Robert Lustig - What is Metabolic Syndrome Anyway?

I want to make it very clear I am NOT a low-carb ER I'm also not a low-fat ER I am NOT in anything okay I am a real food guy okay and I think all real food works it's what we do to the food that doesn't I want to make that clear and I'll show you why I think that as we go the other thing I want to say is you can't solve a problem if you don't know what the problem is and we're trying to solve the problem and I'm gonna tell you we don't have one problem we have three and you can't solve three problems unless you know what the three problems are and that's what we're going to delineate today three separate problems they overlap but they're separate they all fall under this term metabolic syndrome and you think you know what that is you don't know what that is as we're going to talk about today so first of all I did write these two books for the general public I am the chief science officer of a non-profit here in the Bay Area called eat real where we're trying to promote real food we've praise the good we certify restaurants hospitals cafeterias school districts that procure market and sell real food we are teaching fourth graders to cook in the East Bay as a model for being able to change the educational paradigm across the state and then hopefully across the nation and I'm also the chief medical officer of a start-up for-profit called bio luminal apey bioengineered answer to this metabolic syndrome epidemic if anybody's interested we can talk about it later none of that will have any impact on this talk all right if you look at preventable causes of cardiovascular deaths over time you can see smoking down blood pressure down cholesterol down physical activity up we should be reaping a health benefit we are not because obesity is up and diabetes is through the friggin roof in fact this is a paper that was published in Lancet in 2000 and it projected that we would go from 151 million diabetics on the planet in 2000 to 221 so that would be an annualized inflation rate of three point eight eight percent if that were true what we actually ended up seeing in 2010 was that there were 285 million that's an annualized inflation rate of six point five five percent double the rate that we thought we would see and in the next four years to 2014 422 million and that's an annualized inflation rate of ten point three percent in other words while we're trying to fix the problem the problems getting worse maybe because we're causing the problem da w.t.f now you all know that that's why you're here this is the friggin choir okay I love you guys and all my friends are in the room and we're gonna have a love fest okay but you can't fix the problem if you don't know what the problem is here's the problem non-alcoholic steatohepatitis is now the leading cause of liver transplant in America okay a disease that hadn't even been identified before 1980 is now the leading cause of liver transplant and is actually the biggest epidemic even bigger than type 2 diabetes and if you look at the medical cost view so we're looking in the red at hospital costs in green a physician costs in blue at Pharma costs they do not add up to the total medical cost because the rest of its going to the care and treatment of chronic metabolic disease and you can't fix the problem if you don't know what the problem is there are two inconvenient truths that the medical establishment refuses to deal with the first there is no medicalised prevention for chronic metabolic disease there's only treatment and those treatments to be honest with you don't really work oh they treat symptomatology yeah they'll get your blood glucose down yeah they'll get your blood LDL down yeah they'll do you know they'll get your blood pressure down and you die anyway and you die on disability the second is you can't fix healthcare until you fix health you can't fix health until you fix diet and you can't fix diet if you don't know what the hell is wrong these are the two inconvenient truths started here okay basically everything Gary told you is exactly right and this was the culmination of that the US dietary guidelines right and that's what we got instead okay we traded one set of diseases for another we traded cardiovascular disease for metabolic syndrome and this is why and this is just another way of saying what Newberg said okay that but coca-cola said it in their words everybody remember the coming together campaign of coca-cola back in 2013 it was played on every football game the entire year and this is a direct quote beating obesity will take action by all of us based on one simple common-sense fact all calories cannot no matter where they come from including Coca Cola and everything else with calories in other words calories are fungible doesn't matter where they come from they all enter one big engine and the engine burns them exactly the same way no matter where they come from and therefore why pick on our calories go pick on somebody else's calories this was their method for swaging their culpability so they say it's about calories they say it about it's about obesity is it I'm gonna give you five separate reasons why this is not true here's one here is a scattergram of all the countries in the world obesity prevalence on the x-axis diabetes prevalence on the y-axis and you would look at this and you would say well very clearly dr. Lustig there's a correlation and there is agreed there is a correlation but correlation is not concordance they're not the same 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% diabetes rate and they're not fat we are the fattest nation in the world have a nine point four percent diabetes rate if diabetes is just a manifestation of obesity how come they have more diabetes than we do problem number one problem number two obesity is increasing worldwide at the amortized rate of two point seven eight percent per year yet diabetes is increasing worldwide at the rate of four point zero seven percent per year if diabetes is just a subset of the largest subgroup of obese individuals how come it's going up faster problem number two problem number three here we have from JAMA all that the increase in prevalence of type two diabetes diagnoses over a 25 year period and you can see it going up over here on the left now take a look on the right where it's stratified by weight status and you'll notice that what's too fast 25% increase in the obese but there's also been a 25% increase in the normal weight population if diabetes is due to obesity how come the normal way people are going up just as fast problem number three problem number four anybody here an endocrinologist aside from David Ludwig who knows this better than I do okay one or two okay these are the little women of loja they are an Ecuadorian cohort that have a defect in their growth hormone receptor they are very short they are a very fat you can see them okay and they are protected from heart disease diabetes and every other chronic metabolic