The Peter Attia Drive - Rick Johnson, M.D.: Metabolic Effects of Fructose (Ep. #87 Rebroadcast)

Episode Date: November 22, 2021

Today’s episode of The Drive is a rebroadcast of the conversation with Rick Johnson (originally released January 6th, 2020). This episode was one of the most popular discussions to-date and is a prelude to an upcoming follow-up discussion which will be coming out in February 2022 along with the release of Rick’s new book. In this episode, Rick Johnson, professor of nephrology at the University of Colorado, explains how his research into the causes of blood pressure resulted in a change of research direction to focus more on how fructose has such profound metabolic effects. Rick begins by talking about the relationship between salt and high blood pressure, then provides a masterclass into uric acid, and then expertly reveals the mechanisms and pathways by which sugar (specifically fructose) can profoundly impact metabolic health. From there, he explains how he applies this information to real life patients as well as touches on some of the most promising ideas around pharmacotherapy that are being developed in response to the epidemics of fatty liver, insulin resistance, diabetes, and obesity. Furthermore, Rick gives his take on artificial sweeteners compared to real sugar, discusses cancer’s affinity for fructose, and much more. We discuss: The connection between blood pressure and fructose that shifted Rick’s professional focus [3:00]; The relationship between salt and blood pressure (and the role of sugar) [4:45]; Defining fructose, glucose, and sugar [18:30]; An ancient mutation in apes that explains why humans turn fructose into fat so easily [22:00]; The problems with elevated uric acid levels, and what it tells us about how sugar causes disease [30:30]; How sugar causes obesity—explaining the difference in glucose vs. fructose metabolism and the critical pathway induced by fructose [39:00]; Why drinking sugar is worse than eating it [49:00]; Unique ability of sugar to drive oxidative stress to the mitochondria, insulin resistance, and diabetes [53:00]; Why cancer loves fructose [59:20]; The many areas of the body that can use fructose [1:04:00]; Fructokinase inhibitors—a potential blockbuster? [1:06:15]; Treating high uric acid levels—Rick’s approach with patients [1:09:00]; Salt intake—what advice does Rick give his patients? [1:15:30]; How excess glucose (i.e., high carb diets) can cause problems even in the absence of fructose [1:20:00]; Artificial sweeteners vs. real sugar—which is better? [1:28:15]; Umami, MSG, alcohol, beer—do these have a role in metabolic illness? [1:32:45]; Fructose consumption—Is any amount acceptable? Is fruit okay? Where does Rick draw a hard line? [1:37:45] How does Rick manage the sugar intake of his young kids? [1:42:00]; and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/rickjohnson/  Subscribe to receive exclusive subscriber-only content:  https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, I'll focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of the space to the next level. At the end of this episode, I'll explain

what those benefits are, or if you want to learn more now, head over to peteratia MD dot com forward slash subscribe. Now without further delay, here's today's episode. Welcome to a special episode of The Drive for this week's episode, we are going to re-broadcast one of our most popular episodes, which is my conversation with Rick Johnson, which was recorded in the fall of 2019 and released in January 2020. As Rick has a new book coming out in February, I'm going to sit down again with Rick for around two of this podcast shortly. And because of this, we want to ensure that everyone is aware of our original discussion. Additionally, if there are any follow-up questions or topics that you think Rick and I should

discuss, we'd love to hear those as well going into this. You can help make my prep easier by giving me some questions to ask. As a reminder, Rick is a professor of medicine and nephrology in the renal medicine disease hypertension division at the University of Colorado. He attended medical school at the University of Minnesota and did his internship and fellowship at the University of Washington in this episode. We talk about all things fructose. We talk about how it relates to high blood pressure insulin resistant type two diabetes

and obesity. We also talk about why drinking sugar is worse than eating it. Why cancer? Loves fructose. We talk about uric acid, salt artificial sweeteners, and more. So without further delay, please enjoy or re-enjoy my conversation with Rick Johnson prior to round two. Rick, thanks so much for opening up your office today in making time. It's great.

I'm very happy to have you here. I've wanted to sit down with you for about a year in this format because I guess we've probably known each other for maybe about six years now and every discussion has been one of those discussions where at the end of the discussion I think, man, how am I ever going to remember all of this stuff and how will I be able to sort of synthesize this to translate it into sort of what I'm doing and I've said this sort of many times before. But that is the whole kind of reason that I started a podcast was I just found myself every week having a discussion with someone, usually scientists, where I thought this

something's got to be shared. So you would certainly be one of the three or four people in indirectly that was a real catalyst for the podcast because of the frequency with which we would either have these dinner discussions or discussions over the phone. And so anyway for that, I want to thank you. And hopefully the listeners do as well. But in the introduction, I've set this up a little bit as to why this is such an important discussion. And because there's so much to talk about, I just kind of want to jump right into the meat of things. It would be not an exaggeration to say you were one of the world's experts on fructose. And I guess I would just start with the why.

Where did that interest come from? You've obviously been doing this for a long time and that passion has been sustained. So what brought you to this point? Well, I'm a kidney doctor. So normally we wouldn't be studying sugar. So it was kind of a secuitous way that I got there. I was very interested in the cause of high blood pressure, and it'd been known for a long

time that high blood pressure is linked with kidney. And in fact, the going theory for years was that the kidney in high blood pressure has a defect in its ability to excrete salt and so that you end up retaining salt in that leads to an elevated blood pressure. And when we were studying, trying to understand how the kidney handles salt in high blood pressure and so forth, we were trying to understand potential pathways. And we stumbled on the fact that hyper-uricemia or elevated uric acid could be a very significant risk factor for high blood pressure. And when we started studying

uric acid, we realized that when you raised uric acid and animals, they developed high blood pressure. From there, we started to try to understand what made the uric acid go up, and we knew from the literature that sugar and particularly fructose raised uric acid go up. And we knew from the literature that sugar and particularly fructose raised uric acid. So we started studying fructose. And pretty soon we were so excited about what we were finding that we just kind of changed our research direction to focus more on how fructose has all of its metabolic effects.

Well, there's a lot to unpack there. So let me kind of go back to bits of it. You sort of gloss over the fact that the conventional approach to high blood pressure is that sodium is the culprit. And isn't it still safe to say that most advice around reducing blood pressure comes down to reducing sodium intake? Well, we've actually been studying this pretty extensively.

There's a lot of pearls I can teach you, or I can talk about, related to salt. And when I was in training, I was taught that you restrict a certain amount of salt. You should be on a low salt diet as a mechanism to prevent high blood pressure. It was always about the amount of salt. In fact, we were teaching that for a long time that if you want to have a low blood pressure, you should restrict your salt intake. Or if you want to try to treat your high blood pressure,

you should restrict your salt intake. What's happened in the last couple of decades has been the increasing knowledge that it isn't really the salt amount that makes a difference, but the salt concentration. So when you eat salt, like if you eat a salty soup, the salt concentration goes up in your blood first, and it translates into a thing called osmolality.

And so your serm osmolality goes up. So osmolality is sort of like the ionic pressure build up in a fluid is that I waited? It's sort of like the number of molecules in a set of volume. So literally when you eat salt, if it's really salty, let's say you have a serum sodium concentration of 140 millimoles per liter. If you eat a really salty soup, your serum sodium may go up to 142 or 143. What looks like pretty insignificant? But that actually is what triggers a rise in blood pressure. And so we've actually done the study where we took people and gave them soup with or without salt.

And when they drink the salty soup, their serum sodium goes up and their blood pressure shoots up. How much would a person's blood pressure go up if their sodium went from 140 to 142? It's about 6 millimeters. Okay, so they'd go from 120 to 126. Yeah, and that happens acutely. And how long does it take to resolve? Maybe a couple of hours.

So if we give, and we did this study, we published it last year, if you give salty soup with water so that the serum sodium doesn't go up, they got the same amount of salt, guess what? The blood pressure doesn't go up. And the serum sodium, so not go up or does go up. Right, does not go up. So if you black the serum sodium from going up. So basically the closer you can bring

the total accumulated concentration of what you ingest down the more likely you are to prevent this transient rise in serimus malality and blood pressure. Yeah, well it turns out that serimus malality has a real major role not only in blood pressure but also in obesity and we're going to talk about that in a second but when you take a high salt diet and your serum sodium goes up, it triggers a rise in blood pressure, and it's working through the brain, and actually through the liver and other sites too. Pause for a moment.

Tell the listeners why it would be better to have a blood pressure of 120 over 80, than 140 over 100. Well, there's a pretty good epidemiologic data that shows that when your blood pressure is high, that you have an increased risk for heart failure and stroke. Those are the two major ones, but it also increases the risk for heart attacks and heart disease in general. Interestingly, there's a very significant inflection point. And what I mean by that is when the blood pressure gets around 160 to 180,

right in that range, the risk for stroke goes significantly up and the risk for mortality goes up. And that's because our body tries to auto-regulate to blood pressure. So when the blood pressure goes up, for example, the kidney, the arterials will constrict to reduce the pressure load to the kidney. But when it gets to about 170, it will overcome that restriction and the blood pressure will injure the kidney. Likewise, the brain kind of responds to flow more. So it tries to maintain blood flow. But if the pressure gets high, it tries to protect itself from the high pressure

by constricting. But when the pressure is like 170, the risk it can't constrict enough, and you don't want it to constrict that much because it has to maintain flow. And so the pressure ends up increases to the brain and increases the risk for stroke. Now, current guidelines seem even more aggressive. We would manage class one hypertension. We would consider something in the mid-130s to be treatable. Yeah. So, let me get there.

So originally, when the studies came out, it was very, very clear that if your blood pressure was like 170 or higher, that you had a dramatic increase risk for stroke, and that's because it would pass the audit regulatory point. But then what happened was epidemiologic studies show that even a blood pressure of like 140 over 90 conferred increased risk. It's just it was much less than the 170. So at 170, it just takes off.

