The Peter Attia Drive - #87 - Rick Johnson, M.D.: Fructose—The common link in high blood pressure, insulin resistance, T2D, & obesity?

Episode Date: January 6, 2020

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 discusses the relationship between salt and high blood pressure, provides a masterclass into uric acid, and 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 [4:00]; The relationship between salt and blood pressure (and the role of sugar) [5:45]; Defining fructose, glucose, and sugar [19:30]; An ancient mutation in apes that explains why humans turn fructose into fat so easily [23:00]; The problems with elevated uric acid levels, and what it tells us about how sugar causes disease [31:30]; How sugar causes obesity—explaining the difference in glucose vs. fructose metabolism and the critical pathway induced by fructose [40:00]; Why drinking sugar is worse than eating it [50:00]; Unique ability of sugar to drive oxidative stress to the mitochondria, insulin resistance, and diabetes [54:00]; Why cancer loves fructose [1:00:15]; The many areas of the body that can use fructose [1:05:00]; Fructokinase inhibitors—a potential blockbuster? [1:07:15]; Treating high uric acid levels—Rick's approach with patients [1:10:00]; Salt intake—what advice does Rick give his patients? [1:16:30]; How excess glucose (i.e., high carb diets) can cause problems even in the absence of fructose [1:21:00]; Artificial sweeteners vs. real sugar—which is better? [1:29:15]; Umami, MSG, alcohol, beer—do these have a role in metabolic illness? [1:33:45]; Fructose consumption—Is any amount acceptable? Is fruit okay? Where does Rick draw a hard line? [1:38:45] How does Rick manage the sugar intake of his young kids? [1:43:00]; 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 Attia. This podcast, my website, and my weekly newsletter all 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 this 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 peteratiamd.com forward slash subscribe. Now, without further delay, here's today's episode. I guess this week is Dr. Rick Johnson.

Rick is a professor of medicine in the Department of Nephrology at the University of Colorado, where he's been since 2008. He's basically spent the last 17 years being a division chief across three very prestigious medical schools. He's unbelievably prolific as an author. He has well over 700, approaching 800 publications seemingly every week in JAMA, New England Journal of Medicine, Science, etc. He's lectured across 40 countries, authored two books, one of which we discuss in great detail in this podcast called The Fat Switch, which he wrote about seven or eight years ago. He's been funded extensively by NIH and, in fact, has received the most prestigious grants that NIH has to offer.

His primary focus in research has been on the mechanisms causing kidney disease, but it was doing this that he became really interested in obesity, diabetes, heart disease. And what connected me to Rick, I guess about seven years ago now, maybe a bit longer, was his work on fructose and fructose metabolism. And that's really what we talk a lot about in this podcast. So we start by talking about high blood pressure, the relationship between salt and high blood pressure, which is something that is incredibly controversial. And I actually learned a lot in this podcast.

I'm really glad we had this discussion. because I kind of thought I had this thing figured out in it. I clearly don't. We talk about one of the most interesting bifurcations in evolution with respect to an enzyme that allowed us to use fructose in a certain way that was obviously advantageous. Millions of years ago today, not so much. We talk a lot about uric acid, which you've probably heard me talk about on other podcasts.

This will then be the master's class in it. We talk about artificial sweeteners, and we sort of touch on some of the most promising ideas around pharmacotherapy that are being developed in response to the epidemics of metabolic disease, especially in response to sugar. So this episode gets a little bit deep on some of the biochem. We're going to have, obviously, the show notes will, as usual, provide a great background and a list of references. And I hope you enjoy my discussion with Dr. Rick Johnson. Hey, Rick, thanks so much for opening up your office today and making time.

