The Peter Attia Drive - #312 - A masterclass in lactate： Its critical role as metabolic fuel, implications for diseases, and therapeutic potential from cancer to brain health and beyond

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

00:00:16.540 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

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00:00:53.200 of the subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.020 head over to peteratiyahmd.com forward slash subscribe. My guest this week is George Brooks.

00:01:06.500 George is a professor in the Department of Integrative Biology at UC Berkeley and is the

00:01:10.360 director of the Exercise Physiology Lab. You may recognize George's name as it's come up a couple

00:01:15.060 of times in interviews with Inigo San Milan. I also wrote about George briefly in Outlive when I referred

00:01:22.380 to his work in lactate. George was the scientist who first proposed the lactate shuttle theory in the

00:01:28.260 1980s, arguing that lactate was actually a fuel source rather than an unfortunate byproduct of

00:01:33.580 exercise. His research has focused on the metabolic adjustments to exercise and explores many topics

00:01:39.460 surrounding exercise physiology, including the pathways and controls of lactate formation and removal

00:01:45.000 before, during, and after exercise. My conversation with George dives deep into all things

00:01:50.500 is lactate. It's a little bit technical, but again, not particularly egregious relative to the depth

00:01:56.700 that we normally will cover things. But I do encourage you to stay with this, even if at times

00:02:01.720 it seems a bit heavy on the biochemistry. We probably start a little bit in that direction,

00:02:06.580 but I promise it's a very fascinating episode. We obviously start with some semantics and definitions.

00:02:12.360 We clear the air a little bit on the difference between lactate and lactic acid. We touch briefly

00:02:17.080 on a historical discussion looking back at the work of Meyerhoff and the early misconceptions around

00:02:21.460 lactic acid and its role in muscle activity and fatigue. Talk about George's work, which highlights

00:02:25.980 lactate's integral role in energy processes, and not just merely as a waste product, as I said a moment

00:02:31.020 ago. We talk about the monocarboxylate transporters, and I learned quite a bit in this podcast because up

00:02:37.060 until this point, I had no idea that the MCTs, as they're called, were also located on mitochondrial

00:02:42.300 membranes. We talk about some misconceptions in the educational practices today, including

00:02:47.320 what I learned, and basically discover a lot, at least for me, about the relationship between

00:02:52.340 lactate and other disease states such as type 2 diabetes, cancer, and most surprisingly to

00:02:57.460 me, brain injuries. There's a lot more we go into here, but I think I will leave it to say

00:03:03.280 that I emerged from this podcast with both a better understanding of what I already knew, and

00:03:09.600 more importantly, perhaps a new understanding of what the potential of lactate is in the therapy

00:03:14.660 of human conditions in ranging everything from cancer to, as I said, traumatic brain injury.

00:03:20.140 So without further delay, please enjoy my conversation with George Brooks.

00:03:28.700 Hey George, thank you so much for making time to sit down with me today. This has been a long time

00:03:34.500 coming. As you know, your colleague and partner in crime on much of the work you've done, Inigo San

00:03:40.340 Milan, has been a multiple-time guest on this podcast. And of course, your name has come up many

00:03:45.760 times. I've referenced you and your work in my book. So it's great to be sitting down with you

00:03:50.720 to talk about lactic acid, which is something that I think it would be safe to say at the outset is

00:03:56.020 probably a misunderstood molecule. Would that be a safe statement to start this out?

00:04:00.080 Yes, it is. And thank you, Peter, for having me on. It really helped make my career because

00:04:05.180 my physician wife's friends know my name, but after reading your book, they say,

00:04:10.880 that's George. So that's really great. Not to be difficult, but you did mention lactic acid.

00:04:17.940 Yeah. I was about to say, and I'm glad you brought that up, but I assume you're going to say,

00:04:21.340 should we really think about this as lactate or lactic acid? And let's have you get the semantics

00:04:25.440 right out of the gate for us. We can say lactate. The body does not make lactic acid.

00:04:31.600 Right. Makes lactate, and then there's a hydrogen ion, and presumably if there's a hydrogen ion near

00:04:35.640 the lactate, it's lactic acid. That's been a historical mistake, a 100-year mistake.

00:04:42.320 Lactate is not just an innocent bystander. It's a participant in the process of powering muscle.

00:04:49.320 In fact, all cells. So let's go back in time, a hundred years, because it was about a hundred

00:04:55.200 years ago that Otto Meyerhoff made a seminal discovery. Can you tell us a little bit about

00:05:00.780 what that was and how that started a chain of understanding that brought us to where we are

00:05:05.800 today? The early 20th centuries, people were trying to unite what was known from fermentation

00:05:12.020 technology to what was coming out of studies of muscle metabolism. And Meyerhoff was a great man,

00:05:19.820 a great investigator. And one of the things he did was to quantify how much glycogen is in muscle and

00:05:25.860 how it, when it degrades, it produces lactate, at that time thought to be lactic acid. So we're

00:05:33.040 projecting now a picture of the seminal kind of experimental setup that Meyerhoff and colleagues used.

00:05:39.660 And they had a half a frog in a jar without oxygen supplementation, without any perfusion that is

00:05:47.860 blood flow. And this half a frog, the muscles were made to contract. And they contracted until they

00:05:54.860 couldn't contract anymore. And then quantitatively, Meyerhoff could say, well, there was X amount of

00:06:01.060 glycogen and there was X amount of lactate produced. And so that was really instrumental in developing this

00:06:08.020 pathway. But if you look at this, this is really not what we are. These muscles are made in nature to

00:06:15.120 contract once or twice. The frog hops, it gets away or gets eaten. The muscle doesn't, is not

00:06:20.920 representative of us. But in this situation, they stimulated the muscle to contract. It stimulated

00:06:28.040 glycolysis to produce ATP. And at the end, the muscle fatigued. And at the end, there was a lot of

00:06:34.780 lactate. And there was also a lot of acid. So this is how we came to associate lactate or lactic acid

00:06:41.880 production and oxygen lack. Because there was no oxygen around here. So it had to happen. It was a

00:06:47.440 fait accompli. And this led to the idea of lactic acidosis and the anaerobic threshold and the oxygen debt.

00:06:55.220 But if you just look at this simple, simple apparatus where you have a half a frog made to contract,

00:07:00.680 this is really the aegis of our understanding of how carbohydrate is used in the body.

00:07:06.720 All textbooks, most textbooks, well, not mine, talk about glycolysis going to make pyruvate and

00:07:14.220 when there's no oxygen, lactic acid. So this has been a problem. And this spills over not only

00:07:20.780 into muscle physiology, but it spills over into pulmonary medicine. It spills over into cardiology.

00:07:27.740 It spills over into nutrition. Now we know a lot of things that were not known or could not be known

00:07:35.240 at that time. And right now, I think I'm going to talk more directly about our new research.

00:07:42.680 Well, I want to go back to that for a second, though, before we get there,

00:07:45.620 George, to make sure everybody kind of understands the experiment and the interpretation. So some folks

00:07:52.180 couldn't see that image, but basically you were showing a schematic of an experiment.

00:07:55.680 So let's just kind of explain what was going on there and maybe try to understand the

00:07:59.800 interpretation. So the musculature of part of a frog is put into an anaerobic chamber. This is a

00:08:05.060 chamber that has no oxygen and it's not perfused. So there was no blood to carry hemoglobin, to carry

00:08:12.900 oxygen to the muscles. Presumably electrodes were placed somewhere on the musculature within the

00:08:19.160 chamber and the electrodes provided the stimulation for muscle contraction. And then the question became,

00:08:27.160 what is it that fueled the contraction? Well, obviously it's the glycogen within the muscle,

00:08:33.980 but if glycogen or glucose is being used to fuel contraction without oxygen, it somehow must be

00:08:42.740 happening in the absence or exclusion of the mitochondria. And so what they were measuring

00:08:49.480 was the consumption of glycogen, the production of lactate, and presumably they could measure the pH

00:08:59.440 in the solution. And I'm assuming that the pH, which is a measure of acidity, was going down. Is that

00:09:05.400 all correct? That's all correct. And so the interpretation of that observation was what

00:09:12.680 at the time? Well, first of all, that was important in terms of quantifying glycolytic pathway,

00:09:18.500 precursor and product. You start with a certain amount of precursor and you wind up with a certain

00:09:22.700 amount of product. But since then, people have associated the appearance of lactate with oxygen

00:09:29.280 lack. That's a mistake. There was no oxygen there. It's a stress-strain kind of relationship. The muscle

00:09:36.120 is stressed to perform. It uses what it has. It uses glycogen. It produces lactate. And there's also an

00:09:44.880 acidosis. So there's an association with lactate and lactic acid, acidosis and fatigue. So this whole thing

00:09:52.720 was boiled up in one knot. So when I learned exercise physiology, it was all those same things,

00:09:59.460 fatigue, acidosis, lactic acid. So George, in the experiment that Meyerhoff did almost exactly a

00:10:06.780 hundred years ago, at some point, I assume the frog's leg stopped contracting in the presence of

00:10:13.720 the stimulus. And is it believed that that was due to a depletion of glycogen? Or was it believed that

00:10:24.520 the degree of acidosis had become so significant that the acidosis crippled in some way the actin and

00:10:34.180 myosin filaments of the muscle and prevented either further contraction or relaxation? Exactly. At that time,

00:10:42.700 people were trying to understand why muscles contracted. And it was just a simple kind of

00:10:47.440 thing like, let's have tea. Would you like tea with cream or would you like it with lemon? Oh,

00:10:53.000 I would like it with both. So right then, you get this curdling with the acidosis. One idea of muscle

00:11:00.060 contraction was that actually the actin and myosin kind of curdle. And then they have to uncurdle.

00:11:06.140 So it was believed that the accumulation of acid, lactic acid, caused fatigue.

00:11:11.740 And when you look back at that experiment, I'm going to jump around a little bit because there's

00:11:16.980 a bit more history I want to get into. But just so people can understand how you think about this

00:11:22.100 problem today, based on the entirety of your work, what do you believe was the explanation for why

00:11:30.460 the frog's muscles ceased to contract in the presence of an ongoing stimulus?

00:11:36.000 I think what happened was there was ATP and creatine phosphate depletion in this anaerobic

00:11:42.800 environment. Interesting. By the way, how much does, in an experiment of that nature,

00:11:49.560 how much does the pH go down? I don't think they reported the pH,

00:11:53.920 but the pH would probably go just a bit under seven. Got it. And just for folks listening who

00:11:59.220 aren't familiar with pH, pH, the number, I guess, can be as low as one and as high as 14. Is that

00:12:07.140 effectively the range of pH, something like that? That's right.

00:12:10.460 Although physiologically, I mean, that would be in a chemistry lab. Physiologically, in a mammal,

00:12:16.220 it's very hard to get too much below the high sixes and too high above the high sevens. And the higher the

00:12:24.660 number, the more basic and the lower the number, the more acidic. But would you agree with that,

00:12:29.260 that physiology tends to exist in the sevens with 7.4 being perfectly neutral?

00:12:35.540 I'm teaching physiology now, 7.38, 7.4. And you're right. It's really hard to get the pH book

00:12:43.380 to seven or even a little bit below. Yeah. I'll tell you just a funny anecdote,

00:12:48.000 maybe a not so funny anecdote, unfortunately, but a very common story when I was training in surgery.

00:12:52.760 Obviously, when trauma patients are brought in to the trauma bay, one of the pieces of data that

00:12:59.080 the paramedics have on the way in is the pH. They can measure blood pH very quickly and easily.

00:13:04.240 And that became a way that we would triage readiness in the ICU and in the operating room.

00:13:10.480 When gunshot wound victims or stab victims were being brought in, even if they were alive,

00:13:15.480 if their pH was 7 or 6.9, we knew that it was very unlikely that they would survive,

00:13:24.060 even if their heart was still beating at the moment that that was reported to us.

00:13:27.840 I can think of one case that was a miraculous case where a guy

00:13:31.020 was brought in with a pH of 6.9 on arrival and he managed to survive, which is kind of an amazing

00:13:37.700 story. But it is funny how the body really, really regulates acid-base balance. So let's fast forward

00:13:46.180 a little bit, George. So if I'm not mistaken, did Meyerhoff win the Nobel Prize for that observation

00:13:50.620 in 1922? Yeah, he was awarded it along with A.V. Hill. And A.V. Hill is a very famous name in

00:13:57.860 physiology. We sometimes refer to him as the father of physiology or the father of muscle physiology or the

00:14:04.980 father of exercise physiology. So A.V. Hill and Otto Meyerhoff shared the Nobel Prize.

00:14:12.320 Okay. I don't remember exactly when Warburg made his seminal observation that also bears his name,

00:14:18.960 but I'm guessing it was about two decades later. It was probably in the 1940s. Is that

00:14:23.380 approximately right? Otto Warburg was actually Meyerhoff's professor in Germany. So you're talking

00:14:30.420 about the Warburg effect, cancer cells. Cancer cells will take sugar, glucose, and make lactate.

00:14:37.440 And they do that under fully aerobic conditions, under room air, where the oxygen is actually higher

00:14:43.180 than it ever is in the body. And these cancer cells will just break down carbohydrate, break down glucose

00:14:49.760 quantitatively. You wind up with this lactate and acid. So we don't need to go out into any more

00:14:58.980 than we have. But if you look at the glycolytic pathway, at the end, there's pyruvate anion and a proton,

00:15:07.340 NADH, this redox carrier. It gives us lactate anion and NAD+. So the last step in glycolysis does not

00:15:20.760 make acid. It's actually an alkalizing step. But in metabolism, there's a lot of things that can give

00:15:28.320 rise to acid. And some of the intermediates in the glycolytic pathway are acids. So there's lactate

00:15:37.080 and there's acid. So your observations in the ICU, to be concerned about pH, of course, that's really

00:15:44.680 important. That's essential. Sometimes people also measure lactate. For instance, in sepsis or other

00:15:51.200 kinds of conditions, people will be measuring lactate. But I think you're making an important

00:15:56.100 distinction between pH and lactate. Yeah, I assume, because we did, we would measure

00:16:01.140 lactate all the time if we thought sepsis was brewing. But I suppose, and we'll get to this in

00:16:07.100 more detail, that we were using lactate as a surrogate for something that was of greater concern to us,

00:16:13.460 which was actually the pH balance, correct? That's right.

00:16:17.080 George, I want to go back to some fundamentals. I was a little delinquent in not doing this out

00:16:21.560 of the gate because I wanted to sort of jump right in. But it occurs to me as we're talking now that

00:16:25.460 I don't want to take for granted that our listeners really might be as familiar as you and I are with

00:16:32.400 metabolism and frankly, the breakdown of a carbohydrate into what ultimately becomes ATP.