It's almost the line goes up vertically. But between 140 and 160, there is still a stepwise increased risk, but it's just a kind of a more gradual risk. In fact, for things like a stroke, you can start showing an increased risk from 120 over 80 to 140 over 90, leading people to view 120 over 80

as kind of the optimal blood pressure. As you get older, if the blood pressure is really low, you lose your auto regulation for low blood pressure, and so it increases the risk for kidney disease and problems as well. So you don't want to be extreme on either end, especially as you get older. This whole thing is kind of such a, it's a real clinical mystery in some ways still because in medical school, we learn about this term called essential hypertension, which is kind of a waste basket term for hypertension or high blood pressure for which we don't have an obvious cause. The problem is, and so having sort of that waste basket term would be okay if it accounted

for the minority of cases, but then you get to the clinic and you realize everybody walk in and around with high blood pressure basically is getting labeled as having, quote unquote, essential hypertension. So it really is this epidemic without a clear description. Now we're going to come to a lot of reasons that I mean, I think you have arguably one of the most compelling cases for what is at the root of essential hypertension. But for people listening to this, for doctors listening to this who treat hypertension, I feel like we just haven't made much progress

in the 20 years since I've been out of medical school. There have been some real breakthroughs in the understanding of primary hypertension just in the last five, 10 years. And there's two major aspects I can talk about. The first one is that it does appear that salt really is important. And one of the key discoveries was that the kidneys are often normally handle salt fine.

But they develop or acquire a change in the kidneys that lead them to hold on to sodium. And the mechanism has been identified just in the last few years. It's due to the fact that there's an inflammatory inflammation that occurs in the kidney. And that inflammation, which is driven by T cells and macrophages, causes a constriction of the blood vessels that leads to low-grade ischemia in the kidney. And that ischemia can translate into increased sodium absorption, which then leads to high serum sodium and the effects. Is there a correlation between serum, sodium, and blood pressure across normal physiologic ranges of, say, 135 to 145 millequivalence per liter? Yeah, I believe so. I'm not sure I can quote the paper, but yes, I think that's true.

So what you're saying is, in people with high blood pressure that's otherwise viewed as quote unquote essential, there's an inflammatory response mediated by both T cells and macrophages that injures the kidney, schemically, meaning it for the listener that results in reduced blood flow and tissue damage due to reduced blood flow and reduced oxygen. And it's that injury that then leads to a barren retention of sodium. So there's actually been really a lot of studies looking at the mechanism of the inflammation. And originally it looked like it was people thought it might be a reactive response of the kidney. So we think that there may be external stimuli that initially cause a decrease in blood flow to the kidney like a sympathetic nervous system response.

You can do it transently by giving medicines or drugs that can cause a constriction of blood vessels. When you do that, you get a transient reduction blood flow to the kidney. That induces an inflammatory response that then causes persistent reduction in blood flow. And what we've learned in the last few years, and I'm an author in one of these studies, is that this inflammatory reaction can actually be an autoimmune reaction. And we've even identified certain proteins that there's an autoimmune response to, and one is a heat shock protein.

And you can actually create high blood pressure in animals by inducing an immune response to this. And you can block the immune response and block the high blood pressure. And now there's even data showing that in humans that there's evidence for an autoimmune response to heat shock proteins in people with essential hypertension. Which is not to say heat shock proteins are necessarily bad

because so many of the benefits we get out of sauna or exercise may be transmitted through these, but you're saying in a subset of people where the heat shock protein itself becomes the nitase for inflammation via an autoimmune mechanism. Yeah, so heat shock proteins are great, just as you say. They do all these really good things. But what happens is they're involved in the clearance of misfolded proteins and they're

helping keep a clean system. But what happens is when you trigger injury to the kidney, for example, these heat shock proteins get produced to help fix problems, but the immune system can sometimes get confused and make an immune response that actually is against the heat shock proteins. And when that happens, you can develop high blood pressure in the animal and there's some evidence for it in humans. So anyway, so that's one of the big breakthroughs has been the discovery that inflammation in the kidney can be a mechanism for triggering persistent elevations and blood pressure and probably has a big role in the cause of primary high

pretension. Before you go on Rick, how prevalent do you think that particular mechanism is that you just elucidated? It's very major. In fact, we've even looked at genetic polymorphisms that link with the development of primary hypertension, and most of them are involved with the immune response, and it looks like this is a major pathway. This creates a bit of a

quandary for someone who's trying to rid themselves of hypertension, because wouldn't the implication of this be that exercise or things like exercise that induce heat shock proteins may paradoxically increase their hypertension? I don't think so. So hypertension is kind of a complicated pathway. So there's several different aspects, but exercise is extremely good for improving mitochondrial function, improving the ability for your blood vessels to dilate, it improves kidney function, the benefits of exercise are so much greater. And releasing heat shock proteins, that really occurs with very, I don't know if just general exercise would have

a big effect on heat shock proteins. Yes, you're saying basically the net effective exercise is still going to far outweigh. Yes, absolutely. But I'd like to get back to this the link between salt and sugar if I could. Okay, because there is this data as I say that salt when it increases the serum sodium is what drives the acute blood pressure response. And when the kidneys have trouble getting rid of salt, it's easier to get that effect with a salt load. But even with a normal

person, you can with normal blood pressure, you can raise their blood pressure transiently by giving them salt and you can block it by giving water. Interestingly, in the process of developing high blood pressure, there's the initiators and then there's the things that make it persistent. And the inflammation in the kidney is involved in the persistence, but what it is involved in the initiation turns out that sugar has a major role. And what we discovered is that when you give a high salt diet

to animals, that the high salt increases the serum sodium and the serum sodium when it goes up. It activates an enzyme that converts glucose, which is in our blood and in our tissues, to fructose. And that conversion to fructose is driven by a high salt diet. And it's driven is driven by a high salt diet, and it's driven by an increase in serum osmolality or increase in serum sodium. Once the fructose is made in the body, so this is not fructose coming from the diet, this is made in the body, the fructose gets metabolized and raises blood pressure. And when we gave high salt to animals, they developed an increase in blood pressure, And when we gave high salt to animals, they developed an increase in blood pressure,

and they also were making fructose. And when we blocked the metabolism of fructose, we actually blocked the rise in blood pressure, as well as the hypertrophy of the heart. So let's pause for a moment. I've had Rob Lustig on the podcast before. So anyone who's listened to that will be familiar with what fructose is, what glucose is, what sugar is, all of these things.

But can we spend one minute just defining these things for people who haven't listened to that podcast? Sure. So, there's different types of sugar. And the main one that we call blood sugar is glucose. And this is the primary sugar that our body uses to make energy. It's the main sugar that's used to make energy and it can be stored in the tissues as glycogen and when it's too high we call it diabetes, when the blood glucose is too low it's hypoglycemia

and so glucose is like the principal energy fuel, the carbohydrate fuel that we use. And as you said, we store lots of it in our muscles. Once it gets in the muscles, it can't get out. And we store maybe a quarter to a third of it in our liver. And that's mostly there to buffer the blood supply in particular the brain. What does glucose taste like? A pure drink of glucose. People like it, animals like it, but it isn't as sweet as classic sugar. But it is often very much like by animals, humans like it, you can buy these dextrose pops and stuff like that. Dextrose is another word for glucose. And also the kidneys store glycogen and produce glucose too.

The second type of sugar is fructose. And the best way to think of fructose is it is a fuel, first off it's present in fruit, but it turns out to be the sugar that is involved in energy storage rather than energy production. And so when you eat glucose, you use that to produce energy, but when you eat fructose, it will actually trigger changes in the body that will favor the storage of energy. And this is the sugar that animals use to store energy. So, and you store it in the way of fat, in the way of glycogen,

and all those kinds of anything that will facilitate storing energy is done by fructose. And fructose and glucose, if you were looking at pictures of them in a biochemistry book, look pretty similar. They're both ringed carbon structures. They both have six carbons. One of them has a five ring versus a six ring. But you know, it's sort of interesting to think that molecules that look almost identical

with the exception of a couple of bonds different can have quite different properties. Now, fructose tastes a lot sweeter as well. Yes, and so fructose is like in honey and in fruits, and then that's right. So it tastes a lot sweeter. And the other thing is if you mix the fructose and glucose together, you can get what's called high fructose corn syrup. And if they're bound together, you get table sugar. So table sugar or sucrose is one molecule of glucose and fructose bound together.

And that occurs in nature, in sugar cane, and beets, and things like that. Yes, maple syrup, and things like that. Right. So just to clarify for everybody, when we get a little comfortable with this terminology, throw the word sugar around quite liberally, but it's always important for people to think when we talk about sugar, we could be talking about blood sugar, glucose,

we could be talking about fructose by itself. Oftentimes when we talk about sugar in diets, we're talking about added sugars, such as the sucrose and hyphructose corn syrup you just alluded to. I want to go back to what you just said about the ability of fructose to store something, but if you don't mind, can we do it through the lens of a beautiful story that you've written about in the past about a mutation that basically allowed that to happen? This thing that took place about 12 to 15 million years ago. Sure. So fruit dose, again, is it's in fruit. And many, many animals use fruit

dose as a means, is their primary nutrient or, and also as a way to help store fat. And, for example, animals before they hibernate, often eat a lot of ripe fruit and the ripe fruit gives them the sugar that allows them to store fat. And orangutans will eat huge amounts of fruit at one setting to try to increase their body fat. And we don't get fat from eating fruit, but that's because we eat tart fruit that has less sugar content. And we tend to only eat a few fruit,

whereas if we actually drink fruit juice, that large amounts of fruit juice can actually increase fat. So anyway, so fruit is a nutrient that is used by animals to help store fat. So if you go back about 20 million years ago, the very first fossil apes show up in the world and they show up in West Africa. And the original one was called Pro-Consul. They were living about 22 million years ago and they were, these apes were a big breakthrough in evolution because the prior, the monkeys

were had already been around but these were bigger creatures, the apes where they had bigger brain size, they were talous, but they did live in the trees and they lived in tropical rainforests and woodland rainforests. And they would eat primarily fruit, and they were quite successful, and by about 18 million years ago, there were almost at least 10 to 20 species of ape that were living in this area of Africa. There was a change in climate. There was some global cooling and the Antarctic started building up ice and the Arctic started

building up ice and sea levels fell. And when the sea levels fell, land bridges developed that connected Africa, which had been separated from the other continents, these land bridges opened up so that there was now a way to get out of Africa into Europe and Asia. And many, many species migrated across those land bridges about 17 million years ago. And some of them were the apes. And we see the first apes fossils in places like Paselar Turkey and different places of Europe right around 16 million years ago. At that time, there were still a forest that were fruiting trees, woodlands that was fruit all year round.

