Prof. Robert Lustig - 'Sugar, metabolic syndrome, and cancer'

[Music] thank you so much Victoria thank Jeff and rod for sticking it out my gosh and thank all of you for making it thank me for making it because because I I flew in from Paris long story I was on a Fulbright I was actually doing a sabbatical it's been cancelled because the university's been closed so anyway Here I am so I'm going to talk to you today about something a little bit different but not totally and as you know I believe in the science and I always talk about correlation and causation well today I'm going to talk about correlation and also a plausibility argument and this is the first venue that I've presented this argument so I'm actually going to be interested in your feedback as to whether or not you think this makes sense so be cognizant of the fact that your guinea pigs to some extent but it's a friendly audience on the other hand if you don't like it I'm sure there are a lot of eggs in the room so because it is low-carb so you know hold them to yourself okay no we can so first of all I do have these disclosures I did write these two books for the general public and I am also the chief science officer of a non-profit in San Francisco called eat real because we believe in real food we are bringing real food to schools we have gotten rid of 270,000 pounds of sugar from the Mount Diablo Unified School District in one year ten pounds of sugar per year per child per year and we can do that for your school district too and we'll need to and you'll see why in addition I have another disclosure and that is that I am not really specifically exclusively low-carb I support low-carb I used low-carb in my practice for the right patient but I also used low-fat when necessary for the right patient okay the point is knowing who those patients are and that takes a little bit of science and or work and the little medicine so let's jump in I'm talking about sugar today and cancer so first of all everybody thinks it's about obesity well there's no question that obesity is a risk factor for cancer and it's about a hazard risk ratio of about 1.5 so about 50% increased risk of developing cancer these are different studies that look at that but when you look at the specific cancers that seem to be associated with obesity prostate colon lymphoma esophagus stomach liver pancreas kidney leukemia they are endodermal origin they are not of misa dermal or ectodermal origin so they are not bone they are not muscle they are not fat cancers and from ectodermal they're not a skin and they are not CNS they're endodermal cancers and that actually suggests that there's some specific pathway involved if you look at the International Agency for research on cancer here's the list and again it holds up based on international data that these cancers are specifically related to obesity now the question is why well obesity could predisposed to cancer for several reasons one out of host issue could be a storehouse for toxins because most of them are nonpolar for instance benzene and other specific carcinogens like for instance things that you find in meat after you've grilled it in terms of methyl science etcetera could be due to increased estrogen synthesis because adipose tissue has higher Matei so there's an increase in estrogen load could be due to oxidative stress and reactive oxygen species due to metabolic syndrome as we'll talk about or could be due to hyperinsulinemia as Jeff talked about or igf-1 which is higher in kit and cancer and specifically free igf-1 and lower IGF binding protein one which is insulin regulated negatively so the higher the insulin the lower the IGF bp1 the higher the free igf-1 and the greater risk for cancer because after all these are all growth factors so knowing that the American Society of Clinical Oncology ASCO this is what they put out in 2014 they said yeah we know that there's a relationship between obesity and cancer so we need education and awareness clinical guidance tools and resources research promotion policy and advocacy oh yeah sure sure blah blah blah yada yada yada and weight management too in cancer survivors that's it that's what they said okay so first of all how well you think that works second of all don't we need weight management and everybody to prevent the cancer just the survivors I mean like how dumb is this but that's where we are so they would say to you well obesity is the problem I'm not so sure that that's true and here's three reasons why number one here is a scattergram of all of the countries in the world obesity prevalence on the x-axis diabetes prevalence on the y-axis and you would look at this scatter gram and you would say well very clearly dr. Lustig there is a correlation and here it is and there is I don't know argue that but you know correlation is not the same thing as concordance because there are countries that are obese without being diabetic such as Iceland Mongolia Micronesia and there countries that are diabetic without being obese such as India Pakistan and China India and China today have an 11 percent diabetes rate and they're not fat we are the fattest nation on earth and we have a nine point four percent diabetes rate if obesity is the cause of diabetes the obesity is the cause of metabolic syndrome obesity is the cause of cancer then how do you explain that well the fact is you can't because it's not true in addition problem number two obesity is increasing worldwide at the rate of two point seven eight percent per year amortized over the last 40 years yet diabetes is increasing worldwide at the rate of four point zero seven percent per year amortized for the same period of time if diabetes is just a subset of the larger group of obese individuals then how come it's going up faster problem number two problem number three here are the secular trends in biddies race again diabetes being the sentinel disease of metabolic syndrome in the entire united states and on the left side you can see the total numbers in the black on the right we have them stratified by weight category obese atop and you can see there's been a 25% increase in incidents per year amongst the obese true those also been a 25% increase in the normal weight population as well if diabetes is just a manifestation of obesity then how come the normal weight people are getting diabetes just as fast problem number three so here's the most important thing as many of you have seen this set of slides before but it's the most important thing to explain and Jeff actually had several slides to this point as well this is a Venn diagram of the entire United States population 240 million 30% obese BMI over 30 70 % normal weight BMI under 30 now the standard mantra from the doctors and the dietitians and the Institute of Medicine and the Surgeon General and the National Institutes of Health and the White House and Congress out in the food industry is the following 80% of those obese individuals 80% of those 30% those 57 million people they're sick they're fat and they're sick and they're sick because