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

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

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00:00:41.720 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.740 here's today's episode. I guess this week is Dr. Rick Johnson. Rick is a professor of medicine

00:00:55.420 in the department of nephrology at the university of Colorado, where he's been since 2008. He's

00:01:00.560 basically spent the last 17 years being a division chief across three very prestigious medical schools.

00:01:06.080 He's unbelievably prolific as an author. He has well over 700 approaching 800 publications,

00:01:12.060 seemingly every week in JAMA, New England Journal of Medicine, science, et cetera. He's lectured across

00:01:17.680 40 countries, authored two books, one of which we discuss in great detail in this podcast called the

00:01:24.380 Fat Switch, which he wrote about seven or eight years ago. He's been funded extensively by NIH

00:01:30.600 and in fact has received the most prestigious grants that NIH has to offer. His primary focus

00:01:37.120 in research has been on the mechanisms causing kidney disease, but it was doing this that he became

00:01:41.900 really interested in obesity, diabetes, heart disease. And what connected me to Rick, I guess about

00:01:47.960 seven years ago now, maybe a bit longer, was his work on fructose and fructose metabolism. And that's

00:01:53.440 really what we talk a lot about in this podcast. So we start by talking about high blood pressure,

00:01:58.880 the relationship between salt and high blood pressure, which is something that is incredibly

00:02:02.200 controversial. And I actually learned a lot in this podcast. I'm really glad we had this discussion

00:02:05.980 because I kind of thought I had this thing figured out and I clearly don't. We talk about one of the

00:02:10.460 most interesting bifurcations in evolution with respect to an enzyme that allowed us to use fructose in a

00:02:16.520 certain way that was obviously advantageous millions of years ago today. Not so much. We talk a lot about

00:02:22.060 uric acid, which you've probably heard me talk about on other podcasts. This will then be the

00:02:27.080 master's class in it. We talk about artificial sweeteners and we sort of touch on some of the

00:02:33.000 most promising ideas around pharmacotherapy that are being developed in response to the epidemics

00:02:40.620 of metabolic disease, especially in response to sugar. So this episode gets a little bit deep on

00:02:46.100 some of the biochem. We're going to have, obviously the show notes will, as usual, provide a great

00:02:50.380 background in a list of references. And I hope you enjoy my discussion with Dr. Rick Johnson.

00:03:00.800 Hey Rick, thanks so much for opening up your office today and making time.

00:03:03.900 It's great. I'm very happy to have you here.

00:03:06.100 I've wanted to sit down with you for about a year in this format because I guess we've probably known

00:03:11.320 each other for maybe about six years now. And every discussion has been one of those discussions

00:03:16.340 where at the end of the discussion, I think, man, how am I ever going to remember all of this stuff?

00:03:21.320 And how will I be able to sort of synthesize this to translate it into sort of what I'm doing? And

00:03:27.060 I've said this sort of many times before, but that was the whole kind of reason that I started a

00:03:31.060 podcast was I just found myself every week having a discussion with someone, usually scientists,

00:03:37.940 where I thought this is something that's got to be shared. So you would certainly be one of the

00:03:41.800 three or four people in indirectly. That was a real catalyst for the podcast because of the frequency

00:03:46.380 with which we would either have these dinner discussions or discussions over the phone.

00:03:50.220 And so anyway, for that, I want to thank you and hopefully the listeners do as well. But in the

00:03:54.240 introduction, I've set this up a little bit as to why this is such an important discussion.

00:03:58.800 And because there's so much to talk about, I just kind of want to jump right into the meat of things.

00:04:03.380 It would be not an exaggeration to say you were one of the world's experts on fructose.

00:04:09.820 And I guess I would just start with the why. Where did that interest come from? You've obviously

00:04:14.160 been doing this for a long time and that passion has been sustained. So what brought you to this

00:04:18.200 point? Well, I'm a kidney doctor, so normally we wouldn't be studying sugar. So it was kind of a

00:04:24.340 circuitous way that I got there. I was very interested in the cause of high blood pressure

00:04:29.440 and had been known for a long time that high blood pressure is linked with kidney. And in fact,

00:04:35.360 the going theory is for years was that the kidney in high blood pressure has a defect in its ability

00:04:44.040 to excrete salt. And so that you end up retaining salt and that leads to elevated blood pressure.

00:04:50.060 And when we were studying, trying to understand how the kidney handles salt in high blood pressure

00:04:55.660 and so forth, we were trying to understand potential pathways. And we stumbled on the fact that

00:05:02.700 hyperuricemia or elevated uric acid could be a very significant risk factor for high blood pressure.

00:05:09.840 And when we started studying uric acid, we realized that when you raised uric acid in animals,

00:05:15.280 they developed high blood pressure. From there, we started to try to understand what made the uric acid

00:05:20.960 go up. And we knew from the literature that sugar and particularly fructose raised uric acid. So we

00:05:26.880 started studying fructose and pretty soon we were so excited about what we were finding that we just

00:05:33.000 kind of changed our research direction to focus more on how fructose has all of its metabolic effects.

00:05:39.960 Well, there's a lot to unpack there. So let me kind of go back to bits of it. You sort of gloss over the

00:05:45.900 fact that the conventional approach to high blood pressure is that sodium is the culprit. And isn't it

00:05:52.180 still safe to say that most advice around reducing blood pressure comes down to reducing sodium intake?

00:05:58.340 Well, we've actually been studying this pretty extensively. There's a lot of pearls I can teach

00:06:03.560 you or I can talk about related to salt. And when I was in training, I was taught that you restrict a

00:06:11.700 certain amount of salt. You should be on a low salt diet as a mechanism to prevent high blood pressure.

00:06:18.020 It was always about the amount of salt. In fact, we were teaching that for a long time that if you

00:06:24.640 want to have a low blood pressure, you should restrict your salt intake. Or if you want to try

00:06:30.800 to treat your high blood pressure, you should restrict your salt intake. What's happened in the last

00:06:36.760 couple decades has been the increasing knowledge that it isn't really the salt amount that makes a

00:06:43.880 difference? But the salt concentration. So when you eat salt, like if you eat a salty soup,

00:06:52.100 the salt concentration goes up in your blood first. And it translates into a thing called osmolality.

00:06:59.940 And so your serum osmolality goes up.

00:07:02.580 So osmolality is sort of like the ionic pressure buildup in a fluid? Is that a way to...

00:07:07.920 It's sort of like the number of molecules in a set of volume. So literally, when you eat salt,

00:07:14.500 if it's really salty, let's say you have a serum sodium concentration of 140 millimoles per liter.

00:07:22.020 If you eat a really salty soup, your serum sodium may go up to 142 or 143. What looks like

00:07:27.660 pretty insignificant. But that actually is what triggers a rise in blood pressure. And so we've

00:07:33.820 actually done the study where we took people and gave them soup with or without salt. And when they

00:07:39.180 drink the salty soup, their serum sodium goes up and their blood pressure shoots up.

00:07:44.840 How much would a person's blood pressure go up if their sodium went from 140 to 142?

00:07:49.360 It's about six millimeters.

00:07:51.340 Okay. So they'd go from 120 to 126.

00:07:53.620 Yeah. And that happens acutely.

00:07:55.340 And how long does it take to resolve?

00:07:56.680 Maybe a couple hours. So if we give, and we did this study, we published it last year.

00:08:01.860 If you give salty soup with water so that the serum sodium doesn't go up, they got the same

00:08:07.940 amount of salt. Guess what? The blood pressure doesn't go up.

00:08:11.260 And the serum sodium does so not go up or does go up?

00:08:14.020 Right. Does not go up. So if you block the serum sodium from going up.

00:08:17.900 So basically the closer you can bring the total accumulated concentration of what you ingest

00:08:23.380 down, the more likely you are to prevent this transient rise in serum osmolality and blood pressure.

00:08:30.980 Yeah. Well, it turns out that serum osmolality has a real major role, not only in blood pressure,

00:08:37.760 but also in obesity. And we're going to talk about that in a second. But when you take a high salt

00:08:42.940 diet and your serum sodium goes up, it triggers a rise in blood pressure and it's working through

00:08:48.260 the brain and actually through the liver and other sites too.

00:08:52.340 Pause for a moment. Tell the listeners why it would be better to have a blood pressure of 120

00:08:56.940 over 80 than 140 over a hundred. Well, there's a pretty good epidemiologic data that shows that

00:09:03.920 when your blood pressure is high, that you have an increased risk for heart failure and stroke.

00:09:09.220 Those are the two major ones, but it also increases the risk for heart attacks and heart disease in

00:09:15.020 general. Interestingly, there's a very significant inflection point. And what I mean by that is when the

00:09:22.280 blood pressure gets around 160 to 180, right in that range, the risk for stroke goes significantly

00:09:30.180 up and the risk for mortality goes up. And that's because our body tries to auto-regulate to blood

00:09:36.620 pressure. So when the blood pressure goes up, for example, the kidney, the arterials will constrict

00:09:43.140 to reduce the pressure load to the kidney. But when it gets to about 170, it will overcome that

00:09:50.220 restriction and the blood pressure will injure the kidney. Likewise, the brain kind of responds to

00:09:56.800 flow more. So it tries to maintain blood flow. But if the pressure gets high, it tries to protect

00:10:03.540 itself from the high pressure by constricting. But when the pressure is like 170, the risk,

00:10:09.200 it can't constrict enough and you don't want it to constrict that much because it has to maintain

00:10:14.920 flow. And so the pressure ends up increases to the brain and increases the risk for stroke.

00:10:20.220 Now, current guidelines seem even more aggressive. We would manage class one hypertension. We would

00:10:26.900 consider something in the mid-130s to be treatable.

00:10:29.500 Yeah. So let me get there. So originally, when the studies came out, it was very, very clear that

00:10:36.000 if your blood pressure was like 170 or higher, that you had a dramatic increased risk for stroke.

00:10:41.740 And that's because it would pass the auto-regulatory point. But then what happened was epidemiologic

00:10:47.140 studies show that even a blood pressure of like 140 over 90 conferred increased risk. It just was much

00:10:54.940 less than the 170. So at 170, it just takes off. It's almost the line goes up vertically. But between

00:11:02.320 140 and 160, there is still a stepwise increased risk, but it's just a kind of a more gradual risk.

00:11:09.260 In fact, for things like a stroke, you can start showing an increased risk from 120 over 80 to 140

00:11:16.180 over 90, leading people to view 120 over 80 as kind of the optimal blood pressure. As you get older,

00:11:23.200 if the blood pressure is really low, you lose your auto-regulation for low blood pressure. And so it

00:11:28.060 increases the risk for kidney disease and problems as well. So you don't want to be extreme on either end,

00:11:34.940 especially as you get older. This whole thing is kind of such a, it's a real clinical mystery in some ways

00:11:40.260 still, because in medical school, we learn about this term called essential hypertension, which is

00:11:45.440 kind of a wastebasket term for hypertension or high blood pressure for which we don't have an obvious

00:11:50.340 cause. The problem is, and so having sort of that wastebasket term would be okay if it accounted for the

00:11:56.680 minority of cases. But then you get to the clinic and you realize everybody walking around with high blood

00:12:01.320 pressure basically is getting labeled as having quote unquote essential hypertension. So it really

00:12:05.880 is this epidemic without a clear description. Now we're going to come to a lot of reasons that,

00:12:11.700 I mean, I think you have arguably one of the most compelling cases for what is at the root of

00:12:16.900 essential hypertension. But for people listening to this, for doctors listening to this who treat

00:12:21.360 hypertension, I feel like we just haven't made much progress in the 20 years since I've been out of

00:12:26.220 medical school. There have been some real breakthroughs in the understanding of primary

00:12:30.760 hypertension just in the last five, 10 years. And there's two major aspects I can talk about. The

00:12:37.260 first one is that it does appear that salt really is important. And one of the key discoveries

00:12:45.540 was that the kidneys are often normally handle salt fine, but they develop or acquire a change in the

00:12:55.460 kidneys that lead them to hold on to sodium. And the mechanism has been identified just in the last

00:13:02.000 few years. It's due to the fact that there's an inflammatory inflammation that occurs in the kidney

00:13:09.240 and that inflammation, which is driven by T cells and macrophages, causes a constriction of the blood

00:13:17.900 vessels that leads to low grade ischemia in the kidney. And that ischemia can translate into

00:13:25.200 increased sodium absorption, which then leads to high serum sodium and the effects.

00:13:31.700 Is there a correlation between serum sodium and blood pressure across normal physiologic ranges of

00:13:37.140 say 135 to 145 milliequivalents per liter? Yeah, I believe so. I'm not sure I can quote the paper,

00:13:43.880 but yes, I think that's true. So what you're saying is in people with high blood pressure that's

00:13:49.820 otherwise viewed as quote unquote essential, there's an inflammatory response mediated by

00:13:55.400 both T cells and macrophages that injures the kidney ischemically, meaning it for the listener

00:14:01.980 that results in reduced blood flow and tissue damage due to reduced blood flow and reduced oxygen.