And so the animals, when they moved into Europe, they didn't have to change their habits at all. They were able to continue to eat fruit pretty much all year round. But unfortunately, they continued to get cooler. And by 12 million years ago, the apes started to starve in Europe. And you can tell that from the fossils because they actually have these, like tree rings on their teeth,

the developing teeth get this enamel. The enamel doesn't lay down correctly and they get these like tree rings that show intermittent starvation. They would get a ring every time they would go through a period and the starvation was seasonal. So it was during the cooler months

when suddenly the fruit was not available. And the primary reason was there was a loss of the fig tree. And the fig is a cool fruit that can fruit all year round because the wasp that fertilizes the fruit does so at its own discretion. So the fruit will of a fig tree kind of can occur all year round. So when the fig tree died, suddenly there weren't too many, because of the global cooling, or perhaps it was the wasp, but the fig trees disappeared. And suddenly these apes did not have enough food to survive during the cooler months and they started to starve. And by six to eight million years ago

the last ape became extinct in Europe. But Africa, although there was global cooling there too, it wasn't as cold and the fruit trees survived all year round, the forest just retracted. So the apes there were able to maintain their normal habits. Well, there was a lot of evidence that there was a lot of evolutionary change occurring in our ancestors during this maya-sean period, and this period of time when there was the global cooling. And one of them was a mutation in uric acid metabolism. And as I mentioned, sugar, and particularly fructose, when its metabolized, generates uric acid glucose when it's metabolized is not,

but fruit dose when it's metabolized makes uric acid. And this mutation led to a much stronger uric acid response to fruit because this mutation was an enzyme that degrades the uric acid. And when you block that and you eat fruit, your uric acid levels go up much more. And this mutation basically allowed these apes to maintain a very prominent uric acid response. Our group has shown that the way fruit dose stimulates fat, as well as its other properties like insulin resistance and raising blood pressure, that those abilities are driven in part by the uric acid. So when this mutation occurred for the same amount of fruit, they were able to store more

fat. And so it was like a survival mechanism for this mutation when it showed up. It allowed apes that had very little access to fruit to suddenly maintain more fat stores and so they could live longer and survive those winners. And we were able to show with Peter Andrews at the Natural History Museum in London who studies these apes that this might account for a very interesting finding. And the finding is that although we thought the apes became extinct in Europe, and they certainly did become extinct in Europe, the fossil record shows that it was a European

ape that made it back to Africa and also to Asia to become our ancestors as well as the ancestors of the great apes that live in Africa and in Southeast Asia like the orangutan, that they all came from a common ancestor that was in Europe and that went back to Africa. And we know from the genetics that that ape carried the Yira case mutation. And so this mutation probably occurred at a critical time that provided survival for those apes in Europe to be able to get out of there and make it back to these other regions, but it was now equipped with this mutation that made it sensitive to sugar. And so humans are much more sensitive to sugar than most animals,

and it's because of this mutation. And in fact, we actually resurrected the extinct uricase and proved this using the extinct uricase that showing that when you put it into human cells, that it suddenly made us less sensitive to fructose. So the phenotype there, I mean, I guess just to recap that story,

which I find so fascinating, by the way. You guys wrote a story about this in Scientific American many years ago, right? I know there was a paper that came out as well, but I mean, the sort of the lay person version in Siam was really great. So basically, these apes go from Africa up to Europe, it gets too cold. We sort of think they die out, but the evidence emerges actually a subsub subset of them developed a mutation in Eurocase that gave them a a superpower which was now they could be much more efficient

at turning fructose into fat. They had this little byproduct which is they would also make a boatload of uric acid along the way, but they actually came back to Africa and ultimately seeded the rest of the species and ultimately that's why we as humans are among the very rare animals that have uric acid levels that are quite high relative to cats and dogs, for example. Yes, that's exactly correct. So when we were in medical school, Rick, we learned a lot about uric acid through the lens of a disease called gout. And it didn't get a lot of airtime in school, maybe it gets more today, but at the time it was basically, gout is a disease of civilization.

It's from eating too much meat, and there's no real problem with it, except for the nuisance of your toe hurts, because uric acid crystallizes, it gets inside joints. It seems to favor the first joint of the great toe, and it's a very painful inflammatory condition, and it's what happened to the wealthy people of the last few hundred years as they started

getting and acquiring too much meat and protein. That was sort of the story. What you're describing is a little bit more nuanced. Tell us more about uric acid. The big problem with having too much uric acid is gout, just as you say. All the animals that have the uricase mutation are prone to gout, but humans in particular are very prone to gout. And it's because of our diet. So we do eat diets

that are high in meat and purines that increase our risk for gout. You need to tell folks what purines are specifically since it always shows up in this terminology. Sure. So we have proteins, we have fat, we have carbohydrates, we also have things like RNA and DNA and what we call nucleic acids. So these are the kind of acids that are in the nucleus and that are also in the cell that help drive gene formation and protein, you know, our genetic material and also help dictate the production of proteins. And so DNA and RNA are made up of nucleic acids, and when they're broken down, they're made up of purines. And then uric acid is appearing in it. Basically, the ultimate breakdown product of DNA and RNA.

So the reason protein consumption versus fat or carbohydrate would lead to this is because if you're eating protein, you're eating the DNA and RNA that presumably were still in that tissue. Yes. So the way you get out from protein is from the DNA and RNA and the protein. And so that relates to some extent to how dense the nuclei are. And so like if you have a very cellular thing like anchovies and these small fish that have lots of DNA and RNA, if you have that, they will develop.

You can get gout from that much easier than from other types of meat. And so beer, for example, has brewed yeast, and that is filled with RNA. And so that's why beer can precipitate gout. Now, I follow uric acid levels very closely in all of my patients and myself. And there is an unmistakable difference

between men and women, at least in my small sample size of patients, where men on average have higher uric acid levels than women. Is that true across the general population? Yes, even in boys, they'll start to have a higher uric acid than girls. However, after the men oppose, uric acid levels go up in women. And that's because estrogen helps excrete uric acid. So it's not, I had sort of, I guess, incorrectly assumed it was just unbalanced men consumed more protein than women. I think that also plays a role. I think that's right.

But it sounds like this estrogen explanation makes more sense if it can also explain the observation of menopause. Yes. Going back, God is also increased by sugar. And even Sir William Osler, the famous physician from the 1890s, and his book, Principles and Practice of Medicine, pointed out way back in the 1890s that sugar was a major risk factor for God, as well as very sweet fruits, he wrote. Anyone who's had gout usually will know that real significant sweets can also precipitate gout. And the reason is because of the fructose content, and when the fructose is metabolized, it generates uric acid. When people were developing gout in the 1800s. It was linked to the wealthier groups in England, for example.

They were eating a lot of, as you say, rich foods that included proteins and so forth. But one of the things they were eating a lot of, they were drinking a lot of alcohol, to which they added sugar. I actually did write a paper where we reviewed how much sugar was put in drinks, alcohol drinks back in the 17, 1800s, and it was much more than today. They loved sugar.

They put it in many of their drinks, and in fact, I even have a picture of an old pub outside the Tower of London called the Sugar Loaf. They talked about the old drinks that were served like hypocritesris and some of these drinks and sack and sugar was a name for a drink that they had. I mean, they added a lot of sugar to their drinks. And so part of the rise and gout back in the 1800s and 1700s, and 1600s relates to not only just the alcohol and the rich foods, but also to the sugar they were adding. So you were sort of the person who brought onto my radar that there are other things besides

gout that one needs to be concerned about when it comes to uric acid, and one of them is blood pressure. So how did that understand income about? So originally we were studying what causes high blood pressure, and there was a lot of epidemiologic studies that linked uric acid with high blood pressure. And as I mentioned, we also knew that there was subtle changes going on in the kidney associate with high blood pressure, and people would go out often have low grade kidney disease. So I said, aha, maybe uric acid could have a role in causing kidney disease through causing high blood pressure

through its ability to cause kidney disease. And so we took animals and we gave it this uric case inhibitor to raise the uric acid of an animal. And by gosh, they developed high blood pressure. And then we could lower the blood pressure by lowering the uric acid. And when we looked, we were thinking it might be like crystals of uric acid in the kidney, but- Well, that was my thought, is the crystals would cause the inflammation in the kidney,

and that would- That was my thought, too. And it turned out not to be good. We looked at the kidney, there weren't any crystals there. So then we realized it was an effective soluble uric acid. So we started putting soluble uric acid on cells and so forth. And we saw that it had all these biological effects. And we always had thought uric acid was kind of like a dead end product of something, or

even might be a good thing because some people said it was an antioxidant, but it was causing pro-inflammatory effects. So then we said, aha, fructose, sugar, raises uric acid, maybe sugar could have a role in blood pressure. What year is it that you're having that thought, Rick? 2002, we gave some animals fructose and they developed high blood pressure

and we gave them alopeurinol, which is a drug to lower uric acid and it made their blood pressure go back to normal. And it was like this big discovery. But what was totally exciting was, these animals also developed insulin resistance. They also developed elevated triglycerides in their blood. They had other fatty liver. And when we lowered the uric acid,

we showed benefits on all of those parameters. How does alapurinol work? What's the mechanism by which it lowers uric acid? It blocks uric acid formation. So uric acid is generated from other purines. And when we block that, we blocked a lot of the effects of sugar to cause metabolic syndrome. And so when we first did it, we said, oh, there's got to be something wrong here.

So we repeated it and we did it different ways. And it didn't matter. It looked like uric acid had a role in how sugar worked. So as we studied this, we started realizing that the process by which uric acid is generated is important in how sugar causes disease. No one believed us initially. I have to tell you that everybody said, I, yeah, sugar causes gout, but the idea that sugar raises uric acid that causes gout, but the idea that sugar raises uric acid and that is involved in the obesity and the insulin resistance, we don't believe it. What's happened since then is we've learned that the metabolism of fructose is extremely different from the metabolism of glucose.

glucose. The two look alike, but when fructose is metabolized, there's this process that causes the energy in the cell to fall before it goes up. So normally when you eat a calorie, when you eat any kind of nutrient, we use it to make energy. That's what we do. But when you eat fructose, the energy in the cell falls before it goes up. It's the only nutrient that lowers energy in the cell. See more about what you mean by that. So we're talking about a cell in the liver, for example. Yes, I'm talking about the cells that metabolize the fruit dose. Okay, so we'll contrast it with glucose.

