#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.

28:28We've been teaching glycolysis wrong for a hundred years. Probably you learned that in junior high school or high school and physicians and scientists or smart people. If you hear it at the high school level and healer and in college and hear it in medical school. Well, that's what you think it is. It's an assumption that's really interlaterious. So that lactate that's formed enters the mitochondria and we have shown that there's a mitochondrial carrier for the lactate to get in and we call it the mitochondrial lactate oxidation complex and we have micrographs. We have light micrographs to show how this process works and the enzymes are there for lactate oxidation, but lactate is important as a fuel and as you describe early the first articulation of a lactate shuttle was by the quarries.

29:18They showed that a dog muscle made to contract with adrenaline or otherwise will release pyruvating lactate which will recirculate to the liver and become glucose. So that's the way to supply blood glucose during exercise. So the muscles are actually not only fueling themselves, they're fueling adjacent tissues and they're fueling the brain by this lactate shuttle or a curry cycle. Is it a velocity or a demand dependent process? In other words, if ATP is being demanded at a very high rate, is the body in that scenario preferentially taking the lactate back to the curry cycle, back to the liver to make glucose versus if the body has, quote unquote, the time it can make the long -term investment in getting more ATP per unit carbon by putting lactate into the mitochondria.

30:15Because again, the traditional thinking on this is we go down the lactate pathway when we are demanding ATP faster than oxygen can be supplied to the mitochondria. And that's why it's referred to as this anaerobic pathway. And if we have the time, if the ATP demand is low enough, that we can afford to get oxygen to the mitochondria, well, then we would always preferentially go down the oxidative phosphorylation pathway. So in the discovery that you are talking about, which again, I can't overstate how mind -boggling that is, what determines the path? That's this ADP to ATP ratio. That's what accelerates glycolysis.

31:00Yes. If the ATP to ATP ratio is low, which tells us ATP is being consumed quickly, does that drive lactate into the mitochondria or out to the liver? Yes. So recently, actually, not us, but others have shown that lactate activates the mitochondria. We have shown that lactate is a preferred fuel. Tell me what that means. What do you mean by lactate activates the mitochondria? An activate lactate dehydrogenase, the enzyme, and mitochondria, which allows the carbon flow to go into the mitochondria and for oxidation. Does that mean that it also amplifies other substrates flow through? So in other words, if you have a bunch of acetyl CoA hanging around from fatty acid breakdown, is that also being stimulated to run through the mitochondria at an accelerated rate?

31:50Good point to the contrary. So we compare glucose to lactate to fatty acids. So lactate is preferred over glucose in the brain and muscle wherever. The path of degradation of lactate is to generate the Cecil CoA. And that inhibits the enzymes to transport the Cecil CoA or fatty acids into the mitochondria. So lactate basically shuts the door, blocks fatty acid metabolism. So it inhibits an innoose, and I have shown this, a CPT one and two, the carnitine palm montate transporters. These are transporters that allow fatty acids to get into the mitochondria or oxidation. So yes, there is a competition among substrates, and lactate shuts the door for fatty acid metabolism.

32:41I'm struggling to understand teleologically why that makes sense, which just tells me I'm missing something because I would never for a second suggest my intuition should be better than a billion years of evolution. Why is it that we would ever want to shut down a substrate for which we have an infinite supply? Again, we're carrying around more than a hundred thousand kilocalories of fatty acid. Why wouldn't we always want to maximize our ability to utilize that substrate at the expense of something relatively finite as glycogen, which of course is necessary to even make the lactate? Well, that's part of the fight and flight mechanism.

33:27So in terms of our survival, what are we going to save the fats for, the tiger? Okay, I understand. Good point. Thanks for correcting my stupidity. So you're saying the reason Peter is if you are in a lactate dependent state Something has gone wrong. You're basically in a sympathetic state And you don't have the luxury of slow burning fat Exactly Okay, my fats are really important You can see this play out in and natural world We fight we hunt we escape and this is really Glacagin glucose dependent now our energy stores are depleted And that's in recovery is when we're going to use these fats.

34:08Well, this is very interesting. And now it actually makes more sense with something we're going to talk about later. But I'll plant the seed right now. We discussed this previously within you go, but I know we're going to talk about it again. You look at, you look at lactate levels in individuals at rest who have type two diabetes versus lactate levels at rest in world -class athletes. There's a significant difference. The great irony of that is the very low levels of resting lactate in the athlete mean that at rest they're quite capable of oxidizing fatty acids when sympathetic drive is low and demand is low.

34:48And yet paradoxically, the individual type two diabetes who would most benefit from fatty acid oxidation is presumably now inhibited in doing so because of those elevated levels of lactate. Is that probably a fair assessment? Yeah, that basically shuts down the fat metabolism, but think about this. This is my old thinking. That lactate there is elevated because of lack of disposal. Not necessarily production. It's there because of failure to dispose. My new thinking is the body in a diabetic situation has a hard time taking up glucose because of those insulin signaling and the glute -4 mechanism is not working very well.

35:33So think about lactate not as a stress but as a strain. So now we're going to bypass this inhibition of glucose uptake. We're going to provide actually the preferred carbohydrate. And we see that not only in diabetes we see that in the heart after MI. Lactate is a preferred fuel. We had an MI because we had a Schemia and we had a blockage. Why would the heart prefer fast -acting fuel versus a slow -acting fuel? Because it needs energy because it needs to survive. How does one measure the kinetics by which one mole of lactate versus one One mole of glucose versus one mole of fatty acid can produce ATP.

36:21What are the tools that allow you to make the observation that one fuel is preferred over the others or that the kinetics of one fuel are faster than that of another? Thank you for that question. We use isotope tracers to do that. When our first experiments was rats to give carbon -14 labeled lactate, then we would go went to the tissues and tried to measure it. It's all gone. It's been burned. It had into the atmosphere. Meaning the only place that that C -14 carbon would be found now is in carbon dioxide if you had a calorimeter. Yeah. We have done a number of experiments in collaboration with others or just in our own.

37:01We developed a technique called the Lactate Clamp Technique. And it's analogous to the glucose clamp technique, which some of your physician listeners will know about, that's why you raise those glucose to a certain level, and then you can study the production versus disposal. So we infuse lactate up to 4 million molar, and others have raised lactate even to higher. When we do that, we can measure the arterial venous difference for glucose uptake, and it's suppressed. In a study with UCLA, we did some PET scanning, and this is a fancy way to say we can take a picture where glucose is being metabolized in the brain.

37:40This is done with a traumatic brain injury. Patient and you can see there's a blockage for glucose to get into the left frontal lobe in this patient. The next day we infused lactate to formally molar. It completely stopped the glucose uptake. No glucose update in a PET scan. I can show you the image. I guess my question is this, George. So, I mean, that clearly demonstrates that lactate is preferred over glucose. But I think the jugular question is, is the brain getting more ATP from the lactate as a preferred fuel than the glucose, which has one area of hypoprefusion? In other words, are you able to, by providing the preferred fuel, actually get more energy to the neurons that are injured.

38:33A colleague in a science peer -medjust ready in Switzerland has developed what he calls the astrocyte neuron lactate shuttle. And that's really sparked a lot of interest in metabolism astrocytes. So for years, I taught, maybe you did, and you believe that glucose was the exclusive fuel for the brain. We know at a minimum that beta hydroxybutyrate would also be another fuel for the brain. It could be but not of glucose is around or lactate. In the injured brain, for some reason, maybe there's a block at the splitting enzyme in the glycolytic pathway where you know the injured brain needs glucose, but it only takes up maybe 50 % of what's typical.

39:19So the brain is in a metabolic crisis after an injury. globally it is. So there's some neural networking which just stops glycolysis. Traditionally what physicians would do is give glucose, fuse glucose, and the glucose uptake, well the tabo is blocked so the glucose doesn't get in and doesn't do anything. Or give insulin. Yes, intranasal insulin was one of the tricks there to try to drive more glucose uptake. The brain doesn't express That's not going to do much. But now we have, instead of the six carbon molecule, we have a couple of three carbon molecules, and the lactate transporters are highly expressed in the brain.

40:01And we know that under normal circumstances, what's happening is that the glucose is coming in, being taken up by the astrocyte, spayed into lactate, which are bathing the neurons in lactate, and lactate is the fuel for neurons. By the way, I misspoke a second ago though, George, I could have sworn George K. Hill demonstrated in those very famous fasting studies circa 1960s, 1970s that even in the presence of glucose, the brain was still taking up significant beta hydroxybutyrate. If I'm not misremembering this, these subjects were fasted for a very long period of time. I mean, these were 40 -day water -only fasts.

