29:23.900 I went on a ketogenic diet in May of 2011. The first 12 weeks were hell. I couldn't even imagine

01:29:33.200 approaching my anaerobic fitness. So forget lactate threshold or anything. I couldn't even

01:29:39.820 get to the same aerobic level. I remember, I still remember very clearly, November, 2012,

01:29:46.980 18 months later. It came back and then some. What that suggested to me, and if I could go back in

01:29:55.180 time and do anything different, I would have had muscle biopsies done all along the way. But it

01:30:01.500 struck me at how long it took for that adaptation to take place. Now, I only stayed in that state for

01:30:07.760 three years. So I'm long out of that state now. There's the only time I'm really in ketosis is around

01:30:13.540 fasting. But it's always sort of piqued my curiosity what a very, very, very long-term state,

01:30:21.060 ketogenic state can do for everything outside of peak sprinting capacity. Because I just,

01:30:26.280 I don't think there's any dispute that peak sprinting capacity has to be glycolytic. And

01:30:32.520 anything that impairs glycolytic function makes no sense. So there's such a debate about all of this

01:30:37.000 stuff. I don't think it makes sense for someone trying to win the Tour de France to be on a ketogenic

01:30:41.240 diet. It's just too glycolytic. Even though 96% of that race can be done below peak power output,

01:30:49.760 the race is won and lost under peak conditions. So it makes no sense. But if you're training to win

01:30:57.200 the Western States 100, you technically don't need to sprint ever. If you have a high enough threshold,

01:31:04.080 so I still have that sort of point of view. But again, I'm very curious as to what those adaptations

01:31:09.360 are and how long they take. Because I don't think they're going to take place in a month.

01:31:13.880 You bring up a great, great point. I'm extremely curious about that as well. Because I have never

01:31:20.320 seen an athlete at the elite level adapting. And I'm going to tell you why in a second. But at the

01:31:25.680 same time, I believe that it cannot be possible that thousands of people around the world who are

01:31:32.080 getting into the ketogenic diet, it might be working for them. And they're making it up. So I believe

01:31:38.140 there's something there. At first, when these things come up, I say, come on, man, give me a

01:31:42.360 break. But then I say, there's so many people out there. There's got to be something.

01:31:46.720 Well, there's one other data point I'll add for you. When I was on a ketogenic diet and cycling

01:31:52.300 voraciously, my capacity to consume carbohydrates was much higher than what people think of as a

01:32:00.260 ketogenic diet for someone at rest. As a general rule for somebody who's normal, about 50 grams of

01:32:07.300 carbohydrates is the limit. Above that, you begin to suppress the production of beta-hydroxybutyrate.

01:32:13.140 But I used to do lots of experiments. And at my most extreme, you know, days when you'd have a

01:32:19.880 three-day period where you would do 100 miles each day for three consecutive days at very high output.

01:32:26.120 So for me at the time, that might've been average power of 185 watts, normalized power of 240 watts

01:32:35.820 for seven hours on three consecutive days. When you're at that much demand, I was able to consume

01:32:42.700 600 grams of carbohydrates and stay in ketosis.

01:32:46.960 Now, I think that's because I'd spent so long adapting. I don't think you can show up and go

01:32:55.180 into ketosis and then a week later eat 600 grams. I mean, I was pushing as hard as I could to see how

01:33:00.660 much of this can I consume. But so there's the other thing to keep in mind, which is at some point,

01:33:05.720 the body became flexible enough that I could break all the rules. I could have 200 grams of protein,

01:33:11.860 600 grams of carbohydrate and still maintain beta-hydroxybutyrate levels above two to three

01:33:20.420 millimolar. Because I think the machinery with which the BHB was made was, I'd had two years of,

01:33:26.720 in fact, this would have been probably three years in. This is the summer of 13 maybe. So now I'd really

01:33:33.440 been at it for quite a while. And again, biggest regret is not having that. There are lots of athletes

01:33:38.140 out there that I think would be interesting to study. So that's something worth considering.

01:33:42.180 Sorry to interrupt. The thing where I haven't seen that adaptations in elite athletes is that

01:33:47.020 they cannot afford it. You mentioned that it takes months to get there. You don't have months

01:33:52.440 because you get dropped in the races. Your performance is very poor. Your contract is going

01:33:58.020 to be trashed. They're not going to renew you and you're going to feel like crap. Every single athlete

01:34:03.320 who has tried to go, whether you call it like a ketogenic diet or a carbohydrate restriction,

01:34:09.860 while training and competing for an event, they fail. That's what I've seen in 25 years. And the

01:34:16.820 reason probably is this, because they didn't have one year to say, hey, you're not going to race in

01:34:22.060 one year. You can train very little. Your mission is to get adapted. That's not the way sports works.

01:34:28.300 But what I see is if you restrict carbohydrates, we do blood analysis a lot. We do this metabolic

01:34:34.280 testing in the laboratory. While these athletes are competing, we see right away there's a catabolic

01:34:39.840 response. The body says, holy crap, what's going on here? I need to survive somehow. So you enter in

01:34:46.300 an evolutionary survival mode. So obviously, yeah, your ketones production might increase. Your fat

01:34:53.160 oxidation might increase as well, but your protein breakdown increases substantially as well. And we

01:34:58.800 see this in the blood analysis. That's where you see muscle breakdown all the time. Although again,

01:35:03.200 it's transient, which again speaks to, because if it wasn't transient, I mean, evolution would

01:35:08.360 absolutely demand we preserve protein under long periods of nutrient deprivation, which of course is

01:35:15.440 what the carbohydrate restriction is mimicking. But it's this time course that I think is very unusual.

01:35:21.420 And you're right. There's no professional athlete that could take that chance. And again,

01:35:25.420 we were talking about this earlier. It's like there are some people whose entire lives can be built

01:35:30.040 around chat rooms and discussion boards where they can debate these things endlessly. Neither you nor I

01:35:35.120 have the time for that. So I've largely stopped paying attention to this debate, truthfully. But it's

01:35:39.920 always struck with me how long it took to adapt and the price I paid during that adaptation period.

01:35:46.200 If you were a professional athlete, you would be out of the job.

01:35:49.480 Yeah. Oh, absolutely.

01:35:50.860 And this is why I think that I have never seen that because sooner or later, the athlete,

01:35:54.740 they hit the wall. They just cannot finish races or they just like a, Hey, what's going on here?

01:36:00.460 And then that's when they have to go back. And we see this quite often. Athletes don't always

01:36:05.180 listen to us. They always go to the blocks and see things, you know, internet, or they find what

01:36:10.500 the neighbor is telling them. And a lot of people try many diets and the tendency now,

01:36:15.280 and it was before also was to restrict carbohydrates. And again, I really think that

01:36:20.780 you can adapt because the human physiology is a wonderful machine, but do you have the time to

01:36:26.080 that while you're a competitive athlete? That's what I have a lot of thoughts that I don't think so.

01:36:31.720 Yeah. And again, I think the discussion is, is interesting and academic, but of course,

01:36:36.500 in the end, I still think carbohydrate restriction is a great tool for anyone who's not trying to win

01:36:41.260 the tour de France. I think that's where people sometimes get hung up, right? It's if you want

01:36:45.640 to win an Olympic gold medal, there are very few sports in which you could probably do that on a

01:36:50.240 ketogenic diet. And if you want to be the best cyclist or runner or swimmer on the planet, very

01:36:56.180 hard to do that on a ketogenic diet. Good news is, by the way, if you're at that level, your

01:37:00.220 mitochondria are so remarkable that your carbohydrate tolerance is unbelievable where it comes back to.

01:37:06.980 And I think where the biggest opportunity is, is the person who is not metabolically very healthy,

01:37:12.800 who thinks they need to drink a liter of Gatorade an hour. And no, actually that person

01:37:18.580 can absolutely be on a carbohydrate restricted diet and they can exercise. And yes, maybe their

01:37:24.020 performance initially is less than what it would be if they still mainlined all the carbohydrates in

01:37:30.180 the world. But in the long run, they're going to produce a much more metabolically healthy

01:37:34.160 phenotype, even though they won't be in the top 0.1% of athletes who will.

01:37:39.200 No, exactly. I agree. And the thing with the elite athletes too, is that yes, and this is kind of what

01:37:43.400 I keep bringing up all the time. There's no population on earth who has as many carbohydrates

01:37:50.740 and simple sugars as these athletes by a landslide, right? These guys at the Tour de France, for example.

01:37:56.600 Yeah. Tell people like, let's take a long stage of the tour. So a 250 kilometer stage that has say

01:38:04.520 four high category climbs and one HC climb. So one climb beyond category.

01:38:11.980 Yeah. So these people, they take...

01:38:13.880 First of all, how long would it take them to complete 250 kilometer stage with

01:38:18.400 four high category and one non-category, which means it's just a brutal climb.

01:38:22.860 Yeah. It would be more like a 200 and it would be like a five, five and a half hours.

01:38:27.260 And how long would that take you or I to ride right now?

01:38:29.820 Man, that would take us two hours more easily.

01:38:32.180 Yeah. And how long would it take...

01:38:33.360 For an hour and a half or...

01:38:34.580 Take me two hours more if I'm lucky.

01:38:36.320 Exactly. How long would that take a person who doesn't ride their bike much?

01:38:41.900 Two days.

01:38:42.980 Yeah.

01:38:43.240 I mean, 14 hours, something like that, because they will have to do multiple stops.

01:38:47.520 And at the HC, they might not even make the climb.

01:38:50.020 Yeah. Yeah. Yeah. Yeah. Or much slower. Yeah. While they do this climb, so the Tour de France,

01:38:55.140 depends on the weight, but they usually, they go between six and 6.5 watts per kilogram.

01:38:59.860 Let's say a person of 70 kilos, which is...

01:39:02.360 70 kilos is probably 150.

01:39:05.520 50...

01:39:05.920 154 pounds. So that would be about, yeah, 420, 450 watts. So we cannot do that. You know,

01:39:14.660 like a normal, well-trained person who exercises regularly can maybe do that in 300 watts. But

01:39:22.080 a person who doesn't train can do that in 150 watts only. So that's poof. That's a long, long time.

01:39:28.360 And their weight is usually significantly higher.

01:39:30.240 Exactly.

01:39:30.440 So that day, it's hard to believe they can do that in five to six hours,

01:39:35.400 by the way. But they would consume how much on that day, both on the bike and off the bike.

01:39:40.620 So normally what they do, and I haven't published this, but we keep track of this all the time. We

01:39:46.540 keep track of how the amount of carbohydrates per hour. We keep track of the breakfast, what they eat on the bike, after the bike recovery. Right away, we have these protocols. And these protocols are very up to what they need or what we think they need. And also based on what their demands are, because they're the ones who like, they need it. You know? And again, as I said earlier, I've seen athletes even restricting carbohydrates in the races and they get totally destroyed.

01:40:11.540 So these guys, they consume a lot of weight. So these guys, they consume a total or about 12 grams per kilogram of body weight per day of carbohydrates.

01:40:19.220 So if you're 155 pounds, which could be an average weight, let's say 70 kilos, we're talking about close to 150 grams a day of carbohydrates.

01:40:29.860 More than 150. You said how much? 12?

01:40:32.220 850.

01:40:32.860 850.

01:40:33.420 850. Yeah, yeah, yeah. Sorry, I thought you said 150.

01:40:35.460 Okay, yeah.

01:40:35.800 Which is 850 grams of carbohydrates.