they're fat and if they would only just diet and exercise we'd solve this problem that's what they say garbage total complete trash anybody know why it's on the slide well it is true and Jeff's mentioned it in his talk it is true that 80% of 30% are metabolically oh I don't argue that that is absolutely true but that means 20% of 30% or not they are metabolically healthy we have a name for them mhm Oh metabolically healthy obese that will live a completely normal life diet a completely normal age not cost the taxpayer a dime they even have normal length telomeres the ends of the chromosomes that determine how fast your cell dies and if determines how fast you die they are not bothering anybody they're just fat conversely and this is the important part 40% of the normal weight population have the exact same diseases as devii obese normal weight people get type 2 diabetes hypertension lipid problems cardiovascular disease cancer and dementia - they get it at a lower weight true but if they get it how can it be about behavior this actually looks more like exposure this more it looks more like what influenza does or cholera or for that matter coronavirus okay so this can't be about behavior this is about some exposure that everyone including the normal weight people are exposed to and if you do the math turns out there are more thin sick people 67 million than there arc that's sick people 57 million but the thin sick people are calling the fat sick people the problem and when you do the math on all of them that's more than half the u.s. population and I guarantee you no matter how bad coronavirus gets it will not be half the u.s. population so this is a bigger problem even than coronavirus but that is now a national emergency this is not figure and I can prove it to you and Jeff mentioned it as well okay so here are two equally weighted people okay CT scans through the abdomen of two equally weighted people ones healthy one sick which ones sick a or b b b is sick because a he's got metabolically healthy obesity he's got big love handles he's got subcutaneous or big butt fat B he's got fat all around his organs he's got intra-abdominal fat he's got visceral fat he's got big belly fat and we have a name for this it's called as Jeff said tophi tof i thin on the outside fat on the inside real medical term 1500 MEDLINE citations go look it up so my question to you sitting here right now are you at OFI how would you know how could you know does your doctor know if your NOC doctor knows how come the doctors not telling you and if your doctor did now what would they do about it anyway these are the issues fact matter is you guys are using low-carb for those people which is a good idea and I'm not against it I'm for it and I'm supportive oh okay but I think that that may be not necessary for some of the patients I think that we can do something a little less extreme and help just as many people so that's the issue so what I'm arguing is obesity is not the problem obesity is a marker for the problem metabolic syndrome is the problem that's where the money goes seventy-five percent of all health care dollars and here are the diseases diabetes is the Sentinel disease but cancers on the list and I will show you how and why so if it's not calories and it's not obesity then it's I guess the type of calories and as you've heard already all calories are not the same so if you look at this monograph that came out from ASCO many years ago we know that dietary components do have some relevance to cancer promotion dietary fat can increase colon mammary pancreatic cancer dietary protein can increase colon and mammary cancer dietary starch can increase will variant prostate cancer and dietary fiber will prevent colon cancer and I would argue with Michael he's and I already did that fiber does have a value he said there it had no value I would argue it has a very real value it is not food for you it is food for your bacteria it is food for your microbiome and if you don't feed your microbiome guess what your microbiome will feed on you which is not so good and I am actually writing a whole book about this whole issue right now we can talk about it at the Q&A if you want so the ASCO position doesn't even mention dietary composition it just mentioned weight loss even though they put this monograph out well turns out it depends on what the food is as you can imagine so ultra processed food is now more than half of the UK diet it is 62% of the American diet ultra processed food ok that is food that is basically been stripped of its matrix and conglomerated into new shapes and sizes and if you look at what is ultra processed food okay in the lower-left pretty much three quarters of it is sugar that's what that is the marker for ultra processed food and the reason is because if you didn't put sugar in it it would taste like it is the marker for processed food because that's the only way they can get you to eat it because sugar is addictive so if they could put cocaine though food they would but they can't so they do this instead and you can see that in terms of the quartiles of ultra processed food consumption the highest quartile has the most significant increased in cancer rates and every 10% increase in processed food increases your cancer risk by 12% so here's what our sugar consumption has done over the last 200 years our ancestors getting fruits and vegetables out of the ground with the occasional honey consumed about 4 pounds of sugar per year fine no problem easy with the advent of the pot still and distillation and crystallization and CNH and Domino and hoe Texas and Hawaii and Louisiana we increased our sugar production and our sugar consumption till we stabilized when price equals demand before World War two there's the rationing of World War two came up to the same level and then of course we had many things happen in the 60s we had the high fructose corn syrup enter our world we had the dietary guidelines and we had hurricane Allen which destroyed the sugar crop and so high fructose corn syrup came in to take its place because it was a natural product ok so all these things happen you know basically substituted sugar for fat as you've all heard a zillion times ok so we have increased our consumption of sugar by 25 fold not 4 pounds per year 100 pounds per year and it is that change okay that people don't talk about here's everyone talking about 40% fat and 30% carbohydrate know that okay just look at the sugar okay it's insane so what are we talking about we're talking about two molecules glucose and fructose so on top is high fructose corn syrup on bottom is sucrose table sugar cane sugar beet sugar the stuff you put in your coffee glucose is a six membered ring notice six membered fructose is a five membered ring they are not the same they're not handled the same by the body and I will show you how in a moment now sucrose you'll notice six membered ring five membered ring Oh glycosidic linkage linking the two the enzyme sucrose in your intestine Cleaves this in a nanosecond you absorb the two