So if glucose enters a cell, it gets turned into pyruvate and ultimately ATP is made. So you're saying total energy goes up as a result of metabolizing that glucose. So whenever you metabolize any kind of calorie, any kind of food, you eat food, you're going to metabolize it to make energy. That's what we do. We try to break down the food and we use it to make energy. That energy is called ATP. And ATP is the currency in our body that we use to make us run, walk, think, talk, everything. So this ATP is pretty critical. But to make ATP, you have to spend a little of it to make it. So the process of breaking down and metabolizing food or glucose or fructose or requires spending

a little bit of ATP before you make it. Well, what happens is when you metabolize glucose, you do spend some ATP, but the body has a system whereby feeds back to stop the process before any significant ATP depletion occurs. So for example, there's an enzyme called phosphofructokinase that's used in glucose metabolism. If ATP levels fall, that enzyme gets turned off to stop glucose metabolism, to allow ATP levels to come back up. But when fructose is metabolized, the enzyme that metabolizes fructose is called fructokinase. And when that metabolizes fructose, it consumes ATP in an unregulated way. So if the cell sees a lot of fructose, the ATP

levels complement by 40 or 50% in the cell. And that signals a huge number of effects throughout the body. It's like a Mayday signal. It says, we're under attack, we're running out of energy. And so it switches the animal into a condition in which they're trying to preserve their energy. So they reduce their metabolism. They reduce their expenditure. They're resting the energy expenditure. They shut the energy that they're eating.

The calories are eating into fat and glycogen, as opposed to making more ATP. They're trying to protect the body by putting you into a system where you try to store fuel. It triggers hunger and thirst that makes you want to eat more, so you eat more to restore the energy, but it expects that you're shunting much of it into fat and into fuel storage. So, fruit dose turns out to be used by animals as a mechanism to store fat. Normally, animals will regulate their weight beautifully.

They just maintain their weight normally. If you take an animal and you put a tube down its throat and give it extra food to make it gain weight, if you take the tube out, the animal will go right back to its gain weight. If you take the tube out, the animal will go right back to its normal weight. If you starve an animal, and so it's below its normal weight, and then you let it just eat, it will eat back

to its regular weight. But when it wants to gain fat, it will do so, usually through a mechanism that involves fructose. So what they do is they are like a hibernating animal will start eating a lot of fruit in the fall to increase its weight and increase in deuces insulin resistance. It gets hungry, it drops its metabolism so that most of the energy it eats goes into fat and the same thing with a long distance migrating bird, they'll start eating fruit to get the fructose. thing with a long distance migrating bird, they'll start eating fruit to get the fructose. And so this is a very common pattern.

And it's driven by that ATP depletion. And this is distinct or in parallel, of course, to this uricase mutation. So that can you separate these two phenomenon? In other words, if you can restore uricase to the non-mutated version. Do you still have this problem around the ATP depletion? Yeah. So, the ATP depletion triggers a series of reactions. And what happens, what the key one is, not only does ATP decrease in the cell, but intericellular

phosphate also falls. And that activates an enzyme called AMPDaminase that converts the broken down product of ATP, which is AMP, and it converts it to uric acid. And that process has multiple steps. And we know that that whole pathways involved in the generation and stimulation of fat, insulin resistance, fatty liver, elevations and blood pressure, a variety of effects. And that pathway is what seems to be critical for inducing obesity from sugar. Let's go through that again, because what you sort of talked about at the very end is effectively the thesis

of your book, The Fat Switch. You explain what ATP is, adenosine triphosphate, and the T, of course, stands for tri, there are three phosphates. It's the liberation of a phosphate that is the production of energy. So when you need to breathe, you need to move, when you need to do anything, you have to turn ATP into ADP. So the chemical reaction is adenosine triphosphate, becomes adenosine diphosphate, one phosphate escapes, and that's what gives us the energy. Now that can happen again. ADP can lose one of its two remaining

phosphates and become AMP adenosine monophosphate. What you said after is the really critical, critical piece of this, which is when you have a molecule of adenosine monophosphate, it stands at a proverbial fork in the road. It can either go down a path that is driven by something called AMPK or AMP kinase, or it can go down the pathway of AMPD. Now let's go back to this point because again, it seems everything comes down to that choice. What happens if AMP goes down the AM AMP K pathway versus the AMP D pathway? Yeah, so if it goes down the AMP K pathway, it actually is burning energy, it's burning fat, it does a lot of really positive things. If it goes down the AMP D pathway, it goes down a fat

storage pathway. So it's their exact kind of opposites. AMPD, if you stimulate it, it will cause insulin resistance and eventually diabetes, whereas if you stimulate AMPK, you can actually use that like metformin to actually treat diabetes. So that fork is critical. And what drives that switch is the fallen intracellular phosphate, and the reason that phosphate falls is because it's taken up in the Fructose 1 phosphate,

or it's taken up by Fructose. So the Fructose gets phosphorylated by the ATP, and it becomes Fructose 1 phosphate, that's the Quester's phosphate. And there is this process where both ATP levels fall and intracellular phosphate falls, and that triggers this AMPD pathway. And if we interrupt the AMPD pathway,

we can block a lot of the metabolic effects. Do other animals also have this phenomenon? Oh, yeah. No, we can show this. We actually showed it in hibernating squirrels. So when a squirrel wants to gain weight, it will activate the pathway for AMPD. When it's hibernating and burning the fat, it activates the MPK pathway. I got it.

So even though humans and our most close descendants in primates have the uricase mutation, this ability to toggle between AMPK and AMD is unique to any species that has the potential to gain weight and wants to use it to their advantage. Oh, absolutely. Part of the pathway through which AMPD is working involves the generation of uric acid. So we know that the uric acid, when it's going up inside the cell, is doing all kinds of biological effects, and the AMPD is driving that. There may be other things besides the uric acid.

So the hummingbird or the squirrel can still store fat. They just don't get the bump in uric acid that comes with it, because they don't have the uricase mutation. Well, actually, the hummingbird does have the uricase mutation. Oh, really? I don't know my evolution well enough.

Yeah, so birds have the uricase mutation. Birds bifurcated off after we did. Reptiles have the uricase mutation. Even dinosaurs had the year of case mutation. Sue the dinosaur, the tyranosaurus rex actually had gout. I mean, that's got to be why tyranosaurus rex was so ordinary. Because if you think of the size of the T-rex great toe,

I mean, that would be inferior to every broncus orus out there. Yeah, I think so. Is eating too many of the broncus ori. It's right to get back into the minutiae of this, but it's important. You still have to phosphorylate glucose during its metabolism.

Why is it that the phosphorylation of glucose during its metabolism to pyruvate doesn't result in a strong enough drop in intracellular phosphate to cause the same problem? Because the reaction stops. Whenever there's the phosphate and ATP levels start dropping a little bit. You have that auto-regulatory thing with the... There's an auto-regulatory thing with the enzyme stops functioning. It's inhibited and then that allows the ATP levels to stay normal.

So here's a really cool follow-up of this and that is that sugar is much more likely to cause obesity if you drink it rather than if you eat it. And the reason for that is that when you drink a drink that has fruit dose in it, we tend to drink a lot in a short period of time. So if you have a soft drink, you can drink, not only does it have a lot of sugar, but we tend to drink it fast. And so the concentration of fructose turns out to be high when it gets to the liver. And it's the concentration that triggers this reaction. So if the concentration of fructose is really low,

the ATP depletion may not be significant to drive dramatic metabolic effects. But if the concentration of fructose is really high, then you're gonna get a big metabolic effect. So eating like a candy bar where it's coming with lots of fat, lots of glucose, lots of all sorts of things, lots of protein, you know, if it's like a Snickers bar and it's got nuts or whatever,

even if it's the same amount of fructose, even if you're talking about 25 grams of fructose versus 25 grams of fructose, you would drink very quickly. You're saying equal amounts of fructose can produce a different effect if both the speed and the concentration with which they arrive at the liver are different. Yeah, it's the amount, it's the speed, and it's ultimately, how rapidly it's absorbed. So if you drink something, if you take a lot of fruit dose, like, I mean, candy is very concentrated fruit dose. I mean, if you eat that, for example, on an empty stomach,

that will be absorbed faster than if you eat it with oatmeal or something where there's fiber and so forth. And so the speed of absorption and the makes a difference. So for example, if I was working for a high fructose corn syrup company and I wanted to prove that a soft drink wasn't bad, I could do a study where I would give the soft drinks to people, but I would give it over. You're only allowed to make a tiny sip every 10 minutes. So it takes you three hours to drink the soft drink.

In that case, the amount, even though you're drinking a lot, the concentration may never be enough. And you never let the phosphate depletion get significant enough in magnitude that it really triggers AMPD. Yes, that's it. It's really interesting.

I think of all the sugar, the pro sugar studies I've read that are funded by the sugar industry. I don't think I've ever dug into the methodology to look at factors like that specifically. Well, the other issue is like, if you just take a single dose of fructose, most of the metabolic effects are best seen like in the first four hours following the ingestion. So the triglycerides go up and the uric acid goes up and the blood pressure goes up. But if you just do a single dose study, if you then look the following morning or the effects of now

kind of come back down, then you can't really show it. And a lot of these studies, they design it that way. So they say, aha, fructose doesn't raise uric acid, but we measured it after fasting overnight. But the surgeon, uric acid occurred earlier. So that's the common trick. So all these things you're talking about with fructose seem to fit almost directly into the five

characteristics of metabolic syndrome, which are elevated glucose. So that insulin resistance would be manifested as an elevated glucose, elevated blood pressure, elevated waste circumference, storage of fat, elevated triglycerides, what you just said. And the only one we didn't address is low HDL cholesterol, which is the fifth finding. And now, of course, three out of those five are sufficient to put you in the category, but... Frick just has all five. What is the mechanism by...

So you've already described the mechanism by which it does three of them. We alluded loosely to how it raises triglycerides, but I'd like to talk about that more. And then of course, I'd like to hear how it lowers HDL cholesterol. Okay, so the uric acid generated by fructose has a very pronounced effect to stimulate oxidative stress in the mitochondria. And fructose also generates lactate big time. And the lactate also has effects on mitochondria

as you learned from Dr. Samalans talk. And in addition, fructose preferentially decreases mitochondrial function and stimulates glycolysis. And so all those things cause you get this big oxidative stress to the mitochondria. And there's an enzyme in the mitochondria that drives fat oxidation called enolcoehidritase. I mean, sorry to throw it out there.

This is what we're hearing. No, no, no, no, we're here to talk about it. But basically, the oxidative stress inhibits that. So fatty acid oxidation goes down. So you block fat burning, and then in addition, you block an enzyme called a conatase with oxidative stress to the mitochondria,

and that increases citrate, which drives fat generation. And so you end up with fatty liver that's driven by both increased fat synthesis and a block and fat burning. The mitochondrial oxidative stress also is very much linked with the development of insulin resistance. And then uric acid is also degenerated.