01:40:38.060 That's over three, that's almost 4,000 calories of carbs right there.

01:40:41.540 3,500 calories of carbs. And out of those, at least a good 30% of those to 50 is simple carbohydrates. Let's say 30% of those. So we're talking about these people are having daily about 1,500 grams of sugar. I'm sorry, 1,500 calories of sugar. So almost-

01:41:02.280 Give me an example of what type of sugar they're consuming, like gels and goos.

01:41:05.800 Yeah, the gels, the goos, the drinks, and then obviously at breakfast, at lunch and dinner, they're more complex. But during the race, in the first part, we do more solid versus liquid. But towards the end of the race, we do more liquid. So more pure sugar, simply because it's absorbed faster. And that's why you need more energy.

01:41:25.320 But yeah, these people, again, they do about 1,500 calories a day, just in sugar. Imagine pretty much your entire daily caloric intake of a normal person, a bowl of sugar. If you want to do this, if you go to a nutritionist and you say, I want to do this, they will shoot you.

01:41:40.840 Yeah, look, if I did that, I'd have diabetes in a month.

01:41:42.960 Oh, of course, of course, of course. And we know that they don't have it. In fact, this is the healthiest metabolically population in the planet.

01:41:50.360 Now, the irony of it is, on twofold, one, in many other ways, they're wildly unhealthy. The rate of catabolism, the bone density loss that these guys experience over the Tour de France is debilitating. I mean, these guys, they lose so much muscle, they lose so much bone density.

01:42:06.240 The other thing we see is, for many of these athletes, the transition out of being at that level to being civilian again is devastating.

01:42:15.380 Because especially, I actually read an article on this once. I wonder if I could find it.

01:42:20.540 I believe that the answer was more common in males than females, where the rebound effect to becoming metabolically unhealthy was unbelievable.

01:42:31.860 It's very hard to turn that spigot off of you're basically a nonstop eating machine, and then all of a sudden, you're on the path to having diabetes three years, five years, 10 years after being the fittest person in the world.

01:42:44.760 Yeah. And that happened to me when I quit cycling. Between school, work, I was working and traveling. I was working 70 hours a week, at least. I was from doing 500 kilometers a week to do 500 kilometers a year.

01:43:02.740 I would exercise literally six, seven times a year, and traveling and eating. And one thing that I have observed is like insulin sensitivity. These athletes have the highest insulin sensitivity of any humans as well. There's no insulin resistance. Because first, we know very well that exercise increases insulin sensitivity, and they need it to utilize carbohydrates. It increases insulin sensitivity as well, and the transporters.

01:43:27.380 All that efficiency in the mitochondria comes with another benefit, which we didn't really talk about, which was non-insulin dependent glucose uptake is also going up. So now, if you take a normal person, we are able to take up glucose with insulin. That's the insulin sensitivity. But we have a second door that doesn't get utilized much, which is the non-insulin requiring door to put glucose in the muscle. And there's no better way to stimulate that than zone two.

01:43:55.500 I mean, I don't know if I have a study that I can point to, but I can clinically tell you without a shadow of a doubt, and I'll tell you how I know. It's looking at people with type 1 diabetes.

01:44:05.460 Yeah, exactly. I was going to mention that.

01:44:07.060 Yeah. You take people for whom you know exactly how much insulin they require. I'm actually going to be writing about one of these patients in my book. He's type 1 diabetes, completely dependent on insulin. He's completely maniacal. I love him. Three-hour brisk walk every night.

01:44:22.340 So that's his zone two. Three hours of zone two a day, right? You know how much insulin this person with type 1 diabetes requires a day?

01:44:32.100 Two, five units.

01:44:33.620 About eight to 10 units a day. He has the highest sex hormone binding globulin I've ever seen in a human being, which is inversely proportionate to insulin level. This guy has no insulin. He doesn't require any.

01:44:46.200 I learned from this a lot. I was working with Team Novo Nordisk.

01:44:49.700 Yeah. Tell people about what Team Novo Nordisk is.

01:44:51.520 So Team Novo Nordisk is a professional team where 100% of the cyclists are type 1 diabetics.

01:44:57.280 These are professional cyclists with type 1 diabetes.

01:45:00.040 So the whole purpose of Team Novo Nordisk was first to show the world that you're not going to not only not die if you have type 1 diabetes, but you can become a professional athlete to spread the word.

01:45:11.940 Because a lot of people think it's a devastating diagnosis for many.

01:45:15.220 Oh, you're type 1. You're going to die soon.

01:45:17.460 They're like, no, you're not going to die soon if you take good care of yourself, but even you can become a professional athlete.

01:45:23.360 So that was the one message to spread the word.

01:45:26.720 And the second is that to study diabetes and type 1 diabetes and the metabolic effects of exercise.

01:45:32.800 Because nowadays, most endocrinologists working with diabetics, they're telling to exercise.

01:45:39.060 The problem is like they go to exercise and they have many hypoglycemias or hyperglycemias.

01:45:45.800 And they need to correct it.

01:45:47.400 And all the hormonal system goes all over the map.

01:45:50.040 And they go back to their doctors and they have no answers.

01:45:53.560 So it's the number one barrier that they find from exercise.

01:45:59.200 And many decide not to exercise because they can control their doses very well at home.

01:46:04.080 And let's explain why that's happening to people.

01:46:06.100 We've talked a lot about the consumption of glucose.

01:46:08.820 But as you're alluding to, whether it's you, me, or someone with type 1 diabetes,

01:46:14.220 when I exercise very strenuously, my glucose goes way up.

01:46:18.340 So if I'm doing twice a week, I do high intensity exercise.

01:46:22.460 As you can see on my arm, I wear a continuous glucose meter.

01:46:27.020 It's not uncommon, especially if I do it right after a zone 2.

01:46:30.880 This is funny because zone 2, my glucose steadily falls.

01:46:33.820 Let's say I get on the bike at 100.

01:46:35.760 I do 45 minutes of zone 2.

01:46:37.880 I get off at 75.

01:46:39.420 You get to bunk sometimes even.

01:46:41.940 I don't go long enough to bunk for sure.

01:46:44.140 So then, let's say I get on the air bike and I do a 4-minute protocol.

01:46:50.020 It's not uncommon for me to go from 75 to 160 because of the hepatic glucose output.

01:46:57.000 Yeah, glycogenolysis.

01:46:58.200 Yeah.

01:46:58.600 And that person with type 1 diabetes, that number could easily be 250 because they don't

01:47:04.160 have the insulin to correct it.

01:47:05.480 Exactly.

01:47:06.080 So then they need to correct it and they freak out.

01:47:09.080 So they use a lot of insulin.

01:47:10.540 They overshoot it.

01:47:11.240 Exactly, they overshoot it and this is exactly to what you pointed out about the non-insulin

01:47:15.760 dependent system, which is the muscle.

01:47:17.920 And this is what it was an educational process.

01:47:20.200 So then with JDRF, the Juvenile Diabetes Research Foundation that we put together, they put together

01:47:26.440 like a group of experts, if you will, to train clinicians about this.

01:47:31.520 So what did you learn?

01:47:32.800 I mean, how do people compete in professional cycling without being on that glycemic rollercoaster?

01:47:40.560 So we learned a lot to work on insulin usage, as opposed to insulin correction.

01:47:48.220 And that's what we're taking now to the clinical space because type 1 diabetes has been about

01:47:53.560 correcting insulin and insulin and insulin and eating carbohydrates.

01:47:57.120 Oh, you go low.

01:47:58.080 Sorry, man.

01:47:59.160 It's just keep eating candy or things like that.

01:48:01.340 And we know that that cannot be very healthy for you in the long term.

01:48:04.340 But the approach has been always that, to correct by either eating or using insulin.

01:48:10.540 But we're trying to really correct it by really tackling insulin administration.

01:48:16.340 So using just longer acting forms?

01:48:18.480 Is that the...

01:48:18.860 Either longer acting or less insulin.

01:48:21.020 And therefore also to do exercise.

01:48:23.700 So when you do exercise, as you say, first, your insulin sensitivity increases.

01:48:28.240 So you don't need so much insulin.

01:48:30.960 And as I said earlier, the first tissue that develops type 2 diabetes or insulin resistance

01:48:36.440 is the skeletal muscle.

01:48:38.100 So when you eat carbohydrates, the big percentage of that are going to go into your skeletal muscle.

01:48:43.880 Are people with type 1 diabetes who are exercising even more insulin sensitive at the muscle

01:48:49.800 than non-insulin dependent individuals who are matched?

01:48:53.640 They could probably be.

01:48:55.460 So the long-term exposure.

01:48:57.720 This is what I observed, for example, about glycogen.

01:49:00.700 Unfortunately, it wasn't published because the N was very low.

01:49:04.480 But the reviewers, they didn't understand that.

01:49:06.620 You cannot do muscle biopsies to a professional cycling team.

01:49:09.440 And there's only one professional cycling team in the world.

01:49:11.500 So I did a tour of Colorado.

01:49:13.320 I did the Team Novo Nordisk and another team.

01:49:16.460 And I looked at the glycogen.

01:49:18.000 What did you see?

01:49:18.880 About 25% higher glycogen content before the race.

01:49:22.960 And after the race in type 1 diabetics.

01:49:25.640 And about three times less carbohydrate needs than the non-diabetics.

01:49:31.720 Which we already had seen because we count carbohydrates.

01:49:34.460 And we know that a normal cyclist, they have 20 grams per hour of carbohydrates.

01:49:41.560 They're going to hit the wall in a race.

01:49:43.820 Type 1 diabetics, they have 20-25 average.

01:49:46.660 And they never have any issues.

01:49:48.120 You must see higher free fatty acid levels then.

01:49:50.560 Yes.

01:49:50.840 So all things equal, do they just have higher fat oxidation across the entire spectrum?

01:49:55.320 They're not very good necessarily at that.

01:49:57.400 And I'm trying to understand that puzzle.

01:49:59.560 But what I believe is like they have a higher glycogen content because insulin drives glycogen

01:50:05.680 synthesis.

01:50:06.660 It's the main hormone behind glycogen synthesis.

01:50:09.060 So if you've been for, and the issue of people with type 1 diabetes, they go from a non-physiological

01:50:15.160 state, which is not producing insulin, to the exact opposite.

01:50:19.640 They use a lot more insulin than normal people over years.

01:50:23.400 So 20 years, usually insulin, it must maybe elicit some adaptations that might, one of them

01:50:30.020 could be increased glycogen synthesis.

01:50:32.300 I have no idea, but that was kind of what we would like to explore further.

01:50:35.480 So do you think that those athletes who were able to get by with as little as 20 grams

01:50:40.800 of glucose per hour, which seems impossible to imagine given their energy requirement,

01:50:46.960 do you think at some point that would cease to be the case?

01:50:49.400 And in the tour of Colorado, maybe the longest stage is what, four or five hours?

01:50:54.040 Yeah.

01:50:54.420 Yeah.

01:50:54.760 But still, that's hard to explain.

01:50:56.000 It's still a week-long race, isn't it?

01:50:57.420 Yeah.

01:50:57.940 Yeah.

01:50:58.260 Did you say that their glycogen levels still were 25% higher at the end of the race?

01:51:02.360 Before and after.

01:51:03.300 Yes.

01:51:03.780 That's counterintuitive.

01:51:04.940 Yeah.

01:51:05.380 Sorry, was it, I know it's 25% higher than the non-diabetic, but what about relative

01:51:10.140 to themselves?

01:51:11.220 Oh, they decreased.

