Transcript for:
Lactate's Role in Health and Metabolism

hey everyone welcome to the drive podcast I'm your host Peter [Music] AA hey George thank you so much for making time to sit down with me today this is uh this has been a long time coming as you know your uh your your colleague and and partner in crime on much of the work you've done Inigo on Milan has been uh a multiple Time guest on this podcast uh and of course your name has has come up many times I've referenced you and your work in my book um so it's great to be sitting down with you and to talk about lactic acid um which is something that I I think uh you know I think it would be safe to say at the outset is probably a misunderstood molecule is that a would that be a safe statement to start this out yes it is and thank you Peter for having having me on you're really uh really helped make my career because my physician wife's friends uh know my name but after reading your book they say that's George so that's really great so not to be difficult but uh you did mention lactic acid yeah I was just about to say we I'm glad you brought that up I assume you're going to say should we really think about this as lactate or lactic acid and let's let's have you get the semantics right out of the gate for us we can say lactate yeah the body does not make lactic acid right makes lactate and then there's a hydrogen ion and presumably if there's a hydrogen ion near the lactate it's lactic acid is that the that's been historical M mistake it's a 100 years a 100y year mistake it's like lactate is not just an innocent bystander it's a participant in the process of powering muscle and in fact all cells so so let's go back in time a 100 years right because it was about a hundred years ago that Otto mehoff uh made a made a seminal Discovery um Can can you tell us a little bit about what that was and and um and you know how that sort of uh started a chain of uh of understanding that brought us to where we are today yeah so those the early 20th centuries people were trying to unite what was known from fermentation technology to what was coming out of um studies of muscle metabolism and my office was was a great man a great investigator and one of the things he did was to quantify how much glycogen uh is in muscle and how it when it degrades produces lactate uh at that time thought to be lactic acid so uh we're projecting now a picture of the seminal kind of experimental um setup that myof and colleagues used and they had a half a frog in a jar without oxygen supplementation with without any perfusion that is blood flow and this half a frog the muscles were made to contract and they contracted until they couldn't contract anymore and then quantitatively um myof could say well there was x amount of glycogen and there was x amount of lactate produced and so that was uh really instrumental in developing this pathway but if you look at this this is really not what we are uh these muscles are made in nature to contract once or twice the Frog hops it gets away or gets eaten um so it doesn't the muscle doesn't is not representative of us but in this situation uh they stimulated the muscle to contract it um stimulated glycolysis to produce ATP and at the end the muscle fatigued and at the end there was a lot of lactate and there was also a lot of acid so this is how it came to associate uh um lactate or lactic acid production and oxygen lack because there was no oxygen around here so it had to happen it was a fade compete and this led to the idea of lactic acidosis and the Anor robic threshold and the oxygen debt but if you just look at this simple simple apparatus where we have a half a frog made to contract this is really the egis of our understanding of how carbohydrate is used in the body all textbooks most textbooks well not not mine it talks about talk about uh glycolysis going to make pyruvate and when there's no Oxygen uh lactic acid so this has been a problem and this spills over not only into muscle physiology but it's spills over into pulmonary medicine it's it spills over into Cardiology it spills over uh into nutrition uh now we know uh a lot of things that were not known or not could not be known at that time and um right now I think I'm going to stop sharing the screen to talk more directly about our our new research well I want to go back to that for a second though before we get there George to make sure everybody kind of understands the experiment and the um uh interpretation so um again some folks couldn't see that image but but basically you were showing a schematic of an experiment so let's let's just kind of explain what was going on there and maybe try to understand the interpretation so um the the musculature of of part of a frog is put into an anerobic chamber this is a chamber that has no oxygen and it's not perused so there was no uh blood to carry hemoglobin to carry oxygen to the muscles presumably electrodes were placed uh somewhere on the musculature within the chamber and the electrodes provided the stimulation for muscle contraction and then the question became what is it that fueled the contraction well obviously it's the glycogen within the muscle but if glycogen or glucose is being used to fuel contraction without oxygen it somehow must be happening in the absence or exclusion of the mitochondria and so what they were measuring was the consumption of glycogen the production of lactate um and you're and presumably they could measure the pH in the solution and I'm assuming that the pH which is a measure of acidity was going down is that all correct that's all correct that was the observation and so the interpretation of that observation was what at the time well first of all that was important in terms of quantifying glycolytic pathway pre yeah precursor and product you start with a certain amount of precursor you wi up with a certain amount of product um but since then people have Associated the appearance of lactate with oxygen lack yep and that's that's a mistake there was no oxygen there and it's a stress strain kind of relationship the muscle is stressed to perform it uses what it has it uses glycogen it produces lactate and there's also an acidosis so there's association with lactate and lactic acid uh acidosis and fatigue so this whole thing was all boiled up in one knot so when I learned exercise physiology it was all those same things fatigue acidosis um lactic acid so George in the experiment that myof did almost exactly a hundred years ago at some point I assume the Frog's leg stopped Contracting in the presence of the stimulus and is it believed that that was due to a depletion of glycogen or was it believed that the degree of acidosis had become so significant that the acidosis crippled in some way the actin and masin filaments of the muscle and prevented either further contraction or relaxation exactly so at that at that time people were trying to understand why muscles contracted and it was just a simple kind of thing like let's have tea and uh would you like tea with uh cream or would you like it with lemon oh I would like would both so right then you get this curdling the acidosis and so uh one idea of muscle contraction was that actually the act amiz kind of curdle and then they have uncurdle so it was believed that the accumulation of acid uh lactic acid caused fatigue and when you look back at that experiment and I'm going to jump around a little bit because there's a bit more history I want to get into but just so people can understand how you think about this problem today based on the entirety of your work what do you believe was the explanation for why the frogs muscle ceased to contract in the presence of an ongoing stimulus I think what happened was there was ATP and creating phosphate depletion in this anerobic environment interesting by the way how much does in an experiment of that nature how much does the pH go down I don't think they reported the pH but the pH would probably go just a bit under seven got it and just for folks listen who aren't familiar with with ph uh pH the number I guess can be as low as what one and as high as 14 is that effectively the range of pH something like that that's that's right yeah although physiologically I mean that would be in a chemistry lab physiologically in a mammal um it's it's very hard to get too much below the high sixes and too high above the high sevens and the higher the number the more basic uh and the lower the number the more acidic but would you would you agree with that that physiology tends to exist in the sevens with 7.4 being kind of perfectly neutral yes I'm teaching physiology now 7.38 7.4 and and you're right it's really hard to get the pH 27 or even a a bit below yeah I'll tell you just a funny anecdote that maybe a not so funny anecdote unfortunately but a very common story when I was train in surgery um obviously when trauma patients are brought into the trauma Bay um one of the pieces of data that the paramedics have on the way in is the pH they they know they can measure blood pH very quickly and easily and that became a way that we would triage Readiness in the ICU and in the operating room and so when gunshot wound victims or stab victims were being brought in even if they were alive if their pH was seven or 6 9 um we knew that it was very unlikely that they would survive even if their heart was still beating at the moment that that was reported to us um I I can think of one case that was a miraculous case where a guy was brought in with a pH of 6.9 on arrival um and he managed to survive which is is kind of an amazing story but but it is it is funny how the body really really regulates acidbase balance um so okay so so so let's let's fast forward a little bit George so so if I'm not mistaken did meeroff win the Nobel Prize for that observation in 1922 yeah he was awarded it along with a hill he and a hill is a very famous name and in physiology we sometimes refer to him as the father of physiology or the father of muscle physiology or the father of exercise physiology and uh so AV Hill and um Ado myof shared the Nobel Prize I don't remember exactly when warberg made his seminal observation that also Bears his name but I'm guessing it was about two decades later it was probably in the 1940s is that approximately right ano varberg was actually mof's professor in in Germany and uh so you're talking about the varberg effect cancer cells cancer cells will take sugar glucose and make lactate uh and they do that under fully aerobic conditions under room air where the oxygen is actually higher than it ever is in the body and these cancer cells would just break down carbohydrate uh break down glucose quantitatively and wind up with um this lactate and and acid so we don't need to go out into um uh any more more than we have but if you look at the glycolytic pathway at the end there's pyruvate Anon and a proton uh and nadh this Redux carrier it gives us lactate an ion and NAD plus so the last step in glycolysis does not make acid It's actually an alkalizing step but in metabolism um there's a lot of things that can give rise to acid and some of the intermediates in the glycolytic pathway are acids so there's there's lactate and there's acid so your observations in the ICU to be concerned about pH of course that's really important that's That's essential sometimes people also measure lactate that's right yeah and uh there's in for instance in sepsis or other kinds of conditions people will be measuring lactate but I think you're making an important distinction between pH and lactate yeah I assume that when we because we did we would measure lactate all the time if we thought sepsis was brewing um but I suppose and we'll we'll get to this in more detail that that we were using lactate as a surrogate for something that was of Greater concern to us which was actually the pH balance correct that's right yeah George I I want to go back to some fundamentals and and I was a little little delinquent in not doing this out of the gate because I wanted to sort of Jump Right In but it it occurs to me as