 Alright, thank you very much everybody for coming and this talk so last year I gave a talk if anybody remembers about Something like why you don't want to be a fat burner or whatever and that was kind of like a controversial talk and so to follow that up maybe a more controversial talk and specifically I heard people saying sugar causes insulin resistance, which I think is Incorrect so and the form format that this talk is going to be in is if anybody's familiar with an Oxford style debate of course, I'm just one person, but how it works usually is there's two sides and everybody comes in either being for or against the The what's it called resolution and Whoever changes more minds wins so if 70% of the people are for the resolution and at the end It's just 50% people and there's a 20% change towards that direction Then the against would win and vice versa So what I'm going to do is I'm going to make the case that insulin causes our sugar causes insulin resistance Kind of quickly because most people know that case fairly well. I'm going to try to do a fair Assessment of it and then counter that case and then ask everybody that you mentally take a note of whether you're for that resolution Or against it now And then at the end whether you're for or against it and then I'll ask like raise your hand if you were For it and you're still for it or for it again or whatever So that's what I'm here we go So the resolution is Resolved sugar causes insulin resistance and don't be too picky with the semantics sugar, right? sucrose fructose maybe even to some people glucose and lactose and all that other stuff and insulin resistance Everything from like molecular Biology to maybe like type 2 diabetes and metabolic syndrome. That's the loose Resolution as I'd like it to be defined so make a mental note of how you feel about that resolution And we'll go from there. Okay, so the four position. All right sugar causes insulin resistance It would seem that sugar Causes insulin resistance And I'll go from a big picture perspective to a smaller picture perspective. So the epidemiology This is taken from Stefan Guy and a's website and it shows sugar consumption From 1822 to 2005 It went up a lot obviously especially You know at certain times it it jumped up and at certain times it went up a little bit more slowly But you can see that it basically went up the whole time and Alongside that this is this is a slightly different timescale. So this is starting at 1820. So cut this graph in half more or less and you've got this one starting from 1958 and going to 2009 and this is Diabetes Diagnosis in the US population on a percentage in a total number basis. So these match up pretty well and This graph Also taken from Stefan. This whole thing is derivative of Stefan Guy and a this whole talk He's he's the pinnacle. So every everything I talk about is derivative of of Guy and a So this shows that it's not really macronutrient intake that's changed, right? This sugar consumption has gone up in the 20th century, but if you look carbohydrate consumption It sort of bounces around actually goes down in the middle of the 20th century and then pops back up again So, you know starch went down and then it was replaced by sugar But it hasn't gone up the way sugar has gone up And one of the ways that people say one of the reasons this happened is that you can really cram sugar into processed foods Very easily So just looking at one thing like a soda, right? There's nine teaspoons of sugar per can of soda. Some people drink like I know when I was 11 or 12 maybe five to seven cans of soda a day and so that's as much sugar as I know as Two and a half donuts. So this is like a donut from like Wikipedia definition of what a donut is and how much sugar it has So you can really cram in a lot of sugar and that's one of the ways that the caloric intake of sugar has gone up so quickly and specifically so in that teenager group added sugars Perhaps as much as 15.6% of their caloric intake in that group and then it's a little bit less for the other groups But it's over 10% for all of them So that's the epidemiology like fly-over picture of what's happened to the consumption and then of course the diabetes rate has gone up Which I'll use as a definitional proxy for insulin resistance At the level of physiology. Here's just the regular pancreas Glucose metabolism and insulin and glucagon regulation double loop model and If you have a greater sugar intake, you'll need higher insulinemia to maintain euglycemia It's a pretty simple mechanism and if you do have this higher insulinemia chronically you down-regulate insulin receptor just like everything else insulin receptors have a negative feedback system and Yeah, the pancreas will work harder and harder and harder And there's a certain point in which it can't work harder anymore, and that's where you start to get uncontrolled Diabetes where you have to start taking Exogenous insulin because your pancreas can't keep up with the glycemic load At the liver So that's mostly a glucose and a fructose story But at the liver