 Mae'r mawn i'r ddedw i'n wneud o'ch dwais deall gwyllgo mwy diwethaf. Yn mwyn fwy ymddir i糾od trwy ddechrau y bydd amser a'r bobl mewn ymwneud yw'r gweld yn ll場. Mae'r bobl yn drefnol yw'r newid. Mae'r newid ddioletheol i wyg Dfosig ym Nifer. Dw i'n cymorth yw Nicola. Mae'r cymorth o bachurau bwysig yn cyllidol Jameson. Mae'n mynd i'n ddulig i gael ystod trefn ymddiol ystafell, can inform evolutionary biology and vice versa. In doing so we've tried to show that Native American mortality after European contact need not have derived from so-called differing immunities in a virgin soil, as scholars once argued. Rather we join recent scholarship by Jones, Kelton and others in emphasizing that contingent aspects of colonization, particularly the rupturing of inherited nutritional frameworks, were more than enough to destroy Native American populations. In order to make these arguments therefore we've had to consider very closely the myriad nutritional frameworks enjoyed by indigenous peoples in North America, including in regions such as the Pacific Northwest and Alaska, before European arrivals. In the case of Alaska, Russians were the first to arrive en masse in the 18th century and the aftermath was catastrophic. Among other things, we'd assumed that we would find evidence that indigenous communities in the region would have been in ketosis, at least much of the time, given what we read in the popular ancestral literature. But as we look more closely and consider their nutritional heritage and ecology in light of modern genetic studies, we became, I'd say, more agnostic on this issue and realized just how complex indigenous arctic metabolic science and history can be and how problematic blanket statements regarding assumed metabolic profiles are in this population or maybe even in any human population. So to explain why I believe this is to be the case, I'm going to survey the interaction between ecology and nutrition in the region from 21,000 years ago to the present. Different theories for the migration of indigenous people into North America via Alaska 21,000 years ago and the evolution of nutritional needs during that period. Why reasserting the centrality of the mega-3 fatty acid DHA versus saturated fat is important to understand both the insulin sensitivity and the pre-contact immunological health of indigenous Alaskan populations and what that might tell us more generally. Why the presence of DHA might be used to support the notion that communities might have been likely to spend much time in ketosis but also support a counterargument. How growing evidence of genetic adaptations to extreme cold environments in global communities ought to force us to question the notion that indigenous Alaskan people burn ketones primarily, making us consider instead the potential to oxidise fatty acids efficiently without entering the metabolic state of ketosis or at least as it's popularly defined. How historical and non-genetic factors such as the potential to convert animal tissue into glycogen may unsettle the notion of permanent ketosis in these communities. How ketosis from fasting, for example on long hunts, would possibly or even probably have been more likely to produce the metabolic state than via exogenous consumption of fats. And why, if we have enough time, we ought to consider the indigenous Arctic microbiome as another overlooked factor in health, including as it might have developed in relation to overlooked sources of plants and even starch sources popularly known in the field as resistant starch. I'd like to offer a very quick statement on the word eskimo in the context. I've always found the word problematic, as I guess some of you have as well, as do some indigenous peoples in and out the region. Other indigenous peoples in Alaska and beyond however prefer the term. Others prefer Inuit and it gets very complicated. But in fact what I'd really prefer to use is simply the term indigenous peoples in the Alaskan region to avoid any problems. So until recently scholars suggested that immigration onto a so-called bearing land bridge that many of us will have heard of, the area between the present day far eastern Siberia and Alaska, now covered by the bearing in Chukchi Seas, likely took place more than 13,500 years ago. The movement responded to the area having become gradually available due to lowered sea levels which followed the ice fixation of global fresh water supplies. The newer Beringian standstill hypothesis suggests that the region was actually populated for far longer than once assumed. Perhaps more than 21,000 years ago people, some scholars even say longer before the eventual migration of its population into Alaska and other regions of North America. Genetic studies have suggested some support for this hypothesis, highlighting what's termed a northern Pacific Rim genetic cluster, claiming that movements, at least into the far western part of the region, took place as early as 34,000 years ago or at least that movements from Siberia began as early as then. Now during this period, and there's a map of the region that we're talking about at this point, for thousands of years a so-called shrub tundra refugium provided the setting for hunted land mammals and woody plants to facilitate the burning of bones for fuel. So here we can see