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

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.760 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.800 here's today's episode. Welcome to a special episode of the drive for this week's episode.

00:00:54.040 We are going to rebroadcast one of our most popular episodes, which is my conversation

00:00:58.300 with Rick Johnson, which was recorded in the fall of 2019 and released in January 2020.

00:01:04.980 As Rick has a new book coming out in February, I'm going to sit down again with Rick for round two

00:01:09.980 of this podcast shortly. And because of this, we want to ensure that everyone is aware of our

00:01:13.900 original discussion. Additionally, if there are any follow-up questions or topics that you think

00:01:17.480 Rick and I should discuss, we'd love to hear those as well going into this. You can help make my prep

00:01:22.200 easier by giving me some questions to ask. As a reminder, Rick is a professor of medicine

00:01:25.880 and nephrology in the renal medicine disease hypertension division at the University of

00:01:30.520 Colorado. He attended medical school at the University of Minnesota and did his internship

00:01:34.020 and fellowship at the University of Washington. In this episode, we talk about all things fructose.

00:01:38.900 We talk about how it relates to high blood pressure, insulin resistant, type two diabetes,

00:01:41.900 and obesity. We also talk about why drinking sugar is worse than eating it, why cancer loves fructose.

00:01:47.940 We talk about uric acid, salt, artificial sweeteners, and more. So without further delay,

00:01:51.940 please enjoy or re-enjoy my conversation with Rick Johnson prior to round two.

00:02:02.100 Hey, Rick, thanks so much for opening up your office today and making time.

00:02:05.200 It's great. I'm very happy to have you here.

00:02:07.420 I've wanted to sit down with you for about a year in this format because I guess we've probably known

00:02:12.640 each other for maybe about six years now. And every discussion has been one of those discussions

00:02:17.660 where at the end of the discussion, I think, man, how am I ever going to remember all of this stuff?

00:02:22.660 And how will I be able to sort of synthesize this to translate it into sort of what I'm doing? And

00:02:28.380 I've said this sort of many times before, but that was the whole kind of reason that I started a podcast

00:02:32.680 was I just found myself every week having a discussion with someone, usually scientists,

00:02:39.320 where I thought this is something that's got to be shared. So you would certainly be one of the three or

00:02:43.460 four people in indirectly. That was a real catalyst for the podcast because of the frequency with which

00:02:48.220 we would either have these dinner discussions or discussions over the phone. And so anyway,

00:02:52.340 for that, I want to thank you. And hopefully the listeners do as well. But in the introduction,

00:02:55.900 I've set this up a little bit as to why this is such an important discussion. And because there's so

00:03:01.080 much to talk about, I just kind of want to jump right into the meat of things. It would be

00:03:05.780 not an exaggeration to say you were one of the world's experts on fructose. And I guess I would just

00:03:12.420 start with the why. Where did that interest come from? You've obviously been doing this for a long

00:03:16.340 time and that passion has been sustained. So what brought you to this point?

00:03:20.060 Well, I'm a kidney doctor. So normally we wouldn't be studying sugar. So it was kind of a circuitous

00:03:26.460 way that I got there. I was very interested in the cause of high blood pressure and had been known for

00:03:32.200 a long time that high blood pressure is linked with kidney. And in fact, the going theory is for years

00:03:39.700 was that the kidney in high blood pressure has a defect in its ability to excrete salt.

00:03:47.040 And so that you end up retaining salt and that leads to elevated blood pressure. And when we were

00:03:51.960 studying, trying to understand how the kidney handles salt in high blood pressure and so forth,

00:03:58.200 we were trying to understand potential pathways. And we stumbled on the fact that hyperuricemia or

00:04:05.440 elevated uric acid could be a very significant risk factor for high blood pressure. And when we

00:04:11.740 started studying uric acid, we realized that when you raised uric acid in animals, they developed high

00:04:17.420 blood pressure. From there, we started to try to understand what made the uric acid go up. And we

00:04:23.020 knew from the literature that sugar and particularly fructose raised uric acid. So we started studying

00:04:28.980 fructose. And pretty soon we were so excited about what we were finding that we just kind of changed

00:04:35.100 our research direction to focus more on how fructose has all of its metabolic effects.

00:04:41.660 Well, there's a lot to unpack there. So let me kind of go back to bits of it. You sort of gloss over

00:04:47.040 the fact that the conventional approach to high blood pressure is that sodium is the culprit. And

00:04:52.980 isn't it still safe to say that most advice around reducing blood pressure comes down to reducing sodium

00:04:59.080 intake? Well, we've actually been studying this pretty extensively. There's a lot of pearls I can teach you

00:05:05.100 or I can talk about related to salt. And when I was in training, I was taught that you restrict a

00:05:13.000 certain amount of salt. You should be on a low salt diet as a mechanism to prevent high blood pressure.

00:05:19.620 It was always about the amount of salt. In fact, we were teaching that for a long time that if you want

00:05:26.160 to have a low blood pressure, you should restrict your salt intake. Or if you want to try to treat

00:05:32.680 your high blood pressure, you should restrict your salt intake. What's happened in the last

00:05:38.080 couple decades has been the increasing knowledge that it isn't really the salt amount that makes a

00:05:45.200 difference, but the salt concentration. So when you eat salt, like if you eat a salty soup,

00:05:52.660 the salt concentration goes up in your blood first. And it translates into a thing called

00:05:59.300 osmolality. And so your serum osmolality goes up. So osmolality is sort of like the

00:06:05.720 ionic pressure buildup in a fluid. Is that a way to... It's sort of like the number of molecules

00:06:11.120 in a set of volume. So literally when you eat salt, if it's really salty, let's say you have a serum

00:06:18.500 sodium concentration of 140 millimoles per liter. If you eat a really salty soup, your serum sodium

00:06:26.100 may go up to 142 or 143. What looks like pretty insignificant, but that actually is what triggers

00:06:32.620 a rise in blood pressure. And so we've actually done the study where we took people and gave them

00:06:37.920 soup with or without salt. And when they drink the salty soup, their serum sodium goes up and their

00:06:44.940 blood pressure shoots up. How much would a person's blood pressure go up if their sodium went from 140

00:06:49.500 to 142? It's about six millimeters. Okay. So they'd go from 120 to 126. Yeah. And that happens acutely.

00:06:56.660 And how long does it take to resolve? Maybe a couple hours. So if we give, and we did this study,

00:07:01.900 we published it last year. If you give salty soup with water so that the serum sodium doesn't go up,

00:07:08.340 they got the same amount of salt. Guess what? The blood pressure doesn't go up.

00:07:12.200 And the serum sodium does so not go up or does go up? Right. Does not go up. So if you block the serum

00:07:17.780 sodium from going up. So basically the closer you can bring the total accumulated concentration of

00:07:23.720 what you ingest down, the more likely you are to prevent this transient rise in serum osmolality and

00:07:31.820 blood pressure. Yeah. Well, it turns out that serum osmolality has a real major role, not only in

00:07:38.360 blood pressure, but also in obesity. And we're going to talk about that in a second. But when you

00:07:42.800 take a high salt diet and your serum sodium goes up, it triggers a rise in blood pressure and it's

00:07:49.020 working through the brain and actually through the liver and other sites too. Pause for a moment.

00:07:54.440 Tell the listeners why it would be better to have a blood pressure of 120 over 80 than 140 over 100.

00:08:00.600 Well, there's a pretty good epidemiologic data that shows that when your blood pressure is high,

00:08:07.340 that you have an increased risk for heart failure and stroke. Those are the two major ones,

00:08:12.360 but it also increases the risk for heart attacks and heart disease in general. Interestingly,

00:08:18.200 there's a very significant inflection point. And what I mean by that is when the blood pressure gets

00:08:24.420 around 160 to 180, right in that range, the risk for stroke goes significantly up and the risk for

00:08:32.740 mortality goes up. And that's because our body tries to auto-regulate to blood pressure. So when

00:08:38.680 the blood pressure goes up, for example, the kidney, the arterials will constrict to reduce the pressure

00:08:46.180 load to the kidney. But when it gets to about 170, it will overcome that restriction and the blood

00:08:52.780 pressure will injure the kidney. Likewise, the brain kind of responds to flow more. So it tries to

00:08:59.660 maintain blood flow. But if the pressure gets high, it tries to protect itself from the high pressure by

00:09:06.360 constricting. But when the pressure is like 170, the risk, it can't constrict enough and you don't want

00:09:13.720 it to constrict that much because it has to maintain flow. And so the pressure ends up increases to the

00:09:20.020 brain and increases the risk for stroke. Now, current guidelines seem even more aggressive.

00:09:25.180 We would manage class one hypertension. We would consider something in the mid-130s to be treatable.

00:09:30.820 Yeah. So let me get there. So originally, when the studies came out, it was very, very clear that if

00:09:37.460 your blood pressure was like 170 or higher, that you had a dramatic increased risk for stroke. And that's

00:09:43.680 because it would pass the auto-regulatory point. But then what happened was epidemiologic studies

00:09:48.800 showed that even a blood pressure of like 140 over 90 conferred increased risk. It just was much less

00:09:56.600 than the 170. So at 170, it just takes off. It's almost the line goes up vertically. But between 140

00:10:04.260 and 160, there is still a stepwise increased risk, but it's just a kind of a more gradual risk. In fact,

00:10:11.540 for things like a stroke, you can start showing an increased risk from 120 over 80 to 140 over 90,

00:10:18.800 leading people to view 120 over 80 as kind of the optimal blood pressure. As you get older,

00:10:24.540 if the blood pressure is really low, you lose your auto-regulation for low blood pressure. And so it

00:10:29.400 increases the risk for kidney disease and problems as well. So you don't want to be extreme on either

00:10:35.780 end, especially as you get older.

00:10:38.400 This whole thing is kind of such a, it's a real clinical mystery in some ways still, because

00:10:42.300 in medical school, we learn about this term called essential hypertension, which is kind of a waste

00:10:47.360 basket term for hypertension or high blood pressure for which we don't have an obvious cause.

00:10:52.340 The problem is, and so having sort of that waste basket term would be okay if it accounted for the

00:10:58.000 minority of cases. But then you get to the clinic and you realize everybody walking around with high

00:11:02.480 blood pressure basically is getting labeled as having quote unquote essential hypertension. So it really is

00:11:07.380 this epidemic without a clear description. Now we're going to come to a lot of reasons that,

00:11:13.020 I mean, I think you have arguably one of the most compelling cases for what is at the root of

00:11:18.220 essential hypertension. But for people listening to this, for doctors listening to this who treat

00:11:22.680 hypertension, I feel like we just haven't made much progress in the 20 years since I've been out of

00:11:27.540 medical school.

00:11:28.420 There have been some real breakthroughs in the understanding of primary hypertension just in the

00:11:33.320 last five, 10 years. And there's two major aspects I can talk about. The first one is that it does appear

00:11:41.560 that salt really is important. And one of the key discoveries was that the kidneys are often normally

00:11:50.880 handle salt fine, but they develop or acquire a change in the kidneys that lead them to hold on to

00:11:58.620 sodium. And the mechanism has been identified just in the last few years. It's due to the fact that there's an

00:12:07.780 inflammatory inflammation that occurs in the kidney. And that inflammation, which is driven by T cells and

00:12:15.440 macrophages, causes a constriction of the blood vessels that leads to low-grade ischemia in the kidney. And that

00:12:23.900 ischemia can translate into increased sodium absorption, which then leads to high serum sodium

00:12:31.120 and the effects.

00:12:33.020 Is there a correlation between serum sodium and blood pressure across normal physiologic ranges of,

00:12:38.620 say, 135 to 145 milliequivalents per liter?

00:12:41.920 Yeah, I believe so. I'm not sure I can quote the paper, but yes, I think that's true.

00:12:47.060 So what you're saying is, in people with high blood pressure that's otherwise viewed as quote-unquote

00:12:52.640 essential, there's an inflammatory response mediated by both T cells and macrophages that injures the

00:13:00.600 kidney ischemically, meaning it, for the listener, that results in reduced blood flow and tissue damage

00:13:06.040 due to reduced blood flow and reduced oxygen. And it's that injury that then leads to aberrant

00:13:12.060 retention of sodium.

00:13:13.340 So there's actually been really a lot of studies looking at the mechanism of the inflammation.

00:13:17.980 And originally it looked like it was, people thought it might be a reactive response of the

00:13:23.280 kidney. So we think that there may be external stimuli that initially cause a decrease in blood

00:13:29.240 flow to the kidney, like a sympathetic nervous system response. You can do it transiently by giving

00:13:35.200 medicines or drugs that can cause a constriction of blood vessels. When you do that, you get a transient

00:13:42.140 reduction in blood flow to the kidney that induces an inflammatory response that then causes persistent

00:13:48.240 reduction in blood flow. And what we've learned in the last few years, and I'm an author in one of

00:13:53.480 these studies, is that this inflammatory reaction can actually be an autoimmune reaction. And we've even

00:14:00.500 identified certain proteins that there's an autoimmune response to, and one is a heat shock protein.