00:14:07.080 And it's that injury that then leads to aberrant retention of sodium.

00:14:12.520 So there's actually been really a lot of studies looking at the mechanism of the inflammation.

00:14:16.680 And originally it looked like it was, people thought it might be a reactive response of the

00:14:21.980 kidney. So we think that there may be external stimuli that initially cause a decrease in blood

00:14:27.940 flow to the kidney, like a sympathetic nervous system response. You can do it transiently by giving

00:14:33.900 medicines or drugs that can cause a constriction of blood vessels. When you do that, you get a transient

00:14:40.840 reduction in blood flow to the kidney that induces an inflammatory response that then causes

00:14:46.220 persistent reduction in blood flow. And what we've learned in the last few years, and I'm an author in

00:14:51.900 one of these studies, is that this inflammatory reaction can actually be an autoimmune reaction.

00:14:58.300 And we've even identified certain proteins that there's an autoimmune response to. And one is a heat

00:15:04.100 shock protein. You can actually create high blood pressure in animals by inducing an immune response to

00:15:10.560 this. And you can block the immune response and block the high blood pressure. And now there's

00:15:16.980 even data showing that in humans, that there's evidence for an autoimmune response to heat shock

00:15:22.020 proteins in people with essential hypertension.

00:15:24.240 Which is not to say heat shock proteins are necessarily bad because so many of the benefits

00:15:27.900 we get out of sauna or exercise may be transmitted through these. But you're saying in a subset of

00:15:32.920 people where the heat shock protein itself becomes the nidus for inflammation via an autoimmune

00:15:39.120 mechanism. Yes. So heat shock proteins are great, just as you say. They do all these really good

00:15:44.440 things. But what happens is they're involved in the clearance of misfolded proteins and they're helping

00:15:50.520 keep a clean system. But what happens is when you trigger injury to the kidney, for example, these heat

00:15:57.600 shock proteins get produced to help fix problems. But the immune system can sometimes get confused and

00:16:05.080 make an immune response that actually is against the heat shock proteins. And when that happens,

00:16:10.680 you can develop high blood pressure in the animal and there's some evidence for it in humans. So

00:16:15.920 anyway, so that's one of the big breakthroughs has been the discovery that inflammation in the kidney

00:16:21.580 can be a mechanism for triggering persistent elevations in blood pressure and probably has a big role in

00:16:28.200 the cause of primary hypertension.

00:16:30.080 Before you go on, Rick, how prevalent do you think that particular mechanism is that you just

00:16:35.260 elucidated? Oh, it's very major. In fact, we've even looked at genetic polymorphisms that link with

00:16:41.020 the development of primary hypertension. And most of them are involved with the immune response. And

00:16:46.000 it looks like this is a major pathway. This creates a bit of a quandary for someone who's trying to

00:16:52.300 rid themselves of hypertension, because wouldn't the implication of this be that exercise or things

00:16:57.740 like exercise that induce heat shock proteins may paradoxically increase their hypertension?

00:17:03.120 I don't think so. So hypertension is kind of a complicated pathway. So there's several different

00:17:08.520 aspects. But exercise is extremely good for improving mitochondrial function, improving the ability for your

00:17:16.520 blood vessels to dilate. It improves kidney function. The benefits of exercise are so much greater.

00:17:23.820 And releasing heat shock proteins, that really occurs with very, I don't know if just general

00:17:30.760 exercise would have a big effect on heat shock proteins.

00:17:33.980 Yeah. So you're saying basically the net effect of exercise is still going to far outweigh...

00:17:37.960 Yes, absolutely. But I'd like to get back to this, the link between salt and sugar, if I could.

00:17:43.960 Okay. Because there is this data, as I say, that salt, when it increases the serum sodium is what drives

00:17:53.300 the acute blood pressure response. And when the kidneys have trouble getting rid of salt, it's

00:17:59.460 easier to get that effect with a salt load. But even with a normal person, you can, with normal blood

00:18:06.200 pressure, you can raise their blood pressure transiently by giving them salt and you can block it by giving

00:18:13.180 water. Interestingly, in the process of developing high blood pressure, there's the initiators and then

00:18:20.420 there's the things that make it persistent. And the inflammation in the kidney is involved in the

00:18:25.780 persistence. But what is involved in the initiation turns out that sugar has a major role. And what we

00:18:34.860 discovered is that when you give a high salt diet to animals, that the high salt increases the serum sodium.

00:18:44.060 And the serum sodium, when it goes up, it activates an enzyme that converts glucose, which is in our blood

00:18:53.260 and in our tissues, to fructose. And that conversion to fructose is driven by a high salt diet. And it's

00:19:02.600 driven by an increase in serum osmolality or increase in serum sodium. Once the fructose is made in the

00:19:10.900 body, so this is not fructose coming from the diet, this is made in the body, the fructose gets

00:19:17.000 metabolized and raises blood pressure. And when we gave high salt to animals, they developed an increase

00:19:25.860 in blood pressure. And they also were making fructose. And when we blocked the metabolism of fructose, we actually

00:19:33.460 blocked the rise in blood pressure, as well as the hypertrophy of the heart.

00:19:37.720 So let's pause for a moment. You know, I've had Rob Lustig on the podcast before. So anyone who's listened to that

00:19:42.060 will be familiar with what fructose is, what glucose is, what sugar is, all of these things. But can we spend one minute

00:19:49.460 just defining these things for people who haven't listened to that podcast?

00:19:53.960 Sure. So there's different types of sugar. And the main one that we call blood sugar is glucose. And this

00:20:01.120 is the primary sugar that our body uses to make energy. It's the main sugar that's used to make energy. And it

00:20:09.160 can be stored in the tissues as glycogen. And when it's too high, we call it diabetes. When the blood glucose

00:20:17.980 is too low, it's hypoglycemia. And so glucose is like the principal energy fuel, the carbohydrate

00:20:25.240 fuel that we use. And as you said, we store lots of it in our muscles. Once it gets in the muscles,

00:20:30.500 it can't get out. And we store maybe a quarter to a third of it in our liver. And that's mostly there

00:20:36.180 to buffer the blood supply, in particular, the brain. What does glucose taste like, a pure drink of

00:20:42.060 glucose? People like it, animals like it, but it isn't as sweet as classic sugar.

00:20:47.980 But it is often very much like by animals. Humans like it. You can buy these dextrose pops and stuff

00:20:55.780 like that. Dextrose is another word for glucose. And also the kidneys store glycogen and produce

00:21:02.520 glucose too. The second type of sugar is fructose. And the best way to think of fructose is it is a

00:21:10.980 fuel. First off, it's present in fruit, but it turns out to be the sugar that is involved in energy

00:21:17.880 storage rather than energy production. And so when you eat glucose, you use that to produce energy.

00:21:25.200 But when you eat fructose, it will actually trigger changes in the body that will favor the storage of

00:21:31.900 energy. And this is the sugar that animals use to store energy. And you store it in the way of fat,

00:21:39.460 in the way of glycogen, and all those kinds of anything that will facilitate storing energy is

00:21:45.760 done by fructose. And fructose and glucose, if you were looking at pictures of them in a biochemistry

00:21:51.000 book, look pretty similar. They're both ringed carbon structures. They both have six carbons. One of

00:21:57.000 them has a five ring versus a six ring. But it's sort of interesting to think that molecules that look

00:22:02.840 almost identical, with the exception of a couple of bonds different, can have quite different

00:22:07.180 properties. Now, fructose tastes a lot sweeter as well. Yes. And so fructose is like in honey

00:22:12.920 and in fruits. And then that's right. So it tastes a lot sweeter. And the other thing is if you mix

00:22:18.880 the fructose and glucose together, you can get what's called high fructose corn syrup. And if

00:22:24.680 they're bound together, you get table sugar. So table sugar or sucrose is one molecule of glucose

00:22:31.500 and fructose bond together. And that occurs in nature in sugarcane and beets and things like that.

00:22:37.540 Yes. And maple syrup and things like that. Right. So just to clarify for everybody,

00:22:42.500 we, when we get a little comfortable with this terminology, throw the word sugar around quite

00:22:47.140 liberally. But it's always important for people to think when we talk about sugar, we could be

00:22:51.600 talking about blood sugar, glucose. We could be talking about fructose by itself. Oftentimes when we

00:22:57.840 talk about sugar in diets, we're talking about added sugars such as the sucrose and high fructose corn

00:23:03.240 syrup you just alluded to. I want to go back to what you just said about the ability of fructose

00:23:08.580 to store something. But if you don't mind, can we do it through the lens of a beautiful story that

00:23:13.600 you've written about in the past about a mutation that basically allowed that to happen? This thing

00:23:19.960 that took place about 12 to 15 million years ago? Sure. So fructose, again, it's in fruit. And

00:23:28.160 many, many animals use fructose as a means, as their primary nutrient or, and also as a way to

00:23:36.400 help store fat. And for example, animals before they hibernate will often eat a lot of ripe fruit

00:23:43.540 and the ripe fruit gives them the sugar that allows them to store fat. And orangutans will eat huge

00:23:50.500 amounts of fruit at one setting to try to increase their body fat. And we don't get fat from eating

00:23:56.300 fruit, but that's because we eat tart fruit that has less sugar content. And we tend to only eat

00:24:03.300 a few fruit. Whereas if we actually drink fruit juice, that large amounts of fruit juice can

00:24:08.660 actually increase fat. So anyway, so fruit is a nutrient that, you know, is used by animals to help

00:24:14.980 store fat. So if you go back about 20 million years ago, the very first fossil apes show up in the

00:24:24.060 world and they, they show up in West Africa. And the original one was called proconsul. They were

00:24:30.820 living about 22 million years ago. And they were, these apes were a big breakthrough in evolution

00:24:35.780 because the prior, the monkeys were, had already been around, but these were bigger creatures. The

00:24:41.480 apes were, they had bigger brain size. They were tailless, but they did live in the trees and they lived in

00:24:46.980 tropical rainforests and woodland rainforests. And they would eat primarily fruit. And they were quite

00:24:54.440 successful. And by about 18 million years ago, there were almost at least 10 to 20 species of ape

00:25:01.220 that were living in this area of Africa. There was a change in climate. There was some global cooling

00:25:07.460 and the Antarctic started building up ice and the Arctic started building up ice and sea levels fell.

00:25:14.360 And when the sea levels fell, land bridges developed that connected Africa, which had been separate,

00:25:21.680 separated from the other continents. These land bridges opened up so that there was now

00:25:26.600 a way to get out of Africa into Europe and Asia. And many, many species migrated across those land

00:25:33.980 bridges about 17 million years ago. And some of them were the apes. And we see the first apes

00:25:41.140 fossils in places like Pasolar, Turkey and different places of Europe, right around 16 million years ago.

00:25:49.500 At that time, there were still a forest that were fruiting trees, woodlands, there was fruit all year

00:25:56.640 round. And so the animals, when they moved into Europe, they didn't have to change their habits at all.

00:26:04.400 They were able to continue to eat fruit pretty much all year round. But unfortunately, it continued to get

00:26:09.500 cooler. And by 12 million years ago, the apes started to starve in Europe. And you can tell

00:26:17.760 that from the fossils because they actually have these like tree rings on their teeth that are the

00:26:23.400 developing teeth get this enamel. The enamel doesn't lay down correctly. And they get these like tree

00:26:30.320 rings that show intermittent starvation. They would get a ring every time they would go through a period.

00:26:36.960 And the starvation was seasonal. So it was during the cooler months when suddenly the fruit was not

00:26:43.480 available. And the primary reason was there was a loss of the fig tree. And the fig is a cool fruit

00:26:49.440 that can fruit all year round because the wasp that fertilizes the fruit does so at its own discretion.

00:26:55.900 So the fruit of a fig tree kind of can occur all year round. So when the fig tree died, suddenly there

00:27:02.280 weren't too many because of the global cooling or perhaps it was the wasp, but the fig trees

00:27:07.280 disappeared. And suddenly these apes did not have enough food to survive during the cooler months.