the traditional images that we're often familiar with, the kind of the megafauna some now extinct that we think from archeological and other evidence was in this region. So this is an ice age and we even have a lot of paleoart, something that I've just recently discovered, artists using anthropological archeological evidence and then kind of filling in the blanks with their pencils and paint to give us a picture as to what Beringia might have looked like. So all these images suggest the consumption of large mammals and in the popular literature at least you would suggest or assume there would be a lot of saturated fat consumption therein. But I'd also like to point out that DHA was perhaps more important from 21,000 years ago up until more recent history of the region. And so I'd like to kind of modify what some of us have come to think about the use of megafauna and fats and particularly saturated fats in that context. Several scholars, as we all know, these are not merely a few outliers, have hypothesized that DHA had an important role in cognitive development and some even say more controversially increasing brain size compared to earlier hominids during an overlooked so-called marine coastal stage of human evolution from around 200,000 to even 100,000 years ago. So very recent in our history and much later than that first important step that we all know about associated with the expense of tissue hypothesis, big brain, small gut and all of that. The literature on omega-3s remains relatively controversial, as I've said, though I personally find it quite convincing. Maybe just that I don't know enough about the field that I can sort of move from one to the other and find something convincing after reading a few papers, I guess. But I find it quite convincing. But the literature on the brain and the guts requirement of DHA, we all know, that's far less contentious. And this is why I wish to highlight the overlooked role of DHA in indigenous Alaskan history given the tendency to focus, at least popularly, on the consumption of saturated fats. Just as scholars once focused on the expense of tissue hypothesis, I've often ignored much later marine coastal stages of human development, including potentially of human cognition and immunological development in association with greater consumption of DHA before early humans left Africa, scholars of native American and proto-native American history have overlooked what is now being called the kelp highway or the kelp super highway, which is really another theory as to how the progenitors of native American populations got to North America. So without discounting the land bridge in the Bering Strait, scholars such as Erlundson particularly have suggested that the original pre-native American communities would have hopped over on various islands all the way from what's now, I guess you would call, coastal Alaska, some of the Aleutian islands, and then all the way to North America eventually getting to coastal California and before that Alaska as early as 21,000 or more years ago. So I've become increasingly interested in and convinced by aspects of this hypothesis proposed by Erlundson and others. So here are a few more of the relatively recent studies that are looking at this alternative theory for the coastal migration via marine-rich, DHA-rich, I guess you could also say iodine-rich nutritional frameworks that developed as these communities moved along. So we've even got the National Park Service who talks about a paleoarctic era from 12,000 years ago but even as early as 21,000, depending on who you talk to, when marine consumption was more important than one's thought. Of course we don't need to discount either of these hypotheses when we consider the role of DHA in wild animals. We all know from the earliest paleo literature in the 70s and 80s which some now discount, I say maybe a little bit unfairly, looking at wild animals having a higher proportion of DHA in relation to saturated fat. And so therefore whether you're eating mammals or marine animals on this other alternative coastal way of getting to North America, your DHA consumption will be higher than perhaps we've once thought. It's even worth noting for example this recent study which suggests that Inuit in Greenland who are related to but of course not entirely the same as indigenous communities in Alaska may have genetic and physiological adaptations to consuming a high DHA diet developed over several tens of thousands of years, including and encouraging them to maintain good insulin sensitivity. At least that's the factor that the authors of the study suggest is important to note. Work carried out by the Alaska Siberia project and other studies have suggested that the high consumption of DHA is linked to low blood pressure in these communities which are closely genetically related to those indigenous communities in Alaska. And glucose tolerance of course measures how efficient individuals could clear glucose from the blood with enhanced efficiency due to DHA among other things. So the studies detect an inverse relationship between fasting plasma glucose levels and plasma omega-3. But why should we care that DHA may encourage greater glucose tolerance in human populations more generally and among indigenous Alaskan communities more specifically? After