moieties separately but ultimately what ends up in your portal vein which hits your liver exactly the same so it doesn't matter whether it's high fructose corn syrup or sucrose and the data say that high fructose corn syrup and sucrose are virtually identical yeah they're virtually identically bad they're equally dangerous they're equally toxic and I use that word very specifically because it is not dependent on calories or obesity and we have causation so I'm very comfortable with the word toxicity toxic and it is the fructose moiety that is specifically toxic so is sugar public enemy number one trans fats used to be but we know that and they're coming out of the diet so sugar now is the one that the food industry adds specifically to get you to buy more so yes it is public enemy number one so let's talk about sugar and disease start with obesity now the food industry will tell you that yeah sugar causes obesity but it's not very very significant in fact the data suggests only ten percent of weight gain is related to sugar and that's seen on this slide BMI of about 0.8 BMI points you see the diamonds it's passed the identity line so it's significant but it's only ten percent you know there are things that are much worse in terms of weight gain and that's true actually there are things that are worse in terms of weight gain but they tell you that sugars and related to obesity because of this they also throw this out and this is got to be debunked and I'm doing it right now so if you look at this slide you'll notice from 2000 to 2020 we are sugar consumptions actually gone down which is true it's gone down by about 10 percent because they obesity epidemic because people are trying to cut back true so we've gone from a hundred pounds down to about ninety pounds it's true in the meantime obesity rates continue to escalate so they're saying how could it possibly be sugar because after all sugar is going down obesity is going up and so they use this as an argument against regulation and against culpability for their product is this true well this was a hard one to deal with until just this past year in fact just this past month when it finally came out I actually reviewed this article a group at UT Knoxville actually did a little calculus and they actually remodeled it based on the state of Wisconsin and you can see the data here they had 46 calendar years and seventy-five different life ages that they examine separately and what they did was they applied a mathematical function that did not just look at today's sugar consumption it looked at last year's sugar consumption as well and by doing that and you can see that on the lower left corner how they did that okay they developed a new model and the model now approximates the data almost identically so this is a complicated function but nonetheless a real function in terms of the cumulative effect of sugar probably due to its effect on adipocyte growth and adver genesis now it is true that there are other things that cause weight gain that is true potato chips and french fries numbers one and two i don't argue that sugar comes in third there's you know sweets and desserts and sugar sweetened beverages you add them together they come in third so yeah there are a lot of things that cause weight gain sugar only being one of them this is very interesting this is a group from UC Davis Roberto Diwali what they do they collected the cash register receipts from all of the fast-food restaurants in all 37 oacd developed countries for 20 years how's that okay and ask the question does fast food consumption predict weight gain and the answer is clearly it does there it is right there okay and this is a baseline to you know 20 years later so this is a predictive of prospective correlation so then they ask the question okay fast food predicts weight gain what about fast food predicts weight gain and so they had to model they had to do a multivariate linear regression analysis to ask which of the components was it the hamburger or was it the french fries or was it the soft drinks that was the question and it turned out it was all the soft drinks it wasn't the hamburger it wasn't the French fries I actually have to tell you I was a little surprised okay and when they did all the rest of the modeling that didn't change the effect of the soft drinks so basically the soft drinks are the driver of the fast foods effect on obesity now the problem is that the soft drink companies don't like that they don't want you to know that and so they've published their own data and so this was a meta-analysis that was done in 2013 where they looked at 18 separate data points and asked the question duh do sugar beverages predict weight gain if the food industry sponsored the study five out of six said no effect of sugar beverages on waking if the studies were independently funded 10 out of 12 said yes effective sugar I'm waking so you can see that corporate sponsorship had something to do with the outcome and this was nailed down even more by my colleague at UCSF Dean Schillinger in annals of internal medicine because he had 60 data points okay and you can see that there were 26 that were food industry-sponsored 26 out of 26 no effect of sugar on diabetes or obesity whereas of the 34 that were independently funded 33 out of 34 said yes effective sugar on OBC herbs diabetes so bottom line the literature is polluted its polluted and it's polluted on purpose because then they can go back and save see it's inconclusive which is what they've been doing for the last 50 years okay sugar and diabetes forget sugar and weight gain sugar and diabetes let's talk about the real disease let's talk about metabolic syndrome so I'm going to present to you plausibility mechanism correlation and causation 'el studies so this is what you learned in med school you get fat the fat cell is the problem you get fat and because you get fat the fat drives cytokines TNF alpha il-6 which go via the portal vein to the liver the liver responds to those by becoming insulin resistant increasing hepatic glucose output hgo which thereby increases blood sugar which they're caused by causes the islet cells to have to make more insulin which then drives more energy into fat and so you end up with this vicious cycle but it starts with the fat it's the adipose centric view of metabolic syndrome and then the muscles along for the ride this is what they teach in medical school the question is is it true yes or no we'll talk about it so what I'm going to say to you is it is true for about 10% of the population for about 50% of the population there's a different explanation which has been buried and I'm gonna explain that one to you a little bit differently it starts with the liver not with the fat okay because the liver gets insulin resistant and how so on the Left we have normal liver sinusoids mild canaliculi cooked for cells all good and on the right we have fatty liver disease and you can see the fat vacuoles you can see the macrophages you can see the beginning of scarring and fibrosis the question is what