Uric acid is also causing an oxidative stress to the eyelids, to the pancreatic eyelids as well. Uric acid is actually harmful to the eyelid cells of the pancreas. Uh-huh. In fact, if you give sugar, we did a study where we gave sugar to animals where we actually restricted the amount of calories. The rats were getting...

They were on a diet, basically. They were on a diet. They were on a high sugar low calorie diet. Right. And then we had as a control, rats that got the same number of calories, but they weren't getting the sugar. Right. So just a low calorie low sugar diet.

Yeah. And when we gave the high sugar low calorie diet, all the animals developed fatty liver, hypertension, insulin resistance. Did they actually gain weight? No. No. And this is a trick. Weight gain really requires increased calories, really to show it.

Long term may be just decreasing metabolism. But this is interesting. You're saying both animals lost weight. Did they lose about the same amount of weight? No, they maintained their weight. Even though they're eating 90% of what they normally eat, they were able to maintain. So both groups slowed their metabolism enough to maintain weight at a 10% reduction of calories. So in the outside they looked the same, but the high sugar group still developed fatty liver.

Severe, and they all became diabetic. Do you recall in the study, Rick, what the actual percentage of their macros that came from fructose? 20%. Right, so the critic will say, well, that's highly unnatural, although in reality, it's not that unnatural. There are lots of people, unfortunately, walking around, getting 20% of their energy input from that. It's not physiologically completely out of whack, but as a proof of concept, these animals

got diabetes without gaining weight. They got fatty liver disease without gaining weight. They were, by definition, insulin resistant. Right. When we measured their insulin levels, they first became insulin resistant with high serum insulin levels, which is what we see early diabetes, early to type two diabetes. But over time, the serum insulin levels started to fall. So they almost develop a type one diabetes? Well, just like humans do.

And what we saw is that the islets used to be the phrase was called islet exhaustion, because long-standing type two diabetes, we see the same thing, but it's actually low grade inflammation in the eyelids. We could show that there was low grade inflammation, and it was associated with big time upregulation of urethra transport proteins on the eyelid. When we took isolated eyelids and we put uric acid on them, it induced oxidative stress, and over time, caused a drop in insulin level. So what we think is going on is that sugar causes diabetes

through this pathway that we've been talking about, and it involves initially insulin resistance, but over time, it will cause islet cell dysfunction as well. And this has been confirmed by other groups now. That sort of comes to the triglyceride story, right? If you have a net accumulation of fat in the liver, you're gonna have to export some of that in the form of VLDL, a very low density lipoprotein.

So that would drive up the serum triglyceride. What's driving down the HDL cholesterol? You know, I haven't studied that personally. I don't really know, but I did see that there are reports that fructose can lower HDL, like in the animals and stuff, but I don't really know the mechanism. When you sort of pause for a moment, Rick, do you ever worry that talking about fructose this way just seems, I don't know what the word is. I don't think it's necessarily being

too much of a reductionist, but it almost seems too simple that this one molecule could simultaneously have probably allowed our species to survive during this very cold spell six to twelve million years ago. And obviously evolution wasn't thinking twelve million years into the future that we'd be flush with fructose. And yet here we are today, one could interpret what you're saying to mean if you simply had no fructose in your diet. Most of the bad things we think about

metabolically would go away. Is that a fair assessment? Yeah, I think that's true. So let me give you another one where we've really learned a lot. I don't know if you are aware of the relationship with cancer. But what we've learned is that fructose was an incredible survival nutrient in the setting of near starvation. So as I mentioned, what we're learning is all these animals use fructose. They either get it from their diet or they make it in their body.

And they use that to help them survive. And we can talk about it, but it involves not just storing energy, but they use fructose to store water. And we can talk about that and they use it to become insulin resistant. Insulin resistance is a survival mechanism, whereby increasing blood glucose and preventing glucose from taking up in the skeletal muscle it preserves it for the brain,

which is what you wanna do if you don't have enough food around, you wanna be able to think so you can escape predators and so forth. So it was a survival tool to increase energy. And it actually also protected animals from a low oxygen state. So by switching, by reducing mitochondrial function and stimulating this thing called glycolysis, it allowed the animal to survive with a lower oxygen state. And so we know, for example, that the naked

mole rat, which lives in burrows, very low oxygen burrows, they make fructose to survive when they're in those burrows. So, suddenly the fructose goes up in their blood, and they use it to survive the low oxygen tension there, because they switch from mitochondrial metabolism to glycolysis. But why can't they just rely more on glucose for which we have such an abundant apparatus to store it at large amounts? Is there an energetic reason for fructose? A lot of the fructose is converted to glucose

and to lactate, which can be converted to glucose. And then it's driven through this glycolysis pathway. So it turns out though that what happens is when you metabolize glucose, a lot of it will go through mitochondrial metabolism. And so if we can inhibit mitochondrial metabolism, which uses oxygen, we can live off glycolysis, which doesn't require oxygen. So what happens is in a low oxygen state, like the naked mole rat, we'll use fructose to survive. but cancers. But wait, I'm still confused about this, Rick, because wouldn't that fructose, but they're

not storing that fructose as fat then, because that would be the worst fuel they could have around in a low oxygen environment, right? Well, so fructose is increasing glycogen and lipid, but it's also reducing mitochondrial use. When you're eating fructose, you actually are not burning the fat. You are storing the fat. And then so what it's doing is it's putting you into a glycolytic state. So animals use it to store fat and then they they fast and then they burn the fat. So they hibernate or they go flying long distances where they have no food and then they switch and then the fat that they've stored suddenly becomes their survival. But during the time that during the low oxygen state they want to have fructose on board

because the fructose is helping them to survive low oxygen by switching their metabolism. But unfortunately, like cancers also live in a low oxygen state. And so these cancers love fructose as their fuel, because it helps support them surviving in a low oxygen state. So recently, it's been shown that many cancers, colon, liver, kidney, breasts, brain, all these cancer cells and testinal, they all tend to like fructoses as their preferential fuel. There was just a paper in science a few weeks ago, and if you block that fructose pathway,

the cancers don't do as well. And we say block it. Do you mean block fructokinase? Yes. Which pathways specifically? Fructokinase. So if you take intestinal colon cancer, you put high fructose cancer upon it. They love it. They grow.

They metastasize. And if you block fructokinase and block fructose metabolism, you can block a lot of the growth of those cancers. Do you have a sense of how much you're blocking it? It's pretty remarkable. It's like 50% or more. And we know it's the fructose, not the glucose, presumably, because we don't impair glucose metabolism

at all in that experiment. That's correct. And also, they were able to show that this was driven by that shift from a mitochondrial-based metabolism to a glycolytic metabolism. And what happens to lactate levels in that cell? Oh, very high. Like, meaning that more fructose they have, what happens to lactate levels in that set? Oh, very high. Like, meaning that more fructose they have,

the higher the lactate level. Yes. Again, very counterintuitive, because aren't we sort of taught that the liver is the only organ that can really process fructose and that it all sort of accumulates there? And, I mean, conventional thinking is that fructose really doesn't have much of an interaction outside

of the liver unless converted to glucose, correct? That was said by a lot of people, but the findings show that about 20% of fructose is used by the intestine, or maybe 40% by the liver, and at least 10 to 20% can escape into the circulation. And of course, if the larger the dose, the more that will pass. And the kidneys of big target, there's fructokinase in the brain, there's fructokinase in the eyelids, there's fructokinase in the adipose tissue. Does the muscle have fructokinase?

There's some thought that fructokinase may be in the muscle. It's gotta be very low, but there's some thought that fructose is being metabolized in the skeletal muscle. And one of the things that's interesting is there was a paper in nature that showed that the heart normally doesn't have fructokinase, but when you have a heart attack, the low oxygen state there induces the fructokinase and there's probably production, endogenous production of fructose, and it seems to be involved in cardiac remodeling. So it's probably involved in more things than we

think of. And certainly it's in the brain. Which means that in theory, the brain could actually use free molecules of fructose to make ATP in addition to the mainstay of its endgimentelism, which is glucose-driven and lactate. I think we're now seeing lactate. There is actually some evidence that first off, we know that fructokinases in the brain, we know the brain can make fructose. And there's increasing evidence that insulin resistances can occur in just in the brain and maybe a forerunner for the development of

Alzheimer's. And there are actually reports that AMPD aminase is high in the brains of Alzheimer's patients and it raises the possibility that local fructose metabolism could be involved in disorders like that. Are there any people with naturally occurring mutations in fructokinase that render it less capable? Yeah, so there are people with a condition called the sensual fructose area where they are born without active fructokinase and they live normally. No one's ever been reported to have type 2 diabetes or obesity. So these people, if I'm understanding you correctly, are genetically immune to the

harm of sugar? Yes. And they pee out all the fructose. Yes. Okay, so that seems to be an interesting topic. This must be very rare. I've never heard of it. Yes, it's a rare condition. They actually don't pee out all the fructose. Some fructose can be metabolized by an enzyme called hexokinase, which is normally metabolized as glucose,

but fructose is preferentially metabolized by fructokinase. So these people have very sweet urine going back to Osler, had he tasted their urine, he would have confused them potentially with an even sweeter version than that people would ultimately type to diabetes. That's how they were discovered because they would have reducing sugars, which was fructose in their urine, that was picked up with the old tests they used to use for diabetes, but then they didn't have diabetes when they tested them. And these people could literally just consume all the sugar they wanted and their uric acid

is not going to go up. Their blood pressure is not going to go up. Their trigs don't go up. They don't gain weight. They don't become insulin resistant. That's right. So is there any benefit to having fructokinase if you're not hibernating or in a world where famine is potentially coming your way?

It's really a survival enzyme that was meant to help in situations where there was food shortage. If you live in the western world and you just have to go down to the grocery store, no, I think living without fructokinase would probably solve a lot of the world's health problems. I mean, and there are fructokineis inhibitors that are being developed. Pfizer has one that's now in a finished-of-phase-2 trial. It was quite successful at treating fatty liver, and so now they're taking that drug to phase three. Wow.

That's a potential blockbuster, actually. Of course, it begs an interesting question, which is how will that drug be treated, will it be only used as a way to treat an active condition such as fatty liver, in which case, it's gonna have a smaller, unlabeled market versus what will likely happen, which is people who just wanna be able to have more sugar without the consequences of it would take it, correct?

