#14 - Robert Lustig, M.D., M.S.L.: fructose, processed food, NAFLD, and changing the food system

Foreign.

Hey everyone. Welcome to the Peter Attia Drive. I'm your host, Peter Attia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful, top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics@peterattiamd.com. In this episode I'll be speaking with my friend Dr. Rob Lustig, who I suspect a good number of you will have already heard of and certainly have been familiar with through his pretty impressive presence on YouTube and his talk called Sugar the Bitter Truth that went viral, I believe in 2011. And that's about the time when I met Rob. Now, this podcast kind of grew out of a really interesting discussion that I think I get into in the podcast a little bit, but I think it was in 2016 when Rob and I were both invited to Hong Kong to speak at the Credit Suisse Asian Investment Conference and we were on a panel together. And it just so happened that we were on the same flight back to San Francisco, which was not just a long flight, but more importantly a flight where you weren't going to be sleeping much. And Rob and I ended up huddling together over a laptop going over some really interesting data on nafld, which we'll get into in this podcast. And I remember thinking like, that just kind of left an impression in my mind which was, God, this is the kind of discussion I really enjoy having with people like Rob because it gets into the nuance and away from the headlines and obviously many years later, forward, fast forward to where we are now. I'm starting a podcast. One of the first people I wanted to reach out to was Rob to have this discussion. Rob has very recently stepped down from his clinical responsibilities as a pediatric endocrinologist at ucsf. However, he still has a very active presence in his research department. Rob holds a Bachelor's degree from mit, he got his MD from Cornell, and he also has a Master's of Studies in Law from UC Hastings, something that he did probably about four years ago as he began to realize that only one half of the equation in educating people about sugar was going to come from the scientific standpoint. The other half was going to have to be policy related. In this episode we talk about a Lot of things, but among them, we talk about why Rob believes the food business has really pushed towards having more and more sugar in it, and why these have led to the epidemics of addiction, depression, et cetera. He talks also about how you can combat that. And I think something that people miss in Rob's headlines is that he is not just talking about avoiding sugar. He's also talking about the importance of fiber. And we actually get into a very nice discussion about the differences between soluble and insulin insoluble fiber and how it's actually not uncommon for people to load up too much through processed foods on the soluble fibers, but they're not getting the full benefit without having the insoluble, which is really stuff that's hard to get without looking towards real foods, particularly vegetables. This was really a fun podcast, and I think that comes across in how often we unfortunately probably talk over each other. So I apologize for that in advance. This is also one of the first podcasts I record. So I was still sort of. And I'm still sort of learning the ropes of how to do this. Unfortunately, Rob had to go to, I believe, to a deposition that morning. And so we had a really hard stop that didn't give us nearly as much time as I think we would have spent on this topic. But I do suspect that Rob and I will talk again. We also get into some of the really, I think, kind of practical stuff around what is it like to be a parent when you're trying to balance the desire to, you know, let your kids be kind of normal and deal with the convenience of not making every meal something that requires a day of planning? But how do you prevent them at the other end of that extreme from, you know, sort of mainlining those nasty Capri Suns and Wheat Thins and things like that? So I think some practical advice there is helpful. We do go really deep on fructose, and there is some biochemistry in there. It does get a little nerdy. Rob can talk kind of fast and he really knows his stuff on this topic, so he does not pull back from, from any of that terminology. We're going to do our best to link in the show notes to some of the definitions and some of the things in there that we get into that will give you a little bit of background. We also get into liver function testing, something that I think many people take for granted when they go to their doctor. But it becomes really important when you're trying to screen out people who might have nafld, non alcoholic fatty liver disease, or Nash it's more progressed sibling. We talk about uric acid. We talk about metabolic syndrome. We just talk about a whole bunch of things, including we talk about heart rate variability near the end. And at the time, Rob asked me a question I didn't know the answer to. We have since learned the answer to that question because I was really intrigued by the discussion. And so for anybody who's interested in that little nuance on heart rate variability, we're going to link to that as well. You'll be able to find a lot more information about this, including information about Rob himself and what he's doing, and also just the stuff that we talk about@peter attiamd.com forward slash podcast. So, without further delay, here is my really interesting and intense discussion with Dr. Rob Lustig. All right, Rob, well, thank you so much for making time today to have this discussion.

My pleasure, My pleasure.

We've known each other for, I think, about six or seven years now.

Yeah, about. Right.

And what made me think about talking to you at this point in the podcast, which is to say very early on, as I was thinking back to two years ago when we went to Hong Kong together, and by sort of luck, we ended up on the same flight back to San Francisco. And we were probably the two geekiest guys on the airplane because the laptop.

You're the only ones not sleeping.

Right, right. And then the laptop came out, and then it was all data, all flight, and it was awesome. And it's. It's experiences like that that have made me think, like a podcast can be a fun way to reproduce some of those discussions that I often find myself having. And then thinking, God, I wish everybody could have heard that, because I learned a lot during that time.

It's vice versa, by the way. And people wish they were flies on the wall. So, you know, I'm happy to do this. This is great.

Awesome. Well, you've spoken so much and so eloquently about sugar and fructose, and certainly we're going to talk about a lot of that stuff today. But I also want to talk about some things that I think are a little less understood. For example, the impact of fructose on inflammation and things like that.

Well, what data we have.

Yeah.

By the way, let me qualify. While I do know a whole lot about sugar, fructose, you know, metabolic disease, really, my issue is processed food. Processed food has several things wrong with it, sugar being one of them, but lack of fiber being another. And I think that that is equally important. And I'm very willing to Talk about that issue as well.

Perfect. So let's start with a very brief set of the semantics that I think it's important for people to understand when they do confuse fructose and glucose. They're both carbohydrates. What's the difference?

Well, they're both monosaccharides. Glucose is the energy of life. Every cell on the planet burns glucose for energy. Glucose is so important to functioning in all eukaryotic organisms. Single cell versus multi cell doesn't matter. It's so important that if you don't consume it, your body makes, can make it from amino acids, it can make it from fatty acids called gluconeogenesis. Those amino acids or fatty acids will go to the liver. The liver will metabolize those and produce glucose. And so you can consume zero glucose, but you will still have a blood glucose level. The Inuit, they didn't have any carbohydrate, they didn't have any place to grow a carbohydrate. They had ice, they had whale blubber, they still had a serum glucose level and we knew that as early as 1928. So glucose is super important. And I don't argue that it's so important that your body has a fail safe mechanism. Fructose, however, is completely vestigial to all animal life. It is a storage form of energy in plants. Plants can utilize fructose for energy. We have the capacity to metabolize a limited amount of fructose for energy. Really, when you're consuming fructose, your gut bacteria are more adept, since they're plants, at being able to metabolize that fructose than you are. So when you're consuming fructose, yes, you will absorb some, but for the most part, it's actually more plant food than it is animal food. In addition, there are some very specific biochemical differences between the two molecules. Glucose is a six membered ring. Fructose is a five membered ring. Now that becomes important because both glucose and fructose and every monosaccharide exists in two forms. One is called the ring form and the other one's called the linear form. The linear form has the capacity to bind to proteins called the Maillard reaction. It's what makes hemoglobin A1C in diabetics, also known as the Amadori rearrangement. The this is a biochemical process that occurs normally. It is the browning reaction. It causes bananas to brown, it causes humans to brown. In fact, we're all browning right now because our mitochondria in our cells are engaged in the Amadori rearrangement. It is what makes people age. It is the aging reaction. And I show a slide which shows newborn rib cartilage, nice and white, and 88 year old rib cartilage, nice and brown. Okay, we're all browning. So you can roast your meat in an oven for 375 degrees for an hour, or you can roast your meat at 98.6 degrees for 75 years. Ultimately, the answer is the same. You brown. Why do I bring this up? Because glucose causes that browning reaction at a relatively low rate. Fructose makes that reaction occur at 7 times faster rate.

