welcome to the metabolic link a medical and science focused podcast that explores the common thread of metabolism in health and disease this is where science meets Society hi everyone welcome back to another episode of the metabolic link I'm your host Dr Angela Poff and I'm a research scientist who studies the role of metabolism in health and disease on today's episode we have an outstanding presentation from Dr Jeff volik entitled exploring the keto adapted phenotype focus on muscle Dr volik is a registered dietitian research scientist and a true Pioneer in the world of low carbohydrate and ketogenic nutrition his decad spanning career has contributed some of the most important and fundamental work in this field so I hope that you listen learn a little something and really enjoy this episode Dr bik is our next speaker he is a professor in the department of human science at the Ohio State University for the last two decades Dr bck has his work has contributed to the existing science on ketones and ketogenic diets and the adaptation to ketogenic diets or keto adaptation uh and their use as a therapeutic tool for managing things like insulin resistance but also for optimizing Human Performance and resilience his work has been included uh has has been in more than than 3,000 peer-reviewed scientific Publications uh including manuscripts and five books including New York Times best seller book he has provided more than 200 lectures uh in scientific and Industry conferences around the world he is also the co-founder uh and former uh Chief scientific officer of verta Health uh the first clinically proven treatment to safety to safely sustaining and reversing type 2 diabetes without medic a and without surgery so Dr bik's talk is entitled exploring the keto adapted phenotype focus on muscle without further Ado let's introduce our next speaker thank [Applause] you all right thank you Dom just minor correction that I think you added a zero to my Publications but that's a good goal 3,000 Madison marked that down we got our work work cut out for us uh but it's great to be here good morning everybody uh as Dom mentioned I'm going to talk today about adaptations in muscle um and and you know congratulations Dom and all the uh organizers it's just a fantastic meeting gets better every year you guys didn't give me any real specifics to talk about so I um I'm actually going to go off a little bit the beaten path here and I've identified three areas that I think are underappreciated in terms of how ketones and ketogenic diets impact muscle and one of those is related to uh glycogen metabolism and some interesting data that we published close to a decade ago I guess but really hasn't been followed up on to my knowledge another one is related to the idea of uh Ketone production in in muscle particularly skeletal muscle and then I want to share some really provocative newer data uh that has to do with Ketone metabolism and heart function cardiac function now I know for everyone here uh it's kind of an echo chamber when it comes to talking about the positive effects of ketones but clearly ketones have been beaten up over the last really century and a half and there's a lot of reasons for that uh has to do with the way they were discovered uh has to do with the fact that their substrate is fat uh so there's a lot of ignorance and misunderstanding and misconceptions around ketones in the general uh Health Fields And even in uh you know in medicine and uh in dietetics so uh you know really it's it's it's almost the world turned upside down when you look at the New Evidence around ketones that's emerging on a on a weekly monthly basis uh you know ketones are being described as super fuels now and Longevity metabolites and a Superior Energy Supply so uh you know it's really a fascinating time right now to be rehabilitating this negative connotation around ketones and embracing all this really exciting science around uh ketones as a beneficial molecule so uh following up on that uh I really think it's important to understand Ketone concentrations and what one little fact that's fascinating is that ketones span over four orders of magnitude in the circulation depending on the the stimuli and the type of diet and conditions uh you may be experiencing and so the vast majority of people on a standard American diet are you know their Ketone levels are probably between 0.1 and 0 2 maybe you know occasionally in the morning after an overnight fast up to 3 and when you restrict carbohydrates uh and and adopt a ketogenic diet those levels increase by an order of magnitude and this is not a linear scale by the way this is a loog logarithmic scale uh so they'll go up you know and we we kind of Define this as nutritional ketosis somewhere between around 4.5 at the lower end all the way up to about four or five Millar and of course we know we can achieve this too with exogenous ketones now at least transiently uh so this is quite a bit higher than what you know most people are experiencing on a on a typical American diet and then um you know there is a thing called starvation ketosis and you can bump levels up a little higher than you can with the ketogenic diet so you might see levels six to 7 8 n Millar but that's still quite a bit different than what you experience in keto acidosis which of course is is very serious life-threatening dangerous situation uh so understanding you know where your ketones are in this range is really important and I might you know go as far to propose some different nomenclature