we're talking now that I I don't want to take for granted that our listeners really um might be as familiar as as you and I are with metabolism and um and and frankly you know the the breakdown of a carbohydrate into what ultimately becomes ATP so so I I'd like for you to spend a moment explaining the following so so at a high level this is what I will typically tell a patient if I'm talking about this or if they express an interest I say look food is chemical energy right so you have you eat these things and they have Bonds in them they have you know especially hydrocarbons right they're incredibly rich in stored potential energy within the carbon carbon and carbon hydrogen bonds in particular these are the most energy rich bonds metabolism is a fancy word for taking the chemical energy that is stored within the bonds again primarily between carbon and hydrogen and carbon and carbon and turning that into electrical energy and that electrical energy is used to turn back into chemical energy so you take the electrical energy in the electron transport chain for example and then you shuttle it back back into chemical energy in the form of ATP so basically food to ATP is just changing the form of energy but obviously energy is conserved in this process and that's just kind of like a hand waving highlevel explanation but I think for the purpose of this discussion we should go a little deeper and explain just and we we don't have to even get into fatty acid at this point we'll probably come to it later but even just through the lens of glucose which of course will treat synonymous with glycogen so when a molecule of glucose is being used by a cell and that cell needs to make ATP can you walk through in a little bit of detail how it does it and what are the different uh nodes or paths that it can go down yeah uh well that was a very good explanation I don't think this what I'm about to say is going to advance this understanding much more so when glucose is activated to break break down and we can also talk about getting glucose into the cell yes and there are barriers to that and well actually go ahead and do that George because I know lactate is going to come and figure into insulin so why don't you do that why don't you start at getting glucose into the cell and then we'll keep going yeah so uh glucose is a molecule that can be quite high on the blood but it it can't get into the cell unless it it meets a transporter and some of the Transporters are consti of they are in all cells uh like the brain has a the first uh transporter discovered was named one and then two and three and four four is important because four is expressed in most of our body in our muscles and uh in our fat cells so we need to have these glucose Transporters at the cell surface and uh depending on the various kinds of signaling insulin is is the typical sign also muscle contraction will move these Transporters to the cell surface now glucose can come in so um when I teach glycolysis to my class and I use one of the textbook figures where it starts out with glucose I put the brakes on and say no we need to put a membrane barrier in here we need to get glucose into the cell and then it can be metabolized and it's usually once the glucose is in the cell then there are two things that can happen it can be stored as glycogen but if there's an energy need it will enter the glycolytic pathway and be de be degraded there are a couple of important regulatory steps which are involved phosphate level and Redux but I'll just say that the glucose splits into two and so we have a six carbon molecule that makes two three carbon molecules and depending on who you are and how you drive right this pathway the last step is either pyruvate or it's lactate and what we found uh recently uh because we traced the glucose and see what what it makes glycolysis basically goes to lactate so it's a series of steps one um reactant um one product is a reactant for the next step and and there's a splitting of uh six carbon molecule to two three carbon molecules that progress to uh lactate and so the process itself uh is basically pH neutral let's just let's just make sure people understand that so what you're saying is if I heard you correctly George um the glucose comes into the cell let's just let's just assume we're not in a storage State we're in a utilization State the six carbon ring is split into two three carbon halves now a second ago you said you have two potential Fates there right you could make pyruvate or you could make lactate is that is that correct or did you say that it's all okay and you said that either choice is pH neutral is that correct well actually if you get to lactate It's actually an alkalizing step but the whole process itself is basically pH neutral and for our discussion of muscle so we're we're embedded in muscle now that's been our thinking for my thinking my career 50 years in this and for the whole field that's all muscle but we'll we'll get to what happen happens you know when we take carbohydrate as we go go through this yeah so um we're going to split this molecule and it's as you describ its potential carbon energy so one way to think about metabolism is the flow of of energy and carbohydrate carbon energy carbon derived energy and at some point we could talk about its integration with fatty acid maybe amino acid metabolism but we really in a b basic biological sense talking about the energy Highway which is a uh carbon based and it's it's uh reduced so chemically then when it can be oxidized a lot of energy is released and we can capture that as ATP now actually when we're doing just glycolysis in a muscle and I need to say that when our muscles are working oh about 80% of that carbon flow comes from previously stored carbohydrate glycogen so that's our car carbohydrate energy source and we we have done a numerous experiments looking at carbohydrate oxidation and exercise and the use of glucose and really the body protects um its glucose pool because there are certain cells that really need glucose like our brain and if we got our muscles going they could suck up all the glucose and leave us really hypoglycemic and we would crash uh so actually just the active muscles uh um are going to take up glucose but it's not going to be a major part of the energy it's a significant part maybe 20 25% most of that carbon is going to come from previously uh stored glucose which we call glycogen and for the listener who might not be as familiar with that about 80% of the body's total glycogen or stored glucose is found within the skeletal muscles while the remaining 20 to 25% would be in the liver and um the way I think about it is that the the liver's primary responsibility is regulating blood glucose for the brain whereas having all of that stored glycogen in the muscle is as you said an important source of fueling the muscle so that the muscle doesn't have to you know for lack of a better word steal glucose that from the circulation that would otherwise be imper to keep the brain happy but of course one of the very important things I am sure we will discuss is the role the lactate plays in replenishing the liver uh which if I'm not mistaken was another Nobel Prize probably now somewhere in the in the mid to to late 40s if memory served correctly Visa the Corey cycle um yeah I think 1947 was the year um well let's let's talk a little bit about that I mean I think we're kind of marching our way through history but that that was another big seminal uh involvement and and um so so yeah so let let's talk about what happens to lactate when it is produced in the um uh in the metabolic process of of of breaking down glucose and and and I guess the other question I would have George just for the listener what determines that path Choice let's not talk about a cancer cell for example but let's just talk about a normal muscle cell that needs ATP it's got its glucose it splits it in half it's got its two three carbon units what what are the physiologic pressures that drive towards gluc pardon me towards pyruvate versus lactate yeah so we we have a couple of steps that depend on redo but um one of the things what been noticed by our colleagues who really have done a lot of muscle biopsies is that it's not the ATP level that falls cu the whole system is set up to maintain homeostasis of ATP but we get changes in what NAD nadh Ratio or Redux but we get changes in ADP and then it's in die phosphate so when we have this ATP molecule there are three phosphates and we get energy by splitting one off it gives us ADP turns out that's a big signal to activate these enzymes of processing glucose so uh and we we know that in a lot of ways if we just take an is isolated mitochondria I take a muscle isolate the mitochondria and we want to turn them on and make them start doing something we to add ADP and away they go and they start to phosphorate that ADP and make ATP by the chemiosmotic process which you described is electrical energy so yes the muscle mitochondrial Network work works like a big battery and it's a battery uh it's just not um I don't know if we'll talk about metaconda functionality or about its Arrangement it's a network it's not they're not just little capsules this whole network I call it the energy Highway uh other people have called it the cellular Energy power grid anyhow that's where the ATP is going to be generated and to do that you need this chemical energy fuel which is pyu lactate people have assumed that it's pyruvate that goes into the mitochondria and that's true that happens but most of that chemical energy comes in the form of lactate that goes into the mitochondrial reticulum or network and that's the fuel to run uh the apparatus of oxidative phosphorilation and make ATP and George I just have to stop you there because that is such a um again people who are listening to this who are Physicians or have studied this are going to say wow hang on a second that is the biggest departure from everything we ever learned right so so I just want to restate what every single textbook on this subject says to paint the backdrop for why this discussion is so interesting right so the textbook every textbook says the following when you make pyruvate out of glucose the pyruvate gets shuttled in to the mitochondria and there we undergo the uh kreb cycle where we very very efficiently produce massive amounts of ATP and the only byproduct is carbon dioxide and water and so as we are undergoing uh aerobic respiration we're consuming oxygen and pyruvate generating again incredibly efficient amounts of high volume ATP and outcomes carbon dioxide and water which is what we're breathing out conversely when you take that glucose and you make lactate you do generate ATP but very very little amounts and that lactate now needs to escape the cell make its way into the circulation where it can go back to the liver and be turned back into glucose via the Corey cycle to begin again but unless I missed I don't know like a couple months of my education in medical school I do not remember any discussion of lactate going into the mitochondria directly from the cytoplasm as a substrate for uh ATP production under aerobic respiration um so so it's it's possible I just missed that but is it is it more likely the case that most people would believe my believe uh what I just said we've been teaching glycolysis wrong for a 100 years and uh probably uh you learned that in junior high school or High School and Physicians and scientists are smart people uh and uh if you hear it at at the high school level and you hear it in college and you hear it in medical school well that's what you think it is that's that's an assumption that's really d dilar uh so that lactate uh that's formed enters the mitochondria and we have shown that there's a mitochondrial carrier for the lactate to get in and we've shown this it's and we call it the mitochondrial lactate oxidation complex and we have electron micrographs we have light micrographs to show uh how this process works and the enzymes are there for lactate oxidation but