00:16:39.420 I'd like for you to spend a moment explaining the following. So at a high level, this is what

00:16:44.400 I will typically tell a patient if I'm talking about this or if they express an interest. I say,

00:16:48.920 look, food is chemical energy. You eat these things and they have bonds in them, especially

00:16:57.080 hydrocarbons. They're incredibly rich in stored potential energy within the carbon-carbon and

00:17:03.800 hydrogen bonds in particular. These are the most energy-rich bonds. Metabolism is a fancy word for

00:17:11.000 taking the chemical energy that is stored within the bonds, again, primarily between carbon and

00:17:18.340 hydrogen and carbon and carbon, and turning that into electrical energy. And that electrical energy

00:17:24.340 is used to turn back into chemical energy. So you take the electrical energy in the electron

00:17:31.100 transport chain, for example, and then you shuttle it back into chemical energy in the form of ATP.

00:17:37.500 So basically, food to ATP is just changing the form of energy, but obviously energy is conserved in

00:17:45.540 this process. And that's just kind of like a hand-waving high-level explanation. But I think for the purpose

00:17:51.560 of this discussion, we should go a little deeper and explain, we don't have to even get into fatty acid at

00:17:57.720 this point. We'll probably come to it later. But even just through the lens of glucose, which of

00:18:01.940 course will treat us synonymous with glycogen. When a molecule of glucose is being used by a cell,

00:18:07.940 and that cell needs to make ATP, can you walk through in a little bit of detail how it does it,

00:18:15.700 and what are the different nodes or paths that it can go down?

00:18:19.720 Well, that was a very good explanation. I don't think what I'm about to say is going to

00:18:24.540 advance this understanding much more. So when glucose is activated to break down,

00:18:31.220 and we can also talk about getting glucose into the cell, there are barriers to that.

00:18:35.700 Actually, go ahead and do that, George, because I know lactate is going to come and figure

00:18:39.660 into insulin. So why don't you do that? Why don't you start at getting glucose into the cell,

00:18:44.100 and then we'll keep going?

00:18:45.260 Yeah. So glucose is a molecule that can be quite high on the blood, but it can't get into the cell.

00:18:51.420 It meets a transporter. And some of the transporters are constitutive. They're in all

00:18:57.160 cells. The brain has the first transporter discovered. It was named one, and then two,

00:19:03.860 and three, and four. And four is important because four is expressed in most of our body,

00:19:09.100 in our muscles and in our fat cells. So we need to have these glucose transporters at the cell surface.

00:19:17.500 And depending on the various kinds of signaling, insulin is a typical signal. Also muscle contraction

00:19:23.260 will move these transporters to the cell surface. Now glucose can come in. So when I teach glycolysis

00:19:30.140 to my class, and I use one of the textbook figures where it starts out with glucose,

00:19:35.180 I put the brakes on and say, no, we need to put a membrane barrier in here. We need to get glucose

00:19:40.540 into the cell. And then it can be metabolized. And it's usually once the glucose is in the cell,

00:19:46.780 then there are two things that can happen. It can be stored as glycogen.

00:19:50.060 But if there's an energy need, it will enter the glycolytic pathway and be degraded.

00:19:55.740 There are a couple of important regulatory steps, which are involved, phosphate level and

00:20:00.940 redox. But I'll just say that the glucose splits into two. And so we have a six-carbon molecule that

00:20:08.940 makes two, three-carbon molecules. Depending on who you are and how you drive right this pathway,

00:20:15.760 the last step is either pyruvate or it's lactate.

00:20:20.060 And what we found recently, because we trace the glucose to see what it makes,

00:20:26.140 glycolysis basically goes to lactate. So it's a series of steps. One product is a reactant for

00:20:32.400 the next step. And there's a splitting of six-carbon molecule to two, three-carbon molecules that progress

00:20:39.100 to lactate. And so the process itself is basically pH neutral.

00:20:45.860 Let's just make sure people understand that. So what you're saying is,

00:20:49.080 if I heard you correctly, George, the glucose comes into the cell. Let's just assume we're not

00:20:53.680 in a storage state. We're in a utilization state. The six-carbon ring is split into two,

00:20:58.500 three-carbon halves. Now, a second ago, you said you have two potential fates there.

00:21:03.600 You could make pyruvate or you could make lactate. And you said that either choice

00:21:09.060 is pH neutral. Is that correct?

00:21:11.840 Well, actually, if you get to lactate, it's actually an alkalizing step. But the whole process

00:21:17.040 itself is basically pH neutral. And for our discussion of muscle, we're embedded in muscle

00:21:22.980 now. That's been our thinking, my thinking, my career, 50 years in this. And for the whole field,

00:21:29.700 it's all muscle. But we'll get to what happens when we take carbohydrate as we go through this.

00:21:35.200 Yeah. So we're going to split this molecule. And as you described, it's potential carbon energy.

00:21:41.960 So one way to think about metabolism is the flow of energy, carbon energy, carbon-derived energy.

00:21:49.520 And at some point, we could talk about its integration with fatty acid, maybe amino acid

00:21:53.660 metabolism. But we're really, in a basic biological sense, talking about the energy highway,

00:21:59.580 which is carbon-based. And it's reduced. So chemically, then, when it can be oxidized,

00:22:06.360 a lot of energy is released. And we can capture that as ATP. Now, actually, when we're doing just

00:22:12.060 glycolysis in a muscle, and I need to say that when our muscles are working, oh, about 80% of that

00:22:19.320 carbon flow comes from previously stored carbohydrate glycogen. So that's our carbohydrate energy source.

00:22:25.140 We have done numerous experiments looking at carbohydrate oxidation and exercise and

00:22:30.620 the use of glucose. And really, the body protects its glucose pool because there are certain cells

00:22:37.800 that really need glucose, like our brain. And if we got our muscles going, they could suck up all the

00:22:43.220 glucose and leave us really hypoglycemic, and we would crash. So actually, just the active muscles

00:22:50.280 are going to take up glucose. But it's not going to be a major part of the energy. It's a significant

00:22:57.420 part, maybe 20%, 25%. Most of that carbon is going to come from previously stored glucose,

00:23:04.320 which we call glycogen. And for the listener who might not be as familiar with that,

00:23:10.160 about 80% of the body's total glycogen, or stored glucose, is found within the skeletal muscles,

00:23:17.580 while the remaining 20% to 25% would be in the liver. And the way I think about it is that the

00:23:24.660 liver's primary responsibility is regulating blood glucose for the brain, whereas having all of that

00:23:32.320 stored glycogen in the muscle is, as you said, an important source of fueling the muscle so that the

00:23:39.740 muscle doesn't have to, for lack of a better word, steal glucose from the circulation that would

00:23:45.400 otherwise be imperative to keep the brain happy. But of course, one of the very important things I

00:23:51.120 am sure we will discuss is the role the lactate plays in replenishing the liver, which, if I'm not

00:23:57.520 mistaken, was another Nobel Prize, probably now somewhere in the mid to late 40s, if memory serves

00:24:02.480 correctly, vis-a-vis the Cori cycle. Yeah, I think 1947 was the year. Let's talk a little bit about that.

00:24:09.060 I mean, I think we're kind of marching our way through history, but that was another big seminal

00:24:12.620 involvement. Let's talk about what happens to lactate when it is produced in the metabolic

00:24:20.840 process of breaking down glucose. And I guess the other question I would have, George, just for the

00:24:24.960 listener, what determines that path choice? Let's not talk about a cancer cell, for example, but let's

00:24:31.580 just talk about a normal muscle cell that needs ATP. It's got its glucose. It splits it in half. It's got

00:24:38.540 two, three carbon units. What are the physiologic pressures that drive towards pyruvate versus

00:24:43.960 lactate? We have a couple of steps that depend on redox, but one of the things that's been noticed by

00:24:49.520 our colleagues who really have done a lot of muscle biopsies is that it's not the ATP level that falls

00:24:55.460 because the whole system is set up to maintain homeostasis of ATP. But we get changes in what

00:25:01.880 NAD, NADH ratio or redox, but we get changes in ADP, adenosine diphosphate. So when we have this

00:25:10.340 ATP molecule, there are three phosphates and we get energy by splitting one off and it gives us ADP.

00:25:17.360 Turns out that's a big signal to activate these enzymes of processing glucose. We know that in a lot

00:25:23.880 of ways, if we just take an isolated mitochondria, take a muscle, isolate the mitochondria, and we want to

00:25:29.820 turn them on and make them start doing something, we add ADP. And away they go. And they start to

00:25:36.640 phosphorylate that ADP and make ATP by the chemiosmotic process, which you described as

00:25:42.900 electrical energy. So yes, the muscle mitochondrial network works like a big battery. It's just not,

00:25:49.880 I don't know if we'll talk about mitochondrial functionality or about its arrangement. It's a

00:25:54.840 network. They're not just little capsules, this whole network. I call it the energy

00:25:59.600 highway. Other people have called it the cellular energy power grid. Anyhow, that's where the ATP is

00:26:06.840 going to be generated. And to do that, you need this chemical energy fuel, which is pyruvate or

00:26:12.300 lactate. People have assumed that it's pyruvate that goes into the mitochondria. And that's true,

00:26:17.500 that happens. But most of that chemical energy comes in the form of lactate that goes into the

00:26:23.620 mitochondrial reticulum or network. And that's the fuel to run the apparatus of oxidative phosphorylation

00:26:31.220 and make ATP. And George, I just have to stop you there because again, people who are listening to

00:26:36.520 this, who are physicians or have studied this are going to say, wow, hang on a second. That is the

00:26:42.940 biggest departure from everything we ever learned. I just want to restate what every single textbook on

00:26:49.560 this subject says to paint the backdrop for why this discussion is so interesting. So the textbook,

00:26:57.600 every textbook says the following. When you make pyruvate out of glucose, the pyruvate gets shuttled

00:27:06.040 in to the mitochondria. And there we undergo the Krebs cycle where we very, very efficiently

00:27:14.680 produce massive amounts of ATP. And the only by-product is carbon dioxide and water. And so

00:27:23.660 as we are undergoing aerobic respiration, we're consuming oxygen and pyruvate generating, again,

00:27:32.300 incredibly efficient amounts of high volume ATP. Out comes carbon dioxide and water, which is what

00:27:38.360 we're breathing out. Conversely, when you take that glucose and you make lactate, you do generate

00:27:44.580 ATP, but very, very little amounts. And that lactate now needs to escape the cell, make its way into

00:27:53.060 the circulation where it can go back to the liver and be turned back into glucose via the Corey cycle

00:27:59.220 to begin again. But unless I missed, I don't know, a couple months of my education in medical school,

00:28:06.840 I do not remember any discussion of lactate going into the mitochondria directly from the cytoplasm as

00:28:17.320 a substrate for ATP production under aerobic respiration. So it's possible I just missed that,

00:28:24.080 but is it more likely the case that most people would believe what I just said?

00:28:28.320 We've been teaching glycolysis wrong for a hundred years. Probably you learn that in junior high school

00:28:34.700 or high school, and physicians and scientists are smart people. If you hear it at the high school

00:28:40.460 level and you hear it in college and you hear it in medical school, well, that's what you think it is.

00:28:45.560 That's an assumption that's really deleterious. So that lactate that's formed enters the mitochondria,

00:28:51.820 and we have shown that there's a mitochondrial carrier for the lactate to get in, and we call it the

00:28:57.860 mitochondrial lactate oxidation complex, and we have electron micrographs. We have light micrographs to

00:29:04.740 show how this process works, and the enzymes are there for lactate oxidation. But lactate is important

00:29:11.720 as a fuel, and as you describe early, the first articulation of a lactate shuttle was by the Corys.

00:29:18.580 They showed that a dog muscle made to contract with adrenaline or otherwise will release pyruvate and

00:29:25.400 lactate, which will recirculate to the liver and become glucose. So that's a way to supply blood

00:29:31.520 glucose during exercise. So the muscles are actually not only fueling themselves, they're fueling adjacent

00:29:38.000 tissues and they're fueling the brain by this lactate shuttle or Cori cycle. Is it a velocity or a demand

00:29:46.020 dependent process? In other words, if ATP is being demanded at a very high rate, is the body

00:29:55.020 in that scenario preferentially taking the lactate back to the Cori cycle, back to the liver to make

00:30:01.980 glucose, versus if the body has quote-unquote the time, it can make the long-term investment in getting

00:30:10.840 more ATP per unit carbon by putting lactate into the mitochondria? Because again, the traditional

00:30:16.760 thinking on this is we go down the lactate pathway when we are demanding ATP faster than oxygen can be

00:30:27.280 supplied to the mitochondria, and that's why it's referred to as this anaerobic pathway. And if we

00:30:33.560 have the time, if the ATP demand is low enough that we can afford to get oxygen to the mitochondria,

00:30:41.420 well then we would always preferentially go down the oxidative phosphorylation pathway. So in the

00:30:46.660 discovery that you are talking about, which again, I can't overstate how mind-boggling that is,

00:30:52.900 what determines the path? It's this ADP to ATP ratio. That's what accelerates glycolysis.

00:31:00.820 If the ADP to ATP ratio is low, which tells us ATP is being consumed quickly,

00:31:07.680 does that drive lactate into the mitochondria or out to the liver?

00:31:13.180 Yeah. So recently, actually, not us, but others have shown that lactate activates the mitochondria.

00:31:18.380 We have shown that lactate is a preferred fuel.

00:31:21.740 Tell me what that means. What do you mean by lactate activates the mitochondria?

00:31:25.520 It activates lactate dehydrogenase, the enzyme in mitochondria, which allows the carbon flowed

00:31:32.040 to go into the mitochondria and for oxidation. Does that mean that it also amplifies other

00:31:39.220 substrates flow through? So in other words, if you have a bunch of acetyl-CoA hanging around

00:31:43.780 from fatty acid breakdown, is that also being stimulated to run through the mitochondria at

00:31:50.000 an accelerated rate? Good point. To the contrary. So we have compared glucose to lactate to fatty

00:31:56.340 acids. So lactate is preferred over glucose in the brain and muscle, wherever. The path of

00:32:03.020 degradation of lactate is to generate this acetyl-CoA. And that inhibits the enzymes that

00:32:09.280 transport acetyl-CoA or fatty acids into the mitochondria. So lactate basically shuts the door,

00:32:17.040 blocks fatty acid metabolism. So it inhibits, and Ineos and I have shown this,

00:32:22.900 the CPT1 and 2, the carnitine-palmontate transporters. These are transporters that allow

00:32:30.500 fatty acids to get into the mitochondria for oxidation. So yes, there is a competition among

00:32:37.120 substrates. And lactate shuts the door for fatty acid metabolism. I'm struggling to understand

00:32:43.660 teleologically why that makes sense, which just tells me I'm missing something, because I would never

00:32:48.240 for a second suggest my intuition should be better than a billion years of evolution.

00:32:54.020 Why is it that we would ever want to shut down a substrate for which we have an infinite supply?

00:33:02.980 Again, we're carrying around more than 100,000 kilocalories of fatty acid.

00:33:08.760 Why wouldn't we always want to maximize our ability to utilize that substrate at the expense of

00:33:18.380 something relatively finite as glycogen, which of course is necessary to even make the lactate?

00:33:24.940 Well, that's part of the fight and flight mechanism. So in terms of our survival,

00:33:29.680 what are we going to save the fats for? The tiger?

00:33:32.640 Okay, I understand. Good point. Thanks for correcting my stupidity.