Now this starts with this schiff reaction, correct?

So it forms a schiff base.

Okay.

Right. So it starts with. And it's non enzymatic. It happens just in a test tube with no enzymes needed. You just put it in the sunlight, it will happen. What happens is that the aldehyde moiety of the glucose in the linear form will bind to an epsilon amino group of lysine, which is at position one in hemoglobin, and form a shift base which then spontaneously decomposes to form a covalent linkage which won't come off and basically will stay there until that hemoglobin molecule is recycled by the spleen. So this is why you can measure glucose levels through hemoglobin A1c is because the higher the glucose level in the blood, the more this reaction occurs and therefore the higher the hemoglobin A1C turns out, fructose does it seven times faster. And not only that, every time it happens, it's causing those proteins to become less flexible, so less functional. And every time it happens, it throws off a reactive oxygen species, an oxygen radical, a hydrogen peroxide, which then can do damage unless it's quenched by an antioxidant. So in the face of antioxidant deficiency, which is called processed food, it can actually cause inflammation and non alcoholic steatohepatitis and many other problems related to the inflammatory response. So fructose does that seven times faster than glucose. A third thing that is different is that when you put glucose in the stomach, your hunger hormone called ghrelin goes down. When you put fructose in the stomach, it doesn't change. So when you consume a lot of fructose, your brain doesn't know you've eaten and so you end up consuming more. And lastly, glucose is metabolized in the brain, the areas that basically metabolize glucose and give you a functional MRI signal. Are areas that have to do with the sensory motor cortex for the most part, and for the basal ganglia, Fructose specifically lights up the reward center and has been now been shown to induce the same physiology in the brain that cocaine, heroin, nicotine, alcohol, any hedonic substance also generates. It is the reward signal and in fact we treat it as a reward signal. It's called dessert. So fructose and glucose are not the same. The food industry would have you believe A calorie is a calorie, a sugar is a sugar. You need sugar to live. Those are all food industry mantras. They're all out in the cybersphere and in the blogosphere. It is absolute garbage. They are quite different and it does matter.

I want to go back to just something very minor that you mentioned. I get asked this question all the time and I've never had a compelling answer, but we use hemoglobin A1C as sort of a surrogate proxy for average glucose levels. Now, for reasons we won't get into today, just for time, I'm not particularly convinced hemoglobin A1C in an absolute sense provides great insight.

Oh, I agree.

On a relative basis it can be somewhat helpful. But at least directionally it's helpful within.

Any given patient, A lowering of a hemoglobin A1c from point A to point B would be a good thing. I won't argue that.

So the question becomes, do we have comparable biomarkers that can give us some indication of average exposure to fructose over a given period of time?

Right. Awfully good question. So fructose also binds to hemoglobin, but it does not bind at position 1. Therefore you don't measure it in hemoglobin A1c. So it binds at positions 66 and 110. Now the hemoglobin A1c assay is not set up to look at 66 and 110. This requires a major research lab. It requires tandem mass spec. It's a huge undertaking. It's only done as a research tool and the only lab I know that does it is in Japan. So that's not a rational thing to expect. Right now people are looking for long term biomarkers of fructose consumption. And there have been several papers that have come out that are pointing to individual options, but none have been put into clinical practice. None have been shown to really validate consumption in a meaningful way. So at this point in time, we don't have that for consumption. What we do have are some Indirect measures of fructose, shall we say, biotoxicity.

Yeah, like uric acid or ALT would be.

Exactly. Those are the ones I was going to bring up. Exactly. Uric acid and alt. So we know that the more sugar you consume, the higher your serum uric acid goes and the more risk you have for gout. Benjamin Franklin knew that and wrote about it. The reason that happens is because since fructose can only be metabolized in the liver, because the liver has the GLUT5 transporter, every time a fructose molecule enters a liver cell, it has to be phosphorylated. So it goes from fructose to fructose 1 phosphate. And the enzyme that does that is called fructokinase. Well, the phosphate has to be donated and ATP is the donor. So ATP becomes adp, adenosine triphosphate becomes adenosine diphosphate. Now, there is a scavenger enzyme in the liver called adenosine deaminase 1. And what it does is it then takes ADP down to AMP monophosphate, then to IMP, inositol monophosphate, and finally to uric acid. So the uric acid concentration in the blood is a proxy for total fructose consumption. Now, there are other things that make uric acid go up too, like protein. But all things being equal, they do correlate with each other. And we've shown that serum uric acid in children and adolescents correlate with sugar beverage consumption, for instance. And other people have shown that that uric acid matters because uric acid is the inhibitor of endothelial nitric oxide synthase. That's an enzyme that exists in your vascular tree, that vasodilates the blood vessels and that keeps your blood pressure down. And we have shown that Every increase by 10% in fructose consumption increases your blood pressure by 2 millimeters of mercury consistently, and that increases your risk of stroke by 10%. We have data, and it's also been shown by the Dan Feig at UT San Antonio, that if you give an inhibitor of uric acid synthesis, allopurinol, which is what we give to gout patients, you can actually lower adolescents blood pressures when they have essential hypertension. So this is a mechanistically valid problem, and it is a surrogate proxy biomarker, sort of for sugar consumption. ALT is also a surrogate marker in a similar way. ALT goes up when your liver stores fat.

What's the difference between. I mean, patients are sort of familiar with the difference between ALT and ast, but they both show up as liver function tests. But guys like you and I tend to spend a little more time looking at alt.

Right. So ast, which is aspartate aminotransferase, is a biomarker for mitochondrial function. And ALT is alanine aminotransferase, and it is a biomarker for degree of liver fat. So they're both important, but in different ways. AST is much more minute to minute. Like, what did you eat at your last meal? ALT is a little bit more, shall we say, stable over time, so we tend to use alt. However, we've shown that when you cut sugar back, AST changes suggesting mitochondria are actually getting better.

And the ranges on these things keep drifting upward for what people deem acceptable. I tell my patients I want their alt below 20. And they say, but Peter, the range says up to 42.

Indeed. This is huge, and I'm glad you brought it up. So I entered Medical School in 1976, and at that time, the upper limit for normal for alt was 25. Now when we talk about upper limits for normal, where do those calculations come from? Basically, you take a bunch of quote, normal people and you figure out the mean and you look at two standard deviations around the mean, and that's how you decide what is normal. So in 1976, 25 was two standard deviations above the mean. Today, 40 years later, 40 is two standard deviations above the mean. Did something happen to the assay? No, something happened to us because now everyone has fatty liver disease. In fact, the Dallas Heart study showed that 40% of normal people have hepatic steatosis liver fat. Well, that makes your ALT go up. So what I say is 25 was the upper limit of normal. 25 should still be the upper limit of normal, despite what it says on the lab slip, because that's just looking at two standard deviations above the mean. So we use that very specifically in clinic to show parents and kids what is happening to them and why sugar is the bad guy. Because when we get them off sugar, the altogether drops within a month.

Yeah, and going back to the uric acid thing, I was very influenced by the work of Rick Johnson. And Rick has been always incredibly generous with his time and insights. And indeed, you know, one of the things I started doing probably about three years ago was just basically saying it's non negotiable. All my patients need a uric acid below 5. Even though the assay says we will consider normal up to 7.0.

Exactly. Same issue so in clinic, we basically said 5.5 is sort of the breakpoint. So we're pretty close ALT at 25. Uric acid of 5.5. You know, we can argue about the. We're within an order of magnitude of the.