disease they are protected so here's their glucose tolerance and here's their insulin response to a glucose tolerance test look how much lower their insulin levels are than normal they are insulin sensitive they're fat but their insulin sensitive and if you look at their baseline data it's all better okay whether it's their home on their insulins their lipids so that uh over here or here you can see they're all better they're healthier they're healthier and they're fatter and the reason is because it's their adipose tissue versus their liver and they're not the same and my colleague Ethan Weiss at UCSF has developed knockout mice for each of those to show that we're how growth hormone works on those two are completely opposite and so these you know little women of low ha are actually protected against metabolic disease unrelated to their weight so this is what I'm trying to tell you here's a Venn diagram of the entire US population 30% obese BMI over 30 70 % normal weight BMI under 30 everyone in the room is in one of the two circles and you know who you are the standard mantra from the doctors and the dietitians and the Institute of Medicine the National Institutes of Health and the Surgeon General and the White House and Congress and the food industry is 20% of sorry 80% of these obese people they're ill they're metabolically ill they get type-2 diabetes hypertension lipid problems cardiovascular Z's cancer dementia it's these 57 million people they're fat and they're sick and they're sick because they're fat and therefore if they would only just diet and exercise we could solve this problem that's what they say [ __ ] why is it [ __ ] sorry I'm from New York I can't help it okay why is it [ __ ] it's on the slide come on it's on the slide well it is true that 80% of of 30% are metabolically oh I don't argue that that is true but that means 20% or not 20% are metabolically healthy we have a name for them MHO metabolically healthy obese we study them to try to figure out how come they didn't get sick conversely 40% of the normal weight population have the exact same diseases as did the obese and they're not obese normal weight people get type-2 diabetes hypertension lipid problems cardiovascular dementia - and they get it for the same reason they're just not fat well if you get it unrelated to your weight then how can it be about behavior this looks like exposure and it turns out there are more thin sick people 67 million then there are fat sick people and the thin sick people are calling the fat sick people the problem more [ __ ] and I'll prove it to you so any radiologists in the room good here are 2 here are two CT scans through two abdomens of two equally weighted people notice trunk fat 12.8 ones healthy ones sick which ones the sick one a or B B right because he's got visceral fat right the other guy he's just got big love handles subcutaneous fat that's the fat you can see visceral fat that's the fat you quote can't see right so obesity is not the problem metabolic syndrome and we'll define it now is the problem because that's where all the money goes obesity actually isn't a cost very much okay it's all the diseases that go with it that cost seventy five percent of all health care dollars and here's the list and diabetes being the Sentinel disease of this now what is metabolic syndrome so here are six count'em six separate medical societies professional medical societies and they've all defined metabolic syndrome differently so what's that telling you telling you at least five of them are wrong and maybe all six right because it's a sin Jerome duh I means it's not a disease because it's a sin Jerome keep that mind okay and I was on this task force in metabolic syndrome and children we didn't even try to define it because we didn't have the cardiovascular events to hang our hat on the reason that all of this jumbled mush garbage has been thrown at you is because everyone's seeking to define metabolic syndrome phenomenologically with cut-offs you know greater than 90th percentile for blood pressure greater than 95th percentile for triglyceride level where'd that come from these are skewed critic uni-modal distributions they're not bimodal there's no place to draw the line so you're telling me 90th percentile is metabolic syndrome but 89th percentile would not be metabolic syndrome now how effed up is that I mean that doesn't make any statistical sense whatsoever it's actually much easier to define the metabolic syndrome mechanistically that is where's the insulin resistance the one thing that everyone agrees on is that metabolic syndrome is associated with this phenomenon called insulin resistance the question is where and how and why that's where we're going so if you look here from 1970 to 2014 at a group of healthy healthy Americans oral glucose tolerance testing shows that you glycaemia is maintained in healthy adult Americans there's no change in the glucose tolerance curve of healthy adult Americans in those 34 years 44 sorry 44 years I can't count today but take a look at their insulin levels in order to maintain that glucose level here's 1970 and here's 2014 up here two to fourfold more insulin released for the same level of glucose that's called insulin resistance and if you're if you're impaired Luc tolerance is even worse so in the past forty to fifty years our need for insulin has increased to two fourfold so that's our question for today how did we get two to fourfold more insulin resistant and by the way coming back to that leptin resistance question I asked I mentioned earlier insulins the cause of leptin resistance the higher insulin goes the less well your brain can see it's leptin which of course then makes you eat so we even though you're fat your brain thinks you're starving the higher your insulin goes the more weight you gain and the hungrier you get that's what we're talking about now how does this happen and this is where the three comes in you know the three different diseases this is what you learn in medical school this is what I learned in medical school this is what those of you who went to medical school this is what you learned in medical school you get fat yay too much you exercise too little you got fat the alternative hypothesis says while your insulin did that but you still got fat and it starts with your fat cell your adipose tissue is this is ground zero and because your adipose tissue gets fat it starts making cytokines like tnf-alpha IL 6 you get adipose tissue inflammation and macrophage recruitment and etc and all of those cytokines then go to the liver make the liver sick which then causes the liver to increase gluconeogenesis and so you get increased hepatic glucose output which then feeds back because now you've got a higher blood sugar to deal with and your islet cells therefore have to make more insulin in order to keep your blood sugar constant the graph I showed you before and that drives more fat and so you end up with this vicious cycle but it started in the fat and