00:33:35.800 So you're saying the reason, Peter, is if you are in a lactate-dependent state,

00:33:41.680 something has gone wrong. You're basically in a sympathetic state,

00:33:44.720 and you don't have the luxury of slow-burning fat.

00:33:48.760 Exactly.

00:33:49.720 Okay.

00:33:50.500 But fats are really important. You can see this play out in the natural world. We fight, we hunt,

00:33:57.000 we escape, and this is really glycogen, glucose-dependent. Now our energy stores are depleted.

00:34:03.920 And that's in recovery is when we're going to use these fats.

00:34:08.520 Well, this is very interesting. And now it actually makes more sense with something we're

00:34:13.300 going to talk about later, but I'll plant the seed right now. We discussed this previously with Inigo,

00:34:18.960 but I know we're going to talk about it again. You look at lactate levels in individuals at rest who

00:34:25.820 have type 2 diabetes versus lactate levels at rest in world-class athletes, there's a significant

00:34:32.800 difference. The great irony of that is the very low levels of resting lactate in the athlete mean

00:34:40.800 that at rest, they're quite capable of oxidizing fatty acids when sympathetic drive is low and

00:34:47.640 demand is low. And yet paradoxically, the individual with type 2 diabetes who would most benefit from

00:34:53.140 fatty acid oxidation is presumably now inhibited in doing so because of those elevated levels of

00:34:59.780 lactate. Is that probably a fair assessment? Yeah, that basically shuts down the fat metabolism.

00:35:05.820 But think about this. This is my old thinking. That lactate there is elevated because of lack of

00:35:13.600 disposal, not necessarily production. It's there because of failure to dispose. My new thinking is

00:35:21.860 the body in a diabetic situation has a hard time taking up glucose because of those insulin signaling

00:35:29.280 and the GLUT4 mechanism is not working very well. So think about lactate not as a stress, but as a strain.

00:35:37.900 So now we're going to bypass this inhibition of glucose uptake. We're going to provide actually

00:35:43.560 the preferred carbohydrate. And we see that not only in diabetes, we see that in the heart after MI.

00:35:50.960 Lactate is a preferred fuel. We had an MI because we had ischemia and we had a blockage. Why would the

00:35:57.640 heart prefer fast-acting fuel versus a slow-acting fuel? Because it needs energy, because it needs to

00:36:04.240 survive. How does one measure the kinetics by which one mole of lactate versus one mole of glucose versus

00:36:16.860 one mole of fatty acid can produce ATP? What are the tools that allow you to make the observation

00:36:25.020 that one fuel is preferred over the others or that the kinetics of one fuel are faster than that of

00:36:31.940 another? Thank you for that question. We use isotope tracers to do that. When our first experiments

00:36:37.480 with rats to give carbon-14 labeled lactate, then we would go into the tissues and try to

00:36:43.140 measure it. It's all gone. It's been burned out into the atmosphere.

00:36:48.900 Meaning the only place that that C-14 carbon would be found now is in carbon dioxide if you

00:36:54.000 had a calorimeter.

00:36:55.760 Yeah. We have done a number of experiments in collaboration with others or just in our own.

00:37:01.860 We've developed a technique called the lactate clamp technique. And it's analogous to the glucose

00:37:06.920 clamp technique, which some of your physician listeners will know about. That's where you raise the

00:37:12.780 glucose to a certain level. And then you can study the production versus the disposal. So we infuse

00:37:19.080 lactate up to 4 millimolar. And others have raised lactate even to higher. When we do that, we can

00:37:26.120 measure the arterial venous difference for glucose uptake. And it's suppressed. In a study with UCLA,

00:37:33.000 we did some PET scanning. And this is a fancy way to say we can take a picture where glucose is

00:37:38.260 being metabolized in the brain. This is done with a traumatic brain injury patient. And you can see

00:37:44.620 there's a blockage for glucose to get into the left frontal lobe in this patient. The next day,

00:37:50.820 we infused lactate to 4 millimolar. It completely stopped the glucose uptake. No glucose uptake in a

00:37:57.640 PET scan. I can show you the image.

00:37:59.560 I guess my question is this, George. So, I mean, that clearly demonstrates that lactate is preferred

00:38:07.600 over glucose. But I think the jugular question is, is the brain getting more ATP from the lactate as a

00:38:19.180 preferred fuel than the glucose, which has one area of hypoperfusion? In other words, are you able to,

00:38:27.020 by providing the preferred fuel, actually get more energy to the neurons that are injured?

00:38:33.640 A colleague in science, Pierre Magistretti in Switzerland, has developed what he calls the

00:38:41.420 astrocyte neuron lactate shuttle. And that's really sparked a lot of interest in the metabolism of

00:38:47.360 astrocytes. So, for years, I taught, maybe you did, and you believe that glucose was the exclusive

00:38:54.660 fuel for the brain. We know at a minimum that beta-hydroxybutyrate would also be another fuel

00:39:00.260 for the brain. It could be, but not if glucose is around or lactate. In the injured brain, for some

00:39:06.480 reason, maybe there's a block at this splitting enzyme in the glycolytic pathway where you know

00:39:12.620 the injured brain needs glucose, but it only takes up maybe 50% of what's typical. So, the brain is in a

00:39:20.660 metabolic crisis after an injury. Globally, it is. So, there's some neural networking where it just stops

00:39:27.320 glycolysis. Traditionally, what physicians would do is give glucose, infuse glucose, and the glucose

00:39:34.240 uptake, well, metabolism is blocked, so the glucose doesn't get in and doesn't do anything. Or give

00:39:40.320 insulin. Yes, intranasal insulin was one of the tricks there to try to drive more glucose uptake.

00:39:46.480 The brain doesn't express GLUT4, so that's not going to do much. But now we have, instead of the

00:39:52.980 six-carbon molecule, we have a couple of three-carbon molecules, and the lactate transporters

00:39:59.280 are highly expressed in the brain. And we know that under normal circumstances, what's happening is

00:40:05.340 that the glucose is coming in, being taken up by the astrocytes made into lactate, which are bathing

00:40:12.260 the neurons in lactate. And lactate is the fuel for neurons. By the way, I misspoke a second ago,

00:40:17.980 though, George. I could have sworn George Cahill demonstrated in those very famous fasting studies

00:40:23.900 circa 1960s, 1970s, that even in the presence of glucose, the brain was still taking up significant

00:40:33.660 beta-hydroxybutyrate. If I'm not misremembering this, these subjects were fasted for a very long

00:40:39.140 period of time. I mean, these were 40-day water-only fasts. So these individuals had

00:40:43.420 beta-hydroxybutyrate levels of four to five millimole, which actually exceeded glucose

00:40:49.720 concentration. By this point, glucose concentration would have been about three millimole in steady

00:40:55.740 state. So for folks listening to us who don't think in European terms, three millimole of glucose

00:41:01.440 means these people were walking around with a blood glucose of 55 milligrams per deciliter.

00:41:06.140 But it really never went below that. So that's obviously pretty hypoglycemic. That's still 60%

00:41:12.800 of what you would walk around with normally. And glucose was meeting about 50% of their brain's

00:41:20.740 demand, and about the other 50% was coming from the BHB. So at least in that situation,

00:41:26.800 the brain would split fuels. Now, of course, I don't know that Cahill was measuring it,

00:41:32.680 so we just don't know what lactate was doing there. But it's an interesting observation

00:41:36.380 that the brain would split its fuels in the presence of BHB and glucose.

00:41:42.200 So I'm going to agree with you to the extent that there's competition amongst substrates.

00:41:46.500 More glucose, less fatty acids. More fatty acids, vice versa. Okay, ketones come in by the

00:41:52.500 lactate transporter. So the monocarboxylate transporter allows ketones to get in.

00:41:58.560 Meaning BHB enters the cell through the same MCT transporter that would bring lactate into the

00:42:04.780 cell? Yes. We did this early on, and there's a greater preference for lactate over beta-hydroxybutyrate.

00:42:10.640 So if the concentrations were the same, the transporters would move lactate as opposed to

00:42:16.700 beta-hydroxybutyrate. In other words, if we could do a thought experiment, or actually a literal

00:42:21.440 experiment, so let's say you could clamp everything. You could have a person walk around with

00:42:26.740 four millimole of glucose, four millimole of beta-hydroxybutyrate, four millimole of lactate,

00:42:33.840 and you're peripherally clamping those concentrations. So you have equal concentrations

00:42:39.380 of three fuels that the brain could use. What is your prediction for neuronal uptake based on that

00:42:48.320 scenario? If it's an uninjured person- Yes. Let's start with that.

00:42:52.580 The preference would be for glucose and lactate. And would it be roughly equal amounts of those

00:42:57.700 two in an uninjured brain? Roughly, probably. Okay.

00:43:01.780 We've published on it. We worked with the UCLA Neurosurgery. We did these experiments with

00:43:06.360 diduteroglucose and 13C lactate. So probably about the same. Yeah.

00:43:12.560 Now let's talk about the injured brain. So now you have a TBI patient, and you're doing the exact same

00:43:17.780 thing. You're infusing equal concentrations of glucose, lactate, and BHB. What would you think

00:43:24.220 everybody knows clinically that glucose is going to be suppressed? How much of that is made up for

00:43:28.880 by the lactate versus the BHB? Yeah. So if lactate's around, it's going to suppress the BHB.

00:43:34.560 So lactate could be the dominant fuel in the injured brain.

00:43:38.160 Yeah.

00:43:38.420 So the implication of this, at the risk of stating the obvious, is we should be giving brain-injured

00:43:45.240 people intravenous lactate around the clock to heal their brains.

00:43:50.080 I think so.

00:43:51.260 How many people are aware of that, agree with that?

00:43:54.300 For various reasons, we lost our collaboration with UCLA Neurosurgery. But they were in a stage

00:43:59.800 two clinical trial of infusing lactate. And they weren't the only ones. There's a group in Switzerland

00:44:04.840 who preferentially gives hypertonic lactate to TBI patients. They appear to do better. But we were

00:44:14.060 hoping to have a clinical trial, multi-centered trial, demonstrating the use of lactate as an

00:44:19.740 augmentation to glucose in the TBI state. But I don't know what the status of those studies are.

00:44:27.260 But there was a stage two clinical trial that started at UCLA.

00:44:31.060 George, has anybody labeled lactate with FDG, the equivalent of an FDG, so that you could do a PET

00:44:38.920 scan and actually demonstrate significant uptake of lactate in a brain, and then actually do that

00:44:45.100 experiment in an injured brain? Because what I'm imagining is everybody has seen the images of

00:44:50.760 the injured brain under standard FDG PET, where you have the hypoperfusion in the area. And by the way,

00:44:56.600 this is relevant in diseases like Alzheimer's disease. This is relevant in dementia, where we

00:45:02.040 see hypoperfusion of glucose. But it would be interesting if it hasn't already been done to see

00:45:07.360 what the uptake of lactate is, if you can put an F18 onto lactate, which I assume is a trivial task.

00:45:14.400 I don't know about that, but our colleague here at Berkeley, Tom Buttinger, really helped

00:45:18.880 develop PET, helped make NMR clinically relevant. He did experiments with carbon-11 lactate,

00:45:26.600 in the PET scanner, it gives a signal as does fluorodeoxyglucose. So that way,

00:45:33.040 you could see lactate taken up by the brain. The difficulty with those experiments, I think the

00:45:38.360 half-life of carbon-11 is on the order of minutes, 20 minutes. So those are the first experiments

00:45:45.480 involved somebody in a cyclotron making carbon-11 lactate, putting it in a lead-line station wagon,

00:45:52.280 and driving it down, running it through a column to remove the strontium-82, and then infusing it

00:45:58.240 into the brain and imaging the brain. So it's possible with carbon-11 to do that experiment.

00:46:04.780 But any reason not to just put F18 onto lactate? Is that chemically not feasible?

00:46:10.200 I haven't thought about that.

00:46:11.560 It seems like that would be a very interesting experiment, at a minimum, just to generate a

00:46:17.100 hypothesis that says we can fill an energetic gap by using lactate and simply observing a difference

00:46:25.440 in perfusion pre- and post-lactate infusion.

00:46:28.560 I'm making a note.

00:46:30.560 If it hasn't been done, I'm sure I'm missing something obvious about the chemistry of it.

00:46:35.380 Buttinger would do, when he would do the experiments with glucose or lactate, he also would give

00:46:40.760 rubidium-82, which is a marker of flow. So you would want to do exactly what you described. You

00:46:46.980 would want to know the uptake relative to the flow. So if the flow is depressed in an area,

00:46:52.360 then you would expect the uptake to be less. And so in the Buttinger method, you need to do two

00:46:58.640 isotopes simultaneously, and that's really tricky and hard to do clinically. It's really,

00:47:04.540 as you described, could be a great experiment. But getting it to work in clinical centers would

00:47:10.460 be a real trick.

00:47:12.080 What about just in rodent studies of hypoperfusion? I assume that would be an easier place to look

00:47:17.820 at a TBI model where you ask if lactate can rescue the animal.

00:47:23.600 We could just do that, even without a tracer.

00:47:26.320 Exactly. That's my point. You could get around the whole tracer component by just doing that.

00:47:30.740 Is there any issue with infusing lactates at higher concentrations? Is four millimoles sufficient,

00:47:38.760 or is there any reason you couldn't put in six or eight millimole?

00:47:42.160 I think our friends in Switzerland have got it up to eight millimole. But then, you know,

00:47:46.540 you're using hypertonic lactate. So what you can give vascularly, people need to understand it can't

00:47:52.340 be too concentrated to make the blood really affected poorly.

00:47:56.280 When we give patients like an intravenous bag of lactated ringers, what's the concentration

00:48:01.860 of lactate in that solution?

00:48:03.000 It's really pretty low.

00:48:04.880 Yeah. Okay.

00:48:05.560 What they do is they do half molar sodium lactate. And we need to understand we have half molar

00:48:11.860 sodium. It's half molar sodium and half molar lactate. So the osmolality is twice that. It's a

00:48:18.680 thousand. That's sort of the upper limit of what you can give safely intravascularly

00:48:23.580 without causing phlebitis, without causing a crination of the red blood cells shrinking and

00:48:30.700 getting all distorted.

00:48:32.400 Yep. Makes sense. But four, you can maintain, you can clamp a person at four millimole quite safely and

00:48:38.700 easily.

00:48:39.220 Yeah. And I think, you know, the idea was to do that for a couple hours a day, not continuously.

00:48:44.280 Again, because we would have to make sure that kidneys were not affected because we're giving

00:48:49.660 a lot of sodium.

00:48:51.260 Ah, so I was going to ask you about that. So what's the manner in which the lactate is delivered?

00:48:56.400 In other words, what else has to be delivered with it to balance the solution?

00:49:00.320 Lactate anion has a negative charge. So to put it into the blood, you need to have something

00:49:07.380 with a positive charge. And so the major cation in our blood is sodium. So what's used is sodium

00:49:15.660 lactate. So in our studies, we could clamp to four millimolar and hardly raise the sodium level

00:49:22.940 in the blood. So we thought that would be an approach that would be reasonable to work with a

00:49:28.580 patient. But again, you are going to be giving sodium. So you have to make sure that in the patient

00:49:33.900 to have good kidney function. Now I see you're making notes. That's good.