And the point is the same. And I think it's interesting because when we think about cardiovascular disease, one of the things that the endothelial story gets overlooked a little bit. The inflammation story is now getting its day based on these two very recent trials. Well, one recent trial and one that was halted, likely because of a significant improvement in the outcome of using methotrexate. But when you look at the impact of uric acid on nitric oxide synthase, when you look at the impact of homocysteine on asymmetric dimethyl arginine, which also then in turn inhibits nitric oxide synthase, these things start to make a bit more sense, which is we always kind of knew having high uric acid was bad, and we always kind of knew having high homocysteine was bad. But now we're seeing these mechanistic reasons why all of a sudden, oh, wow, like, that's a bad thing to have, you know, vasoconstriction in your coronary arteries.

I couldn't agree more. The fact of the matter is, we didn't have the empiric data. We always had the plausibility argument, but we didn't know how important it was. Now we have the empiric data, and we have interventional data to say that this phenomenon is quite important, and it's not its own phenomenon. It is another manifestation of this global phenomenon we call metabolic syndrome. And when you look at it that way and say, well, if it's doing this, what else is it doing? All of a sudden, things start piecing together. You know, it's like the puzzle, you know, and you sort of needed the piece in the middle to fit all the other things together to be able to tell what's really going on. And uric acid is part of that puzzle.

Now, Rob, is there any situation under which fructose consumed in its natural state, which is to say with water, with fiber, that is, in fruit, poses an advantage over glucose, because clearly, glucose has many advantages in terms of how metabolically flexible, like, you know, every organ can basically consume it. You don't have a lot of these other negative reactions. And is there something that fructose does better than glucose?

Yes, one thing. So if your liver is glycogen depleted, for instance, if you're a football player. Three hours on the gridiron and you have depleted your glycogen stores from your liver and you consume a, say, energy drink or sports drink, you will replete your glycogen faster. It will do that. I won't argue that. The reason being, but this, to be.

Clear, is only liver glycogen, not muscle glycogen.

Absolutely.

And muscle glycogen is a much bigger store.

Absolutely. You will replete your liver glycogen faster. There is a back door where you can turn fructose back into glucose, which can then restore your liver glycogen. Now, the sports drink industry makes a huge deal about this. I think this is truly a tempest in a teapot. I think this is really irrelevant. And the reason is because after you've spent three hours on the gridiron, you're not going to spend another three hours on the gridiron and you will, by tomorrow have repleted those glycogen stores anyway just from eating real food. So the idea that somehow you have to replete your glycogen rapidly just to me, does not hold well water. Yeah, it's fine to expend your glycogen stores in your liver and real food will get you back to the same place by tomorrow.

It also doesn't even make sense physiologically because the limit to performance is not liver glycogen, it's muscle glycogen.

Well, I'm not even sure that's true.

That's right. When you hit people with glucagon who claim that they've sort of bonked and hit the wall and there is no more glucose left, you'll still see a transient glucose spike.

Absolutely. Plus we have all these people who are now on high fat diets, ketogenic diets, and how about the Ethiopians? They're not eating carbohydrate. The fact is you actually have better sports performance using fatty acids and ketones than you do with carbohydrate. And the reason is insulin. So I don't buy that for a minute as being important. Yes, it is true. You will replete your liver glycogen faster. And that's true, true and unrelated. It's like, so what?

Yeah. You very recently retired clinically. Yeah. You're nowhere near retiring.

No, no, I've got a lot to do.

But you spent a lot of time. You're a pediatric endocrinologist. You spent a lot of time in clinic with children who had diabetes, have been overweight, have been obese. Have had nafld, Nash, et cetera?

You bet.

Do you have a concern that children who undergo such metabolic transformation suffer an epigenetic hit that makes it harder for them later in life?

What I know about epigenetics suggests that that is possible. I would even go so far as to say likely.

I know, and it's frightening if it's. I mean, it's one of these things you hope is so untrue.

Right. But I don't know that. Here's what I do know, and it's related, but not exactly the same. We know from animal work from both Children's of Philadelphia and also from the Liggins Institute in New Zealand that maternal hyperglycemia causes epigenetic changes.

This is in utero.

In utero causes changes in H19, the different epigenetic markers that we have on chromosomes that then portend metabolic dysfunction later on. So if that's true in humans, and no one's proven that that's true in humans, it could explain a lot of the things that we do see. We know from a biochemical standpoint, animals that are stressed or animals that consume large amounts of sugar during pregnancy end up with offspring that will manifest various aspects of the metabolic syndrome later. Do we know that that's through epigenetics? Not yet. But if the rodent studies are similar to, you know, what happens in primates and humans, it's not too far afield and it's not too much of a jump. Yes, I'm very concerned about it because, as you know, epigenetics is the gift that keeps on giving.

Yeah.

You can change the F1 generation and still find that epigenetic change and therefore the metabolic alterations in the F4 generation. So it might explain why things keep getting worse year after year, is because we're adding on all the time and more people are entering this epigenetic disaster. But I don't know that that's a.

It's sort of one of those things where we have to sort of take a little bit of the precautionary principle. Right. So you say, well, if there is an epigenetic reprogramming that occurs, then as parents, we need to be thinking a little bit more about the food environment our kids are in, because this is one of those things. You know, we're pretty familiar with the notion that if you don't discipline your kid, you're really not doing them a favor 20 years down the line. And this would be another variant of that. And of course you would say, well, what if this turns out to be untrue, what if there is no epigenetic signature? It's like, okay, well, what was the downside of trying to get your kids to eat?

Well, no argument. There's one downside, and it's.

It's the effort that's required.

Exactly. That's the downside. So we have these data. How many times do you have to introduce a savory food to an infant before they will accept it?

Oh, I don't know. 3? 4?

Median? 13. Wow. How many times do you have to introduce a sweet food to an infant before they'll accept it?

Let me tell a funny story for that. When my daughter, who is now 10, turned 6 months old, and I have this on video, we took her down to Del Mar for a walk on the beach and got an ice cream cone. And we were like, all right, she's had nothing but breast milk and some formula for the last six months. What will she do with some soft vanilla ice cream? And our thought was the cold would turn her off. It was a foreign substance, whatever. And it's one of the funniest videos I've ever seen. Cause she puts her face into this vanilla ice cream, and I've never seen her eyes open so much. And I joked about it. I was like, holy shit, look at the dopamine. You can almost see the dopamine firing.

You needed to put her in the functional MRI right then and there.

Yeah.

Michael Pollan describes this in the Omnivore's Dilemma. The first time he introduced birthday cake to his son, and he looked at him like, you've been holding out on me. This exists in the world, and this is the first time I'm getting it. I'm gonna devote my entire life to sequestering all this stuff just to spite you.

It's incredible, actually. My youngest son turns 1 on Wednesday of this week. Congratulations. So thank you so much. He's going to get a cupcake. That'll be his first junk food.

You sure you want to do that?

Just because I love watching this reaction going back to this thing. I'll tell you something.

Get the mri.

Yeah, yeah, yeah. When my daughter was growing up, so before she got to school, all she drank was milk and water. And when she was about five years old, she was at a birthday party, and they had these things called Capri sun, which are like. I don't even know how these things are legal because they're basically syrup in a tinfoil bag. They're really gross. I mean, they take it To a new level.

They do.

She took one sip of one and pitched it. And I was like, oh, Olivia, why didn't you drink that? She's like, it's really gross. It is gross. Well, fast forward five years later, she drinks that stuff anytime she's at a kid's house. Even something that seemed so physiologically nauseating at one point in time, she's acclimated to. Right.

And there's data on desensitization of taste buds. And one of the reasons why you keep wanting more and more sweet is because the taste buds get down, regulated. And there's data now that actually supports that in humans. So there's this desensitization issue. There's also the desensitization of dopamine receptors because dopamine receptors go down in response to constant bombardment by dopamine. The phenomenon of tolerance.