things are a little bit differently. So fructose unlike glucose if anybody remembers like the big Fructose Robert Lustig thing it has this pernicious different type of metabolism where it doesn't really get taken up by All the cells equally it's preferentially taken up by the liver it's less insulin dependent and a lot of it can go into liver fat production, so It skips it gets thrown into Glycolysis at a level past where glucose gets thrown in so it's less regulated it gets taken up very rapidly and as much as 25% of de novo lipogenesis can be caused just by this fructose intake and a lot of this de novo lipogenesis if In a certain Context can end up being liver fat. So like non-alcoholic fatty liver Syndrome and that in and of itself is associated independently with insulin resistance and metabolic syndrome at the level of the adipose so just going Also a simple model sugar Raises your blood sugar, so that's a very simple link Which race then goes on to race insulin Which then causes fatty acid uptake in the adipocyte so everybody knows you know You need insulin in order for fatty acids to go into the adipocytes and be taken up as stored triglyceride there and lipid droplets and At a certain point of these adipocytes taking up more and more fatty acids and growing more and more researchers a long time ago found that There was these macrophages getting in the interstitial tissue of adipocytes and What they would start doing is becoming active in secreting all kinds of cytokines these inflammatory proteins that are Pretty much directly causal of insulin resistance. So that's where the peripheral inflammation story comes from And moving on to Experimentation so in mice. This is just one experiment. There's a million of them like this But taking a controlled diet no sugar versus a in this case It's only 13% kilocalories from sugar, but you can see that the fasting insulin is much higher in the mice that are fed sugar a difference of so you have to understand mice are a little bit differently so 228 milligrams per deciliter is kind of normal for a mouse. That's crazy for a human. So they're not all diabetic but And of course these higher sugar animals also got fatter And they got fatter eating less food. So their feeding efficiency was much higher and this is just one representative human experiment so Having either glucose or fructose supplemented into a bunch of people's diets and the people who were given Fructose versus glucose have the at the end of the study but higher fasting glucose and fasting insulin Which just combined together mathematically into a lower insulin sensitivity index which is just a it's a mathematical relationship of Those two things and of course they have more of that de novo lipogenesis specifically eight or so percent more after the end of this particular assay here Okay, so with human experimentation that is the end of my sugar causes insulin resistance for So I hope everybody's absorbed that information and now I'm going to become sugar does not cause insulin resistance person so What if I told you that sugar doesn't cause insulin resistance? Okay, back to epidemiology so a lot of these things are just going to be the exact same slides But I'm going to say the opposite thing so get ready for that So here's the same slide same source and everything and I just want to bring attention to Something that you might have missed on this slide, which is that little blip at the end So there's blips all over But I want to bring your attention to that one and zoom in a little bit So this is also like I said, it's all from guy in a this is also from his website Forget about that obesity line, but just focus on the sugar. What happened is sugar consumption at least in the United States probably Western in general peaked around the year 2000 and has actually been decreasing Since then and has gone back to like maybe 1990s Level so we're in the 90s Back in the 90s, I'm sure everybody's happy about that with their nostalgia videos on the internet. So However, so we're back to 1990 levels of sugar consumption, but going back to this graph. There is no so you would be looking at The double zero on the bottom there is year 2000 and this goes until 2015. There's no pause or Even more over what you'd expect like a reduction in Cases of diabetes or any of these other metabolic syndrome diagnoses To correspond with that decrease in sugar consumption. So the diabetes incidence has just continued to go up as if It was following the same track as the intake of sugar before So it's a little suspicious And this is a international graph. You probably can't see too many of the countries here Now the r-squared value is Point three five nine, which is okay. There's definitely a linear relationship between on the bottom per capita sugar consumption and then diabetes Prevalence but if you look at the individual countries, it wouldn't be unreasonable for somebody to say there's something different between say Sweden and Malaysia so they're on the same Part of the x-axis for sugar intake whereas one of them is very