#87—Rick Johnson, MD: Fructose—the common link in hypertension, insulin resistance, T2D, & obesity?

[Music] hey everyone welcome to the drive podcast i'm your host peter etia this podcast my website and

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[Music] my guest this week is dr rick johnson rick is a professor of medicine in the department of nephrology at the university of colorado where he's been

since 2008 he's basically spent the last 17 years being a division chief across three very prestigious medical schools he's unbelievably prolific as an author he has well over 700 approaching 800

publications seemingly every week in jama new england journal medicine science etc he's lectured across 40 countries authored two books one of which we discuss

in great detail in this podcast called the fat switch which he wrote about seven or eight years ago he's been funded extensively by nih and in fact has received the

most prestigious grants that nih has to offer his primary focus in research has been on the mechanisms causing kidney disease but it was doing this that he became really interested in obesity diabetes heart disease

and what connected me to rick i guess about seven years ago now maybe maybe a bit longer was his work on fructose and fructose metabolism and that's really what we talk a lot about in this podcast so we start by talking about

high blood pressure the relationship between salt and high blood pressure which is something that is incredibly controversial and i actually learned a lot in this podcast i'm really glad we had this discussion because i kind of thought i had this thing

figured out and i clearly don't we talk about one of the most interesting bifurcations in evolution with respect to an enzyme that allowed us to use fructose in a certain way that was obviously advantageous millions of

years ago today not so much we talk a lot about your uric acid which you've probably heard me talk about on other podcasts this will then be the master's class in it we talk about artificial sweeteners

and we sort of touch on some of the most promising ideas around pharmacotherapy that are being developed in response to the epidemics of metabolic disease

especially in response to sugar so this episode gets a little bit deep on some of the biochem we're going to have obviously the show notes we'll as usual provide a great background and a list of references and

i hope you enjoy my discussion with dr rick johnson [Music] hey rick thanks so much for opening up your office today and making time it's great i'm very happy to have you here

i've wanted to sit down with you for about a year in this format because i guess we've probably known each other for maybe about six years now and every discussion has been one of those discussions where

at the end of the discussion i think man how am i ever going to remember all of this stuff and how will i be able to sort of synthesize this to translate it into sort of what i'm doing and i've said this sort of many times before

but that is the whole kind of reason that i started a podcast was i just found myself every week having a discussion with someone usually scientists where i thought this something's got to be shared so

you would certainly be one of the three or four people in indirectly that was a real catalyst for the podcast because of the frequency with which we would either have these dinner discussions or discussions over the phone and so anyway for that i want to thank you

and hopefully the listeners do as well but in the introduction i've set this up a little bit as to why this is such an important discussion and because there's so much to talk about i just kind of want to jump right into

the meat of things it would be not an exaggeration to say you were one of the world's experts on fructose and i guess i would just start with the why where did that interest come from you've

obviously been doing this for a long time and that passion has been sustained so what brought you to this point well i'm a kidney doctor so normally we wouldn't be studying sugar

so it was kind of a circuitous way that i got there i was very interested in the cause of high blood pressure and had been known for a long time that high blood pressure is linked with kidney

and in fact the going theory is for years was that the kidney in high blood pressure has a defect in its ability to excrete salt and so that you end up retaining salt

and that leads to elevated blood pressure and when we were studying trying to understand how the kidney handles salt in high blood pressure and so forth we were trying to understand potential

pathways and we stumbled on the fact that hyperuricemia or elevated uric acid could be a very significant risk factor for high blood pressure and

when we started studying uric acid we realized that when you raised uric acid in animals they developed high blood pressure from there we started to try to understand what made the uric acid go up

and we knew from the literature that sugar and particularly fructose raised uric acid so we started studying fructose and pretty soon we were so excited about what we were finding that we just kind

of changed our research direction to focus more on how fructose has all of its metabolic effects well there's a lot to unpack there so let me kind of go back to bits of it

you sort of gloss over the fact that the conventional approach to high blood pressure is that sodium is the culprit and isn't it still safe to say that most advice around reducing blood pressure comes

down to reducing sodium intake well we've actually been studying this pretty extensively there's a lot of pearls i can teach you or i can talk about related to salt and

when i was in training i was taught that you restrict a certain amount of salt you should be on a low salt diet as a mechanism to prevent high blood pressure

it was always about the amount of salt in fact we were teaching that for a long time that if you want to have a low blood pressure you should restrict your salt

intake or if you want to try to treat your high blood pressure you should restrict your salt intake what's happened in the last couple decades

has been the increasing knowledge that it isn't really the salt amount that makes a difference but the salt concentration so when you eat salt like

if you eat a salty soup the salt concentration goes up in your blood first and it translates into a thing called osmolality

and so your serum osmolality goes up so osmolality is sort of like the ionic pressure buildup in a fluid is that a weighted it's sort of like the number of

molecules in a set of volume so literally when you eat salt if it's really salty let's say you have a serum sodium

concentration of 140 millimoles per liter if you eat a really salty soup your serum sodium may go up to 142 or 143 what looks like pretty insignificant but that actually is what

triggers a rise in blood pressure and so we've actually done the study where we took people and gave them soup with or without salt when they drink the salty soup

their serum sodium goes up and their blood pressure shoots out how much would a person's blood pressure go up if their sodium went from 140 to 142.