lactate is important uh as a fuel and as you describe uh really the first articulation of a lactate shuttle was by the quaries and they showed that a dog muscle made to contract with adrenaline or otherwise will release p ruaan lactate which will recirculate to the liver and become glucose so that's a way to support Supply blood glucose uh during exercise so the muscles are actually uh not only fueling themselves they're fueling adjacent tissues and they're fueling the brain uh by by this lactate shuttle or cury cycle I is that a rate dependent or rate's the wrong word 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 that in that scenario preferentially taking the lactate back to the Corey cycle back to the liver to make glucose um versus if the body has the quote unquote the time it can make the long-term investment in getting more ATP per unit carbon by putting lactate into the mitochondria because 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 anob pathway and if we you know 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 phosphorilation pathway so in in in the discovery that you talking about which again I just I can't overstate how um how how sort of mindboggling that is uh what determines the path well it's this ADP the ATP ratio that's that's what accelerates glycolysis so if ADP is if the ADP to ATP ratio is low M which tells us ATP is being consumed quickly does that drive lactate into the mitochondria or out to the liver yeah so recently actually not us but others have shown that lactate activates the mitochondria we have shown that lactate is a preferred fuel so tell me what that means what do you mean by lactate activates the mitochondria uh it activates lactate dehydrogenase the enzyme uh in mitochondri 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 acetal COA hanging around from fatty acid breakdown is that also being stimulated to run through the mitochondria at an accelerated rate good point to the contrary so lactate is not only if we we have compared glucose to lactate to fatty acids so so lact preferred over glucose in in the brain and muscle wherever but when you um the path of degradation of lactate is to generate this acetal COA and that inhibits the enzymes of that transport aceto COA or fatty acids into the mitochondria so lactate basically shuts the door blocks fatty acid metabolism so it inhibits and inos and I have shown this uh bux the cpt1 and two the carnitine palate Transporters these are Transporters that allow fatty acids to get into the mitochondria for oxidation so yes there is a competition among substrates and lactate shuts the door for fatty acid metabolism I'm struggling to understand te logically why that makes sense which just tells me I'm missing something cuz I would never for a second suggest my intuition should be better than a billion years of evolution but why is it that we would ever want to shut down a substrate for which we have an infinite Supply right because we you know again we're carrying around more than a 100,000 kilo calories 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 so in terms of our survival uh what are we going to save the uh the fats four the tiger okay I understand good good point thanks for catching that uh thanks for correcting my stupidity no no so so you're saying the reason Peter is if you are in a lactate dependence State there's some something has gone wrong from a you're basically in a sympathetic State and you don't have the luxury of slow burning fat exactly yeah okay so but fats are really important uh you can see this play out in in the in the natural world so we we fight we we hunt uh we escape and this is really glycogen glucose dependent now um our energy stores are depleted that's in recovery is when we're going to use these fats well 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 um we discussed this previously with inugo but I know we're going to talk about it again you look at lactate levels in you look at lactate levels uh in individuals at rest who have type 2 diabetes versus lactate levels at rest in worldclass athletes there's a significant difference and 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 and yet paradoxically the individual of type 2 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 that that basically uh shuts down the fat metabolism but think about this this is my my old thinking that lactate there is elevated because of lack of disposal not necessarily production it's there because of failure to dispose so what the new thinking might new thinking is the body uh has it in a diabetic situation has a hard time taking up glucose because of uh insulin signaling and the glute 4 mechanism is not working very well so 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 so uh and we see that not only in diabetes we see that in in the heart after Mi lactate is a preferred fuel well you think that what we had an MI because we had esea and we had a blockage why would the heart prefer a fast acting fuel versus a slow acting fuel because it needs energy because it needs to survive how does one measure um the kinetics by which one mole of lactate versus one mole of glucose versus one mole of fatty acid can produce ATP um what are the tools that allow you to make the observation um that one fuel is preferred over the others or that the kinetics of one fuel are faster than that of another yeah we've used thank you for that question we use isotop tracers to do that so when our first experiments to give uh with rats to give carbon 14 labeled lactate uh then we would go into the tissues and try to measure it it's all gone it's been burned it's out into the atmosphere meaning the only place that that c14 carbon would be found now is in carbon dioxide if you had a calorimeter yeah so we have done a number of experiments uh in collabor ation with others or just in our own we've developed a technique called the lactate clamp technique and it's analogous to the glucose clamp technique which some of our uh some of your physician uh listeners will know about that's where you raise the glucose level to a certain uh raise glucose to a certain level and uh then you can study the production versus the disposal so we Infuse lactate up to four molar and others have raised lactate even to higher when we do that we can measure the arterial venus difference for glucose uptake and it's suppressed in a study with UCLA uh 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 so it's this is done with a was done with a traumatic brain injury uh patient and you can see there's a blockage uh for glucose to get into the left front frontal LOE in this P patient the next day we infused lactate to 4 molar it completely stopped the glucose uptake no glucose uptate in a pet St skin I can show you the image and so I guess my question is this George so if I mean that clearly demonstrates that lactate is preferred over glucose but I think the jugular question is is is the brain getting more ATP from the lactate as a preferred fuel than the glucose which has one area of hypo profusion in other words are you able to by providing the preferred fuel actually get more energy to the neurons that are injured yeah so uh not a colleague but um a colleague in science pier medist in Switzerland has developed what he calls the asite neuron lactate shuttle and that's really sparked a lot of interest in the the metabolism of asites 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 hydroxy beate would also be another fuel for the brain it could be but not if glucose is around or correct y so the lactate will come in through the um so in in the injured brain there's an in for some reason maybe there's a block at this 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 MH so the uh brain is in a metabolic crisis after an injury globally it is so there's some neural networking which it just stops glycolysis so uh traditionally what Physicians would do is uh give glucose Infuse glucose and the glucose uptake well the metabolism is blocked so the glucose doesn't get in and doesn't do anything or give insulin plus glucose yes intranasal insulin was one of the tricks there right to try to drive more glucose uptake yeah but the gluc the brain doesn't Express glute four so uh that's not going to do much but now we have instead of the six carbon molecule we have couple of three carbon molecules and the lactate Transporters are highly expressed in the brain and we know that under nor normal circumstances what's happening is that the glucose is coming in being taken up by the astrocytes made into lactate with which are bathing the neurons in lactate and lactate is the fuel for neurons I misspoke of second ago though uh George I I could have sworn George Cahill demonstrated in those very famous fasting studies uh Circa you know 1960s 1970s that even in the presence of glucose the brain was still taking up significant beta hydroxy butter rate so I if if I'm not 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 so these individuals had beta hydroxy beate levels of four to five Millo which actually exceeded glucose concentration by this point glucose concentration would have been about 3 Millo in steady state so for folks listening to us who don't think in European terms 3 Millo of glucose means these people were walking around with a blood glucose of 55 milligrams per deciliter but it really never went below that so that's obviously pretty hypoglycemic but it's you know that's still 60% of what you would walk around with normally and glucose was meeting about 50% of their brains demand and about the other 50% was coming from the BHB so so at least in that situation the brain would split fuels now of course we I don't know that K Hill was measuring it so we don't we don't we just don't know what lactate was doing there but but it's an interesting observation that 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 among substrates more glucose less fatty acids more fatty acids uh vice versa okay ketones come in by the lactate transporter so the monoc carboxilate transporter is allows ketones to get in meaning BHB enters the cell through the same MCT transporter that would bring lactate into the cell yes okay I think I used to know that we we did this early on and there's a greater preference for lactate over bet hydroxy mutate so if the concentrations were the same the Transporters would move lactate as opposed to Beta hydroxy berate in other words if we could do a thought experiment or actually a literal experiment where um you could Infuse so so let's say you could do a you could clamp everything so you could make you could have a person walk around with four Millo of glucose four Millo of beta hydroxybutyrate 4 Mill of lactate and you're peripherally clamping those concentrations so you have equal concentrations of three fuels that the brain could use M what is your prediction for neuronal uptake based on that scenario if it's an uninjured person yes let's start with that yes the the preference would be for glucose and lactate and would it be roughly equal amounts of of those two in an uninjured brain roughly probably okay so you know we've published on we worked with the UCLA neurosurgery we did these experiments with uh dudo glucose and uh 13 C lactate so probably about the same yeah okay and then in an in an now let's talk about the injured brain so now you have a a TBI patient and you're doing the exact same thing you're infusing equal concentrations of of glucose lactate and and BHB what would you think we've already you you know everybody knows clinically that glucose is going to be suppressed how much of that is made up for by the lactate versus the BHB yeah so if lactates 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 how many people are aware of that agree with that I mean that's a so we uh for various reasons we lost our collaboration with UCLA neurosurgery but they were in the stage two clinical trial of infusing lactate uh and they weren't the only only ones there's a group in Switzerland who uh preferentially gives hypertonic