then the muscle comes along for the ride originally Jerry Schulman thought it was the muscle now that he's got a 3 Tesla magnet that can actually measure what's going on in the liver he agrees it's not the muscle he thinks the muscles a bystander not the cause everybody got that that's what you learned more [ __ ] so here's the relationship between BMI that is sub-q adiposity and insulin sensitivity now you'll notice there is a very clear hyperbolic relationship so the heavier you get the more insulin resistance you get agreed but at any given BMI you could be insulin sensitive or you could be insulin resistant just like we talked about before metabolically healthy obese here they are right here so just being fat has nothing to do with it second problem okay so obesity is potentially a way to make this happen but not necessarily the only way I would actually argue that it's actually a rare way to make metabolic syndrome happen things about ten maybe fifteen percent of the total not very common second problem it's called stress now stress causes release of norepinephrine throughout the entire sympathetic nervous system no arguments there now norepinephrine is lipolytic norepinephrine goes to the adipose item causes hormone sensitive lipase to be activated which then takes triglyceride and turns it into free fatty acids and those free fatty acids then exit the fat cell so adrenergic activation sympathetic activation from stress from acute stress causes fat mobilization you should lose weight but you don't why anybody this is the paradox that has been basically killing this whole field for the last fifteen years the answer is Zofia Zukowski who passed away should brilliant physiology researcher she was head of anatomy in neurobiology at Georgetown she figured it out yes it is true that acutely sympathetic neurons release norepinephrine which then cause thermogenesis and cause fat mobilization that's all true acutely but not chronically in fact chronic stimuli of anything causes death chronics over stimulation of anything causes death and so adrenergic neurons have a thermostat built into them they have another hormone neuropeptide called neuropeptide Y when you release norepi initially in response to an initial sympathetic outflow you just get the norepi but if you chronically stimulate you end up with the norepi and the neuropeptide Y and the neuropeptide wise job is to actually shut down the effects on the beta adrenergic receptor and actually end up leading to lipid storage and actually causing pre adipocyte proliferation and oppisite differentiation in order to put that energy somewhere else so in other words acute stress causes lipolysis chronic stress causes lipogenesis because of neuropeptide Y and then there's this third problem here we have a guy who has metabolic syndrome to beat the band and he's not fat in fact he has too little fat not too much fat he has too little fat there's a disease called lipodystrophy where for some reason the transcription factors that drive fat cell development aren't working right and they don't develop the fat that they should it tends to be excellent to assemble dominant HIV can cause it minimal visceral fat normal or excessive facial fat they've cushingoid facies a dorsal cervical fat pads the only place they seem to have fat and they can't focus negra cancer and they have metabolic syndrome to beat the band they can get thousands of units of insulin and still not get their blood sugar down but they have too little fat not too much too little so let's compare a lipodystrophy with obesity fat mass lipodystrophy down obesity up leptin lipodystrophy down obesity up adiponectin a protective cytokine lipodystrophy down obesity also down maybe that's important could be inflammatory cytokines like TNF alpha il-6 lipodystrophy down because there's no fat cells to make it obesity up and if you have lipodystrophy you have metabolic syndrome big-time whereas if you have obesity maybe you do maybe a don't so what is this telling us telling us metabolic syndrome can occur from too much or too little fat because it's not the fat that counts not the fat you can see anyway what are these think two things share well they share this thing called insulin resistance everything comes back to this phenomenon what about insulin resistance what kind of insulin resistance where how come what do we do about it agreed that's what this is all about and that's why you were sitting here just to understand this phenomenon so let's reframe the debate from what I've told you thus far I'm sorry what happened oh obesity does not cause metabolic syndrome it is a marker for the metabolic dysfunction that attends metabolic syndrome it's just another marker just like impaired glucose tolerance is a marker just like high triglycerides as a marker just like high blood pressure is a marker okay obesity is a marker also it's the result of the problem not the cause obesity is a red herring because everyone's at risk for metabolic syndrome including normal weight people as I showed you before okay so obesity is not enough insulin resistance is not enough because obviously not everyone has lipodystrophy what kind of obesity what kind of insulin resistance in which tissue and they're all insulin pathways affected equally those are the questions we have to answer and I have 14 minutes and 22 seconds to do it this is the most important slide I'm going to show you okay this is from fabrini at all from Sam Klein's group they were the first people who stuck people in a scanner and instead of measuring big but fat you know sub-q fat and big belly fat visceral fat everybody had done that before what they did because they were cool was they measured big belly fat visceral fat and big liver fat got it visceral versus liver fat instead of sub Q versus visceral fat what they showed was that when you looked at their insulin dynamics here on the y-axis turned out that when you held the liver fat constant of the visceral fat contributed nothing to the pathology the visceral fat was along for the ride it was the liver fat that made all the difference the liver fat dictated the insulin dynamic problem so okay liver fat is the problem where the liver fact come from well that's over here in grey non-systemic fatty acids non-systemic now we know where systemic fatty acids come from they come from lipo lipo lysis of peripheral adipose tissue and that can actually be from saturated fat and you need to know that the paper just came out from iki Arvind and just five days ago the saturated fat can actually increased that adipose tissue lipolysis bringing more fat back to the liver or it could be from dietary fat you know so it can be from out of position lipolysis or dietary fat but non-systemic where did that come from well it turns out that's being made right in the liver de novo through a process called dnl de novo lipogenesis and my colleague jean-marc Schwartz is here and he will be talking to you at length about dnl tomorrow and its central role