Yeah. Although it's probably priced to avoid that, I'm guessing. Anyway, yeah, there's a lot of interest in fructokinase inhibitors. There's other big farmer that are working on it now. And so we'll have to see if it turns out to be as powerful as we think it might be. So the work that we've just discussed is sort of been, you've been at this since 2002, basically, specifically with respect to this. Let's go back to Alapurinol and Euric acid in your clinical practice because you've spent 17 years as the division head of nephrology across three world-class medical centers, most currently the University of Colorado.

And yet, I was surprised to learn over dinner the other day that you still have a very heavy clinical practice. You still actually take care of patients on the inpatient ward and you probably spend a quarter of your time in clinic. So how do you put some of this stuff into practice? Do you liberally use alapurinol, even for patients who have high uric acid

but have not developed yet? I do. So our data strongly suggests that lower in uric acid could be beneficial. So what I do is the following. So it turns out that alapyrinol is not totally safe. There is some people who can develop reactions to alapyrinol drug reactions, especially Asians about 3 to 4% of people who are Asian can develop an allergic reaction to alapyrinol where

they can get rashes and it can be pretty severe. And it's about 2% in African Americans and it's about 0.5% in Caucasians. You can test for it. There's a test called the HLAB 58 test. But the point of the matter is that no drug is fully safe. Every drug has side effects. So ideally, you'd want to really be certain that your

drug is going to provide the benefit that you want, and you have to consider the risk versus benefits. Now, although in animals, allopyrinols totally protective or protects a lot against sugar-induced metabolic syndrome, the data in humans is suggestive. So there's been, for example, four pilots that he's showing an improvement in insulin resistance with lower in uric acid and humans all four are positive. There's a lot of trials and kidney disease showing that low in uric acid may benefit kidney disease. There's data on blood pressure. We had a paper in the JAMA showing that low in uric acid could improve blood pressure

control and adolescents with hyper-eurocemia. So there's a lot of supporting data. There are some negative studies too, but the overall weight is now in favor of oin uric acid to benefit. What would the target be? So what I do is when I see a patient in clinic, I measure the uric acid. And currently we know that the risk start to go up when the serum uric acid is over 5.5. So once the serum uric acid is over 5.5, they really start to have increased risk for pre-diabetes, insulin resistance, hypertension, kidney disease, etc.

And what's interesting is most labs, like my lab, for example, doesn't even flag it until it hits about 6.5 as a sort of intermediate risk. And it's really not until about 7.5 that it says, well, this is high risk, but of course, that's only through the lens of gout, I assume. Yes, that's right. So if a uric acid comes back really high, like nine or 10, I have no doubt that that, based on everything I've done, I have no doubt

that that's not good. You not only does it increase the risk for gout, but it increases the risk for kidney disease and all these things. And I talk to the patient about the pros and cons of treatment. I talk about the rash. I tell them to stop the drug if they get a rash and then call me. But I always start allopyrinal when the uric acid is like eight or higher. And certainly when it's nine or higher.

When it's between 5.5 and eight, I'll talk to them about the pros and cons, but we don't have full proof yet. But I tend to do it especially with patients with kidney disease where the data's probably the strongest to start treating. I'll even do it with uric acid of six and a half, for example, with chronic kidney disease where the data is probably the strongest to start treating. I'll even do it with uric acid of six and a half, for example, with chronic kidney disease. But anyway, it's worthwhile discussing it with the patient. But outside of the risk of Steven's Johnson syndrome, which you've

alluded to, what are the other potential risks of alapurino? That's by far the big one. Some people will get just a mild rash without true Stevens Johnson syndrome. Their rare cases where liver function tests may be elevated, but it seems to be rare. If you start at a huge dose right away, it can increase xanthine levels in the urine. Theoretically, there could be risk for xanthine stones, but I've never seen it. So it's really the risk of Stevens-Jots and that. And do you have to use L. Appurinol or can you use Uloric or other drugs that also lower uric acid? Well, the zatin oxidase inhibitors are the best because the way uric acid works to

cause cardiovascular disease and kidney disease and all these things appear to be through its actions inside the cell. As we said, works on mitochondria, and it does all these things. It's not, it's work outside the cell. So, gout is really an extracellular deposition. But when you're thinking about uric acid and its biological effects, that's an intracellular action. So, zanthine oxidase makes uric acid inside the cell. So one of the best ways to reduce Intracilular uric acid is to give a Xanthine oxidase inhibitor like alapurinol or phyboxis that. Now phyboxis that I think it's probably just as good as alapurinol but there was a big clinical trial that was published in the New England Journal that showed that alapurinol was a social with less cardiovascular that was published in the New England Journal that showed that alapurna was associated

with less cardiovascular risk than phoboxicetheth. There seemed to be an increase cardiovascular events in the phoboxiceth stat group. Meaning less of a reduction or more events? Let's see, the problem was there was no placebo group. Oh, yeah, that's a disaster. Yeah, that's a disaster. This is the viox problem with nepraxin.

Yeah, yeah, I mean, so the problem is alapurna is less than phboxistat. But there's no placebo group. Theoretically, the placebo group would be could be higher than both of them. Yeah, it could be higher than both of them. And there's actually evidence that that's probably true. But because of the CARES study,

the way it was designed, we don't know. So the FDA is worried about giving foboxistat to people with cardiovascular problems because they would prefer you to give alapornal. But the trouble is, it's not necessarily that for boxes to have is bad. It's just that it's not as good as alapornal. And it's like a hundred thousand times more expensive too. I mean, it's, although it's, I think, becoming generic now.

So we may see a change in that. I believe it when I see it. And of course, the will you trust the generics, but that's a whole separate issue. Exactly. So what about sodium restriction going back to how we started the discussion? I'll tell you a story from, I maybe even told us on the podcast once before, but in medical school, I remember when we were doing renal physiology, we had a great nephrology professor who was teaching something. And I think he was quite ahead of his time because this was more than 20 years ago. And he was not sort of part of this salt is bad bandwagon, even though he was a nephrologist. And I won't do it because I won't do it justice.

But in a beautiful southern accent, he made the point that if you lined up all of the nephrons in the world, all the functional units of the kidneys in the world from dumbest to smartest, and then all of the nephrologists in the world from dumbest to smartest. And you took that dumbest nephron and put it next to the smartest nephrologist, it's still smarter. His point being, of course, like the kidney is a brilliant organ that is exceptional at auto-regulation of everything from flow to osmolarity to anion,

cation exchange. Again, his point being he didn't buy this argument that salt is the problem. You're saying something much more nuanced and I want to kind of go back to it because I think there are important clinical implications of it. You're saying no, no, salt does play a role, implications of it. You're saying, no, no, salt does play a role, but it's dose timing, bolless concentration that matters. It can also be amplified or mitigated by the state of inflammation. So how do you then translate that information to your patients, acknowledging that they're a very select group of people by definition, they have kidney disease or they wouldn't be seeing you? So it's the combination of salt and water. So if you don't drink any water, as you eat salt, you're going to raise your serum sodium,

you're going to get thirsty. And as soon as you're thirsty, you've triggered that in itself is a sign that you're already making fructose from the salt. So when you eat salt, you're making fructose in your body. And the fructose is then driving a lot of effects. Now we know that high salt diets are associated with obesity, not just high blood pressure. They're associated with the development of diabetes. There's many studies now, but high salt looks like it works by producing fructose.

So, if you drink water with salt, the danger of the salt is much less. If you drink water and then you're pretzel, you would be safer than if you ate your pretzel and then drank the water. Because what triggers it is the rise in salt. And so, when you see someone in the clinic, what we try to do is to tell them to drink a lot of water and to reduce their salt, but it isn't the amount of salt. It's the balance of salt and water. Now, that can be sometimes challenging for patients in a kidney clinic because that would

be one population in which you do have to be mindful of volume. Right, but most patients with chronic kidney disease, they will excrete water normally, or just minimally abnormal. And so, there's actually clinical trials looking at the evidence that water may slow the progression of kidney disease. It might be working in part by blocking the effects of salt and so forth on the kidney. And we experimentally can show that giving water can slow kidney disease progression. So drinking water turns out to be good. Here's another thing. It turns out that many animals use fructose to make fat

as a means for making water. So when you make fat, although there's no water, stored in the fat, when they burn the fat, they make water. So whales don't drink salt water. They are fat because when they break down the fat, they're making the water. We call it metabolic water. So it turns out that fructose

dries fat production and in part to preserve water, not just energy. So animals will use that fat to provide an energy source but also to provide water. So it turns out that if you take an animal on fructose and you give it a lot of water. You can suppress some of the obesity. You can suppress some of the effects of metabolic syndrome. And so the old wives tale that drinking six glasses of water a day is good to help keep you skinny is true. It turns out that water suppresses some of the effects of fructose. And does it need to be water? Could it be tea or coffee or something that's equally the osmilarity of water?

What? Serum is about 280? Yep. Okay, so anything with the zero osmilarity is good enough? Yes. Technically a diet soda should have a zero osmilarity as well. Yeah, a diet soda would work, actually. For the record, you and I are sitting here

drinking just plain water. Right, and diet sugars have their own issues, so. We'll come back to that in a few seconds, because that's interesting. So, Rick, you sort of, you toss these little nuggets out there, like they're nothing, but they sound, I mean, again, just based on the sort of breadth of research you've put into this,

it almost just seems too good to be true and so profound, yet you sort of throw it out there like an after the fact, well, look, as long as you drink enough water and don't eat fructose, and God forbid, don't drink fructose, manage your uric acid levels, et cetera, et cetera. You make it seem like a lot of problems could go away from these things. How would you shape that advice for someone with normal kidney disease, that put me with normal kidneys?

Would you basically just say the same thing, or can you be less restrictive with sodium, for example? If we could reduce our fructose intake, I think it would have a huge, huge effect. But the problem that most people face is that sugar and hyphructose corn syrup are in almost everything. So if you go to the supermarket, like 70% of processed foods have sugar in it,

and packaged foods, actually 70% of packaged foods have sugar or high fructose corn syrup in it. So it's very hard to avoid it. And here's another problem. Our bodies can make fructose. So our bodies, as I mentioned, we can make fructose from a high-salt diet. We can make fructose if we get dehydrated. We can make fructose high-euric acids, stimulates fructose production. And we're making the fructose out of get dehydrated, we can make fructose high-earic acids, stimulates fructose production. And we're making the fructose out of glucose in all of these situations. High glycemic diets.