all, aren't there a population that is archetypally high fat, low, or even close to zero carb? Given the presumed lack of plasma glucose in the population prehistorically, historically, and even in the present day among those who follow an ancestral diet, greater insulin sensitivity due to DHA or any other factor might not be as relevant as we might think. Some suggest, as many of us know, that ketosis in an animal meat-dominated diet is a tricky state to achieve. We've all seen people carrying their knobs of butter and their bits of avocado and MCT oils and so on to try and maintain ketosis. We know what the Mayo Clinic, as it originally, creates its own ketogenic diet. It was about isolating fats above all else. So this is tricky to do. So I would suggest that historical communities likely consume protein alongside fat, which might sometimes produce excess glucose from gluconeogenesis to the point where insulin secretion may be necessary. The body is never completely accurate and may overproduce glucose rather than excreting excess protein or using it in other ways. So the presence of DHA alongside saturated fat and other fats, I guess, might have made a ketotic state more likely in those who might otherwise have been, quote, knocked out of ketosis as people use that phrase by excess protein consumption. Or perhaps not, as we will see, as we examine the period of animal consumption from the period around 13,500 years ago until the field period of proto-eskimo culture to around AD 1,000 and even later in history, where we'll see that evidence suggests a greater variety of animals than those large mammals that have traditionally dominated the narrative, those woolly mammoths and strange North American rhinos and camels and all of that. Some especially smaller mammals, of course, are higher in protein than fat. Others higher in DHA, particularly when we take into account marine consumption, than saturated fats than once thought. Was this ever all high enough, in fact, to maintain regular ketosis, as it was suggested in the popular literature? And more specifically is ketosis likely in diets with a higher ratio of omega-3 fatty acids to saturated fats. Does the mix of polyunsaturated and saturated make a difference to the overall propensity? I don't know the answer to that question or indeed even really whether it's a question that, in fact, makes sense, but I just would throw that out there and there's definitely people in this room who would know much more about that than I do. But before we can even answer that question, we've got to enter that other conceptual hornet's nest. The historical prevalence of ketosis in indigenous communities, even if we assume that they did consume a relatively or even high fat diet. Was it the norm? Well, we know that ketosis from the burgeoning literature in scientific nutritional science is potentially extremely beneficial for neurological disorders. We know it's beneficial more generally in terms of general health, autoimmunity, even human longevity, keeping insulin down and all of that. But was it ever a metabolic state that would have been likely in these particular communities that we're talking about? Would it have been likely, as a metabolic state from exogenously consumed fats or more likely from fasting, which we'll get onto in a moment? Firstly, we need to consider the possibility of specific genetic adaptations to try and get to answering these questions associated with cold adaptation. Over 21,000 years ago, but even as early as 13,500 years ago, if that is a period of time that is indeed a... Some might argue it's too recent to allow adaptations, some might not. But various studies for cold adaptation in cold climates, northern climates, have shown, for example, in Greenland, Inuit, northern Japanese and Siberian communities, the potential for genetic adaptations, such as greater vascularity, dense networks of blood levels, short stature. Recent genome studies have identified mutations that may affect the proportion of fatty acids in the cell membranes in these populations, which in turn may affect growth hormone signaling. Contemporary northern Japanese populations, for example, have been shown to be able to burn more fatty acids the cold of the individual gets. And this has been mimicked by rats who are cold adapted in controlled experiments. The question to ask is, if cold adaptation in genetic ways is possible in northern communities around the world, including in a relatively short time period of 20,000 to 30,000 or less years, in extreme context that make natural selection or genetic drift more likely, we might then ask, were other adaptations possible or likely in these and other related communities, such as those in Alaska, including adaptations that may relate to a greater ability to oxidise fat for energy use without necessarily entering what we might call ketosis. The genetic adaptations to allow fat consumption without ketosis are unlikely to be prevalent if populations are found to be in the metabolic state when consuming their ancestral high fat diet. But as described in a set of characteristically lively and actually quite rigorous commentaries from Richard Nicolai, a number of studies have suggested they were not in ketosis. So this is Eskimo communities who studied, I don't like