00:49:39.300 You have no idea how many notes I make here, George. The highest lactate I've ever measured in

00:49:43.780 myself is about 18 millimole, obviously after a very intense bout of exercise. Not surprisingly,

00:49:51.900 anybody who's measured lactate in themselves, anything over 10 is a very, very uncomfortable

00:49:58.200 situation to be in. Let's go back and talk about what's going on and where my discomfort comes from,

00:50:05.020 because it's not the lactate that's causing me discomfort, correct?

00:50:09.580 No. Lactate is there to moderate. It's a strain response. It's helping to protect you.

00:50:16.660 But you probably have a severe acidosis.

00:50:20.360 Yeah. I'm feeling like I'm about to die because my pH is probably 7.05 or something like that.

00:50:28.140 Yeah. Yeah. And can I ask you a question? Are you ever hungry after one of these episodes?

00:50:33.260 Not at all. In fact, it's usually you're about to vomit if you don't actually vomit.

00:50:39.100 Yeah. So actually lactate crosses the door of the brain barrier and works in the brain in the

00:50:44.840 hypothalamus to inhibit your appetite. So those of us, you know, who run 440 yards,

00:50:50.180 to 400 meters, we're not hungry for three hours right until that lactate level is cleared,

00:50:55.980 which is really a good reason. People have written about this recently. It inhibits

00:51:00.280 appetite. Lactate suppresses ghrelin. It works directly into CNS. So an advantage of doing an

00:51:08.480 exercise, not like that one you did, Peter, but getting lactate up to maybe 3 or 4 millimolar

00:51:14.880 would actually help satiate people. I know there are people who say, well, I exercise and

00:51:20.680 I'm really so hungry afterwards. Well, you're not exercising hard enough. But if you do raise

00:51:26.080 lactate, it will cross the blood-brain barrier. It will inhibit ghrelin secretion and it will suppress

00:51:32.220 the appetite.

00:51:32.920 That's a very interesting point. And I know that people who are listening to this,

00:51:37.160 who are familiar with lactate testing, which I know is a bit esoteric, there is a fundamental

00:51:41.980 difference between having your lactate at 1.5 millimole or 1 millimole, which is where it might

00:51:48.320 be if you go for kind of a risk walk versus being at 4 millimole, which is not a level you can sustain

00:51:55.380 indefinitely, but it's also not so strenuous that you could only do it for a few minutes.

00:51:59.500 A fit person could hold that level of exertion for 30 to 40 minutes.

00:52:04.800 I think listeners will know that 4 millimole is talked about a lot.

00:52:09.000 Yeah. Let's talk a little bit about differences between athletes and non-athletes, which again,

00:52:17.680 I think becomes very illustrative because they're simply different metabolically. It's not just that

00:52:24.480 the athletes are stronger and the non-athletes are not, but what's happening in terms of fuel

00:52:29.060 partitioning that differentiates a highly, highly trained aerobic athlete, like a cyclist,

00:52:36.720 with someone who's got insulin resistance? What are the differences in their ability to utilize fuels?

00:52:42.360 Great. So let's back up just a little bit and go back to the mitochondria.

00:52:47.100 Mitochondria are the sinks or the disposal units. So when anything fluxes, as you described in the body,

00:52:53.940 like carbon flux, it has to go from a production or entry site and has to go to a removal site.

00:53:00.000 And the mitochondrial network is the removal site.

00:53:03.180 Now, when a highly trained athlete exercises, and here we need to talk about relative or absolute power output.

00:53:10.840 So let's say 65% of VO2 max or 65% of effort. For an untrained person, well, that's not very much exercise, really.

00:53:20.160 They'll get to 65% of VO2 max, a very low power output.

00:53:25.360 Now we take the trained athlete, put him or her at their 65%. They're generating a lot of lactate, but they're burning it.

00:53:33.080 And as you described earlier, it's recirculating to the core recycle to support blood glucose.

00:53:39.520 So even if you just measure the concentration, you don't have the whole story.

00:53:44.020 You don't have the flow. You don't have the flux rate. You don't have the partitioning sensation.

00:53:51.100 Now, if you take that same athlete now and you push him to a lactate that elicits maybe 6 or 8 millimolar,

00:53:58.780 there are going to be really a lot of differences there.

00:54:01.140 You've exceeded their capacity of the mitochondria to clear lactate.

00:54:05.900 And also, you're probably going to have shunting away from the gut.

00:54:09.460 This goes back to something we mentioned in passing.

00:54:12.720 So gluconeogenesis, the making of glucose from lactate, depends on good liver blood flow.

00:54:18.800 When you start going really, really hard, your blood's going to go to your muscles, basically.

00:54:23.820 And you're going to clamp down. You're not going to perfuse the liver.

00:54:26.560 So now that gluconeogenesis goes down, regardless of who you are, when you take the liver and the kidneys out of circulation,

00:54:34.880 and of course, those are major organs of lactate disposal as well.

00:54:38.720 I said 20, 25% earlier.

00:54:41.600 If you eliminate those by basically clamping them off, then the lactate level is going to be higher.

00:54:48.300 I want to go back to something I asked you earlier, but I want to make sure I captured what you said.

00:54:52.520 As the individual is increasing energy demand, they're making more and more lactate.

00:54:58.920 Is ADP or ADP to ATP helping to determine when the lactate is going in the mitochondria versus back to the liver?

00:55:08.920 Because in the scenario you described, where energy demand is going up and up and up,

00:55:14.760 and therefore perfusion is going down in the organs that are able to recirculate lactate,

00:55:22.460 you would think that the body would just say,

00:55:24.720 okay, no problem, I'm going to shovel more lactate into the mitochondria.

00:55:28.640 I've got a perfect engine here to generate more ATP.

00:55:32.180 In other words, why is that a problem that the lactate now can't be cleared as efficiently through the gluconeogenic pathways?

00:55:43.280 Yeah, so go again near example of the athlete.

00:55:46.240 When we train, we increase our mitochondrial mass maybe 100%.

00:55:50.440 If we train, we'll raise our VO2 max maybe 10, 15%.

00:55:55.520 There's more plasticity in the muscle to increase the mitochondrial mass,

00:56:01.100 and I think really that's the key to Ineo's success with his athletes.

00:56:04.920 He trains them so they increase their mitochondrial mass.

00:56:08.560 How much did you say you increase mitochondrial mass by?

00:56:11.580 Well, you can double it.

00:56:13.540 Over what period of time?

00:56:15.180 The first study on this appeared in 1967 in the Journal of Biological Chemistry was in rats.

00:56:21.040 It was by John Halazi, and you could, over the period of several weeks of training rats, you could do that.

00:56:27.640 But after that, we extended those studies a bit with Kelvin Davies when he was here,

00:56:33.220 and again, saw a doubling of the mitochondrial mass.

00:56:36.560 Others have looked into the muscles of athletes and found that they have more than twice the mitochondrial mass of the average person.

00:56:46.140 And that, of course, is a lot of selection.

00:56:48.440 Sorry, just to be clear, this is mitochondrial density.

00:56:53.420 So for one gram of vastus lateralis in an athlete versus one gram of vastus lateralis in a non-athlete,

00:57:01.300 you'll see 2x the mitochondria?

00:57:03.620 You'll see 2x the mitochondrial mass.

00:57:06.760 Yeah, not necessarily the number of mitochondria.

00:57:08.960 Yeah.

00:57:09.440 And how is that conveyed?

00:57:11.000 Is that larger mitochondria plus more mitochondria that amounts to that doubling?

00:57:15.480 We talk about the mitochondrial reticulum.

00:57:18.460 Think about a tree budding and branching out, leaves.

00:57:22.020 So if you do a thin section, you'll see, and you do point counting,

00:57:27.540 one mitochondrion, two mitochondrion, three mitochondrion, a thousand mitochondrion.

00:57:32.040 But they're all part of a network.

00:57:34.360 So what you have is a bigger energy delivery system

00:57:38.140 that goes from the cell surface deep within the fiber to this network.

00:57:43.420 Some people call it the cellular energy power grid.

00:57:47.780 And to your point, which is, has the experiment been done to demonstrate the causality of exercise

00:57:53.960 there?

00:57:54.500 In other words, do we have the experiment where you take untrained individuals, do the muscle

00:58:00.640 biopsy, compute mitochondrial density, mass of mitochondria per unit mass of muscle, train

00:58:08.120 them for four to six months, repeat the biopsy, and see if the training is leading to the doubling

00:58:14.920 rather than just saying, well, athletes are athletes because they have more mitochondria?

00:58:19.780 Yeah.

00:58:20.040 Well, it works both ways.

00:58:21.460 If you're born with that and you go into athletics, you're successful.

00:58:26.480 That's right.

00:58:26.940 Yeah.

00:58:27.260 And then if you're not, then you become a professor.

00:58:31.340 That's sort of something I'm curious about.

00:58:32.920 It goes up proportionally and interesting, all the enzymes that are, as far as we could

00:58:38.080 tell, all the constituents that make up this mitochondrial network go up proportionally.

00:58:43.000 So you get twice as much Krebs cycle enzymes, twice as much electron transport cycle enzyme.

00:58:49.680 You basically activate the whole system.

00:58:53.420 So George, I was taught the following, which I'm now almost assuming is going to be at best

00:58:58.960 an oversimplification, and at worst, I might just be abjectly wrong.

00:59:03.160 You mentioned something called MCTs a moment ago.

00:59:05.680 Do you want to tell folks what an MCT is?

00:59:08.060 Hey, I had to explain this to my wife, Rosemary, the sports medicine doctor.

00:59:11.480 What's an MCT?

00:59:13.080 Well, we were looking for the lactate transporter protein, and we got scooped.

00:59:20.040 Somebody found it, and she called it.

00:59:22.760 It was Dr. Christine Kim-Garcia in the Goldstein lab in Dallas, and it's a Nobel Prize lab, and

00:59:30.100 she found they were looking for transporters of things that contributed to cholesterol metabolism,

00:59:36.480 and she found this protein, and she didn't know what it was, and she found out it was a

00:59:41.380 lactate transporter.

00:59:42.880 And so they were called monocarboxylate transporters, and now it's like the glucose transporter

00:59:48.240 field, where we have the first isoform, and the second one, and the third, and the fourth.

00:59:53.580 There are actually more than four now that have been discovered.

00:59:57.580 When was the first one?

00:59:58.800 About 2000.

01:00:00.860 So what I was taught, again, we'll see how far off base I am, was that one of the benefits

01:00:08.180 of training was increasing the density of MCTs.

01:00:14.160 So in other words, the harder I trained, the more I increased the density of these MCTs

01:00:22.320 in my muscle cells, and what that allowed me to do was produce more lactate, but get it

01:00:31.060 out of the cell and back to the liver.

01:00:33.440 So imagine a little cartoon where I've got a muscle cell, I'm untrained, and I've got 50

01:00:39.500 MCTs.

01:00:40.780 After training, I've now got 100 MCTs.

01:00:43.700 After a period of time, not acutely, but years of training or whatever.

01:00:48.100 And therefore, I can now make twice as much lactate and get that lactate out.

01:00:53.180 Now, of course, all of this was predicated on the model that said more lactate in the

01:00:58.820 muscle is bad because with lactate goes hydrogen, and hydrogen inhibits performance.

01:01:05.480 So again, that was all viewed through that lens.

01:01:07.520 But was there any truth to the idea that as we train more, we increase the density of

01:01:13.520 MCTs, which if nothing else, I assume would give us more flexibility in this lactate flux

01:01:19.640 game?

01:01:20.740 Yes.

01:01:21.240 We've done this in animals, and we've done it in looking at trained and untrained people.

01:01:26.000 And we can see an increase in the abundance of the MCTs.

01:01:30.300 That helps two ways, because getting lactate into the mitochondrial network requires an MCT.

01:01:38.060 So we were bold enough to look at the mitochondria and find MCTs.

01:01:42.700 So people think, well, it's just on the cell membrane, and it's good for export.

01:01:47.900 And that's true.

01:01:49.340 But in oxidative muscle fibers, with an abundance of transporters, many of them are in the mitochondria.

01:01:58.660 So the lactate will move into the mitochondria as well as can be exported.

01:02:04.280 So then we see a difference between fiber type.

01:02:07.260 Fast glycolytic fibers will be pale in color.

01:02:10.040 They're pale because of less heme oxygen compounds.

01:02:14.800 They'll have less blood flow through capillaries, through fiber.

01:02:19.020 They'll have less myoglobin, and mitochondria are the color of liver, or vice versa.

01:02:24.880 Liver is the color of mitochondria.

01:02:27.180 Those fibers, when they're made to contract, have lesser mitochondrial density.

01:02:32.440 They will export lactate.

01:02:34.320 But they can export it to a neighboring red fiber.

01:02:36.960 So we call this the cell-cell lactate shuttle, where a fast glycolytic fiber produces lactate,

01:02:44.680 and it's consumed by an adjacent fiber, and never even appears in the venous blood except as CO2.

01:02:52.180 I'd never heard that, George.

01:02:53.320 So just to make sure the listeners are following and that I'm following,

01:02:56.180 we've had many podcasts where, of course, we discuss type 1 and type 2 muscle fibers,

01:03:01.900 colloquially referred to as fast-twitch and slow-twitch fibers.

01:03:05.360 The slow-twitch fiber, the type 1 fiber, is the red fiber.

01:03:08.500 It's the fiber that is dense in mitochondria.

01:03:12.780 It is the one that has the capacity for oxidative phosphorylation.

01:03:17.840 It is less powerful, but much slower to fatigue.

01:03:21.720 Then you have these type 2 fibers, and I'm oversimplifying a little bit because there are

01:03:26.280 subtypes of them, I understand.

01:03:27.840 But the type 2 fiber, it's a more contractile.

01:03:31.180 It's a more powerful fiber.

01:03:33.380 Twitches a little faster, but it's very fast to fatigue.

01:03:36.020 It's the white fiber because it is lacking in the mitochondria.

01:03:39.420 Does it outright lack mitochondria?

01:03:41.340 And basically, it's just a pure glycolytic fiber, correct?

01:03:44.500 No, there are mitochondria in there.

01:03:45.880 There are, just a much lower density.

01:03:48.180 Lower density, yeah.

01:03:49.580 Yeah.

01:03:50.020 So what you just said a second ago was, as those cells accumulate lactate, they realize

01:03:57.920 that their neighboring type 1 cells can make even more use of the lactate, given that they

01:04:02.980 have a greater density of mitochondria.

01:04:04.800 So they'll shuttle the lactate from the 2s to the 1s.

01:04:08.340 Is that correct?

01:04:09.140 Yeah.

01:04:09.940 That's actually part of the discovery of the lactate shuttle.

01:04:13.260 So early on, when we started doing the studies on rats, and you see 14-lactate and tritiated

01:04:19.020 glucose in comparing the flux rates of the two and looking at the various fates of where

01:04:24.300 the carbon goes, we knew that there was an exercise that was a large flux.