lactate to TBI patients and they they appear to do better but uh we were hoping to have a clinical trial multi- Center trial demonstrating you know the use of lactate as as an augmentation to glucose in the TBI state but um I don't know what the status of those studies are but there was a stage two clinical trial that has started at UCLA George has anybody labeled lactate with fdg so that like or or you know some some like 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 so because because what I'm imagining is you everybody has seen the images of the injured brain under standard fdg pet where you have the hypo perfusion in the area and by the way this is relevant in diseases like Alzheimer's disease this is relevant in dementia where we see hypo perfusion of glucose um but it would be interesting if if it has already been done to see what the uptake of lactate is if you can put an F18 onto lactate which I assume is a trivial task right uh I don't know about that but uh our our colleague here at Berkeley Tom Budinger really helped develop pet and um help make NMR clinically relevant uh he did experiments with carbon 11 lactate so it g in the pet scanner it gives a signal as do fluo deoxy glucose so that way uh you could see lactate taken up by the brain the difficulty with those experiments I think the half-life of carbon carbon uh 11 is on the order of minutes 20 minutes so the first experiments involved somebody in the cyclotron making carbon 11 lactate putting it in a lead Line Station Wagon driving it down running it through a column to remove the strum 82 and then infusing it into a brain and 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 it seems like that would be a very interesting experiment though right I mean or at a minimum just to generate a hypothesis right that says we can fill an energetic Gap by using lactate and simply observing a difference in profusion pre and post lactate infusion uh I'm making a note okay I I I yeah it's possible it's if it hasn't been done I'm sure I'm missing something obvious about the the chemistry of it Budinger would do when he would do the experiments with glucose or lactate he also would give ridium 82 which is a uh an 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 uh and so you in the buttinger method you need to do two isotopes uh simultaneously and that's really tricky and hard to do clinically it's really as you described could be a great experiment but getting it to um work in uh clinical centers would be a real trick really yeah what about just in in sort of rodent studies of hypoperfusion um uh assume that would be an easier place to look at you know a TBI model where you ask if lactate can rescue the animal well we could just do that even without a tracer right exactly that's my point yeah you can you could get around the whole Tracer component by just doing that uh is there any issue with um infusing lact at higher concentrations is 4 M sufficient or is there any reason you couldn't put in 6 or 8 Millo yeah I think our friends in in Switzerland have got it up to 8 m but then you know you're using hypertonic lactate so but you can give vascular people need to understand it can't be too concentrated to make the blood uh really affected poorly when when we give patients like an intravenous bag of lactated ringers what's the concentration of lactate in that it's pretty low yeah okay yeah so uh 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 so there's that's sort of the upper limit of what you can give safely intravascularly without causing fitis or without causing crenation of the or the red blood cells shrinking and getting all distorted yep makes sense but four you can maintain you can clamp a person at 4 M quite safely and easily yeah and I think you know the idea was to do that for a couple hours a day not continuously again because we would have to make sure that uh the kidneys were not affected because we're giving a lot of sodium that was a concern so I was going to ask you about that so what's the manner in which the lactate is delivered uh in other words what else has to be delivered with it to balance the solution so a lactate uh an ion as a negative charge so to have put it into the blood you need you need to have something um with a positive charge and so uh the major cation in our blood is sodium so what's used is sodium lactate so in our studies we uh we could clamp to 4 mli 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 but again you are get going to be giving sodium so you have to make sure that in the patient they have good uh kidney function now I see you're making notes that's good oh you have no idea how many notes I make here George um the highest lactate I've ever measured in myself uh is about 18 Mill uh obviously after a very intense bout of exercise um 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 no lactate is there to moderate it's a strain response it's helping to protect you but you probably are uh have a severe acidosis I'm feeling like I'm about to die because my pH is probably 7.05 or something like that yeah yeah and I can I ask 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 blow brain barrier and works in the brain in the dentate not in the dentite gyus in the hypothalamus to inhibit your appetite so those of us you know who run 440 yards or 400 m we're not hungry for 3 hours right until that lactate levels is cleared which is really a good reason people have written about this recently it inhibits appetite lactate suppresses gin it works directly in the CNS so an advantage of doing an exercise not like that one you did Peter but getting lactate up to maybe three or four Millar would actually help satiate people I know there are people say well I exercise and I'm really so hungry afterwards while you're not exercising hard enough but if you do raise lactate it will cross the bloodb brain barrier it will inhibit grin secretion and it will suppress the appetite that's a very interesting point and and I know that people who are listening to this who are familiar with lactate testing um which I know is is a bit esoteric um but there is a fundamental difference between having your lactate at 1.5 Millo or 1 Millo which is where it might be if you go for kind of a brisk walk versus being at four Millo which is you know not a level you can sustain indefinitely but it's um it's it's not you know it's also not so strenuous that you could only do it for a few minutes I mean that's sort of uh you know uh a fit person could hold that that level of exertion for 30 to 40 minutes I think youren listeners will know that 4 mli m is talked about a lot let's talk a little bit about um differences between athletes and non-athletes uh which again I I think becomes very illustrative because they're simply different metabolically right so that it's not just that the athletes are stronger and the non-athletes are not um but but what's happening in terms of fuel partitioning that differentiates uh a highly highly trained aerobic athlete like a cyclist uh with you know someone who's got insulin resistance what what 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 mondria are the sinks or the disposal units so when any fluxes as you describe 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 uh a highly trained athlete exercises and here we need to talk about relative or absolute power output so let's say 65% of V2 Max or 65 % of effort for an untrained person well that's not very much exercise really they'll get to 65% of V2 Max a 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 and as you described earlier it's recirculating to the core recycle to support blood 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 uh sensation now if you take that same athlete now and you push him to a lactate that elicits maybe six or 8 Millar they're going to be really a lot of differences there and now 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 we mentioned in passing so glucan Genesis to making of glucose from lactate depends on good liver blood flow when you start going really really hard all your blood's going to go to your muscles basically and you're going to clamp down you're not going to profuse the liver so now that glucan Genesis goes down regardless of who you are when you sort of take the liver and the kidneys out of circulation now 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 I I I captured what you said as the individual is increasing um energy demand they're making more and more lactate um 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 glucogenic pathways yeah so go again your example of the athlete when we train we increase our mitochondrial Mass maybe 100% if we train we'll raise our V2 Max maybe 10 15% so the there's more plasticity in the muscle to increase the mitochondrial mass and I think really that's the key to Ino success with his athletes he trains them so they increase their mitochondrial Mass wait how did you say how much did you say you increase mitochondrial mass by well you can double it over what period of time well as far the first study on this perod in 1967 the journal biological chemistry was in rats was by John Hai uh and you could over the per period of several weeks of training rats you could do that uh after that we uh extended those studies a bit with Kevin Kelvin Davies when he was here and we again saw a doubling of the mitochondrial Mass uh uh others have looked into the the muscles of athletes and find found that uh 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 a for one gram of vastest lateralis in an athlete versus one gram of vastest lateralis in a non-athlete you'll see 2x the mitochondria you'll you'll see 2x the mitochondrial Mass so I I don't talk about yeah not necessarily the number of mitochondria because the volum yeah and and how is that um conveyed is that larger mitochondria plus more mitochondria that amounts to that doubling we talk about the mitochondrial reticulum so think about a tree budding and branching out leaves yep so if you do a thin section you'll see and you do Point counting one mitochondrian two mitochondrian three mitochondrian a th000 mitochondrian but they're all part of a network uh so what you have is a bigger bigger Energy Delivery system that goes from the cell's surface deep within the fiber through this network again some people call it the cellular Energy power grid and to your point which is you know has the experiment been done to demonstrate the causality of exercise there in 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 4 to 6 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 yeah well it works both ways if you're if you're if you're uh born with that and you go into Athletics you're successful and then that's right yeah and then if you're not then you become a professor that's sort of something I'm curious about I yeah it it goes up proportionally and interesting all the enzymes that are as far as we can tell all the constituents that make up this mitochondrial Network go up proportionally so you get twice as much CB cycle enzyme is twice as much electron transport cycle enzyme you basically activate the whole the whole system so George I was taught the following which I'm now almost assuming is going to be at best an oversimplification and at worst I might just be abjectly wrong um you you mentioned something called MCTS a moment ago do you want to tell folks what an MCT is oh yeah I I had to explain this to my wife Rosemary the sports medicine doctor what's an MCT well we were looking for the lactate transporter protein and uh said ah we got scooped somebody found it and and she called it her it was Dr K Christine Kim Garcia in the Goldstein lab in in Dallas and where it's a Nobel Prize lab and she found they were looking for Transporters of um um things that contributed to cholesterol metabolism and she found this protein and she didn't know what it was and she found out it was a lactate transporter and so they were called monoc carboxilate Transporters and now it it's like the glucose transporter