it's about six millimeters okay so they'd go from 120 to 126 yeah and that happens acutely and how long does it take to resolve maybe a couple hours so if we give and we did the study we

published it last year if you give salty soup with water so that the serum sodium doesn't go up they got the same amount of salt guess what the blood pressure doesn't go

up and the serum sodium does so not go up or down right does not go up so if you block the serum sodium from going up so basically the closer you can bring the total accumulated concentration of

what you ingest down the more likely you are to prevent this transient rise in serum osmolality and blood pressure yeah well it turns out that serum

osmolality has a real major role not only in blood pressure but also in obesity and we're going to talk about that in a second but when you take a high salt diet and your serum sodium

goes up it triggers a rise in blood pressure and it's working through the brain and actually through the liver and other sites too pause for a moment tell the listeners why it would be

better to have a blood pressure of 120 over 80 than 140 over 100. well there's

a pretty good epidemiologic data that shows that when your blood pressure is high that you have an increased risk for heart failure and stroke those are the two

major ones but it also increases the risk for heart attacks and heart disease in general interestingly there's a very significant inflection point and what i

mean by that is when the blood pressure gets around 160 to 180 right in that range the risk for stroke goes significantly up and the risk for mortality goes up

and that's because our body tries to auto regulate to blood pressure so when the blood pressure goes up for example the kidney the arterials will

constrict to reduce the pressure load to the kidney but when it gets to about 170 it will overcome that restriction and the blood pressure will injure the

kidney likewise the brain kind of responds to flow more so it tries to maintain blood flow but if the pressure gets high it tries to protect itself from the high pressure

by constricting but when the pressure is like 170 the risk it can't constrict enough and you don't want it to constrict that much because it has to maintain flow

and so the pressure ends up increases to the brain and increases the risk for stroke now current guidelines seem even more aggressive we would manage class one hypertension we would consider something in the mid

130s to be treatable yeah so let me get there so originally when the studies came out it was very very clear that if your blood pressure was like 170 or higher

that you had a dramatic increased risk for stroke and that's because it would pass the autoregulatory point but then what happened was epidemiologic studies showed that even a

blood pressure of like 140 over 90 conferred increased risk it just was much less than the 170. so at 170 it just takes off

it's almost the line goes up vertically but between 140 and 160 there's still in stepwise increased risk but it's just a kind of a more gradual risk

in fact for things like a stroke you can start showing an increased risk from 120 over 80 to 140 over 90.

leading people to view 120 over 80 is kind of the optimal blood pressure as you get older if the blood pressure is really low you lose your auto regulation for low blood pressure and so it increases the risk for kidney disease

and and problems as well so you don't want to be extreme on either end especially as you get older this whole thing is kind of such a it's a real clinical mystery in some ways still because

in medical school we learn about this term called essential hypertension which is kind of a wastebasket term for hypertension or high blood pressure for which we don't have an obvious cause the problem is and so having sort of

that waste basket term would be okay if it accounted for the minority of cases but then you get to the clinic and you realize everybody walking around with high blood pressure basically is getting labeled as having quote unquote essential

hypertension so it really is this epidemic without a clear description now we're going to come to a lot of reasons that i mean i think you have arguably one of the most compelling cases for what

is at the root of essential hypertension but for people listening to this for doctors listening to this who treat hypertension i feel like we just haven't made much progress in the 20 years since i've been out of

medical school there have been some real breakthroughs in the understanding of primary hypertension just in the last five ten years and there's two major aspects i can talk about

the first one is that it does appear that salt really is important and one of the key discoveries was that

the kidneys are often normally handle salt fine but they develop or acquire a change in the kidneys that lead them to hold on to sodium

and the mechanism has been identified just in the last few years it's due to the fact that there's an inflammatory inflammation that occurs in the kidney

and that inflammation which is driven by t cells and macrophages causes a constriction of the blood vessels that leads to low-grade ischemia in the

kidney and that ischemia can translate into increased sodium absorption which then leads to high serum sodium and the effects is there a