40:42So these individuals had beta hydroxyputerate levels of four to five millimole, which actually exceeded glucose concentration. By this point glucose concentration would have been about three millimole in steady state. So for folks listening to us who don't think in European terms, three millimole of glucose means these people were walking around with a blood glucose of 55 milligrams per desoleter. But it really never went below that. So that's obviously pretty hypoglycemic. That's still 60 % of what you would walk around with normally. And glucose was meeting about 50 % of their brains demand.

41:21And about the other 50 % was coming from the BHB. So at least in that situation, the brain would split fuels. Now of course, I don't know that K -hill was measuring it, so we just don't know what lactate was doing there. But it's an interesting observation that the brain would split its fuels in the presence of BHB and glucose. So I'm going to agree with you to the extent that there's competition amongst substrates. More glucose, less fatty acids, more fatty acids, vice versa. Okay, ketones come in by the lactate transporter. So the monocarboxylate transporter allows ketones to get in. Meaning BHB enters this cell through the same MCT transporter that would bring lactate into the cells.

42:05We did this early on, and it's a greater preference for lactate over beta hydroxybutyrate. So if the concentrations were the same, the transporters would move, lactate, as opposed to beta hydroxybutyrate. In other words, if we could do a thought experiment or actually a literal experiment, so let's say you could clamp everything. You could have a person walk around with four millimole of glucose, four millimole of beta hydroxybutyrate, four millimole of lactate, and you're peripherally clamping those concentrations. So you have equal concentrations of three fuels that the brain could use. What is your prediction for neuronal uptake based on that scenario?

42:49If it's an un -injured person, yes, let's start with that. The preference would be for glucose and lactate. And would it be roughly equal amounts of those two in an un -injured brain? Roughly, probably. Okay. We've published on the reworked with UCLA neurosurgery. We did these experiments with Diaduroclucose since 13C lactate, so probably about the same. Now let's talk about the injured brain. So now you have a TBI patient and you're doing the exact same thing. You're infusing equal concentrations of glucose lactate and BHB. What would you think everybody knows clinically that glucose is going to be suppressed?

43:27How much of that is made up for by the lactate versus the BHB? Yeah, so if lactates are around, it's going to suppress the BHB. So lactate could be the dominant fuel in the injured brain. Yeah. So the implication of this at the risk of stating the obvious is we should be giving brain injured people intravenous lactate around the clock to heal their brains. I think so. How many people are aware of that? Agree with that. For various reasons, we lost our collaboration with UCLA neurosurgery, but they were in stage to clinical trial and infusing lactate. And they weren't the only only ones as a group in Switzerland who preferentially gives hypertonic lactate to TBI patients.

44:11They appear to do better, but we were hoping to have a clinical trial, multi -center trial demonstrating the use of lactate as an augmentation to glucose in the TBI state. But I don't know what the status of those studies are, but there was a stage two clinical trial that started at UCLA. George, has anybody labeled lactate with FDG, the equivalent of an FDG, so that you could do a PET scan and actually demonstrate significant uptake of lactate in a brain and then actually do that experiment in an injured brain? Because what I'm imagining is everybody has seen the images of the injured brain under standard FDG PET where you have the hypo perfusion in the area.

44:56And by the way, this is relevant in diseases like Alzheimer's disease. This is relevant in dementia where we see hypo perfusion of glucose. But it would be interesting if it hasn't already been done to see what the uptake of lactate is if you can put an F18 on to lactate, which I assume is a trivial task. I don't know about that, but our colleague here at Berkeley, Tom Buttinger, really helped develop pet help make an MR clinically relevant. He did experiments with carbon 11 lactate. In the pet scanner it gives a signal as does fluoride -oxyglucose. So that way you could see lactate taken up by the brain.

45:36The difficulty with those experiments I think the half -life of carbon 11 is on the order of minutes, 20 minutes. So there's a first experiments involves somebody in the cyclotron making carbon -11 lactate, putting it into the lead -line station wagon, driving it down, running it through a column to remove the strontzium 82, and then infusing it into an imaging the brain. So it's possible with carbon -11 to do that experiment. But any reason not to just put F18 on to lactate? Is that chemically not feasible? I haven't thought about that. It seems like that would be a very interesting experiment at a minimum just to generate a hypothesis that says we can fill an energetic gap by Using lactate and simply observing a difference in perfusion pre and post lactate infusion I'm making a note If it hasn't been done, I'm sure I'm missing something obvious about the chemistry of it Buttinger would do it when he would do the experiments with glucose or lactate.

46:39He also would give ribidium -82, which is a marker of flow. So you would want to do exactly what you described. You would want to know the uptake relative to the flow. So if the flow is depressed in an area, then you would expect the uptake to be less. And so you would be in the buttinger method. You need to do two isotopes simultaneously. And that's really tricky in how to do clinically. Basically, it's really as you describe could be a great experiment, but getting it to work in clinical centers would be a real trick. What about just in rodent studies of hypoperfusion? I assume that would be an easier place to look at a TBI model where you ask if lactate can rescue the animal.

47:23We could just do that even without a tracer. Exactly. That's my point. You could get around the whole tracer component by just doing that. But is there any issue with infusing lactates at higher concentrations? Is four millimoles sufficient or is there any reason you couldn't put in six or eight millimoles? I think our friends in Switzerland have got it up to eight millimoles. But then you know, you're using hypertonic lactate. So what you can give vascularity, people need to understand it can't be too concentrated to make the blood really affected poorly. When we give patients like an intravenous bag of lactated ringers, what's the concentration of lactate in that?

48:03It's really slow. Yeah, okay. What they do is they do half molar sodium lactate. And we need to understand we have half molar sodium, it's half molar sodium and half molar lactate. So the osmolality is twice that. It's a thousand. That's sort of the upper limit of what you can give safely and trivasculate with our causing flabitis without causing a creation of the red blood cells shrinking and getting all distorted. Yeah, makes sense. But for you can maintain, you can clamp a person at four millimole quite safely and easily. Yeah, and I think, you know, with the idea was to do that for a couple hours a day, not continuously.

48:45Again, because we would have to make sure that kidneys were not affected because we're giving a lot of sodium. So, that was going to ask you about that. So, what's the manner in which the lactate is delivered? In other words, what else has to be delivered with it to balance the solution? Lactate anion has a negative charge. So to put it into the blood, you need to have something with a positive charge. And so the major cation in our blood is sodium. So what's used is sodium lactate. So in our studies, we could clamp to 4 million more and hardly raise the sodium level in the blood. So we thought that would be an approach that would be reasonable to work with a patient.

49:29But again, you are going to be giving sodium, so you have to make sure that in the patient to have good kidney function. Now I see you're making notes. That's good. You have no idea how many notes I make here, George. The highest lactate I've ever measured in myself is about 18mm. Obviously after a very intense bout of exercise, not surprisingly anybody who's measured lactate in themselves, anything over 10 is a very, very uncomfortable situation to be in. Let's go back and talk about what's going on and where my discomfort comes from because it's not the lactate that's causing me discomfort, correct?

50:09No. Lactate is there to moderate. It's a strain response. It's helping to protect you. But you probably have a severe acidosis. Yeah. I'm feeling like I'm about to die because my pH is probably 7 .05 or something like that. Yeah. And the guy asks you a question, are you ever hungry after one of these episodes? Not at all. In fact, It's usually you're about to vomit if you don't actually vomit. Yeah, so actually lactate crosses the blood brain barrier and works in the brain in the hypothalamus to inhibit your appetite. So those of us, you know, have run 440 yards or 400 meters, we're not hungry for three hours.

50:53Right until that lactate level is cleared, which is really a good reason people are written about this recently. It inhibits appetite, lactate, suppresses, It works directly in a CNS, so an advantage of doing an exercise, not like that one you did Peter, but getting lactate up to maybe three or four million more actually helps assiate people. I know there are people say, well, I exercise and I'm really so hungry after what's well. Not exercising hard enough. But if you do raise lactate, it will cross the blood brain barrier. it will inhibit crellance, secretion, and it will suppress the appetite.

51:33That's a very interesting point. I know that people who are listening to this who are familiar with lactate testing, which I know is a bit esoteric. There is a fundamental difference between having your lactate at 1 .5 millimole or 1 millimole, which is where it might be if you go for kind of a risk walk versus being at 4 millimole, which is not a level you can sustain indefinitely, but it's also not so strenuous that you could only do it for a few minutes. A fit person could hold that level of exertion for 30 to 40 minutes. I think listeners will know that four million Mueller has talked about a lot.