around this uh because you know this idea of what is normal what is the you know what is the normal Ketone level um or maybe a better question is what is the optimal Ketone level for an individual or for a particular therapeutic Target uh these are really important questions and I think a good argument can be made that this level of ketones in the range of nutritional ketosis is an optimal range for many people and so terminology we might consider um is that a normal range of ketones is ukia is this 0.5 to four five Millar much like with glucose we have hypoglycemia UG glycemia and hyperglycemia so if you're on a typical American diet you are hypo you have hypo ketonemia and then Reserve hyper ketonemia is is something that's more along the lines of Keto acidosis so there are many ways to elevate your ketones and traditionally we've we've thought about ketogenic diets as a as a standard way to do that uh we now have a variety of exogenous Ketone formulas that range from salts to free acid to uh Esters and those clearly acutely raise ketones transiently uh but if you use those repe L you can keep your ketones levels quite quite elevated over time fasting uh will raise ketones because they're naturally low in carbohydrate uh exercise transiently you get a you get a bump in ketones um you know experimentally there are studies where you can Infuse beta hydroxybutyrate salts and induce acute levels of ketones I'll actually show some data in terms of cardiac function later and interestingly if some drugs also uh induce ketosis like the sglt2 Inhibitors that result in mild uh ketosis and this idea of Keto adaptation you know I really think that's should be reserved for the set of adaptations that occur to a ketogenic diet or carb restriction because I don't think you're going to get the same adaptations from taking exogenous ketones repeatedly and still consuming carbohydrates there's just a fundamental difference in terms of some of the underlying physiological responses and adaptations that occur but that takes time we're just beginning to unravel some of the various adaptations that occur uh to ketogenic diets and and various forms of uh of elevating ketones I thought I'd i' show this paper it it uh doesn't get a lot of attention that I'm aware of uh but I think it's makes a really important um point that when you look at the response to fasting uh you know a lot of people think that's due to the caloric restriction you're not eating any calories and so your body's adapting to that by upregulating uh especially lipolysis and and then its ability to uh oxidize fat but um in this what I think is really elegant study they showed the lipolytic response in particular to fasting is due not to the caloric restriction but specifically due to the carb restriction so they had five healthy participants and they had participated in two conditions one was a uh fasting 84 hours of fasting and the other was a lipid infusion so no carbs but adequate energy in the form of fat uh to maintain uh their energy balance and there was no difference in variety of the markers there including nitrogen glucose triglycerides uh even ketones were similar and plasma insulin similar but um but in the graphs there you see the rate of glycerol and fatty acid ptic acid uh appearance which is basically a measure of fat breakdown uh in adapost tissue uh is is uh similar between the two so it is it's the carb restriction that is driving the lipolytic response to fasting so I think this is kind of a review for most of you but um just quickly uh you know what is ketogenesis so uh first of all ketones are partial products of fatty acid breakdown um and that fat can be derived from either dietary sources or in the case of fasting it's going to be exclusively from your adapost tissue stores at any rate those fatty acids whether they're from diet or endogenous stores uh get delivered to the liver and are the substrate for ketogenesis and in particular when you have an increased delivery of these fatty acids to the liver you funnel more of these fatty acids into the penic pathway versus the kreb cycle and these partial products of fatty acid breakdown these four carbon molecules beta hydroxybutyrate and acetoacetate which are probably coming out in about equal amounts from the liver are sent into the systemic circulation and pretty much most non-hepatic tissues can utilize ketones I think we tend to focus on the brain because from an evolutionary standpoint that was critical that we had an alternative source of fuel for the brain because it can't really use longchain fatty acids and if you don't have a lot of glucose available that was really important during prolonged periods without access to food but we know the heart uses ketones we know skeletal muscle uses ketones and other tissues as well denova connect powered by Genova Diagnostics offers simple atome Advanced lab testing that's grounded and research and takes the guesswork out of understanding your health Jova has been pioneering Advanced Health testing for over three decades and they have a wide variety of innovative testing options that you can order online and use in the comfort of your own home their diverse panel of tests include ones like metabolomics plus which is a comprehensive nutritional test that looks at an individual's need for over 125 markers including antioxidants vitamins minerals amino acids and fatty acids it even assesses for toxic exposures this is just one of the many options they have available to gain in-depth insight into your health whether