It's great. I'm very happy to have you. 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 was 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 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. 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 circuitous way that I got there. I was very interested in the cause of high blood pressure and had been known for a long time that high blood pressure is linked with kidney. And in fact, the going theory is 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 and that leads to 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 hyperuricemia 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 in 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. So we started studying fructose. dose, 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 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, the salt, concentration goes up in your blood first. And it translates into a thing called osmolality. And so your serum osmolality goes up. So osmolality is sort of like the ionic pressure build up in a fluid. Is that a way to? 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 1.4. 40 to 142. It's about 6 millimeters. Okay. So they'd go from 120 to 126. Yeah. And that happens acutely. And how long it's take to resolve? Maybe a couple 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 does not go up or does go up? Right. Right. Does not go up. So if you block 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 serum osmolality and blood pressure. Yeah. Well, it turns out that serum osmolality 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 auto-regulatory point. But then what happened was epidemiologic studies showed that even a blood pressure of like 140 over 90 conferred increased risk. It just 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's still a stepwise increase 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's 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 wastebasket 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 walking 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, ten 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 handled 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 inflathingy, 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 physiological ranges of, say, 135 to 145 mill equivalents 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, ischemically, meaning it, for the listener, that results in reduced blood flow and tissue damage due to reduce blood flow and reduced oxygen. And it's that injury that then leads to aberrant 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 transiently by giving medicines or drugs that can cause a constriction of blood vessels.

When you do that, you get a transient reduction of 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. 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 and people with essential hypertension.

Which is not to say heat shock proteins are necessarily bad because so many of the best, 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 nitis 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 hypertension. Before you go on, Rick, how prevalent do you think that particular mechanism is that you just elucidated? Well, 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. Yeah, so you're saying basically the net effective exercise is still

going to far outweigh. Yes, absolutely. But I'd like to get back to 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 the 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 by an increase in serum osmality 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 they also were making fructose. And when we block the metabolism of fructose, we actually block the rise in blood pressure,

as well as the hypertrophy of the heart. So let's pause for a moment. You know, 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. 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 bond together. And that occurs in nature and sugar cane and beets and things like that. Yes, and maple syrup and things like that. Right. So just to clarify for everybody, we, 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 high fructose 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 fructose, again, is a, it's in fruit. And many, many animals use fructose as a means as their primary nutrient or, and also as a way to help store fat. And for example, animals before they hibernate will 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, you know, 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 Proconsul.

They were living about 22 million years ago. and these apes were a big breakthrough in evolution because the prior, the monkeys had already been around, but these were bigger creatures, the apes were, they had bigger brain size, they were tailless, but they did live in the trees, and they lived in tropical rainforests and woodland rainforest, 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 separate, 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 Pasolark, 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, there 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 that are 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 Miocene 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 it's metabolized, generates uric acid. Glucose, when it's metabolized, is not, but fructose, when it's metabolized, makes uric acid. And this mutation led to a much stronger uric acid response to fruit because this mutation was of 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 fructose 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 winters. 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 orangutene, 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 uricase 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 layperson 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 sub subset of them developed a mutation in Euric case. That gave them a superpower, which was now they could be much more efficient to 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 ceded the rest of the rest of the product.

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 air time 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 sort of the wealthy people of the last few hundred years as they started getting and acquiring too much meat and protein. And that was sort of the story. What you're describing is a little bit more nuanced. So tell us more about uric acid. Yeah. So the big problem with having too much uric acid is gout, just as you say. And 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. Can you 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. But 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, are 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's 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 gout from protein is from the DNA and RNA in the protein.

And so, and 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 brewers 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 menopause, 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 that just on balance, 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, gout is also increased by sugar. And even Sir William Osler, the famous physician from the 1890s in his book, Principles and Practice of Medicine, pointed out way back in the 1890s that sugar was a major risk factor for gout, 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 metabolism, 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 Sugarloaf. They talk about the old drinks that

were served like hypocrites 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 in gout back in the 1800s and 17-16-hundred 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 understanding come 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 associated with high blood pressure, and people with gout 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. uricase 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 that was my thought is the crystals would