in this process turns out this fatty liver is the real problem because fatty liver is worldwide even in normal weight people it is the liver manifestation of metabolic syndrome and the question is how'd you get there well if you look over here women versus men men have more of it even at normal weights and diabetics have it even at normal weights in fact in the Korean population non-alcoholic fatty liver disease is the precursor to type-2 diabetes it comes first so here's how you need to think about this problem here's it what we call an MRI that fraction map done by my colleagues sooner illowsky at UCSF notice obese love handles right but take a look at that guy's liver 2.6 percent fat this is metabolically healthy obese MMH oh nothing wrong with this guy he'll outlive you now here is what you more likely expect here's love handles take a look at this guy's deliver 24% liver fat that's non-alcoholic fatty liver disease that's metabolic syndrome agreed that's not good now take a look at this guy notice no lit handles take a look at that guy's liver 23% this guy's just as sick as this guy thin sick fat sick fat healthy they're not the same okay so we need to understand how that liver got sick as it turns out Ron Khan at Joslin at Harvard constructed for us eight count'em eight separate tissue specific insulin receptor knockout mice to ask the question which organs matter which organs make the disease and here are those eight it turns out six of them are actually protected from obesity they have their own diseases not like these are good but they don't get fat all right my favorite by the way is this one at the bottom the glomerular pota site insulin receptor and knockout Mouse the pa'dar komme aus the insulin receptor has been lifted out of the kidney everyone everywhere else Mouse is totally normal that's all they did was take the insulin receptor out of the kidney got it normal blood sugars normal glucose tolerance tests normal insulin response to glucose normal insulin dynamics the worst diabetic nephropathy of any model ever normal glucose diabetic nephropathy how does that happen anyone because it's not the glucose that made the nephropathy it's the insulin resistance in the kidney that made the nephropathy and we know that because you can find the microalbuminuria in metabolic syndrome patients before they ever get glucose intolerant and you know that think about it okay I hope I'm hitting you over the head I'm trying really hard to hit you over the head to bang some sense into you alright but oh sorry go back the only two insulin receptor knockout mice that actually get fat are liver and brain the lurk oh and the Newark Kyle Mouse okay now the Newark on Mouse is another two hours we don't have time for that today it's maybe some day a short like me back and I'll talk to you about that but today we're gonna talk about the liver one okay the liver so here's what insulin does in the liver okay pancreas makes insulin there are two pathways after insulin binds to its receptor the first is the phosphorylation of this forked protein called foxhole one when phospho one gets phosphorylated it excludes it from the nucleus and therefore it prevents the transcription of gluconeogenic enzymes this is therefore decreasing hepatic glucose output thereby reducing total glucose in the blood keeping glucose levels normal that's how insulin lowers glucose got it the second pathway is here stimulating this transcription factor here called srebp-1c sterol regulatory element binding protein 1c this is the transcription factor that drives that phenomenon I just talked about de novo lipogenesis so when insulin meets a sensitive liver you lower your glucose and you take your fat you put it into triglyceride you attach a poby and you export it out as tri glycerin triglyceride and so it enters the bloodstream and then insulin peripherally at the fat cell will clear it and this is how you stay metabolically healthy but can put energy into fat cells got it this for lack of a better word is good now let's take that insulin receptor out of the liver so the liriko mouse okay so now this animal only is missing the insulin receptor from the liver well pancreas is making insulin great guns to beat the band trying to make the liver do its job but it can't because the insulin receptor is gone so the FOXO one doesn't get phosphorylated and so gluconeogenic enzymes go sky-high and so you end up with hyperglycemia diabetes fare in addition there's no insulin receptor to stimulate srebp-1c so your triglyceride levels are low high blood glucose low triglycerides is that metabolic syndrome it's diabetes but it's at metabolic syndrome no this is not metabolic syndrome what is metabolic syndrome well it's this here's insulin you can't phosphorylate FOXO one so glucose is high diabetes okay but somehow someway through some mechanism that srebp one is still going great guns because it's making triglyceride to beat the band's releasing that triglyceride and so you end up with hypertriglyceridemia as well now the 64 zillion dollar question is there's only one insulin receptor it's been knocked out so how do you get one pathway working and not the other how do you dissociate those two pathways when you only have one insulin receptor and you've knocked it out this is the Nobel Prize for metabolic syndrome whoever figure this out will win the Nobel Prize everybody got it so in order to explain metabolic syndrome we are looking for a ubiquitous factor that promotes obesity preferably visceral adiposity and in particular liver City promotes hypertension and induces this phenomenon called selective hepatic insulin resistance dissociating these two phenomena in the liver so that you block FOXO one to promote gluconeogenesis and therefore hyperglycemia but at the same time can stimulate de novo lipogenesis to drive hypertriglyceridemia and a thorough sclerosis does anybody want to make a guess what that ubiquitous factor might be Nobel Prize so as Gary will tell you fructose is toxic he wrote a whole article it you've now wrote a whole book about it the case against sugar and we wrote this nature comment back in 2012 the toxic truth about sugar which I wrote with my colleagues from UCSF Laura Schmidt and Claire Brandis and the question of course is everyone says what really thought dose I mean sugar I mean it's been around for thousands years it's natural comes out of the ground it you know helps keep foods from spoiling it's fourth of July and apple pie and Valentine's Day I mean aren't you just guilty of hyperbole well so we have to look at the word toxic toxicity what does it mean the degree to which a substance can damage an organism right out of the dictionary anybody got a problem with that definition now notice the definition does not distinguish acute toxicity from chronic toxicity so we have acute toxins like sarin and ricin and cyanide and VX gas you know parts per billion keel over and die on the spot okay no one would argue those are acute toxins right but we