01:04:30.580 But from the tracer itself, you can't tell where.

01:04:33.180 So a colleague of mine at UC Irvine, Ken Baldwin, did his studies on rats, and he made them exercise

01:04:41.000 hard.

01:04:41.800 Then he measured the lactate levels in blood, in red muscle, and in white muscle.

01:04:47.320 So a rat made to run hard has a very high level of lactate in the fast glycolytic type 2 fibers.

01:04:57.960 Can you give me the approximate concentrations in that type of an experiment between blood type

01:05:03.320 1 and type 2?

01:05:04.300 Yeah.

01:05:04.760 So I'll give you this.

01:05:06.200 Just finish the analogy.

01:05:07.780 We can put some numbers on it.

01:05:08.880 So then he measured the lactate level in the arterial blood.

01:05:13.160 And of course, it was lower.

01:05:14.780 And the red muscles, the lactate level was lower than in arterial blood.

01:05:20.000 And that gave rise to the idea that the fast fibers were sharing lactate, not just to the

01:05:26.440 venous blood, but to the red fibers that were adjacent.

01:05:30.660 So the numbers, I'm trying to remember, this is back 30 years, what the numbers were.

01:05:34.460 In the fast fibers, it would be something like 10 to 12 milliequivalents.

01:05:39.080 In the blood, it would be four.

01:05:41.000 And in the red fibers, it would be three.

01:05:43.560 But the four was in venous blood, correct?

01:05:46.040 In blood?

01:05:46.880 No, that would be arterial.

01:05:48.240 That was in arterial blood.

01:05:49.600 Got it.

01:05:50.300 So that gave rise to this idea of the shunt or shuttle.

01:05:53.560 Some people call it a shunt from white fibers to red fibers.

01:05:57.440 And as you described, it's easy for the white fiber to export the lactate, but it will export

01:06:04.160 it in a three-dimensional sense, being surrounded by slow red fibers who can oxidize lactate.

01:06:12.720 When did you first find MCTs on mitochondrial membranes?

01:06:16.840 What year did you first publish that?

01:06:19.000 About 95.

01:06:20.640 So what percentage of the relevant scientific community acknowledges that now?

01:06:26.400 Is it taken for granted within your world that that is completely settled?

01:06:31.220 And is it just that it hasn't made it out to any of the textbooks yet?

01:06:35.060 Tom Fay and I are revising our textbook.

01:06:37.180 We're going to get it right.

01:06:38.500 But yes, there's been a stonewall silence.

01:06:41.000 For instance, in Science Magazine, they published papers on the mitochondrial pyruvate transporter,

01:06:46.760 two papers simultaneously about this discovery of the pyruvate transporters.

01:06:51.240 Previously, we had shown the mitochondrial lactate transporter wasn't even cited.

01:06:56.760 Neither the editors or the reviewers knew about it.

01:07:00.280 So now things are changing, Peter.

01:07:02.940 So actually, right now, there is a lot of interest in lactate.

01:07:07.920 These are difficult questions to answer, so I'm sensitive to that.

01:07:10.420 But why do you think something that was discovered 30 years ago that appears quite germane to the

01:07:16.920 physiology of everything, but if nothing else, just through the physiology of exercise,

01:07:23.200 but it clearly extends beyond that.

01:07:24.980 Why do you think that this isn't more widely understood,

01:07:29.160 even in the physiologic circles that you travel in?

01:07:32.700 I think I said it earlier.

01:07:34.120 People who do science and medicine are smart people.

01:07:37.180 They learned it a certain way, and that's their set point.

01:07:39.940 But I tend to differ between scientists and physicians.

01:07:43.540 And I say this as no disrespect to my profession.

01:07:45.980 I think that that makes more sense at the physician level where, look, medical school is drinking

01:07:51.180 from a fire hose.

01:07:52.520 It's almost beat out of you to question things because you frankly don't have the time, right?

01:07:56.680 You've got two years to learn so much.

01:08:00.480 I would have to think that that's quite different for people who choose a scientific pathway where

01:08:05.680 discovery, questioning orthodox beliefs, that is the name of the game.

01:08:11.660 Is there something I'm missing here?

01:08:13.020 So maybe there is a difference between science and medicine in this regard.

01:08:17.780 Given the opportunity, I will talk to, for instance, the Washington Thoracic Society and

01:08:24.000 go to a meeting and talk to the docs.

01:08:26.680 Because when they see lactate, they start infusing bicarbonate or they give oxygen.

01:08:32.280 In the medical field, there's a character, maybe someday you would really enjoy meeting this.

01:08:36.940 His name is Ronaldo Bellamo.

01:08:39.180 He's a world-renowned physician, emergency room physician.

01:08:43.120 And he's written about the fact that pulmonologists need to be more like exercise physiologists with

01:08:49.920 regard to understanding lactate metabolism.

01:08:52.980 He challenges his colleagues to do that.

01:08:55.340 Bellamo is a big name in the field.

01:08:57.560 There's been a lot of inertia in this, but I think we're getting some momentum.

01:09:02.100 I want to use an example, a real-life example, to have you explain the difference in metabolism

01:09:09.060 between two people, me and one of my friends.

01:09:13.520 I'm not going to name him, but I already talked with him about maybe potentially telling his story.

01:09:18.340 So there's a friend of mine who is really an exceptional cyclist.

01:09:22.920 Okay, he is probably in the top, he would easily be in the top 10 amateur cyclists in the country.

01:09:31.440 Okay, so again, for people who, you would understand these numbers, but I should just throw out some

01:09:36.500 numbers so people understand what we're talking about.

01:09:38.260 So this is a guy who's in his late 40s and he can still put out 5.3 watts per kilogram for an hour.

01:09:48.360 So that's what we would call his functional threshold power.

01:09:51.340 So when he is on a bike, he can put out 420 to 430 watts for 60 minutes.

01:10:01.440 He weighs about 80 kilos.

01:10:04.520 I understand that people listening to us might not understand what 430 watts feels like,

01:10:09.800 let alone what it would feel like for an hour.

01:10:12.560 But I know you understand this and I think there are enough people listening to us that

01:10:16.100 understand this that we can still justify the time on this topic.

01:10:19.180 So I just want to explain to you, here he is, this incredible cyclist and actually a great

01:10:24.280 triathlete as well.

01:10:25.440 So great swimmer and runner, but really on the bike is where he shines.

01:10:29.620 And these are numbers that at his age are almost unheard of and frankly would still be at the

01:10:35.900 levels of a low level professional cyclist.

01:10:38.840 Okay, contrast that with me.

01:10:41.020 For me, I'm a very mediocre cyclist.

01:10:44.280 Even at my best, my FTP was lower than his at my very best.

01:10:50.700 And today, I don't know, my FTP, if I'm lucky, might be three to three and a half watts per

01:10:56.360 kilo.

01:10:56.840 Very low.

01:10:57.760 He was over at my house last week, George, and we were lifting weights together.

01:11:02.920 Now he doesn't lift weights anymore.

01:11:04.520 All of his energy goes into cycling and I do everything.

01:11:08.340 I'm kind of a jack of all trade, master of nothing.

01:11:11.260 So he was lifting weights with me.

01:11:12.640 We were doing some leg exercises and 80 kilos is pretty big for a cyclist.

01:11:18.380 So he doesn't look like a tiny little cyclist, especially in the legs.

01:11:22.160 And so I put him on a machine where I was doing some squats.

01:11:27.080 I just assumed he would start at a weight very close to what I was doing, a little bit less.

01:11:32.140 I maybe had him at 20% less weight than me.

01:11:35.020 And I said, tell me how this feels.

01:11:36.460 And he said, oh, there's no way in hell I could move this.

01:11:39.500 We ended up having to take it down to half the weight that I move for him to be able

01:11:44.920 to do the exercises.

01:11:46.460 And I was really thinking to myself, this is a very interesting lesson in physiology because

01:11:52.280 his legs are so superior to mine in generating absurdly high wattage for a long period of time.

01:12:02.140 Yet when I'm asking him to do this different type of task, which is clearly more recruiting of a type 2 muscle fiber, he doesn't have the contractile force.

01:12:12.800 He and I ended up having a great discussion about this because it was like, oh, it's so interesting that you're not as strong in this regard as I would have expected.

01:12:20.460 And yet you're so superior in this other way.

01:12:23.440 And what we got talking about was the differences in our metabolism, which is clearly he is able to do something.

01:12:30.460 Because again, what's more interesting to me is not that he's not as strong as me on a squat.

01:12:35.180 It's how much stronger he is than me on a bike.

01:12:40.360 So that's a long-winded background.

01:12:42.860 But now I want you to imagine you had muscle biopsies of both of us.

01:12:47.680 Now you've got his quads and my quads.

01:12:51.920 What is it about him that is allowing him to hold 430 watts for an hour?

01:13:01.120 However, what is happening at the level of fuel utilization that allows him to be so different from the rest of us, regardless of how strong we are?

01:13:11.840 And that's really the point I'm trying to make.

01:13:13.360 What is it that he is doing that is so special and that which all exceptional athletes can do?

01:13:19.000 Well, not at all.

01:13:20.340 It's sports specific.

01:13:22.100 Yeah.

01:13:22.760 All exceptional cyclists, right?

01:13:24.340 Or endurance athletes.

01:13:25.240 You described it earlier as the flow of energy.

01:13:27.820 And so I would guess that he was mostly type 1 fibers.

01:13:33.360 These red fibers that are highly profused that have the mitochondrial reticulum really highly expressed.

01:13:40.520 So he can have a high carbon flux and sustain it.

01:13:45.360 He can generate large amounts of lactate and clear it.

01:13:50.060 And some of the lactate probably goes into his blood and helps maintain his blood sugar level.

01:13:54.820 So the fact that he can't exert as great a force as you probably means he's got the slow red fiber type.

01:14:04.200 And he also hasn't learned how to do it.

01:14:06.320 He probably could work with him a couple of times.

01:14:08.680 He might improve.

01:14:09.600 Just jump up a little bit by learning.

01:14:12.360 Yeah.

01:14:12.500 By the way, I want to make that point.

01:14:14.200 I am totally confident that in three weeks he would be doing the same amount of weight than me.

01:14:20.580 Again, the point is not so much that I don't want to suggest that he wouldn't be as strong.

01:14:26.220 It's more that if you gave me the rest of my life, I would not be able to get to five watts per kilo.

01:14:33.180 That's the bigger point, even though ostensibly I'm stronger.

01:14:37.960 Yeah.

01:14:38.900 We're talking about different metabolic systems or a metabolic system surplus versus a contractual entity that coexists together in the same muscle.

01:14:49.180 Of course, one feeds the other.

01:14:51.660 So in his case of cycling, his muscle power output is limited by the carbon flow that he can sustain.

01:14:58.300 Ah, okay.

01:14:58.940 So thank you.

01:14:59.540 That's exactly where I want to go with this.

01:15:02.100 How much is he limited by carbon flux input versus metabolic byproduct output?

01:15:12.360 In other words, why isn't he at six watts per kilo, which would make him among the best cyclists on planet Earth?

01:15:19.860 Well, I think it's a matter of degree.

01:15:22.220 I think if we looked at a really top cyclist, we would find that they could clear lactate more efficiently than he could.

01:15:28.620 And a lot of that would have to do with his fiber type and the mitochondrial mass that they had.

01:15:35.340 I see.

01:15:35.640 So in the final analysis, you think that what differentiates the absolute best performers on planet Earth is going to be lactate clearance?

01:15:47.860 Yeah.

01:15:48.740 Or we're talking about carbon flux because that glycolytic flux goes to lactate.

01:15:54.380 And nobody knew that until we traced it.

01:15:56.680 That gets oxidized.

01:15:58.900 So what you have is this production versus disposal capacity.

01:16:04.660 When he is on that bike for 60 minutes at 430 watts, if you had to guess, if you could sample his arterial blood, his venous blood, his type 1 and his type 2 fibers for lactate concentration, what would be your prediction?

01:16:26.380 We haven't done this with trained athletes, but we've done it with some people who are physically fit and recreationally competent.

01:16:35.740 So you can see lactate very high in the venous effluent of a working muscle.

01:16:41.760 I'm going to just make up some numbers, 10 to 12.

01:16:44.760 And at the same time, since we had arterial sampling versus femoral venous sampling, when the blood goes around the body, not even one complete passage, it's down to 4 millimolar.

01:16:58.340 So there are lactate pyruvate conversions happening in the blood, in part by the red blood cells and in part by the lung parenchyma, because all the blood goes through the lungs.

01:17:09.620 Yeah, I was about to say, when you sample that venous blood at 10 to 12 millimole, would it matter if you're doing that pre or post portal vein?

01:17:19.680 Because I would think you could not do that easily, but just if you were sampling it above the liver, wouldn't it be significantly lower, given that the liver is also going to be a huge sink for lactate?

01:17:32.520 That's a good point.

01:17:33.460 It wasn't a mixed venous sample, but we had a femoral sample.

01:17:37.640 So in part dilution.

01:17:40.060 So you're doing it pre-liver, obviously.

01:17:42.400 So you're getting the absolute peak level of lactate.

01:17:45.940 That's very interesting, George.

01:17:46.940 I never thought of this.

01:17:47.780 All those times I'm sitting there poking my finger in my earlobe, I'm probably underestimating the venous concentration of lactate because it's already had a hepatic pass.

01:17:59.620 It hasn't had a hepatic pass.

01:18:01.780 It's had a hepatic dilution and it's gone through the lungs.

01:18:05.660 So that's potentially a double reduction in lactate.

01:18:09.340 Yeah.

01:18:10.080 Well, that's interesting.

01:18:11.400 So you're saying if you're measuring 16 millimole in your finger or earlobe, and assuming you're generating this on a bike, and someone had a femoral transducer in you, you could be more than 20 millimole in the femoral blood supply as it's exiting the muscle, correct?

01:18:28.300 It hasn't been explored much.

01:18:30.420 We just have a couple of papers on it.

01:18:32.520 Both are by Matthew Johnson and another by Greg Henderson.

01:18:37.340 You know, Matt Johnson, there's two actually.

01:18:41.960 I don't.

01:18:43.060 He's a research scientist at Dexcom.

01:18:45.780 They make the glucose analyzers.

01:18:47.740 Yep.

01:18:48.200 Maybe I have crossed paths with him.

01:18:49.700 I know some people at Dexcom and, oh, actually, no, no.

01:18:52.760 I take that back.

01:18:53.500 I do know Matt Johnson.

01:18:54.600 That's exactly right.

01:18:55.240 He did a postdoc in your lab.

01:18:57.080 He was a graduate student.

01:18:58.620 He was a graduate student.

01:18:59.280 Yep.

01:18:59.400 Yeah.

01:18:59.660 And he was a postdoc with Shreen Air at the Mayo Clinic.

01:19:03.100 So he was really highly trained.

01:19:04.340 And his dissertation was just to infuse femoral venous lactate and look on the arterial side.

01:19:11.240 And you can see there's a huge change in concentration.

01:19:14.120 And we attributed that to the pulmonary function.

01:19:17.000 You're pointing out we probably missed the hepatic dilution effect.