cause the inflammation in the kidney and that would that was my thought too and that turned out not to be we looked at the kidney there weren't any crystals there so then we realized it was an effect of 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 allopurinol, 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 alipurinol 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 blocked that, we blocked a lot of the effects of sugar to cause metabolic syndrome. And so when we first did it, we said, ah, there's got to be. something wrong here. So we repeated it and we did it different ways and 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 had to tell you that everybody said, ah, 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. 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 fructose. 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 can plummet by 40 or 50 percent in the cell. And that signals a huge number of effects throughout the body. It's like a May Day 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, 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 at expense that you're shunting much of it into fat and into fuel storage. So fructose 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 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, like a hibernating animal, will start eating a lot of fruit in the fall to increase its weight and increase induces 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. 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 Euricase mutation. So can you separate these two phenomena? In other words, if you can restore Euracase 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 intracellular phosphate also falls. And that activates an enzyme called A&P deaminase 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 pathway is 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 that, what you sort of talked about at the very end is effectively the thesis of your book, the fat switch. You explained what ATP is, adenosine tri-phosphate. 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 a mp 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 AMPK pathway versus the AMPD pathway? Yeah, so if it goes down the AMPK pathway, it actually is burning energy, it's burning fat.

it does a lot of really positive things. If it goes down the AMPD 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 phosphorated by the ATP and it becomes fructose 1 phosphate that sequesters 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 AMPD 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 yeah i don't know my evolution well yeah so birds have bifurcicicated off yeah reptiles have the uricase mutation even dinosaurs had the uracase mutation sue the dinosaur the tyrannosaurus rex actually had gout i mean that's got to be why tyrannosaurus rex

was so ornery because if you think of the size of the t-rex great toe i mean that would be infuriating to every bronchosaurus out there. Yeah, I think so. He's eating too many of the bronchosauri. It's ready 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 it. 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 fructose in it, we tend to drink a lot in a short period of time. So if you have a soft drink, you can drink that 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 going to 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 fructose, like, I mean, candy is very concentrated fructose. 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, you know, 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 a soft drink. In that case, the amount of. even though you're drinking a lot, the concentration may never be enough. You never let the phosphate depletion get significant enough in magnitude that it really triggers AMPD. Yes, that's it. You know, 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 have 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 surge in 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 waist circumference, so 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. Now, of course, three out of those five are sufficient to put you in the category. But fructose does 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

is 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. Sanmilan's 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 enochoy hydrotase. I mean, sorry to throw it out there.

Yeah, I'm so sorry. No, no, no, we're here to talk about it. But basically, the oxidative stress inhibits that. So fat acid oxidation goes down. So you block fat burning. And then in addition, you block an enzyme called a conotase 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 islets to the pancreatic islets as well. Uric acid is actually harmful to the islet 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. This is a trick. Weight gain really requires increased calories, really to show it. You know, long-term, maybe just decreasing metabolism will do it. But this is interesting.

You're saying both animals lost weight. Did they lose about the same amount of weight? No, they maintain their weight. Even though they were 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 look the same. But the high sugar group still developed fatty liver. Severe.

And they all became diabetic. Do you recall in that 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.

So 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. And when we measured their insulin levels, they first became insulin resistant with high serum insulin levels, which is what we see. Early diabetes, basically.

With early type 2 diabetes. But over time, the serum insulin levels started to fall. So they almost develop a type 1. diabetes? Well, just like humans do. And what we saw is that the islets used to be the phrase was called islet exhaustion because longstanding type 2 diabetes, we see the same thing. But it's actually low-grade inflammation in the islets. And we could show that there was low-grade inflammation. And it was associated with big-time upregulation of urate transport proteins on the islet. And when we took isolated islets and we put uric acid on them and 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 going to have to export some of that. 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 12 million years ago. And obviously evolution wasn't thinking 12 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're 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.

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 want to do if you don't have enough food around. You want to 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 will use fructose to survive. But, but wait, I'm still confused about this, Rick, because wouldn't that fructose, but they're not storing that fructose is 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 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 they're in a 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, breast, brain,

all these cancer cells, intestinal. 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 when you say block it, do you mean block fructokinase? Yes, which pathway specifically? The fructokinase. So if you take intestinal colon cancer, you put high fructose corn syrup on 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 set? Oh, very high. Like, meaning the 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% of the liver. And at least 10, to 20% can escape into the circulation. And of course, the larger the dose, the more that will pass.