also have chronic toxins like carbon Tet arsenic benzene tobacco smoke they don't kill you today but they'll kill you just takes a little longer right still toxins just not today now in order for me to prove that fructose this sweet molecule and sugar is a chronic dose dependent hepatotoxic I have to meet four criteria I have to show that fructose is an independent risk factor for these diseases with time not just correlation I have to show it's exclusive of calories because otherwise calories are toxic in which case coca-cola is right I have to show it's exclusive of obesity because then obesity is toxic and I've just shown you normal way people get this - and I have to establish causation correlation will not do right everybody knows the difference between correlation and causation you better because if you don't understand the difference between that you should not be practicing medicine alright now there are a whole bunch of critics of this as you know they're out in force food industry employs all of them they say animal models not human studies and you have to give excessive doses of fructose in order to see these effects not relevant to humans so I will limit my discussion today to human data only human consumption only in dose this is routinely ingested by humans maybe your children okay here's what's happened to our consumption of sugar our ancestors getting fruits and vegetables out of the ground with the occasional honey got about four pounds of sugar per year here's the growth of the sugar industry see an H and Domino Texas Hawaii Louisiana finally reached stabilization where you know price equal demand here's the rationing of World War two came back to the same level afterwards and then we had three things happen number one we had high fructose corn syrup number two we had the dietary guidelines and number three we had the change in our farming practices all happening at the same time in the 70s we had Nixon telling us make food cheap and that drove things all the way up point is the fructose is not glucose because a calorie is not a calorie they are not the same and I'll show you that they're not the same in fact fructose is seven times more likely than glucose to form advanced glycation end-products AG es which are very specifically detrimental and toxic to cells and humans fructose does not suppress the hunger hormone ghrelin so david is in the room he and Kara emblem did this study years ago if you take a kid and you get preloaded with a soda and you let him loose at the fast-food restaurant do they eat less or do they more the more they took on hundred fifty calories they eat more how come because the brain didn't recognize that eating so clearly not the same acute fructose does not stimulate insulin it does chronically because it causes insulin resistance but it doesn't cause insulin secretion which actually means that the brain doesn't know that you ain't and you also don't get leptin out of it immediately so that also doesn't activate the sympathetic nervous system and finally hepatic fructose metabolism liver fructose metabolism is completely different from that of glucose they burn no relation to each other and I'm going to show you the chronic fructose exposure alone alone can cause metabolic syndrome now it may not be the only cause of metabolic syndrome I'm not suggesting that but it is clearly a primary cause and an identifiable cause and a malleable cause something you can fix so here's the metabolism of glucose coming into the liver cell here and virtually all of it ends up as glycogen liver starch that's what your liver wants to do with glucose that's why marathoners carb-load before a race is to make glycogen glycogen is non toxic a little bit of it will seep down here via the EM de Meyer off glycolytic pathway to pyruvate into the mitochondria here generate the TCA cycle you know ATP and carbon dioxide the reaction of life a little bit of it maybe gets thrown off as citrate exits the mitochondria through a process known as the citrate shuttle and then that citrate can act here in the cytosol as the nightís and the start of this process over here driven by these three enzymes ATP citrate lyase sto koi carboxylase one fatty acid synthase these three ends our denovo lipogenesis new fat making and look what they're under the control of our friend srebp one got it but how much of this VLDL you think you're gonna make out of that glucose not a whole lot because it went to glycogen and most of it ended up actually outside the liver because 80% of the glucose got chewed up by all the other organs in the body but here's what happens to fructose a hundred percent enters the liver because only the liver has the flute five transporter so the whole bolus ends up there so you're dealing with a whole lot more substrate first step fructose one phosphate turns out that fructose one phosphate activates this enzyme called c-jun n-terminal kinase one which then in activates the insulin receptor now you've got hepatic insulin resistance in addition fructose one phosphate will come down to the mitochondria and now you've got a lot of it because all of it ended up in the liver the TCA cycle is overwhelmed the mitochondria are overwhelmed and remember this term mitochondrial overload when your mitochondria are overloaded then the citrate comes back out through that situation and now you've got a lot of citrate to drive this pathway to VLDL so the LDL gets exported and here's the hypertriglyceridemia of sugar consumption and that can serve as a substrate for obesity it could also serve as a substrate for a thorough Genesis in addition some of the ass fatty acyl Co a won't even make it out and will precipitate as a lipid droplet now you got non-alcoholic fatty liver disease not only that but because you have hepatic insulin resistance you can't phosphorylate that foxhole one so now your blood glucose goes up and they got hyperglycemia too so what do you got you got hyperglycemia hypertension here because of the nitric oxide reduction because of uric acid which is the endogenous Scimitar of endogenous in the philia nitric oxide synthase hepatic insulin resistance dis lipedema muscle in some resistance obesity atherosclerosis and leptin resistance because of the insulin resistance what do you got you got metabolic syndrome but that's only problem number one now comes problem number two on this slide there are five pictures of food they all share one thing in common what is it nope not carbs does that look like carbs to you no huh captain right they're all brown they're all brown that's right okay the common link is the Browning reaction known as the mired reaction non-enzymatic glycation is why glucose binds to hemoglobin to form hemoglobin a1c right so here's how you need to think about this problem you can roast your meat at 375 degrees for an hour or you can roast your meat at 98.6 degrees for 75 years the answer is the same you are browning you are browning right now you are browning even as we speak and if you