caused it prior to 1980 if you saw this under the microscope bingo it's alcohol but now five-year-olds get this and they don't drink alcohol it turns out sugar does the exact same thing and the reason is because sugar and alcohol are handled by the liver virtually identically that's why kids are getting the diseases of alcohol without alcohol because fructose and ethanol are handled by the liver virtually identically and it makes sense that that would be the case because after all where do you get alcohol from fermentation of sugar it's called wine we do it in Napa and Sonoma every day not during coronavirus but otherwise yeah all the time so the big difference between fructose and alcohol is that for fructose that for alcohol the yeast does the glycolysis the first step for for fructose we do our own first step but after that the mitochondria of the liver have to handle it virtually the same way and this is mitochondrial overload from whatever the substrate is that caused the overload it could also be branched chain amino acids by the way from corn-fed beef also causes this so all you lo carvers keep that in mind so here is a fat fraction map from an MH Oh metabolically healthy obese notice the love handles on the sides okay but take a look at this guy's liver dark 2.6 percent fat this is mah oh this guy will outlive you now take a look at this guy in the center this is more like what you'd see okay notice the obesity but take a look at this guy's liver 24% liver fat this guy's got non-alcoholic fatty liver disease this guy's got metabolic syndrome now take a look at this guy is he fat no love handles take a look at his liver 23% liver fat this guy is thin but he's got the same diseases as the guy in the center fin sick fat sick fat healthy so you cannot tell from the outside what's going on on the inside because it's the fat you can't see that makes the difference and the fat you can't see is in your liver and how did it get there that's the point and it didn't get there from the grass-fed beef but it could have gotten there from the corner fed beef but it most assuredly got there from the sugar Naf old is the liver manifestation of metabolic syndrome and it correlates with all the other manifestations of metabolic syndrome so large waist high glucose low HDL high triglycerides high blood pressure all the things you've heard about in both adults on top and in children on the bottom fatty liver disease is liver metabolic syndrome it is 45% of Latinos and that's one of the reasons why Latinos are so predisposed to getting diabetes because they have get fatty liver faster because they have two polymorphisms that drive liver fat faster than it does in Caucasians african-americans however are protected from fatty liver disease they are much more likely to export the fat out of their liver to take up residence in the peripheral adipose tissue which is why they increase their sub-q fat so that's why they have more obesity why they have a higher BMI before they get sick now about one out of 20 people with liver fat will go on to develop steatohepatitis that is fatty liver plus inflammation and of those 25% will develop cirrhosis and will die of their disease if they don't get over transplant now this is probably the other most important slide I'm going to show you so the question is which fat causes the disease we all assumed it was just how fat you were know then we assumed okay it's all the belly fat the visceral fat this was the first study that said no it's the liver fat so this was work from Sam Klein's group at Washu st. Louis and what they did was they when they finally got a three tesla scanner because you need a big scanner to be able to look at liver fat and it took a while what they did was they put a whole bunch of fat people in a scanner and they measured visceral fat versus liver fat and what they showed in this study was that when they held the liver fat constant the visceral fat explained none of the effect on insulin resistance whereas when they held the visceral fat constant the liver fat explained all of the difference in insulin resistance it's the liver fat that makes the difference not the visceral not the subcutaneous it's the liver fat and 45 percent of adults in the United States now have fatty liver disease you want to talk about epidemics that's the epidemic okay I guarantee a corona virus will not reach 45% now the question is where that fat come from that liver fat and that's in the right picture and you'll notice in the gray non-systemic fatty acids non-systemic now we know where systemic fatty acids come from they come from adipose tissue lipolysis or from diet but this is non systemic where do those come from the fat made right in the liver through a process called de novo lipogenesis dnl new fat making this is what your liver does to sugar to get it out of the liver it turns it into fat and then exports it out in VLDL which we measure in the serum triglyceride okay so here's how the liver handles glucose glucose comes in and first of all only 20% of a glucose bolus actually hits the liver because the other 80% is metabolized by the rest of the body and pretty much all the glucose ends up as glycogen liver starch non-toxic non-dangerous is what your liver wants to do with excess glucose that's why marathoners carb-load is to increase their hepatic glycogen stores okay now can glucose get turned into fat in the liver yeah but you've got to really work at it okay so you know there's not going to be very much pyruvate reaching the mitochondria and so there's you know that it's regulated because insulin is going to keep the pyruvate at the right level for the mitochondrial carboxylic acids Vmax so you're not going to end up overwhelming your mitochondria with glucose okay you might end up gaining weight with glucose but you're not going to overwhelm your mitochondria with glucose right now a little bit of it might end up as citrate and then the citrate will get thrown off via the citrate shuttle exit the mitochondria and then that citrate will act as the substrate for these three enzymes that you can see there a CL ATP citrate lyase AC C sto a carboxylase one and FAS fatty acid synthase and those build citrate into fatty acyl Co a fatty acids which then get hooked onto a triglycerol backbone to form a triglyceride which then get packaged with a PO B with phosphatidylcholine and then get exported out as VLDL and that's what you measure in your serum triglyceride everybody see how that works got it so for any molecule of glucose how much of its going to end up as fat not very much but here's fructose now fructose is a whole nother story because only the liver can metabolize fructose so a hundred percent of the fructose load ends up at the liver and do you see glycogen anywhere no glycogen doesn't go to glycogen go straight down to the mitochondria the mitochondria end up with a huge pyruvate can't they'll deal with the whole thing and so it sends out a whole bunch of citrate which then ends up being built up into fatty acyl Koei's now some of that will get