00:14:06.160 And you can actually create high blood pressure in animals by inducing an immune response to this.

00:14:12.400 And you can block the immune response and block the high blood pressure. And now there's even data

00:14:18.900 showing that in humans, that there's evidence for an autoimmune response to heat shock proteins in

00:14:23.940 people with essential hypertension.

00:14:25.300 Which is not to say heat shock proteins are necessarily bad, because so many of the benefits we get out of

00:14:29.960 sauna or exercise may be transmitted through these. But you're saying in a subset of people where the

00:14:35.300 heat shock protein itself becomes the nidus for inflammation via an autoimmune mechanism.

00:14:41.260 Yes. So heat shock proteins are great, just as you say. They do all these really good things.

00:14:46.500 But what happens is they're involved in the clearance of misfolded proteins, and they're

00:14:51.360 helping keep a clean system. But what happens is when you trigger injury to the kidney, for example,

00:14:58.440 these heat shock proteins get produced to help fix problems. But the immune system

00:15:03.860 can sometimes get confused and make an immune response that actually is against the heat shock

00:15:10.240 proteins. And when that happens, you can develop high blood pressure in the animal, and there's some

00:15:15.760 evidence for it in humans. So anyway, so that's one of the big breakthroughs has been the discovery

00:15:20.840 that inflammation in the kidney can be a mechanism for triggering persistent elevations in blood pressure,

00:15:27.780 and probably has a big role in the cause of primary hypertension.

00:15:31.440 Before you go on, Rick, how prevalent do you think that particular mechanism is that you just

00:15:36.560 elucidated? Oh, it's very major. In fact, we've even looked at genetic polymorphisms that link with

00:15:42.320 the development of primary hypertension, and most of them are involved with the immune response. And

00:15:47.300 it looks like this is a major pathway. This creates a bit of a quandary for someone who's trying

00:15:53.220 to rid themselves of hypertension, because wouldn't the implication of this be that exercise or things

00:15:59.040 like exercise that induce heat shock proteins may paradoxically increase their hypertension?

00:16:04.040 I don't think so. So hypertension is kind of a complicated pathway. So there's several different

00:16:09.820 aspects. But exercise is extremely good for improving mitochondrial function, improving the ability

00:16:17.320 for your blood vessels to dilate. It improves kidney function. The benefits of exercise are so much

00:16:24.620 greater. And releasing heat shock proteins, that really occurs with very, I don't know if just general

00:16:32.060 exercise would have a big effect on heat shock proteins. Yeah. So you're saying basically the net

00:16:36.360 effect of exercise is still going to far outweigh. Yes, absolutely. But I'd like to get back to this,

00:16:42.340 the link between salt and sugar, if I could. Okay, because there is this data, as I say, that salt,

00:16:49.580 when it increases the serum sodium, is what drives the acute blood pressure response. And when the

00:16:57.920 kidneys have trouble getting rid of salt, it's easier to get that effect with a salt load. But even with a

00:17:05.280 normal person, you can, with normal blood pressure, you can raise their blood pressure transiently

00:17:10.600 by giving them salt, and you can block it by giving water. Interestingly, in the process of developing

00:17:18.000 high blood pressure, there's the initiators, and then there's the things that make it persistent. And

00:17:24.080 the inflammation in the kidney is involved in the persistence. But what is involved in the initiation

00:17:30.300 turns out that sugar has a major role. And what we discovered is that when you give a high salt

00:17:39.900 diet to animals, that the high salt increases the serum sodium, and the serum sodium, when it goes up,

00:17:48.380 it activates an enzyme that converts glucose, which is in our blood and in our tissues, to fructose.

00:17:57.260 And that conversion to fructose is driven by a high salt diet. And it's driven by an increase in serum

00:18:06.980 osmolality or increase in serum sodium. Once the fructose is made in the body, so this is not fructose

00:18:13.720 coming from the diet, this is made in the body, the fructose gets metabolized and raises blood

00:18:20.860 pressure. And when we gave high salt to animals, they developed an increase in blood pressure. And they

00:18:29.160 also were making fructose. And when we block the metabolism of fructose, we actually block the rise in

00:18:36.040 blood pressure, as well as the hypertrophy of the heart.

00:18:39.040 So let's pause for a moment. You know, I've had Rob Lustig on the podcast before. So anyone who's

00:18:42.800 listened to that will be familiar with what fructose is, what glucose is, what sugar is, all of these

00:18:48.860 things. But can we spend one minute just defining these things for people who haven't listened to that

00:18:54.200 podcast?

00:18:55.340 Sure. So there's different types of sugar. And the main one that we call blood sugar is glucose. And this is the

00:19:03.020 primary sugar that our body uses to make energy. It's the main sugar that's used to make energy. And

00:19:10.360 it can be stored in the tissues as glycogen. And when it's too high, we call it diabetes.

00:19:17.960 When the blood glucose is too low, it's hypoglycemia. And so glucose is like the principal

00:19:24.160 energy fuel, the carbohydrate fuel that we use.

00:19:28.000 And as you said, we store lots of it in our muscles. Once it gets in the muscles, it can't

00:19:32.260 get out. And we store maybe a quarter to a third of it in our liver. And that's mostly there to buffer

00:19:38.080 the blood supply, in particular, the brain. What does glucose taste like? A pure drink of glucose.

00:19:44.140 People like it. Animals like it. But it isn't as sweet as classic sugar. But it is often very much

00:19:51.680 liked by animals. Humans like it. You can buy these dextrose pops and stuff like that. Dextrose,

00:19:57.980 is another word for glucose. And also the kidneys store glycogen and produce glucose too.

00:20:05.720 The second type of sugar is fructose. And the best way to think of fructose is it is a fuel. First off,

00:20:13.340 it's present in fruit. But it turns out to be the sugar that is involved in energy storage rather

00:20:21.200 than energy production. And so when you eat glucose, you use that to produce energy. But when you eat

00:20:27.440 fructose, it will actually trigger changes in the body that will favor the storage of energy. And

00:20:33.840 this is the sugar that animals use to store energy. And you store it in the way of fat,

00:20:40.760 in the way of glycogen, and all those kinds of anything that will facilitate storing energy is

00:20:47.060 done by fructose. And fructose and glucose, if you were looking at pictures of them in a biochemistry

00:20:52.320 book, look pretty similar. They're both ringed carbon structures. They both have six carbons.

00:20:58.080 One of them has a five ring versus a six ring. But, you know, it's sort of interesting to think that

00:21:02.840 molecules that look almost identical with the exception of a couple of bonds different

00:21:07.340 can have quite different properties. Now, fructose tastes a lot sweeter as well.

00:21:11.840 Yes. And so fructose is like in honey and in fruits. And then that's right. So it tastes a lot sweeter.

00:21:18.120 And the other thing is if you mix the fructose and glucose together, you can get what's called

00:21:23.860 high fructose corn syrup. And if they're bound together, you get table sugar. So table sugar or

00:21:29.860 sucrose is one molecule of glucose and fructose bond together.

00:21:34.720 And that occurs in nature in sugar cane and beets and things like that.

00:21:39.120 Yes. And maple syrup and things like that.

00:21:41.420 Right. So just to clarify for everybody, we, when we get a little comfortable with this terminology,

00:21:46.340 throw the word sugar around quite liberally. But it's always important for people to think when

00:21:51.660 we talk about sugar, we could be talking about blood sugar, glucose. We could be talking about

00:21:56.040 fructose by itself. Oftentimes when we talk about sugar in diets, we're talking about added sugars,

00:22:02.500 such as the sucrose and high fructose corn syrup you just alluded to.

00:22:05.760 I want to go back to what you just said about the ability of fructose to store something.

00:22:11.220 But if you don't mind, can we do it through the lens of a beautiful story that you've written

00:22:15.320 about in the past about a mutation that basically allowed that to happen? This thing that took place

00:22:21.820 about 12 to 15 million years ago?

00:22:23.520 Sure. So fructose, again, it's in fruit. And many, many animals use fructose as a means,

00:22:34.240 as their primary nutrient, and also as a way to help store fat. And for example, animals before

00:22:42.060 they hibernate will often eat a lot of ripe fruit, and the ripe fruit gives them the sugar that allows

00:22:47.740 them to store fat. And orangutans will eat huge amounts of fruit at one setting to try to increase

00:22:54.520 their body fat. And we don't get fat from eating fruit, but that's because we eat tart fruit that has

00:23:01.880 less sugar content, and we tend to only eat a few fruit. Whereas if we actually drink fruit juice,

00:23:07.960 that large amounts of fruit juice can actually increase fat. So anyway, so fruit is a nutrient

00:23:13.520 that is used by animals to help store fat. So if you go back about 20 million years ago,

00:23:20.720 the very first fossil apes show up in the world, and they show up in West Africa. And the original one

00:23:30.120 was called proconsul. They were living about 22 million years ago, and these apes were a big breakthrough

00:23:36.420 in evolution because the prior, the monkeys were, had already been around, but these were bigger

00:23:42.020 creatures. The apes were, they had bigger brain size. They were tailless, but they did live in the

00:23:47.340 trees and they lived in tropical rainforests and woodland rainforests. And they would eat primarily

00:23:53.940 fruit. And they were quite successful. And by about 18 million years ago, there were almost at least

00:24:00.600 10 to 20 species of ape that were living in this area of Africa. There was a change in climate.

00:24:07.320 There was some global cooling and the Antarctic started building up ice and the Arctic started

00:24:13.160 building up ice and sea levels fell. And when the sea levels fell, land bridges developed that connected

00:24:20.420 Africa, which had been separate, separated from the other continents. These land bridges opened up so

00:24:27.040 that there was now a way to get out of Africa into Europe and Asia. And many, many species migrated

00:24:33.940 across those land bridges about 17 million years ago. And some of them were the apes. And we see the

00:24:41.440 first apes fossils in places like Pasolar, Turkey and different places of Europe right around 16 million

00:24:49.640 years ago. At that time, there were still forests that were fruiting trees, woodlands. There was fruit

00:24:57.360 all year round. And so the animals, when they moved into Europe, they didn't have to change their habits

00:25:05.040 at all. They were able to continue to eat fruit pretty much all year round. But unfortunately, it

00:25:10.020 continued to get cooler. And by 12 million years ago, the apes started to starve in Europe. And you can

00:25:18.620 tell that from the fossils because they actually have these like tree rings on their teeth that are

00:25:24.580 the developing teeth get this enamel. The enamel doesn't lay down correctly. And they get these

00:25:31.020 like tree rings that show intermittent starvation. They would get a ring every time they would go

00:25:37.420 through a period. And the starvation was seasonal. So it was during the cooler months when suddenly the

00:25:44.000 fruit was not available. And the primary reason was there was a loss of the fig tree. And the fig is a

00:25:49.960 cool fruit that can fruit all year round because the wasp that fertilizes the fruit does so at its

00:25:56.260 own discretion. So the fruit will of a fig tree kind of can occur all year round. So when the fig tree

00:26:02.600 died, suddenly there weren't too many because of the global cooling or perhaps it was the wasp, but the fig

00:26:08.140 trees disappeared. And suddenly these apes did not have enough food to survive during the cooler months

00:26:16.820 and they started to starve. And by six to eight million years ago, the last ape became extinct in

00:26:24.820 Europe. But Africa, although there was global cooling there too, it wasn't as cold and the fruit trees

00:26:31.980 survived all year round. The forest just retracted. So the apes there were able to maintain their normal

00:26:38.840 habits. Well, there was a lot of evidence that there was a lot of evolutionary change occurring in

00:26:44.260 our ancestors during this Miocene period and this period of time when there was the global cooling. And

00:26:52.200 one of them was a mutation in uric acid metabolism. And as I mentioned, sugar and particularly fructose,

00:27:00.740 when it's metabolized, generates uric acid. Glucose, when it's metabolized, does not. But fructose,

00:27:08.400 when it's metabolized, makes uric acid. And this mutation led to a much stronger uric acid response

00:27:17.220 to fruit because this mutation was an enzyme that degrades the uric acid. And when you block that

00:27:22.940 and you eat fruit, your uric acid levels go up much more. And this mutation basically allowed these

00:27:30.520 apes to maintain a very prominent uric acid response. Our group has shown that the way fructose

00:27:38.560 stimulates fat, as well as its other properties like insulin resistance and raising blood pressure,

00:27:47.140 that those abilities are driven in part by the uric acid. So when this mutation occurred,

00:27:53.800 for the same amount of fruit, they were able to store more fat. And so it was like a survival

00:27:59.860 mechanism for this mutation when it showed up. It allowed apes that had very little access to fruit

00:28:05.700 to suddenly maintain more fat stores. And so they could live longer and survive those winters.

00:28:11.900 And we were able to show with Peter Andrews at the Natural History Museum in London, who studies

00:28:17.900 these apes that this might account for a very interesting finding. And the finding is that

00:28:24.160 although we thought the apes became extinct in Europe, and they certainly did become extinct in

00:28:29.540 Europe, the fossil record shows that it was a European ape that made it back to Africa and also to Asia

00:28:37.700 to become our ancestors, as well as the ancestors of the great apes that live in Africa and in Southeast

00:28:45.520 Asia, like the orangutan, that they all came from a common ancestor that was in Europe, and that went

00:28:52.480 back to Africa. And we know from the genetics that that ape carried the uricase mutation.