Normally, if you take an animal and you give it starch, they will not really get fat. But we all know that French fries, which don't have sugar in it, they don't have fructose, they are fattening. But you've got potatoes which raise your glucose. And what we showed is that if you just give glucose to an animal, the high glucose is it hits the liver, induces this enzyme to convert glucose to fructose.

Which enzyme is that that converts glucose into fructose? Aldoce reductase. So when we took mice and we gave them glucose and we were thinking we might not see much because we were believing that fructose is the culprit but over time these animals got really fat. They got insulin resistant, everything. But you had to overfeed them glucose. We put the glucose in their drinking water. So they were drinking a lot of glucose. But they would eat less chow. So we gave them chow and glucose in their drinking water. And their chow had, it was normal chow, it wasn't the high fat, high sugar

chow. No, just regular chow. And these animals started getting really, really fat. And when we looked at the portal vein, which goes into the liver, the glucose levels were high. And when we looked in the liver, we found that this enzyme was activated. It's also activated in diabetics, for example, because of the high glucose in the blood. And when that enzyme got activated, it started to make fructose. So even though these animals were eating no fructose, they were producing fructose in their liver. And then, when we blocked their fructose metabolism, they're eating the same amount of glucose,

no change. Exactly. The, suddenly they're not getting as fat. They have no fatty liver. They're not insulin resistant. But this suggests Rick that a diet in excess carbohydrate, even if it's not high in sugar, could lead to fatty liver disease? Yes.

Yeah, absolutely. If you have that enzyme induced, but let's say that you are a young person, when you're young, the senzine is really not present in the liver. Once you're eating sugar, though, if you eat a lot of sugar, it will induce that enzyme. For how long? I don't fully know. But let's say that you eat a lot of sugar and you get obese. So sugar itself, it looks like the induction of this enzyme probably would be reversible. I don't fully know. But let's say that you eat a lot of sugar and you get obese. So sugar itself, it looks like the induction of this enzyme probably would be reversible within a few weeks.

But once your uric acid goes out, that will keep it elevated. So that's another reason potentially to use alapurinol, if necessary, in addition to fructose restriction, to keep uric acid low is to prevent or mitigate the induction of this enzyme. Oh yeah, right. So it turns out that if you give a starch or potatoes to a skinny person who does not have all those reductase induced, they can eat the potatoes they want. And Ireland back in the 1700s where potato was basically the main thing they were eating, there wasn't a lot of obesity. But you wait until you eat sugar and then develop the metabolic syndrome.

Now you stop eating sugar, but you continue to eat carbs, and the carbs are going to continue to activate through the same pathway. So a low carb diet is really great because it's necessary if you're overweight or fasting, but that's basically reducing carbs, too. But a low-carb diet, when you're overweight, is removing the high glycemic carbs that are also driving the disease, but it's through fructose. So, it seems that fructose reduction obviously comes with its own benefits. Do you have a sense of how much fructose can be produced in a fructose

free intake environment just from glucose? Is it a meaningful amount? Well, we did our study by putting glucose in the drinking water. They're getting a lot of glucose. What you haven't done the study is the one that you're talking about trying to figure out what the range is. I do think that if you just give high glucose alone, you probably have to give a lot. But if you've already triggered the production of this enzyme aldose reductase, you probably don't have to give a lot.

What about fat? What if you did that same experiment with rats or mice? Which would be hard, because to eat pure fat is difficult. But if there was a way that somehow you could make it palatable enough that they could, you could overfeed them to the same extent using fat and protein. Let's say they're getting a normal amount of glucose, but the overfeed was coming through the fat.

Would that induce any of these properties? In other words, is part of this due to an absolute sense of total energy being too high, or is this really about a particular carbohydrate? It's definitely about a particular carbohydrate, because we've actually done what's called parafeeding, where you control how much they eat, and you can have your control group. The spructose effects will still, as I mentioned, cause fatty liver. Yeah, explain what parafeeding is for people, because it's a clever little tool done in this type of research. So the way fructose works is it works by making you eat more.

And that's how you gain weight. But even when you control so that you don't eat more, fructose will not cause weight gain, but it will cause fatty liver, insulin resistance, diabetes, and so forth. And the way we can show that is by pair of feeding. In pair of feeding, we give each animal eats the same amount of food. So if you give one animal sugar, which normally makes it want to eat more, because it causes this thing called leptin resistance where they want to eat more, but if we don't give them any more food, we only give them the same amount as the control, then there will be no difference

in weight, but there will be differences in fatty liver, metabolic syndrome, and so forth. The sugar industry has used this to their advantage. So what they say is, okay, we're going to look at clinical trials where we've given sugar, and we're going to see if sugar causes weight gain. But it's only fair to do that if we have a control where we control the energy intake to be equal among groups. So they have a control group where they've restricted.

There's a caloric restriction on both sides. So you have a high sugar and a non-high sugar group, but it's not where you get to, the people get to eat as much as they want. Basically, is this problem of not having ad libidum feeding? So it's sort of like what the sugar industry is saying is, look, a calorie is a calorie. If I give you 100 calories of sugar and Completely control what you can eat in response to that and compare you to another person who's eating the same number of calories

You're really not gonna gain weight then the problem with that experiment is it's not the real world in the real world You don't have a clamp on your response exactly in the real world, you don't have a clamp on your response. Exactly. So when you give sugar to animals, they become leptin-resistant over time, and they lose their ability to control their appetite. So then they eat more, and so then their weight goes up. But the fructose is also doing stuff where even if you control for the weight gain, they still get the fatty liver and stuff which the controls don't.

Now, a second ago, you sort of alluded to artificial sweeteners. So comparing, I mean, I'm sure you get this question asked all the time by your patients, which is, I just really love Coca-Cola. Is having a diet coke, it must be significantly better, right? I mean, there's no fructose in it. There's no glucose in it. So is there a downside to it? Yeah, I think there are downsides.

But first, let me just say the positive side. We have taste buds that sense sweet. And so when we eat sugar, the taste buds are activated and it stimulates this dopamine response in the brain that tells us that we like this sugar. If you actually knock out the sweet taste buds, you're just knock out the taste in general. Animals will still like sugar. They will still eat sugar, a lot of sugar. How hard is it to do experimentally to knock out the sweet tasting capacity? It's been done and we actually have also done it where we knock out all taste. Can you do it to me? No. It's like a genetic knockout. But anyway, these animals will still like sugar,

but they won't like artificial sugar. So the artificial sugar is really driven by this sweet taste, but what makes animal-like real sugar is through its metabolism. I mean, it is true. If you knock out taste, they will tend to eat a little bit less sugar, but they actually

still develop metabolic syndrome. That's super interesting. So you're saying part of our affinity for sugar is not just in our taste buds and in our brain, but also in our periphery, where the metabolism takes place. And the elegant way you demonstrate that is you give something of equal sweetness concentration that's non-nutritive, and you completely reduce the appetite for it. Even though it might have the same central effect, it doesn't have the peripheral effect.

Probably the sweet taste bud developed to try to encourage us to eat these foods that at the time were survival foods. But the food itself, the sugar itself stimulates dopamine and other effects independently of the sweet taste. Whereas an artificial sugar just is activating the sweet taste. Now, if you give a mouse or a rat artificial sugar, they don't gain weight, but if you give them regular sugar, they do. So there is some evidence that artificial sugars are better than sugar. And if a person says to me, oh, doc, I'm afraid to drink this diet coke because it's got chemicals in it.

I want to drink regular coke because of that. That's an error. Regular coke is more dangerous than a diet coke. However, there is truth that things like Aspartame and Superlose, we don't know fully the safety of these. Aspartame, when last I checked, had been studied more by the FDA than any other molecule ingested by humans.

It's hard to make the case that at the small doses that people would consume them. I'm talking about someone who has a serving of this stuff a day. I don't know. I've always found that argument that what we don't know, the full safety profile of these things to be, it's like, what else do we need on this one? I think Asperityam's kind of gross, truthfully, like, I don't really like it that much, but it just think it's definitely the lesser of two evils, isn't it? It's definitely the lesser of two evils. That part's for sure, but we don't fully know

the safety of some of these. Like, saccharin, for example, has been associated with little bladder tumors in mice. My recollections that aspartane can generate small, tiny concentrations of formalahidu. I think it really comes down to dose. Yes, I think it is. I think those studies were really based on rats

or rodents consuming doses that simply couldn't be replicated by humans. That's probably true. Nevertheless, water is good. Yeah, that's generally been my take to people as well as look, all things equal by certainly consume water, tea, things like that. But yeah, there's this lesser of two evils approach, but this point you made, this is completely news to me and very interesting because certainly much of the neurobiology today would suggest that the response we have to

sugar is mostly centrally mediated. The quote-unquote addictive, because everyone loves to talk about functional MRI and what happens in your brain when you're eating sugar and all of these other things. But I guess I haven't seen this side by side, but presumably the FMRI would light up the same for non-nutritive versus like an aspartame and sugar, correct? Yeah. So let's talk about another taste, which is umami. I remember we were having sushi one night when we discussed this.

What is umami? What is that taste? So umami is the savory taste. And this is different from salt, isn't it? So there's five taste buds. So there's salt, there's sweet. And as I mentioned, both of these taste buds seem to drive a weight gain.

Sugar is by far the fastest. It takes only a two months and a laboratory animal and salt takes four months, five months. So high salt generates fructose, but it's a much slower process than just eating sugar. Then you have umami, which is the savory taste, then you have bitter and sour. And the bitter and sour probably developed

to help you avoid eating certain foods. So coffee is an example of bitter, like a coffee bean or something like a ground? I think so. Yeah, okay. Anyway, so umami is driven by glutamate, but it's markedly enhanced by purines, like IMP and even uric acid.

So it turns out that umami is sort of a taste receptor for uric acid type foods, foods that raise uric acid. Now, is MSG the purest form of umami that we would eat? Yes. MSG is the primary stimulant and people put it in foods to encourage food intake. Now, there's some link of umami with obesity in epidemiologic studies, and there are situations where you can give umami-type foods, and especially if you can do it in a liquid form, you can induce obesity. So umami may not be as safe as we think of this.