field where we have the first ISO forum and the second one and the third and the fourth there are actually more more than four now that have been discovered when was the first one about 2000 okay so so what I was taught uh again uh we'll see we'll see how far off base I am was that one of the benefits of training was increasing the density of M 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 you know you imagine a little cartoon where I've got a muscle cell I'm untrained and I've got 50 MCTS and after training I've now got 100 MCTS after a period of time not acutely but you know years of training or whatever and therefore I can now make twice as much lactate and get that lactate out now 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 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 uh lactate flux game yes we've done this in animals and we've done it in uh looking at trained and untrained people and we can see an increase in the abundance of the MCTS now that that helps two ways because getting lactate into the mitochondrial Network requires an MCT so we were bold enough to look at the mitochondria and find MCTS so people think well it's just on the cell me membrane and it's good for E uh export and that's true but uh in um oxidative muscle fibers with a 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 um fast glycolytic fibers will be pale in color and they're they're pale because of less heem oxygen compounds they'll have less blood flow f capillaries PR fiber they'll have less myoglobin and mitochondria are the color of liver or vice versa liver is the color of mitochondria so uh those fibers when they made to contract they have less mitochondrial density they will export lactate but they can export it to a neighbor neighboring red fiber so we call this the cell cell lactate shuttle where a fast glycolytic fiber produces lactate and it's consumed by an adjacent fiber and never even appears in the Venus blood except as CO2 I'd never heard that George so just to make sure the listeners are following and that I'm following uh we've had many podcasts where of course we discuss type one and type two muscle fibers uh colloquially referred to as fast twitch and slow twitch fibers um so the the the slow twitch fiber the type one fiber is the red fiber it's the fiber that is uh dense in mitochondria it is the one that has the capacity for oxidative phosphorilation it is less powerful but much slower to fatigue right then you have these type two fibers and I'm oversimplifying a little bit because there are subtypes of them I understand but the type 2 fiber you know it's a more contractile it's a more powerful fiber uh Twitches a little faster but it's very fast to fatigue it's the White Fiber because it is lacking in the mitochondria does it outright lack mitochondria uh and and basically it's just a pure glycolytic fiber correct no 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 uh accumulate lactate they realize that their neighboring type one cells can make even more use of the lactate given that they have a greater con or greater density of mitochondria so they'll shuttle the lactate from the twos to the ones is that correct yeah wow yeah so that's that's actually part of the discovery of uh the lactate shuttle uh so early on when we started doing the studies on rats and using using c14 lactate and trated glucose and comparing the flux rates of the of the two and looking at the various fates of where the carbon goes um uh we knew that there was a with in exercise was a large flux but from the 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 made measure the lactate levels in blood in 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 two yeah so but let's I'll give you this just the 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 and and the red muscles the lactate level was lower than in arterial blood and that gave rise to the idea that the fast fibers were sharing lactate not just to the Venus blood but to the red fibers that were adjacent so the numbers I'm trying to remember this is back 30 years what the numbers were it would be something like in the fast fibers would be something like 10 to 12 mil equivalents in the blood it would be four and in the red fibers it would be three and then in the arterial and then that but the four was in Venus blood correct in blood no that would be arterial that was an arterial blood got it so that gave rise to this idea of the shunt or a shuttle some people call it a shunt mhm from white fibers to red fibers but and as you described it's easy for the White Fiber to export the lactate but it will exported in a three-dimensional sense being surrounded by slow red fibers um who can oxidize lactate God this is just so so so when when did you first find uh MCTS on mitochondrial membranes what year did you first publish that about 95 so what percentage of the relevant scientific Community acknowledge is that now again am I just taking this is it is it taken for granted within your world that that is completely uh settled and is it just that it I mean that hasn't made it out to any of the textbooks yet oh Well Tom Fay and I are revising our textbook we're going to get it right but yes yes said there's been Stonewall silence for instance in Science magazine azine they published papers on the mitochondrial pyu transporter two papers simultaneously about this discovery of the pyu Transporters previously we had shown the mitochondrial lactate transporter 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 so so this is interesting why why I mean I I know this is kind of a these are difficult questions to answer so I'm sensitive to that but but why do you think that something that was discovered 30 years ago uh that appears quite gerine to the physiology of everything but if nothing else just through the physiology of exercise but it clearly extends beyond that um why why do you think that this isn't more widely understood even in the the the the physiologic circles that you you travel in yeah I think I said it earlier people who do science and medicine or smart people they learned it a certain way and that's what they it's their set point but I tend to differ between scientists and Physicians and and I say this as no disrespect to my profession but I I think that that makes more sense at the physician level where look you know medical school is drinking from a fire hose you don't it's sort it's almost beat out of you to question things because you you frankly don't have the time right you've got two years to learn so much um but I I I would have to think that that's quite different for people who choose uh a scientific pathway where Discovery uh questioning Orthodox beliefs you know that is the name of the game uh I'm is is there something I'm missing here so maybe there is a a difference between science and medicine this regard so when I given the opportunity I will talk to for instance the Washington thoracic society and go to a meeting and and talk to the docs and because when they see lactate they start infusing bicarbonate uh right and or they give oxygen so uh in the medical field there's a character maybe someday you would really enjoy meeting this his name is Ronaldo Bello he's a world-renowned uh physician mer room physician and he's written about the fact that pulmonologists need to be more like exercise physiologist with regard to understanding lactate metabolism he challenges his colleagues to to do that and B was Bello is a big name in the field so there's has been a lot of inertia in this but I think we're getting some momentum so I want 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 so this is this is I I'm not going to name him but but I but but I already talked with him about uh you know maybe potentially telling his story so so this is a friend of mine who is really an exceptional cyclist okay he is probably in the top he would he would easily be in the top 10 uh am cyclists in the country okay so um 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 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 um and you know whatever he weighs about 80 kilos um so again for I understand that people listening to us might not understand what 430 Watts feels like uh let alone what it would feel like for an hour but 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 uh and and and actually a great triathlete as well so great swimmer and Runner but really on the bike is where he shines and these are you know 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 uh even at my best I was my FTP was lower than his right at my very best um 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 okay um he was over at my house last week George and we were lifting weights together now he doesn't lift weights anymore he is all of his energy goes into uh cycling and I do everything I'm kind of a a a jack of all trade master of nothing and 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 some squats right and um 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 and I said tell me how this feels and he said oh there's no way in hell 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 right because his legs are so Superior to mine in generating absurdly High wattage for a long period of time yet when I'm you know asking him to do this different type of task which is clearly more recruiting of a type two muscle fiber um he doesn't have the contractile Force so we he and I ended up having a great discussion about this because it was like oh it's so interesting that you know you're not as strong in this regard as I would have expected and yet you're so Superior in this other way and what we got talking about was the differences in our metabolism right 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 you know a squat it's how much stronger he is than me on a bike right so that's a long- winded background but now I want you to imagine you had muscle biopsies of both of us right so you now you've got his quads and my quads what is it about him that is allowing him him to hold 430 watts per kilo uh pardon me 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 and that's really the point I'm trying to make right what is it that he is doing that is so special and and that which all you know exceptional athletes can do well not all it's uh Sports specific so yeah all exceptional cyclists right or endurance athletes you described it earlier as the flow of energy and so I would guess that he had was mostly type one fibers these red fibers that are highly profused that have the mitochondrial reticulum really highly expressed so he can have a high carbon flux um 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 so the fact that he can exert a as greater force as you probably um means that uh he's a he's got the slow red fiber type and he also hasn't learned how to do it he probably could work with him a couple times he might improve you know just jump up a little bit by learning well that that yeah by the way that I want to make that point I am totally confident that in three weeks he would be leg he would be squatting his he he would be doing his you know the same amount of weight than me again the point is not so much that he yeah 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 yeah that's that's the bigger Point even though ostensibly I'm stronger yeah because it's different you we're talking about different metabolic systems or a metabolic system surfit Surplus versus a contractable uh entity that coexist together in the same muscle of course one feeds the other so in his case of cycling he's his muscle power output is limited by the carbon flow that he can sustain ah okay so thank you that's exactly where I want to go with this how much is he limited by carbon flux input versus uh 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 yeah I would 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 and a lot has of that would have to do with this the 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 it's going to or we're talking about carbon