01:51:12.400 How much do they decrease?

01:51:13.640 I don't remember.

01:51:14.580 Because not a whole lot, because, I mean, in this stage, you have to do it in the same

01:51:18.720 time.

01:51:19.540 And in the tour of Colorado, in the mountains, one hotel is here, the other one is 20

01:51:22.940 minutes away.

01:51:23.760 So I had to do it in one stage where all of them were on the same floor, two teams.

01:51:28.280 That was a short stage.

01:51:29.300 It was like two and a half hour stage.

01:51:30.700 So they eat normally, and they decreased like 15%, 20% or something like that.

01:51:35.100 So they didn't deplete completely by no means.

01:51:36.900 You could make the case that that team had some of the highest levels of non-insulin-dependent

01:51:42.100 glucose uptake you've probably ever measured.

01:51:44.160 Probably.

01:51:44.960 Probably.

01:51:45.760 Yeah.

01:51:45.980 So that's what, to your question of that, the non-insulin uptake of glucose by the skeletal

01:51:50.580 muscle, that's what is a great approach.

01:51:53.460 We don't have a way to measure this in those of us who don't have type 1 diabetes.

01:51:56.900 We're sort of taking a leap of faith that the more we work on our mitochondrial efficiency,

01:52:01.020 the more we will drive that non-insulin-dependent pathway.

01:52:04.380 But really, it's only the person in type 1 diabetes where that can be quantified.

01:52:08.640 And it's a skeletal muscle contraction.

01:52:10.500 First of all, insulin, what it does, it initiates the cascade of events that translocate the

01:52:18.140 transporters of insulin, called the glute force, to the surface of the muscle.

01:52:22.080 Glute force.

01:52:22.640 Yeah.

01:52:22.780 Yeah.

01:52:23.080 Glute force.

01:52:23.500 Yeah.

01:52:24.180 Sorry.

01:52:24.860 To the surface of the muscle.

01:52:26.640 And those transporters are stimulated by insulin.

01:52:29.980 So a skeletal muscle does the exact same action.

01:52:33.480 It translocates those glute force to the surface.

01:52:36.720 So therefore, there's that non-insulin-dependent.

01:52:39.720 And why does exercise increase that ability?

01:52:44.620 We don't know the exact mechanisms.

01:52:47.040 It just seems too good to be true.

01:52:48.520 I want to make sure that the person listening to this understands what you just said.

01:52:52.080 So I'm just going to repeat it because it's so profound.

01:52:54.380 And you said it like sort of, you know, you said it sort of like matter-of-factly, because

01:52:58.120 of course, for you, it's common knowledge.

01:52:59.760 When insulin hits the insulin receptor on a muscle, it sends a cascade of chemical reactions

01:53:07.140 inside the muscle that ultimately results in a tube called the group for transporter

01:53:12.200 being raised to the surface of the muscle and translocating across the membrane.

01:53:17.480 And now you have by passive diffusion, glucose can enter the muscle.

01:53:21.580 The key is this insulin in the lock is the insulin receptor.

01:53:26.740 And the downstream effect that occurs inside the house opens the door and lets the glucose

01:53:31.500 in.

01:53:32.080 What you said after that is you explained how non-insulin-dependent glucose works, which

01:53:37.660 is somehow just the contraction of the muscle.

01:53:41.180 So something that's going on inside the house squeezes and out comes the same beautiful GLUT4

01:53:48.560 transporter, which now allows the same passive diffusion of glucose into the cell, but this

01:53:54.180 time it didn't require insulin.

01:53:55.620 This is the best of both worlds.

01:53:57.540 This is what Henry Richer from Denmark and Lori Goodyear from Harvard, they've been dedicating

01:54:04.500 many years to study these pathways.

01:54:06.460 So they found that this muscle contraction stimulates these pathways to translocate those GLUT4 transporters

01:54:13.700 to the surface.

01:54:15.020 And this is why the pancreas in regular people who don't have type 1 diabetes decreases insulin

01:54:21.720 secretion about 50% during exercise because the muscle, they do the rest.

01:54:27.400 And this is what causes also that hypoglycemia in athletes.

01:54:31.640 If they don't correct their insulin before exercise, they go hypo.

01:54:37.040 So what we were doing, and now we're doing clinically, we're telling people to reduce the

01:54:42.840 dose.

01:54:43.180 Wait a minute.

01:54:43.700 This is interesting now.

01:54:45.280 This is suggesting that the reduction that I'm seeing in glucose when I do my zone 2, which

01:54:51.620 is by far the most profound thing.

01:54:53.980 You don't see this at higher levels of intensity.

01:54:56.240 You see the opposite.

01:54:56.880 You see the opposite.

01:54:57.560 You see glucose going up.

01:54:58.320 But zone 2 is a sweet spot where my glucose level always falls precipitously.

01:55:03.440 I shouldn't say precipitously.

01:55:04.760 Steadily and consistently.

01:55:06.740 I never thought of it this way.

01:55:08.620 It must be almost entirely the non-insulin dependent glucose uptake because it's a low enough

01:55:16.000 level of intensity that my internal glycogen stores are easily providing what is needed.

01:55:23.360 So this is an additional amount through that.

01:55:26.540 I feel like this is another metric I want to start keeping track of each day I'm doing

01:55:31.180 zone 2.

01:55:31.860 It's not just power.

01:55:32.800 It's not just heart rate.

01:55:33.600 It's not just lactate.

01:55:34.500 It's the delta in glucose from start to finish could be yet another metric we look at.

01:55:39.640 And in fact, one of the things is like I'm trying to try to take this to the clinic for

01:55:44.160 people with type 2 diabetes.

01:55:45.340 It's like if you eat, go exercise right away.

01:55:49.340 Because when you exercise right away, that muscle contraction is going to translocate

01:55:54.320 these gluteal transporters without the need of insulin.

01:55:57.400 And I thought it was the opposite.

01:55:58.800 You know, I thought that exercising will increase the insulin dependent portion.

01:56:04.300 And therefore, the best time for someone with diabetes to eat was right after exercise.

01:56:09.020 It could be both.

01:56:10.320 It could be both.

01:56:11.100 Yes, I think there might be in a patient by patient base.

01:56:14.540 But if you have insulin resistance, you're going to need to use more insulin after you

01:56:20.080 eat, which it's a patch.

01:56:21.760 It doesn't solve the problem.

01:56:23.100 But if you exercise, then you might need half of the insulin because the other half is going

01:56:28.740 to be provided of the glucose intake into the cell by the muscle contraction.

01:56:33.180 So learning a lot from type 1 diabetics, we can apply things to type 2, I believe.

01:56:38.140 One of the things that we see the opposite effect that we saw in the races, normal people

01:56:42.980 who are told to exercise, they're not fit enough, and they start jogging, right?

01:56:48.460 And they're in zone 4 already, very glycolytic.

01:56:51.500 They see the opposite.

01:56:52.400 They see post-exercise hyperglycemia where they're, as you said, in the 260s.

01:56:57.840 So and they inject themselves insulin and they go down and sometimes in the middle of the

01:57:02.920 night.

01:57:03.120 And then they go home.

01:57:03.900 If it's towards the evening, they eat and they correct it again, and sometimes end up

01:57:07.960 in the ER because they have a severe hypoglycemia.

01:57:11.680 But so one of the things that I started to apply first to the cyclists and then to patients

01:57:17.400 is the cool down.

01:57:19.580 So after people would have this post-exercise hyperglycemia, the muscle contraction stops.

01:57:26.660 And that's why I believe this is why it is happening.

01:57:29.640 First, you have a very high adrenergic activity, high intensity, a lot of adrenaline, and that's

01:57:34.140 what causes the breakdown of glycogen into glucose, as well as the glucose export from

01:57:40.240 the liver.

01:57:42.380 But then when you stop, that muscle contraction stops completely.

01:57:47.540 So you don't have that.

01:57:48.400 You've taken away one of your sinks.

01:57:49.960 Exactly.

01:57:51.000 So that's when you start doing the cool down.

01:57:53.300 And that's a study, another study.

01:57:54.800 I have the data I have to publish, but we could see clearly that everybody started to

01:57:59.260 go down.

01:58:00.020 There's definitely going to be some University of Colorado medical students or undergraduates

01:58:04.160 who have just lined up potentially a half a dozen interesting things to write with you.

01:58:08.540 We start to see the cool down and the cool down will take care of it.

01:58:12.440 So people to the point that they would not need insulin anymore to correct it, whereas

01:58:16.680 before they might need three, four, five units.

01:58:18.540 And now they don't need it anymore because that cool down took care of it.

01:58:22.420 So through JDRF, we've been traveling throughout the country and other places in Europe and

01:58:27.380 even Australia, training clinicians about this so they can go back to their patients.

01:58:32.280 And the cool down has been a basic thing.

01:58:34.660 And the feedback we're getting is awesome.

01:58:37.720 This is incredible.

01:58:38.300 You know, it's such a shame that the disease type 1 diabetes and the disease type 2 diabetes

01:58:42.980 share the same name in diabetes.

01:58:44.640 Because I do think for many people, they just sort of think someone has diabetes, but the

01:58:49.760 nomenclature of 1 versus 2 is profound.

01:58:52.700 They are really different diseases.

01:58:54.280 Very different.

01:58:54.720 They're completely different.

01:58:55.640 They almost have nothing in common except for high glucose as a potential consequence.

01:59:00.580 I agree 100%.

01:59:01.580 It's a real shame.

01:59:02.860 There's an artifact of history.

01:59:04.220 And this is what I'm trying to also bring the concept of double diabetes that very few

01:59:09.080 people talk about it because it's mixed.

01:59:12.120 Type 2 diabetics, especially now in the US, Novo Nordisk told me that I think about two

01:59:17.160 thirds of the entire insulin that is sold in America, it's for type 2s, not for type 1s.

01:59:23.000 And this is the animal that is different.

01:59:25.660 The type 2 diabetic people is a way different animal than it was 50 years ago.

01:59:29.860 I've always been sort of critical of these companies like Novo Nordisk because I feel

01:59:34.360 like there's just too great a conflict of interest for them, right?

01:59:36.920 I mean, first of all, insulin should be basically free.

01:59:39.840 There's absolutely no, from an IP perspective, there's absolutely no reason insulin should

01:59:44.700 cost anything above some nominal amount.

01:59:47.860 So it's this cash cow for drug companies like Novo Nordisk.

01:59:51.360 Don't worry, I'm not going to put you on the spot and have you speak critically at all.

01:59:54.140 I'm going to do all the critical speaking.

01:59:55.800 Yeah, no, because we get funded.

01:59:57.060 This group is funded by Novo Nordisk, the GDRF.

01:59:59.960 Indirectly, what I'm going to do is come around and sort of pay them this compliment and say,

02:00:03.120 I like realizing that there's something good that's done by an entity that I generally view

02:00:07.100 not favorably.

02:00:07.960 Because again, one, the price gouging on insulin to me is the most unethical part of pharma.

02:00:13.060 But then on top of that, there's this issue of two thirds of your sales come from a patient

02:00:20.480 who shouldn't be using your drug.

02:00:22.640 The drug really is for people with type 1 diabetes.

02:00:26.000 If you have type 2 diabetes, almost without exception, changing the way you eat and exercise

02:00:32.040 will at least get rid of the insulin requirement.

02:00:35.340 You may still require other medications, but you shouldn't require insulin.

02:00:39.060 And that's been repeatedly demonstrated.

02:00:40.980 So all that said, rant over.