00:27:15.500 And they started to starve. And by six to eight million years ago, the last ape became extinct in

00:27:23.520 Europe. But Africa, although there was global cooling there too, it wasn't as cold. And the fruit trees

00:27:30.680 survived all year round. The forest just retracted. So the apes there were able to maintain their normal

00:27:37.540 habits. Well, there was a lot of evidence that there was a lot of evolutionary change occurring in

00:27:42.960 our ancestors during this Miocene period and this period of time when there was the global cooling. And

00:27:50.920 one of them was a mutation in uric acid metabolism. And as I mentioned, sugar and particularly fructose,

00:27:59.780 when it's metabolized, generates uric acid. Glucose, when it's metabolized, does not. But fructose,

00:28:07.100 when it's metabolized, makes uric acid. And this mutation led to a much stronger uric acid response to

00:28:16.220 fruit because this mutation was an enzyme that degrades the uric acid. And when you block that and you eat fruit,

00:28:23.160 your uric acid levels go up much more. And this mutation basically allowed these apes to maintain a very

00:28:31.660 prominent uric acid response. Our group has shown that the way fructose stimulates fat, as well as its other

00:28:40.960 properties like insulin resistance and raising blood pressure, that those abilities are driven in part by

00:28:49.400 the uric acid. So when this mutation occurred, for the same amount of fruit, they were able to store more

00:28:56.220 fat. And so it was like a survival mechanism for this mutation when it showed up. It allowed apes that

00:29:02.580 had very little access to fruit to suddenly maintain more fat stores and so they could live longer and

00:29:08.660 survive those winters. And we were able to show with Peter Andrews at the Natural History Museum in

00:29:15.060 London, who studies these apes, that this might account for a very interesting finding. And the

00:29:21.800 finding is that although we thought the apes became extinct in Europe, and they certainly did become

00:29:27.640 extinct in Europe, the fossil record shows that it was a European ape that made it back to Africa

00:29:34.500 and also to Asia to become our ancestors as well as the ancestors of the great apes that live in Africa

00:29:42.580 and in Southeast Asia, like the orangutan, that they all came from a common ancestor that was in Europe

00:29:50.140 and that went back to Africa. And we know from the genetics that that ape carried the uricase mutation.

00:29:58.540 And so this mutation probably occurred at a critical time that provided survival for those apes in Europe

00:30:07.540 to be able to get out of there and make it back to these other regions. But it was now equipped with

00:30:13.960 this mutation that made it sensitive to sugar. And so humans are much more sensitive to sugar than most

00:30:23.060 animals. And it's because of this mutation. And in fact, we actually resurrected the extinct uricase

00:30:29.520 and proved this using the extinct uricase that showing that when you put it into human cells,

00:30:35.940 that it suddenly made us less sensitive to fructose.

00:30:39.940 So the phenotype there, I mean, I guess just to recap that story, which I find so fascinating,

00:30:44.280 by the way, you guys wrote a story about this in Scientific American many years ago, right? I know

00:30:48.340 there was a paper that came out as well. But I mean, the sort of the layperson version in Siam was really

00:30:52.560 great. So basically, these apes go from Africa up to Europe, it gets too cold, we sort of think they

00:30:58.600 die out. But the evidence emerges, actually, a sub sub subset of them developed a mutation in uricase

00:31:04.340 that gave them a superpower, which was now they could be much more efficient at turning fructose into fat.

00:31:10.960 They had this little byproduct, which is they would also make a boatload of uric acid along the way.

00:31:15.520 But they actually came back to Africa and ultimately seeded the rest of the species. And ultimately,

00:31:20.760 that's why we as humans are among the very rare animals that have uric acid levels that are quite

00:31:26.760 high relative to cats and dogs, for example. Yes, that's exactly correct. So when we were in medical

00:31:32.460 school, Rick, we learned a lot about uric acid through the lens of a disease called gout. And

00:31:38.500 it didn't get a lot of airtime in school, maybe it gets more today. But at the time, it was basically

00:31:42.820 gout is a disease of civilization. It's from eating too much meat. And there's no real problem with it,

00:31:49.200 except for the nuisance of your toe hurts, because uric acid crystallizes, it gets inside joints,

00:31:54.060 it seems to favor the first joint of the great toe. And it's a very painful inflammatory condition.

00:32:01.340 And it's what happened to sort of the wealthy people of the last few hundred years as they

00:32:06.120 started getting and acquiring too much meat and protein. And that was sort of the story. What

00:32:10.760 you're describing is a little bit more nuanced. So tell us more about uric acid.

00:32:14.400 Yeah. So the big problem with having too much uric acid is gout, just as you say. And all the

00:32:21.020 animals that have the uricase mutation are prone to gout. But humans in particular are very prone to

00:32:27.060 gout. And it's because of our diet. So we do eat diets that are high in meat and purines that

00:32:33.540 increase our risk for gout. Can you tell folks what purines are specifically, since it always shows up

00:32:38.360 in this terminology? Sure. So we have proteins, we have fat, we have carbohydrates. We also have

00:32:46.480 things like RNA and DNA and what we call nucleic acids. So these are the kind of acids that are in

00:32:54.120 the nucleus and that are also in the cell that help drive gene formation and protein, you know,

00:33:01.420 our genetic material, and also help dictate the production of proteins. And so DNA and RNA are made

00:33:08.040 of nucleic acids. And when they're broken down, they're made up of purines. And then uric acid

00:33:14.820 is a purine and it's basically the ultimate breakdown product of DNA and RNA.

00:33:20.620 So the reason protein consumption versus fat or carbohydrate would lead to this is because if

00:33:26.040 you're eating protein, you're eating the DNA and RNA that presumably were still in that tissue?

00:33:30.840 Yes. So the way you get gout from protein is from the DNA and RNA in the protein. And that relates to

00:33:38.980 some extent to how dense the nuclei are. And so like if you have a very cellular thing like anchovies and

00:33:48.700 these small fish that have lots of DNA and RNA, if you have that, they will develop. You can get

00:33:56.840 gout from that much easier than from other types of meat. And so beer, for example, has brewer's yeast

00:34:05.740 and that is filled with RNA. And so that's why beer can precipitate gout.

00:34:13.180 Now I follow uric acid levels very closely in all of my patients and myself. And there is an

00:34:18.580 unmistakable difference between men and women, at least in my small sample size of patients,

00:34:24.580 where men on average have higher uric acid levels than women. Is that true across the general

00:34:30.840 population?

00:34:31.400 Yes. Even in boys, they'll start to have a higher uric acid than girls. However, after the menopause,

00:34:39.640 uric acid levels go up in women. And that's because estrogen helps excrete uric acid.

00:34:45.540 So it's not, I had sort of, I guess, incorrectly assumed it was that just on balance,

00:34:50.500 men consumed more protein than women. I think that also plays a role. I think that's right.

00:34:55.800 But it sounds like this estrogen explanation makes more sense if it can also explain the

00:35:00.360 observation of menopause. Yes. Going back, gout is also increased by sugar. And even Sir William

00:35:08.020 Osler, the famous physician from the 1890s in his book, Principles and Practice of Medicine,

00:35:14.080 pointed out way back in the 1890s that sugar was a major risk factor for gout, as well as very sweet

00:35:22.860 fruits, he wrote. Anyone who's had gout usually will know that real significant sweets can also

00:35:30.020 precipitate gout. And the reason is because of the fructose content. And when the fructose is

00:35:35.980 metabolized, it generates uric acid. When people were developing gout in the 1800s,

00:35:41.700 it was linked to the wealthier groups in England, for example. They were eating a lot of, as you say,

00:35:49.320 rich foods that included proteins and so forth. But one of the things they were eating a lot of,

00:35:55.260 they were drinking a lot of alcohol, to which they added sugar. I actually did write a paper where we

00:36:01.160 reviewed how much sugar was put in drinks, alcohol drinks back in the 1700s, 1800s. And it was much more

00:36:08.360 than today. They loved sugar. They put it in many of their drinks. And in fact, I even have a picture

00:36:15.420 of an old pub outside the Tower of London called the Sugar Loaf. They talk about the old drinks that

00:36:21.600 were served, like hypocrites, and some of these drinks. And sack and sugar was a name for a drink

00:36:27.860 that they had. I mean, they added a lot of sugar to their drinks. And so part of the rise in gout back

00:36:34.700 in the 1800s and 1700s relates to not only just the alcohol and the rich foods, but also to the

00:36:43.100 sugar they were adding. So you were sort of the person who brought onto my radar that there are

00:36:48.280 other things besides gout that one needs to be concerned about when it comes to uric acid.

00:36:54.020 And one of them is blood pressure. So how did that understanding come about?

00:36:58.040 So originally, we were studying what causes high blood pressure. And there was a lot of

00:37:03.500 epidemiologic studies that linked uric acid with high blood pressure. And as I mentioned, we also

00:37:09.880 knew that there was subtle changes going on in the kidney associated with high blood pressure.

00:37:14.320 And people with gout often have low-grade kidney disease. So I said, aha, maybe uric acid could have

00:37:21.080 a role in causing kidney disease through causing high blood pressure through its ability to cause

00:37:26.640 kidney disease. And so we took animals and we gave it this uricase inhibitor to raise the uric acid

00:37:35.940 of an animal. And by gosh, they developed high blood pressure. And then we could lower the blood

00:37:41.200 pressure by lowering the uric acid. And when we looked, we were thinking it might be like crystals

00:37:46.380 of uric acid in the kidney.

00:37:47.980 Although that was my thought is the crystals would cause the inflammation in the kidney.

00:37:51.540 And that was my thought too. And that turned out not to be the case.

00:37:55.920 We looked at the kidney, there weren't any crystals there. So then we realized it was an

00:37:59.920 effect of soluble uric acid. So we started putting soluble uric acid on cells and so forth. And we saw

00:38:06.600 that it had all these biologic effects. And we always had thought uric acid was kind of like a

00:38:11.460 dead end product of something, or even might be a good thing because some people said it was an

00:38:16.000 antioxidant, but it was causing pro-inflammatory effects. So then we said, aha, fructose, sugar

00:38:24.120 raises uric acid. Maybe sugar could have a role in blood pressure.

00:38:30.120 What year is it that you're having that thought, Rick?

00:38:32.820 2002. We gave some animals fructose and they developed high blood pressure. And we gave them

00:38:39.740 alopurinol, which is a drug to lower uric acid. And it made their blood pressure go back to

00:38:45.800 normal. And it was like this big discovery. But what was totally exciting was these animals also

00:38:54.020 developed insulin resistance. They also developed elevated triglycerides in their blood. They had

00:39:00.120 other fatty liver. And when we lowered the uric acid, we showed benefits on all of those parameters.

00:39:07.020 How does alopurinol work? What's the mechanism by which it lowers uric acid?

00:39:10.860 It blocks uric acid formation. So uric acid is generated from other purines. And when we blocked

00:39:19.540 that, we blocked a lot of the effects of sugar to cause metabolic syndrome. And so when we first did

00:39:28.680 it, we said, ah, there's got to be something wrong here. So we repeated it and we did it different ways

00:39:33.320 and it didn't matter. It looked like uric acid had a role in how sugar worked. So as we studied this,

00:39:41.880 we started realizing that the process by which uric acid is generated is important in how sugar

00:39:48.760 causes disease. No one believed us initially. I have to tell you that everybody said, ah, yeah,

00:39:56.740 sugar causes gout, but the idea that sugar raises uric acid that causes gout, but the idea that sugar

00:40:03.020 raises uric acid and that is involved in the obesity and the insulin resistance, we don't believe

00:40:08.960 it. What's happened since then is we've learned that the metabolism of fructose is extremely different

00:40:17.460 from the metabolism of glucose. The two look alike, but when fructose is metabolized, there's this process

00:40:27.020 that causes the energy in the cell to fall before it goes up. So normally when you eat a calorie,

00:40:34.180 when you eat any kind of nutrient, we use it to make energy. That's what we do. But when you eat

00:40:40.180 fructose, the energy in the cell falls before it goes up. It's the only nutrient that lowers energy

00:40:49.840 in the cell. Say more about what you mean by that. So are we talking about a cell in the liver, for

00:40:54.180 example? Yes. I'm talking about the cells that metabolize the fructose. Okay. So we'll contrast

00:40:58.900 it with glucose. So if glucose enters a cell, it gets turned into pyruvate and ultimately ATP is made.

00:41:06.880 So you're saying total energy goes up as a result of metabolizing that glucose.

00:41:11.520 So whenever you metabolize any kind of calorie, any kind of food, you eat food, you're going to

00:41:18.300 metabolize it to make energy. That's what we do. We try to break down the food and we use it to make

00:41:23.600 energy. That energy is called ATP. And ATP is the currency in our body that we use to make us run,

00:41:32.220 walk, think, talk, everything. So this ATP is pretty critical. But to make ATP, you have to spend a

00:41:42.320 little of it to make it. So the process of breaking down and metabolizing food or glucose or fructose

00:41:51.560 requires spending a little bit of ATP before you make it. Well, what happens is when you metabolize

00:41:59.020 glucose, you do spend some ATP, but the body has a system whereby feeds back to stop the process before

00:42:08.620 any significant ATP depletion occurs. So for example, there's an enzyme called phosphofructokinase that's

00:42:16.100 used in glucose metabolism. If ATP levels fall, that enzyme gets turned off to stop glucose metabolism,

00:42:25.560 to allow ATP levels to come back up. But when fructose is metabolized, the enzyme that metabolizes

00:42:33.540 fructose is called fructokinase. And when that metabolizes fructose, it consumes ATP in an unregulated

00:42:42.200 way. So if the cell sees a lot of fructose, the ATP levels can plummet by 40 or 50% in the cell.

00:42:51.240 And that signals a huge number of effects throughout the body. It's like a May Day signal.

00:42:58.800 It says, we're under attack. We're running out of energy. And so it switches the animal into a

00:43:06.080 condition in which they're trying to preserve their energy. So they reduce their metabolism.