This would be very. Is this a controversial point? Because this is the sine qua non of what makes cocaine so dangerous. I mean, I have a number of patients who recreationally use cocaine. And I. I don't wanna be like the alarmist who just says, don't do drugs, cause drugs are bad. I wanna make the point that says, look, not all drugs are necessarily bad. But cocaine has two problems, at least as far as I can see. The first is you have a nonlinear asymmetric risk of something really bad happening as far as cardiac dysrhythmia. So why would you take that risk? But the second issue is this down regulation of dopamine receptors that develops this tolerance and therefore makes it actually harder for you to experience joy subsequently.

Indeed. So here's the deal. Neurotransmitters are either excitatory or inhibitory. Now, neurons like to be excited. That's why they have receptors in the first place. But neurons like to be tickled, not bludgeoned. They like to receive the neurotransmitter fire and then come back to baseline. Chronic overstimulation of any neuron leads to neuronal cell death, period. And we know this because we take care of all these kids with chronic seizure disorders in the icu. And we're doing our best to try to stop those seizures, not because of the seizure, but because of the brain damage that occurs from continued overstimulation. So any neuron that is an excitatory, that's downstream of an excitatory stimulus, it wants to protect itself. It has a plan B, it has a fail safe. What it does is it down regulates the receptor. That means that there's less likelihood that any given molecule will find a receptor to bind to, thereby reducing the risk for cell death. So what does this mean in human terms? You get a hit, you get a rush, receptors go down. Next time, you need a bigger hit to get the same rush, and the receptors go down. And then a bigger hit and a bigger hit and a bigger hit until finally you get a huge hit to get nothing. That's called tolerance. And then when the neurons actually do start to die because chronic stimulation causes neuronal cell death, that's called addiction. And those neurons don't come back once they're dead, they're dead. And that actually limits your ability, even after rehab, of being able to experience that same level of reward, because now you don't even have the dopamine to be able to do it, because those neurons are dead. So not every drug is stimulatory. There are drugs that are inhibitory. If you're inhibiting the next neuron, do you have to downregulate the receptor? No. So like a benzodiazepine, for example, benzodiazepines are inhibitory. Turns out psychedelics are inhibitory. So serotonin 2a and 1a are inhibitory. So when the DEA clamped down in 1970 with the controlled Substances act, that made marijuana and psychedelics and, you know, everything, schedule one and, you know, unavailable, There were a whole bunch of people using psychedelics. They didn't end up in the emergency room. They didn't end up with withdrawal. And the reason was because they didn't have downregulation of their receptors because those were inhibitory. So not every drug fries neurons, but cocaine does.

Yeah. Help me understand how alcohol fits into this, because alcohol is, of course, a gaba. Ethanol per se, is a GABA agonist. So it should be at least depressing in that sense. But yet ethanol has some of these negative properties in the brain that you've just alluded to.

Well, the problem is ethanol in the brain also, because it's polar and it dissolves lipids, it also creates acetaldehyde. So that's the first step in terms of metabolism of ethanol, which then can cause that Maillard reaction, because you've made an aldehyde, which then generates reactive oxygen species. So you can kill neurons not necessarily from excitation, but from the biochemistry of the molecule.

So we talk a lot, and we might not even get into it today because you've spoken so eloquently about it elsewhere, about the similarities between ethanol and fructose in the liver.

In the liver, yes.

How are they similar in the brain, if at all?

So they both stimulate the reward center.

Though, it seems through different mechanisms.

Yes, likely through different mechanisms. There are a lot of different dopamine stimulators. There are substances, and they're all different. Cocaine, alcohol, nicotine, sugar, heroin. They have different mechanisms, but they all ultimately impact on dopamine the same way. We also have behaviors that are addictive. Gambling, shopping, Internet, social media, pornography. Okay, there's an aholic next to every one of those, too, right? Chocoholic, sexaholic, whatever. Because they're stimulating dopamine also. But they're not chemicals, they're behaviors. But they still generate that same dopamine response, and therefore, they still induce the same phenomenon of tolerance. Now, they don't have withdrawal. Withdrawal is the effects of these substances on the peripheral body, not the brain, but the peripheral body. Because cocaine has effects at every adrenergic synapse. Morphine has effects on other places other than the brain, et cetera, et cetera. Caffeine, too.

You know, and it's interesting how withdrawal can sometimes be physiologically deadly. For example, ethanol. The DTs, we know this stuff. I mean, when we'd operate on patients who were alcoholics, we would actually just continue giving them ethanol throughout surgery.

I got it.

Keep them on alcohol the whole time they're in hospital. So you can kill a patient if you take alcohol away from them too abruptly, whereas opiates, the withdrawal is unbearable. But you won't kill the patient by removing it. I find the physiology of withdrawal to be quite interesting.

Well, it's true. In fact, the way to deal with opiate withdrawal is get rid of the opiates or give naloxone to counteract the opiates, which is now going on, you know, everywhere. And now the police, you know, carry Narcan, and when they find opioid overdoses in the field, and they're even having schools, which is really bizarre and horrible. So. Yes, they are.

Earlier point. Right. Which is. And Gabor Mate, who has written about this quite eloquently stated that we're all addicts.

Oh, yeah.

And so you just get to choose.

Your substance of abuse or your behavior. Abuse.

That's right. And as you said, it's not. And it can be work. The point is, sometimes it can be things that are not socially punished, and sometimes those are the hardest addictions to treat.

I'm gonna admit to you right now, I'm a caffeine addict. I've already had four cups of coffee this morning. And as soon as we're done with this, I'm gonna have my next. And, you know, if you take my Starbucks away from me, I will kill you. On the other hand, caffeine is not dangerous, unless you mix it with alcohol, in which case, then you have Four Loko, and you end up with arrhythm and other things, and it's still socially acceptable. Nicotine is now not socially acceptable. But it took a long time. It took an entire generation of teaching kids why cigarettes were bad before it became not socially acceptable. So we have a long way to go with sugar because it's still socially acceptable.

I want to get into some more geeky biochemistry stuff, but I also know that there's probably at least one person listening to this who's a parent, who's thinking, oh, man, do I have to simmer down how much sugar my kids are eating? So when you saw kids in the clinic, obviously you're seeing their parents. That's one of the advantages of pediatrics.

Is it's also one of the disadvantages.

That's right. That's right. You have two patients.

Two patients. And I don't get paid for both.

But the beauty of it is you have. You have a patient who you need to take care of, which is this child. But then you also have another caregiver who, for the most part, wants what's best for that child, mostly. And how would you counsel a parent who would say, Look, Dr. Lustig, there's no way my kid's gonna have no sugar in their life. Can you give me a way to create a sustainable environment and set of rules that's gonna prevent my kid from having the metabolic derangement that hoses them for the rest of their life but allows them to still be a kid?

Yes. So that's what we did in clinic every single day. Here's the problem. It's not the added sugar. You know, it's the added sugar. You don't know.

It's almost. There's like a Rumsfeld tone to that, right?

Well, yeah. I mean, there's the known knowns and then there's the unknown knowns. And the fact is, when you look at the amount of sugar that is in sodas, it's bad. When you look at the amount of sugar that's in candy, cake, ice cream, it's about half as much. That adds up to 50% of the added sugar consumed by children.

And what is that number, by the way, in grams per day? Approximately.

It runs the gamut. But the median is 18 teaspoons.

So that's about 90 grams of sugar per day.

Yeah. And it used to be 120. It's actually come down because of the obesity epidemic. 90 to 94 grams of added sugar per day. Half of the sugar is in foods you didn't know had it.