And the kidneys are a big target. There's fructokinase in the brain. There's fructokinase in the islets. 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 got to 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, actually use free molecules of fructose to make ATP in addition to the mainstay of its energy metabolism, which is glucose-driven, and lactate. I think we're now seeing lactate. There's 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 just in the brain and maybe a forerunner for the development of Alzheimer's. And there are actually reports. that A&PD aminesis 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 essential fructosheria 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 even heard of this. 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 metabolizes glucose. But fructose is preferentially metabolized by fructokinase. So these people have very sweet urine going back to Osler, had he tasted their urine? And and he would have confused them potentially with an even sweeter version than the 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's 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 fructokinase inhibitors that are being developed. Pfizer has one that's now in a finished of phase two 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 going to have a smaller on-label market versus what will likely happen, which is people who just want to 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 pharma 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 alipurinol and uric acid. in your clinical practice because you're still, 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 pretty heavy clinical practice. You still actually take care of patients in 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 alipurinol, even for patients who have high uric acid but have not developed gout yet? I do. So our data strongly suggests that lowering uric acid could be beneficial. So what I do is the following. So it turns out that alipurinol is not totally safe. There are some people who can develop reactions to alipurinil drug reactions, especially Asians, about three to four percent of people who are Asian can develop an allergic reaction to alpineal 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's going to provide the benefit that you want, and you have to consider the risk versus benefits. Now, although in animals, alipurinol is totally protective or protects a lot against sugar-induced metabolic syndrome, the data in humans is suggestive. So there's been, for example, four pilot studies showing in improvement in insulin resistance with lowering uric acid in humans. All four are positive. There's a lot of trials in kidney disease showing that lowering uric acid may benefit kidney disease. There's data on blood pressure. We had a paper in the JAMA showing that oil in uric acid could improve blood pressure control in adolescence with hyperurisemia. So there's a lot of supporting data. There are some negative studies too, but the overall weight is now in favor of

lowering 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

based on everything I've done, I have no doubt that that's not good. 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 alipurinol when the uric acid is like eight or higher, and certainly when it's nine or higher. When it's between 5.5 and 8, 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 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 Stevens-Johnson syndrome, which you've alluded to, what are the other potential risks of allopurinol? That's by far the big one. Some people will get just a mild rash without true Stevens Johnson syndrome. They're rare cases where liver function tests may be elevated, but it seems to be rare. If you start it 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 Johnson. And do you have to use alipurinol or can you use euloric or other drugs that also lower uric acid? Well, the xanthin 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 its work outside the cell. So gout is really an extracellular deposition. But when you're thinking about uric acid and its biologic effects, that's an intracellular action. So xaninoxidase makes uric acid inside the cell. So one of the best ways to reduce intracellular uric acid is to give a xanthinoxid inhibitor like alipurinol or fiboxysdate. Now phiboxysstate, I think it's probably just as good as alpurnal, but there was a big clinical trial that was published in the New England Journal that showed that alpyrino was associated with less cardiovascular risk than fiboxusat. There seemed to be an increased cardiovascular events

in the phiboxostat group, meaning less of a reduction or more events? Well, see, the problem was there was no placebo group. Oh yeah, that's a disaster. Yeah, that's a disaster. This is the Vioxx problem with neprachshin. Yeah, yeah. I mean, so the problem is alipurinol is less than phiboxostat. But there's no placebo group. Theoretically, the placebo group would be... Could be higher than both of them. Yeah, could be higher than both of them. And there's actually evidence that that's probably true. But because of the care study, the way it was designed, we don't know. So the FDA is worried about giving phoboxus debt to people with cardiovascular problems because they would prefer you to give allopurinol. But the trouble is, it's not necessarily that phoboxus debt is bad. It's just that it's not