low below the line on the diabetes Prevalence and one is far above it wouldn't be unreasonable to say I think that there's differences between these countries that are Causing them to be at different parts on that graph that Are not their sugar intake and that perhaps are more important than their sugar intake ease of overwork consumption. So remember coca-cola as much sugar as two and a half donuts, but Let is actually in those donuts. So again, this is a Wikipedia donut your average donut And there is a lot of sugar 11 grams of sugar, which is half the carbohydrate But look at the fat 11 grams of fat And everybody knows there's more more than twice as many kilocalories per gram in fat So you end up with a little bit more of the calories from fat as from carbohydrate in general and then more than twice as much as for sugar And so the point is outside of straight-up sugary candy and sugary beverages It's it's easy to over consume fat too if you Consider that something you're over-consuming you can consume a lot of it in junk food Just the same as sugar Going back to the pancreas question. So again, remember the sugar increases Glycemia which has to increase insulin emi to keep up with that to dispose of that sugar and that that Persistent increased insulin emia can downregulate the insulin receptor system itself, which is completely true So these are pancreatic cells that are incubated in a insulin receptor They're just you know incubated with or without insulin and then their insulin receptors are measured afterwards and It does go down so in the farthest left panel there going from ten to the negative eight ten to the negative six So that's a hundred times increase in the insulin that these things are incubated in The percentage of insulin receptor that it decreases is ten percent So that's not like a huge difference and if you think about it That's actually a proof that the insulin Receptors and the whole system is insulin sensitive because the downregulation system of insulin and insulin receptor or any ligand in its receptor Requires that the ligand binds to its receptor and has some sort of downstream signaling That then causes the cell to produce less mRNA of that receptor or translate less of it into protein or degrade it faster or something like that and That's that's one of the ways that Insulin signaling can be decreased But it sort of presupposes that the cells are sensitive insulin if they weren't sensitive to insulin They would just keep producing insulin receptors regardless of how much insulin they were Incubated with or in the body how much was circulating At the liver, so this is the de novo lipogenesis causing Perhaps fatty liver or just producing a lot of fatty acids that might make their way to a dippasites story And this 25% number looks pretty big but And it looks big on a percentage basis But really if at the most generous level maybe as much as 5% of fructose is Converted into fatty acids that make their way into triglycerides Which ends up being if you're consuming like a normal American diet, maybe 1% Chlorically speaking of the amount of fat that you consume So at like the highest de novo lipogenesis from fructose consumption Level that you could achieve you'd be contributing to maybe 1% of the fatty acids that you're taking in dietarily so doesn't seem Super significant and furthermore those fatty acids are overwhelmingly saturated mostly palmitic acid stearic acid I think a little bit of oleic acid, so Outside of coconut oil. There's really not a better Dietary source of saturated fat other than fructose If you're into saturated fat that is Okay, so and then at the level of adipose it's true that insulin definitely causes fatty acid uptake and when you have a system that has a lot of fatty that a Large adipocyte depose an obese person. There's often macrophage infiltration and These cytokine production that you can find locally or systemically and which does indeed cause insulin resistance but What causes the macrophage infiltration and specifically for the macrophages to adopt the phenotype where they secrete the most inflammatory cytokines is secretion of fatty acids from the adipocytes so if you think of these adipocytes taking up fatty acids in a Insulinemic environment so insulin is stuffing fatty acids into them for fatty acids to be secreted out of them that recruit these macrophages you need a Low insulin environment, so it's actually the opposite of insulin signaling from Sugar which makes sense because if you have adequate glucose or sugar you do not want to be pulling fatty acids out of the Out of the fat because you don't need them and because insulin is is storing fat So this is something that I believe happens more when you have say if you had a lot of adipocytes And you were fast in and then you started relying on free fatty acids That's what starts to recruit macrophages into the adipocyte tissue All right moving on to experimentation so remember this one as a mouse experiment you've got your 13% sugar group killer calories from sugar and your control group with no