Bread, pasta sauce, pretzels.

Why pretzels have sugar in them? Okay, bread. Right. Why do they put sugar in bread? Any idea?

I guess it probably helps with preserving it, doesn't it?

Exactly. So if you buy a loaf of bread at the bakery, how soon before it stales?

Two days.

Typically two days. If you buy a loaf of bread at the grocery store, how long before it stales?

Ten days, three weeks even.

Okay. Why they're both bread, right? Well, what they did in the grocery store bread was they added sugar very specifically because the sugar doesn't boil off when you put it in the oven, water does. So it acts as a humectant.

That's why it's so much moisture when you have store bought bread.

Exactly. That's why if you threw a loaf of bread at my head, it would just bounce off is because it's kind of spongy. Right. But there are also breads like German fitness bread, which don't have that. They're real bread. They use whole grains. They're lumpy, bumpy, and they're small. The loaves, they're the size of a weapons and they're weapons. Right. You could like kill somebody if you threw a German fitness bread at their head. Okay. It is dense. They're both bread. But the store bought bread had sugar added very specifically to hold on to water because sugar's polar and so the water stays in and therefore the bread doesn't stale as quickly. Therefore you can put a sell on by date way later. Decreased depreciation, increased profit.

So if a kid came in and a kid's got NAFLD, and you've surmised that this child's eating about 100 grams of sugar a day, do you say to the parent, our Target is what, 20 grams per day?

What we say is we don't worry about target numbers. What we say is processed food is the problem. Because processed food is high sugar, low fiber. What you want is a low sugar, high fiber diet. That's called real food. Every diet out there that works, and there are a whole bunch of diets that work. Okay. Certain vegan diets work. Remember, Coke is vegan, so it's not like every vegan diet's okay.

The college vegan diet doesn't necessarily work.

Yes. The college vegan diet does not work exactly right. The traditional Japanese diet, the Atkins diet, ketogenic diet, Paleo diet, Mediterranean diet, all.

Of these diets, plant based diets.

Sure. They all work because they're all real food. Every diet that works is real food. And every diet that doesn't is because it's processed food. The problem is parents don't know the difference. They don't understand that grocery store bread is processed food. They think it's food. They think, you know, if it's sold in the supermarket, it's food. No, there's real food and you know what that is. But the parents don't. And what we teach them in clinic is if there's a label on the food, that's a warning label because that means it's been processed, because real food doesn't need a label. Is there a, you know, nutrition facts label on broccoli? Is there a nutrition facts label on carrots? No. Is there a nutrition facts label on the meat in the meat case? No. The reason is because it's all real food. Now when we get to meat, you know, there's ways of making meat a problem too. It's called corn fed. But the bottom line is at least.

They'Re real food because you don't necessarily fixate on targets. You say, look, we don't talk about, we're going to make a conceptual change.

We don't ask them to do meth. We ask them to purchase and consume real food. Now we have to teach them what that is. So what we do, we bring all of the new patients in on the same day. We see all the new patients on one day. It's like chaos. And they all meet with a dietitian. They come in fasting, and we draw their blood and, you know, we evaluate them. And then they all sit down at a communal table and we do an hour long teaching breakfast. And the dietitian narrates why those foods are available for breakfast. So whole grain bread, natural peanut butter, you know, not Skippy Jif, Peter Pan, but you know, the real stuff, plain yogurt, et cetera. And we explain why these foods were chosen and how they meet the criteria of real food as opposed to what they're currently buying. Most parents get it now. There are some who don't. There are some who say, I'm sorry, that takes too long, I can't spend the time preparing the real food.

And then is there an economic consideration also? Do you have a sense of what it costs? All things equal. So a parent's going to basically have to double their food budget if they want to start eating real food.

That's right. They're going to have to double their food budget and they're also going to have to double their food time in terms of preparation.

That's a big ask.

It is for.

I mean, when the CDC last looked at this, the estimates of nafld, which we'll get into in a moment so we can let you explain that in some detail. But when you look in particular along ethnic lines, at the time I last looked at this, 50% of Hispanic boys who were obese had NAFLD. My guess is that's a gross underestimation.

Likely. The fact is that Latinos are more risk of developing right.

There's a genetic predisposition.

They have a specific polymorphism of a specific gene called PNPLA3, patent like phosphoprotein domain A3. And it's been shown that if you have the homozygous form, the GG mutation polymorphism of this gene, a little sugar in your diet makes a lot of liver fat and 19% of Latinos have it. So this is particularly worrisome for the Latino population. And yes, they have fatty liver like nobody else. So there are people at more risk. And so it becomes even more important to get the sugar out of their diet. And we explain all of this to them. We explain why this is. And we show them the lab data. We show them the Acanthosis nigricans on the back of the kid's neck to explain how the environment changes the biochemistry. We also then explain how the biochemistry changes the behavior. We know from our study where we actually substituted starch for sugar, that kids actually couldn't even eat as much food as we had to supply. They all of a sudden.

Let's talk for a moment about that. This is the isocaloric substitution of fructose or glucose for fructose.

That's right.

So let's take a step back and explain what NAFLD is. Let me start with one anecdote before we get which you'll appreciate. When I was in my residency, so we're talking about, you know, what, 18, 20 years ago. One of the questions, if you're a young surgical resident, you're always asking the patient during pre op is how much alcohol do you consume? And the reason is, going back to the DT thing, we don't want to ever get into a situation where two days post op a patient's having DTs right. So I remember on at least three occasions, but probably more, where a patient claimed they did not consume alcohol or that they're, you know, they consume like a beer twice a week. And then we'd get in there to do the case and they'd have fatty liver. And we would look at each other and go, God damn it, this guy lied to me. I can't believe this. You know, I wasn't there to judge him. I just needed to know he clearly is drinking like his life depends on it, and he was in denial. Well, it never registered to me what was going on until 10 years later when I learned about NAFLD. And I said, wait a minute. Those patients weren't lying to me. They had non alcoholic fatty liver disease.

And you can't tell the difference under the microscope. They look the same. So my first NAFLD patient was in 1996. I had just moved to Memphis, Tennessee, and I had a patient who had alts in the 3 hundreds, and the liver was enormous. And they were just sure this. And it was a kid, so it wasn't an alcohol thing, but they were sure this kid had hepatitis or something else. It turned out they went and did a liver biopsy and it was fatty liver disease. I said, what the hell is this? And soon all my patients had it. Same thing with type 2 diabetes. I saw my first pediatric type 2 diabetic back in 1992, and now one third of all new diabetes diagnoses in kids is type two. What's going on? You know, we were at the beginning, we, both of us were seeing this at the beginning of this epidemic, and now everyone's got it. You know, this can't be genetic. This is an environmental insult. And the good news is we figured out what the insult is. The bad news is there are dark forces on the other side keeping it that way.

Let's talk for a moment about that. About four or five years ago, there was certainly a controversy around the etiology of nafld. There were camps that said, look, it's got to be the fructose, for reasons that you'll articulate. There were other camps that said, actually it's fatty acids, it's kids that are consuming too much fat. Others said, actually it's just a proxy for obesity. In other words, quote unquote, caloric excess leads to adiposity, which leads to nafld. I'd like to hear your thoughts on in the most unbiased way we could, how do you make the case that it's fructose? That is disproportionately driving this versus some of these other factors.

It's very easy to imagine how you get liver fat. There's production and then there's clearance. Okay. And the amount of liver fat is the equilibrium between those two phenomena. There are two methods for production. One is through diet. So dietary fat can contribute to hepatic fat, but there's also de novo lipogenesis, which is new fat making. It's the process of turning sugar into fat. Now, that had been discounted for years because of a one study.