00:29:00.720 And so this mutation probably occurred at a critical time that provided survival for those apes in Europe

00:29:08.820 to be able to get out of there and make it back to these other regions. But it was now equipped with

00:29:15.240 this mutation that made it sensitive to sugar. And so humans are much more sensitive to sugar than

00:29:23.840 most animals. And it's because of this mutation. And in fact, we actually resurrected the extinct

00:29:30.240 uricase and proved this using the extinct uricase that showing that when you put it into human cells,

00:29:36.860 that it suddenly made us less sensitive to fructose.

00:29:41.240 So the phenotype there, I mean, I guess just to recap that story, which I find so fascinating,

00:29:45.560 by the way, you guys wrote a story about this in Scientific American many years ago, right? I know

00:29:49.620 there was a paper that came out as well, but I mean, the sort of the layperson version in Siam was

00:29:53.620 really great. So basically, these apes go from Africa up to Europe, it gets too cold, we sort of

00:29:59.520 think they die out. But the evidence emerges, actually, a sub sub subset of them developed a mutation in

00:30:05.000 uricase, that gave them a superpower, which was now they could be much more efficient at turning

00:30:10.560 fructose into fat. They had this little byproduct, which is they would also make a boatload of uric

00:30:15.300 acid along the way. But they actually came back to Africa and ultimately seeded the rest of the

00:30:21.220 species. And ultimately, that's why we as humans are among the very rare animals that have uric acid

00:30:27.180 levels that are quite high relative to cats and dogs, for example.

00:30:30.660 Yes, that's exactly correct. So when we were in medical school, Rick, we learned a lot about uric

00:30:35.900 acid through the lens of a disease called gout. And it didn't get a lot of airtime in school,

00:30:41.840 maybe it gets more today. But at the time, it was basically gout is a disease of civilization,

00:30:45.860 it's from eating too much meat. And there's no real problem with it, except for the nuisance of

00:30:51.560 your toe hurts, because uric acid crystallizes, it gets inside joints, it seems to favor the first

00:30:57.500 joint of the great toe. And it's a very painful inflammatory condition. And it's what happened to

00:31:04.020 sort of the wealthy people of the last few hundred years as they started getting and acquiring too

00:31:08.960 much meat and protein. And that was sort of the story. What you're describing is a little bit more

00:31:13.420 nuanced. So tell us more about uric acid.

00:31:16.220 Yeah. So the big problem with having too much uric acid is gout, just as you say. And all the animals

00:31:22.660 that have the uricase mutation are prone to gout. But humans in particular are very prone to gout.

00:31:28.720 And it's because of our diet. So we do eat diets that are high in meat and purines that increase our

00:31:35.680 risk for gout.

00:31:36.480 Can you tell folks what purines are specifically, since it always shows up in this terminology?

00:31:40.780 Sure. So we have proteins, we have fat, we have carbohydrates, but we also have things like

00:31:48.680 RNA and DNA and what we call nucleic acids. So these are the kind of acids that are in the nucleus and

00:31:56.520 that are also in the cell that help drive gene formation and protein, you know, our genetic

00:32:03.240 material and also help dictate the production of proteins. And so DNA and RNA are made up of nucleic

00:32:10.280 acids. And when they're broken down, they're made up of purines. And then uric acid is appearing and

00:32:16.960 it's basically the ultimate breakdown product of DNA and RNA.

00:32:22.020 So the reason protein consumption versus fat or carbohydrate would lead to this is because if

00:32:27.320 you're eating protein, you're eating the DNA and RNA that presumably were still in that tissue?

00:32:32.280 Yes. So the way you get gout from protein is from the DNA and RNA in the protein. And so,

00:32:39.020 and that relates to some extent to how dense the nuclei are. And so like, if you have a very

00:32:46.160 cellular thing like anchovies and these small fish that have lots of DNA and RNA, if you have that,

00:32:56.100 they will develop, you can get gout from that much easier than from other types of meat. And so beer,

00:33:04.540 for example, has brewer's yeast and that is filled with RNA. And so that's why beer can precipitate gout.

00:33:14.340 Now I follow uric acid levels very closely in all of my patients and myself. And there is an

00:33:19.840 unmistakable difference between men and women, at least in my small sample size of patients,

00:33:25.840 where men on average have higher uric acid levels than women. Is that true across the general population?

00:33:32.960 Yes. Even in boys, they'll start to have a higher uric acid than girls. However, after the menopause,

00:33:40.240 uric acid levels go up in women. And that's because estrogen helps excrete uric acid.

00:33:46.640 So it's not, I had sort of, I guess, incorrectly assumed it was that just on balance,

00:33:51.920 men consumed more protein than women.

00:33:54.540 I think that also plays a role. I think that's right.

00:33:57.200 But it sounds like this estrogen explanation makes more sense if it can also explain the

00:34:01.660 observation of menopause.

00:34:03.040 Yes. Going back, gout is also increased by sugar. And even Sir William Osler, the famous

00:34:11.040 physician from the 1890s in his book, Principles and Practice of Medicine, pointed out way back in

00:34:17.260 the 1890s that sugar was a major risk factor for gout, as well as very sweet fruits, he wrote.

00:34:25.680 Anyone who's had gout usually will know that real significant sweets can also precipitate gout.

00:34:32.260 And the reason is because of the fructose content. And when the fructose is metabolized,

00:34:38.160 it generates uric acid. When people were developing gout in the 1800s, it was linked

00:34:44.360 to the wealthier groups in England, for example. They were eating a lot of, as you say, rich foods

00:34:51.380 that included proteins and so forth. But one of the things they were eating a lot of, they were drinking

00:34:57.020 a lot of alcohol, to which they added sugar. I actually did write a paper where we reviewed

00:35:02.880 how much sugar was put in drinks, alcohol drinks, back in the 1700s and 1800s. And it was much more

00:35:09.640 than today. They loved sugar. They put it in many of their drinks. And in fact, I even have a picture

00:35:16.700 of an old pub outside the Tower of London called the Sugar Loaf. They talk about the old drinks that

00:35:22.880 were served, like hypocrites and some of these drinks. And sack and sugar was a name for a drink

00:35:29.140 that they had. I mean, they added a lot of sugar to their drinks. And so part of the rise in gout

00:35:35.500 back in the 1800s and 1700s and 1600s relates to not only just the alcohol and the rich foods,

00:35:43.140 but also to the sugar they were adding.

00:35:45.380 So you were sort of the person who brought onto my radar that there are other things besides

00:35:50.900 gout that one needs to be concerned about when it comes to uric acid. And one of them is blood

00:35:56.480 pressure. So how did that understanding come about?

00:35:59.540 So originally we were studying what causes high blood pressure and there was a lot of

00:36:04.800 epidemiologic studies that linked uric acid with high blood pressure. And as I mentioned, we also knew

00:36:11.400 that there was subtle changes going on in the kidney associated with high blood pressure and

00:36:15.820 people with gout often have low grade kidney disease. So I said, aha, maybe uric acid could

00:36:22.140 have a role in causing kidney disease through causing high blood pressure through its ability to cause

00:36:27.920 kidney disease. And so we took animals and we gave it this uricase inhibitor to raise the uric acid of

00:36:37.420 an animal. And by gosh, they developed high blood pressure. And then we could lower the blood pressure

00:36:42.840 by lowering the uric acid. And when we looked, we were thinking it might be like crystals of uric acid

00:36:48.540 in the kidney.

00:36:49.320 Although that was my thought is the crystals would cause the inflammation in the kidney and that would

00:36:53.540 That was my thought too.

00:36:55.460 And that turned out not to be the case.

00:36:57.220 We looked at the kidney, there weren't any crystals there. So then we realized it was an effect of soluble

00:37:02.340 uric acid. So we started putting soluble uric acid on cells and so forth. And we saw that it had all

00:37:08.640 these biologic effects. And we always had thought uric acid was kind of like a dead end product of

00:37:14.400 something or even might be a good thing because some people said it was an antioxidant, but it was

00:37:19.420 causing pro-inflammatory effects. So then we said, aha, fructose, sugar raises uric acid. Maybe sugar

00:37:29.160 could have a role in blood pressure.

00:37:31.000 What year is it that you're having that thought, Rick?

00:37:34.020 2002. We gave some animals fructose and they developed high blood pressure and we gave them

00:37:41.020 alopurinol, which is a drug to lower uric acid, and it made their blood pressure go back to normal.

00:37:47.940 And it was like this big discovery. But what was totally exciting was these animals also developed

00:37:55.740 insulin resistance. They also developed elevated triglycerides in their blood. They had other

00:38:01.900 fatty liver. And when we lowered the uric acid, we showed benefits on all of those parameters.

00:38:08.300 How does alopurinol work? What's the mechanism by which it lowers uric acid?

00:38:12.320 It blocks uric acid formation. So uric acid is generated from other purines. And when we block that,

00:38:21.220 we blocked a lot of the effects of sugar to cause metabolic syndrome. And so when we first did it,

00:38:30.080 we said, ah, there's got to be something wrong here. So we repeated it and we did it different ways

00:38:34.600 and it didn't matter. It looked like uric acid had a role in how sugar worked. So as we studied this,

00:38:43.160 we started realizing that the process by which uric acid is generated is important in how sugar

00:38:50.060 causes disease. No one believed us initially. I have to tell you that everybody said, ah, yeah,

00:38:58.120 sugar causes gout. But the idea that sugar raises uric acid that causes gout, but the idea that sugar

00:39:04.300 raises uric acid and that is involved in the obesity and the insulin resistance, we don't believe it.

00:39:10.800 What's happened since then is we've learned that the metabolism of fructose

00:39:16.000 is extremely different from the metabolism of glucose. The two look alike, but when fructose is

00:39:25.200 metabolized, there's this process that causes the energy in the cell to fall before it goes up. So

00:39:33.820 normally when you eat a calorie, when you eat any kind of nutrient, we use it to make energy. That's

00:39:39.580 what we do. But when you eat fructose, the energy in the cell falls before it goes up. It's the only

00:39:48.760 nutrient that lowers energy in the cell. Say more about what you mean by that. So are we talking

00:39:54.280 about a cell in the liver, for example? Yes. I'm talking about the cells that metabolize the

00:39:58.660 fructose. Okay. So we'll contrast it with glucose. So if glucose enters a cell, it gets turned into

00:40:04.800 pyruvate and ultimately ATP is made. So you're saying total energy goes up as a result of metabolizing

00:40:12.000 that glucose. So whenever you metabolize any kind of calorie, any kind of food, you eat food, you're

00:40:19.440 going to metabolize it to make energy. That's what we do. We try to break down the food and we use it to

00:40:24.620 make energy. That energy is called ATP. And ATP is the currency in our body that we use to make us run,

00:40:33.520 walk, think, talk, everything. So this ATP is pretty critical. But to make ATP, you have to spend a

00:40:43.580 little of it to make it. So the process of breaking down and metabolizing food or glucose or fructose

00:40:52.840 requires spending a little bit of ATP before you make it. Well, what happens is when you metabolize

00:41:00.280 glucose, you do spend some ATP, but the body has a system whereby feeds back to stop the process before

00:41:09.880 any significant ATP depletion occurs. So for example, there's an enzyme called phosphofructokinase that's

00:41:17.380 used in glucose metabolism. If ATP levels fall, that enzyme gets turned off to stop glucose metabolism,

00:41:26.820 to allow ATP levels to come back up. But when fructose is metabolized, the enzyme that metabolizes

00:41:34.820 fructose is called fructokinase. And when that metabolizes fructose, it consumes ATP in an unregulated

00:41:43.460 way. So if the cell sees a lot of fructose, the ATP levels can plummet by 40 or 50% in the cell.

00:41:52.500 And that signals a huge number of effects throughout the body. It's like a May Day signal.

00:42:00.060 It says, we're under attack. We're running out of energy. And so it switches the animal into a

00:42:07.340 condition in which they're trying to preserve their energy. So they reduce their metabolism.

00:42:13.640 They reduce their expenditure. They're resting the energy expenditure. They shunt the energy that

00:42:20.440 they're eating. The calories they're eating into fat and glycogen as opposed to making more ATP.

00:42:26.840 They're trying to protect the body by putting you into a system where you try to store fuel.

00:42:32.680 It triggers hunger and thirst that makes you want to eat more. So you eat more to restore the energy,

00:42:39.920 but at expense that you're shunting much of it into fat and into fuel storage.

00:42:45.980 So fructose turns out to be used by animals as a mechanism to store fat. Normally animals will

00:42:52.920 regulate their weight beautifully. They just maintain their weight normally. If you take

00:42:57.460 an animal and you put a tube down its throat and give it extra food to make it gain weight,

00:43:03.060 if you take the tube out, the animal will go right back to its normal weight. If you starve an animal

00:43:08.760 and so it's below its normal weight, and then you let it just eat, it will eat back to its regular weight.