exported out as triglyceride and that's why you have the hypertriglyceridemia of sugar consumption but some of it won't make it out some of it will stay in the liver will stick in the liver and now you've got a lipid droplet now you've got fatty liver disease and once you have fatty liver disease now you have insulin resistance at the level of the liver so fructose and it's not insulin regulated so basically when you hit your intestine with a 20 ounce coke you are basically generated a tsunami of sugar that your liver can't handle and your liver has no choice but to take that whole tsunami and turn it into fat some of it will go out and be risk factor for heart disease and obesity and some of it will stick and be a risk factor for fatty liver disease and diabetes so I guess you can choose which one you want to die off but that's where the draw that's the driver of the phenomenon and we've proven that by doing a study where we basically took 43 kids from our own UCSF pediatric obesity clinic with metabolic syndrome african-american and Latino all high sugar consumers and what we did was we figured out what they were eating on their home diet we studied them on their home diet and then for the next nine days we catered their meals no added sugar we took their % consumption of sugar from 28% of calories to 10% of calories everybody got that 28% down to 10% so that's a loss of about 350 to 400 calories per day as sugar now if you do that for 10 days 9 days you're going to lose some weight we didn't want them to lose weight because if they lost weight and they got better people would say well of course they got better they lost weight we wanted them to stay the same weight so we had to replace what we took out with something else we gave them refined starch got it so in the vernacular we took the pastries out we put the bagels in we took the sweetened yogurt out we put the baked potato chips in we took the chicken teriyaki out we put the turkey hotdogs in okay so we can give him good food we gave him crappy food we hadn't processed food we get him kid food we gave him food kids would eat we bought it at Safeway okay but it was no added sugar food it was high starch low sugar food and we gave him a scale and every day we'd call him up on the phone say would you weigh and if they were losing weight eat more in order to keep them weight constant over the course of the 10 days and then we studied him again and we published these three papers and actually a fourth and we're about to we're writing the fifth and the sixth now on the study so this is just describing what I just told you all of their labs got better their fasting glucose went down five points their blood pressure went down five points their fasting lactate and that's really important they had a lactate level at baseline you're not supposed to have a lactate level at baseline if you have a lactate level where's mark if you have a lactate level at baseline that means you are either post-exercise or you have cancer or you have a mitochondrial encephalomyelitis gids had a lactate level and it went down just by switching starch for sugar they're fasting insulin went down 25% the glucose area to the curve went down 8% their insulin the area to the curve went down 25% their triglycerides went down 46% every aspect of their metabolic health improved with no change in calories and no change in weight we reverse their metabolic syndrome and I'll show it to you so here's their oral glucose tolerance test before and after on the left is the glucose down 8% and there's the insulin curve the Kraft curve if you will and you'll notice that before it wasn't coming down because they were insulin resistant and even though they were getting more glucose they actually had a more sensitive insulin curve their insulin Aryan to the curve went down 25% and they started clearing the insulin because their liver was working better so we wanted to see whether or not their liver was turning that sugar into fat so what we did was he gave them c-13 labelled acetate which got incorporated into new palmitate which we could then measure in the VLDL and here's what their Denova lipogenesis did it got cut in half so they're making less fat in their liver even though they're getting just as many calories and more glucose now what happened to their fat stores now remember they didn't lose weight kept the same weight so there's subcutaneous fat did not change at all but take a look at their visceral fat went down 7% but take a look at their liver fat went down 22% 22% with no change in calories in no change in weight and as it turns out their change in liver fat predicted their change in insulin sensitivity and now we actually have data that showed that they had non-alcoholic fatty pancreas disease - and that got better when we took the sugar out of their diet so in cartoon form fatty liver with lots of triglyceride lots of VLDL lots of liver fat nine days of isocaloric fructose restriction the liver fat went down the de novo lipogenesis went down the VLDL went down and the insulin sensitivity and the insulin secretion improved in other words we reversed their metabolic syndrome with no change in calories no change in weight QED proof positive fu so we think that the adipose centric of your version of metabolic syndrome is actually the problem it can happen yes but you have to get really fat to have that happen what more likely happens is your liver gets insulin resistant because of the sugar bolus that now all of us are exposed to from processed food which drives fatty liver which then drives hepatic glucose output which then drives the beta cell to make extra insulin which then drives increased out of agenesis at the level of the fat cell this is the HEPA docent review of metabolic syndrome and then the muscles along for the ride but that's not all you think that's all there's more reactive oxygen species we know this is very important for metabolic syndrome so here are five pictures of food they all share one thing in common what is it they're all brown thank you this is called the Browning reaction or the my yard reaction it's the reason for hemoglobin a1c it's the non enzymatic glycation of proteins so here's how you should think about it you can slow roast your meat at 375 degrees for an hour or you can slow roast your meat at 98.6 degrees for 75 years the answer is the same your browning you're just all browning your browning right now as we speak it's part of life okay death is part of life this is what kills you okay it's just a question of how fast and if you don't believe me here's newborn rib cartilage in the upper left nice and white and there's 88 year old rib cartilage nice and brown okay you're browning and if you add orange juice this morning you're browning seven times faster but I already know you didn't because this is the low carb conference okay so why is this happen because the aldehyde moiety of the linear form of glucose binds to epsilon amino groups of lysine on the hemoglobin molecule which forms a shift base and then spontaneously