had orange juice this morning you are browning seven times faster and if you don't believe me here's newborn rib cartilage nice and white and here is 88 year old rib cartilage nice and brown you're all browning it is the aging reaction and the faster you Brown the quicker you die period well-documented we know this slam dunk now here's why so here's glucose here's in the linear form here's an aldehyde group and here's an amino group you put an aldehyde and amino group together you get a shift base which then decomposes to form this covalent linkage which we can measure then as hemoglobin a1c and every time this reaction occurs in cells RL outside okay you generate a reactive oxygen species a little oxygen radical which can then do damage on its own can cause lipid peroxidation protein denaturation cell aging react oxidative stress you've heard it oxidative stress it's part of living but it's also part of eating badly right okay and every time that happens have to quench it you have to quench that reactive oxygen species with an antioxidant in the liver that would be glutathione you know their cells it could be other things like vitamin C or vitamin E but glutathione in the liver why does this happen well so here's glucose over here in the linear form here's glucose in the ring form here's the space-occupying model notice six membered ring hydroxy methyl groups sticking up axially not bothering anybody this is a what we would call a happy compound at pH 7.4 37 degrees ninety-nine point two percent of the glucose in your bodies in the ring form only 0.8% is in the linear form where this aldehyde group is available to bind to proteins non enzymatic Allah everybody got that now it is true that your serum glucose level is high or high or I should say you know it's in the 6100 range so what's gonna happen I mean you can't not have it happen but the lower you keep your glucose the less it'll happen fair okay now down here you got fructose so here's the linear form here's the ring form here's the space-occupying model notice five membered ring five membered ring ionic strain trying to break this thing apart because it's wound tightly notice two hydroxy methyl groups axially in the same plane button heads allosteric interaction driving this ring apart so at pH 7.4 37 degrees 97% of the fructose is in the ring form 3% is in the linear form compared to 0.8% for glucose and this reactive keto group is just as reactive as the reactive aldehyde group and so it will happen seven times faster with fructose than with glucose and I can prove it you can do this experiment at home take two test tubes add fructose glucose and then add water and some bovine serum albumin equal amounts cap it with some parafilm and put it in the sunlight and each day you come back and you put it in you home spectrophotometer and you read out the fluorescence okay and this is how fast the glucose does it and this is how fast the fructose forms that reaction seven times faster 100 times the number of reactive oxygen species that have to be dealt with by an antioxidant what happens when you don't have enough antioxidants that's called gnash so how do we know this is true well we have empiric data so here's the consumption of sugar in the u.s. population adult population this is a histogram of the percent of calories as added sugar done by Frank whose group the median is at 18 percent the red line through the center is the hazard risk ratio for cardiovascular mortality in the same population over the same period of time the inflection point is at 15% so does that mean means that more than half the u.s. population is an increased risk of dying of a heart attack because of their added sugar consumption this was done in Europe it's called the epic interact study it's the same as our in Haynes okay what they want to ask was does sugar beverages predict diabetes and the answer is if you take into account the energy intake and the BMI 29 percent increase in in risk for diabetes same for meta-analyses looking at the same thing and here's sugar beverages and here's fruit juice showing the same effect everyone says fruit juice is healthy take a friggin pill our group my colleague Luis Rodriguez my grad student and my dietician took the Ann Haynes Adolescent database and asked the question does sure added sugar consumption in the adolescent database predict metabolic syndrome we get up to the fourth quintile there's a tenfold increase in metabolic syndrome we did an econometric analysis looking at sugar availability instead of sugar consumption and what we saw was the only sugar gave us a signal yeah I know I'm at the zero I got it only sugar gave us a signal and it was a significant signal here's the adjusted Association of sugar with diabetes prevalence around the world here's the take-home message only changes in sugar availability correlated with changes in diabetes prevalence if a country had a extra hundred 50 calories per person per day within its borders diabetes prevalence went up a total of 0.1% but if those hundred 50 calories happen to be a can of soda instead diabetes prevalence went up 11 fold 1.1 percent these these data actually meet the Bradford Hill criteria for causation for causal medical inference the same level of proof we have for tobacco and lung cancer today because we showed dose more sugar more diabetes we showed directionality longer cervix I'm sorry showed duration longer sugar exposure more diabetes we showed directionality those countries where sugar went up more diabetes those countries where sugar went down and there were 10 of them less diabetes and finally precedence something has to precede something else to be causative right 3 years 3 years whenever sugar change in a country diabetes changed in the same direction 3 years later that's causation and now we have the proof proof because we have the interventional proof and this is the study that my colleagues at Troy University and UCSF did Sean mark Schwartz is here and he can address this study tomorrow in part as well what we did was we took 43 kids from our OBC clinic at UCSF and we figured out what they were eating at baseline we studied them at baseline and then we catered their meals for nine days no added sugar now if you do that you're gonna take 350 to 400 calories out of their diets in which case they might lose weight because they'd be in caloric deficit we didn't want them to lose weight we wanted to keep them the same weight so we had to substitute something that was equi caloric we gave them refined starch got it we did a starch for sugar a glucose for fructose exchange 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 everybody got it we can give them good food we get crappy food we gave him processed food we give him kid food food kids would eat but it was no added sugar food and we gave him a scale and every day we'd call him up on the phone would your way if they were losing weight anymore to keep their way constant over the course of the ten days and then we studied