it's gut health hormonal balance or nutritional insights goova connect allows you to set a Baseline and provide Clarity along your journey to Better Health we want to thank Genova connect for sponsoring today's episode of the metabolic link goova connect is offering you 15% off any of their test kits when you use the code metabolic Link at gdx.net slth metabolic link and I'm going to focus my talk more I'm G to ignore the brain um not you know for any other reason then I just want to focus on muscle for this particular talk because there's an incredible science going on with a ketone fueled brain and there's so many positive things likely emanating from that but I'm going to focus on on muscle and I'm going to start first here with um some data on keto adaptation in glycogen metabolism and showing you a graph here from uh a study we published back I believe it was 2015 uh an elite group of ultra endurance athletes that were either following a traditional High carbohydrate or traditional low carbohydrate diet I'm not going to go through all the data that paper but the low carb athletes were prodigious fat burners they had twice the level of fat oxidation and um performed a three-hour B of exercise using about 90% fat compared to the high carb athletes which were using more along the lines of 40 or 50% fat uh but what was actually absolutely astonishing uh to me uh was that their resting glycogen their post exercise glycogen and their recovery glycogen levels were almost exactly the same and and you're seeing the individual responses here so there's also a remarkable homogeneity in the responses here there's no real outliers um and and then this is in the context of these low carb athletes eating a very low amount of carbohydrate so quite unexpected because I think we're we're taught that to maintain optimal glycogen levels you need to be consuming a lot of exogenous carbo hydrate so how how could this you know how could this happen uh so first of all if you look at the rate of glycogen breakdown and calculate that out um you know again it's nearly identical no difference at all between low carb and high carb uh in terms of glycogen utilized per unit time and if you but if you do the math here there's something quite odd um so if you kind of make a few assumptions here in terms of uh you know the uh amount of active tissue involved uh you can calculated in actual gram amounts how much glycogen was utilized So based on these calculations about 160 grams of glycogen was depleted during exercise but we actually have indirect calorimetry data on the total amount of glucose oxidized that actually was terminally oxidized to generate ATP and that was only around 60 a little over 60 grams so the big question is what the heck happened to 100 grams of glycogen if it can't be accounted for in breath and glucose oxidation and I'm not sure I have the answer it's uh it really has not been followed up on but if we take a look here um drill down a a little deeper into the biochemistry so you've got glycogen break broken down into glucose and then of course glycolysis and typically if you look at the end product of glycolysis pyate u a lot of that is being converted to acetylcoa through pyrovate dehydrogenase and that's the entry point into the kreb cycle for terminal oxidation and of course fatty acids can also serve as a source of acetylcoa but we know that ketogenic diets actually decrease pdh activity uh and most of the aceto COA that's being used to generate atps coming from fatty acids because you have an abundance of fatty acids when you're keto adapted so that's why I kind of have that Rd it out um it's unlikely a lot of pyate is going in that direction but pyate can also it has other Fates so it can be converted into oxelo acetate and this is interesting because o oo acetate is necessary it's kind of an anapol actic substrate for the kreb cycle you need Oxo acetate uh for the CB cycle to run in fact I don't know if if it's still in the textbooks or not but you I was taught that fat Burns in the flame of carbohydrate which doesn't make a whole lot of sense um when you think about it um but the basis of that was that if you're uh burning fat you have to have a source of axilo acetate and typically exilo acetate is is derived from from glucose so that's where that comes from even though it doesn't make a lot of sense but that's likely perhaps one reason why in a keto adapted State you need to have a fully functioning kreb cycle that perhaps breaking down glycogen and going through glycolysis helps keep the kreb cycle running by providing a source of axillo acetate pyate could also be converted to lactate uh and that also I have that you know green because I think that likely occurs to a greater extent in these keto adapted athletes and lactate is a great you know source of carbon uh for the cell and can even be used directly as an energy source and then you also have this sort of other pathway parallel to glycolysis uh the pentos phosphate pathway and that produces some important um products as well like reducing equivalents uh and a dph as well as uh five carbon sugars that are necessary for nucleotide synthesis for RNA DNA repair so there could be advantages to having a source of glucose in the keto adapted state in terms of promoting reducing power and and five carbon sugars as well so I think this is all hypothetical but all reasons why from an evolutionary perspective uh being keto adapted um you still might want to have normal glycogen levels typical glycogen levels now what