sugar, but I tricked you because actually the group that had 13% of their killer calories from sugar also had 30% of their calories from triglycerides So it was a high sugar and high fat group compared to the control group Which was low fat and mostly starch and this is what you will see in 99% of animal studies If you just go to PubMed and you put in high sugar diet Actually look at the methods and look what they're feeding in order to induce obesity insulin resistance or any of these Symptoms in animals they always combine sugar with fat and There are a handful of studies that do not do that and compare directly sugar and fat so in this study There's LL LH HL and HH so L means low and H means high and the left column means Let's see fat. Thank you, and the right column means sugar So LL is low fat low sugar LH is low fat high sugar and HL is high fat low sugar and HH is high in both of them All right, so everybody remember that so and this is the effects of those four diets on two strains of mice the A slash J mice are Regular mice and the B slash six J mice are the same type of mice But they're genetically prone to things like type 2 diabetes and obesity a little bit more So if you look there the low low so the mice that are given, you know, kind of their normal starchy diet in both the a slash J and the six J mice they have lower glucose and Insulin fasting glucose and insulin than the high fat high sugar animals But the low fat high sugar animals Especially in the six J mice actually have lower plasma glucose and plasma insulin than the high fat Low sugar animals and the low fat low sugar animals So the sugar basically is having there of a less metabolic syndrome phenotype than even the low fat low sugar Which you know the researchers would consider the one that would be best For human experimentation, I couldn't even find a decent study a recent one that just put people on a high sugar diet with low fat That's just Not done But what what does exist is this really super old study from 1938 From a group that's related to the group that discovered essential fatty acids the burrs and They wanted to see if they can induce a fatty acid deficiency in humans. So they took one of their Research assistants and they forced him to eat Everybody knows about you know lab grad students research assistants. So it's always been that way So this diet What would you expect from this diet? So sucrose provided the bulk of the carbohydrate allowance And this is a zero fat diet. So the bulk of the caloric allowance. It was also de-fatted milk some type of Biscuit made from starch with like fat-free whatever less than two grams of fat per day, which for a human is essentially nothing 2,500 calories per day for a hundred and fifty two pound man. So that's pretty, you know decent amount of calories and So it starts to talk about what what happened to this guy and this is just a proof of concept paper So they didn't actually go through and like give him a Glucose sensitivity or insulin sensitivity or glucose disposal assay I don't even think those things existed back then, but they say his blood chemistry stayed the same He lost weight. So again, he's eating pretty much sugar and starch and nothing else and protein de-fatted dairy protein He lost like over 10 pounds He remained clinically well, they said and he had sort of like a chronic Fatigue condition that went away and also migraines that he had since a child went away and strangely enough have never recurred And here's where they talk about his feeling of fatigue at the end of the day's work And they actually have a little point here where Whether the sedative or slightly toxic effect of the ketone bodies Accumulating in the tissues as a result of the latter type of diet is responsible for this effect is Is a question that they're asking which People don't look at that too much anymore the ketone bodies are considered a different type of thing now okay, so So that is the sugar does not cause insulin resistance argument So restating the resolution resolved sugar causes insulin resistance Now if you were for that resolution and are now against that resolution raise your hand Okay, like one person if you were against that resolution and are now for that resolution raise your hand That should be nobody If you were for that resolution and maintain to be for that resolution raise your hand, okay, so that's me And if you were already against that resolution and have continued to be against the resolution raise your hand Okay, all right, okay, so most people did not change their mind However, it looks like one or two people changed resolution from pro to against Which means that I win the oxy-style debate with myself I would have You know in case you don't realize I would have won either way All right five minutes up so now I have Some some bonus slides. So what does cause insulin resistance and here so a lot of this is a semantic question like what does that really mean cause and I want to focus here on what's been demonstrated in the lab to cause insulin resistance at a molecular level