decomposes to form this amid linkage and that basically stays for three months and that's why you commissioner hemoglobin a1c and every time this reaction occurs you throw off an ro s a reactive oxygen species in oxygen radical oxidative stress which has to be quenched by an antioxidant in the liver that would be glutathione or vitamin E in other organs they have other antioxidants but primarily we're talking about liver here okay everybody with me and it doesn't matter if it's glucose or fructose but it turns out glucose doesn't do this very fast it does it but it doesn't do it very fast okay the reason is because of that ring form remember that six membered ring well there it is on top so there's the linear form of glucose the ring form there's the space-occupying model notice six membered ring hydroxy methyl group sticking up not bothering anybody this is a happy compound at pH 37 a pH 7.4 37 degrees only 0.8% of the glucose in your body is in the linear form where it can bind to proteins but now take a look at fructose below linear form ring form space-occupying model five membered ring tighter wound easier to break apart called ionic strain two hydroxy methyl groups axially button heads called allosteric interaction basically driving them apart so at pH 37 degree at the h7 point for 37 degrees 3% of the fructose will be in the linear form and that reactive keto group is just as reactive as the reactive aldehyde group so more fructose more oxygen radicals and we can show that and you can do the study at home if you want take two test tubes fill them with albumin bovine serum albumin in water okay add equal amounts of glucose or fructose to each cap them with parafilm put them in the sunlight and each day come back and stick it in your home spectrophotometer and this is how fast the reaction occurs you see for glucose you see for fructose seven times faster 100 times the number of oxygen radicals well you have to do something with those you have to quench them you have to make them you know basically die and that's what the peroxisomes do and that's why people use tea CDs for metabolic syndrome is because that increases the number of peroxisomes and we know because if the more greater the fructose consumption the greater the steatosis or fibrosis so this is basically what we're saying is fructose enters the liver cell combined cause the my yard reaction which will then generate reactive oxygen species the mitochondria will generate reactive oxygen species in addition of course the cytokines that come from the peripheral fat will also generate reactive oxygen species so you have this ro s pool sitting in the liver that has to be quenched and they go to the peroxisome to die unless the peroxisome doesn't have enough antioxidants in which case then the RO s's can damage the liver cell it can cause lipid peroxidation because protein denaturation can cause what we call ER stress and the plasmic reticulum stress you may have heard that term okay and what that means is you will end up not being able to fold your insulin molecule or being able to fold your insulin receptor molecule known as the unfolded protein response so now you've got cellular metabolic dysfunction and potentially cell death that is metabolic syndrome okay I've got one minute and 13 seconds to tell you about cancer so I'm gonna talk about plausibility mechanisms correlation no causation yet and that's the issue so you've probably heard the cancers of metabolic disease because different things affect its ability to progress and all of those things are related to metabolic syndrome so the question is the plausibility how does sugar make the happen so who here has ever heard of otto warburg good the Warburg effect he was the person who figured out that cancer cells do not need oxygen to grow he won the Nobel Prize in 1931 so can anybody else think of a cell that doesn't need oxygen to grow how about a fetus the oxygen tension in a fetus the po2 is 30 so how does this how does the fetus grow it grows faster turns out actually that the more oxygen the less growth the less oxygen the more growth this makes absolutely no sense except it does and this is the key so differentiated tissue have mitochondria cancer cells don't anaerobes grow but they don't have mitochondria either in fact mitochondria burn energy all the way to carbon dioxide but cancer cells and fetal cells and anaerobes they need the glucose they need the carbon backbone of glucose for other stuff if they burn it all the way to carbon dioxide guess what no other stuff they needed for ribose for DNA they needed for lipids for membranes they needed for amino acids to build their cells that's how cells grow so you can either burn or you can grow you can't do both and at any given point in a cell's life they will have to do either one or the other never both at the same time and that's important for you to understand there is a growth paradigm there is a burning paradigm okay we're going to talk about in a minute what those are and what causes that so when a cell is doing the right thing nutrient transporters bring stuff in and the glycolysis occurs you get two pyruvates you have two NADH s and two ATP's so you don't get a whole lot of ATP out of Peyer of it out of glucose from the glycolysis but the pyruvate will enter the TCA cycle throw off a lot of nadh which will then of course act as a oxidative reaction later and you get 30 ATP out of the TCA cycle burning of of pyruvate okay and you will make a little bit of lactate not very much and that will recycle and that will come in and will also end up as asked your Co way through that process I just showed you and it will throw off 108 ATP so when your cell is in burning mode you can generate a whole lot of ATP from glucose or from fat and protein the same thing but when you have a cancer cell you do not have mitochondria the mitochondria can't keep up with the cell division in addition because the cells growing so fast it outgrows this blood supply so there are a lot of cells in cancers that can't be fed with oxygen so they are growing without oxygen the question is if you're only getting 2 ATP out of glycolysis because that's what you can do without oxygen how can they do that how can they stay alive and the answer is because they're putting in 400 times more because they have opened up the floodgates so that that cancer cell is now being flooded with glucose that's why so glucose is absolutely vital for cancer cell growth to make ATP short but mostly by via glycolysis but there's 400 times as much but you need ribose for DNA you need fat for membranes the pentose phosphate shunt makes that happen so if you burn it all the way to carbon dioxide that's an end product you're done okay yeah makes a lot of ATP but that's it you can't grow on that so you don't want oxygen you don't want mitochondria in a cancer cell so cancer cells are all about making new cells now you got a whole bunch of glucose coming in so you got a whole bunch of pyruvate a whole bunch of ATP you're not going to do much in the mitochondria at