that word, in the early 20th century up until the 1970s. They were not necessarily found to show evidence for what we would think of as ketosis, metabolically, while consuming ancestral foods. Others, of course, have doubled down on their assertion that these communities are ketogenic par excellence, so let's consider these studies for ourselves. All early 20th century studies noted that the historical diet of Eskimos has consisted of meat, fish, a few carbs, and a few carbohydrates, sometimes none, to a greater extent than other global populations. Four to eight pounds of land mammal meat every day diet that's very low in carbs. The big study that people often refer to is by Peter Heindbecker studies on the metabolism of Eskimos, one study in 28, another related one in 31 and 32. Some might suggest that these studies were not rigorous or efficient enough to measure ketones in the way that we might today. However, the controls and methods were actually very well advanced, in my opinion. Not nearly amusing a keto strip here or there, but rigorous attempts to characterize the metabolism, controls, respiratory tents, and many other measurements to explore the metabolism in detail. Acetone, diacetic, and beta-hydroxybutyric acid was measured in the urine, following consumption of what was assured to be an ancestral native diet. This wasn't just epidemiology, without any intervening Western sources of carbs. Glucose levels, ketone blood levels measured, acetone levels measured in the breath. Respiratory quotients were also measured in the Heindbecker study and several others, representing the ratio with a volume of CO2 relative to that of oxygen consumed by an organism, tissue, or cell in a given time. And it gives kind of a rough estimation of the proportion of fat and carbs being oxidized. Heindbecker's results and conclusions suggested that the metabolism may have differed from that of non Eskimos. The levels of urinary ketones were lower than expected, suggesting only a mild level of ketosis. Glucose tolerance was found to be very good, also supporting the conclusion that subjects were only in a mild state, given that glucose tolerance is expected to decrease in the deeper state of ketosis. Though, of course, it can come back very quickly, as we know. It was suggested that the high protein content of the diet prevented ketosis, whether historically or during a present era, or even that fats could be converted to glucose. I know Chris Masterjohn once wrote an interesting piece that I've learned a lot from on that matter while trying to make sense of some of this stuff myself. They detected the presence of ketones during fasting, but at a lower level than found in non Eskimos. As a further control, higher levels were found in a woman who was breastfeeding, and in subsequent experiments, higher levels were found in seven day fasts. In another control of sorts, higher levels were found in a subject who was nursing and at the later stage of pregnancy, on days three and four of a fast. I had to reread that several times. Subjects were found to have had a lower respiratory quotient, the ratio of CO2 to oxygen, again, which is associated with the greater metabolism of fat in proportion to carbs. On fasting, the respiratory quotient of two out of three subjects was below that expected for the metabolism of fat in no carbs. Again, Heinebecher explained the low quotient as due to the formation of carbs from ingested fat, as well as protein potentially, the conversion of triglycerides to fat. From our analytical perspective, good tolerance of glucose suggests that indigenous Arctic communities have historically utilized a low carb rather than necessarily a ketogenic diet. Though, of course, populations such as the Hadza can also demonstrate good insulin sensitivity with a relatively high carb diet, cure rolling eyes of some, that the Hadza are being trotted out again, but just that bears noting. Studies in 1972, this is a different study by Ho, measuring ketone levels in the urine of what we're referred to at the time as Eskimos, using the strip paper technique, and in the breath also found no evidence of ketosis. The study stated that carbohydrate accounted for 15 to 20% of calories, largely in the form of glycogen in their interpretation from starches in frozen or raw animal meat. Candidate with 15 to 20% carbs be ketogenic. Perhaps not the more research needed. We need to take into account how much exercise people were doing and all of that. But other studies have corroborated behind Becker and Ho conclusions. So let's explore a little bit more as to what this might mean. Consider two explanations in further detail. Potential genetic factors and that indigenous Arctic diet and food preparation. Recent genetic research suggests that Inuit in Canada may have adapted to high levels of nutritional fatty acids by a mutation that limits ketone body production while still allowing a high level of fatty acid oxidation. And so Alaskan indigenous peoples might enjoy similar mutations, just a hypothesis, thereby explaining how they could be eating a high fat diet without necessarily measuring high ketones, at least as shown by the studies detailed so far. So to repeat, this is defined as a mutation that stops individuals whose nutritional profile might otherwise be