This is Hellerstein's study that basically looked at.

Right. The Parks Hellerstein study from Journal of Clinical Investigation. 98.

98. Okay.

1998, where they said, oh, this is a minor pathway. The fractional DNL was only 3%. Well, the reason it was only 3% was because, number one, these were healthy people. Number two, they were fasting, which means they were glycogen depleted. And so the fructose went into repleting the glycogen like we talked about. And there were also people who hadn't been large fructose consumers in advance. And we now know that fructose absorption at the level of the gut is inducible. We learn this every Halloween because the kid eats a lot of sugar and then ends up having diarrhea like crazy because basically they've got malabsorption. They've got malabsorption because their enzyme hadn't been induced yet. But if you continue to supply it, the process increases. And we now know the reason for that is a protein in the intestinal epithelial cell called thioredoxin inhibitory protein, or txnp. This is work from Richard Lee at Harvard. There were a whole bunch of reasons why people thought that de novo lipogenesis was a minor pathway. It's not a minor pathway. It is a major pathway. And Donnelly showed in 2005 that de novo lipogenesis was worth about 25% of the fat in the liver.

Wow. And then, I mean, you're going to get to this, but how much of that is getting exported? In vldl, that's the clearance side.

There are two ways to clear. There's oxidation, fatty acid oxidation. This is why diseases that cause mitochondrial dysfunction, like Reye's syndrome, end up with fatty liver. And then there's export. And the export can be through VLDL or can be through phosphatidylcholine, but it's basically export out of the liver. So there's oxidation as clearance and export as clearance. So you have two ways coming in.

Two inputs, two outputs.

Two inputs, two outputs. And so the question is, what's changed? And the answer is our dietary fat's gone down, so that ain't it. But our de novo lipogenesis has gone up. And when you look at the exports, we now have fatty liver, which actually makes things worse because it causes inflammation, which ends up making mitochondria less functional, which causes less fatty acid oxidation. And we have data on that. And we have high triglycerides in patients who consume fructose. So if that pathway out is going up, then you know that if you've got fatty liver, it's because more is coming in. Bottom line, DNL is the driver.

So we could say, because triglycerides typically go up with nafld, that says it's not a problem of exporting, it's not ineffective exporting.

Patients who have a beta lipoproteinemia, they can't export, they can't make the vldl. You know how many patients that is? Okay, that's like 1 in 10,000. We have a 40% NAFLD rate in this country. It ain't 1 in 10,000. It's not because of the fatty acid oxidation defects, it's not because of the export problem, it's not because of the increased saturated fat. It's because of the de novo lipogenesis by process of exclusion. That's the only pathway that's gone up.

Do you believe that insulin resistance is the result of nafld, or is NAFLD the result of insulin resistance? Yes, the two feed off each other.

Let's talk about metabolic syndrome, because the one aspect of metabolic syndrome that everyone agrees on is this phenomenon called insulin resistance. The question is, where does the insulin resistance come from? Everyone assumes, well, you get fat, therefore your fat cells make cytokines like TNF alpha and IL6. Those then go via the portal system to the liver and cause the liver to be dysfunctional and therefore you increase hepatic glucose output. That then causes your beta cells to have to overproduce insulin and then that drives the insulin resistance. That's what you learn in medical school. Undoubtedly there are some patients where that is the pathway. I actually think that's actually a rare way that this happens. Maybe 10%. I don't think that's the majority, but that is one way. We'll call it the adipogenic hypothesis of.

Metabolic syndrome, because clearly that patient is not insulin resistant at the adipocyte, as evidenced by the fact that that they can increase the size of their adipocyte.

Exactly right. So they have liver insulin resistance, but their adipocytes are insulin sensitive because they keep storing.

And in that model, you haven't necessarily specified what's happening at the level of the muscle, which some would argue is the harbinger of bad things. In other words, once the muscle stops disposing of glucose, taking it in.

Yep. In fact, muscles don't need insulin to import glucose. If they did, then every diabetic would be paralyzed. The reason insulin works at the muscle is for import of amino acids. So for muscle growth, but not for muscle metabolism.

So the transporter on muscle is which? Glute? GLUT2.

It is glute.

Or 4.

It's not 4. That's in adipocytes. GLUT2 is in liver. I'm pretty sure it's 3. One is in the brain. I'm pretty sure it's three. I gotta look at that again, but I'm just trying to remember. But it's not glut 4. So that's one pathway of metabolic syndrome starting at the fat cell. But I think that's rare. There's a second metabolic syndrome. We see it in clinical depression. Now, clinical depression causes weight loss, so you'd think that that would actually obviate metabolic syndrome. But in fact, clinical depression increases metabolic syndrome. It decreases obesity, but it increases metabolic syndrome. And when you do CT scans or MRIs across the abdomen of people with clinical depression, they have increased visceral fat. Now, why do they have increased visceral fat? Cortisol drives visceral fat accumulation. We know that from the Cushing syndrome patients. Okay. Glucocorticoids drive that. So the question is, why are stressed people accumulating visceral fat irrespective of their sub Q fat? The answer is because the sympathetic nervous system, normally, which is lipolytic, at least acutely, becomes lipogenic chronically. And the reason is because of the CO factor that's released with the norepinephrine called neuropeptide Y. Neuropeptide Y actually changes what would be a lipolytic stimulus to a lipogenic stimulus. So chronic overstimulation of the sympathetic nervous system leads to visceral fat accumulation. And of course, chronic stress increases cortisol. The two together increase visceral fat. Well, that visceral fat will be.

This is independent, you're saying, independent of subcutaneous fat, but also the cortisol and the sympathetic piece, the norepi piece. You're Saying are both basically conspiring to be both pro. Lipogenic.

Yes, exactly.

It's funny, I knew about the. Obviously the cortisol connection, didn't realize the norepi connection.

So acutely, norepi will cause lipolysis through the beta 3 adrenergic receptor @ the level of the adipocyte, but it causes lipogenesis when neuropeptide Y is.

Available. Can neuropeptide Y be measured or is it too short lived.

To. Too short.

Lived. Can you measure urinary metabolites of.

It? Not to my.

Knowledge. You know, I wear a continuous glucose monitor and everybody says to me, you know, why the hell do you wear that thing? You're not diabetic. But I will tell you, the insights I glean from this are remarkable. And now that I wear this thing called bora ring. So this thing's measuring heart rate variability. So every morning when I wake up, to me, the most interesting thing I can look at is what was my glucose over the last eight hours and what was my heart rate and heart rate.

Variability.

Okay. And the interesting correlation I've noticed, which now maybe you've provided an explanation for, is when heart rate variability is lowest. We know that we are under.

Which heart rate variability, low frequency or high frequency? It.

Matters. I'm looking at the RMSSD of the total signal. So the way that it's quantified here is. I don't know that it's specifying it matters. Interesting. Well, let me tell you what I've.

Noticed. High frequency heart variability is vagal and low frequency is a bunch of things thrown on top of each other. Baroreceptor, respiratory rate and sympathetic. So it's the low to high ratio that gives you the sympathovagal balance because you cancel out the other things. So taking your HRV and binning them into low and high frequency matters if.

The. Do you know what the frequency cutoff.

Is?

0.3. Okay, I'll look into this. This is interesting. Just looking at it at the level that it's reported, the lower the hrv, obviously the imputed or inferred higher. Sympathetic tone. Well, generally the higher the glucose.

Level. I believe.

That. And I've always assumed it was just cortisol coming along for the ride. I never actually thought of.

It. Cortisol does go up 5, 6, 7, 8am you know, it's the diurnal variation, so maybe that's.