00:43:15.200 But when it wants to gain fat, it will do so usually through a mechanism that involves fructose.

00:43:22.280 So what they do is they, like a hibernating animal, will start eating a lot of fruit in the fall to

00:43:28.780 increase its weight and increase, induces insulin resistance. It gets hungry. It drops its metabolism

00:43:34.780 so that most of the energy it eats goes into fat. And the same thing with a long distance migrating

00:43:41.560 bird, they'll start eating fruit to get the fructose. And so this is a very common pattern.

00:43:48.820 And it's driven by that ATP depletion.

00:43:52.500 And this is distinct or in parallel, of course, to this uricase mutation. So can you separate these

00:43:58.740 two phenomenon? In other words, if you can restore uricase to the non-mutated version,

00:44:05.740 do you still have this problem around the ATP depletion?

00:44:09.600 Yeah. So the ATP depletion triggers a series of reactions. And what happens, what the key one is,

00:44:17.500 not only does ATP decrease in the cell, but intracellular phosphate also falls. And that

00:44:24.160 activates an enzyme called AMP deaminase that converts the broken down product of ATP, which is AMP,

00:44:32.260 and it converts it to uric acid. And that process has multiple steps. And we know that that whole

00:44:39.420 pathway is involved in the generation and stimulation of fat, insulin resistance, fatty liver,

00:44:47.880 elevations in blood pressure, a variety of effects. And that pathway is what seems to be critical

00:44:56.800 for inducing obesity from sugar.

00:44:59.320 Let's go through that again, because what you sort of talked about at the very end is effectively the

00:45:04.720 thesis of your book, The Fat Switch. You explained what ATP is, adenosine triphosphate. And the T,

00:45:12.460 of course, stands for tri. There are three phosphates. It's the liberation of a phosphate that is the

00:45:17.360 production of energy. So when you need to breathe, you need to move, when you need to do anything,

00:45:22.600 you have to turn ATP into ADP. So the chemical reaction is adenosine triphosphate becomes adenosine

00:45:31.860 diphosphate. One phosphate escapes, and that's what gives us the energy. Now that can happen again. ADP can

00:45:41.180 lose one of its two remaining phosphates and become AMP, adenosine monophosphate. What you set after is the

00:45:49.800 really critical, critical piece of this, which is when you have a molecule of adenosine monophosphate,

00:45:57.480 it stands at a proverbial fork in the road. It can either go down a path that is driven by something

00:46:05.340 called AMPK or AMP kinase, or it can go down the pathway of AMPD. Now let's go back to this point,

00:46:17.000 because I, again, it seems everything comes down to that choice. What happens if AMP goes down the

00:46:24.680 AMPK pathway versus the AMPD pathway? Yeah. So if it goes down the AMPK pathway,

00:46:30.800 it actually is burning energy. It's burning fat. It does a lot of really positive things. If it goes

00:46:37.860 down the AMPD pathway, it goes down a fat storage pathway. So it's their exact kind of opposites.

00:46:44.260 AMPD, if you stimulate it, it will cause insulin resistance and eventually diabetes. Whereas if

00:46:51.300 you stimulate AMPK, you can actually use that like metformin to actually treat diabetes. So that fork

00:46:57.580 is critical. And what drives that switch is the fall in intracellular phosphate. And the reason that

00:47:05.460 phosphate falls is because it's taken up in the fructose one phosphate, or it's taken up by fructose.

00:47:11.220 So the fructose gets phosphorylated by the ATP and it becomes fructose one phosphate that sequesters

00:47:17.260 phosphate. And there is this process where both ATP levels fall and intracellular phosphate falls,

00:47:24.520 and that triggers this AMPD pathway. And if we interrupt the AMPD pathway, we can block a lot

00:47:31.700 of the metabolic effects. Do other animals also have this phenomenon?

00:47:35.940 Oh yeah. No, we can show this. We actually showed it in hibernating squirrels. So when a squirrel wants

00:47:42.060 to gain weight, it will activate the pathway for AMPD. When it's hibernating and burning the fat,

00:47:49.460 it activates the AMPK pathway.

00:47:51.680 I got it. So even though humans and our most close descendants in primates have the uricase mutation,

00:47:59.600 this ability to toggle between AMPK and AMPD is unique to any species that has the potential to

00:48:06.900 gain weight and wants to use it to their advantage.

00:48:09.040 Oh, absolutely. Part of the pathway through which AMPD is working involves the generation of uric acid.

00:48:15.280 So we know that the uric acid, when it's going up inside the cell, is doing all kinds of biologic

00:48:21.860 effects. And the AMPD is driving that. There may be other things besides the uric acid.

00:48:27.360 So the hummingbird or the squirrel can still store fat. They just don't get the bump in uric acid that

00:48:32.100 comes with it because they don't have the uricase mutation.

00:48:34.620 Well, actually the hummingbird does have the uricase mutation.

00:48:37.280 Oh really?

00:48:37.780 Yeah.

00:48:38.080 I don't know my evolution well enough.

00:48:39.540 Yeah. So birds have the uricase.

00:48:40.800 Birds bifurcated off after then.

00:48:42.200 Yeah. Reptiles have the uricase mutation. Even dinosaurs had the uricase mutation.

00:48:47.960 Sue, the dinosaur, the Tyrannosaurus rex actually had gout.

00:48:52.080 I mean, that's got to be why Tyrannosaurus rex was so ornery. Because if you think of the size of the T-Rex,

00:48:57.140 it's great toe. I mean, that would be infuriating to every bronchosaurus out there.

00:49:01.740 Yeah, I think so.

00:49:02.760 He's eating too many of the bronchosauri. Sorry to get back into the minutiae of this,

00:49:06.380 but it's important. You still have to phosphorylate glucose during its metabolism.

00:49:12.020 Why is it that the phosphorylation of glucose during its metabolism to pyruvate doesn't result

00:49:16.580 in a strong enough drop in intracellular phosphate to cause the same problem?

00:49:20.880 Because the reaction stops. Whenever there's the phosphate and ATP levels start dropping a little

00:49:27.400 bit.

00:49:27.420 You have that autoregulatory thing with the-

00:49:29.160 There's an autoregulatory thing with it. The enzyme stops functioning. It's inhibited.

00:49:34.680 And then that allows the ATP levels to stay normal. So here's a really cool follow-up of this. And that

00:49:41.480 is that sugar is much more likely to cause obesity if you drink it rather than if you eat it. And the

00:49:49.980 reason for that is that when you drink a drink that has fructose in it, we tend to drink a lot

00:49:57.340 in a short period of time. So if you have a soft drink, you can drink, not only does it have a lot

00:50:02.580 of sugar, but we tend to drink it fast. And so the concentration of fructose turns out to be high

00:50:12.320 when it gets to the liver. And it's the concentration that triggers this reaction. So

00:50:17.140 if the concentration of fructose is really low, the ATP depletion may not be significant to drive

00:50:23.960 dramatic metabolic effects. But if the concentration of fructose is really high,

00:50:29.680 then you're going to get a big metabolic effect.

00:50:33.080 So eating like a candy bar where it's coming with lots of fat, lots of glucose, lots of all sorts of

00:50:39.620 things, lots of protein, you know, if it's like a Snickers bar and it's got nuts or whatever,

00:50:44.440 even if it's the same amount of fructose, even if you're talking about 25 grams of fructose versus

00:50:50.120 25 grams of fructose, you would drink very quickly. You're saying equal amounts of fructose can

00:50:55.840 produce a different effect if both the speed and the concentration with which they arrive at the

00:51:01.280 liver are different.

00:51:02.100 Yeah, it's the amount, it's the speed, and it's ultimately how rapidly it's absorbed.

00:51:08.360 So if you drink something, if you take a lot of fructose, like, I mean, candy is very concentrated

00:51:13.620 fructose. I mean, if you eat that, for example, on an empty stomach, that will be absorbed faster than

00:51:19.980 if you eat it with oatmeal or something, you know, where there's fiber and so forth. And so the speed

00:51:25.280 of absorption in the, makes a difference. So for example, if I was working for a high fructose corn

00:51:32.620 syrup company, and I wanted to prove that a soft drink wasn't bad, I could do a study where I would

00:51:40.240 give the soft drinks to people, but I would give it over, you're only allowed to make a tiny sip

00:51:46.400 every 10 minutes. So it takes you three hours to drink a soft drink. In that case, the amount,

00:51:54.500 even though you're drinking a lot, the concentration may never be enough.

00:51:58.260 You never let the phosphate depletion get significant enough in magnitude that it

00:52:02.960 really triggers AMPD.

00:52:05.380 Yes, that's it.

00:52:07.120 You know, it's really interesting. I think of all the sugar, the pro-sugar studies I've read that are

00:52:11.780 funded by the sugar industry. I don't think I've ever dug into the methodology to look at factors

00:52:18.320 like that specifically.

00:52:20.040 Well, the other issue is like, if you just take a single dose of fructose, most of the metabolic

00:52:25.180 effects are best seen like in the first four hours following the ingestion. So the triglycerides go up

00:52:32.100 and the uric acid goes up and the blood pressure goes up. But if you just do a single dose study,

00:52:38.300 if you then look the following morning, or the effects have now kind of come back down,

00:52:43.840 then you can't really show it. And a lot of these studies, they design it that way. So they say,

00:52:49.380 aha, fructose doesn't raise uric acid, but we measured it after fasting overnight. But the surge

00:52:56.240 in uric acid occurred earlier. So that's the common trick.

00:53:00.400 So all these things you're talking about with fructose seem to fit almost directly into the

00:53:07.840 five characteristics of metabolic syndrome, which are elevated glucose. So that insulin resistance

00:53:15.440 would be manifested as an elevated glucose, elevated blood pressure, elevated waist circumference,

00:53:22.420 so storage of fat, elevated triglycerides, what you just said. And the only one we didn't address

00:53:30.280 is low HDL cholesterol, which is the fifth finding. Now, of course, three out of those five are

00:53:36.280 sufficient to put you in the category, but fructose does all five.

00:53:39.800 What is the mechanism by, so you've already described the mechanism by which it does

00:53:42.860 three of them. We alluded loosely to how it raises triglycerides, but I'd like to talk about that more.

00:53:48.920 And then, of course, I'd like to hear how it lowers HDL cholesterol.

00:53:51.740 Okay. So the uric acid generated by fructose has a very pronounced effect to stimulate oxidative stress

00:54:01.460 in the mitochondria. And fructose also generates lactate big time. And the lactate also has effects

00:54:08.700 on mitochondria, as you learned from Dr. Sammelan's talk. And in addition, fructose preferentially

00:54:16.980 decreases mitochondrial function and stimulates glycolysis. And so all those things cause,

00:54:24.680 you get this big oxidative stress to the mitochondria. And there's an enzyme in the

00:54:29.380 mitochondria that drives fat oxidation called enol-coahydritase. I mean, sorry to-

00:54:35.340 Throw it out there.

00:54:36.260 Yeah, I'm so sorry, man.

00:54:37.080 No, no, no. We're here to talk about it.

00:54:38.560 But basically, the oxidative stress inhibits that. So fatty acid oxidation goes down. So

00:54:44.240 you block fat burning. And then in addition, you block an enzyme called aconitase with oxidative

00:54:51.080 stress to the mitochondria. And that increases citrate, which drives fat generation. And so

00:54:56.580 you end up with fatty liver that's driven by both increased fat synthesis and a block in fat

00:55:02.460 burning. The mitochondrial oxidative stress also is very much linked with the development of insulin

00:55:09.160 resistance. And then uric acid is also degenerated. Uric acid is also causing oxidative stress to the

00:55:15.880 islets, to the pancreatic islets as well.

00:55:18.840 Uric acid is actually harmful to the islet cells of the pancreas?

00:55:22.820 Uh-huh. In fact, if you give sugar, we did a study where we gave sugar to animals where we

00:55:29.660 we actually restricted the amount of calories. The rats were getting, they were on a diet,

00:55:35.440 basically. They were on a diet.

00:55:36.920 They were on a high sugar, low calorie diet.

00:55:38.900 Right. And then we had as a control, rats that got the same number of calories, but they weren't

00:55:44.240 getting the sugar.

00:55:45.180 Right. So just a low calorie, low sugar diet.

00:55:47.120 Yeah. And when we gave the high sugar, low calorie diet, all the animals developed fatty liver,

00:55:55.500 hypertension, insulin resistance.

00:55:57.660 Did they actually gain weight?

00:55:59.820 No, no. This is a trick. Weight gain really requires increased calories really to show

00:56:06.800 it. You know, long-term, maybe just decreasing metabolism will do it.

00:56:10.180 But this is interesting. You're saying both animals lost weight. Did they lose about the

00:56:13.460 same amount of weight?

00:56:14.120 No, they maintained their weight. Even though they're eating 90% of what they normally eat,

00:56:18.880 they were able to maintain.