00:43:12.320 They reduce their expenditure. They're resting the energy expenditure. They shunt the energy that

00:43:19.160 they're eating. The calories they're eating into fat and glycogen, as opposed to making more ATP.

00:43:25.580 They're trying to protect the body by putting you into a system where you try to store fuel.

00:43:31.400 It triggers hunger and thirst that makes you want to eat more. So you eat more to restore the energy,

00:43:38.640 but at expense that you're shunting much of it into fat and into fuel storage.

00:43:44.720 So fructose turns out to be used by animals as a mechanism to store fat. Normally,

00:43:51.080 animals will regulate their weight beautifully. They just maintain their weight normally. If you take

00:43:56.200 an animal and you put a tube down its throat and give it extra food to make it gain weight,

00:44:01.800 if you take the tube out, the animal will go right back to its normal weight. If you starve an animal

00:44:07.500 and so it's below its normal weight, and then you let it just eat, it will eat back to its regular weight.

00:44:13.940 But when it wants to gain fat, it will do so usually through a mechanism that involves fructose.

00:44:21.040 So what they do is they, like a hibernating animal, will start eating a lot of fruit

00:44:26.240 in the fall to increase its weight and increase, induces insulin resistance. It gets hungry. It

00:44:32.300 drops its metabolism so that most of the energy it eats goes into fat. And the same thing with a long

00:44:39.440 distance migrating bird, they'll start eating fruit to get the fructose. And so this is a very common

00:44:46.080 pattern. And it's driven by that ATP depletion.

00:44:51.240 And this is distinct or in parallel, of course, to this uricase mutation. So can you separate these

00:44:57.480 two phenomenon? In other words, if you can restore uricase to the non-mutated version,

00:45:04.440 do you still have this problem around the ATP depletion?

00:45:08.660 Yeah. So the ATP depletion triggers a series of reactions. And what happens, what the key

00:45:14.780 one is, not only does ATP decrease in the cell, but intracellular phosphate also falls. And that

00:45:22.880 activates an enzyme called AMP deaminase that converts the broken down product of ATP, which is AMP,

00:45:31.000 and it converts it to uric acid. And that process has multiple steps. And we know that that whole

00:45:38.160 pathway is involved in the generation and stimulation of fat, insulin resistance, fatty liver,

00:45:46.620 elevations in blood pressure, a variety of effects. And that pathway is what seems to be critical

00:45:55.520 for inducing obesity from sugar.

00:45:58.040 Let's go through that again. Cause that, what you sort of talked about at the very end is

00:46:02.600 effectively the thesis of your book, the fat switch. You explained what ATP is, adenosine triphosphate.

00:46:09.860 And the T of course stands for tri. There are three phosphates. It's the liberation of a phosphate

00:46:15.560 that is the production of energy. So when you need to breathe, you need to move, when you need to do

00:46:20.820 anything, you have to turn ATP into ADP. So the chemical reaction is adenosine triphosphate becomes

00:46:29.840 adenosine diphosphate. One phosphate escapes, and that's what gives us the energy. Now that can happen

00:46:37.240 again. ADP can lose one of its two remaining phosphates and become AMP, adenosine monophosphate.

00:46:46.640 What you said after is the really critical, critical piece of this, which is when you have

00:46:53.300 a molecule of adenosine monophosphate, it stands at a proverbial fork in the road. It can either

00:47:00.940 go down a path that is driven by something called AMPK or AMP kinase, or it can go down the pathway of

00:47:11.040 AMPD. Now let's go back to this point. Cause I, again, it seems everything comes down to that

00:47:18.840 choice. What happens if AMP goes down the AMPK pathway versus the AMPD pathway?

00:47:26.760 Yeah. So if it goes down the AMPK pathway, it actually is burning energy. It's burning fat.

00:47:33.400 It does a lot of really positive things. If it goes down the AMPD pathway, it goes down a fat storage

00:47:40.180 pathway. So it's their exact kind of opposites. AMPD, if you stimulate it, it will cause insulin

00:47:46.540 resistance and eventually diabetes. Whereas if you stimulate AMPK, you can actually use that like

00:47:52.860 metformin to actually treat diabetes. So that fork is critical. And what drives that switch

00:47:59.420 is the fall in intracellular phosphate. And the reason that phosphate falls is because it's taken up in

00:48:06.320 the fructose 1-phosphate or it's taken up by fructose. So the fructose gets phosphorylated by

00:48:12.080 the ATP and it becomes fructose 1-phosphate that sequesters phosphate. And there is this process where

00:48:19.220 both ATP levels fall and intracellular phosphate falls, and that triggers this AMPD pathway. And if

00:48:26.180 we interrupt the AMPD pathway, we can block a lot of the metabolic effects.

00:48:31.600 Do other animals also have this phenomenon?

00:48:35.020 Oh yeah. No, we can show this. We actually showed it in hibernating squirrels. So when a squirrel

00:48:40.160 wants to gain weight, it will activate the pathway for AMPD. When it's hibernating and burning the fat,

00:48:48.220 it activates the AMPK pathway.

00:48:50.420 I got it. So even though humans and our most close descendants in primates have the uricase mutation,

00:48:58.340 this ability to toggle between AMPK and AMPD is unique to any species that has the potential to

00:49:05.640 gain weight and wants to use it to their advantage.

00:49:07.780 Oh, absolutely. Part of the pathway through which AMPD is working involves the generation of uric acid.

00:49:14.020 So we know that the uric acid, when it's going up inside the cell, is doing all kinds of biologic

00:49:20.600 effects. And the AMPD is driving that. There may be other things besides the uric acid.

00:49:26.100 So the hummingbird or the squirrel can still store fat. They just don't get the bump in uric acid that

00:49:30.820 comes with it because they don't have the uricase mutation.

00:49:33.360 Well, actually the hummingbird does have the uricase mutation.

00:49:36.000 Oh, really?

00:49:36.520 Yeah.

00:49:36.820 I don't know my evolution well enough.

00:49:38.260 Yeah. So birds have the uricase.

00:49:39.520 Birds bifurcated off after then.

00:49:41.120 Yeah. Reptiles have the uricase mutation. Even dinosaurs had the uricase mutation.

00:49:46.680 Sue, the dinosaur, the Tyrannosaurus rex actually had gout.

00:49:50.580 I mean, that's got to be why Tyrannosaurus rex was so ornery. Because if you think of the size

00:49:55.000 of the T-Rex great toe, I mean, that would be infuriating to every bronchosaurus out there.

00:50:00.480 Yeah, I think so.

00:50:01.500 He's eating too many of the bronchosauri. Sorry to get back into the minutia of this,

00:50:05.120 but it's important. You still have to phosphorylate glucose during its metabolism.

00:50:10.840 Why is it that the phosphorylation of glucose during its metabolism to pyruvate doesn't result in

00:50:15.500 a strong enough drop in intracellular phosphate to cause the same problem?

00:50:19.600 Because the reaction stops. Whenever the phosphate and ATP levels start dropping a little bit.

00:50:26.160 You have that autoregulatory thing with the-

00:50:27.920 There's an autoregulatory thing with it. The enzyme stops functioning. It's inhibited.

00:50:33.720 And then that allows the ATP levels to stay normal. So here's a really cool follow-up of this.

00:50:39.740 And that is that sugar is much more likely to cause obesity if you drink it rather than if you

00:50:47.420 eat it. And the reason for that is that when you drink a drink that has fructose in it,

00:50:54.360 we tend to drink a lot in a short period of time. So if you have a soft drink, you can drink,

00:51:00.040 not only does it have a lot of sugar, but we tend to drink it fast. And so the concentration

00:51:07.180 of fructose turns out to be high when it gets to the liver. And it's the concentration that

00:51:14.180 triggers this reaction. So if the concentration of fructose is really low, the ATP depletion may

00:51:20.940 not be significant to drive dramatic metabolic effects. But if the concentration of fructose is

00:51:27.640 really high, then you're going to get a big metabolic effect. So eating like a candy bar where

00:51:34.160 it's coming with lots of fat, lots of glucose, lots of all sorts of things, lots of protein,

00:51:40.220 you know, if it's like a Snickers bar and it's got nuts or whatever, even if it's the same amount

00:51:45.160 of fructose, even if you're talking about 25 grams of fructose versus 25 grams of fructose,

00:51:50.180 you would drink very quickly. You're saying equal amounts of fructose can produce a different effect

00:51:55.620 if both the speed and the concentration with which they arrive at the liver are different.

00:52:00.680 Yeah. It's the amount, it's the speed, and it's ultimately how rapidly it's absorbed.

00:52:07.220 So if you drink something, if you take a lot of fructose, like, I mean, candy is very concentrated

00:52:12.340 fructose. I mean, if you eat that, for example, on an empty stomach, that will be absorbed faster

00:52:18.460 than if you eat it with oatmeal or something, you know, where there's fiber and so forth. And so the

00:52:23.620 speed of absorption makes a difference. So for example, if I was working for a high fructose corn

00:52:31.360 syrup company, and I wanted to prove that a soft drink wasn't bad, I could do a study where I would

00:52:38.980 give the soft drinks to people, but I would give it over, you're only allowed to make a tiny sip every

00:52:45.560 10 minutes. So it takes you three hours to drink a soft drink. In that case, the amount, even though

00:52:53.560 you're drinking a lot, the concentration may never be enough.

00:52:57.020 You never let the phosphate depletion get significant enough in magnitude that it really triggers AMPD.

00:53:04.120 Yes, that's it.

00:53:05.840 You know, it's really interesting. I think of all the sugar, the pro-sugar studies I've read that are

00:53:10.500 funded by the sugar industry. I don't think I've ever dug into the methodology to look at factors

00:53:17.060 like that specifically. Well, the other issue is like, if you just take a single dose of fructose,

00:53:22.900 most of the metabolic effects are best seen like in the first four hours following the ingestion. So

00:53:29.360 the triglycerides go up and the uric acid goes up and the blood pressure goes up. But if you just do a

00:53:35.800 single dose study, if you then look the following morning where the effects have now kind of come

00:53:41.680 back down, then you can't really show it. And a lot of these studies, they design it that way. So

00:53:47.600 they say, aha, fructose doesn't raise uric acid, but we measured it after fasting overnight. But the

00:53:54.640 surge in uric acid occurred earlier. So that's the common trick.

00:53:59.140 So all these things you're talking about with fructose seem to fit almost directly into the

00:54:06.580 five characteristics of metabolic syndrome, which are elevated glucose. So that insulin resistance

00:54:14.000 would be manifested as an elevated glucose, elevated blood pressure, elevated waist circumference,

00:54:21.160 so storage of fat, elevated triglycerides, what you just said. And the only one we didn't address

00:54:29.020 is low HDL cholesterol, which is the fifth finding. And now, of course, three out of those five are

00:54:35.020 sufficient to put you in the category, but fructose does all five. What is the mechanism by

00:54:39.480 so you've already described the mechanism by which it does three of them. We alluded loosely to how it

00:54:45.420 raises triglycerides, but I'd like to talk about that more. And then, of course, I'd like to hear how

00:54:48.880 it lowers HDL cholesterol. Okay, so the uric acid generated by fructose has a very pronounced effect to

00:54:57.920 stimulate oxidative stress in the mitochondria. And fructose also generates lactate big time. And the

00:55:06.020 lactate also has effects on mitochondria, as you learned from Dr. Sam Malan's talk. And in addition,

00:55:14.060 fructose preferentially decreases mitochondrial function and stimulates glycolysis. And so all those

00:55:22.560 things cause, you get this big oxidative stress to the mitochondria. And there's an enzyme in the

00:55:28.100 mitochondria that drives fat oxidation called enolcoahydritase. I mean, sorry to throw it out

00:55:34.660 there. No, no, no. We're here to talk about it. But basically, the oxidative stress inhibits that. So

00:55:41.020 fatty acid oxidation goes down. So you block fat burning. And then in addition, you block an enzyme

00:55:47.560 called aconitase with oxidative stress to the mitochondria. And that increases citrate, which

00:55:52.960 drives fat generation. And so you end up with fatty liver that's driven by both increased fat synthesis

00:55:59.920 and a block in fat burning. The mitochondrial oxidative stress also is very much linked with

00:56:06.940 the development of insulin resistance. And then uric acid is also degenerated. Uric acid is also causing

00:56:13.260 oxidative stress to the islets, to the pancreatic islets as well. Uric acid is actually harmful to

00:56:20.200 the islet cells of the pancreas? Uh-huh. In fact, if you give sugar, we did a study where we gave sugar

00:56:27.080 to animals where we actually restricted the amount of calories. The rats were getting, they were on a

00:56:33.700 diet, basically. They were on a diet. They were on a high sugar, low calorie diet. Right. And then we had

00:56:39.140 as a control rats that got the same number of calories, but they weren't getting the sugar.

00:56:43.960 Right. So just a low calorie, low sugar diet. Yeah. And when we gave the high sugar, low calorie diet,

00:56:50.240 all the animals developed fatty liver, hypertension, insulin resistance.