expected to push them into ketosis. And it's been suggested that some northern Japanese communities may have similar mutations. Other genome-wide scans of Siberians, Greenland Inuit and Canadian Inuit, again related to Arctic Ashkimo, Arctic indigenous peoples, show the potential for genes increasing the rate and efficiency of fatty acid oxidation as opposed to ketosis per se. Now the authors suggest a selective advantage may be the protection of Inuit against high ketone levels. However, more research is needed to test that hypothesis and of course such a claim might of course be biased by suppositions that ketosis itself might be somehow problematic going back to all those studies that conflate ketosis with ketoacidosis and so on. But still there ought to be much food for thought here. I know Sarah Ballentine has recently discussed some of these studies. So let us return to some, here's some of the more studies that mention this as well. But let's return to some non-genetic factors that may have prevented or at least reduced the level of ketosis. Ho and others have suggested a low level of atherosclerosis and a high total cholesterol in the 70s and 80s in another set of studies. At this point this was suggested to be a paradox but like many of these paradoxes like the French paradox it's possibly not a paradox at all but more akin to what we might call an anti-inflammatory, low-ish carb diet but not necessarily one in ketosis and thus one which might be good for heart health. Secondly, as Nicolae and others have pointed out in reference to a number of studies there's always that overlooked potential for a relatively high glycogen content from carbs often described in the early 20th century quite quaintly but I like it as animal starch in raw or frozen meat sources. Now some might say that these substances will quickly degrade to lactic acid but when raw or frozen this may be less likely to take place and so therefore glycogen in these forms may have been consumed to a greater extent than we've previously thought. There's also a relatively high glycogen content of whale blubber for those who are interested and this goes back to several studies going back to the early 20th century. So again whale blubber itself which is sometimes dominated the literature on high fat consumption may actually have had more glycogen than thought. Some historical accounts also suggest that blubber itself was consumed far less in Alaska going back several hundreds of years in even thousands of years some suggested based on ethnographic and other data it was consumed less because it was used as a fuel to make fire rather than eaten itself. Also we should think about the potential role of these things called glycans. Again many in the room will know a lot more about their exact biochemical makeup than I do but we can call them as something akin to a resistant starch that are in animal tissue and again which when consumed may tell us more about the consumption of what some would call resistant starch than solely the consumption of fatty acids. There's the slide on those marine blubber also consumed less than thought. So there are some takeaways so far I won't go into them because they're a bit push for time but I've just been thinking recently about some insights from Altafani one of his posts where he says ketosis possibly more likely in any global historical community from what you don't eat than what you do eat. That is possibly something that we should think about when thinking about indigenous arctic peoples or indeed any indigenous people in North America or anyone from what we know about histories, ethnographies, anthropologies. So not necessarily fixed time for meals, long hunts, people waiting while hunts are going on. So long periods of what we would call fasting or intermittent fasting rather than necessarily ketosis from exogenous consumption. Of course this is all very extremely difficult to measure historically anthropologically but it's just something that we should all try and is worth thinking about. In the last four or five minutes, moving beyond, I think it's important perhaps to move beyond animal protein, hit some more, I guess we call hot button issues, the way I describe them might be a bit crude, may irritate some people but there we are, there's some nice slides of some plants that we can find coming up for those who want something to look forward to. Resistance starch and what we might call the indigenous microbiome in Alaska. We need to think about that perhaps a bit more or even a lot more rather than necessarily being obsessed with whether or not these communities were or not in ketosis and rather than just being solely obsessed with their fat consumption above all else. We know from a substantial ethnobotanical literature, so it's a literature looking at what is consumed in indigenous Arctic communities and making sure to ascertain that that reflects that which they consumed before European contact using various other forms of evidence to try and show us that this goes back hundreds if not in many more years than that, there were plant sources that were consumed that we've often forgotten and that we've tended to forget, some of which, as we'll see, are a potentially good form of resistant starch, i.e. that which produces short chain fatty acids