01:19:22.200 Yeah.

01:19:22.420 And wouldn't there be a way to, I mean, wouldn't you just be able to use like C14 lactate, infuse it,

01:19:32.760 and then look at how much C14 glucose you're forming in the liver?

01:19:37.820 That would actually tell you what concentration of the lactate is being extracted by the liver, right?

01:19:42.800 Well, in people, we've gone C13, which is stable, non-radioactive.

01:19:47.980 Okay.

01:19:48.460 Yeah, yeah, yeah.

01:19:48.940 So C13 glucose production in the liver would give you that fraction.

01:19:54.240 And of course, if you did this in direct calorimetry or indirect calorimetry, rather,

01:19:58.260 you could measure the C13 CO2 coming out of the lungs, right?

01:20:03.120 Yeah, well, it gets tricky because measuring CO2 content is, you know, really hard.

01:20:08.980 Because most of the CO2 is carried as bicarbonate, carbamino.

01:20:13.200 It's temperature dependent, pH dependent.

01:20:15.820 We've done some of that, getting what's called the RQ.

01:20:18.900 But we haven't done it as you described, Peter.

01:20:21.200 So based on Matt's work, though, you would say, look, when we infuse massive amounts of lactate into the femoral vein and then resample the femoral artery,

01:20:32.560 the mass balance tells us it had to go somewhere.

01:20:35.220 So it's either some of it's going to make glucose in the liver and some of it is being expired.

01:20:40.960 Yep.

01:20:42.160 In all our studies, we get oxidation is about 75 to 80 percent.

01:20:46.680 So your initial hypothesis about really we're talking about carbon flow, energy flow.

01:20:52.700 The lactate can float around the body and be removed in diverse ways.

01:20:57.260 It can be reconverted to glucose, which then gets oxidized.

01:21:00.760 Or it can be just oxidized directly in the muscle or in other muscles.

01:21:06.380 So, for instance, we're working really hard.

01:21:09.040 Maybe we see this in cross-country skiers.

01:21:11.620 Our arms are highly glycolytic, release a lot of lactate.

01:21:15.660 Our legs are redder, more oxidative.

01:21:19.560 So here we are.

01:21:20.680 We have poling, generating lactate, going into the arterial circulation, perfusing the muscle, fueling the muscle, fueling the brain.

01:21:30.760 Fueling the liver.

01:21:32.580 That's very interesting, George.

01:21:33.580 You know, I had always assumed that the reason I could both see in myself and other athletes the highest levels of lactate following a swim, 200 or 400-yard medley swim, where you're doing all four strokes.

01:21:52.260 It's a several-minute effort.

01:21:54.560 If the goal was how high can you make your lactate, that's the exercise to do it.

01:21:58.580 Maybe followed by rowing.

01:22:00.200 I just assumed it was because you had more muscles involved.

01:22:04.140 I didn't know about what you just said.

01:22:06.560 What you're saying is, no, the reason whole body activity would produce so much lactate is presumably you're using more muscles, but you have disproportionate type 2 fibers in the upper body relative to the lower body.

01:22:21.620 Did I hear you correctly in that regard?

01:22:23.640 Ask somebody if they like changing a light bulb.

01:22:28.160 I get tired right away.

01:22:31.720 That's so, how did I not know that?

01:22:33.660 I mean, I feel like, what have I been doing for the last 30 years?

01:22:36.540 Like, clearly not learning.

01:22:37.840 You haven't been changing light bulbs.

01:22:39.540 That's such a good point.

01:22:43.200 Yeah.

01:22:43.480 The upper body really can get pretty fatigued relative to the lower body.

01:22:47.760 Super interesting.

01:22:49.200 So if we look at fiber typing and, you know, but we're evolved to use our arms in different ways.

01:22:54.440 We use them at a low level.

01:22:56.760 And at some point, maybe we want to talk about the size principle.

01:23:00.460 So our type 1 fibers are easily recruited to low level things, help us writing, taking notes.

01:23:07.440 We're using type 1 fibers.

01:23:09.120 But now, if we have to do lift something heavier, now we need to recruit those type 2 fibers.

01:23:15.720 And working overhead, we're using type 2 fibers and we're really having clearance problems.

01:23:21.640 So that's really fatiguing.

01:23:24.880 Let's talk a little bit about cancer.

01:23:27.060 We alluded to it at the outset with the Warburg or Warburg effect where cancer cells seemingly in the presence of unlimited oxygen still seemingly choose a metabolic pathway that avoids the mitochondria.

01:23:45.380 Although I'm going to come back and ask you about that now because we're going to call everything into question.

01:23:48.960 But again, let's just go through the traditional thinking.

01:23:50.980 Traditional thinking is you take cancer cells in a dish, you give them unlimited access to every substrate under the sun and what do they do?

01:23:59.620 They don't want to use fatty acids.

01:24:01.220 They just want to use glucose and they just want to make lactate.

01:24:04.880 I know that the first hypothesis put forward there was, oh, well, cancer cells must have defective mitochondria.

01:24:12.020 That's why they can't use anything else.

01:24:14.620 That's why they have to make so much lactate.

01:24:15.720 That hypothesis doesn't seem to be the case and it seems that there are other reasons.

01:24:24.000 Famously, Lou Cantley, Craig Thompson, and I think at least one other colleague wrote, it was Matt Vander Heiden, if I'm not mistaken,

01:24:31.620 that the cancer cell is not optimizing for ATP and it doesn't care that it's being inefficient in making lactate.

01:24:38.980 It's optimizing for cellular building blocks because it's a cell that has to replicate without stopping.

01:24:45.580 And that's why it's doing that.

01:24:47.100 It's going down the lactate pathway to generate more carbon, nitrogen, whatever else it needs to actually build a cell.

01:24:55.460 Tell me a little bit now about where your discoveries kind of fit into this hypothesis around why a cancer cell would follow the principle of the Warburg effect.

01:25:05.420 Well, maybe that's a Nobel Prize, right?

01:25:07.680 Understand that?

01:25:09.000 To rephrase that, I think the answer has been staring us in the face.

01:25:14.600 Cancer is a problem of glycolysis, unrestrained glycolysis.

01:25:19.840 And Ineo and I have some papers together, and in fact, he was kind enough to put my name on his most recent paper,

01:25:27.680 which is now being reviewed for publication and has to do with the expression of certain glycolytic enzymes.

01:25:34.560 And I don't want to spill Ineo's beans here about this.

01:25:38.480 It has to do with the expression of glycolytic enzymes.

01:25:41.180 It looks as if in all the various stages of cancer progression, lactate stimulates those.

01:25:51.320 So Ineo is now looking at sort of the mitochondrial basis for that.

01:25:55.880 So to repeat what you said, cancer cells do have mitochondria.

01:26:00.240 We've seen that.

01:26:01.040 Other people have seen that.

01:26:02.440 And they're capable of oxidizing different substrates, including lactate.

01:26:07.940 But the lactate is generated.

01:26:11.140 The high lactate production seems to stimulate a lot of things that are untoward in cancer.

01:26:17.260 And one of the papers that Ineo and I first wrote was to look at all the adaptations in muscle, the training,

01:26:24.120 and look at where cancer cells differ from the norm.

01:26:27.900 And then look at those points of difference between training and cancer.

01:26:32.740 And it has to do in part with lactate clearance.

01:26:35.400 So those cancer cells do generate a lot of lactate.

01:26:41.160 And the lactate is injurious in those cells.

01:26:45.040 It would be easy to listen to that statement and say a cancer patient should never be exercising.

01:26:50.320 And that might be one implication, although another implication might be cancer patients

01:26:54.760 need to be exercising because they need a sink for all that lactate.

01:26:59.200 So which of those two do you think is more accurate?

01:27:02.480 I used to believe the first one.

01:27:03.960 Oh my gosh, we don't want to generate lactate, but we thought more about it.

01:27:09.260 Well, lactate is low because you clear it.

01:27:12.280 And when you do regular exercise, you increase your clearance capacity.

01:27:18.020 And so in that sense, if lactate is carcinogenic, by removing it, you lessen the chance for carcinogenesis.

01:27:28.600 That's just simply kind of remarkable statements.

01:27:31.900 First of all, that lactate is carcinogenic is kind of remarkable.

01:27:36.120 And then it feeds to the difference between concentration and flux or flow.

01:27:42.300 This is the most, I think in physiology, one of the hardest things for people to wrap their

01:27:46.840 mind around.

01:27:47.680 I'll give you another example, but it's something near and dear to my heart, right?

01:27:50.720 Which is you look at intramyocellular fatty acids.

01:27:55.440 Why is it?

01:27:56.300 I mean, you know the answer, but I'm leading you down the path for the listener.

01:27:59.440 Why is it that both the best athletes in the world and the most metabolically unhealthy people

01:28:05.460 with type 2 diabetes both have high amounts of intramyocellular fat?

01:28:10.660 Well, of course, the difference is in the person with type 2 diabetes, it's static, it's stagnant,

01:28:16.340 it sits there, and it is one of the causative drivers of insulin resistance.

01:28:21.060 Yet in the athlete, it's a carbon flow.

01:28:24.260 It's moving.

01:28:25.380 It's the difference between a stagnant pond and a flowing river.

01:28:29.040 And I think we get into this trap with lactate, don't we, where we measure concentrations

01:28:33.740 and we just assume high is high, low is low, high is bad, low is good.

01:28:38.280 But we can't measure flux without the complex instrumentation you use in a lap.

01:28:44.020 Yeah, that's true.

01:28:45.660 And just elaborate more on the marathoner paradox, if you do an EM and you find a mitochondrial

01:28:51.700 network, you'll see a fat globule right next to it.

01:28:55.840 The potential for fat oxidation is great.

01:28:58.440 In our work, we've done some MRS and MRI, and we've looked at athletes.

01:29:05.060 They don't use much fat during exercise.

01:29:08.280 But in the recovery period, when glycogen is low, that's the period of fat burning.

01:29:14.360 Those fats there are preconditioning, prepositioning fuel supply in recovery.

01:29:21.440 When glycolysis switches off and people start to relax.

01:29:26.400 So you're right about this whole idea of flux.

01:29:29.500 Also in diabetes, glucose is high.

01:29:32.540 Why?

01:29:33.360 Was it produced too much or not cleared?

01:29:35.660 Right.

01:29:35.780 It's a great point.

01:29:37.140 Yeah.

01:29:37.580 So that's easier to explain with glucose than with lactate.

01:29:40.780 People more readily understand the dynamics of appearance versus disappearance.

01:29:46.380 The level is informative, but it's not the whole story.

01:29:50.040 We've talked a little bit about, well, quite a bit about lactate in athletic performance.

01:29:55.160 I have a much better understanding of that.

01:29:56.660 You've talked about something very tantalizing with respect to brain health and TBI, and I'm

01:30:04.320 very much hoping that this is being investigated.

01:30:06.700 I mean, again, TBI is something where fortunately people are so much more aware of it today, but

01:30:11.440 yet we still seem relatively poor in therapies.

01:30:15.680 And if we had a tool, a metabolic tool to aid following a concussion, I mean, imagine if there's

01:30:22.960 a concussion protocol that said every time a person got a concussion, they were to receive

01:30:27.160 intravenous lactate for X number of consecutive days, four hours a day at four millimole.

01:30:33.280 Again, very testable hypotheses here.

01:30:35.540 It's a little frustrating to think that this type of work isn't being funded given, I mean,

01:30:40.340 heck, I would have the NFL Players Association look into this because you clearly have a high

01:30:45.960 volume of individuals who are susceptible to concussions, and it would be easy to test

01:30:50.020 that.

01:30:50.680 We've talked a little bit about the role of lactate in cancer, although we'll save that

01:30:54.200 for maybe the next time I have Inigo back on and let him be the one to talk about that.

01:30:58.340 But the big takeaway there is, yes, lactate may be carcinogenic, but the bigger problem is not

01:31:05.180 the accumulation of lactate, it's the accumulation of lactate in the absence of an effective clearance

01:31:09.880 mechanism.

01:31:10.900 And if one thing has become demonstrated over and over in our discussion today, it is that

01:31:15.960 if you want to increase lactate flow and you want to increase lactate clearance, you must

01:31:20.740 exercise.

01:31:22.080 Are there other disease states besides these conditions we've discussed where lactate plays

01:31:28.980 an important role in the pathophysiology?

01:31:31.680 You suggested earlier on brain health, dementia, Alzheimer's, it's really looking at exercises

01:31:39.560 protective, not just card game kind of mental exercises, but physical exercise, and people

01:31:46.240 talking about brain blood flow and the delivery of substrates.

01:31:50.400 And in fact, some people are talking about the role of lactate in stimulating neurogenesis and

01:31:56.000 the dentate gyrus, looking at development of new brain cells, which used to be a really

01:32:02.500 heretical idea.

01:32:03.720 The original idea was that when we're born, we have a certain number of brain cells.

01:32:07.600 Now we know that there's a turnover of brain cells and they're renewed.

01:32:11.400 And we know that problems can occur when the progenitor cells are damaged or injured or not

01:32:16.920 stimulated in some way.

01:32:18.240 I think there's a big future for investigators to be working in the field of physical activity

01:32:25.660 and aging and the health span.

01:32:29.800 We talked very briefly about the role of lactate specifically in, as a precursor or a canary

01:32:35.800 in the coal mine around sepsis.

01:32:37.640 Do you believe that that is still a valuable tool?

01:32:40.920 Definitely.

01:32:41.260 So to follow Bellamo's argument, okay, show me where there's an anoxic area in your patient.

01:32:49.740 He challenges his colleagues, show me where there's hypoxia.

01:32:53.740 And so then the attitude becomes, well, it's not the cause, it's a response.

01:33:00.160 It's a strain and understanding stress and strain.

01:33:04.800 Sorry, just to back up for a second.

01:33:05.960 He's saying this to ask the question, if you're telling me that lactate is the response to

01:33:13.980 anoxia or hypoxia, why, when we see lactate going up in a septic patient, can you not point

01:33:21.540 to the area of anoxia?

01:33:24.380 And then tell me what the response is to that.

01:33:26.740 Well, I don't know what the response is to that.

01:33:29.240 Nobody can identify it.

01:33:30.560 And I've written about this, anticipating this kind of general question.

01:33:34.680 Where is this lactate coming from?

01:33:37.100 I think it might be coming from the gut, personally.

01:33:40.260 That's what we were taught, George.

01:33:41.700 When I was in the ICU, we were taught when you see these rising lactate levels in patients,

01:33:49.300 it is hypoperfusion of the gut.

01:33:52.240 Now, okay, so I measured a lactate level in a patient and it's up to 10 millimole.

01:33:57.900 That's bad news.

01:33:59.560 But am I supposed to take that patient to the operating room and look for ischemic bowel?

01:34:04.060 Well, that's a lot of smoke, but it doesn't tell you where the fire is, even if you believe

01:34:08.780 it's a gut perfusion issue.

01:34:10.720 Well, I think part of it is because the microbes are producing racemic lactate.

01:34:16.260 They're producing L-lactate and D-lactate.