about the resynthesis of glycogen so when you th this is looking at the post exercise and then the two-hour recovery time point and and the low carb athletes here did not get any carbohydrate during this time period whereas the high carb athletes did and still they synthesized glycogen over two hours at the same rate so it's kind of slightly different phenomenon here but still not expected right I mean if you're eating carbohydrate you would think there wouldd be a higher rate of resynthesis so how can you synthesize glycogen without any exogenous carbohydrate intake um and so the question is can there be glycogen repletion in the absence of any carbohydrate intake and typically I think a lot of us would have said no um but if you look at the literature especially across different species the answer is absolutely yes there's a variety of different animal models that have demonstrated glycogen synthesis after some type of physical demand uh and shown glycogen synthesis question is how does it happen what are the carbon sources for glycogen if it's not uh exogenous glucose well it could be lactate uh lactate um can be recycled back to the liver and and converted to glucose amino acids uh some are glucon neogenic and can be used to as a source of glucose glycerol U as well and there's a lot of glycerol being released from adapost tissue in the keto adapted state so this is just showing you know glycogen if it's being broken down into glucose and converted to lactate within skeletal muscle that could be released in and and delivered to the liver converted to glucose and then the glucose could be used as a substrate to form glycogen so it's likely that process is upregulated in the keto adapted State and interestingly the Transporters involved um the MCTS the monoc carboxilic Transporters um don't distinguish between ketones and lactate they're both organic acids and use the same transporter so you'd expect they're upregulated in the keto adapted State I don't know anyone who's actually measured these in um in a human or an animal study um in this context though so again hypothetical fatty 15 is the world's first and only science-backed patented and award-winning c-15 supplement that supports your long-term health and 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interestingly if uh you look at the actual circulating substrates during recovery lactate and glycerol were actually higher in the low carb athletes post exercise and then you see a dramatic decrease in those substrates over that 2hour recovery period so where are they going uh to account for that pretty dramatic lowering of blood concentrations uh again perhaps into glycogen again those carbons clearly could be recycled into glycogen now I don't know anyone who's followed up on that that data in in any human study um which is a little surprising we should have probably done that by now but um anyone looking for a good Master's thesis or doctoral dissertation that's uh I think really needs to be validated uh the there is some animal studies though that are are consistent with what we showed and this is um using a a mouse model uh swimming model so they had mice um tread water for 60 minutes and that that's more or less how I swim um up there this this feels pretty brutal for these mice so they're treading water for 60 minutes and it's a model of glycogen breakdown um and fatigue and then they extracted um muscle out of the uh the mice and exposed them X Vivo uh to glucose and insulin and different levels of ketones so uh I think they had one with no ketones and then one two and four Millar of ketones and measured glycogen levels and this just demonstrating the model so the the 60-minute swim model did decrease glycogen as you can see um in in the panel a panel B shows with no ketones um you're not getting any resynthesis or I guess that's one Millar Ketone excuse me uh no real difference but with two and four Millar you're getting a progressive increase in glycogen synthesis uh over a 2-hour incubation period so um evidence again that ketones might have a role in restoring glycogen from exercise okay so moving on to another um underappreciated aspect of uh keto adaptation in muscle uh and this has to do with the question of can skeletal muscle produce Ketone so traditionally we think Ketone production or synthesis occurs in the liver um maybe to a smaller extent in the kidneys but um generally not in to an appreciable amount in other tissues um so if you look at some of the enzymes in ketogenesis uh they're very low in skeletal muscle so Scott being one one of them uh and that kind of makes sense because skeletal muscle has a lot of different ways to utilize fatty acids there's a range of different Transporters to get fatty acids into skeletal muscle so there's not a real need to use ketones like there is for the brain so it makes sense the body body would prioritize ketones for the brain and other tissues maybe but uh not not skeletal muscle uh but very few people have done human work um in a keto adapted State uh and and measured any kind of muscle adaptations so this was one study we did um that involved taking muscle biopsies out of uh individuals that were fed a ketogenic diet for 12 weeks and trained uh as well during that time period um and we had a control group that consumed a traditional high carb diet and we did demonstrate um my doctoral student at the time uh Vin Miller uh isolated mitochondria from those skeletal muscle and showed increased mitochondrial protein content and an enhanced ability of