as good as alpurnal. And it's like a hundred thousand times more expensive, too. I mean, it's a 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, well, 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 may have even told this 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 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 in a 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 osmularity to anion-cadion 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, no, salt does play a role. but it's dose timing bolus 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 ate your 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 some 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 drives fat production and in part to preserve water. 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 osmolarity of water is 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 osmality as well, right? 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 issue. 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, pardon 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 high fructose 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. 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 uric acid 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 as it hits the liver induces this enzyme to convert glucose to fructose. Which enzyme is that that converts glucose into fructose? Aldous 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 the 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 block their fructose metabolism. They're eating the same amount of glucose, no change. Exactly. 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, this enzyme 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 within a few weeks. But once your uric acid goes out, that will keep it elevated. So that's another reason potentially to use alipurinol, 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 starch or potatoes to a skinny person who does not have all those reductase induced, they can eat the potatoes they want. In 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. We 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 pear feeding where you control how much they eat and you can have your control group.

This fructose effects will still, as I mentioned, cause fatty liver. Yeah, explain what parapheding 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, and diabetes and so forth. And the way we can show that is by parapheding. In paroffeeding, 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 it controlled where we control the energy intake to be equal among groups.

So they have a control group where they have a control group where they, restricted, there's a caloric restriction on both sides. So you have a high sugar in 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. 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 going to 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. 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 the sugar. If you actually knock out the sweet taste buds or just knock out the tastes in general, animals will still like sugar. They will still

eat sugar, a lot of sugar. How hard is that 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 the 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-nutrative, 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 sucralose, 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, well, 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 aspirin is 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 saccharine, for example, has been associated with little bladder tumors in mice. My recollections that aspartame can generate small, tiny concentrations of formaldehyde.

I think it really comes down to dose. Yes, I think it is dose. 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 is, 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-nutrative versus like 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. in 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,

and 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 amami 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. 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 it is 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 warm and 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 website. it is often promoted. But if the umami foods have a lot of purings which enhance the amami flavor, it actually may raise uric acid and kind of bypass the sugar pathway. And we think that that may turn out to be somewhat of a risk factor too. So do you add this to the list of things that you caution people about? We've already got the pare your salt with water idea, the restrict fructose, and please God don't have ever.

or 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 as in like chips, potato chips? Yeah, potato chips. So you're giving potatoes two votes out of four. Yeah, well, our corn chips are, you know. Okay, got it, got it. The kind of things that people put out on their table. before you eat dinner. And they coat it with salt, which isn't good. Anyway, so high glycemic carbs, 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 it's one of the reasons we like beer. This is that cellular density issue you spoke about. Exactly. And so a beer raises uric 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 if 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 is 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 fructose or high fructose corn syrup. That's fine. So we're going to draw a hard line there. 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 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. You may be right then. Let's talk about natural fruit.

So we've actually done trials in patients with low fructose diet with or 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? And 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 bowls. Yeah. So the data suggests that a single fruit, maybe not the giant food. Okay. 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 dose. 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 other berries in general are very good. Grapes, they have a fair amount of sugar. You eat a bowl of grapes, you're going to probably raise your uric acid and trigger the activation of this pathway. You eat a bowl of grapes, you might as well be eating raisins based on what my blood glucose meter tells me. 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 Knott's, Cheryl Knott's, 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 orangutanes go in there, and they won't eat one fruit. They'll eat 100 fruit at one time. I'm descendants of Those are orangutans. Me too. So 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 were 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 going to 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. There's so many good things in fruit. There's vitamin C. There's epicatacin and flavonals 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 a bowl of 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 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 there 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'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. At 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 game 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 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 teach kids about sugar. 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's true. 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? Is that a no-no?

You know, it was so disappointing when I realized that dried fruit was the fructose 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. 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 a kick out of. Two things have amused me to no end.

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 non-clinical 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 JAMA, the New England 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 to 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. Really enjoyable. And thank you.

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