01:34:19.860 And most of our body runs on the form of lactate that's identified as L-lactate.

01:34:25.600 But I think in sepsis, there's a lot of D-lactate going on that is formed in the lower bowel as

01:34:32.540 opposed to the upper bowel.

01:34:34.300 How easy is it to distinguish between those two?

01:34:36.680 It's been so long since I've done organic chemistry.

01:34:38.680 I don't remember how we distinguish.

01:34:40.200 I understand the difference between a D and an L, but I don't remember how one measures it.

01:34:44.880 Most of all the analyzers we have, hospital elsewhere, measure the L form.

01:34:48.960 I'm holding up my hands here on purpose to say one is the mirror image of the other.

01:34:54.780 The L is the form we usually make and utilize.

01:34:58.900 But if we make this other form, now we have this stuff which is neurotoxic and pro-inflammatory.

01:35:06.500 And I think that in large part, people can't really see the extent of lactatemia that occurs

01:35:12.940 in sepsis.

01:35:13.680 Wait a minute.

01:35:14.880 You're saying that when we measure the 10 millimole in the septic patient, the 10 millimole

01:35:20.760 is only the L-lactate concentration because that's all the assay measures.

01:35:24.860 But there could be 20 millimole of D-lactate there that is actually causing a problem.

01:35:31.320 Yeah.

01:35:31.800 How could we confirm or refute that?

01:35:34.360 This is your field, not mine.

01:35:36.240 There's a term D-lactic acidosis.

01:35:39.220 And we know D-lactate is toxic.

01:35:41.420 So now we would need a special kind of analyzer to detect it.

01:35:47.300 And that's not the common analyzer that's around.

01:35:50.300 All the analyzers, the blood gas analyzers, the portable devices, most of the enzyme techniques.

01:35:56.800 The recipe in Bergmaier's textbook is for L-lactate.

01:36:01.740 Do you have the ability in your lab if you wanted to measure D-lactate to do so?

01:36:05.920 In the past, I've submitted some grant applications with clinicians who would want to do this.

01:36:11.700 And we haven't gotten very far.

01:36:13.980 Interesting.

01:36:14.640 Where do we derive the belief that D-lactate is neurotoxic and pro-inflammatory?

01:36:21.040 Because if you give it, it is.

01:36:23.540 And when people can measure it, it's associated.

01:36:26.080 Interesting.

01:36:28.080 So your hypothesis is that the bacteria are making the lactate and they're disproportionately making

01:36:37.540 the less desirable form of it.

01:36:40.060 And that the L-lactate, that which you're actually measuring, is probably not causing any of the

01:36:44.320 problems associated with the sepsis.

01:36:46.960 It's telling you that something else is going on.

01:36:48.800 Yeah, and those microbes will make lactate regardless of the presence of oxygen.

01:36:54.040 So if you were saying, well, there's gut ischemia, you mentioned it would be very hard to demonstrate

01:36:59.320 that and you wouldn't want to actually maybe bother measuring it if you have a microbe that

01:37:04.320 is the site of this lactate generation.

01:37:08.120 What is the most interesting question that you are asking today that you still don't have

01:37:14.180 an answer to in your mind with respect to lactate metabolism?

01:37:17.460 Yeah, thank you for that.

01:37:19.900 Our most recent paper touches on this.

01:37:23.220 So for 100 years, everybody, including us, have been thinking about muscle and related

01:37:28.980 tissues, tissues that can use lactate, but it's all been a muscle thing.

01:37:34.420 So we did a very simple test.

01:37:37.040 We used our isotopes as we usually do.

01:37:39.820 We had a board, carbon-13 labeled lactate, and then diduteroglucose and D5-glycerol.

01:37:48.780 So we could measure lactate, glycerol, and glucose all at the same time.

01:37:53.180 And then we gave people an oral glucose tolerance test.

01:37:57.440 And the first thing that came out in the arterial blood, and this is arterial blood, not venous

01:38:03.600 blood.

01:38:03.920 The first thing that came out after taking glucose is lactate.

01:38:09.540 So there's enteric glycolysis that takes place.

01:38:14.440 And this is the way the body participates in distributing carbohydrate energy to make lactate.

01:38:22.360 So this just changes our mind completely.

01:38:25.940 But sorry, George, did we not know before this that when you consume glucose, lactate goes

01:38:30.780 up?

01:38:31.060 We know that, and nobody would understand why.

01:38:35.180 It's part of the lactate shuttle.

01:38:37.240 I presented this in our most recent studies last year at the American Diabetes Association.

01:38:42.420 There was a doc there from NIH, and he said, well, we feed carbohydrate.

01:38:46.660 We get 2-millimolar lactate.

01:38:48.580 So what's the deal?

01:38:50.740 That's the way the body's working.

01:38:52.980 In sports, we would say it's hiding the ball.

01:38:56.260 In baseball, we hide the ball.

01:38:58.100 In football, we try to hide the ball.

01:38:59.900 Here the body's trying to minimize the glucose load, but still deliver carbohydrate energy.

01:39:06.460 And it starts with the enterocytes and the gut.

01:39:09.500 There are plenty of studies where people would incubate enterocytes under air, give glucose

01:39:14.660 immediately.

01:39:15.940 You have lactate.

01:39:17.360 And just give me a sense of scale.

01:39:18.900 So when you give somebody an oral glucose tolerance test, this is 75 grams of glucose, you gave

01:39:24.840 a standard dose, I'm assuming?

01:39:26.240 Yeah.

01:39:27.120 Okay.

01:39:27.560 So plasma glucose in these subjects will easily double, right?

01:39:32.560 It'll easily go from 75 milligrams per deciliter to 150 milligrams per deciliter, correct?

01:39:39.580 Yeah.

01:39:39.900 And lactate might double, maybe go from 0.6 to 1.2 millimole, correct?

01:39:48.540 Correct.

01:39:49.420 From a mass balance perspective, I'm not smart enough to remember how to do this.

01:39:55.280 Can you remind me how much carbon went in each of those two paths?

01:40:00.020 Good point.

01:40:01.560 We're just talking about the concentration, but earlier we talked about the flux.

01:40:05.400 So it looks like the liver is really, really important in this whole thing.

01:40:10.500 And we did touch on the liver and its importance.

01:40:13.440 It's really underestimated and you're asking about what I think I want to do next is to

01:40:18.980 really explore this problem which you are articulating.

01:40:23.500 How does the body shuttle carbohydrate energy?

01:40:26.500 So you said the blood glucose will rise and it will go double, but it doesn't get that

01:40:34.100 high until 30 minutes after the test.

01:40:38.080 Whereas if I give the glucose, the lactate is spiking in five minutes, reaching a peak

01:40:43.700 at 15 minutes, then subsiding.

01:40:46.320 And now the glucose is starting to become the carbohydrate energy form.

01:40:51.180 But just so that listeners understand something you and I take for granted, when a person's

01:40:56.320 blood glucose goes from 80 to 150 milligrams per deciliter, that's still a trivial amount

01:41:04.880 of absolute glucose difference concentration.

01:41:07.820 It's a difference of five grams of glucose in the entire circulation that would explain

01:41:13.840 that delta.

01:41:15.080 You still gave the person 75 grams.

01:41:18.800 In other words, we have to account for 70 more grams of glucose.

01:41:22.740 And my thinking was that most of that's in the muscle.

01:41:27.860 We do oral glucose tolerance tests on everybody, George.

01:41:30.740 I mean, we just really believe that that is a great functional test of glucose disposal.

01:41:35.780 But truthfully, you know, we're not measuring lactate when we do this.

01:41:38.960 Maybe we should be.

01:41:40.200 But we're basically asking the question, how sensitive are your muscles to insulin?

01:41:47.380 And how much of a reservoir do you have to dispose of glucose?

01:41:51.080 Because we're also measuring insulin every 30 minutes as well as glucose.

01:41:55.400 But now I'm wondering, because we haven't measured lactate, there's another pathway we're

01:42:01.020 not accounting for, which is how much of the glucose are those enterocytes turning into

01:42:06.660 lactate as an alternative fuel source?

01:42:09.280 Yeah, so that's the first part of what happens.

01:42:12.540 We saw it.

01:42:13.400 We were lucky to have arterialized blood so we could see the spike in lactate that comes

01:42:19.240 out after taking glucose, way before the glucose starts to rise.

01:42:23.780 And then from our isotope technology, we could see that when glucose is rising, it's giving

01:42:29.400 rise to lactate.

01:42:30.660 That's been seen before.

01:42:32.040 It's called the indirect pathway.

01:42:34.500 But to go back to an earlier point you raised about the importance of the liver, and this

01:42:38.500 is in our paper we referenced the work of Stender who gave 13C glucose in an OGT, the liver

01:42:46.440 picks up most of it, and the liver basically sequesters about 80% of the glucose load, and then

01:42:53.860 doles it out over time, and it starts to release this glucose after about, I'm trying to remember

01:43:01.200 their study, 30 minutes.

01:43:03.360 Meanwhile, lactate has a big role.

01:43:05.060 It plays a role, and meanwhile, the glucose is still in the liver, and now it starts to

01:43:10.900 be doled out.

01:43:12.000 It's being released as glucose, and that's getting converted to lactate in the muscles,

01:43:17.660 what's called the indirect pathway of glucose metabolism.

01:43:21.980 So the liver is really key.

01:43:23.480 So what I would hope to be able to do in the near future is to really revisit all this dietary

01:43:30.800 nutritive aspects of, okay, glucose is taken up, made into lactate, but what if we have

01:43:38.100 fats there, like a real meal, not just an OGT, maybe a meal tolerance test.

01:43:44.800 We would do this.

01:43:45.940 A version of this was done by somebody named Schlicker in Germany, and they did this really

01:43:50.620 incredible study.

01:43:52.040 They did make a mistake because they forgot about the liver.

01:43:55.240 They grew grain in a high carbon 13CO2 environment, and plants, I think most people know, take CO2

01:44:04.660 from the air when they make sugar.

01:44:06.760 So they did an oral glucose tolerance test with 13C, and also they harvested this grain, and

01:44:14.120 they did a meal test, and they made porridge out of this stuff, and they looked at the appearance

01:44:19.800 of lactate and glucose in the blood, and they saw the same thing we did.

01:44:24.500 Right away, there's a spike in lactate, and they said, well, lactate's the whole story, but

01:44:30.140 they forgot about the liver.

01:44:32.600 So you're saying in a standard oral glucose tolerance test, your belief is that most of the

01:44:38.260 glucose that is being disposed of is actually being disposed of initially by the liver.

01:44:44.120 And then the liver starts doling that back out.

01:44:47.340 The muscle picks it up.

01:44:48.980 Your secondary production of lactate is by the muscle.

01:44:51.420 Your primary production is by the enterocyte on immediate.

01:44:54.580 That's why you get two peaks of lactate.

01:44:56.540 You get the first fast peak in response to the enterocyte making lactate, and then you get

01:45:02.040 a second delayed slower peak when the muscles get the glucose from the liver and start making

01:45:07.300 lactate.

01:45:08.300 Yeah.

01:45:08.880 And one of our core investigators is Umesh Masherani.

01:45:11.880 He's a diabetologist at UCSF.

01:45:14.640 And he said, well, maybe that's how metformin works.

01:45:19.060 So for our listeners, your listeners, metformin is the most popularly prescribed drug for high

01:45:27.260 blood sugar.

01:45:28.220 And one of the concerns is when you give that drug, lactate rises.

01:45:32.900 And Umesh is very comfortable saying, well, the body's making lactate.

01:45:35.940 So metformin is encouraging enterocytes to make lactate.

01:45:39.840 That's why the lactate's high.

01:45:42.200 And that's a good thing.

01:45:44.180 Very interesting.

01:45:45.360 As you know, there's a body of literature suggesting that metformin may impede exercise

01:45:51.920 performance.

01:45:52.620 And again, the problem with metformin is, despite the fact that this drug's been around, it's

01:45:57.800 almost as old as God, it seems to have so many points of action that it's very difficult

01:46:03.040 to know what it's doing or how much of its net outcome, which is reducing hepatic glucose

01:46:08.340 output, can be attributed to what?

01:46:10.600 I guess the conventional thinking on metformin is it's inhibiting complex one of the mitochondria,

01:46:16.420 correct?

01:46:17.340 Yeah.

01:46:17.800 And if you inhibit complex one, God, you're activating AMP kinase.

01:46:22.840 That should reduce hepatic glucose output, correct?

01:46:26.020 It does that.

01:46:27.260 But it's always been, I mean, as sure as God made little green apples, anybody on metformin

01:46:32.940 has higher lactate levels.

01:46:34.680 That's a bad thing.

01:46:36.440 Or it was a bad thing.

01:46:37.600 But maybe it's a way to deliver carbohydrate energy.

01:46:42.700 I had always assumed that the doubling, at least doubling, if not 3x increase in resting

01:46:51.000 lactate levels in the case of metformin were due to the mitochondrial, the complex one inhibition.

01:46:57.540 Obviously, it may be naive assumption, but it was, hey, if you're inhibiting the electron

01:47:02.320 transport chain, of course, you're going to have more lactate.

01:47:04.520 But that may be true, true and unrelated.

01:47:06.400 Yeah, that's why I want to give carbon-13C lactate or carbon-13C glucose and look at the

01:47:13.600 appearance of carbon-13C lactate in the blood and see and do the quantitation you described.

01:47:19.600 Where does the glucose go?

01:47:21.860 How much would it cost to do the definitive experiments on the full flux disposal of lactate?

01:47:31.360 This doesn't strike me as staggeringly high amounts of money to do this type of research.

01:47:37.060 We could start very well with an R01 research grant.

01:47:41.980 That's $2.5 million.

01:47:44.100 That would be a start.

01:47:45.420 That's just a handle of glucose.

01:47:46.880 But the real interesting stuff would be when glucose appears as it does in a meal with other

01:47:53.340 things.

01:47:53.720 You know, it would be interesting.

01:47:55.740 Have you done the experiments you just described, the OGTT experiment, to individuals both on

01:48:02.320 and off metformin?

01:48:03.920 It would be interesting to see the difference in lactate production in those two individuals.

01:48:09.720 And it would be interesting to also see if there was a way to quantify this enterocyte production.

01:48:15.680 Yeah, Dr. Mascherati and I want to do that.

01:48:18.960 With metformin, if we give metformin and there's an increase in lactate in the plasma, is that

01:48:25.660 due to production, outstripping removal, or are we actually increasing the oxidative disposal

01:48:33.100 of glucose?

01:48:35.720 Or is the glucose high because of increased gluconeogenesis?

01:48:40.000 We could answer all of these things with a combination of tracers we use.

01:48:43.780 Again, let's go back to conventional wisdom.

01:48:47.740 What were we taught in medical school and residency?

01:48:51.660 Be careful of metformin because you increase the risk of lactic acidosis.

01:48:57.760 So a person on metformin is at an increased risk for lactic acidosis if they get dehydrated,

01:49:04.480 if they get contrast in a CT scan.

01:49:07.240 When viewing that concern through the lens of what we've just discussed, does it be a

01:49:13.760 Well, caution is always advised.