flux because that glycolytic flux goes to lactate and nobody knew that until we traced it and and that that gets oxidized so what he what you have is this um production versus disposal capacity and he's got a great disposal capacity for carbohydr when he 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 Venus blood his type one and his type two fibers for lactate concentration what would be your prediction so we've we haven't done this with trained athletes but we've done it with some people who are physically fit and uh Recreation recreationally competent so you can see um lactate uh very high in the Venus effin of a working muscle I'm going to just make up some numbers here 10 to 12 and uh at the same time we since we had arterial sampling versus femal venous sampling when the blood goes around the body not even one complete passage it's down to 4 molar so there are lactate pyate conversions happening in the blood in part by the red blood cells and in part by the lung parenchima cuz all the blood goes through the lungs yeah I was about to say when you sample that Venus uh blood at 10 to 12 Millo um it wouldn't matter if you're doing that pre or post portal vein because I would think that the if if you I mean you could not do that easily but just you know if you 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's it's it wasn't a mixed Venus sample but we had a femoral sample so in part dilution so so you're doing it pre- liver obviously so you're getting the absolute peak level of lactate that's that's very interesting George I never thought of this all those times I'm sitting there poking my finger and my earlobe I'm probably underestimating the Venus concentration of lactate because it's already had a hepatic pass right it hasn't had a hepatic pass it's had a hepatic dilution and it's gone 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 MMO 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 Millo in the in the femoral blood supply as it's exiting the muscle correct it hasn't been explored much we just have a couple of papers on it and one is by um Matthew both are by Matthew Johnson and another by Greg Henderson Matt is uh you know Matt Johnson there's two actually I don't okay uh so Matt is works at DES Dexcom he's a a research scientist at tecom they make the glucose analyzers yep uh maybe maybe I have crossed paths with him I know some people at at Dexcom and um but but oh actually no no I'm I take that I do know I do know Matt Johnson that's exactly right he did a post in your lab he was a graduate student he was a graduate student yep yeah and he was a with Shir at the Mayo Clinic so he really highly trained uh uh so his his dissertation was just to infuse Venus femoral Venus lactate and look in the arterial side and you can see there's a huge change in concentration and we attributed that to the pulmonary function but you're you're pointing out we probably missed the hepatic dilution uh effect yeah and wouldn't there be a way to I mean wouldn't you just be able to use like C4 14 lactate Infuse it and then look at how much c14 uh 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 in 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 calorimetry or indirect calorimetry rather you could measure the C13 CO2 coming out of the lungs right yeah well it you know it gets tricky cuz measuring CO2 content is you know really hard because most of the CO2 is carried as bicarbonate carbamino it's temperature dependent pH dependent we've done some of that um getting What's called the RQ um but we haven't done it as you described Peter so 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 it's either going some of it's going to make glucose in the liver and some of it is being expired yep and again in all our studies we get oxidation is about 75 to 80% H so your initial premonition or a premonition hypothesis but really we're talking about carbon flow energy flow G lactate can flow to around the body and be removed in diverse ways can be reconverted to glucose which then gets oxidized uh or it can be just oxidized directly in the muscle or in other muscles so for instance so working 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 that's very interesting George you know I had always assumed that the reason um I could both see in myself and other athletes the highest levels of lactate following a swim right like a a a 200 or 400 yard medley swim where you're doing all four strokes um you know it's a you know several minute effort um that that was if your if the goal was how high can you make your lactate that's the exercise to do it um maybe followed by rowing I just assumed it was because you had more muscles involved I didn't uh 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 this disproportionate uh two type two fibers in the upper body relative to the lower body is that yeah did I hear you correctly in that regard yeah ask somebody if they like changing a light bulb I get tired right away that's so how did I not know that I mean I feel like what have I been doing for the last 30 years like clearly not learning you haven't been changing light bulbs that's such a good point yeah the upper body really can get pretty fatigued relative to lower body um uh super interesting so if we look at fiber typing and you know but we have we're evolved to use our arms in different ways uh we use them at a low level and at some point maybe we want to talk about uh the size principle so our type one fibers are easily recruited do lowlevel things help us writing taking notes uh we're using type 1 fibers but now uh if we have to to lift something heavier now we need to recruit those type two fibers and working overhead uh where using type two fibers and we really having clearance problems so that's really fatiguing let's talk a little bit about um cancer um we alluded to it at the outset with the warberg or varberg effect where cancer cells seemingly in the presence of unlimited oxygen still seemingly choose a metabolic pathway that avoids the mitochondria although 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 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 they they don't want to use fatty acids they just want to use glucose and they just want to make lactate uh um 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 lack date um that hypothesis doesn't seem to be the case uh and it seems that there are other reasons um famously Luke Hanley Craig Thompson and I think uh at least one other uh colleague wrote uh it was Matt vanderheiden if I'm not mistaken that well this the cancer cell is not optimizing for ATP and 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 uh without stopping and that's why it's it's doing that it's it's making it's going down the lactate Pathway to generate more carbon nitrogen whatever else it needs to actually build a cell um tell me a little bit now about where your uh your discoveries kind of fit into this hypothesis around why a cancer cell would follow the principle of the warberg effect yeah well um maybe that's a Nobel Prize right understand that because I do uh to rephrase that I think the answer has been staring Us in the face cancer is a is a problem of glycolysis unrestrained G glycolysis and Ino 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 um the expression of certain glycolytic enzymes and I don't want to spill any of those uh beans here um about this uh it has to do with the expression of glycolytic enzymes and it looks as if that in all the various stages of cancer progression lactate um stimulates those so uh and anyo is now looking at sort of the mitochondrial basis for that so my so to repeat what you said cancer cells do have mitochondria we've seen that other people have seen that and they're capable of oxidizing uh different substrates in including lactate but the lactate is generated uh the high lactate production seems to stimulate a lot of things that are unto in cancer and one of the papers that Ino and I first wrote was to look at all the adaptations in muscle to training and look at uh 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 uh cancer cells do generate a lot of lactate and the lactate is injurious in those cells so you know it would be easy to listen to that statement and say a cancer patient should never be exercising but 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 so I I used to believe the first one oh my gosh we don't want to generate lactate but then I 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 uh if lactate is carcinogenic by removing it you lessen the chance for carcinogenesis yeah I mean that that that that's just simply kind of remarkable statements right I mean if um first of all that lactate is is carcinogenic is is kind of remarkable um and then it feeds to the difference between concentration and flux or flow this is the most I 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 it's something near and dear to my heart right which is you look at intramyocellular 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 2 diabetes both have high amounts of intram cellular fat yeah well of course the difference is in the person with type 2 diabetes it's static it's stagnant it sits there and it is one of the positive drivers of insulin resistance uh yet in the athlete it's just a it's a carbon flow it's just it's moving it's it's not you know it's the difference between a stagnant pond and a flowing river yeah um 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 you know the complex instrumentation you use in a lap yeah that's true and just to elaborate more on so the the marathon or Paradox if you do an em and you find a mitochondrial n network you'll see a fat globule right next to it so the potential for fat oxidation is great uh in our work we've done some uh m mrss and MRI and we've looked at athletes and um they don't use much fat during exercise but in the recovery period you know when glycogen is low that's the period of fat burning so those those fats there are um preconditioning prepositioning fuel supply in recovery when glycolysis switches off and people start to relax so you're right about this whole idea of flux also in diabetes glucose is High Why was it produced too much or not cleared right y yeah it's a great Point yeah so that's easier to explain with glucose than with lactate people more readily ex understand the Dynamics of appearance versus disappearance and the H the level tell is informative but it's not the whole story so we've talked a little bit about well quite a bit about lactate in athletic performance I have a much better understanding of that we you've talked about something very very tantalizing with respect to brain health and TBI and I'm very much hoping that that this is being investigated I mean again TBI is something where uh fortunately people are so much more aware of it today but yet we still seem relatively um poor in therapy and if we had a tool a metabolic tool to Aid following a concussion Ian I mean imagine if there was a concussion protocol that said every time a person got a concussion they were to receive intravenous lactate you know for X number of consecutive days four hours a day at four Millo um again very testable hypotheses here it's it's a little uh frustrating to think that that this type of work isn't being funded given I mean heck I would have the NFL uh player Association be you know you know look into this right because you clearly have a high volume uh of individuals who are susceptible to concussions and it would be easy to test that we've talked a little bit about the role of lactate in cancer although we'll we'll save that for maybe the next time I have in you go back on and let him uh 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 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 La lactate clearance you must exercise yes are there other disease States besides these conditions we've discussed where lactate plays an important role in the pathophysiology well you you suggested earlier on brain health dementia Alzheimer's so