00:56:20.120 So both groups slowed their metabolism enough to maintain weight at a 10% reduction of calories.

00:56:25.200 So on the outside, they look the same, but the high sugar group still developed fatty liver.

00:56:30.820 Severe. And they all became diabetic.

00:56:33.040 Do you recall in that study, Rick, what the actual percentage of their macros that came from

00:56:37.380 fructose?

00:56:38.220 20%.

00:56:38.660 Right. So the critic will say, well, that's highly unnatural. Although in reality,

00:56:41.700 it's not that unnatural. There are lots of people, unfortunately, walking around getting 20%

00:56:45.380 of their energy input from that. So it's not physiologically completely out of whack,

00:56:49.920 but as a proof of concept, these animals got diabetes without gaining weight. They got fatty

00:56:55.320 liver disease without gaining weight. They were, by definition, insulin resistant.

00:56:59.440 Right. And when we measured their insulin levels, they first became insulin resistant with high serum

00:57:05.300 insulin levels, which is what we see.

00:57:07.920 Early diabetes, basically.

00:57:08.540 With early type 2 diabetes. But over time, the serum insulin levels started to fall.

00:57:14.020 So they almost develop a type 1 diabetes.

00:57:15.840 Well, just like humans do. And what we saw is that the islets used to be, the phrase was called

00:57:21.440 islet exhaustion because longstanding type 2 diabetes, we see the same thing, but it's actually

00:57:28.140 low grade inflammation in the islets. And we could show that there was low grade inflammation

00:57:32.580 and it was associated with big time upregulation of urate transport proteins on the islet. And when we

00:57:41.060 took isolated islets and we put uric acid on them, it induced oxidative stress and over time caused a

00:57:47.580 drop in insulin level. So what we think is going on is that sugar causes diabetes through this pathway

00:57:56.400 that we've been talking about. And it involves initially insulin resistance, but over time it

00:58:01.520 will cause islet cell dysfunction as well. And this has been confirmed by other groups now.

00:58:06.960 That sort of comes to the triglyceride story, right? If you have a net accumulation of fat in

00:58:12.000 the liver, you're going to have to export some of that in the form of VLDL, a very low density

00:58:17.380 lipoprotein. So that would drive up the serum triglyceride. What's driving down the HDL cholesterol?

00:58:22.960 You know, I haven't studied that personally. I don't really know, but I did see that there are

00:58:27.220 reports that fructose can lower HDL like in animals and stuff, but I don't really know the mechanism.

00:58:33.480 When you sort of pause for a moment, Rick, do you ever worry that talking about fructose this way

00:58:39.580 just seems, I don't know what the word is. I don't think it's necessarily being too much of a

00:58:43.820 reductionist, but it almost seems too simple that this one molecule could simultaneously have probably

00:58:52.400 allowed our species to survive during this very cold spell six to 12 million years ago.

00:58:58.480 And obviously evolution wasn't thinking 12 million years into the future that we'd be

00:59:05.100 flush with fructose. And yet here we are today. One could interpret what you're saying to mean

00:59:11.660 if you simply had no fructose in your diet, most of the bad things we think about metabolically would

00:59:18.800 go away. Is that a fair assessment? Yeah, I think that's true. So let me give you another

00:59:23.480 one where we've really learned a lot. I don't know if you are aware of the relationship with

00:59:28.760 cancer, but what we've learned is that fructose was an incredible survival nutrient in the setting

00:59:36.520 of near starvation. So as I mentioned, what we're learning is all these animals use fructose. They

00:59:43.000 either get it from their diet or they make it in their body and they use that to help them survive.

00:59:49.780 And we can talk about it, but it involves not just storing energy, but they use fructose to store

00:59:56.040 water. And we can talk about that and they use it to become insulin resistant. Insulin resistance is a

01:00:01.340 survival mechanism whereby increasing blood glucose and preventing glucose from taking up in the skeletal

01:00:07.900 muscle, it preserves it for the brain, which is what you want to do if you don't have enough food

01:00:12.420 around. You want to be able to think so you can escape predators and so forth. So it was a survival

01:00:18.600 tool to increase energy. And it actually also protected animals from a low oxygen state. So by switching,

01:00:28.260 by reducing mitochondrial function and stimulating this thing called glycolysis, it allowed the animal

01:00:35.440 to survive with a lower oxygen state. And so we know, for example, that the naked mole rat, which lives in

01:00:42.860 burrows, very low oxygen burrows, they make fructose to survive when they're in those burrows. So suddenly

01:00:51.220 the fructose goes up in their blood and they use it to survive the low oxygen tension there because they

01:00:57.440 switch from mitochondrial metabolism to glycolysis. But why can't they just rely more on glucose for which

01:01:05.500 we have such an abundant apparatus to store it at large amounts? Is there an energetic reason for

01:01:12.220 fructose? A lot of the fructose is converted to glucose and to lactate, which can be converted to

01:01:17.760 glucose. And then it's driven through this glycolysis pathway. So it turns out though, that what happens is

01:01:24.580 when you metabolize glucose, a lot of it will go through mitochondrial metabolism. And so if we can

01:01:29.900 inhibit mitochondrial metabolism, which uses oxygen, we can live off glycolysis, which doesn't require

01:01:37.220 oxygen. So what happens is in a low oxygen state, like the naked mole rat will use fructose to

01:01:44.960 survive. But cancers... But wait, I'm still confused about this, Rick, because wouldn't that fructose,

01:01:51.080 but they're not storing that fructose as fat then, because that would be the worst fuel they could have

01:01:55.760 around in a low oxygen environment, right? Well, so fructose is increasing glycogen and lipid,

01:02:03.080 but it's also reducing mitochondrial use. When you're eating fructose, you actually are not burning

01:02:09.880 the fat. You are storing the fat. And then, so what it's doing is it's putting you into a glycolytic

01:02:16.720 state. So animals use it to store fat and then they fast and then they burn the fat. So they hibernate or

01:02:25.620 they go flying long distances where they have no food and then they switch. And then the fat that

01:02:31.680 they've stored suddenly becomes their survival. But during the time that they're in a low oxygen

01:02:37.320 state, they want to have fructose on board because the fructose is helping them to survive low oxygen

01:02:44.440 by switching their metabolism. But unfortunately, like cancers also live in a low oxygen state.

01:02:50.740 And so these cancers love fructose as their fuel because it helps support them surviving in a low

01:02:58.360 oxygen state. So recently, it's been shown that many cancers, colon, liver, kidney, breast, brain,

01:03:07.500 all these cancer cells, intestinal, they all tend to like fructoses as their preferential fuel.

01:03:14.560 There was just a paper in Science a few weeks ago. And if you block that fructose pathway,

01:03:19.080 the cancers don't do as well.

01:03:21.500 And when you say block it, do you mean block fructokinase?

01:03:24.560 Yes.

01:03:24.700 Which pathway specifically?

01:03:25.780 The fructokinase. So if you take intestinal colon cancer, you put high fructose corn syrup

01:03:30.760 on it, they love it. They grow, they metastasize. And if you block fructokinase and block fructose

01:03:37.340 metabolism, you can block a lot of the growth of those cancers.

01:03:40.840 Do you have a sense of how much you're blocking it?

01:03:43.280 It's pretty remarkable. It's like 50% or more.

01:03:45.940 And we know it's the fructose, not the glucose, presumably because we don't impair glucose

01:03:51.240 metabolism at all in that experiment.

01:03:53.260 That's correct. And also they were able to show that this was driven by that shift from a

01:03:58.540 mitochondrial-based metabolism to a glycolytic metabolism.

01:04:02.200 And what happens to lactate levels in that setting?

01:04:04.900 Oh, very high.

01:04:05.540 Like meaning the more fructose they have, the higher the lactate level?

01:04:08.340 Yes.

01:04:08.720 Again, very counterintuitive because aren't we sort of taught that the liver is the only organ

01:04:15.160 that can really process fructose and that it all sort of accumulates there? And I mean,

01:04:20.020 conventional thinking is that fructose really doesn't have much of an interaction outside of

01:04:24.520 the liver unless converted to glucose, correct?

01:04:27.220 That was said by a lot of people, but the findings show that about 20% of fructose is used by the

01:04:33.620 intestine or maybe 40% by the liver. And at least 10 to 20% can escape into the circulation. And of

01:04:42.200 course, if the larger the dose, the more that will pass. And the kidney's a big target. There's

01:04:48.380 fructokinase in the brain. There's fructokinase in the islets. There's fructokinase in the adipose

01:04:56.240 tissue.

01:04:56.620 Does the muscle have fructokinase?

01:04:58.680 There's some thought that fructokinase may be in the muscle. It's got to be very low,

01:05:03.080 but there's some thought that fructose is being metabolized in the skeletal muscle.

01:05:07.240 And one of the things that's interesting is there was a paper in Nature that showed that the heart

01:05:13.420 normally doesn't have fructokinase, but when you have a heart attack, the low oxygen state there

01:05:19.420 induces the fructokinase. And there's probably production, endogenous production of fructose.

01:05:26.320 And it seems to be involved in cardiac remodeling. So it's probably involved in more things than we

01:05:31.560 think of. And certainly it's in the brain.

01:05:34.040 Which means that in theory, the brain could actually use free molecules of fructose to make

01:05:41.320 ATP in addition to the mainstay of its energy metabolism, which is glucose driven and lactate.

01:05:47.180 I think we're now seeing lactate.

01:05:48.540 There's actually some evidence that first off, we know that fructokinase is in the brain. We know

01:05:54.180 the brain can make fructose and there's increasing evidence that insulin resistances can occur just in

01:06:01.820 the brain and may be a forerunner for the development of Alzheimer's. And there are actually

01:06:07.820 reports that AMPD aminase is high in the brains of Alzheimer's patients. And it raises the possibility

01:06:14.480 that local fructose metabolism could be involved in disorders like that.

01:06:18.480 Are there any people with naturally occurring mutations in fructokinase that render it less

01:06:22.460 capable?

01:06:23.440 Yeah. So there are people with a condition called the essential fructose area where they

01:06:27.520 are born without active fructokinase and they live normally. No one's ever been reported to have

01:06:32.960 type 2 diabetes or obesity.

01:06:34.980 So these people, if I'm understanding you correctly, are genetically immune to the harm of sugar?

01:06:41.060 Yes.

01:06:41.340 And they pee out all the fructose?

01:06:43.400 Yes.

01:06:44.020 Okay. So that seems to be an interesting topic. This must be very rare. I've never even heard of

01:06:48.900 this.

01:06:48.920 Yeah. It's a rare condition. They actually don't pee out all the fructose. Some fructose can be

01:06:53.340 metabolized by an enzyme called hexokinase, which normally metabolizes glucose. But fructose is

01:07:01.040 preferentially metabolized by fructokinase.

01:07:04.020 So these people have very sweet urine. Going back to Osler, had he tasted their urine, he would have

01:07:09.300 confused them potentially with an even sweeter version than the people with ultimately type 2

01:07:13.940 diabetes.

01:07:14.460 That's how they were discovered because they would have reducing sugars, which was fructose in their

01:07:20.260 urine, that was picked up with the old test they used to use for diabetes, but then they didn't have

01:07:25.800 diabetes when they tested them.

01:07:27.280 And these people could literally just consume all the sugar they wanted and their uric acid is not

01:07:32.020 going to go up. Their blood pressure is not going to go up. Their trigs don't go up. They don't

01:07:35.300 gain weight. They don't become insulin resistant.

01:07:37.160 That's right.

01:07:37.640 So is there any benefit to having fructokinase if you're not hibernating or in a world where

01:07:43.400 famine is potentially coming your way?

01:07:46.020 It's really a survival enzyme that was meant to help in situations where there was food shortage.

01:07:52.460 If you live in the Western world and you just have to go down to the grocery store, no. I think

01:07:59.120 living without fructokinase would probably solve a lot of the world's health problems. I mean,

01:08:04.280 there are fructokinase inhibitors that are being developed. Pfizer has one that's now in a finished

01:08:09.900 a phase two trial. It was quite successful at treating fatty liver. And so now they're taking

01:08:16.440 that drug to phase three.

01:08:18.260 Wow. That's a potential blockbuster actually. Of course, it begs an interesting question, which is

01:08:23.580 how will that drug be treated? Will it be only used as a way to treat an active condition such as fatty

01:08:30.080 liver, in which case it's going to have a smaller on-label market versus what will likely happen,

01:08:35.960 which is people who just want to be able to have more sugar without the consequences of it would

01:08:40.480 take it, correct? Yeah.

01:08:41.600 Although it's probably priced to avoid that, I'm guessing.

01:08:44.480 Anyway, yeah. There's a lot of interest in fructokinase inhibitors. There's other big pharma

01:08:48.960 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

01:08:55.500 might be. So the work that we've just discussed is sort of been, you've been at this since 2002,

01:09:00.440 basically, specifically with respect to this. Let's go back to allopurinol and uric acid in your

01:09:06.380 clinical practice, because you're still, you've spent 17 years as the division head of nephrology

01:09:13.500 across three world-class medical centers, most currently the University of Colorado. And yet I was

01:09:19.120 surprised to learn over dinner the other day that you still have a very pretty heavy clinical practice.