52:09Yeah. Let's talk a little bit about differences between athletes and non -athletes, which again, I think becomes very illustrative because they're simply different metabolically. It's not just that the athletes are stronger and the non -athletes are not. But what's happening in terms of fuel partitioning that differentiates a highly, highly trained aerobic athlete like a cyclist with someone who's got insulin resistance? What are the differences in their ability to utilize fuels? Great. So let's back up just a little bit and go back to the mitochondria. Mitochondria are the sinks or the disposable units.

52:50So in any thing, fluxes, as you described in the body like carbon flux, it has to go from a production or entry site and has to go to a removal site. And the mitochondrial network is a removal site. Now when a highly trained athlete exercises, and here we need to talk about relative or absolute power output. So let's say 65 % of VO2 max or 65 % of effort for an untrained person, well, that's not very much exercise really. They'll get to 65 % of VO2 max very low power output. 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.

53:33And as you described earlier, it's recirculating to the quarry cycle to support plug glucose. So even if you just measure the concentration, you don't have the whole story. You don't have the flow, you don't have the flux rate, you don't have the partitioning sensation. Now, if you take that same athlete now and you push him to a lactate that elicits maybe 6 or 8 millimolar, they're going to be really a lot of differences there. You've exceeded their capacity of the mitochondria to clear lactate. And also, you're probably going to have shunting away from the gut. This goes back to something we mentioned in passing.

54:12So gluconeogenesis to making glucose from lactate depends on good liver blood flow. When you start going really, really hard, all you, your blood is going to go to your muscles basically and you're going to clamp down and not going to profuse the liver. So now that gluconeogenesis goes down regardless of who you are when you take the liver and the kidneys out of circulation. And of course those are major organs of lactate disposal as well. I said 20, 25 % earlier. If you eliminate those by basically clamping them off, then the lactate level is going to be higher. I want to go back to something I asked you earlier, but I want to make sure I captured what you said.

54:52As the individual is increasing energy demand, they're making more and more lactate, is ADP or ADP to ATP helping to determine when the lactate is going in the mitochondria versus back to the liver because in the scenario you described where energy demand is going up and up and up and therefore Perfusion is going down in the organs that are able to recirculate lactate You would think that the body would just say okay, no problem. I'm going to shovel more lactate into the mitochondria I've got a perfect engine here to generate more ATP In other words, why is that a problem that the lactate now can't be cleared as efficiently through the gluconeogenic pathways?

55:43Yeah, so go again, the example of the athlete. When we train, we increase our mitochondrial mass, maybe 100%. If we train, we'll raise our VO2 max, maybe 10, 15%. There's more plasticity in the muscle to increase the mitochondrial mass. And I think really that's the key to any of success with his athletes. He trains them so they increase their mitochondrial mass How much did you say you increase mitochondrial mass by? Well, you can double it over what period of time? The first study on this appeared in 1967 the journal Biological Chemistry was in rats who was by John Halazi And you could all over the period of several weeks of training rats.

56:27You could do that But after that, we extended those studies a bit with Kelvin Davies when he was here and again saw a doubling of the mitochondrial mass. Others have looked into the muscles of athletes and found that they have more than twice the mitochondrial mass of the average person. And that, of course, is a lot selection. Sorry, just to be clear, this is mitochondrial density. So for one gram of vastus lateralis in an athlete versus one gram of vastus lateralis in a non -athlete, you'll see two X the mitochondria. You'll see two X the mitochondrial mass. Yeah, not necessarily the number of mitochondria.

57:09And how is that conveyed? Is that larger mitochondria plus more mitochondria that amounts to that doubling? We talk about the mitochondrial reticulum. Think about a tree budding and branching out leaves. So if you do a thin section, you'll see, and you do point counting, one mitochondria, two mitochondria, and three mitochondria, and a thousand mitochondria, but they're all part of a network. So what you have is a bigger energy delivery system that goes from the cell surface deep within the fiber through this network. Some people call it the cellular energy power grid. And to your point, which is, has the experiment been done to demonstrate the causality of exercise there?

57:54In other words, do we have the experiment where you take untrained individuals? Do the muscle biopsy? Compute mitochondrial density, mass of mitochondria per unit mass of muscle. Train them for four to six months, repeat the biopsy, and see if the training is leading to the doubling rather than just saying, well, athletes are athletes because they have more mitochondria? Now it works both ways. If you're born with that and you go into athletics, you're successful. That's right. Yeah. And then if you're not, and you become a professor, that's sort of something I'm curious about. It goes up proportionately.

58:34And interesting, all the enzymes that are as far as we can tell, all the constituents that make up this mitochondria network go up proportionally. So you get twice as much crep cycle enzymes, twice as much electron transport cycle enzyme. You basically activate the whole system. So George, I was taught the following, which I'm now almost assuming is going to be at best in oversimplification and at worst I might just be abjectly wrong. You mentioned something called MCTs a moment ago. Do you want to tell folks what an MCT is? Hey, I had to explain this to my wife Rosemary, the sports medicine doctor, what's an MCT?

59:13Well, we were looking for the lactate transporter protein. And we got scooped. Somebody found it and she called it. It was Dr. Christine Kim Garcia in the Goldstein lab in Dallas and it's a Nobel Prize lab. And she found they were looking for transporters of things that contributed to cholesterol metabolism. And she found this protein that she didn't know what it was. And she found out it was a lactate transporter. And so they were called monocarboxylate transporters. And now it's like the glucose transporter field where we have the first isoform and the second one and the third and the fourth, they're actually more than four now that have been discovered.

59:57When was the first one? About 2000. So what I was taught, again, we'll see a far off base I am, was that one of the benefits of training was increasing the density of MCTs. So in other words, the harder I trained, the more I increased the density of these MCTs in my muscle cells, and what that allowed me to do was produce more lactate, but get it out of the cell and back to the liver. So imagine a little cartoon where I've got a muscle cell, I'm untrained, and I've got 50 MCTs. After training, I've now got 100 MCTs after a period of time, not acutely, but years of training or whatever. And therefore, I can now make twice as much lactate and get that lactate out.

1:00:53Now, of course, all of this was predicated on the model that said more lactate in the muscle is bad because with lactate goes hydrogen and hydrogen inhibits performance. So again, that was all viewed through that lens. But was there any truth to the idea that as we train more, we increase the density of MCTs, which if nothing else, I assume, would give us more flexibility in this lactate flux game. Yes, we've done this in animals and we've done it in looking at trained and untrained people. And we can see an increase in the abundance of the MCTs. That helps two ways because getting lactate into the mitochondrial network requires an MCT.

1:01:38So we were bold enough to look in the mitochondria and find MCTs. So people think, well, it's just on the cell membrane and it's good for export. And that's true. But in oxidative muscle fibers with the abundance of transporters, many of them are in the mitochondria. So the lactate will move into the mitochondria as well as can be exported. So then we see a difference between fiber type. Fast, This glycolytic fibers will be pale in color. They are pale because of less hemoxygen compounds. They'll have less blood flow, fewer capillaries per fiber. They'll have less myoglobin and mitochondria are the color of liver, or vice versa.

1:02:24They're the color of mitochondria. Those fibers, when they may be to contract, have lesser mitochondrial density. They will export lactate. But they can export it to an adering red fiber. So we call this the cell cell lactate shuttle, where a fast, glycolic fiber produces lactate and it's consumed by an adjacent fiber and never even appears in the venous blood except as CO2. I'd never heard that, George, so just to make sure the listeners are following and that I'm following. We've had many podcasts where, of course, we discuss type 1 and type 2 muscle fibers colloquially referred to as fast twitch and slow twitch fibers.

1:03:05The slow twitch fiber, the type 1 fiber, is the red fiber. It's the fiber that is dense in mitochondria. It is the one that has the capacity for oxidative phosphorylation. It is less powerful but much slower to fatigue. Then you have these type 2 fibers and I'm oversimplifying a little bit because there are subtypes of of them I understand, but the type 2 fiber, it's a more contractile, it's a more powerful fiber, twitches a little faster, but it's very fast to fatigue. It's the white fiber because it is lacking in the mitochondria. Is it outright lack mitochondria? And basically, it's just a pure glycolytic fiber, correct?