correlation between serum sodium and blood pressure across normal physiologic ranges of say 135 to 145 ml equivalents per liter yeah i believe so i'm

not sure i can quote the paper but yes i think that's true so what you're saying is in people with high blood pressure that's otherwise viewed as quote unquote essential there's an inflammatory response

mediated by both t cells and macrophages that injures the kidney ischemically meaning it for the listener that results in reduced blood flow and tissue damage due to

reduced blood flow and reduced oxygen and it's that injury that then leads to aberrant retention of sodium so there's actually been really a lot of studies looking at the mechanism of the inflammation

and originally it looked like it was people thought it might be a reactive response of the kidney so we think that there may be external stimuli that initially cause a decrease in blood flow to the kidney

like a sympathetic nervous system response you can do it transiently by giving medicines or drugs that can cause a constriction of blood vessels when you do that

you get a transient reduction blood flow to the kidney that induces an inflammatory response that then causes persistent reduction in blood flow and what we've learned in the last few years and i'm an author in one of these

studies is that this inflammatory reaction can actually be an autoimmune reaction and we've even identified certain proteins that there's an autoimmune

response too and one is a heat shock protein you can actually create high blood pressure in animals by inducing an immune response to this and you can block the immune response

and block the high blood pressure and and now there's even data showing that in humans that there's evidence for an autoimmune response to heat shock proteins in people with essential hypertension which is not to

say heat shock proteins are necessarily bad because so many of the benefits we get out of sauna or exercise may be transmitted through these but you're saying in a subset of people where the heat shock protein itself

becomes the nidus for inflammation via an autoimmune mechanism yes so heat shock proteins are great just as you say they do all these really good things but what happens is they're involved in the

clearance of misfolded proteins and they're helping keep a clean system but what happens is when you trigger injury to the kidney for example these heat shock

proteins get produced to help fix problems but the immune system can sometimes get confused and make an immune response that actually is against the heat shock

proteins and when that happens you can develop high blood pressure in the animal and there's some evidence for it in humans so anyway so that's one of the big breakthroughs has been the discovery that

inflammation in the kidney can be a mechanism for triggering persistent elevations and blood pressure and which probably has a big role in the cause of primary hypertension before you go on rick

how prevalent do you think that particular mechanism is that you just elucidated oh it's very major in fact we've even looked at genetic polymorphisms that link with the development of primary hypertension

and most of them are involved with the immune response and it looks like this is a major pathway this creates a bit of a quandary for someone who's trying to rid themselves of hypertension because wouldn't the

implication of this be that exercise or things like exercise that induce heat shock proteins may paradoxically increase their hypertension i don't think so so hypertension is kind of a complicated

pathway so there's several different aspects but exercise is extremely good for improving mitochondrial function improving the ability for your blood

vessels to dilate it improves kidney function the benefits of exercise are so much greater and releasing heat shock proteins that

really occurs with very i don't know if just general exercise would have a big effect on heat shock proteins so you're saying basically the net effective exercise is still going to far outweigh

yes absolutely but i'd like to get back to this the link between salt and sugar if i could okay because there is this data as i say that salt

when it increases the serum sodium is what drives the acute blood pressure response and when the kidneys have trouble getting rid of salt

it's easier to get that effect with a salt load but even with a normal person you can with normal blood pressure you can raise their blood pressure transiently

by giving them salt and you can block it by giving water interestingly in the process of developing high blood pressure there's the initiators and then there's the things that make it

persistent and the inflammation in the kidney is involved in the persistence but what is involved in the initiation

turns out that sugar has a major role and what we discovered is that when you give a high salt diet to animals that the high salt increases

the serum sodium and the serum sodium when it goes up it activates an enzyme that converts glucose which is in our blood and in our tissues

to fructose and that conversion to fructose is driven by a high salt diet and it's driven by an increase in serum

osmolality or increase in serum sodium once the fructose is made in the body so this is not fructose coming from the diet this is made in the body the fructose gets

metabolized and raises blood pressure and when we gave high salt to animals they developed an increase in blood pressure

and they also were making fructose and when we block the metabolism of fructose we actually block the rise in blood pressure as well as the hypertrophy of the heart so let's pause for a moment

you know i've had rob lustig on the podcast before so anyone who's listened to that will be familiar with what fructose is what glucose is what sugar is all of these things but can we spend one minute just

defining these things for people who haven't listened to that podcast sure so there's different types of sugar and the main one that we call blood

sugar is glucose and this is the primary sugar that our body uses to make energy it's the main sugar that's used to make energy and it can be stored

in the tissues as glycogen and when it's too high we call it diabetes when the blood glucose is too low it's hypoglycemia and so glucose is like the principal