01:09:24.160 You still actually take care of patients in the inpatient ward, and you probably spend a quarter

01:09:29.440 of your time in clinic. So how do you put some of this stuff into practice? Do you liberally use

01:09:35.020 allopurinol even for patients who have high uric acid, but have not developed gout yet?

01:09:39.580 I do. So our data strongly suggests that lowering uric acid could be beneficial. So what I do is the

01:09:47.440 following. So it turns out that allopurinol is not totally safe. There's some people who can develop

01:09:53.500 reactions to allopurinol drug reactions, especially Asians. About three to four percent of people who

01:10:00.580 are Asian can develop an allergic reaction to allopurinol where they can get rashes and it can

01:10:06.680 be pretty severe. And it's about two percent in African-Americans and it's about 0.5 percent

01:10:12.980 in Caucasians. You can test for it. There's a test called the HLA-B58 test. But the point of the

01:10:18.820 matter is that no drug is fully safe. Every drug has side effects. So ideally, you'd want to really

01:10:25.840 be certain that your drug's going to provide the benefit that you want, and you have to consider

01:10:31.200 the risk versus benefits. Now, although in animals, allopurinol is totally protective or protects a lot

01:10:38.320 against sugar-induced metabolic syndrome, the data in humans is suggestive. So there's been, for example,

01:10:44.340 four pilot studies showing an improvement in insulin resistance with lowering uric acid in humans. All

01:10:50.440 four are positive. There's a lot of trials in kidney disease showing that lowering uric acid may

01:10:56.680 benefit kidney disease. There's data on blood pressure. We had a paper in the JAMA showing that

01:11:02.660 lowering uric acid could improve blood pressure control in adolescents with hyperuricemia. So there's

01:11:08.920 a lot of supporting data. There are some negative studies too. But the overall weight is now in favor

01:11:15.880 of lowering uric acid to benefit. What would the target be? So what I do is when I see a patient in

01:11:22.580 clinic, I measure the uric acid. And currently, we know that the risks start to go up when the serum

01:11:30.260 uric acid is over 5.5. So once the serum uric acid is over 5.5, they really start to have increased

01:11:36.900 risk for pre-diabetes, insulin resistance, hypertension, kidney disease, et cetera.

01:11:42.240 And what's interesting is most labs, like my lab, for example, doesn't even flag it until it hits about

01:11:47.360 6.5 as a sort of intermediate risk. And it's really not until about 7.5 that it says, well,

01:11:53.400 this is high risk. But of course, that's only through the lens of gout, I assume.

01:11:56.920 Yes, that's right. So if a uric acid comes back really high, like 9 or 10, I have no doubt that that,

01:12:03.140 based on everything I've done, I have no doubt that that's not good. Not only does it increase

01:12:08.380 the risk for gout, but it increases the risk for kidney disease and all these things. And I talk

01:12:12.720 to the patient about the pros and cons of treatment. I talk about the rash. I tell them to stop the drug

01:12:18.360 if they get a rash and then call me. But I always start allopurinol when the uric acid is like 8 or

01:12:25.720 higher. And certainly when it's 9 or higher. When it's between 5.5 and 8, I'll talk to them

01:12:33.300 about the pros and cons. But we don't have full proof yet. But I tend to do it, especially with

01:12:39.360 patients with kidney disease where the data is probably the strongest to start treating. I'll

01:12:44.240 even do it with uric acid of 6.5, for example, with chronic kidney disease. But anyway, it's worthwhile

01:12:50.260 discussing it with the patient.

01:12:52.060 But outside of the risk of Stevens-Johnson syndrome, which you've alluded to,

01:12:56.160 what are the other potential risks of allopurinol?

01:12:58.680 That's by far the big one. Some people will get just a mild rash without true Stevens-Johnson

01:13:04.420 syndrome. There are rare cases where liver function tests may be elevated, but it seems to be rare.

01:13:11.160 If you start at a huge dose right away, it can increase xanthine levels in the urine.

01:13:16.560 Theoretically, there could be risk for xanthine stones, but I've never seen it. So it's really

01:13:23.780 the risk of Stevens-Johnson.

01:13:25.660 And do you have to use allopurinol or can you use euloric or other drugs that also lower uric acid?

01:13:32.700 Well, the xanthine oxidase inhibitors are the best because the way uric acid works to cause

01:13:37.800 cardiovascular disease and kidney disease and all these things appear to be through its actions inside

01:13:44.320 the cell. As we said, it works on mitochondria and it does all these things. It's not, it's work

01:13:49.500 outside the cell. So gout is really an extracellular deposition. But when you're thinking about uric acid

01:13:57.460 and its biologic effects, that's an intracellular action. So xanthine oxidase makes uric acid inside

01:14:04.420 the cell. So one of the best ways to reduce intracellular uric acid is to give a xanthine oxidase

01:14:11.460 inhibitor like allopurinol or fibroxastat. Now fibroxastat, I think it's probably just as good

01:14:17.640 alopurinol, but there was a big clinical trial that was published in the New England Journal

01:14:21.460 that showed that allopurinol was associated with less cardiovascular risk than fibroxastat. There

01:14:27.460 seemed to be an increased cardiovascular events in the fibroxastat group.

01:14:32.020 Meaning less of a reduction or more events?

01:14:35.020 Well, see, the problem was there was no placebo group.

01:14:37.360 Oh yeah, that's a disaster.

01:14:38.640 Yeah, that's a disaster.

01:14:39.520 This is the Vioxx problem with napraxen.

01:14:42.480 Yeah, yeah. I mean, so the problem is allopurinol is less than fibroxastat,

01:14:46.540 but there's no placebo group. Theoretically, the placebo group would be-

01:14:50.800 Could be higher than both of them.

01:14:51.720 Yeah, it could be higher than both of them. And there's actually evidence that that's probably

01:14:55.660 true. But because of the CARES study, the way it was designed, we don't know. So the FDA

01:15:01.400 is worried about giving fibroxastat to people with cardiovascular problems because

01:15:06.840 they would prefer you to give allopurinol. But the trouble is, it's not necessarily that

01:15:12.060 fibroxastat is bad. It's just that it's not as good as allopurinol.

01:15:16.120 And it's like a hundred thousand times more expensive too. I mean, it's a-

01:15:19.740 Although it's, I think, becoming generic now. So we may see a change in that.

01:15:23.580 I believe it when I see it. And of course, well, you trust the generics, but that's a whole separate

01:15:28.100 issue. Exactly.

01:15:29.360 So what about sodium restriction, going back to how we started the discussion? I'll tell you a story

01:15:34.560 from, I may have even told this on the podcast once before, but in medical school, I remember when we

01:15:38.520 were doing renal physiology, we had a great nephrology professor who was teaching something.

01:15:44.480 And I think he was quite ahead of his time because this was more than 20 years ago. And he was not sort

01:15:49.680 of part of this salt is bad bandwagon, even though he was a nephrologist. And I won't do it because I

01:15:55.780 won't do it justice, but in a beautiful Southern accent, he made the point that if you lined up all

01:16:00.980 of the nephrons in the world, all the functional units of the kidneys in the world from dumbest to

01:16:06.320 smartest, and then all of the nephrologists in the world from dumbest to smartest, and you took that

01:16:11.400 dumbest nephron and put it next to the smartest nephrologist, it's still smarter. His point being,

01:16:17.540 of course, like the kidney is a brilliant organ that is exceptional at auto-regulation of everything

01:16:25.020 from flow to osmolarity to anion-cation exchange. Again, his point being, he didn't buy this argument

01:16:32.600 that salt is the problem. You're saying something much more nuanced, and I want to kind of go back

01:16:37.280 to it because I think there are important clinical implications of it. You're saying, no, no, no,

01:16:41.820 salt does play a role, but it's dose timing bolus concentration that matters. It can also be

01:16:48.940 amplified or mitigated by the state of inflammation. So how do you then translate that information

01:16:56.420 to your patients, acknowledging that they're a very select group of people by definition,

01:17:01.160 they have kidney disease or they wouldn't be seeing you?

01:17:03.220 So it's the combination of salt and water. So if you don't drink any water, as you eat salt,

01:17:08.760 you're going to raise your serum sodium, you're going to get thirsty. And as soon as you're thirsty,

01:17:13.700 you've triggered that in itself is a sign that you're already making fructose from the salt.

01:17:19.300 So when you eat salt, you're making fructose in your body. And the fructose is then driving a lot

01:17:26.380 of effects. Now we know that high salt diets are associated with obesity, not just high blood

01:17:32.000 pressure. They're associated with the development of diabetes. There's many studies now, but high salt

01:17:37.420 looks like it works by producing fructose. So if you drink water with salt, the danger of the salt

01:17:44.160 is much less. If you drank water and then ate your pretzel, you would be safer than if you ate your

01:17:49.900 pretzel and then drank the water. Because what triggers it is the rise in salt. And so when you see

01:17:56.980 someone in the clinic, what we try to do is to tell them to drink a lot of water and to reduce their salt.

01:18:02.640 But it isn't the amount of salt. It's the balance of salt and water.

01:18:07.600 Now that can be sometimes challenging for patients in a kidney clinic because that would be one

01:18:11.980 population in which you do have to be mindful of volume.

01:18:15.200 Right. But most patients with chronic kidney disease, they will excrete water normally or just

01:18:20.500 minimally abnormal. And so there's actually clinical trials looking at the evidence that water may slow

01:18:26.720 the progression of kidney disease. It might be working in part by blocking the effects of salt

01:18:32.700 and so forth on the kidney. And we experimentally can show that giving water can slow kidney disease

01:18:39.480 progression. So drinking water turns out to be good. Here's another thing. It turns out that many

01:18:44.800 animals use fructose to make fat as a means for making water. So when you make fat, although there's

01:18:52.200 no water stored in the fat, when they burn the fat, they make water. So whales don't drink salt water.

01:18:58.120 They are fat because when they break down the fat, they're making the water. We call it metabolic

01:19:03.020 water. So it turns out that fructose drives fat production and in part to preserve water, not just

01:19:10.860 energy. So animals will use that fat to provide an energy source, but also to provide water. So it turns

01:19:19.220 out that if you take an animal on fructose and you give it a lot of water, you can suppress some of

01:19:26.000 the obesity. You can suppress some of the effects of metabolic syndrome. And so the old wives tale that

01:19:32.800 drinking six glasses of water a day is good to help keep you skinny is true. It turns out that water

01:19:39.140 suppresses some of the effects of fructose. And does it need to be water? Could it be tea or coffee or

01:19:45.800 something that's equally, the osmolarity of water is what? Serum is about 280? Yep. Okay. So anything

01:19:51.020 with the zero osmolarity is good enough? Yes. Technically a diet soda should have a zero

01:19:56.020 osmolarity as well, right? Yeah, diet soda would work actually. For the record, you and I are sitting

01:19:59.800 here drinking just plain water. Right. And diet sugars have their own issues. So we'll come back to that in

01:20:05.340 a few seconds because that's interesting. So Rick, you sort of, you toss these little nuggets out there

01:20:10.400 like they're nothing, but they sound, I mean, again, just based on the sort of breadth of research

01:20:15.240 you've put into this, it almost just seems too good to be true and so profound. Yet you sort of

01:20:20.600 throw it out there like an after the fact, well, look, as long as you drink enough water and don't

01:20:25.040 eat fructose and God forbid, don't drink fructose, manage your uric acid levels, et cetera, et cetera.

01:20:30.740 You make it seem like a lot of problems could go away from these things. How would you shape that

01:20:36.340 advice for someone with normal kidney disease? Pardon me, with normal kidneys, would you basically

01:20:40.660 just say the same thing or can you be less restrictive with sodium, for example? If we

01:20:45.100 could reduce our fructose intake, I think it would have a huge, huge effect. But the problem that most

01:20:51.160 people face is that sugar and high fructose corn syrup are in almost everything. So if you go to the

01:20:57.220 supermarket, like 70% of processed foods have sugar in it and packaged foods, actually 70% of packaged

01:21:05.780 foods have sugar or high fructose corn syrup in it. So it's very hard to avoid it. And here's

01:21:11.260 another problem. Our bodies can make fructose. So our bodies, as I mentioned, we can make fructose

01:21:17.480 from a high salt diet. We can make fructose if we get dehydrated. We can make fructose, high uric acid

01:21:24.280 stimulates fructose production. And we're making the fructose out of glucose in all of these situations?

01:21:29.280 High glycemic diets. Normally, if you take an animal and you give it starch, they will not

01:21:34.980 really get fat. But we all know that French fries, which don't have sugar in it, they don't have

01:21:41.140 fructose, they are fattening. But you've got potatoes, which raise your glucose. And what we

01:21:47.720 showed is that if you just give glucose to an animal, the high glucose as it hits the liver

01:21:52.340 induces this enzyme to convert glucose to fructose. Which enzyme is that that converts glucose into

01:21:57.760 fructose? Aldose reductase. So when we took mice and we gave them glucose, and we were thinking

01:22:03.920 we might not see much because we were believing that fructose is the culprit. But over time,

01:22:10.540 these animals got really fat. They got insulin resistant, everything.