01:49:17.700 First, do no harm.

01:49:19.380 So when we prescribe this medicine, we don't know if it increases lactate production or inhibits

01:49:25.640 disposal.

01:49:27.080 Right.

01:49:27.280 But let's go back to the very beginning, right?

01:49:29.440 Which is, just because you increase lactate production, does that mean you're causing acidosis?

01:49:35.520 Well, that was another important consideration.

01:49:38.780 Lactate rises.

01:49:39.700 What's the change in pH?

01:49:40.880 Yeah.

01:49:41.900 What happens when you take those subjects, the TBI subjects, and you clamp them at four

01:49:48.440 millimole?

01:49:49.720 You said, if I recall, there was no change in sodium, but I think you also said there was

01:49:55.280 no change in pH.

01:49:57.180 Oh, there's a slight alkalosis.

01:49:58.720 Slight alkalosis.

01:50:01.000 How much?

01:50:02.020 7.38 to what?

01:50:03.980 7.38 to 7.35.

01:50:07.360 Well, that would be a slight acidosis.

01:50:09.140 Excuse me.

01:50:09.540 Opposite way.

01:50:10.920 7.4.

01:50:12.540 Okay.

01:50:12.940 Okay.

01:50:13.560 The colleagues that you referenced in Germany, I think, or Switzerland, who were taking people

01:50:18.080 up to eight millimole, were they seeing an acidosis?

01:50:21.380 They did not report it.

01:50:22.580 Okay.

01:50:23.520 So, does that mean it's possible that high levels of lactate do not materially alter acid-base

01:50:30.820 physiology?

01:50:31.820 Well, in your experience, is sodium lactate given in metabolic acidosis?

01:50:37.100 Sometimes it is.

01:50:38.080 Yeah, but the lactate concentration is very low in that setting.

01:50:42.500 The examples you're citing are much better examples to ask this question.

01:50:47.580 You're clamping people at a really, really high lactate that you just don't get to.

01:50:52.280 But again, it seems to me that if what you're saying is correct, George, there's a lot we're

01:50:57.940 misinterpreting from, for example, sepsis literature, where you get that patient in the

01:51:05.200 ICU who's got high lactate, well, they also have a low pH.

01:51:09.820 But those two things could be driven by different processes.

01:51:13.620 Yeah, exactly.

01:51:14.800 We addressed this earlier.

01:51:15.920 I think if you see a low pH, yeah, you need to do something.

01:51:19.860 If you see a higher lactate and the absence of a change in pH, I would be very inclined

01:51:24.960 not to do much.

01:51:26.140 You've given me and everybody listening a lot to think about here, George.

01:51:29.800 So it seems to me that understanding the full flux, the full mass balance of lactate, both

01:51:39.260 exogenous and endogenous, is a necessary step to fulfill our understanding of metabolism

01:51:45.820 in a more complete manner, correct?

01:51:48.040 Yeah.

01:51:48.540 Thank you.

01:51:49.220 I think so.

01:51:50.260 Oh, and you mentioned endogenous versus exogenous.

01:51:53.800 Exogenous means we're going to infuse lactate, put it in the body some way.

01:51:57.600 Well, I learned in organic chemistry, the salt of an acid is a base.

01:52:03.080 So it's not unexpected that when you give it, pH will rise slightly.

01:52:09.060 And maybe part of that also is sodium.

01:52:11.500 So yeah, what does it mean to use this exogenous stuff?

01:52:17.540 So lactate is distinguished from pyruvate and lactate is reduced.

01:52:23.240 It has more hydrogen on it.

01:52:25.320 There's one more hydrogen than pyruvate.

01:52:26.940 So that keto bond on pyruvate, the double bond oxygen, becomes hydrogen.

01:52:33.200 So it's more reduced.

01:52:34.560 Now, when you start putting in this reduced equivalent into the blood, it's going to go

01:52:39.220 around the whole body and change redox in a number of tissues, all the tissues, basically,

01:52:45.200 where the lactate is going to go.

01:52:46.420 So lactate is a powerful signal, and it works in diverse ways to activate various pathways,

01:52:55.580 including by changing cell redox.

01:52:58.040 What does lactate do in terms of gene expression?

01:53:00.800 We haven't talked about that, but given how potent a signaling molecule it is in both metabolism

01:53:07.440 directly and vis-a-vis redox, what do we know about other forms of signaling and expression

01:53:14.660 of genes?

01:53:15.860 Yeah.

01:53:16.460 So there's a new field now.

01:53:17.920 So we used to think genes are regulated in part epigenetically by acetylation or methylation.

01:53:24.140 Now we realize they're also lactylated.

01:53:26.580 We've done some of those experiments here in our lab.

01:53:28.780 We haven't published it, but the lactate is a predominant metabolite, and it can bind to

01:53:35.360 genes, and it can affect gene expression.

01:53:38.420 Acetylation, methylation, lactylation, that's actually a term, and I was going to compliment

01:53:48.500 you on your reading of the literature, because you can look that up in PubMed, and you can

01:53:52.540 see that people are starting to look at lactylation of histones by raising lactate.

01:54:00.180 So it's not through histone acetylation.

01:54:03.260 It's direct lactate binding.

01:54:06.060 Yeah, and it's called lactylation.

01:54:09.180 Dr. Otea, you've got us up into the stratosphere here of where science needs to go.

01:54:15.060 Starting with the premise, exercise is healthful.

01:54:18.600 How can it affect the body corpus, promote healthful living, possibly in part by lactylation

01:54:26.820 of histones promoting mitochondrial biogenesis?

01:54:31.180 It's very interesting, because we've talked about all of these benefits of exercise, right?

01:54:35.140 We talk about how my friend clearly has more mitochondria than I do.

01:54:40.420 He has more MCTs, and he's so much better at clearing lactate and all of these things.

01:54:45.640 But of course, what we're missing in that is the how and the why.

01:54:49.000 Why is he doing that?

01:54:51.360 What is it about his training stimulus that does that?

01:54:54.120 And what you're suggesting, at least as a hypothesis, is what if the lactate itself is signaling the

01:55:01.260 gene expression that leads to the more favorable phenotype seen in the athlete?

01:55:05.680 Yeah, well, with Takeshi Hashimoto, we published a paper.

01:55:09.200 If you just take muscles, put them in a muscle cells in a dish, you had lactate, you activate 500 genes.

01:55:15.740 But here's the thing.

01:55:16.780 There has to be something, if I'm just thinking about this perhaps a bit too quickly, I would

01:55:23.180 have to believe it also must involve something favorable with consumption.

01:55:27.720 In other words, I have a hard time believing, if you took my friend and you took me, and

01:55:32.100 you would argue, based on his training and based on my training, I'm on a bike three or

01:55:36.120 four hours a week, he's on a bike 15 to 20 hours a week, he's clearly making more lactate

01:55:41.680 in any given week than I am.

01:55:43.480 And he's clearly using more lactate in any given week than I am.

01:55:47.160 But if you came up with an experiment, imagine you could do this, where you could pair feed

01:55:52.720 us lactate, okay?

01:55:54.500 So in other words, for every millimole of lactate he produces endogenously, you exogenously deliver

01:56:03.120 the same lactate to me.

01:56:05.060 I still don't think we'd end up the same, even though we have the same input of lactate,

01:56:10.380 because he's using it during exercise, whereas I'm sitting around on my butt while you're

01:56:17.100 giving me all of that lactate.

01:56:19.440 So it's hard for me to imagine that lactate by itself would be the signal.

01:56:24.620 I have to think there's something associated with the benefits of how lactate is consumed

01:56:30.780 during exercise.

01:56:32.480 So yeah, this is an interest in the literature now.

01:56:34.760 People are doing lactate clamps on people and looking for increases in mitochondrial protein

01:56:40.600 expression.

01:56:41.720 And what are they seeing?

01:56:43.080 There's sometimes yes and sometimes no.

01:56:45.660 So this sounds a lot like amino acids.

01:56:48.080 This has to do with the endogenous versus the exogenous, because you get completely different

01:56:53.200 signals.

01:56:54.300 So it's the endogenous lactate when it's high, seems to stimulate mitochondrial biogenesis

01:56:59.640 rather than just infusing it.

01:57:01.620 Okay.

01:57:02.140 But why would that be?

01:57:03.880 Well, a lot of these pathways are redox sensitive.

01:57:07.360 Ah, I want to make sure the listener understands that.

01:57:09.600 That's a very important point.

01:57:10.540 Because it's redox sensitive, that's just fancy speak for saying it depends on the amount

01:57:16.960 of protons or pH balance of what's going on.

01:57:20.100 And if you just give somebody lactate without actually creating the slight alteration in pH

01:57:28.180 that is naturally going to be accompanied by exercise, you don't reap the benefits.

01:57:33.580 Whereas if the lactate is produced in concert with exercise, you get the lactate, but you

01:57:39.520 also get the pH perturbation that is the key to unlock its potential.

01:57:44.680 That's a very good explanation of what I'm seeing.

01:57:47.300 This is, again, work of others who are really serious scientists.

01:57:51.320 And I think it has to do the mixed results they are getting.

01:57:54.760 It depends on whether it's exogenous or endogenously produced lactate.

01:57:58.880 So, of course, it would beg a question, which, again, if I were czar, George, if I were in

01:58:04.840 charge of NIH funding, I'd be throwing much more than just a paltry little RO1 at this,

01:58:09.640 because I think it's such an interesting question.

01:58:11.580 But going back to the TBI example, I would want to study as follows.

01:58:16.300 I would want to take a whole bunch of people with traumatic brain injuries or concussions.

01:58:20.460 So you've got a placebo group.

01:58:21.860 You've got a group where you just infuse more glucose and insulin, intranasal insulin and

01:58:26.980 glucose.

01:58:27.240 Another group where you just infuse lactate, you take them to equal concentration of lactate

01:58:33.060 glucose.

01:58:33.580 So you take them up to five millimole of both.

01:58:36.060 Then you have another group where you do that, but they exercise two hours a day.

01:58:40.540 Steady state.

01:58:41.440 Zone two, just enough to get their own endogenous lactate up to about two millimole and then get

01:58:48.480 that clearance.

01:58:49.180 You might argue that it's that exercising group that's also being given exogenous lactate might

01:58:55.040 actually have the best outcomes because they're getting the redox potential as well as the

01:59:00.620 lactate.

01:59:01.380 We thought about this.

01:59:03.100 So with a TBI patient, it's probably not in the cards for them to doing any exercise.

01:59:09.020 But what about functional electrical stimulation of a comatose patient?

01:59:14.340 I know a lot of people that have had TBIs.

01:59:16.980 I don't think they'd be up for strenuous exercise, but wouldn't they be up for even, you know,

01:59:21.160 Oh, you're talking about mild.

01:59:22.420 Yeah.

01:59:22.660 Yeah.

01:59:22.800 Yeah.

01:59:22.940 The setting was.

01:59:24.040 Sorry.

01:59:24.360 Yeah.

01:59:24.500 I mean, somebody who's had a concussion, but they're still functional, but they're suffering

01:59:28.020 the negative consequences of it.

01:59:29.640 Yeah.

01:59:29.780 Well, I think you would want to encourage mild exercise on these people.

01:59:34.260 I was talking about the.

01:59:35.860 Yeah.

01:59:36.060 Someone who's comatose with a significant CNS injury.

01:59:38.640 How do you raise lactate in them endogenously?

01:59:41.900 Mild electrical stimulation.

01:59:43.720 It all comes back to Meyerhoff, right?

01:59:46.160 That's the beginning.

01:59:47.880 Yeah.

01:59:48.140 Yeah.

01:59:48.600 We're back to frogs with electrodes.

01:59:50.800 We're beyond frogs with electrodes.

01:59:52.420 And now I think we were understanding that it's just not a muscle thing.

01:59:56.400 It's the whole thing.

01:59:58.040 And there's glycolysis going on.

02:00:00.440 Simultaneously, back to our story about the muscle fibers, a lactate producer, a lactate

02:00:06.540 consumer, exchanging chemical energy, our studies on healthy people with heart.

02:00:13.480 When we're exercising, our muscles hard enough, our gun will release lactate, but it's now

02:00:19.240 the favorite fuel for the heart.

02:00:21.280 Studies that Hashimoto did of executive function, he did these with Neil Secker in Copenhagen,

02:00:28.320 give people standard cognitive tests.

02:00:32.120 Then they exercise and build up their lactate.

02:00:34.880 They score better.

02:00:36.200 When they recover, their lactate comes down.

02:00:38.640 They go back to their basal scores.

02:00:41.160 It's brain fuel.

02:00:41.720 So think about the PE class, getting kids out to run around.

02:00:46.000 That is not blowing off emotional energy.

02:00:48.960 They're going to fuel their brain for the next hour or so.

02:00:52.300 Yeah.

02:00:52.480 It's so interesting because you just have to believe that there are too many factors in

02:00:56.840 there to identify the amount of contribution of each.

02:00:59.640 For example, we all know that when you exercise, BDNF goes up and clotho goes up.

02:01:03.540 And all of those things have pro-cognitive benefits as well.

02:01:07.280 So it's probably difficult to just assign all of the benefit of, there's a clear, obvious

02:01:13.260 benefit between exercise and cognition.

02:01:15.200 And what it sounds like is that there are many biochemical pathways that feed that.

02:01:20.860 And lactate may indeed be a preferred energy source.

02:01:25.100 There's one study where lactate was infused and BDNF went up.

02:01:29.940 So interestingly, I would love to see, I wonder if anyone has ever looked at lactate

02:01:34.040 infusion and clotho concentrations.

02:01:38.140 I don't know.

02:01:39.000 Yeah.

02:01:39.440 Well, George, this has been very interesting and illuminating.

02:01:43.680 I think that it's safe to say that so much of what I, and I think many others listening

02:01:50.320 thought we knew about lactate was at best incomplete and in some cases incorrect.

02:01:56.200 So I'm glad we have finally had a chance to sit down and go through some of this really

02:02:02.220 incredible work.

02:02:03.520 I do hope that somebody in a position of funding is listening to this and realizes that for

02:02:09.480 a relatively small sum of money relative to the type of money that's thrown at a lot of

02:02:14.060 biomedical research, we could really still answer some fundamental questions about the

02:02:18.320 fate of lactate and the interplay with glucose, especially the role of the liver and the enterocytes.

02:02:23.700 So I'm hopeful that with the reach of this podcast, that someone's listening and they

02:02:29.340 think, yep, this is a good use of funds.

02:02:32.140 Thank you, Peter.

02:02:32.900 I agree completely.

02:02:34.520 And thanks for the opportunity.

02:02:36.260 And again, my physician friends listen to you more than they me.

02:02:39.860 Now that they listen to you, they'll listen to me.

02:02:42.900 Now they're stuck listening to you.

02:02:45.000 All right.

02:02:45.700 Thanks, George.

02:02:46.680 Cheers.

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The Peter Attia Drive - August 05, 2024

#312 - A masterclass in lactate： Its critical role as metabolic fuel, implications for diseases, and therapeutic potential from cancer to brain health and beyond ｜ George A. Brooks, Ph.D.

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