energy fuel the carbohydrate fuel that we use and as you said we store lots of it in our muscles once it gets in the muscles it can't get out and we store maybe a quarter to a third

of it in our liver and that's mostly there to buffer the blood supply in particular the brain what does glucose taste like a pure drink of glucose people like it animals like it but it

isn't as sweet as classic sugar but it is often very much liked by animals humans like it there you can buy these dextrose pops and stuff like that

dextrose is another word for glucose and also the kidneys store glycogen and produce glucose too the second type of sugar is fructose and the best way to think of

fructose is it is a fuel first off it's present in fruit but it turns out to be the sugar that is involved in energy storage rather than energy

production and so when you eat glucose you use that to produce energy but when you eat fructose it will actually trigger changes in the body that will favor the storage of

energy and this is the sugar that animals use to store energy so and you store it in the way of fat in the way of glycogen and all those kinds of anything that

will facilitate storing energy is done by fructose and fructose and glucose if you were looking at pictures of them in a biochemistry book look pretty similar

they're both ringed carbon structures they both have six carbons one of them has a five ring versus a six ring but you know it's sort of interesting to think that molecules that look almost identical with the exception of a

couple of bonds different can have quite different properties now fructose tastes a lot sweeter as well yes and so fructose is like in honey and in fruits and then that's right so it tastes a lot

sweeter and the other thing is if you mix the fructose and glucose together you can get what's called high fructose corn syrup and if they're bound together you get table sugar

so table sugar or sucrose is one molecule of glucose and fructose bond together and that occurs in nature and sugar cane and beets and things like that yes and maple syrup

and things like that right so just to clarify for everybody we when we get a little comfortable with this terminology throw the word sugar around quite liberally but it's always important for people to think when we

talk about sugar we could be talking about blood sugar glucose we could be talking about fructose by itself oftentimes when we talk about sugar in diets we're talking about added sugars

such as the sucrose and high fructose corn syrup you just alluded to i want to go back to what you just said about the ability of fructose to store something but if you don't mind can we do it

through the lens of a beautiful story that you've written about in the past about a mutation that basically allowed that to happen this thing that took place about 12 to 15 million years ago

sure so fructose again is a it's in fruit and many many animals use fructose as a means as their primary

nutrient or and also as a way to help store fat and for example animals before they hibernate will often eat a lot of ripe fruit and the ripe fruit gives them the sugar

that allows them to store fat and orangutans will eat huge amounts of fruit at one setting to try to increase their body fat and we don't get fat from eating fruit

but that's because we eat tart fruit that has less sugar content and we tend to only eat a few fruit whereas if we actually drink fruit juice that large amounts of fruit juice can

actually increase fat so anyway so fruit is a nutrient that you know is used by animals to help store fat so if you go back

about 20 million years ago the very first fossil apes show up in the world and they they show up in west africa and the

original one was called proconsul they were living about 22 million years ago and they were these apes were a big breakthrough in evolution because the prior the monkeys were had already been around but

these were bigger creatures the apes were they had bigger brain size they were tailless but they did live in the trees and they lived in tropical rainforest and woodland rainforests and they would

eat primarily fruit and they were quite successful and by about 18 million years ago there were almost at least 10 to 20 species of ape

that were living in this area of africa there was a change in climate there was some global cooling and the antarctic started building up ice and the arctic started building up

ice and sea levels fell and when the sea levels fell land bridges developed that connected africa which had been separate separated from the other continents

these land bridges opened up so that there was now a way to get out of africa into europe and asia and many many species migrated across those land bridges

about 17 million years ago and some of them were the apes and we see the first apes fossils in places like pasalar turkey and

different places of europe right around 16 million years ago at that time there were still a forest that were fruiting trees

woodlands there was fruit all year round and so the animals when they moved into europe they didn't have to change their habits at all they were able to continue

to eat fruit pretty much all year round but unfortunately continue to get cooler and by 12 million years ago the apes started to starve in europe and you can

tell that from the fossils because they actually have these like tree rings on their teeth that are the developing teeth get this enamel the enamel doesn't lay down

correctly and they get these like tree rings that shows intermittent starvation they would get a ring every time they would go through a period and the starvation was seasonal

so it was during the cooler months when suddenly the fruit was not available and the primary reason was there was a loss of the fig tree and the fig is a cool fruit that can fruit all year round because

the wasp that fertilizes the fruit does so at its own discretion so the fruit will of a fig tree kind of can occur all year round so when the fig tree died suddenly there weren't too many

because of the global cooling or perhaps it was the wasp but the fig trees disappeared and suddenly these apes did not have enough

food to survive during the cooler months and they started to starve and by six to eight million years ago the last ape