it's really looking that exercise as prot protective not just card game kind of mental exercises but physical exercise and people talking about uh brain blood flow and the delivery of substrates and in fact uh some people are talking about the role of lactate and stimulating neurogen neurogenesis and the dentate gyus looking at uh development of new brain cells um which is uh which used to be uh a really heretical idea the the original idea was that when we were born we have a certain number of brain cells now we know that there's a turnover brain cells and they're renewed and we know that the pro problems can occur when the progenitor cells are damaged or injured or not stimulated in some way so I think there's a big future for investigators to be working in the field of uh physical activity and aging um and the health span we talked very briefly about the role of lactic uh well we of lactate specifically in as a precursor um or a canary in the coal mine around sepsis yeah do you believe that that is still a valuable tool oh yes definitely but so the so to follow Bello's argument okay show me where there's 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 and it's it's a strain and understanding stress and strain sorry just just to back up for a second 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 is that is that the question he's posing okay and then tell me what their response is to that question I don't know what the response is to that nobody can identify it but my own and I've written about this anticipating this kind of general question where is this la coming from I think it might be coming from the gut um personally that's 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 um now okay so I measured a lactate level in a patient and it's up to 10 Millo that's bad news but am I supposed to take that patient to the operating room and look for aeic bowel like it there's still a bit of a that tells you that 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 the part of it is because the microbes uh are producing reic lactate they're producing L lactate and D lactate and most of our body runs on the the form of lactate it's identified as L lactate but I think in there's a lot of deact going on that is formed in the lower bow uh as opposed to the upper bow is that how how easy is it to distinguish between those two what uh it's been so long since I've done organic chemistry I don't remember how we distinguish I I I understand the difference between a d and an L but I don't remember how one measures it oh so most of most of all the analyzers we have Hospital elsewhere measure the L form and these are like I'm holding up my hands here on purpose to say one is the mirror image of the other and the L is the form we usually um 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 in large part people can't really see the extent of the lactatemia that occurs in sepsis wait a minute you're saying that when we measure the 10 Millo in the septic patient the 10 Millo is only the L lactate concentration because that's all the assay measures but there could be 20 MMO of delate there that is actually causing a problem yeah H how could we confirm or refute that well we would need to have a special I think there is this is your field not mine there's a term deacti acidosis and we know delaat is is toxic so now we would need a special kind of uh analyzer to detect it and it's not the common analyzer that's around all the analyzers the blood gas analyzers uh the portable devices um most of the enzyme techniques um the the recipe in B bergm Tech book is for lactate do you have the uh ability in your lab if you wanted to measure Del lactate to do so no I've in the past I've submitted some Grant applications with clinicians who would would want to do this and we haven't gotten very far interesting so where from where where do we derive the belief that delate is neurotoxic and pro-inflammatory yeah because if if you give it it is and 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 uh the less desirable form of it and that the L lactate that which you're actually measuring is probably not causing any of the problems associated with the sepsis it's just the it's you know it's telling you that something else is going on yeah and those those microbes will make lactate regardless of the presence of oxygen so if if you were saying well there got es schia and you you mentioned it would be very hard to demonstrate that and you wouldn't want to actually maybe bother bothering to measure it measuring it if you have microbe that's gener is the S of this lactate generation so 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 it's all been a muscle thing so we did a very simple test we Ed our Isotopes as we um usually do we had had aboard carbon 13 labeled lactate and then uh dudo glucose and uh D5 glycerol so we could measure lactate glycerol and glucose o at the same time and then we gave uh 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 an enteric glycolysis that takes place and this is the way the body participates in distributing carbohydrate energy to make lactate so that's so this just changes our mind completely but sorry George did we not know before this that when you consume gluc lactate goes up we know that and nobody would understand why it's part of the lactate shuttle I presented this uh in our most recent studies at last year at the American Diabetes Association there was a doct there from NIH and he said well we feed carbohydrate we get 2 Millar lactate so must a deal that's that's the way the body is working in sports we would say it's hiding the ball in baseball we hide the ball in football we try to hide the ball here are the bodies Trying to minimize the glucose load but still deliver carbohydrate energy and it starts with the interos sites and they got so there are plenty of studies where people would incubate inyes under air give glucose immediately you have lactate and just give me a sense of scale right so when you give uh somebody an oral glucose tolerance test this is 75 gram 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 uh milligrams per deciliter to 150 milligrams per deciliter correct yeah and lactate might double maybe go from 6 to 1 2 Millo correct correct from a mass balance perspective I'm not smart enough to remember how to do this can you remind me how much carbon went in each of those two paths yeah so uh good point we're just talking about the concentration but earlier we talked about the flux yeah okay so so it looks like the liver is really really important in this whole thing and we did touch on the liver and its importance 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 uh shuttle carboh carbohydrate energy so you said the blood glucose will rise and it will go will double but it doesn't get uh that high until 30 minutes after the test whereas if I give the glucose the lactate is spiking in 5 minutes reaching a Peak at 15 minutes then Sub sub uh subsiding and now the glucose is starting become the carbohydrate energy form but 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 a that's still a trivial amount of absolute glucose difference concentration it's a difference of five grams of glucose in the entire circulation that would explain that Delta you still gave the person 75 G in other words we have to account for 70 more grams of glucose and my thinking was that most of that's in the muscle right that's when we we do oral glucose tolerance tests on everybody George I mean we we are you know we 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 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 um 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 ocytes turning into lactate as an alternative fuel source yeah so that's that's the first part of what happens we we saw it and we were we were uh lucky uh to have arterialized blood so we could see the spike and lactate that comes out after taking glucose way before the glucose starts to rise and then from our isotope uh technology we could see that when glucose is rising it's giving rise to lactate that's the 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 uh in our paper we referen the work of stender who gave 13 C uh glucose in an ogt the liver the liver picks up most of it and the liver is basically sequesters about 80% of the glucose load and then dos it out over time and it starts to release this glucose after about uh trying to remember their study 30 minutes meanwhile lacta has a big role it plays a role and meanwhile the glucose is still in the liver and now it starts to be doled out it's being released is glucose and that's getting converted to lactate in the muscles and that's what's called the sort of indirect pathway uh 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 these dietary nutritive aspects of okay glucose gets taken up or and lact lactate is glucose is taken up made into lactate or what if we have fats there like a real meal not not just an O GT maybe a meal tolerance test we would um we would do this a version of this was done by somebody named schlicker in Germany and they did this really incredible study they 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 uh a meal test and they made porridge out of this stuff and they looked at the appearance of um lactate and glucose in the blood and they saw the same thing we did right away is's a spike and lactate and they said well lactates the whole story but they forgot about the liver so you're saying in most 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 and then the liver starts doing that back out the muscle picks it up and then the muscle is your your secondary production of lactate is by the muscle your primary production is by the osy on immediate and then that's why you get two peaks of lactate right you get the first fast peak in response to the anosy making lactate and then you get a second delayed slower Peak when the muscles get it from get the glucose from the liver and start making lactate yeah and one of our core investigators is UMES masharani he's a diabetologist at UCSF and he said well if he that's how metformin works so um for our uh our listeners ERS your listeners uh metformin is the most popularly prescribed drug for high blood sugar and one of the concerns is that when you give that drug lactate Rises and umash is very comfortable saying well the body is making lactate so metformin is encouraging and terites to make lactate that's why the lactates high and that's a good thing very interesting um as you know there's a a body of literature suggesting that metformin May enhance exercise performance pardon me May impede exercise performance um and again the problem with metformin is for the You know despite the fact that this Drug's been around it's almost as old as God um 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 you know reducing hepatic gluc output can be attributed to what right so the I guess the conventional thinking on Metformin is it's inhibiting complex one of the mitochondria correct yeah and if you inhibit complex one you're God you're activating am kinas that should reduce hepatic glucose output correct it does that but it's it's always been I mean it's it's as as sure as God made little green apples anybody on Metformin has higher lactate levels and that that's that's a bad thing or was a bad thing maybe it's a way to deliver carbohydrate energy well yeah I mean I I I I had always assumed that the the doubling at least doubling if not 3x increase in uh resting lactate levels in the case of Metformin were due to the mitochondrial the complex one inhibition right I mean that's you know just again obviously a maybe naive assumption but it was hey if you're inhibiting the electron transport chain of course you're going to have more lactate um but that may be true true and unrelated that's what yeah that's why I want to give carbon 13 C lactate uh 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 you could really we could start very well with an ro1 uh basic research Grant uh that's $2.5 