1:03:44No, there are mitochondria in there. There are, just a much lower density. Lower density, yeah. Yeah. So what you just said a second ago was, as those cells accumulate lactate, they realize that their neighboring type 1 cells can make even more use of the lactate, given that they have a greater density of mitochondria. So they'll shuttle the lactate from the 2's to the 1's. Is that correct? Yeah. That's actually part of the discovery of the lactate shuttle. So early on when we started doing the studies on rats and you see 14 lactate and triad glucose comparing the flux rates of the two and looking at the various fates of where the carbon goes.

1:04:26We knew that there was an exercise with large flux, but from a tracer itself you can't tell where. So a colleague of mine at UC Irvine, Ken Baldwin did his studies on rats and he made them exercise hard, then he measured the lactate levels in blood and red muscle and in white muscle. So a rat made to run hard has a very high level of lactate in the fast glycolytic type 2 fibers. Can you give me the approximate concentrations in that type of an experiment between blood type 1 and type 2? Yeah, so I'll give you just the enough, finish the analogy, we can put some numbers on it. So then he measured the lactate level in the arterial blood and of course it was lower.

1:05:14And the red muscles, the lactate level was lower than an arterial blood. And that gave rise to the idea that the fast fibers were sharing lactate not just to the venous blood, but to the red fibers. They were adjacent. So the numbers I'm trying to remember, this is back 30 years what the numbers were, and the fast fibers would be something like 10 to 12 million equivalents in the blood. It would be four and then the red fibers would be three. But the four was in venous blood, correct? In blood? No, that would be arterial blood. That was an arterial blood. Got it. So that gave rise to this idea of the shunt over a shuttle.

1:05:53Some people call it a shunt from white fibers to red fibers. And as you described, it's easy for the white fiber to export the lactate, but it will export it in a three -dimensional sense, being surrounded by slow red fibers who can oxidize lactate. When did you first find MCTs on mitochondrial membranes? What year did you first publish that? About 95. So what percentage of the relevant scientific community acknowledges that now? Is it taken for granted within your world that is completely settled and is it just that hasn't made it out to any of the textbooks yet? Tom Faye and I are revising our textbook.

1:06:37We're going to get it right. But yes, there's been a stonewall silence. For instance, in Science Magazine, they published papers on the mitochondrial pyruvate transporter. Two papers simultaneously about this discovery of the pyruvate transporters. Previously, we had shown the mitochondrial lactate transporter. It wasn't even cited. Neither the editors or the reviewers knew about it. So now things are changing, Peter. So actually right now, there is a lot of interest in lactate. These are difficult questions to answer, so I'm sensitive to that. But why do you think something that was discovered 30 years ago that appears quite germane to the physiology of everything, but if nothing else just through the physiology of exercise, but it clearly extends beyond that?

1:07:25Why do you think that this isn't more widely understood even in the physiologic circles that you travel in? I think I said it earlier, people who do science and medicine are smart people. They learned it a certain way and that's their set point. But I tend to differ between scientists and physicians. And I say this is no disrespect to my profession. I think that that makes more sense at the physician level where, look, medical school is drinking from a fire hose. It's almost beat out of you to question things because you frankly don't have the time, right? You've got two years to learn so much.

1:08:00I would have to think that that's quite different for people who choose a scientific pathway where discovery, questioning orthodox beliefs, that is the name of the game. Is there something I'm missing here? So maybe there is a difference between science and medicine in this regard. Given the opportunity, I will talk to, for instance, the Washington Theresec Society and go to a meeting and talk to the docs. Because when they see lactate, they start infusing bicarbonate, or they give oxygen. In the medical field, there's a character, maybe someday you would really enjoy meeting this. His name is Ronaldo Belamo.

1:08:39He's a world renowned physician, emergency room physician, and he's written about the fact that pulmonologists need to be more like exercise physiologists with regard to understanding lactate metabolism. He challenges his colleagues to do that. Belamo was a big name in the field. He's been a lot of inertia in this, but I think we're getting some momentum. I want to use an example, a real life example, to have you explain the difference in metabolism between two people, me and one of my friends. I'm not going to name him, but I already talked with him about maybe potentially telling his story. So there's a friend of mine who is really an exceptional cyclist.

1:09:23Okay. He is probably in the top, he would easily be in the top 10 amateur cyclists in the country. Okay. So again, for people who you would understand these numbers, but I should just throw out some numbers so people understand what we're talking about. So this is a guy who's in his late 40s and he can still put out 5 .3 watts per kilogram gram for an hour. So that's what we would call his functional threshold power. So when he is on a bike, he can put out 420 to 430 watts for 60 minutes. He weighs about 80 kilos. I understand that people listening to us might not understand what 430 watts feels like, let alone what it would feel like for an hour.

1:10:12But I know you understand this. And I think there are enough people listening to us that understand this, that we can still justify the time on this topic. So I just want to explain to you, here he is, this incredible cyclist, and actually a great triathlete as well. So great swimmer and runner. But really on the bike is where he shines. And these are numbers that at his age are almost unheard of, and frankly would still be at the levels of a low level professional cyclist. Okay. Contrast that with me, I'm a very mediocre cyclist. even at my best, my FTP was lower than his at my very best. And today, I don't know, my FTP, if I'm lucky, might be three to three and a half watts per kilo, very low.

1:10:57He was over at my house last week, George, and we were lifting weights together. Now, he doesn't lift weights anymore. All of his energy goes into cycling, and I do everything. I'm kind of a jack -of -altred master of nothing. So he was lifting weights with me. we were doing some leg exercises. And 80 kilos is pretty big for a cyclist. So he doesn't look like a tiny little cyclist, especially in the legs. And so I put him on a machine where I was doing some squats. I just assumed he would start at a weight very close to what I was doing. A little bit less. I maybe had him at 20 % less weight than me.

1:11:35And I said, tell me how this feels. And he said, oh, there's no way in how I could move this. We ended up having to take it down to half the weight that I move for him to be able to do the exercises. And I was really thinking to myself, this is a very interesting lesson in physiology, because his legs are so superior to mine in generating absurdly high wattage for a long period of time. Yet, when I'm asking him to do this different type of task, which is clearly more recruiting of a type two muscle fiber, he doesn't have the contractile force. 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.

1:12:20And yet you're so superior in this other way. And what we got talking about was the differences in our metabolism, which is clearly he is able to do something. Because again, what's more interesting to me is not that he's not as strong as me on a squat. It's how much stronger he is than me on a bike. So, that's a long -winded background, but now I want you to imagine you had muscle biopsies of both of us. Now you've got his quads and my quads. What is it about him that is allowing him to hold 430 watts for an hour? 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?

1:13:11And that's really the point I'm trying to make. What is it that he is doing that is so special and that which all exceptional athletes can do? Well, not all. It's sports specific. Yeah, all exceptional cyclists, right? Or endurance athletes. He described it earlier as the flow of energy. And so I would guess that he was mostly type 1 fibers. These red fibers that are highly profused that have the mitochondrial reticulum really highly expressed. So he can have a high carbon flux and sustain it. He can generate large amounts of lactate and clear it. And some of the lactate probably goes into his blood and helps maintain his blood sugar level.

1:13:55So the fact that he can't exert as greater force, as you probably means he's got the slow red fiber type and he also hasn't learned how to do it. We probably could work with him a couple of times he might improve, just jump up a little bit by learning. Yeah, by the way, I want to make that point. I am totally confident that in three weeks he would be doing is the same amount of weight than me. Again, the point is not so much that I don't want to suggest that he wouldn't be as strong. 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. That's the bigger point, even though, ostensibly, I'm stronger.

1:14:38Yeah. We're talking about different metabolic systems, or a metabolic system surplus, versus a contractual entity that co -exist together in the same muscle. Of course, one feeds the other. So in his case of cycling, his muscle power output is limited by the carbon flow that he can sustain. Oh, okay. So thank you. That's exactly where I want to go with this. How much is he limited by carbon flux input versus metabolic byproduct output? In other words, why isn't he at six watts per kilo, which would make him among the best cyclists on planet Earth? Well, I think it's a matter of degree. I think if we looked at a really top cyclist, we would find that they could clear -lactate more efficiently than he could.

1:15:29And a lot of that would have to do with his fiber type and the mitochondrial mass that they had. I see so in the final analysis, you think that what differentiates the absolute best performers on planet earth is going to be lactate clearance? Yeah, or we're talking about carbon flux because that glycolytic flux goes to lactate. And nobody knew that until we traced it, that gets oxidized. So, what do you have? Is this production versus disposal capacity? And he's got a great disposal capacity. 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?