became extinct in europe but africa although there was global cooling there too it wasn't as cold and the fruit trees survived all year

round the forest just retracted so the apes there were able to maintain their normal habits well there was a lot of evidence that there was a lot of evolutionary

change occurring in our ancestors during this miocene period and this period of time when there was the global cooling and one of them was a mutation in

uric acid metabolism and as i mentioned sugar and particularly fructose when it's metabolized generates uric acid

glucose when it's metabolized is not but fructose when it's metabolized makes uric acid and this mutation led to a much stronger uric acid response

to fruit because this mutation was of an enzyme that degrades the uric acid and when you block that and you eat fruit your uric acid levels go up much

more and this mutation basically allowed these apes to maintain a very prominent uric acid response our group has shown that the way

fructose stimulates fat as well as its other properties like insulin resistance and raising blood pressure

that those abilities are driven in part by the uric acid so when this mutation occurred for the same amount of fruit they were able to store more fat

and so it was like a survival mechanism for this mutation when it showed up it allowed apes that did had very little access to fruit to suddenly maintain more fat stores and so they

could live longer and survive those winters and we were able to show with peter andrews at the natural history museum in london who studies these apes that this

might account for a very interesting finding and the finding is that although we thought the apes became extinct in europe and they certainly did become extinct in europe

the fossil record shows that it was a european ape that made it back to africa and also to asia to become our ancestors as well as the

ancestors of the great apes that live in africa and in southeast asia like the orangutan that they all came from a common ancestor that was in europe and that went back to

africa and we know from the genetics that that ape carried the uricase mutation and so this mutation

probably occurred at a critical time that provided survival for those apes in europe to be able to get out of there and make it back to these other regions but it was now equipped with

this mutation that made it sensitive to sugar and so humans are much more sensitive to sugar than most animals and it's because of

this mutation and in fact we actually resurrected the extinct ura case and proved this using the extinct ura case that showing that when you put it into human cells

that it suddenly made us less sensitive to fructose so so the phenotype there i mean i guess just to recap that story which i find so fascinating by the way you guys wrote a story about this in

scientific american many years ago right i know there was a paper that came out as well but i mean the sort of the layperson version in siam was really great so basically these apes go from africa up to europe

it gets too cold we sort of think they die out but the evidence emerges actually a sub-sub-subset of them developed a mutation in ura case that gave them a superpower which was

now they could be much more efficient at turning fructose into fat they had this little by-product which is they would also make a boatload of uric acid along the way but they actually came back to africa and ultimately

seeded the rest of the species and ultimately that's why we as humans are among the very rare animals that have uric acid levels that are quite high relative to cats and dogs for example

yes that's exactly correct so when we were in medical school rick we learned a lot about uric acid through the lens of a disease called gout and it didn't get a lot of air time in school maybe it gets more today but at

the time it was basically gout is a disease of civilization it's from eating too much meat and there's no real problem with it except for the nuisance of your toe hurts because

uric acid crystallizes it gets inside joints it seems to favor the first joint of the great toe and it's a very painful inflammatory condition and it's what happened to sort of the

wealthy people of the last few hundred years as they started getting and acquiring too much meat and protein and that was sort of the story what you're describing is a little bit more nuanced so tell us more about uric acid

yeah so the big problem with having too much uric acid is gout just as you say and all the animals that have the uric case mutation are prone to gout but humans in particular are very prone

to gout and it's because of our diet so we do eat diets that are high in meat and purines that increase our risk for gout can you tell folks what purines are specifically since it always shows up in

this terminology sure so we have proteins we have fat we have carbohydrates but we also have

things like rna and dna and what we call nucleic acids so these are the kind of acids that are in the nucleus and that are also in the cell that help drive

gene formation and protein you know our genetic material and also help dictate the production of proteins and so dna and rna are made up of nucleic acids and when

they're broken down they're made up of purines and then uric acid is appearing and it's basically the ultimate breakdown product of dna and rna so the reason protein

consumption versus fat or carbohydrate would lead to this is because if you're eating protein you're eating the dna and rna that presumably were still in that tissue yes so the way you get

gout from protein is from the dna and rna in the protein and so and that relates to some extent to this how dense the nuclei are and so like if you have

a very cellular thing like uh anchovies and these small fish that have lots of dna and rna if you have that

they will develop you can get gout from that much easier than from other types of meat and so beer for example has brewers

yeast and that is filled with rna and so that's why beer can precipitate gout now i follow uric acid levels very closely

in all of my patients and myself and there is an unmistakable difference between men and women at least in my small sample size of patients where men on average have higher uric

acid levels than women is that true across the general population yes even in boys they'll start to have a higher uric acid than girls however after the menopause