him again all their baseline levels got better these will be online so you'll be able to see all of them all of them got better we wanted to measure de novo lipogenesis so we gave them c-13 labelled acetate which gets incorporated into VLDL and here's how fast the reaction reduced in ten days we cut it in half here's their glucose tolerance test 8% reduction of glucose area under the curve remember we're giving a more glucose they should have a higher glucose Thomasin's that'll lower glucose gnosis and the reason is because their insulin levels went down because now their insulin sensitive we turn them from insulin resistant to insulin sensitive and most importantly the fat depots so notice the subcutaneous fat the big butt fat no change because we didn't let him lose weight the visceral fat down 7% that's good liver fat down 22% with no change in calories no change in weight and the change in the liver fat predicted the change in all the metabolic improvements so cartoon fatty liver it's brown the LDL making being made nine days of fructose restriction the liver fats down the DL is down the vldls down and the insulin kinetics have reversed we reversed their metabolic syndrome and we didn't even have to change their calories all we did was change the food got rid of the sugar that's it so we have causation causation not correlation causation for sugar and for diseases diabetes heart disease fatty liver disease and tooth decay we have correlation for sugar and cancer and sugar and dementia we're working on those so I would propose to you a different model of insulin resistance starts here in the liver you get liver fat instead and fructose being a primary driver that because of the fatty liver the liver now is sick you end up with increased hepatic glucose output now you've got beta cells making extra insulin and that drives excess energy into fat cells driving the obesity but if you get rid of the liver fat the insulin goes down if the insulin goes down then the patient lose weight and that's what we did at UCSF in our OBC clinic every friggin day for 17 years now just so you don't think I'm a fructose centric there are actually four items that are all metabolized the same way in the liver do the same thing with de novo lipogenesis trans fats do this but we know that and they're coming down so that's not the answer anymore branched chain amino acids leucine isoleucine valine all essential amino acids protein powder okay corn-fed beef chicken fish high and branched chain amino acids you guys are low-carb USA branch chain amino acids also do this alcohol but kids don't drink alcohol but boy oh boy do they consume fructose so what do these four foodstuffs have in common number one the livers the only site for energy regulation number two they're not insulin regulated number four three there's no glycogen Popoff and the mitochondria become overwhelmed and that is what metabolic syndrome is mitochondrial overload in whatever tissue you're looking at if it's in the kidney you got kidney disease if it's in the heart you got heart disease if it's in the liver you got liver disease got it that's what this is I'll skip this for time and there's no drug target for this mitochondrial overload promotes turnover lipogenesis leading to insulin resistance metabolic syndrome mitochondrial overload in releases those reactive oxygen species really leading to cell funk this function aging and death the only options are reduced substrate availability that's called diet but not any old diet and certainly not a weight loss diet and certainly not a processed food diet reduce hepatic flux that's called fiber fiber reduces the amount of glucose and fructose that get absorbed from the duodenum into the liver thereby keeping your liver safe and if you don't miss orbit in the liver then it goes further down the jejunum where the bacteria will chew it up the microbiome will get it so just because you ate it didn't mean you got it and all of these energy calorimeter zall these whole body calorimeter x' they're not studying humans they're studying the human microbiome unit they don't know what's happening in human cells versus bacterial cells you gotta feed your bacteria you've got ten trillion cells in your body you got a hundred trillion bacteria in your intestine you're just a big bag of bacteria with legs you got to feed your bacteria fibers the way you feed it now low-carb USA doesn't exclude fiber but it doesn't promote it either you need to okay in fact what I hope I've shown you is that there is not one problem there are three three problems three metabolic syndromes the first one do two sub acute fat the one everyone knows the one everyone talks about the one everyone thinks is the only one we can call that the bucket hypothesis you got a bucket you fill the bucket you overflow the bucket you get problems okay I think it's rare visceral fat call that the stress hypothesis that's why depressed people have metabolic syndrome they're losing weight but they're increasing visceral fat you can see it on MRI and finally liver fat which we can call the mainlining hypothesis and I mean that very specifically since fructose is addictive and that's another story and the thing is we knew it we knew it fifty years ago we knew there was a problem but we were driven off course through some of the things that Gary talked about earlier and because the sugar Research Foundation actually made us go off course on purpose because they sponsored a whole program within the sugar Research Foundation to basically obfuscate the truth started in 1965 with a literature review published in the New England Journal by Fred Astaire the head of nutrition at Harvard School of Public Health and his assistant Marc hagstead who became the head of the USDA which singled out fat and cholesterol as the dietary cause of coronary disease and downplayed the evidence that sucrose was also a risk factor the srf said the reviews objective contributed articles for conclusion and received drafts and the s ahrefs funding and role were not disclosed it's all been a big fraud the whole thing the last 50 years of nutrition information in America is a big fraud all of it and that's why diabetes has continued to increase not just in prevalence but in incidence because we actually put the Bunsen burner underneath it to make it boil over because we relied to now you guys know that the problem is you've got to get everyone else to understand it too so it is sugar public enemy number one trans fats used to be but now they're gone so now this is public enemy number one because you could we could do something about this okay and you wouldn't even have to go low-carb you just have to go low sugar it's called real food so with that I want to thank my collaborators many of whom are in the room today okay at UCSF Toro San Francisco general Hastings Berkeley Health evolution partners and I'm happy to answer any all questions I'll be around please feel free to come up thank you for your attention [Applause]