in the healthy microbiome might not necessarily only have been produced via glycans consumed from meat but also potentially via the consumption of these overlooked plants in Alaska alongside a very high fat, high protein diet. Here is some Indian celery in the interior Alaskan region. Here's some Indian celery, Arctic dark, Alaskan willow, alpine sweet veg. Some of these are leafy plants. Some of them have got tubers that contain inulin. We should also think about tree in a bark and the carbohydrate in lichens, partially digested in animal stomachs as well as seaweed that were eaten. There's quite a lot of ethnographic evidence for the prized consumption of lichens from within, say, a caribou stomach alongside seaweed and there's a longer statement on that for us all to read in our own time. Here's some more on the edible plants of the Arctic and more on a study on the vitamin content of lichens. We should also think about a preserved skeleton from around 600 years ago in the St. Elias Mountains in BC. Estimated to be up to 600 years old, thought to have moved from Alaska to the indigenous interior, the young man was found with preserved herbaceous items, mountain sweets, Sicily, these very poetic sounding plants that are thought to have eaten. Needles of mountain hemlock and a large proportion of channel pod pollen in stomach samples thought to be the edible perennial glasswort alongside evidence of crab and salmon also traced to the bodies as 600 years ago. So here we have plants and alongside animal products, particularly those high in DHA. Historical traveller accounts have also talked about fat and protein combined with plant materials and these are accounts that precede the arrival of Russians and others in the mid to later part of the 18th century which is often thought to be the quote contact period for European indigenous peoples, even a kind of pemican made from dried caribou meat with several berries and herbs. I know a lot of people often complain that pemican, as it's made for the public market, is always combined with berries and high fructose fruity things but it's a lot more indigenous than some might actually say. And so just in the last minute, should that resistant starch debate come to Alaska, maybe particularly when we think about wood fern, rice root, sweet veg, all of these, many of these I should say, contain Inuit and oligofructose, so non-fermentable carbs that could be acting as a prebiotic and there's some general stuff on the potentially positive effects of Inuit. Some more stuff here that we don't have time to get into on the Pacific Northwest, corn and tuber consumption, wild potatoes and how it was particularly used in a way that we would define as resistant starch. We know that these substances can help the microbiome potentially. And we also know that Native American communities elsewhere in North America were often founded on what are called big acorn complexes, so ground up acorn powders. You can now find that at HMAR and other Asian food stores for those who wish to consume ground acorn powder as a kind of resistant starch. The question that we need to ask ourselves is were similar forms of resistant starch consumed in a way that we've completely overlooked in the Alaskan interior? We know they were in the Pacific Northwest but does the evidence that we have for the consumption of these plants which include corn, tubers and so forth, rhizomes, did this complement the consumption of fats and proteins, make those more digestible, I guess you could say, as well as enhancing indigenous immunity so that when the Europeans arrive with all their diseases and as your nutritional framework is threatened, it is going to be a double whammy. You're going to have all your good proteins, a good DHA, your relatively high consumption of saturated fats, that's all going to be destroyed but also might be, what also might be destroyed is your ability and availability of sources of RS. Put it all together and you have a kind of an ancestral diet that itself will be destroyed, thus lowering your immunity even before you talk about differing immunities and so on. So some conclusions, DHA more important than thought nutritionally including an insulin sensitivity, communities not necessarily historically in ketosis, we need to think about genetic differences, glycogen in frozen raw meat, if keto perhaps more likely from fasting then exogenously and the need to think about potential RS and carb sources in the region but whatever we say, European disruption destroys these ancestral nutritional frameworks, reduces immunity and can be an important factor to account for extensive loss of lice and this is just something I found a couple of weeks ago. It's indigenous peoples in Alaska are now at the forefront of a new fight I guess against farmed salmon but I won't get into that but DHA important. Thank you for listening to all of this. Sorry I had to breathe through it so quickly. We have about five minutes for questions. If anybody does have a question you can move over to that microphone if you're on that side and if you're on this side I can bring the microphone to you. Hello Gideon, thank you for your talk and for bringing up many of these controversial points that I think are important to discuss. I take issue with some of them but I