01:22:14.580 But you had to overfeed them glucose.

01:22:16.880 We put the glucose in their drinking water. So they were drinking a lot of glucose. But they

01:22:22.140 would eat less chow. So we gave them chow and glucose in their drinking water.

01:22:26.320 And their chow had, it was normal chow. It wasn't the high fat, high sugar chow.

01:22:29.880 No, just regular chow. And these animals started getting really, really fat. And when we looked at

01:22:35.560 the portal vein, which goes into the liver, the glucose levels were high. And when we looked in

01:22:40.860 the liver, we found that this enzyme was activated. It's also activated in diabetics, for example,

01:22:47.460 because of the high glucose in the blood. And when that enzyme got activated, it started to make

01:22:52.940 fructose. So even though these animals were eating no fructose, they were producing fructose

01:22:58.680 in their liver. And then when we blocked their fructose metabolism, they're eating the same

01:23:05.000 amount of glucose, no change. Exactly. Suddenly, they're not getting as fat. They have no fatty

01:23:12.140 liver. They're not insulin resistant.

01:23:14.060 But this suggests, Rick, that a diet in excess carbohydrate, even if it's not high in sugar,

01:23:20.620 could lead to fatty liver disease? Yes. Yeah, absolutely. If you have that enzyme induced.

01:23:26.100 But let's say that you are a young person. When you're young, this enzyme is really not present

01:23:33.140 in the liver. Once you're eating sugar, though, if you eat a lot of sugar, it will induce that enzyme.

01:23:39.160 For how long?

01:23:39.900 I don't fully know. But let's say that you eat a lot of sugar and you get obese. So sugar itself,

01:23:46.120 it looks like the induction of this enzyme probably would be reversible within a few weeks. But once

01:23:52.300 your uric acid goes up, that will keep it elevated. So that's another reason potentially to use

01:23:57.440 allopurinol, if necessary, in addition to fructose restriction to keep uric acid low,

01:24:02.820 is to prevent or mitigate the induction of this enzyme.

01:24:07.460 Oh, yeah. Right. So it turns out that if you give a starch or potatoes to a skinny person who does

01:24:14.180 not have all those reductase induced, they can eat the potatoes they want. In Ireland, back in the

01:24:20.520 1700s, where potato was basically the main thing they were eating, there wasn't a lot of obesity.

01:24:25.460 But you wait until you eat sugar and then develop the metabolic syndrome. Now you stop eating sugar,

01:24:32.120 but you continue to eat carbs, and the carbs are going to continue to activate through the same

01:24:37.940 pathway. So a low carb diet is really great because it's necessary if you're overweight or fasting,

01:24:46.280 but that's basically reducing carbs too. But a low carb diet when you're overweight is removing

01:24:51.280 the high glycemic carbs that are also driving the disease, but it's through fructose.

01:24:56.740 So it seems that fructose reduction obviously comes with its own benefits. Do you have a sense of

01:25:02.640 how much fructose can be produced in a fructose-free intake environment just from glucose? Is it a

01:25:10.080 meaningful amount? Well, we did our study by putting glucose in the drinking water. They're getting a lot

01:25:15.960 of glucose. We haven't done the study is the one that you're talking about, trying to figure out what

01:25:21.480 the range is. I do think that if you just give high glucose alone, you probably have to give a

01:25:27.520 lot. But if you've already triggered the production of this enzyme aldose reductase, you probably don't

01:25:33.140 have to give a lot. What about fat? What if you did that same experiment with rats or mice, which would

01:25:38.560 be hard because to eat pure fat is difficult. But if there was a way that somehow you could make it

01:25:43.680 palatable enough that you could overfeed them to the same extent using fat and protein, let's say

01:25:49.800 they're getting a normal amount of glucose, but the overfeed was coming through the fat. Would that

01:25:54.400 induce any of these properties? In other words, is part of this due to an absolute sense of total

01:26:00.440 energy being too high? Or is this really about a particular carbohydrate? It's definitely about a

01:26:06.480 particular carbohydrate because we've actually done what's called pair feeding, where you control how

01:26:10.960 much they eat and you can have your control group. The fructose effects will still, as I mentioned,

01:26:16.300 cause fatty liver. Yeah. Explain what pair feeding is for people because it's a clever little

01:26:19.780 tool done in this type of research. So the way fructose works is it works by making you eat

01:26:26.460 more. And that's how you gain weight. But even when you control so that you don't eat more,

01:26:33.060 fructose will not cause weight gain, but it will cause fatty liver, insulin resistance,

01:26:37.300 and diabetes and so forth. And the way we can show that is by pair feeding. In pair feeding, we give

01:26:42.520 each animal eats the same amount of food. So if you give one animal sugar, which normally makes it want

01:26:49.280 to eat more because it causes this thing called leptin resistance, where they want to eat more.

01:26:54.240 But if we don't give them any more food, we only give them the same amount as the control, then there

01:26:59.640 will be no difference in weight. But there will be differences in fatty liver, metabolic syndrome,

01:27:05.600 and so forth. The sugar industry has used this to their advantage. So what they say is, okay, we're going

01:27:11.920 to look at clinical trials where we've given sugar. And we're going to see if sugar causes weight gain.

01:27:17.300 But it's only fair to do that if we have it controlled where we control the energy intake

01:27:22.660 to be equal among groups. So they have a control group where they've restricted, there's a caloric

01:27:28.400 restriction on both sides. So you have a high sugar and a non-high sugar group, but it's not where you

01:27:35.140 get to, the people get to eat as much as they want. Basically, it's this problem of not having

01:27:39.280 ad libitum feeding. So it's sort of like what the sugar industry is saying is, look, a calorie is a

01:27:43.780 calorie. If I give you 100 calories of sugar and completely control what you can eat in response

01:27:50.560 to that and compare you to another person who's eating the same number of calories, you're really

01:27:55.800 not going to gain weight. And the problem with that experiment is it's not the real world. In the real

01:28:00.840 world, you don't have a clamp on your response. Exactly. And so when you give sugar to animals,

01:28:06.500 they become leptin resistant over time and they lose their ability to control their appetite. So then

01:28:12.240 they eat more. And so then their weight goes up. But the fructose is also doing stuff where even if

01:28:18.180 you control for the weight gain, they still get the fatty liver and stuff, which the controls don't.

01:28:22.880 Now, a second ago, you sort of alluded to artificial sweeteners. So comparing, I mean,

01:28:26.900 I'm sure you get this question asked all the time by your patients, which is, I just really love

01:28:31.020 Coca-Cola. Is having a diet Coke, it must be significantly better, right? I mean, there's

01:28:35.960 no fructose in it. There's no glucose in it. So is there a downside to it?

01:28:40.460 Yeah, I think there are downsides. But first, let me just say the positive side. We have

01:28:44.980 taste buds that sense sweet. And so when we eat sugar, the taste buds are activated and it stimulates

01:28:55.340 this dopamine response in the brain that tells us that we like the sugar. If you actually knock out

01:29:02.400 the sweet taste buds or just knock out the tastes in general, animals will still like sugar. They will

01:29:09.160 still eat sugar, a lot of sugar. How hard is that to do experimentally to knock out the sweet

01:29:14.920 tasting capacity? It's been done. And we actually have also done it where we knock out all taste.

01:29:21.360 Can you do it to me? No, it's like a, it's like a genetic knockout. But anyway, these animals will

01:29:28.420 still like sugar, but they won't like artificial sugar. So the artificial sugar is really driven by

01:29:33.440 the sweet taste. But what makes animal like real sugar is through its metabolism. I mean, it is true.

01:29:40.060 If you knock out taste, they will tend to eat a little bit less sugar, but they actually still

01:29:45.460 develop metabolic syndrome. That's super interesting. So you're saying part of our affinity for sugar is

01:29:51.400 not just in our taste buds and in our brain, but also in our periphery where the metabolism takes

01:29:56.960 place. And the elegant way you demonstrate that is you give something of equal sweetness concentration

01:30:01.980 that's non-nutritive and you completely reduce the appetite for it. Even though it might have the

01:30:08.040 same central effect, it doesn't have the peripheral effect. Probably the sweet taste bud developed to try

01:30:14.500 to encourage us to eat these foods that at the time were survival foods. But the food itself,

01:30:20.640 the sugar itself stimulates dopamine and other effects independently of the sweet taste. Whereas

01:30:29.160 an artificial sugar just is activating the sweet taste. Now, if you give a mouse or a rat artificial

01:30:38.180 sugar, they don't gain weight. But if you give them regular sugar, they do. So there is some evidence

01:30:44.360 that artificial sugars are better than sugar. And if a person says to me, oh, doc, I'm afraid to drink

01:30:52.640 this Diet Coke because it's got chemicals in it. I want to drink regular Coke because of that. That's an error.

01:31:00.080 Regular Coke is more dangerous than a Diet Coke. However, there is truth that things like aspartame and

01:31:08.720 sucralose, we don't know fully the safety of these.

01:31:12.220 Aspartame, when last I checked, had been studied more by the FDA than any other molecule ingested

01:31:18.880 by humans. It's hard to make the case that at the small doses that people would consume them.

01:31:24.760 I'm talking about someone who has a serving of this stuff a day. I don't know. I've always found

01:31:29.860 that argument that, well, we don't know the full safety profile of these things to be,

01:31:33.900 it's like, what else do we need on this one? I think aspartame is kind of gross, truthfully.

01:31:37.540 I don't really like it that much, but I just think it's definitely the lesser of two evils.

01:31:42.220 It's definitely the lesser of two evils. That part's for sure. But we don't fully know

01:31:47.300 the safety of some of these. Saccharin, for example, has been associated with little bladder

01:31:51.640 tumors in mice. My recollection is that aspartame can generate small, tiny concentrations of

01:31:57.500 formaldehyde.

01:31:58.320 I think it really comes down to dose.

01:31:59.800 Yes, I think it is.

01:32:00.700 I think those studies were really based on rats or rodents consuming doses that simply couldn't

01:32:06.460 be replicated by humans. That's probably true. Nevertheless, water is good.

01:32:10.680 Yeah, that's generally been my take to people as well is, look, all things equal by certainly

01:32:16.040 consume water, tea, things like that. But yeah, there's this lesser of two evils approach. But

01:32:20.540 this point you made, this is completely news to me and very interesting because certainly much of

01:32:25.580 the neurobiology today would suggest that the response we have to sugar is mostly centrally

01:32:30.000 mediated. The quote unquote addictive, because everyone loves to talk about functional MRI and

01:32:35.000 what happens in your brain when you're eating sugar and all of these other things. But I guess I

01:32:40.160 haven't seen this side by side, but presumably the fMRI would light up the same for non-nutritive

01:32:45.520 versus like aspartame and sugar, correct?

01:32:48.120 Yeah.

01:32:48.760 So let's talk about another taste, which is umami. I remember we were having sushi one night

01:32:53.680 when we discussed this. What is umami? What is that taste?

01:32:56.720 So umami is the savory taste.

01:32:59.560 And this is different from salt, isn't it?

01:33:01.280 So there's five taste buds. So there's salt, there's sweet. And as I mentioned, both of these

01:33:06.900 taste buds seem to drive a weight gain. Sugar is by far the fastest. It takes only two months

01:33:13.580 in a laboratory animal and salt takes four months, five months. So high salt generates fructose,

01:33:20.340 but it's a much slower process than just eating sugar. Then you have umami, which is the savory

01:33:25.060 taste. And then you have bitter and sour. And the bitter and sour are probably developed to

01:33:30.180 help you avoid eating certain foods.

01:33:32.760 So coffee is an example of bitter, like a coffee bean or something, like a ground?

01:33:36.440 I think so.

01:33:37.140 Yeah. Okay.

01:33:37.580 Anyway, so umami is driven by glutamate, but it's markedly enhanced by purines like IMP

01:33:44.760 and even uric acid. So it turns out that umami is sort of a taste receptor for uric acid type foods,

01:33:54.680 foods that raise uric acid.

01:33:56.440 Now is MSG the purest form of umami that we would eat?

01:34:00.340 Yes. MSG is the primary stimulant and people put it in foods to encourage food intake.

01:34:06.840 Now there's some link of umami with obesity in epidemiologic studies. And there are situations

01:34:14.960 where you can give umami type foods. And especially if you can do it in a liquid form, you can induce

01:34:21.280 obesity. So umami may not be as safe as we think it is. So it's got a lot of good things written

01:34:31.200 about it in the literature.

01:34:32.740 Don't most people view MSG as evil?

01:34:35.700 Yeah. I think MSG is viewed as evil.

01:34:38.140 But that seems to be largely unfounded based on my view of the literature. I can't really

01:34:41.920 find evidence that umami is harmful.