like cause of resistance to the binding of insulin to sensitive cells with insulin receptors versus something that's Speculated or assumed based on epidemiological data or like whole-body metabolic or anatomical data so one thing that Causes insulin resistance in the sense that it causes more insulin To have to be present in order to use the same amount of glucose is just simply using fatty acids as fuel so if Somebody's in the hospital and they're on like parental nutrition or intravenous you can dial up and down Insulin sensitivity just by increasing fatty acids in that mixture So this is called the Randall cycle and it's just a basic substrate Competition between glucose or any sugar that ends up getting thrown into the glucose type of burning and fatty acids Which is totally normal In times when you have a lot of fat you want to spare your glucose and times when you have a lot of glucose You want to spare your fat makes sense But another thing happens when you are primarily running on fat as fuel the counter-regulatory hormones, which also makes sense specifically cortisol growth hormone that's one people don't think about a lot it could be called Insulin resistance hormone just as likely and the catecholamines which are a more acute effect but they they act to directly Phosphorylate insulin receptor and more so insulin receptor substrate Which is the primary effect of how insulin resistance is caused as it gets phosphorylated by searing and gets in the way of the downstream signaling from insulin binding to its receptor so the counter-regulatory hormones when you are in a hypoglycemic state Causes insulin resistance, which again makes sense because if you're in a hypoglycemic state you don't want to be rapidly using a lot of glucose and then one that is less talked about but I think might be the most important is endotoxin so lipopolysaccharide produced by gram-negative bacteria and this is just some data taken from a study comparing high-fat fed animals with animals that are just given injections of lipopolysaccharide and Showing that the high-fat diet Brings in endotoxin into their system. It's It stabilizes the endotoxin being brought in through the enterocytes and that this causes Plasma insulin to increase in order to dispose of glucose that's present because of the insulin resistance of the cytokines that are produced by macrophages in response to this endotoxin and If you look at this big mess just focus on the insulin receptor and the Lipopolysaccharide has basically the same effect as the counter-regulatory hormones which is that it supposedly binds to this receptor called toll-like receptor for TLR for and One of the effects of that receptor Being liganded is to also serine phosphorylate the insulin receptor substrate which messes with the whole downstream signaling of insulin itself Which also makes sense in the sense that if you had an infection that you wouldn't necessarily want to be using glucose in the same way as when you do not have an infection and One minute left perfect. That's it. Thank you very much everybody and I will take hopefully a lot of interesting questions Thank you. I had a hard time figuring out where to raise my hand because I The belief I came in with is that maybe there's a pathway in which sugar can cause insulin resistance but that it's not the only pathway and that high-fat can also cause insulin resistance and Especially when I saw your slides at the end about the different possible ways that insulin resistance can be caused I'm wondering if it's worth distinguishing different types of insulin resistance and how benign or Dangerous they might be given different kinds of causes yes, or maybe if if there is something to the idea that sugar could cause insulin resistance In one pathway and fat could in another pathway and the combination might cause it both ways It could it be the case that one of those ways is more dangerous than the other or is it just matter what the end result is Is this working yeah, okay so just Don't think that sugar causes insulin resistance at all and that it's Misunderstood so this last slide here I think what happens is people see that they if somebody's on a high sugar diet or somebody consume sugar and then they all have like chronically high And insulinemia and And that the sugar I see so I'll repeat the answer I Think what you're saying is that the insulin resistance was already there the high sugar Shows what happens it when the insulin resistance is there and that's when the that's when it becomes pathological If you remove the sugar the insulin resistance may still be there, but you won't see any bad effect of it Thank you for clarifying I'll just quit a quick comment before my question is that I noticed that the Research assistant was male, and I personally have never met a woman who would have improved mood on a zero fat diet So I just wanted to point that out just from what I've observed my my Question then again going back to what I've observed in myself and many others You made a quick comment about growth hormone potentially