think the crux of my, what I think is important to distinguish is the level of ketosis that we're talking about. Does mild ketosis count as ketosis when you're talking about somebody who is in a weight stable position? I feel we're to go by the levels of ketosis that I reach at a weight stable zero carbohydrate diet. I would never reach the levels where the kind of detection methods that they were using in the papers back then would have been able to detect particularly if it's just acetoacetate which is about one quarter, one fifth of the amount that beta hydroxybutyrate would reach. And so I guess what I would ask is how are we defining ketosis and if we were to define it as a lower keto adapted state would your conclusions be different? Yes I guess they would be and your question and greater knowledge of this top on this issue goes to show that we need a large scale I guess you could say meta-analysis taking into account history and evolutionary biology taking indigenous Arctic communities into account because they've been used and misused in so many respects. As far as differentiating between I guess what you could call mild and deep ketosis I only go by that Heimbecker study and the others and the way that they use controls. I guess the problem with what you might say with some of their controls is is the metabolic state different from that which is induced by not eating stuff as opposed to that which is induced from eating stuff that's a question that I'm sure opens up a whole can of worms many which I wouldn't possibly myself be able to comment much on but I would say yeah I go by those controls that Heimbecker used which is to say they did detect ketones in the way that they detect them from fasting or in other states and they also use controls in other populations who ate a higher fat diet but they just didn't find it among those who were in ketosis. I guess another thing to add to that might be of course I would also suggest that the ability to measure ketones might be contingent upon the metabolic state so far as to say that the ketones might have been used already before they've even been measured I know that's something that many nutritionists and scientists are looking at right now as we speak as to whether or not when you have a very high fat diet would that mean that your metabolism is such that those ketones are going to be burned basically too quick for you to detect in a way that you would detect it in other ways but yeah it needs to be more of a wide scale analysis taking into account all these contingent factors of measurement and so on and so forth. We have time for just one more question. Thank you for your very interesting talk. I had trouble following your argument around CPT-1 so my understanding of biochemistry is CPT-1 allows fatty acids to get into the mitochondria whereas which is where they undergo beta-oxidation which is what leads to ketogenesis. So I was confused first of all about whether the mutation decreases CPT-1 or increases it. If it decreases it, it should allow more beta-oxidation more ketogenesis. If it decreases it, it should allow less beta-oxidation and less ketogenesis. How would the mutation either way lead to less ketogenesis and more efficient beta-oxidation? Yeah with my head spinning I would say that consult my research partner on this who is much more familiar with the scientific terminology and the various what you might even call counterintuitive ways that you can understand how these mutations work. Going back to this, going back to the study from the way that I read it, the enzyme is quote the major rate limiting enzyme for long chain fatty acid oxidation. It's the transporter that allows fatty acids into the mitochondria through the inner mitochondrial membrane. What I took it, the authors see it as a defect in fatty acid oxidation. Oh well so where I first read about this was in my textbook on inborn errors of metabolism where it's regarded as something that stops you from oxidizing fatty acids at all and as far as I know from that textbook this is the only example of an inborn error of metabolism that is ever fully penetrated into a population. So I haven't studied it directly. My impression was that it was a fatty acid oxidation disorder like the authors of the paper you just cited said it was. But you're saying differently. From how I interpreted it, the fatty acid oxidation disorder somehow reduces, goes hand in hand with the potential reduction of the measured ketones at the same time. Well right, because if you can oxidize fatty acids you can't make ketones. Yeah, that's the point. Nobody's really been able to answer that. I mean you cited other data saying they're doing other things with fat like turning it into glucose and stuff like that. I don't know, I mean that kind of makes sense to me. Or just somehow oxidizing fat before the liver Well, I mean I don't know what the Inuit are doing but someone with CPT1 deficiency would have to eat things that are not fat in order to be able to get enough energy to do well. I guess with the earlier 20th century studies would say they're going to possibly be getting even glycogen from fat going back some of the stuff that you've written about. That part of it does make sense. Thank you for your time, I appreciate it. Thank you Dr Gideon-Mailer.