02:00:43.340 It's nice to see that this type of research is being done because these patients offer us

02:00:48.000 a beautiful physiologic milieu in which you otherwise couldn't see this.

02:00:52.840 So this kind of brings me to, while we're on the topic of diabetes, something else that

02:00:57.080 I want to talk with you about, which is my recent, and by recent, I mean over the last

02:01:02.260 six months, frankly, maybe nine months, sort of back and forth exploration of my use of

02:01:08.180 metformin.

02:01:08.780 When we very first time met a year ago, we talked about how I use metformin.

02:01:12.180 I've been using it for years with the basic belief that even though I don't have diabetes

02:01:17.560 or insulin resistance, it offers some measure of protection from cardiometabolic disease,

02:01:23.040 inclusive of cancer.

02:01:24.500 And that's all based on data that unfortunately is confined to people with insulin resistance,

02:01:31.360 hyperinsulinemia, or type 2 diabetes.

02:01:33.040 So there was always a leap of faith I was taking that if you took a metabolically healthy

02:01:37.840 individual, they would still have some benefit.

02:01:40.780 And when patients would ask me about it, I would say, my belief is that I'm probably receiving

02:01:46.660 less benefit than someone who's more metabolically unhealthy, but I think I'm receiving benefit

02:01:53.440 and I don't see a downside.

02:01:54.760 And then all of that changed a year ago when we met and I started keeping track of my zone

02:02:00.960 two numbers.

02:02:03.120 And what I immediately realized was a gross mismatch between where I knew physiologically

02:02:10.380 I was clearly in a zone two just based on perceived effort and my understanding of my fitness level.

02:02:17.520 But I couldn't get over how high my lactate levels were.

02:02:20.620 And then I remember you and I would speak and you would say, well, what is your lactate level

02:02:24.060 fasting?

02:02:24.700 And I'd say, you know, sometimes it's like 1.6.

02:02:27.780 Even before I started, I mean, this was back when I was in the business.

02:02:30.940 Of using as many strips as possible.

02:02:32.960 So expensive, those stupid things.

02:02:35.280 So I would check two times fasting and then every 10 minutes, check.

02:02:41.560 Double, double, double, double, double, double.

02:02:43.980 And there was no denying it.

02:02:45.800 I mean, my lactate levels were through the roof.

02:02:48.700 And I said to you, do you think it could be the metformin?

02:02:51.120 And then around this time, a couple of papers came out that suggested that metformin could

02:02:54.980 be blunting the benefits of exercise.

02:02:57.880 So, I mean, let's go back to then.

02:02:59.880 And then we'll talk about where we are today and our thinking.

02:03:01.920 But at the time that I told you all of this, what was your thinking about my use of metformin

02:03:05.900 and these numbers we were seeing?

02:03:07.520 Did it make sense to you?

02:03:08.660 Yeah.

02:03:09.000 They make sense in a way that we know that I've seen patients with metformin pre-type

02:03:15.240 two diabetic or type two diabetic right before entering insulin states, where at rest, I

02:03:20.400 have even seen two millimoles also.

02:03:22.800 Are you able to differentiate how much of that was due to the metformin versus their,

02:03:27.120 because there's such a confounder when you look at that population.

02:03:30.100 Had you seen anybody like me where they're?

02:03:32.180 No.

02:03:32.300 I've seen these high levels of lactate at rest.

02:03:35.440 But again, I could not differentiate that, but all these people coincided, they were on

02:03:40.420 metformin.

02:03:41.080 One of the side effects of metformin is lactic acidosis, right?

02:03:45.200 It's rare, but it can happen.

02:03:47.060 So we know there's something wrong with the lactate.

02:03:49.960 What we don't know are the mechanisms.

02:03:51.260 It would be great to study the mechanisms, whether they are to improve the cardiometabolic

02:03:57.880 health, or maybe we might find that might not be what we thought.

02:04:03.040 We know there are some studies that show that metformin decreases mitochondrial function

02:04:08.280 and could be that magical drug against cancer.

02:04:11.560 Because one of the things that we see in cancer, many forms of cancer have a mitochondrial

02:04:15.720 dysfunction, yet not enough for that cancer cell to be apoptootic.

02:04:20.540 Oh, I see.

02:04:21.660 So you're saying that maybe in that patient, metformin pushes them over the edge towards

02:04:26.840 apoptosis.

02:04:28.180 Towards a cliff.

02:04:28.960 That's what I believe, if in case that is true, that metformin can cause mitochondrial

02:04:34.060 dysfunction.

02:04:34.920 But the fact that the metformin increases lactate, it's either because it increases the glucose

02:04:41.680 flux into the cell and saturates PDH.

02:04:45.520 And then PDH dehydrogenase has a very, what we call low Michaelis constant.

02:04:51.200 So it saturates very rapid.

02:04:52.960 And in my opinion, acts as a fuse in the body from an evolutionary perspective.

02:04:57.740 If the body sees there's a lot of high flux of glucose, the body might mean, hey, what's

02:05:02.520 going on here?

02:05:03.160 We need to stop it because it's not good to become hypoglycemic.

02:05:06.140 And maybe the majority of those glycolytic enzymes in the downstream action of glycolysis,

02:05:13.300 they usually have a high Michaelis constant.

02:05:16.460 But when they get to PDH, it's like a fuse.

02:05:19.380 So when that fuse goes, then pyruvate is converted to lactate.

02:05:24.500 So that could be, it either increases the flux of glucose into the cell, and that's why it

02:05:29.160 could work well for diabetes or acts as others have shown.

02:05:32.980 This is very interesting.

02:05:33.880 So this suggests that, let's just talk for a moment about someone with type 2 diabetes

02:05:37.620 who's not taking metformin.

02:05:39.820 Their lactate levels are higher at baseline.

02:05:42.600 You're now really offering two explanations for it.

02:05:46.500 The first is PDH because their PDH is seeing higher glucose than the non-diabetic.

02:05:54.280 So that's the first thing it's doing is, as you say, I like that analogy of the fuse.

02:05:59.280 It's just triggering the fuse and shunting more glucose down the pyruvate to lactate pathway.

02:06:06.320 And then, of course, there's everything we spent the first hour talking about, which

02:06:09.900 is, in addition to that, their mitochondria just tap out very early.

02:06:14.560 They're not working well.

02:06:15.800 So those two things that are related but quite distinct would both push up lactate.

02:06:21.580 So now the question is, which one of those is more likely being driven by metformin?

02:06:25.980 Is it the inhibition of complex 2 in the mitochondria and it's simply reducing mitochondrial efficiency?

02:06:33.120 If you picture a curve where the x-axis is mitochondrial function, it's just moving you to the left.

02:06:39.220 Exactly.

02:06:40.100 It could be that and maybe it could be both.

02:06:43.820 What we know, epidemiologically speaking, is that metformin doesn't cure diabetes.

02:06:50.720 And the immense majority of patients, they end up using insulin down the road.

02:06:54.660 So we know that metformin is not that magical drug for type 2 diabetics.

02:06:59.340 It just kind of gets them by.

02:07:01.700 It buys them time.

02:07:03.180 But eventually, the majority enter insulin.

02:07:06.020 If they don't change their lifestyle, their nutrition, exercise, they enter insulin.

02:07:10.400 So why?

02:07:11.700 I mean, so the first thing I did, so I used to take one gram twice a day, a gram in the

02:07:15.800 morning and a gram before bed.

02:07:17.060 I always do my zone 2 first thing in the morning.

02:07:18.900 So I was basically doing a zone 2 right after taking a gram and basically 12 hours after

02:07:24.580 having taken another gram.

02:07:25.800 So you could argue I had very high levels.

02:07:28.040 So I think the first change I made was I just stopped taking a gram in the morning and increased

02:07:33.720 my nighttime dose to 1,500 milligrams.

02:07:36.360 So I reduced my overall dose by 25% but shifted it to the nighttime thinking, well, I should have

02:07:41.640 a lower concentration in my bloodstream in the morning.

02:07:44.540 I saw no meaningful effect.

02:07:46.260 So 1,500 at night was still producing basically the same effect as a gram twice a day.

02:07:52.960 Now, again, keep in mind when you're doing an N of 1, you can't actually make any statistics

02:07:57.180 out of this.

02:07:58.040 It has to be a big signal for me to notice it.

02:08:00.400 So then I lowered it to a nighttime dose of 1 gram.

02:08:03.700 I still didn't really see much of a difference.

02:08:05.840 And then what I did is I stopped taking it the night before doing zone 2.

02:08:15.120 So that meant I now went from taking 14 grams a week, a gram twice a day, to only one gram

02:08:21.860 three nights a week because there's only three nights a week where I don't follow the workout

02:08:28.220 by a zone 2.

02:08:29.180 So you've gone from taking 14 grams a week to three grams per week.

02:08:32.660 You could argue, why are you taking any of it at that point?

02:08:35.280 And that's when I saw the reduction.

02:08:37.480 That's when I saw the lactate levels start to come down.

02:08:40.640 Okay.

02:08:40.960 And in fact, that latter part of the experiment's only been going on for about three weeks.

02:08:45.360 So the next step is to stop metformin altogether and ride this out, which makes me think we

02:08:51.600 should do a little experiment in me, which is, yeah, we should do muscle biopsies, complete

02:08:58.080 proteomics, complete metabolomics, everything that is doable in vitro in the muscle tissue,

02:09:04.700 along with the lactate testing and all the other metrics under three states of physiology.

02:09:11.100 One, under full dose of metformin.

02:09:13.880 Two, under a complete washout, say 30 days of no metformin.

02:09:18.560 And then the third one I think would be very interesting is under complete water fast.

02:09:23.640 Where I also, by the way, whenever I water fast, I have no metformin.

02:09:26.920 And I'd like to see what seven days of water fasting with no metformin looks like versus,

02:09:33.280 again, these other two states.

02:09:34.460 So I think there's an interesting pilot study here.

02:09:36.920 You should come to our study and be part of it and we can do extra biopsies.

02:09:41.000 Yeah, yeah.

02:09:41.480 I'm totally game to do this.

02:09:42.740 Yeah.

02:09:43.080 It would be very interesting because it's fascinating the whole role of metformin and

02:09:47.320 also how it can be used in other diseases as well.

02:09:49.820 And it's fascinating the little that we know about the mechanisms of action at the molecular level yet.

02:09:57.600 I think you bring a great point is to try metformin in different states and try to learn what happens

02:10:03.680 at the mixed level, metabolomics, proteomics level, especially the latter ones.

02:10:08.700 Because, yeah, we might see pathways.

02:10:10.680 Maybe it's a mitochondrial dysfunction that causes that and we can see that quite well.

02:10:15.200 Or maybe it's at that translocational level of the transporters.

02:10:18.900 And it would be really interesting, assuming the IRB gives a quick approval for this little

02:10:23.700 added protocol that includes me, if we could recruit somebody with type 2 diabetes and have

02:10:29.340 them parallel me without the metformin, without the FAST.

02:10:34.000 Because my new hypothesis around metformin is, I just have a stronger conviction, I think,

02:10:39.320 around my old hypothesis, which is the healthier you are, the less helpful it is.

02:10:43.660 I'm now wondering if it goes one step further, which is the healthier you are, the less,

02:10:47.820 I mean, it might actually cease to be healthy.

02:10:49.220 In other words, let's take the extreme example.

02:10:51.740 What would you predict would happen if you gave a Tour de France team a gram of metformin

02:10:57.440 twice a day during the tour?