uric acid levels go up in women and that's because estrogen helps excrete uric acid uh so it's not i had sort of i guess incorrectly assumed it was that just on balance

men consumed more protein than women i think that also plays a role i think that's right but it sounds like this estrogen explanation makes more sense if it can also explain the observation of menopause yes going back

gout is also increased by sugar and even sir william osler the famous physician from the 1890s in his book principles and practice of

medicine pointed out way back in the 1890s that that sugar was a major risk factor for for gout as well as very sweet fruits he wrote anyone who's

had gout usually will know that real significant sweets can also precipitate gout and the reason is because of the fructose content and when the fructose

is metabolized it generates uric acid when people were developing gout in the 1800s it was linked to the wealthier groups in england for example

they were eating a lot of as you say rich foods that included proteins and and so forth but one of the things they were eating a lot of they were drinking a lot of alcohol

to which they added sugar i actually did write a paper where we reviewed how much sugar was put in drinks alcohol drinks back in the 17 1800s and it was much more than today they

loved sugar they put it in in many of their drinks and in fact i even have a picture of an old pub outside the tower of london called the sugar loaf

they talk about the old drinks that were served like hypocrites and some of these drinks and sack and sugar was a name for a drink that they had i mean they added a lot of sugar to

their drinks and so part of the rise and gout back in the 1800s and 17 1600s relates to not only just

the alcohol and the rich foods but also to the sugar they were adding so you were sort of the person who brought onto my radar that there are other things besides gout that one needs to be concerned

about when it comes to uric acid and one of them is blood pressure so how did that understanding come about so originally we were studying what causes high blood pressure and there was a lot of epidemiologic

studies that linked uric acid with high blood pressure and as i mentioned we we also knew that there was subtle changes going on in the kidney associated with high blood pressure and people with gout often have low

grade kidney disease so i said aha maybe uric acid could have a role in causing kidney disease through causing high blood pressure through its ability to cause kidney

disease and so we took animals and we gave it this uricase inhibitor to raise the uric acid of an animal and by gosh they developed high blood

pressure and then we could lower the blood pressure by lowering the uric acid and when we looked we were thinking it was might be like crystals of uric acid in the kidney but that was my thought is the crystals would cause the

inflammation in the kidney and that would that turned out we looked in the kitty there weren't any crystals there so then we realized it

was an effect of soluble uric acid so we started putting soluble uric acid on cells and so forth and we saw that it had all these biologic effects and we always had thought uric acid was

kind of like a dead end product of something or even might be a good thing because some people said it was an antioxidant but it was causing pro-inflammatory effects

so then we said aha fructose sugar raises uric acid maybe sugar could have a role in blood pressure what year is it that you're

having that thought rick 2002 we gave some animals fructose and they developed high blood pressure and we gave them allopurinol which is a drug to lower

uric acid and it made their blood pressure go back to normal and it was like this big discovery but what was

totally exciting was these animals also developed insulin resistance they also develop elevated triglycerides in their blood they had other fatty liver and when we lowered

the uric acid we showed benefits on all of those parameters how does allopurinol work what's the mechanism by which it lowers uric acid

it blocks uric acid formation so uric acid is generated from other purines and when we blocked that we blocked

a lot of the effects of sugar to cause metabolic syndrome and so we when we first did it we set out there's got to be something wrong here so we repeated it and we did it different ways

and it didn't matter it looked like uric acid had a role in how sugar worked so as we studied this we started realizing that the process by which uric acid is

generated is important in how sugar causes disease no one believed us initially i have to tell you that

everybody said i yeah sugar causes gout but the idea that sugar raises uric acid that causes gout but the idea that sugar raises uric acid and that is involved in the obesity and the

insulin resistance we don't believe it what's happened since then is we've learned that the metabolism of fructose is extremely different from the

metabolism of glucose the two look alike but when fructose is metabolized there's this process that causes the

energy in the cell to fall before it goes up so normally when you eat a calorie when you eat any kind of nutrient we use it to make energy

that's what we do but when you eat fructose the energy in the cell falls before it goes up it's the only nutrient that

lowers energy in the cell say more about what you mean by that so are we talking about a cell in the liver for example yes i'm talking about the cells that metabolize the fructose okay so we'll contrast it with glucose so if glucose

enters a cell it gets turned into pyruvate and ultimately atp is made so you're saying total energy goes up as a result of metabolizing that glucose

so whenever you metabolize any kind of calorie any kind of food you eat food you're going to metabolize it to make energy that's what we do we try to break down the food and we use it to make energy

that energy is called atp and atp is the currency in our body that we use to make us

run walk think talk everything so this atp is pretty critical but to make atp you have to spend a little of it to make it so