the mitochondria to utilize fat in particular but interestingly he also looked at Ketone oxidation in those mitochondrial isolates and showed very very low levels so that's kind of consistent with this idea that muscles probably not producing or utilizing ketones to any great extent not that it's zero but a pretty low extent and then this is uh this is also data from the faster studies so the ultra endurance athletes that were low carb or high carb so we did from muscle biopsies in that study uh at three different time points points we looked at uh transcriptome analysis so we looked at gene expression of all known genes uh I think we had quantitative data on over 23,000 genes uh at each time point and of all of those data the gene that had the most significant difference between the low carbon the high carb group was HMG COA synthes which is a rate limiting codes for the rate limiting enzyme in ketogenesis so that is not happened by chance um there's something for some reason um this particular enzyme is increased in athletes who are keto adapted and it occurs pre-exercise and post exercise so I I don't know why this would go up if you're not producing ketones in uh in skeletal muscle but it it's gene expression is highly uh expressed in these keto adapted athletes uh now we know that ketones can actually be produced from Lucine um through an alternative breakdown of or pathway of Lucine degradation uh and people have studied this as well mostly animal models though um and it's a pretty low percentage of the total ketones but uh it's been estimated in animal studies that about 4% of total Ketone production is from Lucine breakdown and that probably decreases as you become keto adapted because of the Lucine sparing effect but nonetheless um in the truest sense Ketone production does occur in muscle from Lucine to some extent and what's even more interesting here and this is a little nuance but um it's not evence evidence that ketones are produced in muscle but there is some transformation going on within skeletal muscle so um there's been about a half a dozen studies published now and most of these use the forearm arterial venus difference model so they'll literally catheterize uh an artery and a vein that that feed and drain the forearm muscle in in people and look at the delivery of substrates in this case ketones and then what comes out on the Venus side um and what you see is uh so if you focus on the first two um rows there that those are the Ketone levels um that are in the Venus I'm sorry the arterial side so you've got Ketone levels over 60 hours or so of fasting and you see um those are micromolar but um less than 0.1 um Millar that then they increase to almost 0.5 and for acetoacetate and then almost one Millar and then beta hydroxy butter rates quite a bit higher now the two rows below there that's the flux and you see the Flux Of aceto acetate is much higher and beta hydroxy butat is actually negative so what's Happening Here is there's a dramatic increase in aceto acid acetoacetate uptake into skel muscle as you become keto adapted or during in this case prolonged fasting but what comes out the other side is beta hydroxy berate so there's a conversion happening within skeletal muscle and of course that you know that enzyme is beta hydroxy dehydrogenase so there's uptake of acetoacetate but then a release of beta hydroxybutyrate and this is almost Surly the reason why we always have more beta hydroxy berate in the circulation than we do acetoacetate usually you know it's it's around 60 70 80% of the total ketones can vary depending on the condition but um what's coming out of the liver is not that ratio it's more of a 50/50 ratio so this peripheral conver conversion of acetoacetate to BHB is happening specifically in skeletal muscle now you could say well so what um does maybe that's because the brain prefers beta hydroxy butter um I don't think that's the case I've asked a lot of experts the brain doesn't care if it's acetoacetate or beta hydroxy beate in fact you got to convert it back to ceto acetate to oxidize it anyway uh but if you look at that reaction beta hydroxy dehydrogenase um look at the co-actors it's one of these Redux reactions right it produces nad+ so being keto adapted and undergoing this transformation provides a source of NAD Plus for muscle cells and if you haven't followed that literature at all NAD plus is super hot molecule right now um it's being linked to all sorts of uh positive cellular functions within cells particularly related to longevity uh and so forth is just one of many recent reviews out on NAD so um here we have um a ketogenic diet um probably you could say is a really good way to keep adequate stores of NADA uh cuz we know those go down for example in aging what's something that we could all probably use a little more of especially if we want optimal metabolic health for me it's sleep many experts argue that sleep is as important to metabolic function as things like your diet and exercise but did you know that sometimes poor sleep is associated with magnesium deficiency and research suggests that as many as 75% of American adults may be deficient it's no wonder so many of us struggle to get consistent quality sleep so I wanted to tell you about Mello magnesium from NED a powerful daily super blend that contains the three most bioavailable and nutrient-dense forms of chelated magnesium along with stress busting aminos like Gaba and alamine and over 70 trace minerals it comes in four delicious flavors there's lemon lavender