1:16:26We haven't done this with trained athletes, but we've done it with some people who are physically fit and recreationally Compinent. So you can see Lactate very high in the venous effluent of a working muscle. I'm gonna just make up some numbers 10 to 12 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. So there are lactate paruvate conversions happening in the blood and part by the red blood cells and in part by the lung parankyma. Because all the blood goes through the lungs.

1:17:10Yeah, it's about to say when you sample that venous blood at 10 to 12 millimole, wouldn't matter if you're doing that pre or post portal vein, 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? That's a good point. It wasn't a mixed venous sample, but we had a femoral sample. So in part delusion. So you're doing it pre -liver, obviously, so you're getting the absolute peak level of lactate. That's very interesting, George. I never thought of this.

1:17:47All 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. It hasn't had a hepatic pass It's had a hepatic dilution and it's gone through the lungs So that's potentially a double reduction in lactate. Yeah Well, that's interesting. 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?

1:18:28It hasn't been explored much. We just have a couple of papers on it. Both are by Matthew Johnson and another by Greg Henderson.

1:18:41You know, Matt He's a research scientist at Texcom. May they make the glucose analyzers? Yep, maybe I have crossed paths with him. I know some people at Texcom and, oh, actually, no, no. I take that back. I do know Matt Johnson. That's exactly right. He did a postdoc in your lab. He was a graduate student. He was a graduate student, yep. Yeah, and he was a postdoc at Bush Rehner at the Mayo Clinic. So he's really highly trained. His dissertation was just infuse femoral venous lactate and look on the arterial side. and you can see there's a huge change in concentration. And we attributed that to the pulmonary function.

1:19:17You're pointing out we probably missed the hepatic delusion effect. Yeah, and wouldn't there be a way to, I mean, wouldn't you just be able to use like C14 lactate infuse it and then look at how much C14 glucose you're forming in the liver? That would actually tell you what concentration of the lactate is being extracted by the liver, right? Well, and people we've gone C13, which is stable, non -radioactive. Okay. Yeah, yeah, yeah. So, C13 glucose production in the liver would give you that fraction. And of course, if you did this in direct calorie or indirect calorie rather, you could measure the C13 CO2 coming out of the lungs, right?

1:20:03Yeah. Well, it gets tricky because measuring CO2 content is really hard because this is a CO2 is carried as by carbonate, carbamino. Its temperature -dependent, pH -dependent. We've done some of that, getting what's called the RQ, but we haven't done it as you describe it, Peter. 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, the mass balance tells us it had to go somewhere. So it's either some of it's going to make glucose in the liver and some of it is being expired. Yep, and all our studies we get oxidation is about 75 to 80%.

1:20:46So your initial hypothesis about really we're talking about carbon flow, energy flow, the lactate can float around the body and be removed in diverse ways. It can be reconverted to glucose, which then gets oxidized, or it can be just oxidized directly in the muscle or in other muscles. So for instance, we're working really hard. Maybe we see this in cross -country skiers. Our arms are highly glycolytic. Release a lot of lactate. Our legs are redder, more oxidative. So here we are. We have polling, generating lactate, going into the arterial circulation, profusing the muscle, fueling the muscle, fueling the brain, fueling the liver.

1:21:32That's very interesting, George. 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. It's a several minute effort. If the goal was how high can you make your lactate, that's the exercise to do it, maybe followed by rowing. I just assumed it was because you had more muscles involved. I didn't know about what you just said. 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.

1:22:21Is that, do I hear you correctly in that regard? Ask somebody if they like changing a light bulb. We get tired right away. How did I not know that? I feel like what have I been doing for the last 30 years? Clearly not learning. You haven't been changing light bulbs. Such a good point. Yeah. The upper body really can get pretty fatigued relative to lower body. Super interesting. So if we look at fiber typing and you know, but we're evolved to use our arms in different ways. We use them at a low level and at some point maybe we want to talk about the size principle. So our type 1 fibers are easily recruited to low level things, help us writing, taking notes, or using type 1 fibers.

1:23:09But now if we have to do lifts something heavier now we need to recruit those type 2 fibers. And working overhead we're using type 2 fibers and we really having clearance problems. So that's really fatiguing. Let's talk a little bit about cancer. We alluded to it at the outset with the Warburg or Vorburg effect, where cancer cells seemingly in the presence of unlimited oxygen still seemingly choose a metabolic pathway that avoids the mitochondrial, though I'm going to come back and ask you about that now, because we're going to call everything into question. But again, let's just go through the traditional thinking.

1:23:51Traditional 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? They don't want to use fatty acids. They just want to use glucose and they just want to make lactate. I know that the first hypothesis put forward there was, oh well, cancer cells must have defective mitochondria. That's why they can't use anything else. That's why they have to make so much lactate. And that hypothesis doesn't seem to be the case. And it seems that there are other reasons famously, Lou Cantley, Craig Thompson, and I think at least one other colleague wrote, I was Matt Vanderhiden if I'm not mistaken, that the cancer cell is not optimizing for ATP.

1:24:36And it doesn't care that it's being inefficient in making lactate. It's optimizing for cellular building blocks because it's a cell that has to replicate without stopping. and that's why it's doing that. It's going down the lactate pathway to generate more carbon, nitrogen, whatever else it needs to actually build a cell. 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. Well, maybe that's a Nobel Prize, right? Understand that. To rephrase that, I think the answer has been staring us in the face.

1:25:14cancer is a problem of glycolysis. Unrestrained glycolysis in I, in Io and I, have some papers together, and in fact, he was kind enough to put my name on his most recent paper, which is now being reviewed for publication and has to do with the expression of certain glycolytic enzymes. And I don't want to spill Ineos beans here about this has to do with the expression of glycolic enzymes. It looks as if in all the various stages of cancer, progression, lactate stimulates those. So Ineos now looking at sort of the mitochondrial basis for that. So to repeat what you said, cancer cells do have mitochondria.

1:25:59We've seen that, other people have seen that, and they're capable of oxidizing different substrates, including lactate, but the lactate is generated, the high lactate production seems to stimulate a lot of things that are untoward in cancer. And one of the papers that any of, and I first wrote, was to look at all the adaptations and muscle, the training, and look at where cancer cells differ from the norm, and then look at those points of difference between training and cancer and it has to do in part with lactate clearance. So those cancer cells do generate a lot of lactate and the lactate is injurious in those cells.

1:26:44It would be easy to listen to that statement and say a cancer patient should never be exercising and that might be one implication, although another implication might be cancer patients need to be exercising because they need a sink for all that lactate. So which of those two do you think is more accurate? I used to believe the first one. Oh my gosh, we don't want to generate lactate, but we thought more about it. Well, lactate is low because you clear it. And when you do regular exercise, you increase your clearance capacity. And so in that sense, if lactate is carcinogenic by removing it, you'll lessen the chance for carcinogenesis.

1:27:29That's just simply kind of remarkable statements. First of all, that lactate is carcinogenic is kind of remarkable, and then it feeds to the difference between concentration and flux or flow. This is the most, I think, in physiology, one of the hardest things for people to wrap their mind around. I'll give you another example, but it's something near and dear to my heart, right? which is you look at intramiosellular fatty acids. Why is it, I mean, you know the answer, but I'm leading you down the path for the listener. Why is it that both the best athletes in the world and the most metabolically unhealthy people with type two diabetes, both have high amounts of intramiosellular fat?

1:28:11Well, of course, the difference is in the person with type two diabetes, it's static, It's stagnant, it sits there, and it is one of the causative drivers of insulin resistance. Yet in the athlete, it's a carbon flow. It's moving. It's the difference between a stagnant pond and a flowing river. And I think we get into this trap with lactate, don't we? Where we measure concentrations and we just assume high is high, low is low, high is bad, low is good. But we can't measure flux without the complex instrumentation you use in a lab. Yeah, that's true. And just elaborate more on the marathon or paradox if you do an EM and you find a mitochondrial network, you'll see a fat globule right next to it.

1:28:55The potential for fat oxidation is great. In our work, we've done some MRS and MRI, and we've looked at athletes. They don't use much fat during exercise, but in the recovery period when glycogen is low that's the period of fat burning. Does fats there are preconditioning, prepositioning, fuel supply in recovery when glycologists switches off and people start to relax? So you write about this whole idea of flux. Also in diabetes glucose is high. Why? Was it produced too much? You're not cleared. Right. It's a great point. Yeah. So that's easier to explain with glucose than with lactate people more readily understand the dynamics of appearance versus disappearance The level is informative, but it's not the whole story We've talked a little bit about well quite a bit about lactate in athletic performance I have a much better understanding of that you've talked about something very tantalizing with respect to brain health and TBI and I'm very much hoping that this is being investigated.