the process of breaking down and metabolizing food or glucose or fructose or requires spending a little bit of atp

before you make it well what happens is when you metabolize glucose you do spend some atp but the body has

a system whereby feeds back to stop the process before any significant atp depletion occurs so for example there's an enzyme called

phosphofructokinase that's used in glucose metabolism if atp levels fall that enzyme gets turned off to stop glucose metabolism to allow atp

levels to come back up but when fructose is metabolized the enzyme that metabolizes fructose is called fructokinase

and when that metabolizes fructose it consumes atp in an unregulated way so if the cell sees a lot of fructose

the atp levels can plummet by 40 or 50 percent in the cell and that signals a huge number of effects throughout the body

it's like a may day signal it says we're under attack we're running out of energy and so it switches the animal into a condition in which they're trying to

preserve their energy so they reduce their metabolism they reduce their expenditure they're resting the energy expenditure they shunt the energy that they're

eating the calories they're eating into fat and glycogen as opposed to making more atp they're trying to protect the body by putting you into a system

where you try to store fuel it triggers hunger and thirst that makes you want to eat more so you eat more to restore the energy but at

expense that you're shunting much of it into fat and into fuel storage so fructose turns out to be used by animals as a mechanism to store fat normally

animals will regulate their weight beautifully they just maintain their weight normally if you take an animal and you put a tube down its throat and give it extra food to make it gain weight if you

take the tube out the animal will go right back to its normal weight if you starve an animal and so it's below its normal weight and then you let it just eat it will eat back to its regular

weight but when it wants to gain fat it will do so usually through a mechanism that involves fructose so what they do is they like a hibernating

animal will start eating a lot of fruit in the fall to increase its weight and increase induces insulin resistance it gets hungry it drops its metabolism so that most of the energy it eats goes

into fat and the same thing with a long distance migrating bird they'll start eating fruit to get the fructose and so this is a very common

pattern and it's driven by that atp depletion and this is distinct or in parallel of course to this uricase mutation so that can you separate these two phenomenon in

other words if you can restore uricase to the non-mutated version do you still have this problem

around the atp depletion yeah so the atp depletion triggers a series of reactions and what happens what the key one is not only does atp

decrease in the cell but intracellular phosphate also falls and that activates an enzyme called amp deaminase that converts the broken down product of

atp which is amp and it converts it to uric acid and that process has multiple steps and we know that that whole pathway is involved in the generation

and stimulation of fat diet insulin resistance fatty liver elevations and blood pressure a variety of effects

and that pathway is what seems to be critical for inducing obesity from sugar let's go through that again because that what you sort of talked about at the

very end is effectively the thesis of your book the fat switch you explained what atp is adenosine triphosphate and the t of course stands for tri there are three phosphates

it's the liberation of a phosphate that is the production of energy so when you need to breathe you need to move when you need to do anything you have to turn a t

p into a d p so the chemical reaction is adenosine triphosphate becomes adenosine diphosphate one phosphate escapes and that's what

gives us the energy now that can happen again adp can lose one of its two remaining phosphates and become

a mp adenosine monophosphate what you said after is the really critical critical piece of this which is when you have a molecule of adenosine

monophosphate it stands at a proverbial fork in the road it can either go down a path that is driven by something called ampk

or amp kinase or it can go down the pathway of amp d that's right now let's go back to this point because i again it seems

everything comes down to that choice what happens if amp goes down the ampk pathway versus the ampd pathway yeah so if it goes down the ampk

pathway it actually is burning energy it's burning fat it does a lot of really positive things if it goes down the amp pathway it goes down a fat storage pathway

so it's their exact kind of opposites ampd if you stimulate it it will cause insulin resistance and eventually diabetes whereas if you stimulate ampk you can

actually use that like metformin to actually treat diabetes so that fork is critical and what drives that switch is the fallen intracellular phosphate

and the reason that phosphate falls is because it's taken up in the fructose-1-phosphate or it's taken up by fructose so the fructose gets phosphorylated by the atp

and it becomes fructose-1-phosphate that sequesters phosphate and there is this process where both atp levels fall and intracellular phosphate falls and that

triggers this ampd pathway and if we interrupt the ampd pathway we can block a lot of the metabolic effects do other animals also have this phenomenon oh yeah no we

can show this we actually showed it in hibernating squirrels so when a squirrel wants to gain weight it will activate the pathway for ampd

when it's hibernating and burning the fat it activates the npk pathway i got it so even though humans and our most close descendants in primates

have the uricase mutation this ability to toggle between am and ampd is unique to any species that has the potential to gain weight and wants to use it to their advantage oh

absolutely part of the pathway through which ampd is working involves the generation of uric acid so we know that the uric acid when it's going up inside the cell is