million yeah that would be a to start that's just a handle of 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 uh both on and off met Forin it would be interesting to see the difference in lactate production uh in those two uh individuals and it would be interesting to also see if there was a way quantify this uh osy production yeah Dr M and I want to do that so with with metformin uh if we give metformin and there's an increase in lactate uh in the plasma is that uh due to um production outstripping removal or is are we actually increasing the oxidation the oxidative disposal of um glucose or is the glucose H High because of increased glucogenesis we could answer all of these things with our combination of tracers we use again let's go back to Conventional wisdom what were we taught in medical school and residency be careful of Metformin because you increase the risk of lactic acidosis so a person on metet foran is at an increase risk for lactic acidosis if they get dehydrated if they get contrast in a CT scan um when viewing that uh that that uh that concern through the lens of what we've just discussed does it make sense well caution is always advised first Do no harm right so when we we're prescribing this medicine we don't know if it increases uh lactate production or inhibits disposal right but let's go back to the 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 what's the change in PH yeah what happens when when you take those subjects the TBI subjects and you give you clamp them at 4 Millo you said if I recall there was no change in sodium but I think you also said there was no change in PH oh there's a slight alkalosis slight alkalosis how much 7.38 to what uh 7.38 to 7.35 well that would be a slight acid excuse me just the opposite way 7.4 okay okay and the colleagues that you referenced in Germany I think or Switzerland who were taking people up to 8 Millo were they seeing an acidosis uh they did not report it okay so does that mean it's possible that high levels of lactate do not materially alter acidbase physiology well uh in your experience is is sodium lactate given in metabolic acidosis sometimes it is yeah but the lactate concentration is very low in that setting like it wouldn't be as high as what you're I mean you're the examples you're citing are much better examples to ask this question because of the you know you're clamping people at a really really high lactate that you just don't get to but again it seems to me that if what you're saying is correct George there's a lot we're we're misinterpreting from for example sepsis literature right 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 D by given by driven by different processes yeah exactly so when you when you uh we addressed this earlier I I I think if you see a low PH yeah you need to do something if you see a higher lactate and the absence of a change in pH I would be very uh inclined not to do much very interesting you you you you've given me and and everybody listening a lot to think about here George um so it seems to me that that understanding the the the full flux the full mass balance of lactate both exogenous and endogenous is a necessary step to to to to fulfill our understanding a metabolism in a more complete manner correct yeah thank you I think so all right and you mentioned endogenous versus exogenous so when we in exogenous means we're going to infuse lactate or put it in the body some way um well I learned in organic chemistry the salt of an acid is a base so it's not unexpected that U when you give it pH will rise slightly and maybe part of that also is sodium uh so uh yeah what what does it mean to to use this exogenous stuff so lactate uh is distinguished from pyruvate and lactate is um reduced it has more hydrogen on it there one more hydrogen than pyruvate so that double that keto Bond on pyruvate a double bond oxygen uh becomes uh hydrogen so it's more reduced now when you start putting in this reduced equivalent into the blood it's going to go around the whole body and change redoxin a number of tissues all the tissues basically to which it's going to where the lactate is going to go so lactate is is a powerful signal and it works in diverse ways to activate various Pathways in including by changing cell Redux 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 uh directly and Visa Redux what do we know about uh other forms of of signaling and expression of genes so there's a new field now so we used to think genes are regulated in part epigenetically by acetalation or methylation now we realize they're also lacated so uh we've done some of those experiments here in our lab we haven't P published it but the lactate is a predominant uh um metabolite and it can binded to a genes and it it can affect gene expression mean meaning it it can covalently bind mhm A cation methylation lacation that's actually a term and I was it going to compliment you on you're reading the literature CU you can look that up in PubMed and you can see that people are starting to look at lacation of histones by uh raising lactate so it's not through histone acetalation it's direct lactate binding La yeah and it's called lacation yeah Dr AA you've got us up into the into the stratosphere here of where science needs to go starting with the premise exercise is healthful uh how can it affect um body Corpus promote healthful Living Well prob possibly in part by uh lacation of histones promoting mitochondrial biogenesis it's very interesting because we we we we've talked about all of these benefits of exercise right we talk about how you know my friend clearly has more mitochondria than I do and he's he has more MCTS and he's so much better at clearing lactate and all of these things but 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 was teih Hashimoto we publish a paper um if you just take muscles put them in a 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 I would have to believe it it also must involve something favorable with consumption it can't just be INF like in other words I have a hard time belie leaving if you took my friend and you took me right and you would argue based on his training and based on my training you know I'm on a bike 3 or 4 hours a week he's on a bike 15 to 20 hours a week um 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 if you came up with an experiment that you imagine you could do this where you could give you could pair feetus lactate okay so in other words for every Millo 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 M so it's hard for me to imagine that lactate by itself would be the signal I I have to think there's something associated with the benefits of how lactate is consumed during exercise so yeah this is a this is of interest in the literature now people are doing lactate clamps on people and uh looking for increases in mitochondrial protein expression and what are they seeing there's sometimes yes and sometimes no this this sounds a lot like amino acids has to do with the endogenous for versus the exogenous because you get a completely different signal so it's the endogenous lactate when it's high seems to stimulate mitochondrial biogenesis rather than just infusing it okay but why would that be well a lot of these pathways are redo sensitive ah okay so make sure I want to make sure the listener understands that that's a very important point because it's redo sensitive that's just fancy speak for saying it depends on the amount of 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 in in in concert with exercise you get the lactate but you also get the pH pertubation that is the the key to unlock its potential that's a very good explanation of what seeing this is again work of others or really serious scientists and uh and I think it has to do the mix results they they are getting it depends on whether it's exogenous or endogenously produced lactate so of course it would beg a question which again if if 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 right I would want to take you know take a whole bunch of people with traumatic brain injuries or concussions you give what so you got a placebo group you've got a group where you just Infuse more glucose and Insulin intranasal insulin and glucose right another group where you just Infuse lactate you take them to equal concentration of lactate glucose so you take them up to five Millo of both then you have another group where you do that but they exercise two hours a day steady state like Zone to you know just enough to get their own endogenous lactate up to about 2 Millo and then you know get that clearance because you 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 Redux potential as well as the lactate yeah so we've we thought about this so the TBI patient is probably not in the card to doing any exercise but what about functional electrical stimulation of a comose patient yeah although I think I mean I I know a lot of people that have had tbis I don't think they'd be up for strenuous exercise but I wouldn't they be up for even you know just oh you're talking about M well yeah yeah yeah the setting was you know sorry yeah I I mean like somebody who's had a concussion but they're still functional but they're suffering sort of the the the the negative consequences of it yeah well I think you would want to encourage mild exercise on these people yeah I was talking about the the yeah someone who's comos with a significant CNS injury yeah well how do you raise lactate in them endogenously mild electrical stimulation it's it it all comes back to uh to meoff right well it that's the beginning yeah yeah we're back to frogs with electrodes well we're not 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 uh so and get back to our story about the muscle fibers a lactate producer a lactate consumer exchanging chemical energy or our studies um on healthy people with heart when we're exercising our muscles hard enough are going to release lactate but it's now the favorite fuel for the heart uh studies that Hashimoto did of executive function he did these with Neil seer in Copenhagen give people uh tests of standard cognitive tests then they exercise and build up their lactate they score better then they recover their lactate comes down they go back to their basil scores it's brain fuel so think about the PE class getting kid out to run around 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 the you know the ex the the amount of of contribution of each for example we all know know that when you exercise bdnf goes up and clotho goes up and all of those things have procognitive benefits as well yeah um so it's probably difficult to just um assign all of the benefit of exercise there's a clear obvious benefit between exercise and cognition um and what it sounds like is that there are many uh biochemical Pathways that feed that and and lactate May indeed be a preferred energy source there's one study where lactate was infused and bdnf went up interestingly I I'd love to see I wonder if anyone has ever looked at lactate infusion and clotho uh uh concentrations I don't know yeah well George this has been very interesting and Illuminating um 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 um at best incomplete and in some cases incorrect um so uh I'm I'm glad we have finally had a CH to sit down and go through some of this really incredible work I I do hope that somebody uh in a position of funding is listening to this and realizes that for a relatively small sum of money uh 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 um and the interplay with glucose especially uh and the role of the liver and the Enos sites um so anyway I'm I'm I'm hopeful that with the reach of this podcast that uh that that someone's listening and uh they think Yep this is a good use of funds thank you Peter I agree completely and thanks for the opportunity uh and again my physician friends listen to you more than they me and now that they listen to you they'll listen to me now they're stuck listening to you all right thanks George cheers [Music] w