02:10:58.900 No other change.

02:10:59.800 You just give them a gram of metformin throughout the tour.

02:11:02.100 Do you think it would have no impact on performance or a negative impact?

02:11:05.780 I mean, based on looking at that, it can affect mitochondrial function.

02:11:09.640 And we see because there's increased lactate, in my opinion, and that's the very first take.

02:11:14.160 And by no means I'm an expert on this, it might be detrimental.

02:11:17.340 That's my first take.

02:11:18.560 If you think you had a hard time getting professional cyclists to volunteer for muscle biopsies,

02:11:22.780 think about how much harder it'll get them to volunteer for the take metformin and go

02:11:26.800 off and do the Vuelta.

02:11:29.060 I know.

02:11:29.880 It would be really, really difficult to get out before that in the first place.

02:11:34.540 And the permission from the manager.

02:11:35.460 Destroy someone's livelihood.

02:11:37.100 Yeah.

02:11:38.060 There's so much more I want to talk about.

02:11:39.380 And I want to talk real quick that the double diabetes, I forgot, and I'm sorry to interrupt

02:11:43.220 you, is that that's something that worries me because there are many people with type

02:11:47.740 1 who also have type 2 and they're not diagnosed.

02:11:50.920 And I think we need to raise awareness because if about 50% of US adult population has type

02:11:57.120 2 diabetes, yeah, a big number of people with type 1 diabetes are going to have also type

02:12:01.580 2.

02:12:01.760 Is that a projection of how many people in the United States will have type 2 diabetes?

02:12:05.800 Right now, about 50% of US adult population have either pre-diabetes or diabetes.

02:12:10.620 Correct.

02:12:11.020 Yeah.

02:12:11.200 And it's about, is it maybe 10% have type 2 diabetes and the remaining 40% is pre-diabetes?

02:12:17.360 Yeah.

02:12:18.000 And I was thinking there's not such state as being pre-pregnant or pregnant.

02:12:21.960 You're pregnant or you're not.

02:12:23.520 So yeah, that pre-type 2 diabetes wouldn't see clinical symptoms yet, but the disease is

02:12:28.200 there already.

02:12:29.040 Yeah.

02:12:29.280 It's just, I mean, our definition of diabetes is so arbitrary and stupid that it's just a

02:12:34.040 continuum and we somehow decide, oh, your hemoglobin A1C crossed this threshold.

02:12:37.720 And now you need or not.

02:12:38.480 It's kind of like with the same thing with cholesterol.

02:12:40.460 Oh, you're 200, boom, you need a statin or 220, you need a statin.

02:12:44.620 And that, no, that's the other thing with statins.

02:12:46.600 We know that they affect my kind of function.

02:12:48.840 How do we see this?

02:12:49.700 Because in the published literature, 5% to 10% of people experience muscle symptoms from

02:12:55.620 statins.

02:12:56.300 But what is the functional impact?

02:12:59.100 The functional impact, I mean, we don't know much about it.

02:13:01.640 So you're talking outside of myalgias and muscle pain.

02:13:04.460 The good news is, I always say this to patients when you're taking a statin, you're going to

02:13:08.840 get the feedback very quick.

02:13:10.420 One in 10 of you is not going to tolerate this and it won't be very subtle and you'll

02:13:16.160 stop the medication and within a week you'll feel better.

02:13:19.460 And again, what's interesting is the disparate data based on how it's studied.

02:13:25.120 But at the individual level, it's pretty straightforward.

02:13:27.980 Yeah, it is pretty straightforward.

02:13:29.200 And one thing that we know too is that it increases also, and there's research done,

02:13:34.020 it increases the possibilities of becoming diabetic.

02:13:36.760 Yeah.

02:13:37.300 So that's the two things I usually say to a patient.

02:13:39.020 I said, there's, because everyone says, look, if you're going to do a statin, what are the

02:13:42.080 risks?

02:13:42.380 And I say, the short-term risk is myalgias.

02:13:45.560 And again, I just say directionally, it's one in 10 people.

02:13:48.700 Maybe it's 15%, maybe it's 5%.

02:13:50.700 But you get the feedback quickly and you move on.

02:13:53.100 So the second risk is a long-term risk, which is about a 4% increase in the risk of diabetes.

02:13:58.160 The good news there is that's not a sudden thing.

02:14:00.620 I think the literature is still pretty clear that the benefit still outweighs that risk

02:14:05.720 in terms of mortality.

02:14:07.460 But again, it comes back to the idea of the most potent drugs we have are food and exercise.

02:14:13.680 Absolutely.

02:14:14.380 And it comes back to me as well.

02:14:15.820 It's not about how many years we live, our longevity, and it's how are the last years

02:14:20.400 that we live, right?

02:14:21.420 And if statins are going to come back to haunt you in 20 years because they're going to have

02:14:26.500 extra or increase in diabetes, for example, yeah, it might buy you extra time now.

02:14:31.520 But again, if you have food and exercise as your main medicine.

02:14:35.320 The zone two training for me, it's just become such an important part of my training for myself

02:14:40.160 and for my patients.

02:14:41.140 A question I get asked a lot that I don't know the answer to, so I'm going to ask you

02:14:44.680 is what's the minimum effective dose?

02:14:47.100 Because obviously I would love it if I could wave a magic wand and have one hour per day

02:14:53.040 to do zone two.

02:14:54.200 And then on top of that layer in all other exercise, that would be amazing, but it's not.

02:14:59.360 I only do three hours a week of zone two, typically in four 45-minute to an hour sessions.

02:15:06.880 Do you think that's enough?

02:15:08.420 Yes.

02:15:08.920 So this is what I've seen and I've learned from the athletes.

02:15:12.060 And I would love to do this now with patients.

02:15:14.760 What's the right dose?

02:15:15.780 But we know, or at least I've seen with athletes that if you do that two days a week, one is

02:15:20.900 the dose and the other thing is the frequency.

02:15:22.940 So if you do that two days a week, you maintain.

02:15:26.840 And we see athletes who in the off season, cyclists, for example, or runners or triathletes

02:15:31.740 or swimmers or rowers.

02:15:33.560 If you do the zone two five days a week, for example, you really push the needle.

02:15:39.080 Then once the season starts, you need to do more higher intensity exercise and training.

02:15:43.980 And then you have the races and you need to recover.

02:15:46.580 So definitely you cannot do a zone two every day.

02:15:48.960 So what we see is like two days a week, it tends to maintain.

02:15:53.100 So that's the frequency.

02:15:54.240 What's the dose?

02:15:55.200 Yeah.

02:15:55.220 And the dose, what I see is like, obviously these elite athletes, they need to keep pushing

02:15:59.780 the needle.

02:16:00.560 One hour is not going to do much for them because they have that stimulus already or two hours.

02:16:05.060 They might need four or five hours.

02:16:07.180 But a patient with type one diabetes, maybe one hour is enough.

02:16:10.440 And that's what I'm trying to fine tune, you know, what would be.

02:16:14.300 What I know very well is that three days a week, it starts moving the needle for five

02:16:19.720 for sure.

02:16:20.780 And what I've seen or guessing that that's because we don't have any real data.

02:16:25.860 This is about one hour to one hour and a half.

02:16:29.340 It does the trick for those who have type two diabetes or pre-type two diabetes, for example.

02:16:34.860 So we have last year a patient who was diagnosed with a, that's what we're saying is like late

02:16:41.560 pre-type two.

02:16:42.560 What the heck is that?

02:16:43.500 You know, and then with one year, doing an hour into an hour and a half, four days a

02:16:48.560 week, she reversed that completely.

02:16:51.560 Okay.

02:16:51.600 That's a pretty big dose.

02:16:52.760 So, I mean, for me, just, it's always for me, Tuesday, Thursday, Saturday, Sunday is zone

02:16:56.620 two.

02:16:57.320 It might be that those Saturday, Sunday workouts, I need to push them longer.

02:17:00.820 Maybe I need to do 90 minutes on each of those days and stay at 45 minutes on Tuesday,

02:17:05.200 Thursday.

02:17:05.740 It could be, but at the same time, it might be your right dose because you're not in that

02:17:09.800 unhealthy population side.

02:17:11.840 So your dose might be lower.

02:17:13.360 But my thinking now is that this is such an important part of cellular longevity that

02:17:19.280 this is the difference between being a healthy 90-year-old and being, in my framework, it's

02:17:24.860 one quarter of the equation.

02:17:27.420 What would you do?

02:17:28.640 I would do, and this is my case, when I stopped cycling, when I told you earlier, right, I gained

02:17:32.540 65 pounds because I was working 70 hours a week and exercising six, seven days a year.

02:17:38.340 And still eating like a cyclist?

02:17:40.040 And eating like a cyclist.

02:17:41.460 And I'm from the Basque country and we like to eat food because it's one of the best areas

02:17:45.180 in the world.

02:17:46.500 And probably also I had insulin sensitivity developed from I was a cyclist, which I would

02:17:51.800 just pull, pull carbohydrates, you know, and then I would not burn them.

02:17:56.140 So maybe I just transform her into fat.

02:17:58.040 I also have a familiar dyslipidemia.

02:18:01.220 So I have a high triglycerides and high cholesterol genetically.

02:18:05.640 So I didn't take care of myself.

02:18:07.700 I would not exercise and eat a lot.

02:18:09.360 So I gained 65 pounds in about eight years or so.

02:18:12.960 And then I said, wow, I went and did myself a checkup.

02:18:16.760 And then my blood pressure was 125.

02:18:20.440 I was in my mid thirties, 125 over 85.

02:18:25.580 So I was getting there in my triglycerides.

02:18:29.120 Once I saw them 800, which is huge off the chart, right?

02:18:32.680 Back in the days, people didn't do A1C.

02:18:35.200 That's when I started to work on these concepts too.

02:18:37.860 And so I started to apply this to myself.

02:18:39.400 So I started doing four days a week.

02:18:42.100 Even one hour was poof, I was bunking because I was not used to that.

02:18:45.440 It was very depressing going to-

02:18:46.900 I was about to say, that must've just been devastating.

02:18:49.540 Oh my gosh.

02:18:50.440 To go from being a professional cyclist

02:18:52.540 to struggling to do four hours a week of cycling.

02:18:55.700 Yeah.

02:18:56.140 And knowing the same roads that you go to

02:18:58.460 and that you couldn't go up the hill.

02:19:00.960 But I lost 35 pounds within seven months.

02:19:04.600 Did you make much change to your nutrition?

02:19:06.260 Exactly.

02:19:06.620 I decided to, I was willing to eat a little bit less,

02:19:11.240 but not sacrifice many things.

02:19:13.100 Because again, I mean, for me, nutrition is very important from my culture standpoint.

02:19:17.640 I love chocolate.

02:19:19.320 I love wine.

02:19:20.240 I love pasta and bread.

02:19:21.920 It's ingrained in my culture.

02:19:24.080 I was not going to renounce to these things.

02:19:26.320 So that's why I said, okay, I'm going to try to give it a shot.

02:19:28.480 So you weren't going to go on a ketogenic diet.

02:19:30.360 And it's an interesting example of there's give and take.

02:19:32.980 The more you're willing to push this type of training,

02:19:36.800 the more you can keep on the other side versus, you know,

02:19:40.940 I've seen more patients than I can count with type 2 diabetes,

02:19:44.600 not exercise at all, but go on ketogenic diets.

02:19:47.980 Within six months, they're off insulin.

02:19:50.060 Within a year, they have a normalized hemoglobin A1C.