Adding. Well, my peak glucose was at 2am yesterday. My peak for 24 hours was at 2am Now I was sleeping in a hotel, having a shitty sleep. Who knows what I was stressed out about. I remember I had to weirdest dreams imaginable. But it's really interesting how much cortisol plays a role in.

This. I agree. Cortisol plays a major role in it. And we know this from all the data from the Whitehall study in terms of stress that workers are under, et cetera. And shift workers really have problems with cortisol. So anyway, the point is you can have visceral fat which releases cytokines and goes to the liver. So it can come from the sub Q fat, that would be obesity. And come from, from the visceral fat, that would be stress. And then there's a third way and that is making the liver sick straight away, mainlining the toxin that's called.

Sugar. And what is.

The. And that's the one I think is the biggest.

Problem. It's probably the one that's increasing the most. What is the actual mechanism by which all of those things which lead to things we know are bad? Right. The homocysteine going up, the uric acid going up, the alt going up, fat actually accumulating the.

Grossly.

Right. How does that translate to a peripheral problem that actually becomes the Runway to.

Diabetes? If you have liver dysfunction which occurs due to those cytokines from either the sub Q fat or the visceral fat, or because you have primary hepatic dysfunction as in nafld, what's going to happen is you're going to have increased hepatic glucose output because now you're insulin resistant at the level of the liver. So your liver can't inhibit the enzymes that cause gluconeogenesis. So the process of hepatic glucose output is because the insulin phosphorylates Foxo1, which is a fork head protein that normally goes into the nucleus of the liver cell and transcribes the enzymes that are involved in glycogenolysis and gluconeogenesis. That's how you raise your serum glucose when insulin is unavailable. Insulin is supposed to suppress that by phosphorylating the FOXO one. If you're insulin resistant because there's liver fat or because of the cytokines coming in now you can't phosphorylate FoxO1, you can't transduce that insulin signal. So now your hepatic glucose output goes up, which then increases your serum glucose, which then goes to your beta.

Cell. But then there's no off.

Switch. There's no off switch. Correct. And your beta cell then has to make extra insulin, and it's making it fasting. It's not just making it in response to a meal, it's making it all the time. And insulin is both good and bad. It's good when it lowers your blood sugar, it's bad when it does everything else. Insulin's job is to store energy. Okay? It is not to keep your glucose normal, it is to store energy. It keeps your glucose normal as a function of storing energy. If you're storing energy, you're going to gain weight. In addition, insulin stimulates a different pathway in cells that is the proliferation pathway. It's called MAP kinase and erk. This pathway is responsible for vascular smooth muscle proliferation, coronary artery vascular smooth muscle proliferation, thereby making your coronaries tighter and less likely to be able to vasodilate when they need to, thus increasing risk for heart attack. It also causes cell division because insulin is a mitogen, it causes cells to divide. Well, if it causes your breast cell to divide, you might end up with breast cancer. And so hyperinsulinemia is associated with all of the chronic metabolic diseases we know about because of this second phenomenon that insulin does not just lowering glucose, which it does as a sidelight of storing energy, but in fact because it causes both inflammation and cell.

Division. My hope is that as time goes on, more and more physicians will realize that hyperinsulinemia per se, independent of what's happening at of glucose. In other words, you have a patient with a quote unquote normal hemoglobin A1C, but they're hyperinsulinemic, that that is taken as seriously as we would take.

Diabetes. Absolutely. And this is one of the reasons why, if you look at all of the diabetes studies that are out there in terms of diabetes control, they all improve hemoglobin A1C and the patient dies anyway. The UK PDS, the ACCORD study and several others all show that you can lower blood glucose, you can reduce microvascular complications, diabetic retinopathy, neuropathy, nephropathy, all small vessel complications by lowering the glucose. But what you do is you exacerbate the large vessel complications like coronary heart disease, disease or cancer, and you end up dying just the same. So getting your blood glucose down is only half the job in diabetes. Getting your blood insulin down is the other half. And taking drugs that increase your insulin ain't the.

Way. Yeah, yeah, it's an awkward way.

To go about doing it is totally the object is to increase your insulin sensitivity. And the only Way to do that is by diet, not even by exercise alone. You can't outrun a bad diet. You have to fix the insulin problem, and exercise won't fix the insulin problem by.

Itself. It seems to me that a large part of this now becomes a policy issue, which I know you went back to graduate.

School. Law.

School. Yeah, about what, six years.

Ago? Five years.

Ago. Yeah, yeah. And I know that even though you've retired from your clinical practice, that's simply given you more. More time to focus on these other.

Issues. Yeah, no, in fact, it's one of the reasons I retired. I realized, oh, about seven, eight years ago that I could actually take care of a million kids easier than I could take care of one. And so I'm devoting my time now to research. We have a study now that is ultimately, if all goes well, and so far it is, we'll put the final nail in the coffin on. A calorie is not a calorie and will basically prevent the food industry from ever saying it again. That's my.

Goal. And currently the food industry says, I mean, I haven't really paid much attention to this, to be honest with you, in the last few years. But is the food industry basically still saying that while a can of Coke is not ever deemed even by Coca Cola to be as nutritious as a carrot, in the end, are they basically saying that all calories contribute equally to adiposity and insulin.

Resistance? Yes, they are all saying it's about obesity and therefore it's about energy balance, therefore it's about calories, therefore all calories are the same. That's what they say. It is absolutely not true. And we have all the reasons in the world to show why it's not true. We have empiric data, we have mechanistic data, we have plausibility data, we have hard data that show that is just not the case. And if you want, I'll give you examples of it. All right, let's start. Yeah, let's talk about fiber. You eat 160 calories in almonds. How many do you.

Absorb? Two.

Thirds? 130? Yeah. I mean, 75%. Okay, well, what happened to the other.

30? Presumably, it's going to drag some stuff out in your.

Colon. Well, no, what happens is the soluble and insoluble fiber in the almonds forms a gel on the inside of the intestine. You can actually see it on electron microscopy. A whitish gel that's going to act as a secondary barrier preventing absorption of some of those almond calories early on. Well, if they don't get absorbed in the duodenum, where do they go.

Next? Jejunium.

Jejunum. Jejunum. Well, what's in the jejunum that's not in the duodenum? The.

Microbiome.

Yeah. The duodenum is essentially sterile. It's got a PH of one. Only H. Pylori can live there. You have to get the.

Bicarbonate. So you're saying that that lining is formed in the.

Duodenum? Duodenum, yeah, exactly. To prevent your liver from getting the whole dose. Because anything that's absorbed in the duodenum goes straight to the.

Liver. So how much fiber is in an.

Apple? A lot. I mean, I can't give you.

But I'm just directionally, I'm making this number up. But let's say there's how many grams of fructose in an apple?

20. There's 30 calories in a standard apple, half of which would be fructose of.

15. That seems low. An apple, like a super fast.

Food chain, not a big mother apple, but like an apple. Apple.

But. So based on that, you're saying only half the fructose that you would eat in a piece of fruit might actually get to the.

Liver? Yeah, or less. Most of it's going to end up in the jejunum. And once it goes to the jejunum, it's a free for all. Do you absorb it or do the bacteria digest it and metabolize it for their own use? Remember, you have 10 trillion cells in your body, but you have 100 trillion bacteria in your intestine. Every one of us is just a big bag of bacteria with legs. Those bacteria have to survive if.

The fructose gets absorbed at the level of the junum. In other words, if the gut out competes the bacteria, can it still get back to the.

Liver? Oh, yeah, yeah. But the area under those curves will be wider, which means the insulin response will be lower, which is what you want because it took longer. But a lot of it won't get absorbed, it'll be digested. Doesn't come out in the stool. It gets digested by the gut bacteria who use it for their own purposes. Now here's the thing that I only learned about a month and a half ago, which is absolutely essential. If you don't consume fiber, that means that your gut bacteria are not getting the food they need because you're absorbing it all early. Well, they still have to survive. So what do they do? They proteolyze and lipolyze the mucin.