00:56:56.940 Did they actually gain weight? No, no. This is a trick. Weight gain really requires increased calories

00:57:03.900 really to show it. You know, long-term, maybe just decreasing metabolism will do it.

00:57:08.880 But this is interesting. You're saying both animals lost weight. Did they lose about the

00:57:12.220 same amount of weight? No, they maintained their weight. Even though they were eating 90%

00:57:15.700 of what they normally eat, they were able to maintain. So both groups slowed their metabolism

00:57:20.860 enough to maintain weight at a 10% reduction of calories. So on the outside, they look the same,

00:57:26.400 but the high sugar group still developed fatty liver. Severe. And they all became diabetic.

00:57:31.800 Do you recall in that study, Rick, what the actual percentage of their macros that came from

00:57:36.140 fructose? 20%. Right. So the critic will say, well, that's highly unnatural. Although in reality,

00:57:40.460 it's not that unnatural. There are lots of people, unfortunately, walking around getting 20% of

00:57:44.260 their energy input from that. So it's not physiologically completely out of whack, but as

00:57:48.980 a proof of concept, these animals got diabetes without gaining weight. They got fatty liver disease

00:57:54.680 without gaining weight. They were by definition, insulin resistant. Right. And when we measured their

00:57:59.780 insulin levels, they first became insulin resistant with high serum insulin levels, which is what we

00:58:06.200 see. Early diabetes, basically. With early type 2 diabetes. But over time, the serum insulin levels

00:58:11.880 started to fall. So they almost develop a type 1 diabetes. Well, just like humans do. And what we

00:58:17.260 saw is that the islets, used to be the phrase was called islet exhaustion, because longstanding type 2

00:58:23.580 diabetes, we see the same thing. But it's actually low grade inflammation in the islets. And we could

00:58:29.680 show that there was low grade inflammation. And it was associated with big time upregulation of uric

00:58:35.740 transport proteins on the islet. And when we took isolated islets, and we put uric acid on them, it

00:58:43.060 induced oxidative stress, and over time, caused a drop in insulin level. So what we think is going on is

00:58:49.520 that sugar causes diabetes through this pathway that we've been talking about. And it involves

00:58:57.120 initially insulin resistance. But over time, it will cause islet cell dysfunction as well. And this

00:59:03.400 has been confirmed by other groups now. That sort of comes to the triglyceride story, right? If you have

00:59:08.980 a net accumulation of fat in the liver, you're going to have to export some of that in the form of VLDL,

00:59:15.420 a very low density lipoprotein. So that would drive up the serum triglyceride.

00:59:19.340 What's driving down the HDL cholesterol? You know, I haven't studied that personally. I don't

00:59:23.900 really know. But I did see that there are reports that fructose can lower HDL, like in animals and

00:59:30.500 stuff. But I don't really know the mechanism. When you sort of pause for a moment, Rick, do you ever

00:59:34.600 worry that talking about fructose this way just seems, I don't know what the word is. I don't think

00:59:41.120 it's necessarily being too much of a reductionist. But it almost seems too simple, that this one

00:59:46.500 molecule could simultaneously have probably allowed our species to survive during this very cold spell

00:59:55.260 six to 12 million years ago. And obviously evolution wasn't thinking 12 million years into

01:00:02.500 the future that we'd be flush with fructose. And yet here we are today. One could interpret what

01:00:09.300 you're saying to mean if you simply had no fructose in your diet, most of the bad things we think about

01:00:16.720 metabolically would go away. Is that a fair assessment?

01:00:19.540 Yeah, I think that's true. So let me give you another one where we've really learned a lot.

01:00:24.920 I don't know if you are aware of the relationship with cancer. But what we've learned is that fructose was

01:00:31.660 an incredible survival nutrient in the setting of near starvation. So as I mentioned, what we're

01:00:39.140 learning is all these animals use fructose. They either get it from their diet or they make it in

01:00:44.140 their body. And they use that to help them survive. And we can talk about it, but it involves not just

01:00:51.440 storing energy, but they use fructose to store water. And we can talk about that and they use it to

01:00:57.540 become insulin resistant. Insulin resistance is a survival mechanism whereby increasing blood glucose

01:01:03.700 and preventing glucose from taking up in the skeletal muscle, it preserves it for the brain,

01:01:08.680 which is what you want to do if you don't have enough food around. You want to be able to think

01:01:12.920 so you can escape predators and so forth. So it was a survival tool to increase energy. And it actually

01:01:20.700 also protected animals from a low oxygen state. So by switching, by reducing mitochondrial function

01:01:29.280 and stimulating this thing called glycolysis, it allowed the animal to survive with a lower oxygen

01:01:36.660 state. And so we know, for example, that the naked mole rat, which lives in burrows, very low oxygen

01:01:43.620 burrows, they make fructose to survive when they're in those burrows. So suddenly the fructose

01:01:50.680 goes up in their blood and they use it to survive the low oxygen tension there because they switch

01:01:56.660 from mitochondrial metabolism to glycolysis. But why can't they just rely more on glucose for which

01:02:04.260 we have such an abundant apparatus to store it at large amounts? Is there an energetic reason for

01:02:10.980 fructose? A lot of the fructose is converted to glucose and to lactate, which can be converted to

01:02:16.520 glucose. And then it's driven through this glycolysis pathway. So it turns out, though, that what happens

01:02:23.040 is when you metabolize glucose, a lot of it will go through mitochondrial metabolism. And so if we can

01:02:28.640 inhibit mitochondrial metabolism, which uses oxygen, we can live off glycolysis, which doesn't require

01:02:35.980 oxygen. So what happens is in a low oxygen state, like the naked mole rat, will use fructose to

01:02:43.720 survive. But cancers... But wait, I'm still confused about this, Rick, because wouldn't that fructose...

01:02:49.840 But they're not storing that fructose as fat then, because that would be the worst fuel they could have

01:02:54.500 around in a low oxygen environment, right? Well, so fructose is increasing glycogen and lipid, but it's

01:03:02.600 also reducing mitochondrial use. When you're eating fructose, you actually are not burning the fat. You are

01:03:09.900 storing the fat. And then, so what it's doing is it's putting you into a glycolytic state.

01:03:16.920 So animals use it to store fat, and then they fast, and then they burn the fat. So they hibernate,

01:03:24.280 or they go flying long distances where they have no food, and then they switch. And then the fat that

01:03:30.440 they've stored suddenly becomes their survival. But during the time that they're in a low oxygen state,

01:03:36.460 they want to have fructose on board, because the fructose is helping them to survive low oxygen

01:03:43.180 by switching their metabolism. But unfortunately, cancers also live in a low oxygen state. And so

01:03:50.060 these cancers love fructose as their fuel, because it helps support them surviving in a low oxygen state.

01:03:58.100 So recently, it's been shown that many cancers, colon, liver, kidney, breast, brain, all these

01:04:06.800 cancer cells, intestinal, they all tend to like fructoses as their preferential fuel. There was

01:04:13.560 just a paper in Science a few weeks ago, and if you block that fructose pathway, the cancers don't do

01:04:19.720 as well. And when you say block it, do you mean block fructokinase? Yes. Which pathway specifically?

01:04:24.300 So if you take intestinal colon cancer, you put high fructose corn syrup on it, they love it. They

01:04:30.820 grow, they metastasize. And if you block fructokinase and block fructose metabolism,

01:04:36.580 you can block a lot of the growth of those cancers. Do you have a sense of how much you're

01:04:41.420 blocking it? It's pretty remarkable. It's like 50% or more. And we know it's the fructose, not the

01:04:47.220 glucose, presumably, because we don't impair glucose metabolism at all in that experiment.

01:04:51.900 That's correct. And also they were able to show that this was driven by that shift from a

01:04:57.300 mitochondrial-based metabolism to a glycolytic metabolism. And what happens to lactate levels

01:05:02.760 in that setting? Oh, very high. Like meaning the more fructose they have, the higher the lactate

01:05:06.900 level? Yes. Again, very counterintuitive because aren't we sort of taught that the liver is the only

01:05:13.560 organ that can really process fructose and that it all sort of accumulates there? And I mean,

01:05:18.700 conventional thinking is that fructose really doesn't have much of an interaction outside of

01:05:23.280 the liver unless converted to glucose, correct? That was said by a lot of people, but the findings

01:05:29.040 show that about 20% of fructose is used by the intestine or maybe 40% by the liver. And at least

01:05:37.140 10 to 20% can escape into the circulation. And of course, if the larger the dose, the more that will

01:05:43.400 pass. And the kidneys are a big target. There's fructokinase in the brain. There's fructokinase

01:05:50.780 in the islets. There's fructokinase in the adipose tissue. Does the muscle have fructokinase?

01:05:57.420 There's some thought that fructokinase may be in the muscle. It's got to be very low, but there's

01:06:02.400 some thought that fructose is being metabolized in the skeletal muscle. And one of the things that's

01:06:07.040 interesting is there was a paper in Nature that showed that the heart normally doesn't have

01:06:13.240 fructokinase, but when you have a heart attack, the low oxygen state there induces the fructokinase

01:06:21.400 and there's probably production, endogenous production of fructose. And it seems to be

01:06:26.120 involved in cardiac remodeling. So it's probably involved in more things than we think of. And

01:06:31.120 certainly it's in the brain. Which means that in theory, the brain could actually use free

01:06:38.320 molecules of fructose to make ATP in addition to the mainstay of its energy metabolism, which is

01:06:44.240 glucose driven and lactate. I think we're now seeing lactate. There is actually some evidence that first

01:06:50.240 off, we know that fructokinase is in the brain. We know the brain can make fructose and there's

01:06:55.800 increasing evidence that insulin resistances can occur just in the brain and may be a forerunner

01:07:03.000 for the development of Alzheimer's. And there are actually reports that AMPD aminase is high in the

01:07:09.000 brains of Alzheimer's patients. And it raises the possibility that local fructose metabolism could

01:07:15.300 be involved in disorders like that. Are there any people with naturally occurring mutations in

01:07:19.600 fructokinase that render it less capable? Yeah. So there are people with a condition called

01:07:24.380 essential fructose area where they are born without active fructokinase and they live normally. No one's

01:07:30.520 ever been reported to have type 2 diabetes or obesity. So these people, if I'm understanding

01:07:35.620 you correctly, are genetically immune to the harm of sugar? Yes. And they pee out all the fructose?

01:07:42.140 Yes. Okay. So that seems to be an interesting topic. This must be very rare. I've never even heard of

01:07:47.660 this. It's a rare condition. They actually don't pee out all the fructose. Some fructose can be

01:07:52.080 metabolized by an enzyme called hexokinase, which is normally metabolized as glucose. But

01:07:58.620 fructose is preferentially metabolized by fructokinase. So these people have very sweet

01:08:04.220 urine going back to Osler. Had he tasted their urine, he would have confused them potentially with

01:08:09.580 an even sweeter version than the people with ultimately type 2 diabetes. That's how they were

01:08:13.940 discovered because they would have reducing sugars, which was fructose in their urine that was picked up

01:08:20.580 with the old tests they used to use for diabetes, but then they didn't have diabetes when they tested

01:08:25.740 them. And these people could literally just consume all the sugar they wanted and their uric acid is not

01:08:30.760 going to go up. Their blood pressure is not going to go up. Their trigs don't go up. They don't gain

01:08:34.280 weight. They don't become insulin resistant. That's right. So is there any benefit to having fructokinase

01:08:39.360 if you're not hibernating or in a world where famine is potentially coming your way? It's really a

01:08:45.620 survival enzyme that was meant to help in situations where there was food shortage. If you live in the

01:08:53.140 Western world and you just have to go down to the grocery store, no. I think living without

01:08:58.580 fructokinase would probably solve a lot of the world's health problems. I mean, and there are

01:09:03.580 fructokinase inhibitors that are being developed. Pfizer has one that's now in a finished a phase 2 trial.

01:09:09.920 It was quite successful at treating fatty liver. And so now they're taking that drug to phase 3.

01:09:17.000 Wow. That's a potential blockbuster, actually. Of course, it begs an interesting question, which is

01:09:22.360 how will that drug be treated? Will it be only used as a way to treat an active condition such as fatty

01:09:28.860 liver, in which case it's going to have a smaller on-label market versus what will likely happen, which is

01:09:35.200 people who just want to be able to have more sugar without the consequences of it would take it,

01:09:39.660 correct? Yeah. Although it's probably priced to avoid that, I'm guessing. Anyway, yeah, there's a

01:09:44.520 lot of interest in fructokinase inhibitors. There's other big pharma that are working on it now. And so

01:09:50.440 we'll have to see if it turns out to be as powerful as we think it might be. So the work that we've just

01:09:56.140 discussed has sort of been, you've been at this since 2002, basically, specifically with respect to

01:10:00.780 this. Let's go back to allopurinol and uric acid in your clinical practice, because you've spent 17

01:10:08.640 years as the division head of nephrology across three world-class medical centers, most currently

01:10:15.660 the University of Colorado. And yet I was surprised to learn over dinner the other day that you still

01:10:20.760 have a very pretty heavy clinical practice. You still actually take care of patients in the

01:10:25.620 inpatient ward and you probably spend a quarter of your time in clinic. So how do you put some of

01:10:30.680 this stuff into practice? Do you liberally use allopurinol even for patients who have high uric

01:10:36.520 acid but have not developed gout yet? I do. So our data strongly suggests that lowering uric acid could

01:10:43.560 be beneficial. So what I do is the following. So it turns out that allopurinol is not totally safe.