02:19:53.540 But again, so it's almost like two levers.

02:19:55.640 How hard are you willing to pull on each of the levers?

02:19:59.240 Exactly.

02:19:59.360 No, that's a great, great comment for sure.

02:20:01.680 And I think it's a debate.

02:20:03.120 Many, for some people, giving up chocolate is not a problem.

02:20:06.840 For me, it's death, you know?

02:20:08.840 I just love chocolate.

02:20:10.320 It's not that I eat it every day, a whole bar, but it is, or bread, you know?

02:20:14.960 That's one of the things too that is the balance.

02:20:18.420 I lost 33 pounds and I stopped there.

02:20:21.000 I could not lose more than that.

02:20:22.920 I needed to then increase my dose.

02:20:25.140 So I went from one hour to an hour and a half, four days a week.

02:20:28.300 I lost another 10 pounds.

02:20:29.860 So I lost a total of around 50 pounds, 47 to 50 pounds.

02:20:35.340 That was 11 years ago before coming here.

02:20:37.860 And I kind of keep it like that.

02:20:39.420 Now, this is interesting.

02:20:40.340 As you're probably aware, the exercise and weight loss literature suggest that exercise

02:20:45.440 alone is not sufficient for weight loss.

02:20:48.140 I've always wondered if that was an artifact of the fact that they're studying exercise

02:20:52.580 incorrectly.

02:20:53.140 That the prescription, it's either the dose or the frequency or the intensity were not

02:20:59.480 optimized.

02:21:00.260 You were doing a very specific type of exercise.

02:21:03.060 You were not exercising for the number of calories you burned.

02:21:06.740 You were training your mitochondria to become better at fuel partitioning.

02:21:11.820 That's a very technical description of what you did.

02:21:13.880 I think it's important for people who are listening to this to appreciate that nuance.

02:21:17.800 You were not there calorie counting saying, okay, I'm doing six hours a day at this many

02:21:22.220 calories because you can achieve that in many different ways.

02:21:25.300 It was almost the maniacal specificity with which you approached this that you basically

02:21:30.680 said you didn't think of it as I'm exercising six hours a week.

02:21:33.420 It's I'm doing mitochondrial conditioning or reprogramming six hours a week.

02:21:38.000 Exactly.

02:21:38.980 Yeah, I believe so.

02:21:40.140 And that's what we know now with patients when we study in the laboratory that they always

02:21:44.200 tell you, I always train at this intensity and you know that intensity they burn zero

02:21:48.240 grams of fat.

02:21:49.620 They burn a lot of calories, but zero are derived from fat.

02:21:52.760 Yeah, they're actually working too hard.

02:21:54.160 Too hard.

02:21:54.780 And eventually, number one, you don't burn much fat.

02:21:57.600 You burn about fat in the post-exercise because you might increase your metabolic rate, but

02:22:03.480 can that override the fat burning from the exercise itself?

02:22:07.780 And second, it's too hard.

02:22:09.980 You haven't exercised in a long time to start with and you get into these high intensity

02:22:15.100 programs that they might not suit you or they might injure you.

02:22:20.100 And many people give up.

02:22:21.140 We see the rate of people giving up from gyms is about 50% or so within X amount of months.

02:22:27.560 They either give up or their adherence decreases a lot.

02:22:30.800 So when I ask these people who get into this extreme, either exercise or diets, I always

02:22:37.840 ask them, and they're successful.

02:22:39.900 I ask them, can you do this for the rest of your life?

02:22:43.120 And the question is, hell no.

02:22:45.040 Yeah.

02:22:45.280 If you can't do it for the rest of your life, you have to come back to the, why am I doing

02:22:48.720 this using an extreme example to do hill repeats up Alpe d'Huez?

02:22:53.880 Can you do that for the rest of your life?

02:22:55.320 No.

02:22:55.920 Can you do it if your goal is to win the Tour de France?

02:22:58.500 Yes.

02:22:58.900 You're going to do it for five years.

02:23:00.280 You're going to train that hard for five years.

02:23:02.300 You're probably going to take a chunk of time off your life, by the way, but that's

02:23:05.780 your job.

02:23:06.260 You have to be the best climber in the world.

02:23:08.260 Exactly.

02:23:08.720 And to the point of the nutrition, the nutrition is a must.

02:23:12.080 You need to do something with it or do a lot more exercise.

02:23:15.160 But I think it's the balance that we all, I think, need to understand better.

02:23:18.960 Well, that's for me why fasting has become so important.

02:23:21.440 Now, you were laughing at me earlier before we started recording about how crazy it is

02:23:25.720 that I can do these long fasts.

02:23:27.380 But in many ways, it's a way to provide me balance.

02:23:30.060 It's like sprinting.

02:23:31.100 It's basically every month, there's just a frequency with which every quarter I do one

02:23:36.080 type of fast and every month, a different type and every week, a different kind.

02:23:39.520 It allows me to keep a balance and it allows me to say, yes, I could do this for the rest

02:23:43.200 of my life.

02:23:43.620 Whereas the reality of it is I couldn't do a ketogenic diet for the rest of my life.

02:23:46.700 As powerful as it was in me, I couldn't do it the rest of my life.

02:23:50.040 So a couple other questions I want to ask you about.

02:23:52.520 You've alluded to cancer twice now.

02:23:54.420 We've spent a lot of time talking about type 2 diabetes as a disease state in which the

02:24:00.080 mitochondria are not functioning well.

02:24:02.040 And they provide this great contrast, but you've touched briefly on cancer.

02:24:07.880 Is there any evidence that a patient with cancer has a higher lactate level on account

02:24:13.920 of the fact that they have mitochondria that aren't working as well, the same way that the

02:24:19.100 prism of type 2 diabetes has?

02:24:20.380 So it is a fact in 1923, almost 100 years ago, Otto Warburg from Germany discovered the

02:24:28.040 transformation of a normal cell into a cancer cell at the metabolic level.

02:24:31.720 And the characteristic of cancer cells was that they use a lot of glucose for energy

02:24:36.280 purposes.

02:24:36.860 Now, they use a lot of glucose.

02:24:38.480 Back in the days, there was no genetics or anything.

02:24:41.740 But what struck Warburg is the amount of lactate that they produced.

02:24:46.680 Was that what struck him more than the fact that they use so much glucose, even in the presence

02:24:51.220 of sufficient cellular oxygen and insufficient ATP demand?

02:24:55.180 So it was more of the lactate accumulation.

02:24:56.700 It was more of the lactate accumulation.

02:24:58.100 And that's why he came to conclusion that cancer was a metabolic disease caused by an injury

02:25:04.780 of the respiration system in the cell, which is the mitochondria.

02:25:07.880 And that's what was the thought for many years because of the lactate.

02:25:11.840 Even before glycolysis was invented, Meyerhoff, who discovered glycolysis, sometimes it's called

02:25:18.220 Mden-Meyerhoff pathway, which is glycolysis, Meyerhoff was a student of Warburg.

02:25:23.500 Before they had even found out about glycolysis, the way they measure glycolysis is by measuring

02:25:30.660 lactate.

02:25:31.800 So they would measure how much lactate the cell produces.

02:25:35.220 And that's where they would say, wow, they're using a lot of glucose.

02:25:37.980 But what he saw in cancer cells, there was an aberrant amount of lactate production.

02:25:42.820 And that was one of the things that struck Warburg the most.

02:25:45.360 And now what we see is that lactate is a typical feature of cancers.

02:25:50.940 Cancers produce a large amount of lactate, which is also responsible of the famous microenvironment

02:25:57.360 that a lot of people are talking about nowadays.

02:26:00.200 The lactate microenvironment, I mean, the microenvironment of cancer cells is more acidic

02:26:05.420 than non-cancer cells.

02:26:07.220 And it's a niche for carcinogenesis.

02:26:09.960 The responsible for that microenvironment is lactate.

02:26:12.480 And what we know is that, yes, it's a fact that multiple studies showing that, or every

02:26:18.440 study showing that every study trying to find lactate in cancer, they're going to find higher

02:26:23.040 lactate levels.

02:26:24.400 So this would suggest three distinct, but not necessarily mutually exclusive explanations

02:26:30.940 for the Warburg effect.

02:26:32.460 The first being what Warburg proposed, which is in cancer, there is an injury to the mitochondria.

02:26:39.140 As a result of that injury, the cancer produces, it takes an inefficient path to go.

02:26:45.260 Then there's the 2009 explanation proposed by Thompson, Cantley, van der Heiden in that

02:26:51.400 science paper that was sort of a very important landmark paper that said, no, no, that's probably

02:26:56.120 not it.

02:26:57.160 It's the glycolysis and the lactate production is a byproduct of metabolic demand for building

02:27:03.300 blocks.

02:27:03.800 It's the cellular nucleotides that are necessary to build the cells.

02:27:07.580 So the mitochondria work okay.

02:27:09.500 What you're seeing is a deliberate and obligate choice to grow.

02:27:14.060 And the need to grow literally from a mass balance perspective requires taking this pathway

02:27:20.040 versus that pathway.

02:27:21.200 And now you're saying, well, a possible third explanation is the cancer relies on lactate

02:27:26.460 as a signaling molecule.

02:27:28.640 And again, these could all be true on some level.

02:27:32.640 We know that they're not all always true.

02:27:35.120 I mean, at least we know that in the case of the Warburg effect, that's not universally

02:27:38.820 true that the cancer damages the mitochondria.

02:27:41.920 What are the next steps in figuring this out?

02:27:43.920 And perhaps more importantly, much more importantly, how do we use this information therapeutically?

02:27:50.020 Yeah.

02:27:50.200 So one of the things is that we have just finished a study.

02:27:53.220 It's under review now.

02:27:54.180 And we're going to replicate it now with more cancer cells.

02:27:57.140 But we have done a study with the MCF7 cancer cells, which are the most common type of breast

02:28:02.120 cancer or one of the most common type of breast cancer cells.

02:28:06.080 And what we have seen is like we expose the cancer cells to glucose.

02:28:11.740 So we did an experiment.

02:28:13.160 One, exposing the cancer cells to a media that contains nothing.

02:28:17.620 No glucose, no glutamine, which is also highly expressed in cancer.

02:28:20.660 And this can survive a couple of days in that state.

02:28:23.960 Then in another experiment, we just expose them to glucose.

02:28:28.140 That's it.

02:28:28.700 And in the other two other experiments, we added to that glucose media, we added 10 millimoles

02:28:34.280 of lactate and 20 millimoles of lactate.

02:28:37.080 What we did then is like we extracted the DNA.

02:28:40.300 By the way, are those physiologically accurate doses?

02:28:42.640 Do we believe the micro environment of cancer is that high?

02:28:46.360 It's about 10.

02:28:47.080 Yes.

02:28:47.480 It's 10 times the normal level.

02:28:49.280 There's been studies showing up to 40.

02:28:51.560 But normally, yeah, 10 is a typical.

02:28:54.140 And what pH?

02:28:55.380 The pH is usually between 6 and 7.

02:28:58.320 I was about to say that has to be below 7.

02:29:00.340 Yes, for sure.

02:29:01.340 In fact, the more aggressive in general, the more aggressive the cancer is, the more glycolytic

02:29:06.540 is, and the more lactate is found, and the more acidic the micro environment is.

02:29:11.780 So we published an idea to propose lactate being the explanation for the world war effect.

02:29:17.840 Because what we looked into the medical research is that the genetics stops in how the first

02:29:26.500 cancer cell happens, and maybe proliferation in cell cycle genes.