01:34:43.680 There's this Chinese restaurant syndrome where people get warm and headaches and it's thought

01:34:49.200 to be due to excessive MSG. But foods that are umami rich are often foods that we love. I mean,

01:34:55.860 shrimp has umami, Caesar salad, the Parmesan and things like that have umami. And so in general,

01:35:04.000 people like umami foods and it's certainly in the websites, it is often promoted. But if the umami

01:35:11.280 foods have a lot of purines, which enhance the umami flavor, it actually may raise uric acid and kind of

01:35:18.080 bypass the sugar pathway. And we think that that may turn out to be somewhat of a risk factor too.

01:35:25.300 So do you add this to the list of things that you caution people about? We've already got the

01:35:30.920 pair your salt with water idea, the restrict fructose and please God don't ever drink it.

01:35:38.400 Do you then add the MSG containing high umami foods to that playbook for ways to reduce metabolic disease?

01:35:46.760 I think so. Yeah. I think that foods like shrimps and things like that, if you eat a lot of them,

01:35:53.140 they probably activate this pathway too. We're still trying to learn more about it, but it looks

01:35:59.900 like it could be a contributor. I think it's, if you rank it, number one is sugar and then everything

01:36:07.900 else is less. High glycemic carbs can be converted to sugar. What I usually say is the big four are

01:36:15.540 bread, potatoes, chips, and rice. Those four are the foods that you should reduce a little bit.

01:36:23.600 Wait, chips as in like chips, potato chips? Yeah, potato chips. So you're giving potatoes two votes

01:36:27.720 out of four. Yeah, or corn chips or, you know. Okay, got it, got it. The kind of things that people put

01:36:33.020 out on their table before you eat dinner. And they coat it with salt, which isn't good. Anyway,

01:36:40.880 so high glycemic carbs, I think really salty foods drink water. I mean, that's really important.

01:36:47.860 And umami, so for example, what makes beer so much more dangerous than other alcohols for inducing

01:36:56.300 obesity is because beer has all this yeast in it, brewer's yeast, which basically is activating umami

01:37:04.160 pathways. And it's one of the reasons we like beer. This is that cellular density issue you spoke

01:37:08.400 about. Exactly. And so a beer raises uric acid more. And there really is this beer belly syndrome.

01:37:15.420 And if you look at people who drink a lot of beer, it isn't just that they get abdominal obesity,

01:37:20.220 they get fatty liver, they get high blood pressure, their triglycerides go up, they basically have

01:37:26.000 metabolic syndrome. Alcohol, especially beer, can also mimic sugar. And it's probably because of the

01:37:33.960 umami component coupled with the alcohol. Those two. This is the part that can sometimes drive a

01:37:38.820 person insane when they're trying to think about all of these things is it's very difficult to provide

01:37:44.700 clear advice to people because there's so many caveats that are required because the dose makes

01:37:51.300 the poison, the speed of delivery, what it's combined with all of these things. I'm using that as a

01:37:56.260 preface to ask a question that I'm sure you get asked a lot, which is really a dose question around

01:38:01.340 fructose. So let's ask it in two questions. If a person is going to drink something in the form of

01:38:07.420 fructose, whether it be fruit juice or soda or sports drinks, which are from a fructose standpoint,

01:38:12.540 all basically the same. Is there a dose of fructose above which you think it really makes no sense under

01:38:17.780 any circumstance or below which you think once in a while is not the end of the world? I mean,

01:38:22.260 personally, I would not drink any liquids that have sugar in it or a fructose or high fructose

01:38:28.200 corn syrup. That's fine. So we're going to draw a hard line there. Hard line. Okay. Now what about

01:38:31.740 eating fructose in the form of fruit? Because remember there's some big ass fruits out there.

01:38:35.700 Like you look at a Fuji apple, which is my favorite apple. I mean, I like these monster Fuji apples.

01:38:41.980 So they're like half the size of my head or maybe a third the size of my head. That's got to have 30

01:38:46.520 grams of fructose in it. I don't think it has that much. Oh, really? I really don't. Most apples and

01:38:51.740 that would be a big one, maybe 10 grams at most, I would think. No way. You think more?

01:38:56.680 Well, think about it. These are the really big ones. Yeah. Yeah. I'm not talking about a little

01:38:59.880 Macintosh. I'm talking about a huge apple and they're so sweet too. So you may be right then.

01:39:05.480 Let's talk about natural fruit. So we've actually done trials in patients with a low fructose diet,

01:39:11.760 with or without natural fruit supplements. And generally speaking, natural fruit supplements

01:39:16.200 do not seem to block the benefits of a low fructose diet. Sorry, what does that mean? And you mean

01:39:21.040 that if you took a patient and restrict all fructose except fruit? That's correct. They tend

01:39:26.400 to do okay? They did just as well as the low fructose alone. And can you quantify how much fruit?

01:39:31.600 Because here's the problem. When you're talking to someone like me, Rick, I don't do anything in

01:39:34.820 moderation. So we have these bowls in my kitchen. They're called manly bowls, which by definition,

01:39:40.360 a manly bowl is a bowl that you can wear on your head like a hat. It will come over your head.

01:39:44.300 And when I consume fruit, I consume it in that bowl. Yeah. I would be careful. So no manly bowls.

01:39:49.580 Yeah. So the data suggests that a single fruit, maybe not the giant food. I don't know the last

01:39:55.780 time I had a single fruit. Yeah. But a single fruit has like some fruits like kiwi and lime and

01:40:00.780 lemon have almost no fructose and they're totally safe. And other fruits. Pineapple and stuff.

01:40:07.020 You have a fair amount of sugar. Berries, for example, blueberries have so many good things in it.

01:40:12.480 You can eat a big bowl of blueberries, no problem. Raspberries, strawberries, all the berries in

01:40:18.160 general are very good. Grapes, they have a fair amount of sugar. You eat a bowl of grapes,

01:40:23.460 you're going to probably raise your uric acid and trigger the activation of this pathway.

01:40:27.300 You eat a bowl of grapes, you might as well be eating raisins based on what my blood glucose

01:40:30.980 meter tells me. It's a disaster. Yeah. What I would recommend is to try to not eat too many fruit at

01:40:38.540 one time. So for example, there was a lady named Knott's, Cheryl Knott's, I believe is her name.

01:40:43.980 And she's an anthropologist and she was studying orangutans. And there's a time when the masting

01:40:50.020 season where all these fruit trees bloom and then fruit at the same time. And then these orangutans go

01:40:56.620 in there and they won't eat one fruit. They'll eat a hundred fruit at one time.

01:41:01.440 I'm descendants of those orangutans. Me too. So anyway, what she did is she would go up and

01:41:08.460 collect the urine off the trees and show that by measuring things like ketones and so forth,

01:41:13.720 she could show that when they're eating the fruit, they were actually impairing fat oxidation and they

01:41:18.760 were storing energy and their weights go way up. And it's because they ate so many fruit. If you eat

01:41:24.100 one fruit, you're not going to do that. But if you eat a huge amount of fruit and get all that

01:41:28.500 fructose, it will start to overwhelm the good things in fruit. But there's so many good things

01:41:33.720 in fruit. There's vitamin C, there's epicatechin and flavanols and potassium and all these things

01:41:40.520 that help fight the effects of fructose. So we generally, for patients that have

01:41:45.080 non-alcoholic fatty liver disease, we tend to restrict them to 10 grams a day of fructose

01:41:51.080 only in the form of whole fruit. Do you think that's overly stringent or is that reasonable?

01:41:55.640 I think that's wonderful if they can do it. Yeah. It basically comes down to,

01:42:00.140 you can have a bowl of berries, no bananas, no apples, none of the high fructose fruits or even

01:42:04.600 large fruits. How do you handle this with your kids? You have two kids. They're not that young

01:42:09.860 anymore, but they were young during the time in which you were learning all of this stuff.

01:42:14.180 How did you balance the knowledge that you have? It sucks when your dad knows more about sugar than

01:42:20.840 almost any human on the planet and you're a kid and we're wired to want sugar. How did you balance

01:42:25.360 the sane delivery of this knowledge to your family?

01:42:29.280 So first of all, things like birthdays and stuff, I let them have birthday cake. But we try to make

01:42:35.220 sugar-free Splenda type cakes at home. So if we make cookies or cakes at home, we try to use Splenda.

01:42:41.660 Now there's still high carb and there can be chocolate in it occasionally, you know. So they do

01:42:46.520 get some exposure to sugar. We don't give them fruit juice and we don't give them soft. They are now

01:42:51.880 allowed regular soft drinks, but they can have a diet soft drink. I have a 12 year old and a 15 year

01:42:56.800 old. What we try to do is not to be so restrictive that it's disruptive, but we try to be encouraging

01:43:04.460 them to understand that sugar is playing a big role in obesity and diabetes and that it's unhealthy to

01:43:12.420 eat a lot. What age do you think kids start to, I think that makes sense, which is to me, it's much

01:43:17.120 more important that you would explain to your kids why you might be putting these rules in place as

01:43:21.920 opposed to just come down as an authoritarian sort of, this is the way it's going to be. At what age

01:43:26.120 did your kids start to understand that dad wasn't just being a pain, but there's a real reason that

01:43:31.920 he's in the short run asking us to make a sacrifice? Also, I've been involved in local school programs

01:43:38.180 and there's a foundation called Living Closer Foundation that I've worked with where we've gone

01:43:42.580 into schools and tried to teach children elementary school to learn from fourth through sixth grade. We

01:43:49.060 try to teach them how to look at labels on foods to understand the amount of sugar. We do a game

01:43:55.760 where we have someone come up with a cup of tea and add a spoonful of sugar to it and the person likes

01:44:03.340 it. And then we say, okay, now we're going to make it like a soft drink. And we put in like

01:44:07.580 eight teaspoons of sugar and it's like, you can't drink it, but that's the equivalent of what is in

01:44:13.300 a soft drink of the same volume. By the way, do you think the carbonation masks some of that sugar?

01:44:18.400 Because when you put it that way, which is a great way to do it, I've never thought of that

01:44:21.940 experiment. It's almost grotesque. It is. It's a great way to teach kids about sugar.

01:44:27.480 But do you think the carbonation makes it a little easier to consume such a high amount of sugar in a

01:44:31.880 soft drink? I suspect so. I haven't tested it, but I suspect that's true. Or the phosphoric acid.

01:44:36.720 Like there's something else in there that makes it more palatable. Yeah. Maybe it's the carbonation.

01:44:42.240 Probably is. What about dried fruit? Is that a no-no? You know, it was so disappointing when I

01:44:46.880 realized that dried fruit was the fructose of fruits without the good things in it. So when you

01:44:52.320 make dried fruit, a lot of the good things and natural fruits are lost. It's like pure fructose.

01:44:59.080 It's disappointing because I love dried fruit, but I realize it's not the best food for you. Now,

01:45:06.320 if you're out hiking the mountains and you're spending a lot of energy, maybe it's good.

01:45:11.180 Yeah, exactly. That's the thing I've always got a kick out of. Two things have amused me to no end.

01:45:15.460 One is trail mix. The other are sports drinks. Trail mix probably makes sense when you're

01:45:19.920 mountaineering. Sports drinks might make sense when you're a professional athlete. But paradoxically,

01:45:25.180 most trail mix is consumed off the trail and most sports drinks are not consumed by athletes

01:45:30.520 actively playing sports. So again, the dose makes the poison. Context matters.

01:45:35.540 Absolutely true.

01:45:36.640 Well, Rick, this has been awesome. I want to be mindful of your time. And I know that

01:45:41.100 this is a non-clinical day for you, which means every minute we're talking, you're not in your lab

01:45:45.560 and I want you to get back to the lab. So I want to thank you very much. Again, not just for this

01:45:50.520 discussion today, which for me is super interesting. And I think the listeners will agree, but much more

01:45:56.640 importantly for the work you've done, you've taken a very different approach to quote unquote,

01:46:01.200 the war on sugar. You're less involved on the policy side of this and the sort of advocacy side

01:46:07.120 of this. But I think what your work has done is created the strongest scientific foundation to the

01:46:15.140 harm of fructose. And you've done it in a largely, and I say this in a complimentary way, but in a

01:46:20.420 largely unceremonious way, which is you've sort of had your head down and a lot of people don't know

01:46:24.960 who you are. So I hope that more people become familiar with your work because you're, I mean,

01:46:29.500 your CV is comical in terms of like, it's like every week you seem to publish something in either

01:46:34.260 JAMA or the New England Journal of Medicine. The paper we talked about yesterday, which we can't talk

01:46:39.020 about today because it's not yet, we're not there yet. I look forward to seeing that paper in

01:46:43.160 science, hopefully in the next six months, but that's an unbelievable tour de force that almost

01:46:48.240 requires us coming back to have a talk about it. So.

01:46:51.360 Well, thank you very much. Those are very kind words.

01:46:53.800 Thank you, Rick.

01:46:54.320 Really enjoyable. And thank you.

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The Peter Attia Drive - November 22, 2021

Rick Johnson, M.D.： Metabolic Effects of Fructose (Ep. #87 Rebroadcast)

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