01:10:50.540 There's some people who can develop reactions to allopurinol, drug reactions, especially Asians.

01:10:57.020 About 3% to 4% of people who are Asian can develop an allergic reaction to allopurinol where they can

01:11:03.420 get rashes and it can be pretty severe. And it's about 2% in African-Americans and it's about 0.5%

01:11:11.720 in Caucasians. You can test for it. There's a test called the HLA-B58 test. But the point of the

01:11:17.600 matter is that no drug is fully safe. Every drug has side effects. So ideally, you'd want to really

01:11:24.620 be certain that your drug's going to provide the benefit that you want and you have to consider the

01:11:30.160 risks versus benefits. Now, although in animals, allopurinol is totally protective or protects a

01:11:36.880 lot against sugar-induced metabolic syndrome, the data in humans is suggestive. So there's been,

01:11:42.420 for example, four pilot studies showing an improvement in insulin resistance with lowering

01:11:47.660 uric acid in humans. All four are positive. There's a lot of trials in kidney disease showing

01:11:53.640 that lowering uric acid may benefit kidney disease. There's data on blood pressure. We had a paper in

01:11:59.900 the JAMA showing that lowering uric acid could improve blood pressure control in adolescents with

01:12:05.740 hyperuricemia. So there's a lot of supporting data. There are some negative studies too,

01:12:11.540 but the overall weight is now in favor of lowering uric acid to benefit.

01:12:17.100 What would the target be?

01:12:18.320 So what I do is when I see a patient in clinic, I measure the uric acid. And currently, we know that

01:12:25.760 the risks start to go up when the serum uric acid is over 5.5. So once the serum uric acid is over 5.5,

01:12:34.080 they really start to have increased risk for prediabetes, insulin resistance, hypertension,

01:12:39.440 kidney disease, etc. And what's interesting is most labs, like my lab, for example, doesn't even

01:12:44.420 flag it until it hits about 6.5 as a sort of intermediate risk. And it's really not until

01:12:50.260 about 7.5 that it says, well, this is high risk. But of course, that's only through the lens of gout,

01:12:55.180 I assume. Yes, that's right. So if a uric acid comes back really high, like 9 or 10,

01:13:00.380 I have no doubt that that, based on everything I've done, I have no doubt that that's not good.

01:13:05.880 Not only does it increase the risk for gout, but it increases the risk for kidney disease and all

01:13:10.060 these things. And I talk to the patient about the pros and cons of treatment. I talk about the rash,

01:13:15.900 I tell them to stop the drug if they get a rash, and then call me. But I always start allopurinol when

01:13:23.080 the uric acid is like 8 or higher, and certainly when it's 9 or higher. When it's between 5.5 and 8,

01:13:30.740 I'll talk to them about the pros and cons. But we don't have full proof yet. But I tend to do it,

01:13:37.340 especially with patients with kidney disease, where the data is probably the strongest to start

01:13:42.080 treating. I'll even do it with uric acid of 6.5, for example, with chronic kidney disease.

01:13:47.680 But anyway, it's worthwhile discussing it with the patient.

01:13:50.820 But outside of the risk of Stevens-Johnson syndrome, which you've alluded to,

01:13:54.980 what are the other potential risks of allopurinol?

01:13:57.340 That's by far the big one. Some people will get just a mild rash without true Stevens-Johnson

01:14:03.200 syndrome. There are rare cases where liver function tests may be elevated, but it seems to

01:14:08.880 be rare. If you start at a huge dose right away, it can increase xanthine levels in the urine.

01:14:16.000 Theoretically, there could be risk for xanthine stones, but I've never seen it. So it's really the

01:14:22.860 risk of Stevens-Johnson that...

01:14:24.460 And do you have to use allopurinol or can you use euloric or other drugs that also lower uric acid?

01:14:31.280 Well, the xanthine oxidase inhibitors are the best because the way uric acid works to cause

01:14:36.560 cardiovascular disease and kidney disease and all these things appear to be through its actions

01:14:42.580 inside the cell, as we said, works on mitochondria and it does all these things. It's not, it's work

01:14:48.280 outside the cell. So gout is really an extracellular deposition. But when you're thinking about uric acid

01:14:56.220 and its biologic effects, that's an intracellular action. So xanthine oxidase makes uric acid inside

01:15:03.180 the cell. So one of the best ways to reduce intracellular uric acid is to give a xanthine oxidase

01:15:10.220 inhibitor like allopurinol or fibroxastat. Now fibroxastat, I think it's probably just as good

01:15:16.240 as allopurinol, but there was a big clinical trial that was published in the New England Journal

01:15:20.240 that showed that allopurinol was associated with less cardiovascular risk than fibroxastat. There

01:15:26.240 seemed to be an increased cardiovascular events in the fibroxastat group.

01:15:30.620 Meaning less of a reduction or more events? Well, see, the problem was there was no placebo

01:15:35.740 group. Oh yeah, that's a disaster. That's a disaster. This is the Vioxx problem with napraxin.

01:15:41.260 Yeah, yeah. I mean, so the problem is allopurinol is less than fibroxastat,

01:15:45.320 but there's no placebo group. Theoretically, the placebo group would be... Could be higher than both

01:15:50.380 of them. Yeah, it could be higher than both of them. And there's actually evidence that that's probably

01:15:54.440 true. But because of the CARES study, the way it was designed, we don't know. So the FDA

01:16:00.200 is worried about giving fibroxastat to people with cardiovascular problems because they would

01:16:06.520 prefer you to give allopurinol. But the trouble is, it's not necessarily that fibroxastat is bad.

01:16:12.660 It's just that it's not as good as allopurinol. And it's like a hundred thousand times more

01:16:16.920 expensive too. I mean, it's a... Although it's, I think, becoming generic now. So we may see a

01:16:21.720 change in that. I believe it when I see it. And of course, well, you trust the generics,

01:16:26.080 but that's a whole separate issue. Exactly. So what about sodium

01:16:30.000 restriction, going back to how we started the discussion? I'll tell you a story from... I may

01:16:34.140 have even told this on the podcast once before, but in medical school, I remember when we were

01:16:37.400 doing renal physiology, we had a great nephrology professor who was teaching something. And I think

01:16:43.800 he was quite ahead of his time because this was more than 20 years ago. And he was not sort of part

01:16:48.820 of this salt is bad bandwagon, even though he was a nephrologist. And I won't do it because I won't

01:16:54.700 do it justice, but in a beautiful Southern accent, he made the point that if you lined up all of the

01:17:00.280 nephrons in the world, all the functional units of the kidneys in the world from dumbest to

01:17:05.100 smartest, and then all of the nephrologists in the world from dumbest to smartest, and you took that

01:17:10.160 dumbest nephron and put it next to the smartest nephrologist, it's still smarter. His point being,

01:17:16.320 of course, like the kidney is a brilliant organ that is exceptional at auto-regulation of everything

01:17:23.800 from flow to osmolarity to anion-cation exchange. Again, his point being, he didn't buy this argument

01:17:31.380 that salt is the problem. You're saying something much more nuanced, and I want to kind of go back

01:17:36.040 to it because I think there are important clinical implications of it. You're saying, no, no, no,

01:17:40.600 salt does play a role, but it's dose timing bolus concentration that matters. It can also be

01:17:47.700 amplified or mitigated by the state of inflammation. So how do you then translate that information to

01:17:56.000 your patients, acknowledging that they're a very select group of people by definition,

01:17:59.940 they have kidney disease or they wouldn't be seeing you? So it's the combination of salt and water.

01:18:04.600 So if you don't drink any water, as you eat salt, you're going to raise your serum sodium. You're

01:18:09.980 going to get thirsty. And as soon as you're thirsty, you've triggered that in itself is a sign that

01:18:15.260 you're already making fructose from the salt. So when you eat salt, you're making fructose in your

01:18:21.380 body. And the fructose is then driving a lot of effects. Now we know that high salt diets are

01:18:28.300 associated with obesity, not just high blood pressure. They're associated with the development

01:18:32.380 of diabetes. There's many studies now, but high salt looks like it works by producing fructose.

01:18:38.900 So if you drink water with salt, the danger of the salt is much less. If you drank water and then

01:18:45.220 ate your pretzel, you would be safer than if you ate your pretzel and then drank the water.

01:18:50.780 Because what triggers it is the rise in salt. And so when you see someone in the clinic,

01:18:56.860 what we try to do is to tell them to drink a lot of water and to reduce their salt. But it isn't the

01:19:02.980 amount of salt, it's the balance of salt and water.

01:19:06.180 Now that can be sometimes challenging for patients in a kidney clinic because that would be one

01:19:10.760 population in which you do have to be mindful of volume.

01:19:14.140 Right. But most patients with chronic kidney disease, they will excrete water normally or just

01:19:19.280 minimally abnormal. And so there's actually clinical trials looking at the evidence that water may slow

01:19:25.480 the progression of kidney disease. It might be working in part by blocking the effects of salt and so

01:19:31.880 forth on the kidney. And we experimentally can show that giving water can slow kidney disease

01:19:38.260 progression. So drinking water turns out to be good. Here's another thing. It turns out that many

01:19:43.580 animals use fructose to make fat as a means for making water. So when you make fat, although there's

01:19:50.980 no water stored in the fat, when they burn the fat, they make water. So whales don't drink salt water.

01:19:56.660 They are fat because when they break down the fat, they're making the water. We call it metabolic

01:20:01.800 water. So it turns out that fructose drives fat production and in part to preserve water, not just

01:20:09.640 energy. So animals will use that fat to provide an energy source, but also to provide water. So it turns

01:20:18.000 out that if you take an animal on fructose and you give it a lot of water, you can suppress some of the

01:20:25.080 obesity. You can suppress some of the effects of metabolic syndrome. And so the old wives tale that

01:20:31.580 drinking six glasses of water a day is good to help keep you skinny is true. It turns out that water

01:20:37.900 suppresses some of the effects of fructose. And does it need to be water? Could it be tea or coffee

01:20:44.380 or something that's equally... The osmolarity of water is what? Serum is about 280? Yep. Okay. So anything

01:20:49.800 with the zero osmolarity is good enough? Yes. Technically a diet soda should have a zero

01:20:54.800 osmolarity as well, right? Yeah. Diet soda would work actually. For the record, you and I are sitting

01:20:58.580 here drinking just plain water. Right. And diet sugars have their own issues. So... We'll come back

01:21:03.700 to that in a few seconds because that's super interesting. So Rick, you sort of, you toss these

01:21:08.100 little nuggets out there like they're nothing, but they sound, I mean, again, just based on the sort of

01:21:13.140 breadth of research you've put into this, it almost just seems too good to be true and so profound,

01:21:18.220 yet you sort of throw it out there like an after the fact. Well, look, as long as you drink enough

01:21:22.560 water and don't eat fructose and God forbid, don't drink fructose, manage your uric acid levels,

01:21:28.720 et cetera, et cetera. So you make it seem like a lot of problems could go away from these things.

01:21:33.960 How would you shape that advice for someone with normal kidney disease? Pardon me, with normal

01:21:38.160 kidneys, would you basically just say the same thing? Or can you be less restrictive with sodium,

01:21:42.840 for example? If we could reduce our fructose intake, I think it would have a huge, huge effect.

01:21:48.000 But the problem that most people face is that sugar and high fructose corn syrup are in almost

01:21:54.040 everything. So if you go to the supermarket, like 70% of processed foods have sugar in it and packaged

01:22:02.440 foods. Actually, 70% of packaged foods have sugar or high fructose corn syrup in it. So it's very hard

01:22:08.320 to avoid it. And here's another problem. Our bodies can make fructose. So our bodies, as I mentioned,

01:22:15.220 we can make fructose from a high salt diet. We can make fructose if we get dehydrated. We can make

01:22:21.220 fructose, high uric acid stimulates fructose production. And we're making the fructose out

01:22:26.200 of glucose in all of these situations? Yes. High glycemic diets. Normally, if you take an animal

01:22:31.320 and you give it starch, they will not really get fat. But we all know that French fries, which don't

01:22:38.460 have sugar in it, they don't have fructose, they are fattening. But you've got potatoes which raise

01:22:44.440 your glucose. And what we showed is that if you just give glucose to an animal, the high glucose as

01:22:50.340 it hits the liver induces this enzyme to convert glucose to fructose. Which enzyme is that that

01:22:55.700 converts glucose into fructose? Aldose reductase. So when we took mice and we gave them glucose and we

01:23:01.980 were thinking, we might not see much because we were believing that fructose is the culprit. But

01:23:08.520 over time, these animals got really fat. They got insulin resistant, everything. But you had to

01:23:14.060 overfeed them glucose. We put the glucose in their drinking water. So they were drinking a lot of

01:23:19.320 glucose. But they would eat less chow. So we gave them chow and glucose in their drinking water.