02:29:31.540 But there's a lot more to that in cancer.

02:29:33.560 You need angiogenesis.

02:29:35.220 You need metastasis.

02:29:36.560 You need immunoscape.

02:29:37.480 And you need also the cell-sufficient metabolism that cancer cells have.

02:29:41.320 It's immortal.

02:29:42.020 So that's where, like, what we saw is that lactate is necessary for each of these major

02:29:48.780 steps in carcinogenesis.

02:29:51.220 But what we wanted to see is, like, could lactate also be a signaling molecule?

02:29:55.560 And that's where, like, what we observe is, like, looking at transcriptional activity,

02:30:00.280 looking at the RNA expressions of the key oncogenes, transcription factors, and cell cycle

02:30:06.280 genes and proliferation genes in cancer, lactate overexpressed them between 2 and 8-fold compared

02:30:12.620 to control.

02:30:13.600 And what was the difference between the 10-millimolar and 20-millimolar lactate?

02:30:17.200 Did you see a difference in transcription?

02:30:18.920 In 10 and 20, we didn't see much of a difference.

02:30:21.520 But we saw more than in zero.

02:30:24.300 What struck us, and that's kind of hopefully we can show, is that if you cultivate the cancer

02:30:30.200 cells in glucose alone, I give this presentation on the Anderson, but so we looked at the cancer

02:30:36.520 cells, and we looked at the major oncogenic, I mean, oncogenes, transcription factors, and

02:30:41.220 cell cycle genes, we had no glucose incubation, no glutamine either, just glucose, and then we

02:30:49.700 had a lactate, 10-millimolars, and 20-millimolars.

02:30:52.160 So we did RNA extraction, and we looked at, in the cancer cells, were there without any media?

02:31:00.560 That is, no glucose, no glutamine.

02:31:02.300 We didn't see RNA expression.

02:31:04.260 Did the cells live?

02:31:05.420 Oh, those oncogenes.

02:31:06.800 We killed them.

02:31:07.680 We didn't.

02:31:08.220 In other words, there's a very finite period of time in which you're looking to just see...

02:31:11.840 Yes, we look in 6 hours and 48 hours.

02:31:14.840 So neither in 6, 48 hours was RNA expression.

02:31:17.900 Okay, what about glucose by itself?

02:31:19.420 So when you add glucose by itself, we looked into the media, and it was a very high lactate

02:31:25.840 levels.

02:31:26.600 Looks like on your graph, it's almost 30 millimol.

02:31:28.960 Yes, it was almost 30 millimol in the 6 hours, and because lactate is also used by the cells

02:31:34.440 for energy purposes, over time, we expected also to see, but we still see about 25 millimolar.

02:31:40.120 This is the waterbore effect.

02:31:41.640 This is what waterbore observed, incubating in cells and said, wow, they use a lot of glucose,

02:31:46.560 but why in the world is this lactate?

02:31:48.400 It's amazing, it's that high.

02:31:49.580 So what we saw then is like this lactate alone was enough to trigger the expression of all

02:31:57.120 the major oncogenes, transcription factors, and even depress the cell arrest genes.

02:32:03.180 So is there an experiment that could be done where you constantly change the media?

02:32:08.640 You have a flux of media that allows them to have a finite amount of glucose, but you constantly

02:32:14.140 strip away the lactate to see what the true baseline level of expression is, absent the

02:32:20.200 lactate as the signal.

02:32:21.620 Yeah.

02:32:21.820 So this is now where we're going to be replicating this experiment with multiple cancer cell lines,

02:32:27.540 from liver to pancreas, to lung, to kidney, to a thyroid, more glycolytic, less glycolytic,

02:32:34.100 and then do all these kinds of experiments and include also metabolomics.

02:32:37.900 I mean, this is a complicated media device because you basically have to expose them to

02:32:42.200 a bath of constantly moving media that contains glucose, but no lactate.

02:32:48.200 You see what I'm saying?

02:32:48.980 So you have a negative flux of lactate across the cell, because what you really want to do

02:32:53.540 is see how does this work with glucose, but no accumulated lactate?

02:32:59.180 Because that would answer the question, is lactate specifically signaling?

02:33:03.380 Because you could still argue here glucose is playing a role.

02:33:06.100 Yes, but we believe this is through the lactate.

02:33:08.360 Through the lactate, but now how do we figure that out?

02:33:10.360 That's what we did in the second experiment, the glucose media is the same, we just added

02:33:15.300 more lactate, and we see a much amplified response.

02:33:19.000 How much is it amplified with...

02:33:20.800 So it was, for example, this is the no lactate versus the lactate.

02:33:24.760 We can see...

02:33:25.220 That looks like about 2x?

02:33:26.700 Yeah, sometimes even 2x.

02:33:28.500 So that's where we saw that the media is the same, but the more when we added the lactate,

02:33:33.380 it really overexpressed the transcriptional activity.

02:33:35.940 So if I was going to play devil's advocate, you could say that we know that the lactate

02:33:39.760 could be serving a metabolic fuel.

02:33:42.660 So maybe it's conserving more glucose for more glucose to be signaling transcription.

02:33:48.400 Well, we know that lactate is being used by the mitochondria of cancer cells.

02:33:53.820 Everywhere is mitochondria, there's lactate.

02:33:56.020 What we believe is that it's a signaling molecule to really overexpress the transcriptional activity

02:34:02.320 of oncogenes, transcription factors, and cell cycle genes in a non-hierarchical way, because

02:34:08.340 the traditional view of cancer is that you have the oncogenes, they tap on the transcription

02:34:13.860 factors, and they start an array of different downstream signaling that eventually transforms

02:34:21.300 a normal cell into a cancer cell.

02:34:23.040 This is so interesting because it, again, at the meta level, flies in the face of all

02:34:28.540 of the observational data of how much metformin lowers cancer, unless it comes back to your

02:34:34.840 explanation.

02:34:35.400 Because if you just look at these data, all things equal, and by the way, that would be

02:34:39.500 another interesting experiment.

02:34:40.640 Add metformin to the dish as well.

02:34:42.620 In theory, it should amplify lactate by poisoning the mitochondria further and drive even greater

02:34:51.920 upregulation of these signals, unless, to your point earlier, it becomes so toxic to the

02:34:58.180 mitochondria that the cell undergoes apoptosis.

02:35:00.420 Yeah, that's what's, in my opinion, and this is another thing that we want to do, but it's

02:35:05.040 possibly that, yeah, because you're totally right.

02:35:07.540 It can amplify the lactate, as we know, so it can amplify that oncogenic or oncogenetic

02:35:13.480 signaling for carcinogenesis.

02:35:15.840 Or maybe it just doesn't matter because these amounts of lactate are so high that we're not

02:35:22.680 seeing that from metformin.

02:35:24.460 Maybe metformin isn't that inhibitory to the mitochondria, and that becomes a red herring

02:35:29.780 in the equation, and the benefits of metformin exist totally elsewhere.

02:35:32.600 We don't know, but it would be very interesting to see all this, because it can have some

02:35:37.300 application, and there's some research groups studying already why.

02:35:41.040 I feel like I need to quit my job and come and be a postdoc in your lab, because there's

02:35:44.960 just so much.

02:35:45.820 The more we talk about this stuff, and I know it's going to get way worse tonight when

02:35:48.780 we have dinner with Rick, because it's going to be like 50 other ideas that I just want

02:35:53.400 to...

02:35:53.820 With the fructose as well.

02:35:55.800 Yeah, that's a lot of things going on there.

02:35:57.880 Let's talk for a few minutes about drugs and cycling.

02:36:01.240 Many people argue that the era from about 91 to 2010, there's a 20-year period of time,

02:36:09.640 the 90s and first decade of the 2000s, where the use of drugs was at its highest.

02:36:15.120 I don't think anybody can be a student of this sport and ever say there's been an era

02:36:19.620 when the top athletes weren't using some drug.

02:36:22.640 I mean, even Eddie Merckx, the greatest cyclist of them all, on many occasions was found to be

02:36:28.460 using an amphetamine or something like that.

02:36:30.280 How much of an impact do you think the performance-enhancing drugs of that era, the 90s and 2000s,

02:36:37.460 where, again, it's all out in the open now.

02:36:39.040 Everybody understands how much blood doping and how much EPO was being used.

02:36:43.340 Yet you, a moment ago, gave a number of 6 to 6.5 watts per kilo as an FTP.

02:36:50.160 I recall reading at the time, athletes hitting 7 watts per kilo.

02:36:56.860 Do you think that is about the distinction of with and without EPO?

02:37:02.000 Do you think that's about the magnitude of the improvement?

02:37:03.960 I could not know that number.

02:37:05.760 Yeah, I mean, definitely, we know the times.

02:37:08.400 And back in the days, we didn't have those power meters or cyclists, they didn't use them.

02:37:12.420 So it's difficult to calculate, but it is possible to calculate with the times.

02:37:16.340 I haven't done the numbers.

02:37:17.760 But what we know now is that the times going Tourmalet, Aldues, or so, are the same times

02:37:24.120 that people were doing in the 80s or early 90s.

02:37:26.980 It's hard to see any of today's cyclists being in the top 20 best times now, as they did before.

02:37:33.360 So that's something that shows that, yeah, cycling, I think, goodness, is a very clean sport right now.

02:37:39.780 The other thing is the fact that every cyclist now who wants to do well, they go to altitude.

02:37:47.140 And that's one thing that before didn't happen.

02:37:49.660 And now it's great to see people going to altitude because it's a physiological way to increase oxygen carrying capacity.

02:37:56.940 Is the data on altitude still the following?

02:38:00.000 So when I last looked into this, which is maybe a decade ago, the answer seemed to be the performance-enhancing way to use altitude

02:38:08.160 is to live high, train low, meaning your baseline exposure should be at a low-oxygen environment,

02:38:16.540 your low-intensity training should be at a low-altitude environment,

02:38:19.880 but your high-intensity training should be at sea level.

02:38:23.360 Is that still believed to be the case?

02:38:25.100 That's an ideal scenario, in my opinion, yes.

02:38:27.280 And, I mean, here in Colorado, because we're in Colorado here, by force, we need to know,

02:38:32.200 we must know about altitude because we get a lot of athletes every year and we get to study them.

02:38:38.080 And, yeah, one thing that happens at altitude is your glycolytic capacity, it starts deteriorating.

02:38:43.560 The high exercise intensity is like if you had a cap here at altitude.

02:38:47.700 And this is something that everybody tells you when they're here, like, I cannot keep my 100% here.

02:38:52.860 I cannot open up the same gas as I used to have.

02:38:55.500 And if you don't do that for three and a half weeks or three weeks at your altitude,

02:39:00.160 yeah, your glycolytic capacity is going to deteriorate,

02:39:02.840 which for a marathon runner, they couldn't care less.

02:39:06.220 But for a cyclist, for example, it's important.

02:39:08.740 So that's where, like, the ideal scenario is to really try to find that balance,

02:39:12.920 but it's not easy to do at high altitude levels.

02:39:16.220 Has anyone ever proposed using little portable oxygen-

02:39:19.640 Yes.

02:39:19.900 And producing devices for peak, peak, peak efforts for those who live at altitude to maintain top end?

02:39:25.140 Exactly. And that's done.

02:39:26.500 It is done.

02:39:27.080 Yeah, it is done. Yeah. And that's something that we're building at the university,

02:39:31.760 in one of our campuses in Colorado Springs, a sports medicine and performance center,

02:39:35.700 where we're going to have one room that is going to simulate sea level conditions.