1:30:06I mean, again, TBI is something where fortunately people are so much more aware of it today, but yet we still seem relatively poor in therapies. And if we had a tool, a metabolic tool to aid following a concussion. I mean, imagine if there's a concussion protocol that's at every time a person got a concussion, they were to receive intravenous lactate for X number of consecutive days, four hours a day, at four millimole. Again, very testable hypotheses here. It's a little frustrating to think that this type of work isn't being funded given. I mean, heck, I would have the NFL players' association look into this because you clearly have a high volume of individuals who are susceptible to concussions and it would be easy to test that.

1:30:50We've talked a little bit about the role of lactate in cancer, although we'll save that for maybe the next time I have Inu go back on and let him And be the one to talk about that. But the big takeaway there is, yes, lactate may be carcinogenic, but the bigger problem is not the accumulation of lactate. It's the accumulation of lactate in the absence of an effective clearance mechanism. And if one thing has become demonstrated over and over in our discussion today, it is that if you want to increase lactate flow and you want to increase lactate clearance, you must exercise. Are there other disease states besides these conditions we've discussed where lactate plays an important role in the pathophysiology?

1:31:32You suggested earlier on brain health, dementia, Alzheimer's. It's really looking at exercises protective, not just card game kind of mental exercises, but physical exercise. And people talking about brain blood flow and the delivery of substrates, and in fact some people are talking about the role of lactate and stimulating neurogenesis and the dentate gyrus looking at development of new brain cells. Which used to be a really heretical idea, the original idea was that when we're born we have a certain number of brain cells. Now we know that there's a turnover of brain cells and they're renewed, and we know that problems can occur when the progenitor cells are damaged or injured or not stimulated in some way.

1:32:18I think there's a big future for investigators to be working in the field of physical activity and aging and the health span. We talked very briefly about the role of lactate specifically in as a precursor or a canary in the coal mine around sepsis. Do you believe that that is still a valuable tool? Definitely. So to follow Belamo's argument, okay, show me where it is in an anoxic area in your patient. He challenges his colleagues. Show me where there's hypoxia. And so then the attitude becomes, well, it's not the cause, it's a response, it's a strain and understanding stress and strain. Sorry, just a backup for a second.

1:33:06And he's saying this to ask the question, if you're telling me that lactate is the response to anoxia or hypoxia, why when we see lactate going up in a septic patient, can you not point to the area of anoxia? And then tell me what their response is to that. Well, I don't know what their response is to that. Nobody can identify it. And I've written about this, anticipating this kind of general question. And where is this lactate coming from? I think it might be coming from the gut personally. That's what we were taught, George. When I was in the ICU, we were taught when you see these rising lactate levels in patients, it is hypoperfusion of the gut.

1:33:52Now, okay, so I measured a lactate level in a patient and it's up to 10 mm, that's bad news. But am I supposed to take that patient to the operating room and look for a schematic bowel, that's a lot of smoke, but it doesn't tell you where the fire is. Even if you believe it's a gut perfusion issue. Well, I think part of it is because the microbes are producing a receemic lactate. They're producing L lactate and D lactate. And most of our body runs on the form of lactate that's identified as L lactate. But I think in sepsis there's a lot of de -lactate going on that is formed in the lower bowel, as opposed to the upper bowel.

1:34:34How easy is it to distinguish between those two? It's been so long since I've done organic chemistry. I don't remember how we distinguish. I understand the difference between a D and an L, but I don't remember how one measures it. Most of all the analyzers we have, the hospital elsewhere, measure the L form. I'm holding up my hands here on purpose, say one is the mirror image of the other. the L is the form we usually make and utilize. But if we make this other form, now we have this stuff which is neurotoxic and pro -inflammatory. And I think that in large part people can't really see the extent of lactateemia that occurs in sepsis.

1:35:14Wait a minute. You're saying that when we measure the 10 mmol in the septic patient, the The 10 millimole is only the L lactate concentration because that's all the assay measures, but there could be 20 millimole of D lactate there that is actually causing a problem. How could we confirm or refute that? This is your field, not mine. There's a term D lactocacidosis and we know D lactate is toxic. So now we would need a special kind of analyzer to detect it. And it's not the common analyzer that's around. Well, analyzer, the bloodguest analyzers, the portable devices, most of the enzyme techniques, the recipe and Bergmeyer's textbook is for L lactate.

1:36:01Do you have the ability in your lab if you wanted to measure D lactate to do so? In the past, I've submitted some grant applications with clinicians who wouldn't want to do this and we haven't gotten very far. Interesting. Where do we derive the belief that de -lactate is neurotoxic and pro -inflammatory? Because if you give it, it is. And when people can measure it, it's associated. Interesting. So your hypothesis is that the bacteria are making the lactate, and they're disproportionately making the less desirable form of it, and that the L -lactate, that which actually measuring is probably not causing any of the problems associated with the sepsis.

1:36:47It's telling you that something else is going on. Yeah, I know that microbes will make lactate regardless of the presence of oxygen. So if you were saying, well, there's got to scheme you, you mentioned it'll be very hard to demonstrate that. And you wouldn't want to actually maybe bother measuring it if you have microbes that is the site of this lactate generation. What is the most interesting question that you are asking today that you still don't have an answer to in your mind with respect to lactate metabolism? Yeah, thank you for that. Our most recent paper touches on this. So for a hundred years, everybody, including us, have been thinking about muscle and related tissues, tissues that can use lactate, but it's all been a muscle thing.

1:37:33So we did a very simple test. We used our isotopes as we usually do. We had a board, carbon -13 labeled lactate, and then diluted our glucose and D5 glycerol so we could measure lactate, glycerol, and glucose all at the same time. And then we gave people an oral glucose tolerance test. And the first thing that came out in the arterial blood, and this is arterial blood, not Venus blood. The first thing that came out after taking glucose is lactate. So there's enteric glycolysis that takes place. And this is the way the body participates in distributing carbohydrate energy to make lactate. So this just changes our mind completely.

1:38:25But sorry, George, did we not know before this that when you consume glucose, lactate goes up? We know that and nobody would understand why. It's part of the lactate shuttle. I presented this in far most recent studies at last year at the American Diabetes Association. There was a doc there from NIH and he said, well, we feed copper hydrate. We get two million more lactate. So, what's the deal? That's the way the body is working. In sports, we would say it's hiding the ball. I mean, baseball, we hide the ball and football, we try to hide the ball. Here are the bodies trying to minimize the glucose load, but still deliver carbohydrate energy.

1:39:06And it starts with the enterocytes. And they've got, there are plenty of studies with people who would incubate enterocytes under air, give glucose immediately. They have lactate. And just give me a sense of scale. So when you give somebody an oral glucose tolerance test, this is 75 grams of glucose, you gave a standard dose I'm assuming. Yeah. Okay, so plasma glucose in these subjects will easily double, right? It'll easily go from 75 milligrams per desoleter to 150 milligrams per desoleter, correct? Yeah. And lactate might double, maybe go from 0 .6 to 1 .2 millimole, correct? Correct. From a mass balance perspective, I'm not smart enough to remember how to do this.

1:39:54Can you remind me how much carbon went in each of those two paths? Good point. We're just talking about the concentration, but earlier we talked about the flux. So it looks like the liver is really, really important in this whole thing. And we did touch on the liver, and it's important. It's really underestimated, and you're asking about what I think I want to do next is to really explore this problem, which you are articulating. how does the body shuttle carbohydrate energy? So he said the blood glucose will rise and it will go double. But it doesn't get that high until 30 minutes after the test.

1:40:38Whereas if I give the glucose the lactate is spiking in 5 minutes, reaching a peak at 15 minutes, then subsiding, and now the glucose is starting to become the carbohydrate energy form. But just so that listeners understand something you and I take for granted, when a person's blood glucose goes from 80 to 150 milligrams per deciliter, that's still a trivial amount of absolute glucose difference concentration. It's the difference of five grams of glucose in the entire circulation that would explain that delta. You still gave the person 75 grams. In other words, we have to account for 70 more grams of glucose.