01:23:25.120 And their chow had, it was normal chow. It wasn't the high fat, high sugar chow.

01:23:28.680 No, just regular chow. And these animals started getting really, really fat. And when we looked at

01:23:34.340 the portal vein, which goes into the liver, the glucose levels were high. And when we looked in the

01:23:39.860 liver, we found that this enzyme was activated. It's also activated in diabetics, for example,

01:23:46.260 because of the high glucose in the blood. And when that enzyme got activated, it started to make

01:23:51.720 fructose. So even though these animals were eating no fructose, they were producing fructose in

01:23:57.820 their liver. And then when we blocked their fructose metabolism, they're eating the same

01:24:03.780 amount of glucose, no change. Exactly. Suddenly, they're not getting as fat. They have no fatty

01:24:10.940 liver. They're not insulin resistant. But this suggests, Rick, that a diet in excess

01:24:16.760 carbohydrate, even if it's not high in sugar, could lead to fatty liver disease?

01:24:20.700 Yes. Yeah, absolutely. If you have that enzyme induced. But let's say that you are a young

01:24:26.760 person. When you're young, this enzyme is really not present in the liver. Once you're eating sugar,

01:24:34.580 though, if you eat a lot of sugar, it will induce that enzyme.

01:24:37.960 For how long?

01:24:38.820 I don't fully know. But let's say that you eat a lot of sugar and you get obese. So sugar itself,

01:24:44.920 it looks like the induction of this enzyme probably would be reversible within a few weeks. But once

01:24:51.100 your uric acid goes up, that will keep it elevated. So that's another reason potentially to use

01:24:56.240 allopurinol if necessary, in addition to fructose restriction to keep uric acid low, is to prevent

01:25:02.800 or mitigate the induction of this enzyme. Oh, yeah. Right. So it turns out that if you give

01:25:09.460 starch or potatoes to a skinny person who does not have all this reductase induced, they can eat the

01:25:17.020 potatoes they want. In Ireland, back in the 1700s, where potato was basically the main thing they were

01:25:22.280 eating, there wasn't a lot of obesity. But you wait until you eat sugar and then develop the metabolic

01:25:27.760 syndrome. Now you stop eating sugar, but you continue to eat carbs and the carbs are going to

01:25:34.300 continue to activate through the same pathway. So a low carb diet is really great because it's

01:25:41.960 necessary if you're overweight or fasting, but that's basically reducing carbs too. But a low

01:25:47.660 carb diet when you're overweight is removing the high glycemic carbs that are also driving the disease,

01:25:54.020 but it's through fructose. So it seems that fructose reduction obviously comes with its own

01:25:59.520 benefits. Do you have a sense of how much fructose can be produced in a fructose-free intake environment

01:26:06.640 just from glucose? Is it a meaningful amount? Well, we did our study by putting glucose in the

01:26:12.740 drinking water. They're getting a lot of glucose. We haven't done the study, is the one that you're

01:26:18.720 talking about, trying to figure out what the range is. I do think that if you just give high glucose alone,

01:26:25.040 you probably have to give a lot. But if you've already triggered the production of this enzyme

01:26:30.180 aldose reductase, you probably don't have to give a lot. What about fat? What if you did that same

01:26:34.320 experiment with rats or mice, which would be hard because to eat pure fat is difficult. But if there

01:26:40.740 was a way that somehow you could make it palatable enough that you could overfeed them to the same

01:26:46.080 extent using fat and protein, let's say they're getting a normal amount of glucose, but the overfeed was

01:26:51.120 coming through the fat. Would that induce any of these properties? In other words, is part of this due to

01:26:57.280 an absolute sense of total energy being too high? Or is this really about a particular carbohydrate?

01:27:04.340 It's definitely about a particular carbohydrate because we've actually done what's called

01:27:07.740 pear feeding, where you control how much they eat and you can have your control group. The fructose

01:27:13.480 effects will still, as I mentioned, cause fatty liver. Yeah, explain what pear feeding is for people

01:27:17.660 because it's a clever little tool done in this type of research. So the way fructose works is it works

01:27:24.080 by making you eat more. And that's how you gain weight. But even when you control so that you don't

01:27:30.260 eat more, fructose will not cause weight gain, but it will cause fatty liver, insulin resistance,

01:27:36.100 and diabetes, and so forth. And the way we can show that is by pear feeding. In pear feeding, we give

01:27:41.320 each animal eats the same amount of food. So if you give one animal sugar, which normally makes

01:27:47.760 it want to eat more because it causes this thing called leptin resistance where they want to eat

01:27:52.480 more. But if we don't give them any more food, we only give them the same amount as the control,

01:27:57.860 then there will be no difference in weight. But there will be differences in fatty liver,

01:28:03.740 metabolic syndrome, and so forth. The sugar industry has used this to their advantage. So what they say is,

01:28:09.820 okay, we're going to look at clinical trials where we've given sugar, and we're going to see if sugar

01:28:15.020 causes weight gain. But it's only fair to do that if we have it controlled where we control the energy

01:28:20.920 intake to be equal among groups. So they have a control group where they've restricted, there's a

01:28:26.660 caloric restriction on both sides. So you have a high sugar and a non-high sugar group, but it's not

01:28:33.400 where you get to, the people get to eat as much as they want. Basically, it's this problem of not

01:28:37.820 having ad libitum feeding. So it's sort of like what the sugar industry is saying is, look, a calorie

01:28:42.200 is a calorie. If I give you 100 calories of sugar and completely control what you can eat in response

01:28:49.360 to that and compare you to another person who's eating the same number of calories, you're really

01:28:54.600 not going to gain weight. And the problem with that experiment is it's not the real world. In the

01:28:59.400 real world, you don't have a clamp on your response. Exactly. And so when you give sugar to

01:29:04.760 animals, they become leptin resistant over time and they lose their ability to control their appetite.

01:29:10.500 So then they eat more. And so then their weight goes up. But the fructose is also doing stuff where

01:29:16.620 even if you control for the weight gain, they still get the fatty liver and stuff, which the controls

01:29:21.080 don't. Now, a second ago, you sort of alluded to artificial sweeteners. So comparing, I mean, I'm sure

01:29:25.900 you get this question asked all the time by your patients, which is, I just really love Coca-Cola.

01:29:30.540 Is having a diet Coke, it must be significantly better, right? I mean, there's no fructose in it.

01:29:36.180 There's no glucose in it. So is there a downside to it? Yeah, I think there are downsides. But first,

01:29:41.500 let me just say the positive side. We have taste buds that sense sweet. And so when we eat sugar,

01:29:49.340 the taste buds are activated and it stimulates this dopamine response in the brain that tells us that we

01:29:58.080 like this sugar. If you actually knock out the sweet taste buds or just knock out the tastes in

01:30:03.880 general, animals will still like sugar. They will still eat sugar, a lot of sugar.

01:30:10.500 How hard is that to do experimentally to knock out the sweet tasting capacity?

01:30:15.360 It's been done. And we actually have also done it where we knock out all taste.

01:30:20.140 Can you do it to me?

01:30:20.880 No. It's like a genetic knockout. But anyway, these animals will still like sugar,

01:30:28.200 but they won't like artificial sugar. So the artificial sugar is really driven by the sweet

01:30:32.720 taste. But what makes animal like real sugar, it's through its metabolism. I mean, it is true.

01:30:39.140 If you knock out taste, they will tend to eat a little bit less sugar, but they actually still

01:30:44.260 develop metabolic syndrome. That's super interesting. So you're saying part of our

01:30:48.200 affinity for sugar is not just in our taste buds and in our brain, but also in our periphery where

01:30:54.840 the metabolism takes place. And the elegant way you demonstrate that is you give something of equal

01:30:59.620 sweetness concentration that's non-nutritive and you completely reduce the appetite for it.

01:31:06.060 Even though it might have the same central effect, it doesn't have the peripheral effect.

01:31:09.640 Probably the sweet taste bud developed to try to encourage us to eat these foods that at the

01:31:15.840 time were survival foods. But the food itself, the sugar itself, stimulates dopamine and other

01:31:22.840 effects independently of the sweet taste. Whereas an artificial sugar just is activating the sweet

01:31:31.200 taste. Now, if you give a mouse or a rat artificial sugar, they don't gain weight. But if you give them

01:31:39.440 regular sugar, they do. So there is some evidence that artificial sugars are better than sugar. And if

01:31:47.240 a person says to me, oh, doc, I'm afraid to drink this Diet Coke because it's got chemicals in it. I want

01:31:55.600 to drink regular Coke because of that. That's an error. Regular Coke is more dangerous than a Diet Coke.

01:32:02.480 However, there is truth that things like aspartame and sucralose, we don't know fully the safety of

01:32:10.700 these. Aspartame, when last I checked, had been studied more by the FDA than any other molecule

01:32:17.120 ingested by humans. It's hard to make the case that at the small doses that people would consume

01:32:22.880 them. I'm talking about someone who has a serving of this stuff a day. I don't know. I've always found

01:32:28.660 that argument that, well, we don't know the full safety profile of these things to be,

01:32:32.760 it's like, what else do we need on this one? I think aspartame is kind of gross, truthfully.

01:32:36.420 Like, I don't really like it that much, but I just think it's definitely the lesser of two evils,

01:32:41.020 isn't it? It's definitely the lesser of two evils. That part's for sure. But we don't fully know

01:32:46.100 the safety of some of these. Like saccharin, for example, has been associated with little bladder

01:32:50.440 tumors in mice. My recollection is that aspartame can generate small, tiny concentrations of

01:32:56.300 formaldehyde. I think it really comes down to dose.

01:32:58.660 Yes, I think it is.

01:32:59.480 I think those studies were really based on rats or rodents consuming doses that simply couldn't

01:33:05.240 be replicated by humans.

01:33:06.880 That's probably true. Nevertheless, water is good.

01:33:09.520 Yeah, that's generally been my take to people as well is, look, all things equal by certainly

01:33:14.820 consume water, tea, things like that. But yeah, there's this lesser of two evils approach. But

01:33:19.320 this point you made, this is completely news to me and very interesting because certainly much of

01:33:24.380 the neurobiology today would suggest that the response we have to sugar is mostly

01:33:28.320 centrally mediated. The quote unquote addictive, because everyone loves to talk about functional

01:33:32.820 MRI and what happens in your brain when you're eating sugar and all of these other things. But

01:33:38.260 I guess I haven't seen this side by side, but presumably the fMRI would light up the same for

01:33:42.980 non-nutritive versus like aspartame and sugar, correct?

01:33:47.040 Yeah.

01:33:47.220 So let's talk about another taste, which is umami. I remember we were having sushi one night when we

01:33:52.820 discussed this. What is umami? What is that taste?

01:33:55.600 So umami is the savory taste.

01:33:58.340 And this is different from salt, isn't it?

01:34:00.080 So there's five taste buds. So there's salt, there's sweet. And as I mentioned, both of these

01:34:05.680 taste buds seem to drive a weight gain. Sugar is by far the fastest. It takes only two months

01:34:12.380 in a laboratory animal and salt takes four months, five months. So high salt generates fructose,

01:34:19.120 but it's a much slower process than just eating sugar. Then you have umami, which is the savory

01:34:23.860 taste. And then you have bitter and sour. And the bitter and sour are probably developed to help you

01:34:29.500 avoid eating certain foods.

01:34:31.540 So coffee is an example of bitter, like a coffee bean or something, like a ground?

01:34:35.220 I think so.

01:34:35.760 Anyway, so umami is driven by glutamate, but it's markedly enhanced by purines like IMP

01:34:43.560 and even uric acid. So it turns out that umami is sort of a taste receptor for uric acid type foods,

01:34:53.460 foods that raise uric acid.

01:34:55.500 Now is MSG the purest form of umami that we would eat?

01:34:58.880 Yes. MSG is the primary stimulant and people put it in foods to encourage food intake. Now

01:35:06.260 there's some link of umami with obesity in epidemiologic studies. And there are situations

01:35:13.740 where you can give umami type foods. And especially if you can do it in a liquid form, you can induce

01:35:20.080 obesity. So umami may not be as safe as we think it is. So it's got a lot of good

01:35:28.180 things written about it in the literature.

01:35:31.480 Don't most people view MSG as evil?

01:35:34.780 Yeah, I think MSG is viewed as evil.

01:35:36.920 But that seems to be largely unfounded based on my view of the literature. I can't really

01:35:40.700 find evidence that umami is harmful.

01:35:42.460 There's this Chinese restaurant syndrome where people get a warm and headaches and it's thought

01:35:47.980 to be due to excessive MSG. But foods that are umami rich are often foods that we love.