02:39:41.420 So it's going to be hyperoxic.

02:39:43.940 So it's going to simulate living at sea level,

02:39:46.780 because that is going to allow athletes to do very high-intensity efforts without killing themselves.

02:39:53.520 Because this is the problem that happens here, altitude.

02:39:56.020 These athletes who want to do very high-intensity exercise,

02:39:59.100 which would they really need also to, they get overtrained.

02:40:02.460 We see a lot of people live in altitude in very bad form, and they're going to train,

02:40:07.620 or they live with a high oxygen carrying capacity, but poor glycolytic capacity.

02:40:12.680 So that's where like, yeah, by doing this space,

02:40:15.660 it's going to allow athletes to come and they use these facilities while living at altitude.

02:40:20.920 Because the problem that we have here, you have two days driving to the ocean,

02:40:24.680 so you cannot train low and deep high.

02:40:26.600 But at least train low, high-intensity, you can simulate that while still living in high environment.

02:40:33.440 So interesting.

02:40:34.420 Miguel Indoran, have you ever met him?

02:40:36.380 Yes.

02:40:36.960 An unbelievable specimen?

02:40:38.460 Yeah, yeah.

02:40:39.220 And an incredible person too.

02:40:41.080 I've heard he is, so he's got to be what now?

02:40:43.220 He's got to be 60?

02:40:44.600 Yeah, 50s, in the high 50s or so.

02:40:47.040 50s, yeah.

02:40:47.300 Yeah.

02:40:47.780 Still incredibly fit.

02:40:48.960 I remember reading a paper about him maybe 20 years after he retired.

02:40:53.000 He retired in 95, 96, right?

02:40:55.380 I mean, still unbelievable numbers.

02:40:57.920 I mean, was he just a physical phenom to begin with?

02:40:59.920 Yeah, he was incredible.

02:41:00.940 When I was doing my internship, I was doing it with an endurance physiologist,

02:41:05.220 who was a very, very good physiologist.

02:41:08.160 And I learned a lot.

02:41:09.840 And I remember once I was kind of helping there.

02:41:12.960 And the one thing that struck me also was his numbers were unbelievable.

02:41:16.880 And also the amount of sweat that he had.

02:41:19.780 I have never seen anybody sweating so much in my entire life.

02:41:23.480 He was a big guy, right?

02:41:24.420 He was 80 kilos, six foot one, six foot two.

02:41:27.800 It was incredible.

02:41:28.460 Because usually when you do physiological tests, you might have a few, one towel or a couple of

02:41:33.040 towels, even with fans, people sweat a little bit.

02:41:35.580 And back in the days, I was just wiping the floors.

02:41:39.020 That's kind of, you do internships.

02:41:40.760 In these cases, yeah, if we do it in the rain, you need a mob.

02:41:43.720 And have you seen athletes since?

02:41:45.440 Never.

02:41:45.980 So do you think that's just true, true and unrelated?

02:41:48.120 Or do you think that also spoke to his physiology?

02:41:50.380 Like he had an unusual cooling system.

02:41:51.880 It was like out of this world.

02:41:53.080 I have never seen anybody like him.

02:41:54.760 And if you observed in the truth of France, everybody was with their shirts wide open,

02:41:59.140 right?

02:41:59.380 And in the rain was always, all seeped up, always, always, always, and with a hat on.

02:42:03.760 So he had an amazing capacity to dissipate heat, which is a double-edged sword.

02:42:08.500 So obviously, he drank a lot.

02:42:10.680 But I'm very sure, and back in the days, we didn't have the technology that we have

02:42:14.060 nowadays to measure that.

02:42:15.540 What do we do now?

02:42:16.280 Sodium concentration in sweat.

02:42:17.720 We do sweat tests.

02:42:19.100 We have sweat patches.

02:42:20.540 And we can measure the sodium concentration in the sweat patches and then tell someone,

02:42:25.720 whoa, you're a heavy sweater in the first place, and you also sweat a lot of sodium.

02:42:31.240 But when someone, and it's something that's very typical using young people or people who

02:42:35.480 are not very well adapted to sweating, you see like the white marks in their shorts or

02:42:41.040 in their helmets.

02:42:42.020 That's salt, literally, sodium.

02:42:44.180 But the more mature physiologically enough it gets, the more they sweat.

02:42:49.260 That is, I have never realized that that is a metric.

02:42:52.780 Yet another little trick of the trade to look at sort of metabolic flexibility is the ability

02:42:58.420 to retain the sodium as just the water leaf.

02:43:00.620 Yes, exactly.

02:43:01.740 Makes total sense.

02:43:02.300 Yeah, it's an evolution.

02:43:03.680 And you sweat more.

02:43:04.540 Back in the days, I was just doing, just wiping the floors.

02:43:07.480 But now you'd bet that there's low sodium in there.

02:43:09.980 You'd pull a William Osler and he figured out that diabetes urine tasted like sugar.

02:43:15.200 You'd figure out that Indoran's sweat tastes like water.

02:43:17.920 I would have tested it for sure.

02:43:19.640 I guarantee you.

02:43:20.700 And I'd say, man, there's no salt here.

02:43:22.960 Indoran's interesting because he's right on that precipice where there is no question

02:43:26.580 that the person who won the tour right after him was using Herculean doses of EPO.

02:43:32.980 So Bjorn Reis won in 96, nicknamed Mr. 60, right?

02:43:38.040 I mean, hematocrit somewhere between 60 and 66.

02:43:40.300 So you go from Bjorn Reis to Ulrich to Pantani to Armstrong.

02:43:46.780 That's the era.

02:43:47.540 And then before Indoran is Greg LeMond, who, again, I don't really know anything about

02:43:53.160 what he was or wasn't taking.

02:43:55.420 But Indoran has largely been left out of the discussion on blood doping.

02:43:59.580 And I've read articles that have just talked about how he's generally been left alone.

02:44:03.280 No one has come back to him.

02:44:04.540 So I'm not going to ask you to speculate on that because I know that from a personal standpoint,

02:44:08.460 I don't want to put you on that spot.

02:44:09.680 But do you get the sense that he's just been left out of this discussion because of his

02:44:13.980 place in cycling?

02:44:15.280 And it's almost like people don't want to go back and revisit that.

02:44:18.700 I mean, why do you think that is?

02:44:19.920 I don't know.

02:44:20.520 I have no idea, to be honest.

02:44:22.140 I could never give you an answer.

02:44:24.120 I know that he was a freak of nature because of his size in the same manner that before

02:44:30.260 Indoran was Greg LeMond, who was also a freak of nature, a freak of nature as well.

02:44:35.140 And left out of all this.

02:44:36.560 I have no idea, but I've seen his physiological parameters and I've seen a lot of athletes

02:44:41.320 who don't see those physiological parameters.

02:44:43.740 And also what I always say about Indoran is his head.

02:44:47.660 And I work with a lot of athletes.

02:44:49.540 And in cycling, for example, I have never met any athlete.

02:44:53.100 Well, there's one athlete.

02:44:54.720 I will tell you in a few years.

02:44:57.020 Meaning there's someone you work with now who maybe in a few years you'll tell us.

02:45:00.160 Yeah, I don't want to be-

02:45:00.840 No, you don't want to jinx him.

02:45:01.760 Him too.

02:45:02.160 Yes, exactly.

02:45:03.420 But only one athlete with his head.

02:45:06.040 He was calm.

02:45:06.920 He was relaxed.

02:45:07.780 He was super intelligent.

02:45:09.140 He could read the game ahead of things.

02:45:11.300 He would never get nervous about anything.

02:45:13.380 And he would never doubt about anything, which is rare in athletes.

02:45:17.300 I've seen athletes getting to the top of the game and falling apart and start crying.

02:45:21.780 There's the fear to lose, but also the fear to win.

02:45:25.600 Because when you win, your life changes for the good or for the bad.

02:45:29.040 And many athletes, they were always nervous trying to find an answer or trying to find

02:45:32.620 a new diet or a new training or something, you know?

02:45:35.480 And that's where like, we're very fragile.

02:45:37.780 Athletes at the high level, very, very, very fragile.

02:45:40.600 If you're considered like an expert or you're a coach or you're someone with a little bit

02:45:45.400 of a name in cycling, for example.

02:45:48.260 And if you go to a race and you see a cyclist, wow, you look fat.

02:45:52.020 I think you gain weight.

02:45:53.580 That cyclist is done.

02:45:54.900 Yeah, exactly.

02:45:56.160 Done.

02:45:56.500 I mean, cyclists are like models in that regard, right?

02:45:59.300 Every ounce matters.

02:46:00.880 Exactly.

02:46:01.340 And that's how they are.

02:46:02.340 But Indurant started the tour with two and a half kilos over, for example.

02:46:05.560 Why?

02:46:05.920 The first weekend the tour is flat, no gravity.

02:46:08.460 His head is relaxed and calm and like, okay, I can do this, no problem.

02:46:12.740 And in that week, he loses a kilo, kilo and a half.

02:46:15.640 And then he's entered the second week with the mountains with half a kilo over.

02:46:19.420 Okay, no problem, no big deal.

02:46:21.080 He loses it.

02:46:22.000 And then boom, the last week is in perfect weight.

02:46:24.080 It takes a lot of thinking and confidence, right?

02:46:27.600 And saying, hey, I got it.

02:46:28.740 And that's why I think that his head was also unbelievable.

02:46:32.020 LeMond's head was also incredible.

02:46:33.740 I remember as a kid reading LeMond's book.

02:46:36.680 It really, literally changed my way of looking at cycling.

02:46:40.120 I was 15 when he won the Tour de France.

02:46:42.820 And that's where I started to see his complete book of cycling.

02:46:45.780 I don't know if you've ever read it.

02:46:47.120 It's the best cycling book I've ever read in my life.

02:46:50.140 And it's about how he trained and how he ate and how the way he approached cycling.

02:46:56.780 And back in the days, I'm talking 86, he was super scientific.

02:47:00.040 Yeah, he was so far ahead of everybody else.

02:47:04.400 Everybody else.

02:47:05.160 Yeah, yeah.

02:47:05.680 We could go on for hours.

02:47:07.020 But I think on this note, we'll bring it to a close only because we're already late for dinner.

02:47:12.800 And I don't want to keep Rick waiting.

02:47:14.980 But I want to thank you so much for this.

02:47:16.220 This has been incredibly informative.

02:47:18.460 There is a million follow-up things to do, including we're going to do this biopsy study.

02:47:22.040 So I'm willing to come back to Colorado to do this again because I really am curious about this metformin question around zone two.

02:47:29.640 And I think that this is going to be one of those episodes where hopefully people are able to see the show notes because so much of what we've talked about, I think, benefits from this type of being able to visually see what this stuff we've talked about.

02:47:40.680 And lastly, I do think there's going to be no shortage of medical students and undergraduate students who are looking for summer projects to come and help you get a lot of these really interesting posters published.

02:47:51.800 So thank you for the impact you've had on me personally with respect to how I think about this problem and then hopefully by extension how others have as well.

02:48:00.780 Well, thank you so much.

02:48:01.540 It's truly an honor to have you here and to speak with you and be invited to your podcast.

02:48:05.360 Thank you very much.

02:48:07.120 Thank you for listening to this week's episode of The Drive.

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The Peter Attia Drive - December 27, 2021

Iñigo San Millán, Ph.D.： Zone 2 Training and Metabolic Health (Ep. #85 Rebroadcast)

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