Berry that's my personal favorite pomegranate and naked which is a stripped down flavor free version that's great for adding to your smoothies or protein shakes another great thing about Ned is their commitment to transparency Ned shares all of its third-party lab reports right there for viewing on their website so become the best version of yourself and get 15% off Med products with code metabolic link go to hello.com metabolic link or enter code metabolic Link at checkout that's H ned.com metabolic link to get 15% off okay um third aspect ketones and heart function so uh just like the brain utilizes ketones in proportion to the delivery so there's a really tight correlation between uptake of ketones and the circulating level uh I think stepen Kain has shown that many times in some really beautiful graphs but um that same relationship is true for the heart so uh as ketones are elevated in the circulation the heart takes them up and utilizes them in proportion to the circulation that's certainly not the case with skeletal muscle there's a the the um the uptake is there's a lower C M for the transporter and you saturate that process at a much lower level but with heart the higher they go the more the heart utilizes ketones and a lot of new data coming out now showing that when you have a ketone fueled heart um it's functioning more efficiently and and and better particularly in in disease States like heart failure and so in the context of um heart failure uh there's all this data coming from a variety of different sources indicating a ketone fueled heart is functioning better um now some of this is just from the metabolic side of things is like I just said the heart does utilize ketones if they're available uh it you know it's an organ that needs a lot of energy and it needs it on a regular basis to function so it will tend to oxidize anything that's there but it will preferentially use ketones um there's also clearly a metabolic basis to heart failure um so heart failure is associated with uh impaired ability to utilize substrates in particular fatty acids and an increased Reliance on glucose uh and so there's a lot of different animal models out there now and even human studies showing that the failing heart will utilize ketones to a greater extent and then you've got animal studies I think V published one of the first many years ago showing that a ketone fueled heart in an animal model functioned more efficiently so it prod greater cardiac function per unit ATP when it's run on ketones versus other substrates uh but even in the last say five years or so now we've actually got human studies in both clinical populations as well as healthy populations showing that when you elevate ketones acutely you get beneficial effects and I'll go through a few of these in a minute but we've got Ketone infusion studies and more recently in the last couple years we've got a couple now papers out on Ketone exogenous ketones elevating uh ketones acutely and improving cardiac function and then the last bullet point there I'll just mentioned um this kind of another way in which I think cardiologists are starting to come on board with this uh we have quite a lot of clinical trials now on sglt2 Inhibitors which are used to lower glucose and diabetes but we have um findings now published showing um improved heart outcomes in diabetic patients and even non-diabetic patients now with heart failure showing reduced hospitalizations uh decreased cardiac events uh with just use of these drugs and um you know these drugs cause increased glucose output in the urine but one of the other metabolic effects of these drugs is they elevate ketones modestly so typically up until the lower end of nutritional ketosis so maybe 3 to.5 Millar without following a ketogenic diet but a lot of people have speculated that the cardioprotective effects of these drugs might in part be due to the ketones so that's just another uh level of evidence supporting ke ketones having a beneficial effect on heart function uh one of the first studies this was the Ketone infusion study out of uh Sweden uh where they looked at patients with heart failure reduced ejection fraction and Infused a ketone salt a beta hydroxy berate salt uh into these patients and you can see uh rapid elevation in their circulating Ketone levels and amazingly when they looked at cardiac function then um you get this dramatic increase in cardiac output so and it's kind of a dose response so you can see the upper right bar uh bar graph there showing increase in cardiac output as a function of uh elevation in circulating ketones so the greatest effect was at um is that 3.3 I can't see um but increasing cardiac output with higher levels of ketones a greater increase in ejection fraction and there's a vasodilatory effect as well um that has been observed in most of these studies and and another interesting part of this study is they did the same experiments in healthy controls with no heart failure and showed the same effect so this wasn't just working in people with a defective or impaired heart function it actually is a very robust effect that occurs across the Spectrum from Health to diseased Hearts so um we now have a couple studies looking at exogenous ketones as the method of elevating ketones and one was um uh this is in healthy participants using the Ketone Ester or the product from Human um you'll notice increases in ketones are very similar to the Ketone infusion study I just showed you so a little over three Millar and this is showing the Improvement