all you're gonna generate a whole bunch of lactate cancer cells make lactate like crazy the pentose phosphate Chen is gonna make ribose genomic DNA okay you're gonna generate the de novo lipogenesis you're gonna make fat out of your asset Eelco a like I showed you in the in out of the mitochondria and you're going to take glutamine and you're going to turn that into proteins as well okay so what is fructose do fructose enters that glycolysis remember it doesn't have insulin and it doesn't need anything and it generates more fat and more ribose now the question is why real quick this is the hypothesis part of this this is the cellular metabolism in cancer worked out by Luke and Leia's group at Cornell and there are three count'em three enzymes in each cell that tell the cell what to do with the energy and here they are the first one is called pi3 kinase you may have heard of it pi3 kinase determines whether the cell opens up to let the four hundred times as much glucose in that's it's job is to open the floodgates the next one is am p kinase and that's the one that tells the mitochondria burn or not okay so take that extra glucose and either burn it or don't depending on whether it's turned on or off and then the last one which is not on the slide is called mTOR mammalian target of rapamycin and that's the enzyme that tells the cell whether to live or die it generates otology when it's on okay so we know that this is true because we know that metformin can inhibit cancer and the foreman stimulates an p kinase because it's basically generating mitochondria and by doing so it's improving insulin sensitivity and it's also increasing burning so that you don't have the the tools to make extra cells so metformin is an anti-cancer drug it's also an anti-aging drug because it's allowing stuff to burn to completion so here's the hypothesis there are three enzymes they can either be on or off which means there are eight permutations two to the cubed so one is for growth when pi3 kinase is on the ampa kinase is off and mTOR is on you have growth and that's when you have cancer when it's the opposite when the pi3 kinase is off the ante highnesses on in the mTOR is off that's burning these are the two growth and burning growth and burning so every cell in the body has to be able to do one of these at one time in its life but there are six other permutations and here they are and it turns out that whenever you have one of these other permutations that's when you have disease so when the pi3 kinase is on but the others are not now you have all this extra glucose and you don't know what to do with it that's metabolic syndrome when the mTOR is on and nothing else is on then you have early aging because you can't clear cells because there's no autophagy because that's the garbage crew otology and when you don't have otology you have cellular senescence when you have a good thing about a MP kindnesses it turns off mTOR so you can actually have mTOR being on ik will be turned off by MP kinase point is you can have different aspects of cellular survival and disease based on these different enzymes being set at different places and you know what sets those enzymes in different places food no drugs food a MP kindness is the master regulator I'm gonna go through this really fast okay it promotes all the burning things which are here in green and it stops all the growth things which are here in blue and if you up the iamp kinase you can't even get liver fat because your livers burning like crazy you can't even store it it is exquisitely sensitive to a MP that's why it's called a MP kinase because a MP fits into the active site and a MP goes into that active site and basically turns on that because it says we need more mitochondria because a MP says that so much ATP has been basically used up okay well that active site has three arginine and the fructose gets converted to a meta Futaba light called methylglyoxal and we found this in our studies in kids and what it does is it goes into that active site binds to those arginines through that mired reaction and basically inactivates the ANP kinase and when you have a and P kinase that's dead guess what happens you get growth when you shouldn't so we know that because we measured D lactate D lactates a very specific metabolic byproduct of methylglyoxal not l lactate d lactate different you need a special study and it's higher in the obese and we saw in our children it went down by 38% just by getting rid of the fructose so we're pretty darn sure that methylglyoxal is the business end of the fructose molecule it is the toxic metabolite in the liver that is driving EMP kinase to do all the wrong things and none of the right things so I'm gonna go I'm just going to because of time I'm gonna forget about that I'm just gonna finish with correlation so does sugar consumption correlate with cancer in humans and the answer is yep in certain ones endodermal ones like there and with breast cancer as well but fiber will make that go away and if you look at sugar sweetened beverages against obesity you can see they are synergistic in terms of cancer risk American Heart Association knows this says we need to cut our sugar consumption but we haven't and basically our food dollars are being spent on processed foods loaded with sugar very specifically because the food industry knows when they added you buy more and this is what we are giving cancer patients and sure plus take a look at the ingredients it's a baby milkshake or a Coca Cola either or it's the same thing so do you think that's a good idea to give to a cancer not so much so in summary sugar consumption correlates with a be seeing cancer obesity is associated with cancer development but metabolic syndrome due to insulin resistance is the reason fructose possesses unique metabolic characteristics that promote cellular damage the de novo lipogenesis the liver fat the mired reaction and the reactive oxygen species with the cellular asian sugars an independent risk factor for metabolic syndrome and we have causation on that it's exclusive of calories it's exclusive of obesity it is causation causation meets the definition the scientific and the legal definition for causation and that is why there are now lawsuits that are succeeding against the food companies sugar may also be a risk factor for cancer development and promotion through these mechanisms I just described and we currently consume triple our limit it is driving these processes and nutritional support for cancer provides high fructose content you think that's a good idea I don't think so in fact Memorial sloan-kettering and MD Anderson are now conducting experiments with the ketogenic diet in patients with cancer to see if they they will improve for this reason and I am an advisor to both so with that I want to thank my collaborators at UCSF at Berkeley at Toro University at San Francisco General at University of Sydney Kieran Rooney whom should be known to this group already and with that I will close and answer questions at the Q&A thank you [Applause]