So it's got a lot of good things written about it in the literature. Don't most people view MSG as evil? Yeah, I think MSG is viewed as evil. But that seems to be largely unfounded based on my view of the literature. I can't really find evidence that umami is harmful. There's this Chinese restaurant syndrome

where people get a warm and a headaches and it's thought to be due to excessive MSG. But foods that are umami rich are often foods that we love. I mean shrimp has umami, Caesar salad, the parmesan and things like that have umami. And so in general, people like umami foods and it's certainly in the web sites It is often promoted

But if the umami foods have a lot of purines which enhance the umami flavor It actually may raise uric acid and kind of bypass the sugar pathway and we think that that may turn out to be And we think that that may turn out to be somewhat a risk factor too. So do you add this to the list of things that you caution people about? We've already got the peri or salt with water idea, the restrict fructose, and please God, don't ever drink it. Do you then add the MSG containing high umami foods to that playbook for ways to reduce metabolic disease. I think so. Yeah, I think that foods like shrimps and things like that, if you eat a lot of them, they

probably activate this pathway too. We're still trying to learn more about it, but it looks like it could be a contributor. I think it's, if you rank it, number one is sugar and then everything else is less. High glycemic carbs can be converted to sugar. What I usually say is the big four are bread, potatoes, chips and rice. Those four are the foods that you should reduce a little bit. Wait, chips is in like chips potato chips.

Yep, potato chips. So you're giving potatoes two votes out of four. Yeah, well, our quarrying chips, you know. I forgot, I got it. The kind of things that people put out on their table before you eat dare. And they coat it with salt, which isn't good. Anyway, so high glycemic carbs, I think really salty foods

drink water. I mean, I think really salty foods drink water. I mean, that's really important. And umami, so for example, what makes beer so much more dangerous than other alcohols for inducing obesity is because beer has all this yeast in it, brewer's yeast, which basically is activating umami pathways. And that's one of the reasons we like beer. Isn't that cellular density issue you spoke about? Exactly.

And so beer raises your acid more. And there really is this beer belly syndrome. And if you look at people who drink a lot of beer, it isn't just that they get abdominal obesity. They get fatty liver. They get high blood pressure. Their triglycerides go up. They basically have metabolic syndrome.

Alcohol, especially beer, can also mimic sugar. And it's probably because of the umami component coupled with the alcohol, those two. This is the part that can sometimes drive a person insane when they're trying to think about all of these things. It's very difficult to provide clear Advice to people because there's so many caveats that are required because The dose makes the poison the speed of delivery what it's combined with all of these things

I'm using that as a preface to ask a question that I'm sure you get asked a lot Which is really a dose question around fructose? So let's ask it in two questions. If a person is going to drink something in the form of fructose, whether it be fruit juice or soda or sports drinks, which are from a fructose standpoint, all basically the same, is there a dose of fructose above which you think it really makes no sense under any circumstance

or below which you think once in a while is not the end of the world? I mean, personally, I would not drink any liquids that have sugar in it. Or fruit, dozer, high-fructose corn syrup. That's fine, so we're gonna draw a hard line there. And hard line. Okay, now what about eating fructose in the form of fruit?

Because remember, there's some big-ass fruits out there. Like, you look at a Fuji apple, which is my favorite apple. I mean, I like these monster Fuji apples, so they're like half the size of my head, or maybe a third the size of my head. That's got to have 30 grams of fructose in it. I don't think it has that much. Oh, really?

I really don't. Most apples, and that would be a big one, maybe 10 grams at most, I would think. No way. You think more? Well, think about it. These are the really big ones. Yeah, yeah.

I'm not talking about a little macintosh. I'm talking about a huge apple. And they're so sweet, too. So you may be right then. Let's talk about natural fruit. So we've actually done trials in patients with low fructose diet, whether without natural fruit supplements,

and generally speaking, natural fruit supplements do not seem to block the benefits of a low fructose diet. Sorry, what does that mean? You mean that if you took a patient and restrict all fructose except fruit? That's correct. They tend to do okay. They did just as well as the low fructose alone.

And can you quantify how much fruit? Because here's the problem when you're talking to someone like me, Rick, I don't do anything in moderation. So we have these bowls in my kitchen. They're called manly bowls, which by definition, a manly bowl is a bowl that you can wear on your head like a hat. It will come over your head.

And when I consume fruit, I consume it in that bowl. Yeah, I would be careful. So no manly bowl is a bowl that you can wear on your head like a hat. It will come over your head. And when I consume fruit, I consume it in that bowl. Yeah, I would be careful. So no manly bowls. Yeah, so the data suggests that a single fruit, maybe not the giant fruit. I don't know the last time I had a single fruit. Yeah, but a single fruit has like some fruits like kiwi and lime and lemon have almost no fruit does.

And they're totally safe. And other fruits, pineapple and stuff. You have a fair amount of sugar. Berries, for example, blueberries, have so many good things in it. You can eat a big bowl of blueberries, no problem. Raspberry strawberries, they're all, all the berries in general are very good.

Grapes, they have a fair amount of sugar. You eat a bowl of grapes, you're gonna probably raise your uric acid and trigger the activation of this path. You eat a bowl of grapes. You're gonna probably raise your urethic acid and Trigger the activation of this path. You eat a bowl of grapes. You might as well be eating raisins based on what my blood glucose meter tells you. Exactly. Exactly. Yeah. What I would recommend is to try to not eat too many fruit at one time. So for example, there was a lady named Nats. Cheryl Nats, I believe is her name, and she's an anthropologist, and she was studying orangutans. And there's a time when the massing season where all these fruit trees bloom and then fruit at the same time, and then these orangutans go in there, and they won't eat one fruit.

They'll eat 100 fruit at one time. I'm descendants of those orangutans. Me too. Anyway, what she did is she would go up and collect the urine off the trees and show that by measuring things like ketones and so forth, she could show that when they're eating the fruit, they were actually impairing fat oxidation and they were storing energy and their weights go way up. And it's because they ate so many fruit. If you eat one fruit, you're not gonna do that,

but if you eat a huge amount of fruit and get all that fructose, it will start to overwhelm the good things in fruit, but there's so many good things in fruit. There's vitamin C, there's epicatican and flavonols, and potassium and all these things that help fight the effects of fructose. So we generally for patients

that have non-alcoholic fatty liver disease, we tend to restrict them to 10 grams a day of fructose only in the form of whole fruit. Do you think that's overly stringent or is that reasonable? I think that's wonderful if they can do it. Yeah, it basically comes down to you can have Ebola berries. No bananas, no apples, none of the high fructose fruits, or even large fruits. How do you handle this with your kids? You have two kids. They're not that young anymore, but they were young during the time in which you were learning all of this stuff. How did you balance the knowledge that you have? It sucks when your dad knows more about sugar than

almost any human on the planet, and you're a kid and we're wired to want sugar. How did you balance the sane delivery of this knowledge and to your family? So first of all things like birthdays and stuff I let them have birthday cake. But we try to make sugar free, Splenda type cakes at home. So if we make cookies or cakes at home we try to use Splenda. Now they're still high-carb and you can be chocolate in it occasionally, you know. So they do get some exposure to sugar. We don't give them fruit juice, and we don't give them soft.

They are now allowed regular soft drinks, but they can have a diet soft drink. I have a 12-year-old and a 15-year-old. What we try to do is not to be so restrictive that it's disruptive, but we try to be encouraging them to understand that sugar is playing a big role in obesity and diabetes and that it's unhealthy to eat a lot.

What age do you think kids start to, I think that makes sense, which is, to me, it's much more important that you would explain to your kids why. You might be putting these rules in place as opposed to just come down as an authoritarian sort of, this is the way it's going to be. That what age did your kids start to understand that dad wasn't just being a pain, but there's

a real reason that he's in the short run asking us to make a sacrifice? Also, I've been involved in local school programs and there's a foundation called Living Closer Foundation that I've worked with where we've gone into schools and tried to teach children elementary schools to learn from fourth through sixth grade. We try to teach them how to look at labels on foods to understand the amount of sugar. We do a gain where we have someone come up with a cup of tea and add a spoonful of sugar to it and the person likes it and then we say, okay, now we're going to make it like a soft drink and we put in like eight spoonful of sugar to it and the person likes it and then we say okay now We're gonna make it like a soft drink and we put in like eight teaspoons of sugar

And it's like you can't drink it But that's the equivalent of what is in a soft drink of the same volume By the way, do you think the carbonation masks some of that sugar because when you put it that way which is a great way to do it I'd never thought of that experiment. It's almost grotesque. It is It's a great way to do it. I'd never thought of that experiment. It's almost grotesque. It is. It's a great way to teach kids about shit. But do you think the carbonation makes it a little easier to consume such a high amount of sugar in a soft drink? I suspect so.

I haven't tested it, but I suspect that. Or the phosphoric acid. Like there's something else in there that makes it more palatable. Yeah, maybe it's the carbonation, probably is. What about dried fruit, Sada Nona? You know, it was so disappointing when I realized that dried fruit was the fruit dose of fruits without the good things in it. So when you make dried fruit, a lot of the good things and natural fruits are lost. It's like pure fruit, tons. It's disappointing because I love dried fruit,

but I realize it's not the best food for you. Now, if you're out hiking the mountains and you're spending a lot of energy, maybe it's good. Yeah, exactly. That's the thing I've always got to kick out of two things. Have amused me to know, and one is trail mix. The other are sports drinks. Trail mix probably makes sense when you're mountaineering. Sports drinks might make sense when you're a professional athlete,, but paradoxically most trail mix is consumed off the trail and most sports drinks are not consumed by athletes actively playing sports. So again, the dose makes the poison context matters. Absolutely true. Well, Rick, this has been awesome. I want to

be mindful of your time. And I know that this is a nonclinical day for you, which means every minute we're talking, you're not in your lab, and I want you to get back to the lab. So I want to thank you very much. Again, not just for this discussion today, which for me is super interesting, and I think the listeners will agree. But much more importantly, for the work you've done,

you've taken a very different approach to quote unquote the war on sugar. You're less involved on the policy side of this, and the sort of advocacy side of this, but I think what your work has done is created the strongest scientific foundation to the harm of fructose. And you've done it in a largely,

and I say this in a complimentary way, but in a largely unceremonious way, which is you've sort of had your head down, and a lot of people don't know who you are. So I hope that more people become familiar with your work because your, I mean, your CV is comical in terms of like, it's like every week you seem to publish something in either gym or the journal of medicine. The paper we talked about yesterday, which we can't talk about today because it's not yet, we're not there yet.

I look forward to seeing that paper in science, hopefully, in the next six months, but that's an unbelievable tour de force that almost requires us coming back to have a talk about it. So. Well, thank you very much. Those are very kind words. Thank you, Rick.

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