in in cardiac output um with that um acute elevation uh from Ketone uh supplements and then this is even more fresh off the press I think this was published just in last December um again 20 healthy adults uh this particular supplement was Ketone Aid and again um ketones I guess maybe not quite as high here they got a little over 2 Millar with a single dose of this particular exogenous Ketone and then you can see it on the right um cardiac output progressively increasing over time and then of of course if you look at cardiac output as a product of stroke volume and heart rate um you see it's contributed both are contributing to this increase in cardiac output in this particular study the heart rate is actually driving more the increase in cardiac output than the than the stroke volume so we've been very interested in this in fact we've been planning for about 5 years to get a project off the ground in patients with heart failure and we'll finally have the funding and the people and the resources and Technologies all all all in place to do this and uh a big shout out to my Cardiology colleagues here Uchi Han is is principal investigator as well as Lan Simonetti who's a world expert in cardiac imaging cardiac magnetic resonance imaging so we're doing some really neat functional um Imaging uh with these projects and then Chris ctry there is my doctoral student who's really been living in this Imaging World um to uh to run these projects so we did kind of a pilot preliminary study uh similar to the two previous projects I I just showed you and we're we're studying the um Ketone Esther from juvenessence which is uh this was the older version the C6 diester uh and again single dose delivery of this particular product um to healthy subjects and then serial Imaging and blood draws after that so we've just finished this study we're close to getting this packaged up for submission so these were presented last year at an Imaging conference uh but otherwise unpublished so um we get a nice increase in ketones which is no no big surprise um uh takes a little longer for this C6 diester to elevate Ketone so it's a little more gradual but by two hours we're we're at over 2 Millar and uh get a little bit of a glucose lowering effect with that but the I'm sorry cardiac output data um are very similar to those previous infusion and exogenous Ketone studies so we're seeing a highly significant increase in cardiac output and we did use a placebo as well calorically matched Placebo fat based Placebo um and we didn't see any increase so this was kind of one unique aspect that we added in addition to the Advanced Imaging um so this wasn't just a an effect of food intake and caloric intake that that people have seen uh you now if you look at the heart rate and stroke volume aspects of the cardiac output uh again it's both both are increasing so there is a sort of a chronotropic and inotropic effect both going on here uh increasing as a as a function of elevated ketones and then uh we also do a measure of myio cardio blood flow and that uh increase similar to what's been shown in the infusion studies so to dat no one's really published uh a prospective study though looking at um either repeated use of exogenous ketones to elevate ketones over time to see if this is just an effect of of you know a single dose that then diminishes over time sort of a tack aaxis or um or do you maintain or even augment this response over time and get a therapeutic effect and no one's looked at a ketogenic diet either to my knowledge um over time in patients with heart failure so we have both of those projects underway now that are IRB approved and actively recruiting at Ohio State so uh just final take-home message messages or final thoughts um achieving UK kmia so nutritional ketosis may have under appreciated beneficial effects on muscle both skeletal muscle and and cardiac muscle so one it could promote glycogen metabolism preserve glycolysis in skeletal muscle and I I think I didn't say this but I think this is a big deal because a lot of the Sports Nutrition guidelines are all based around carbohydrate Centric and that and the basis is to keep glycogen levels elevated but uh we can do that without a lot of carbohydrate actually if you're adapted um another uh aspect of muscle metabolism is that there's uh transformation of of acetoacetate to BHB happening and we're providing a sort of a natural source of NAD in the process and that's likely promoting I think a lot of positive cellular health benefits um along with it and then uh I think we're doing good on the heart too with uh various forms of elevating ketones especially in those with with uh impaired heart function so uh stay tuned on on a lot of these fronts I think we need a lot more research to follow through and understand this in more detail so I'll stop there I just do a final thank you to uh all the people in my lab that are in The Trenches doing the hard work um as well as the uh colleagues that we have at OSU particularly College of Medicine and a lot of the sponsors and funders of our work because none of this is uh free or cheap so thank you thanks for listening to this episode of the metabolic link if you like this episode please be sure to leave us a review share it or drop us a comment if you want more content like this including access to our private podcast feed that offers exclusive adree episodes that also provides continuing medical education please visit our medical education platform the 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