1:41:23And my thinking was that most of that's in the muscle. We do oral glucose tolerance tests on everybody, George. I mean, we just really believe that that is a great functional test of glucose disposal. But truthfully, you know, we're not measuring lactate when we do this. Maybe we should be. But we're basically asking the question, how sensitive are your muscles to insulin and And how much of a reservoir do you have to dispose of glucose? Because we're also measuring insulin every 30 minutes as well as glucose. But now I'm wondering because we haven't measured lactate, there's another pathway we're not accounting for, which is how much of the glucose are those enterocytes turning into lactate as an alternative fuel source.

1:42:09Yeah, so that's the first part of what happens. we saw it, we were lucky to have arterialized blood so we could see the spike in lactate comes out after taking glucose. Way before the glucose starts to rise. And then from my isotope technology, we could see that when glucose is rising, it's giving rise to lactate. That's been seen before it's called the indirect pathway. But to go back to an earlier point, you raised about the importance of the liver, and this is in our paper we referenced the work of standard who gave 13 C glucose in an OGT. The liver picks up most of it, and the liver basically sequesters about 80 % of the glucose load, and then doles it out over time, and it starts to release this glucose after about a friend of a member there's study 30 minutes.

1:43:03Meanwhile My lactate has a big role. It plays a role. And meanwhile, the glucose is still in the liver. And now it starts to be dulled out. It's being released as glucose. And that's getting converted to lactate in the muscles. What's called the endovaric pathway of glucose metabolism. So the liver is really key. So what I would hope to be able to do in the near future is to really revisit all this dietary, nutritive aspects of, okay, glucose is taken up, made into lactate. Or what if we have fats there, like a real meal, not just an O2 GT, maybe a meal tolerance test. We would do this, a version of this was done by somebody named Schlicher in Germany, and they did this really incredible study.

1:43:52They did make a mistake because they forgot about the liver. They grew grain in a high carbon 13 CO2 environment and plants, I think most people know, take CO2 from the air when they make sugar. So they did an oral glucose tolerance test with 13C and also they harvested this grain and they did a meal test and they made porijadas stuff and they looked at the appearance of lactated glucose in the blood. And they saw the same thing we did right away is a spike in lactate and they said well, lactates the whole story, but they forgot about the liver. So you're saying in a standard oral glucose tolerance test, your belief is that most of the glucose that is being disposed of is actually being disposed of initially by the liver.

1:44:44And then the liver starts doling that back out. The muscle picks it up. Your secondary production of lactate is by the muscle. Your primary production is by the endoresite on immediate. That's why you get two peaks of lactate. You get the first fast peak in response to the endoresite making lactate. Then you get a second delayed slower peak when the muscles get the glucose from the liver and start making lactate. Yeah. And one of our core investigators is Umesh Mashirani. He's a diet pathologist. Do you see us F? And you see, well, if you just tell him that formin' works. So, for our listeners, your listeners, Metformin is the most properly prescribed drug for a high blood sugar.

1:45:28And one of the concerns is when you give that drug lactate rises. And Omasch is very comfortable saying, well, the body is making lactate. So Metformin is encouraging in terror sites to make lactate. That's why the lactate's high and that's a good thing. Very interesting. As you know, there's a body of literature suggesting that metformin may impede exercise performance. And again, the problem with metformin is, despite the fact that this drug's been around, it's almost as old as God, it seems to have so many points of action that it's very difficult to know what it's doing or how much of its net outcome, which is reducing hepatic glucose output, can be attributed to what?

1:46:10But I guess the conventional thinking on metformin is it's inhibiting complex one of the mitochondria, correct? Yeah. And if you inhibit complex one, God, you're activating AMP kinase that should reduce hepatic glucose output, correct? It does that. But it's always been, I mean, as sure as God made little green apples, anybody on metformin has higher lactate levels. That's a bad thing. Or it was a bad thing. maybe it's a way to deliver carbohydrate energy. I had always assumed that the doubling, at least doubling, if not three X increase in resting lactate levels in the case of metformin were due to the mitochondrial, the complex one inhibition.

1:46:57Obviously, maybe naive assumption, but it was, hey, if you're inhibiting the electron transport chain, of course, you're going to have more lactate, but that may be true, true and unrelated. Yeah, that's why I want to give carbon 13c lactate or carbon 13c glucose and look at the appearance of carbon 13c lactate in the blood and see and do the quantitation you described, where does the glucose go? How much would it cost to do the definitive experiments on the full flux disposal of lactate? This doesn't strike me as staggeringly high amounts of money to do this type of research. We could start very well with an RO1 research grant.

1:47:41That's $2 .5 million. That would be a start that's used to handle glucose, but the real interesting stuff would be when glucose appears as it does in a meal with other things. You know what would be interesting? Have you done the experiments you just described, the OGTT experiment, to individuals both on an off -met formant, it would be interesting to see the difference in lactate production in those two individuals. And it would be interesting to also see if there was a way to quantify this enterocyte production. Dr. Masha Rady and I want to do that with metformant. If we give metformant and is an increase in lactate in the plasma, is that due to production, outstripping removal, are we actually increasing the oxidative disposal of glucose, or is the glucose high because of increased gluconeogenesis?

1:48:40We could answer all of these things with our combination of tracers we use. Again, let's go back to conventional wisdom, what were retarded in medical school, and residency. Be careful of metformin because you increase the risk of lactic acidosis. So a person on metformin is at an increase risk for lactic acidosis. If they get dehydrated, if they get contrast in a CT scan, when viewing that concern through the lens of what we've just discussed, does it make sense? Well, caution is always advised first, doing a harm. So when we prescribe this medicine, we don't know if it increases lactate production or inhibits disposal.

1:49:26Right, but let's go back to the very beginning, right, which is just because you increase lactate production, does that mean you're causing acidosis? Well, that was another important consideration. Lactate rises. What's the change in pH? Yeah, what happens when you take those subjects, the TBI subjects, and you clamp them at four millimole, you said, if I recall, there was no change in sodium, but I think you also also said there was no change in pH. Oh, there's a slight alkylosis. Slight alkylosis. How much? 7 .38 to what? 7 .38 to 7 .35. Well, that would be a slight acidosis. Excuse me. Opposite way.

1:50:107 .4. Okay. Okay. The colleagues that you referenced in Germany, I think, or Switzerland, who were taking people up to eight millimole, were they seeing an acidosis? They did not report it. Okay, so does that mean it's possible that high levels of lactate do not materially alter acid -base physiology? Well, in your experience, is sodium lactate given in metabolic acidosis? Sometimes it is. Yeah, but the lactate concentration is very low in that setting. The examples you're citing are much better examples to ask this question. You're clamping people at a really, really high lactate that you just don't get to.

1:50:52But again, it seems to me that if what you're saying is correct, George, there's a lot we're misinterpreting from, for example, sepsis literature, where you get that patient in the ICU who's got high lactate. Well, they also have a low pH, but those two things could be driven by different processes. Yeah, exactly. We addressed this earlier. I think if you see a low pH, Yeah, you need to do something. You see a high elactate in the absence of a change in pH, I would be very inclined not to do much. You've given me and everybody listening a lot to think about here, George. So, it seems to me that understanding the full flux, the full mass balance of lactate, both exogenous and endogenous is a necessary step to fulfill our understanding of metabolism in a more complete manner, correct?

1:51:48Yeah, thank you. I think so. And you mentioned endogenous versus exogenous. Exogenous means we're going to infuse lactate, put it in the body some way. Well, I learned in organic chemistry, the salt of an acid is a base. So it's not unexpected that when you give it pH will rise slightly. And maybe part of that also is sodium. So yeah, what does it mean to use this exogenous stuff? So lactate is distinguished from pyruvate and lactate is reduced. It has more hydrogen on it. It has one more hydrogen and pyruvate. So that keto bond on pyruvate, a double bond oxygen, becomes hydrogen. So it's more reduced.

1:52:34Now when you start putting in this reduced equivalent into the blood, but it's going to go around the whole body and change redox in a number of tissues. All the tissues, basically, where the lactate's going to go. So lactate is a powerful signal and it works in diverse ways to activate various pathways, including by changing cell redox. What does lactate do in terms of gene expression? We haven't talked about that, but given how potent a signaling molecule it is in both metabolism directly in vis -a -vis redox, what do we know about other forms of signaling and expression of genes? Yeah, so there's a new field now.

1:53:18So we used to think genes are regulated in part, epidemanically, by acetylation or methylation. Now we realize they're also lactolated. We've done some of those experiments here in our lab. We haven't published it, but the lactate is a predominant metabolite and it can bind to genes and it can affect gene expression. Meaning it can covalently bind? Mm -hmm. Acetilation, methylation, lactolation. That's actually a term. And I was going to compliment you on your reading a literature because you can look that up in PubMed and you can see that people are starting to look at lactolation of histones by raising lactate.