Channel: JumpstartMD

Views: 629,245

Rating: 4.7944221 out of 5

Keywords: jumpstartmd, weight of the nation, wotn

Id: zx-QrilOoSM

Length: 58min 41sec (3521 seconds)

Published: Fri Feb 01 2019

Reddit Comments

[u/KetosisMD]

https://i.imgur.com/UI82MGz.jpg

Food causes of Metabolic Syndrome (MS). Better yet (MetS).

[u/intolerantofstupid]

I feel like he needed to explain the BCAA mechanisms more. He just sort of stated that cornfed beef does this (increases NAFLD) without explaining how and why and whether grassfed beef does it too.

I get that his big bogeyman is sugar, and I agree, but just because kids can eat starch and get healthier (per his study), doesn't mean that adults can too. Especially if adults are already obese and have been for decades.

[u/unibball]

I've always found it interesting that on page 69 in his book Fat Chance, he says he cannot figure out how to lose the 45 pounds he gained in his residency. Looks like he still cannot figure it out. So, he changes the focus to fructose and "real food," and comments that obesity is not the problem.

He's confusing the issue with too much nuance. For the vast majority of people, cutting out carbohydrates will benefit them and stabilize their weight at a healthy level, and keep them safe from the diseases Lustig speaks of. Notice he says he is not a low carber. Well, obviously.

I may sound like a broken record, but it is carbohydrates. Saying "real food" just gives people an out to continue to eat carbs. Potatoes are "real food." Corn on the cob is "real food." Boiled rice is "real food." Fruit is "real food." Carrots are "real food." Jams and jellies are "real food." Whole wheat bread is considered "real food." Honey is considered "real food." Maple syrup is considered "real food." Low fat milk is considered "real food." Apple juice is considered "real food." Citing "refined" or "processed" or "real food" is just confusing people.

It's "carbs."

[u/ivanreddit]

https://www.youtube.com/watch?v=tHYu8NlWDLU

Same slides, longer talk. A bit more in depth explanations.

[u/DavidNipondeCarlos]

I’m 60 year old male who was obese and eat a SAD diet. I’m 20 BMI or 9-12% body fat measured by popular consumer scales and slightly less using calipers. I am on the outskirts of pre diabetes. I’ve had many labs done this year and the only time I got a great glucose reading 60mg was after limiting carbs and excess ethanol for a few weeks before testing. I have lost the privilege of just quoting sugar, now I have to limit most carbs to test normal glucose ( I have two meters which I know can be 20% up or down but well within range. I can still drink 24oz of whole milk and not spike but I remember to keep track of the carbs. Erythritol and stevia do not spike or change glucose readings, 2.5 carb beers up to 12 also don’t spike but ethanol is one of the foods he mentioned with corn fed fish chicken beef and sugar and complex long chain amino acids. I am bordering on fatty liver disease. I have seen the solution work for me quickly. If fact I can binge I fast 48 before a glucose test and come out great but for the liver ( AST ) to get better it takes a few months of no or trace ethanol and low carbs. My last take away besides sugar ethanol corn fed and chains is adding fiber. I chose either Spinach or chia seeds for net zero carbs or close enough.

[u/Muttaburrasaurus]

I dont know much about mitochondria, but what I do know is that it is the powerhouse of the cell

[u/DavidNipondeCarlos]

I graze keto until my body fat or weight ( measured by looking at my abs as the final evaluation ) gets out of my parameter. Then I hit with fasting, mostly the 16/8 ones. I extend the fast if it feels easy. I’m in and put mild keto. Never have been fat adapted yet. But I do find it and area to experience.

[u/tsarman]

First time hearing R. Ludwig speak, and I was impressed with his grounded style. Also this was the first I’ve seen fructose indicted by trial as causing MetS /IR.

Without going back over it again, did he really state/cite 3 and only 3 causes of IR? (fructose, ethanol, & ?) I’m having trouble digesting that degree of simplicity. Surely other causes exist, eg refined carbs, excess fat intake, combined carbs/fat excess, genetics, etc?

[u/vincentninja68]

Man Lustig sounds pissed, I love it.