being a factor in insulin resistance. I believe is how you phrase that Except that in therapeutic fasting, which is becoming Common and something I used myself We see a rise in growth hormone with a reduction in fasting insulin So how is the growth hormone not causing insulin or greater insulin resistance if it's we're seeing them go opposite directions So when you're fasting you are not challenging your Insulin the the glucose uptake system. So if you have a lot of group growth hormone floating around because you're fasting and that does induce secretion of growth hormone and You're not consuming a lot of glucose or fructose or the combination of which you're not by definition because you're fasting then you're You're not going to have high-fasting glucose But this is something that's seen a lot in like athletes, you know the whole human growth hormone thing a lot of athletes are ending up with like type 2 diabetes And it's speculated that that's a factor in it in addition to like that weird belly thing that they get and so Insulin resistance is Again, like it's kind of a semantic thing like if you're not challenging the insulin system You won't see it like a canary in the coal mine, but that doesn't mean like if you take the canary out You know then that you can't just say oh look no canaries are dead in the coal mine like so the coal mines Save right so that that's the way I look at it I just wanted to make a comment that I caught the last end of this but I have to really appreciate the message because There are so many variables there is no one thing essentially I think that's the biggest takeaway for me that causes Insulin resistance and I see this in the clients that I work with where they're going on a ketogenic style diet But there's still truck like struggling with insulin resistance and part of that like a case that I have is somebody who has severe chronic insomnia So cortisol growth hormone all of those things are disrupted and it's just metabolic chaos internally is really what's happening So even though we're stripping carbs and sugars from the diet She's still not able to balance because there's all those other variables You can't I appreciate the message and that you can't say that it is just sugar or carbohydrates It's causing it because there's so many other factors I mean our body does not move or function in a singular manner. There's so many different systems that are connected to it So it's just it's pure metabolic chaos. It's happening So you have to work on all the different aspects the variables of it. So have you tried just giving her sugar. I Have actually and that doesn't work for her either. It actually makes the situation worse So she's going on now about 20 years of chronic severe insomnia like has to Multiple doses of Xanax and different types of sleep aids and still wakes up in the middle of the night So a lot of environmental toxins like all kinds of other things that are coming at play with her too Hi, thanks for that talk. That was really great one of the slides Caught me when you showed the the countries and you said why would these two countries be different? One point I might make is that they might have different access to medical care Because it seems like you pointed out two pretty discrepant countries But we study so I'm a professor at UCSF and we study ketogenic diets and randomized controlled trials So I was very interested to see see this talk But the message that I'm also getting from this is whether or not sugar is actually causing the insulin resistance We in our trials are seeing that removing sugar and putting people on ketogenic diets is Reducing the bad things that happen when people have diabetes So maybe it is arbitrary that we're reducing their a1cs. Maybe it is arbitrary that their triglycerides are falling in half but Regardless, we're reducing the rates at which they're having neuropathy Losing limbs going blind all the bad things that come with diabetes So I think it's I mean, would you say that your position is more about you're focusing more on the causes? not necessarily The treatments what in this message? Yes, and no, so I think it's largely a semantic issue And I just like sort of took issue with people just flippantly saying oh sugar causes insulin resistance like as if Out of all the things in biology Sugar blocks its own use in the cell like unlike everything else right like that seems very weird But and and yeah, there's clearly some therapeutic success from taking sugar away, but I Really like to see, you know, how that would stack up against like some different type of therapy, you know, because there's a lot of You know underground credence being given to Low carb right now and a lot of people are seeing success But there's really nothing on the other side sort of like in the literature. There's no zero fat really high-carb experiments going on So I'd like to compare the two Okay. Yeah, that's great We we did compare it to a low-fat diet like an ADA style low-fat diet But not a zero fat diet and we did see that the keto diet worked better Okay