Layer. So.

Autodigest. They auto digest the mucin layer that sits on the surface of your intestinal epithelial cells, protecting them. And you can actually see on electron microscopy an increased opposition of the bacteria with the intestinal epithelial cell, which likely causes damage, possibly leaky gut and possibly GI disease like colitis and even maybe Crohn's. So the idea is to feed your bacteria or your bacteria will digest.

You. And what sources of fiber do you think? I mean, people talk about using psyllium husk and all these other things to sort of augment fiber. Do you think that's necessary or do you think you can get enough of it just.

From. Well, so psyllium is soluble fiber. It's not insoluble fiber. You need both. Fiber has soluble inside. Soluble like pectins, like what holds jelly together. Insoluble fiber like cellulose, you know, stringy stuff in celery. You need both to make that gel. So the insoluble fiber forms the lattice. Work like the net. Let's say you put a layer of petroleum jelly on a strainer, you would have an impenetrable water barrier.

Right? Yeah. So the insoluble is like the strainer, and the soluble becomes the thing that fills in the.

Lattice. That's right, exactly. So when you have both, it works. And there's data that shows that if you have either one or the other doesn't work. You need both. Well, you get both in real food. And this is why the food industry keeps adding soluble fiber like psyllium husk to food. Like fiber one bars doesn't make a damn bit of difference. They have insoluble fiber in things like certain breakfast cereals. But if you don't have the soluble fiber, also doesn't work. You need both. Real food has.

Both. The point is, so the fiber fortified stuff is the easy way to do it, is to add soluble fiber that doesn't.

Work. Okay. And that's what the food industry keeps doing and keeps telling us that it's good because it's got extra fiber. Wrong. Doesn't have functional fiber. Doesn't have the fiber that does what you want it to do. That's the reason a calorie is not a calorie all by.

Itself. I know that you've got to go soon, otherwise we could do this for another two hours. But I do want to ask you one sort of final question or final thought on something which is, I looked into this a few years ago. And maybe the numbers have changed, but directionally I think this is still correct. There were something like nine companies that controlled basically all of CPG consumer packaged.

Goods. 10. There's 10. 10. Okay, 10 control 90% of the.

Food. Yeah, that's basically my calculation was 10 of them controlled 85 of the calories that people consume. You face a very uphill battle because you're trying to get them to change the way they do business. But they answer to shareholders, not to you. And the way they're doing things right now is working out reasonably for their shareholders. Not great. These aren't the most high performing companies in the world, but how in the world when such a small group of companies control so much? And going back to what you said earlier, you're asking parents to double their food budget to feed their kids correctly and spend twice the time doing it. What does this look like in 10 years? How does the story.

End? Well, I don't know how it ends. This is a battle royal, like tobacco was. And it took a long time to win that. And there are people who say we haven't even won that one yet. You know, e cigarettes. Now come. We have another proposition here in San Francisco tomorrow about tobacco to kids. Here's the deal. The food system needs to change. They're not going to change it from the inside because right now, sugar is their business model. It's the thing that increases their sales. When high fructose corn syrup and the dietary guidelines of 1977 were first available, the profit margin of the food industry went from 1% per year to 5% per year. This is their juggernaut. This is their gravy train. They add more sugar, they sell more food, and they know it. And that's why there's sugar in all the food. Because when they add it, you buy more. For all the reasons we've discussed, they have to change the food, which means they have to change the business model. So how do you change the business model? Well, there are four potential ways to change the business model. One is educate the public so that they don't want that food, in which case then they won't sell it. We're trying to do that. That's one reason I am the chief science officer of a nonprofit trying to do just that called Eat Real. Real is an acronym responsible epicurean and agricultural leadership. We are trying to change the food system by praising the good and hoping that that will induce competition amongst restaurants, cafeterias, hospitals, schools to procure, market and sell real food. Or you can have Executive branch efforts like the FDA or the usda, but not in this administration. If anything, they've rolled back opportunities for that, like the nutrition facts label, or you can have Congress legislate specific changes. They're not doing that because they're all paid off from the American Legislative Exchange Council and other concerns like the Koch brothers, what have you. Or you can have judicial impact. And so there are lawsuits against the food industry going on as we speak in an attempt to try to, shall we say, regulate from the bench, which no one thinks is optimal, but seems to be the only thing that's available at the moment, aside from education. So those are the four ways to do this. My goal would be to get rid of food.

Subsidies. Are the food subsidies what, enable the junk food to be basically half the price of real food? Or is it that the real food is twice as much to make, not independent of the.

Subsidy. It's about the subsidy making junk food cheap. If you got rid of the subsidies, then the market would work. Okay, Right now, any subsidy distorts the market, and there's no reason for food subsidies. In fact, there's no economists worth their salt today that believe in food subsidies because they distort the market. So the question is, would food get more expensive if we got rid of all food subsidies? The Giannini foundation at UC Berkeley engaged in this exercise several years ago, and they computed what would happen to the price of food. And it turned out that the price of food wouldn't change except for two items. Corn and sugar would go.

Up. But how would that not impact the cost of all other foods, given how ubiquitous they.

Are? It's a complex modeling, and I'm not an expert in how they arrived at this, but empirically, this is what fell out of it, is that the price of wheat wouldn't change, the price of soy wouldn't change, only corn and sugar. And that is where the dietary sugar in our food comes from. So I think that that would be a really smart way to start. You know, the farm bill is, you know, reapportioned every five years. And right now there's actually tension around that farm bill. It has to do with other things. But I would like to see the issue of the metabolic cost of food built into the farm bill, because right now, our government has not linked or yoked the productivity and economic costs of Medicare, Medicaid, Social Security with food. I would like to see that link strengthened, because we have the.

Data. Is.

There. They.

Do. Is there anything right now that you consider a victory? Because when you look at the smoking story. You had Surgeon General's report. You had changes in advertising. Next you had excise taxes and then ultimately environmental.

Changes. We have excise taxes for.

Soda. Do you have any advertising rule changes.

Yet? Well, here in San Francisco we have a warning label on billboards that is right now there's a temporary injunction about because the food.

Industry. But the smoking one was interesting. I didn't know this until a few years ago, but basically a law came out that said anytime a tobacco commercial was on TV it had to be followed by an anti tobacco.

Commercial. It turned out the Fairness.

Doctrine. Yeah, it turned out the anti tobacco commercials were so popular and so effective that tobacco voluntarily withdrew from.

Television.

Indeed. Is there anything around creating that type of.

Awareness? No, what there is is the question of marketing to children. And the thing is that many of the conglomerates have said they voluntarily will not market to children, at least during certain times of the day when kids are more likely to watch. But in fact, watchdogs have been looking at this and they say that it's lip service, that they're not actually doing it. So you cannot expect the food industry to police.

Itself. I hate to end on this note. I know you have to go. I want to respect your time. I hope we can come back and do this again and talk in more.

Detail. Peter okay. There are a few people that I don't just make myself available for, but that I want to see and you are on that.

List. That means a lot. Thank you.

Rob. My.

Pleasure. You can find all of this information and more@peterattiamd.com podcast. There you'll find the show notes, readings and links links related to this episode. You can also find my blog and the Nerd safari@peterattiamd.com what's a nerd Safari, you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non lame once a week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, etc. On social you can find me on Twitter, Instagram and Facebook, all with the id PeterAttiyamd. But usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional healthcare services, including the giving of medical advice. And note no doctor, patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have, and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and or advise, please please visit peteratiamd. Com.