Channel: Low Carb Down Under

Views: 434,076

Rating: 4.8873053 out of 5

Keywords: Low Carb Down Under, LCDU, www.lowcarbdownunder.com.au, Low Carb Denver 2020, #LowCarbDenver, #LCD2020, Dr Robert Lustig, Fat Chance, Hacking of the American Mind, Sugar and Cancer, Warburg Effect, LCHF, Ketogenic Diet, Keto and Cancer, metabolic syndrome, obesity, weight loss

Id: jpNU72dny2s

Length: 57min 42sec (3462 seconds)

Published: Sat May 16 2020

Reddit Comments

[u/EvaOgg]

Coincidentally, I have just posted part of the Q and A session that followed, and that I found as interesting as the lecture itself!

https://www.reddit.com/r/ketoscience/comments/go52is/branchedchain_amino_acids_from_cornfed_beef/

[u/KetosisMD]

Here are the three key slides Re: Cancer.

https://imgur.com/a/PC92HfP

[u/tuuioo]

great stuff, we can only hope that this goes mainstream.

[u/rad_nomad007]

Lol read a book on this guy! Great book, sugar is the devil.

The Hacking of the American Mind I believe!

[u/elduke717]

This is a great talk, thanks for posting it. Dr. Lustig does great work and his books are all worth reading. I thought The Hacking of the American Mind was particularly interesting and thought provoking.

One thing I thought was interesting is that he mentioned that corn-fed beef can contribute to NAFLD, like fructose.

Has anyone else heard this and know why? The only think that I can think of is fatty acid composition and the higher levels of omega 6 in corn-fed beef?

[u/highview]

https://www.reddit.com/r/ketoscience/comments/2gg2cy/ketosis_may_slow_down_the_aging_process_in_humans/ckj6qhd/

This helped me understand more of what was talked about.