1:54:00So it's not through histone acetylation. It's direct lactate binding. Yeah, and it's called lactolation. Dr. Riteer, you've got us up into the stratosphere here, where science needs to go. Starting with the premise exercises, healthful, how can it affect body corpus, promote healthful living, possibly in part by lactolation of histones, promoting mitochondrial biogenesis. It's very interesting because we've talked about all of these benefits of exercise, right? We talk about how my friend clearly has more mitochondria than I do. He has more MCTs and he's so much better at clearing lactate and all of these things.

1:54:45But of course, what we're missing in that is the how and the why. Why is he doing that? What is it about his training stimulus that does that? And what you're suggesting at least as a hypothesis is what if the lactate itself is signaling the gene expression that leads to the more favorable phenotype seen in the athlete? Yeah, well, to catch your Hashimoto, we publish a paper. If you just take muscles, put them in a muscle cells in a dish, you add lactate, you activate 500 genes. But here's the thing. There has to be something, if I'm just thinking about this, perhaps a bit too quickly, I would have to believe it also must involve something favorable with consumption.

1:55:27In other words, I have a hard time believing. If you took my friend and you took me and you would argue based on his training and based on my training, I'm on a bike three or four hours a week. He's on a bike 15 to 20 hours a week. He's clearly making more lactate in any given week than I am and he's clearly using more lactate in any given week than I am. But if you came up with an experiment, imagine you could do this where you could pair feed us lactate. Okay? So in other words, for every millimole of lactate he produces endogenously, you exogenously deliver the same lactate to me. I still don't think we'd end up the same, even though we have the same input of lactate because he's using it during exercise, whereas I'm sitting around on my butt while you're giving me all of that lactate.

1:56:18So it's hard for me to imagine that lactate by itself would be the signal. I have to think there's something associated with the benefits of how lactate is consumed during exercise. So, yeah, this is an interest in literature. Now people are doing lactate clamps on people and looking for increases in mitochondrial protein expression. And what are they seeing? There's sometimes yes and sometimes no. This sounds a lot like amino acids. It has to do with the endogenous versus the exogenous because you get completely different signals. So it's the endogenous lactate when it's high seems to stimulate mitochondria by a genesis resonant and just infusing it.

1:57:01Okay, but why would that be? Well, a lot of these pathways are redox sensitive. I want to make sure the listener understands that. That's a very important point. Because it's redox sensitive, that's just fancy speak for saying it depends on the amount a protons or pH balance of what's going on. And if you just give somebody lactate without actually creating the slight alteration in pH that is naturally going to be accompanied by exercise, you don't reap the benefits. Whereas if the lactate is produced in concert with exercise, you get the lactate, but you also get the pH perturbation that is the key to unlock its potential.

1:57:44Let's a very good explanation of what I'm seeing. This is what you can't work about. There's how I really see a real scientist. And I think it has to do the mixed results there are getting, it depends on whether it's exogenous or endodigenously produced lactate. So of course, it would beg a question, which again, if I were ZAR, George, if I were in charge of NIH funding, I'd be throwing much more than just a poultry little RO1 at this, because I think it's such an interesting question. But going back to the TBI example, I would want to study as follows. I would want to take a whole bunch of people with traumatic brain injuries or concussions.

1:58:20So you've got a placebo group. You've got a group where you just infuse more glucose and insulin, intranasal insulin and glucose. Another group where you just infuse lactate, you take them to equal concentration of lactate glucose, so you take them up to five millimole of both. then you have another group where you do that, but they exercise two hours a day. Steady state, zone two, just enough to get their own endogenous lactate up to about two millimole and then get that clearance. You might argue that it's that exercising group that's also being given exogenous lactate might actually have the best outcomes because they're getting the redox potential as well as the lactate.

1:59:01We thought about this. So the TBI patient is probably not in the cards to doing any exercise, but what about functional electrical stimulation of a comatose patient? I know a lot of people that have had TBI's. I don't think they'd be up for strenuous exercise, but I wouldn't they be up for even, you know, you're talking about my, yeah, yeah, yeah, sorry. Sorry. I mean, somebody who's had a concussion, but they're still functional, but they're suffering the negative consequences of it. Yeah. Well, I think you would want to encourage mild exercise on these people. I was talking about the... Yeah, someone who's combatose with a significant CNS in life.

1:59:38How do you raise lactated them? Indodgently. Mild electrical stimulation. It all comes back to myrofollow, right? That's the beginning. Yeah. We're back to frogs with electrodes. We're beyond frogs with electrodes, and now I think we were understanding that it's just not a muscle thing. It's the whole thing. And this glycolysis going on simultaneously back to our story about the muscle fibers elactate, producer, elactate, consumer, exchanging chemical energy. Our studies on healthy people with heart when we're exercising our muscles hard enough our gun will release lactate. But it's now the favorite fuel for the heart.

2:00:20studies that Hashimoto did of executive function, a disease with Neil Secker in Copenagin, give people standard cognitive tests, and they exercise and build up their lactate. They score better, and they recover, their lactate comes down. They go back to their basal scores. It's brain fuel. So think about the PE class, getting kids out to run around. And that is not blowing off emotional energy. They're going to fuel your brain for the next hour or so. Yeah, it's so interesting because you just have to believe that there are too many factors in there to identify the amount of contribution of each.

2:00:59For example, we all know that when you exercise BD and F goes up and clotho goes up and all of those things have pro -cognitive benefits as well. So it's probably difficult to just assign all of the benefit of there's a clear obvious benefit between exercise and cognition and what it sounds like is that there are many biochemical pathways that feed that and lactate may indeed be a preferred energy source. There's one study where lactate was infused and BDNF went up. Interestingly, I'd love to see. I wonder if anyone has ever looked at lactate, infusion and clotho concentrations. I don't know. Yeah.

2:01:39Well, George, this has been very interesting and illuminating. I think that it's safe to say that so much of what I and I think many others listening thought we knew about lactate was at best incomplete and in some cases incorrect. So I'm glad we have finally had a chance to sit down and go through some of this really incredible work. I do hope that somebody in a position of funding is listening to this and realizes that for a relatively small sum of money relative to the type of money that's thrown at a lot of biomedical research, we could really still answer some fundamental questions about the fate of lactate and the interplay with glucose especially the role of the liver and the enterocytes.

2:02:24So I'm hopeful that with the reach of this podcast that someone's listening and they think, yep, this is a good use of funds. Thank you, Peter. I agree completely. And thanks for the opportunity. And again, my physician friends listen to you more than they may. Now that they listen to you, they'll listen to me. Now they're stuck listening to you. Alright, thanks, George. Cheers. Thank you for listening to this week's episode of The Drive. It's extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member -only content and benefits above and beyond what is available for free.

2:03:06So if you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. Premium membership includes several benefits. First, comprehensive podcast show notes that detail every topic, paper, person, and thing that we discuss in each episode. And the word on the street is, nobody's show notes rival ours. Second, monthly ask me anything or AMA episodes. These episodes are comprised of detailed responses to subscribe questions, typically focused on a single topic and are designed to offer a great deal of clarity and detail on topics of special interest to our members.

2:03:44They'll also get access to the show notes for these episodes, of course. Third, delivery of our premium newsletter, which is put together by our dedicated team of research analysts. This newsletter covers a wide range of topics related to longevity and provides much more detail than our free weekly newsletter. Fourth, access to our private podcast feed that provides you with access to every episode including AMAs, Sons, the Speel you're listening to now, and in your regular podcast feed. 5. The Qualies. An additional member -only podcast we put together that serves as a highlight reel featuring the best excerpts from previous episodes of the drive.

2:04:24This is a great way to catch up on previous episodes without having to go back and listen to each one of them. And finally, other benefits that are added along the way. If you want to learn more and access these member -only benefits, you can head over to peteratia -md .com forward slash subscribe. You can also find me on YouTube, Instagram, and Twitter, all with the handle peteratia -md. You can also leave us, review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional healthcare services, including the giving of medical advice.

2:05:02No doctor -patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment. Users should not disregard or delay an obtaining medical advice from any medical condition they have and they should seek assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously for all of my disclosures and the companies I invest in or advise please visit peteratiamd .com forward slash about where I keep an up to date and active list of all disclosures.