01:35:53.940 I mean, shrimp has umami, Caesar salad, the Parmesan and things like that have umami. And so in general,

01:36:02.900 people like umami foods and it's certainly in the websites, it is often promoted. But if the umami

01:36:10.080 foods have a lot of purines, which enhance the umami flavor, it actually may raise uric acid and kind

01:36:16.720 of bypass the sugar pathway. And we think that that may turn out to be somewhat of a risk factor too.

01:36:24.100 So do you add this to the list of things that you caution people about? We've already got the

01:36:29.720 pair your salt with water idea, the restrict fructose and please God don't ever drink it.

01:36:37.200 Do you then add the MSG containing high umami foods to that playbook for ways to reduce metabolic

01:36:45.000 disease? I think so. Yeah. I think that foods like shrimps and things like that, if you eat a lot of

01:36:51.740 them, they probably activate this pathway too. We're still trying to learn more about it, but it looks

01:36:58.720 like it could be a contributor. I think it's, if you rank it, number one is sugar and then everything

01:37:06.720 else is less. High glycemic carbs can be converted to sugar. What I usually say is the big four are

01:37:14.380 bread, potatoes, chips, and rice. Those four are the foods that you should reduce a little bit.

01:37:22.400 Wait, chips as in like chips, potato chips? Yeah, potato chips. So you're giving potatoes two votes

01:37:26.520 out of four. Yeah, well, or corn chips or, you know. Okay, got it, got it. The kind of things that people

01:37:31.520 put out on their table before you eat dinner. And they coat it with salt, which isn't good. Anyway,

01:37:39.680 so high glycemic carbs, I think really salty foods drink water. I mean, that's really important.

01:37:46.640 And umami, so for example, what makes beer so much more dangerous than other alcohols for inducing

01:37:55.120 obesity is because beer has all this yeast in it, brewer's yeast, which basically is activating umami

01:38:02.980 pathways. And it's one of the reasons we like beer. This is that cellular density issue you spoke about.

01:38:07.440 Exactly. And so a beer raises uric acid more. And there really is this beer belly syndrome. And if

01:38:14.620 you look at people who drink a lot of beer, it isn't just that they get abdominal obesity. They get

01:38:19.740 fatty liver. They get high blood pressure. Their triglycerides go up. They basically have metabolic

01:38:25.200 syndrome. Alcohol, especially beer, can also mimic sugar. And it's probably because of the umami

01:38:33.240 component coupled with the alcohol. Those two. This is the part that can sometimes drive a person

01:38:37.920 insane when they're trying to think about all of these things is it's very difficult to provide

01:38:43.580 clear advice to people because there's so many caveats that are required because the dose makes

01:38:50.100 the poison, the speed of delivery, what it's combined with all of these things. I'm using that as a preface

01:38:55.360 to ask a question that I'm sure you get asked a lot, which is really a dose question around fructose.

01:39:00.780 So let's ask it in two questions. If a person is going to drink something in the form of fructose,

01:39:06.700 whether it be fruit juice or soda or sports drinks, which are from a fructose standpoint,

01:39:11.340 all basically the same. Is there a dose of fructose above which you think it really makes

01:39:15.860 no sense under any circumstance or below which you think once in a while is not the end of the world?

01:39:20.720 I mean, personally, I would not drink any liquids that have sugar in it or a fructose or high fructose

01:39:27.000 going to. That's fine. So we're going to draw a hard line there. Hard line. Okay. Now what about

01:39:30.560 eating fructose in the form of fruit? Because remember, there's some big ass fruits out there.

01:39:34.580 Like you look at a Fuji apple, which is my favorite apple. I mean, I like these monster Fuji apples.

01:39:40.780 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

01:39:45.340 grams of fructose in it. I don't think it has that much. Oh, really? I really don't. Most apples,

01:39:50.460 and that would be a big one, maybe 10 grams at most, I would think. No way. You think more?

01:39:55.480 Well, think about it. These are the really big ones. Yeah, yeah. I'm not talking about a little

01:39:58.680 Macintosh. I'm talking about a huge apple. And they're so sweet, too. So you may be right then.

01:40:04.300 Let's talk about natural fruit. So we've actually done trials in patients with a low fructose diet

01:40:10.500 with or without natural fruit supplements. And generally speaking, natural fruit supplements

01:40:15.020 do not seem to block the benefits of a low fructose diet. Sorry, what does that mean? And you mean

01:40:19.860 that if you took a patient and restrict all fructose except fruit- That's correct.

01:40:24.780 They tend to do okay? They did just as well as the low fructose alone.

01:40:28.300 And can you quantify how much fruit? Because here's the problem. When you're talking to someone

01:40:31.820 like me, Rick, I don't do anything in moderation. So we have these bowls in my kitchen. They're

01:40:36.900 called manly bowls, which by definition, a manly bowl is a bowl that you can wear on your head like

01:40:41.620 a hat. It will come over your head. And when I consume fruit, I consume it in that bowl.

01:40:45.920 Yeah, I would be careful.

01:40:47.240 So no manly bowls.

01:40:48.160 Yeah. So the data suggests that a single fruit, maybe not the giant foodie apple.

01:40:53.840 I don't know the last time I had a single fruit.

01:40:55.880 Yeah, but a single fruit has like, some fruits like kiwi and lime and lemon have almost no fructose

01:41:01.280 and they're totally safe. And other fruits-

01:41:04.720 Like pineapple and stuff.

01:41:05.820 You have a fair amount of sugar.

01:41:07.720 Berries, for example, blueberries have so many good things in it. You can eat a big bowl of blueberries,

01:41:13.480 no problem. Raspberries, strawberries, they're all, all the berries in general are very good.

01:41:18.520 Grapes, they have a fair amount of sugar. You eat a bowl of grapes, you're going to probably raise

01:41:23.500 your uric acid and trigger the activation of this pathway.

01:41:26.180 You eat a bowl of grapes, you might as well be eating raisins based on what my blood glucose

01:41:29.800 meter tells me.

01:41:30.620 Exactly.

01:41:30.860 It's a disaster.

01:41:31.720 Yeah. What I would recommend is to try to not eat too many fruit at one time. So for example,

01:41:39.320 there was a lady named Knott's, Cheryl Knott's, I believe is her name. And she's an anthropologist

01:41:44.060 and she was studying orangutans. And there's a time when the massing season where all these fruit

01:41:49.980 trees bloom and then fruit at the same time. And then these orangutans go in there and they won't

01:41:56.400 eat one fruit. They'll eat a hundred fruit at one time.

01:42:00.400 I'm descendants of those orangutans.

01:42:02.140 Me too.

01:42:02.760 So anyway, what she did is she would go up and collect the urine off the trees and show

01:42:09.880 that by measuring things like ketones and so forth, she could show that when they're

01:42:13.640 eating the fruit, they were actually impairing fat oxidation and they were storing energy

01:42:18.620 and their weights go way up. And it's because they ate so many fruit. If you eat one fruit,

01:42:23.580 you're not going to do that. But if you eat a huge amount of fruit and get all that fructose,

01:42:27.820 it will start to overwhelm the good things in fruit. But there's so many good things in fruit.

01:42:33.020 There's vitamin C, there's epicatechin and flavanols and potassium and all these things

01:42:39.320 that help fight the effects of fructose.

01:42:41.740 So we generally, for patients that have a non-alcoholic fatty liver disease,

01:42:46.160 we tend to restrict them to 10 grams a day of fructose only in the form of whole fruit.

01:42:52.220 Do you think that's overly stringent or is that reasonable?

01:42:54.620 I think that's wonderful if they can do it.

01:42:57.240 It basically comes down to you can have a bowl of berries, no bananas, no apples,

01:43:01.700 none of the high fructose fruits or even large fruits. How do you handle this with your kids?

01:43:06.920 You have two kids. They're not that young anymore, but they were young during the time

01:43:10.960 in which you were learning all of this stuff. How did you balance the knowledge that you have?

01:43:17.060 It sucks when your dad knows more about sugar than almost any human on the planet and you're a

01:43:21.840 kid and we're wired to want sugar. How did you balance the sane delivery of this knowledge

01:43:27.020 and to your family?

01:43:27.840 So first of all, things like birthdays and stuff, I let them have birthday cake. But we try to make

01:43:34.020 sugar-free Splenda type cakes at home. So if we make cookies or cakes at home, we try to use Splenda.

01:43:40.480 Now there's still high carb and there can be chocolate in it occasionally, you know. So they

01:43:45.160 do get some exposure to sugar. We don't give them fruit juice and we don't give them soft. They are not

01:43:50.700 allowed regular soft drinks, but they can have a diet soft drink. I have a 12-year-old and a 15-year-old.

01:43:55.720 What we try to do is not to be so restrictive that it's disruptive, but we try to be encouraging them

01:44:03.760 to understand that sugar is playing a big role in obesity and diabetes and that it's unhealthy to

01:44:11.220 eat a lot. What age do you think kids start to, I think that makes sense, which is to me,

01:44:15.640 it's much more important that you would explain to your kids why you might be putting these rules in

01:44:20.260 place as opposed to just come down as an authoritarian sort of, this is the way it's going to be.

01:44:24.140 At what age did your kids start to understand that dad wasn't just being a pain, but there's a real

01:44:29.940 reason that he's in the short run asking us to make a sacrifice?

01:44:34.220 Also, I've been involved in local school programs and there's a foundation called Living Closer

01:44:39.500 Foundation that I've worked with where we've gone into schools and tried to teach children,

01:44:44.500 elementary school, to learn from fourth through sixth grade. We try to teach them how to look at labels

01:44:49.700 on foods to understand the amount of sugar. We do a game where we have someone come up with a cup of

01:44:57.940 tea and add a spoonful of sugar to it and the person likes it and then we say, okay, now we're going to

01:45:04.360 make it like a soft drink and we put in like eight teaspoons of sugar and it's like you can't drink it,

01:45:09.500 but that's the equivalent of what is in a soft drink of the same volume.

01:45:14.260 By the way, do you think the carbonation masks some of that sugar? Because when you put it that

01:45:18.200 way, which is a great way to do it, I've never thought of that experiment. It's almost grotesque.

01:45:23.220 It is. It's a great way to teach kids about sugar.

01:45:26.300 But do you think the carbonation makes it a little easier to consume such a high amount of sugar in a

01:45:30.680 soft drink?

01:45:31.200 I suspect so. I haven't tested it, but I suspect that's true.

01:45:34.200 Or the phosphoric acid, like there's something else in there that makes it more palatable.

01:45:38.920 Yeah. Maybe it's the carbonation. Probably is.

01:45:41.840 What about dried fruit? Is that a no-no?

01:45:43.580 You know, it was so disappointing when I realized that dried fruit was the fructose of fruits without

01:45:49.260 the good things in it. So when you make dried fruit, a lot of the good things in natural fruits

01:45:53.980 are lost. It's like pure fructose. It's disappointing because I love dried fruit,

01:46:01.780 but I realize it's not the best food for you. Now, if you're out hiking the mountains and you're

01:46:07.460 spending a lot of energy, maybe it's good.

01:46:09.980 Yeah, exactly. That's the thing I've always got a kick out of. Two things have amused

01:46:13.520 me to no end. One is trail mix. The other are sports drinks. Trail mix probably makes sense

01:46:17.880 when you're mountaineering. Sports drinks might make sense when you're a professional athlete,

01:46:22.640 but paradoxically, most trail mix is consumed off the trail and most sports drinks are not

01:46:28.260 consumed by athletes actively playing sports. So again, the dose makes the poison. Context matters.

01:46:34.200 Absolutely true.

01:46:35.240 Well, Rick, this has been awesome. I want to be mindful of your time. And I know that

01:46:39.920 this is a non-clinical day for you, which means every minute we're talking, you're not in your lab

01:46:44.360 and I want you to get back to the lab. So I want to thank you very much. Again, not just for this

01:46:49.340 discussion today, which for me is super interesting. And I think the listeners will agree, but much more

01:46:55.440 importantly for the work you've done, you've taken a very different approach to quote unquote,

01:47:00.020 quote, the war on sugar. You're less involved on the policy side of this and the sort of advocacy

01:47:05.560 side of this. But I think what your work has done is created the strongest scientific foundation

01:47:12.480 to the harm of fructose. And you've done it in a largely, and I say this in a complimentary way,

01:47:18.560 but in a largely unceremonious way, which is you've sort of had your head down and a lot of people don't

01:47:23.620 know who you are. So I hope that more people become familiar with your work because you're,

01:47:27.560 I mean, your CV is comical in terms of like, it's like every week you seem to publish something in

01:47:32.880 either JAMA or the New England Journal of Medicine. The paper we talked about yesterday, which we can't

01:47:37.520 talk about today because it's not yet, we're not there yet. I look forward to seeing that paper in

01:47:41.980 science, hopefully in the next six months, but that's an unbelievable tour de force that almost

01:47:47.060 requires us coming back to have a talk about it. So. Well, thank you very much. Those are very kind

01:47:51.920 words. Thank you. Really enjoyable. And thank you. Thank you for listening to this week's

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The Peter Attia Drive - January 06, 2020

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

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