doing all kinds of biologic effects and the ampd is driving that there may be other things besides the uric acid so the hummingbird or the squirrel can still store fat they just don't get the bump in uric acid that comes with it

because they don't have the uricase mutation well actually the hummingbird does have the uric case mutation oh really yeah i don't know my evolution well yeah so birds have birds bifurcated off yeah reptiles have the uric case mutation

even dinosaurs had the irrigation sue the dinosaur the tyrannosaurus rex actually had gout i mean that's got to be why tyrannosaurus rex was so ornery

because if you think of the size of the t-rex great toe i mean that would be infuriating to every bronchosaurus out there yeah i think so he's eating too many of the bronchosaurus sorry to get back into

the minutia of this but it's important you still have to phosphorylate glucose during its metabolism why is it that the phosphorylation of glucose during its metabolism to

pyruvate doesn't result in a strong enough drop in intracellular phosphate to cause the same problem because uh the reaction stops whenever there's um the phosphate and atp levels

start dropping a little you have that autoregulatory thing with the there's an autoregulatory thing with it the enzyme stops functioning it's inhibited and then it allows the atp levels to stay

normal so here's a really cool follow-up of this and that is that sugar is much more likely to cause obesity if you drink it rather than if you

eat it and the reason for that is that when you drink a drink that has fructose in it we tend to drink a lot in a short period of time so if you have a soft drink

you can drink not only does it have a lot of sugar but we tend to drink it fast and so the concentration of fructose

turns out to be high when it gets to the liver and it's the concentration that triggers this reaction so if the concentration of fructose is really low

the atp depletion may not be significant to drive dramatic metabolic effects but if the concentration of fructose is really high then you're going to get a big metabolic

effect so eating like a candy bar where it's coming with lots of fat lots of glucose lots of all sorts of things lots of protein you know if it's like a snickers bar and it's got nuts or

whatever even if it's the same amount of fructose even if you're talking about 25 grams of fructose versus 25 grams of fructose you would drink very quickly

you're saying equal amounts of fructose can produce a different effect if both the speed and the concentration with which they arrive at the liver are different yeah it's the amount it's the speed and

it's ultimately how rapidly it's absorbed so if you drink something if you take a lot of fructose like i mean candy is very concentrated fructose

i mean if you eat that for example on an empty stomach that will be absorbed faster than if you eat it with oatmeal or something or you know where there's fiber and so forth

and so the speed of absorption in the makes a difference so for example if i was working for a high fructose corn syrup company and i wanted to prove that a soft drink

wasn't bad i could do a study where i would give the soft drinks to people but i would give it over you're only allowed to make a tiny sip

every 10 minutes so it takes you three hours to drink a soft drink in that case the amount even though you're drinking a lot the concentration may never be never let

the phosphate depletion get significant enough in magnitude that it really triggers amp-d yes that's it you know it's really interesting i think of all the sugar

the pro-sugar studies i've read that are funded by the sugar industry i don't think i've ever dug into the methodology to look at factors like that specifically well the

other issue is like if you just take a single dose of fructose most of the metabolic effects are best seen like in the first four hours following the ingestion so the

triglycerides go up and the uric acid goes up and the blood pressure goes up but if you just do a single dose study if you then look the following morning where the effects have now kind of come

back down then you can't really show it in a lot of these studies they design it that way so they say aha fructose doesn't raise uric acid but we measured it after fasting

overnight but the surge in uric acid occurred earlier so that's the common trick so all these things you're talking about with fructose

seem to fit almost directly into the five characteristics of metabolic syndrome which are elevated glucose so that insulin resistance would be

manifested as an elevated glucose elevated blood pressure elevated waste circumference so storage of fat elevated triglycerides

what you just said and the only one we didn't address is low hdl cholesterol which is the fifth finding now of course three out of those five are sufficient to put you in the category but

frick just does all five what is the mechanism by so you've already described the mechanism by which it does three of them we alluded loosely to how it raises triglycerides but i'd like to talk about that more and then of course

i'd like to hear how it lowers hdl cholesterol okay so the uric acid generated by fructose has a very pronounced effect to

stimulate oxidative stress in the mitochondria and fructose also generates lactate big time and the lactate also has effects on mitochondria as you learned

from dr samalan's talk and in addition fructose preferentially decreases mitochondrial function and stimulates

glycolysis and so all those things cause you get this big oxidative stress to the mitochondria and there's an enzyme in the mitochondria that drives

fat oxidation called enolco hydratase i mean sorry to throw it out there this is what we're hearing no no we're here to talk about it but basically uh the oxidative stress inhibits that so

fatty acid oxidation goes down so you block fat burning and then in addition you block an enzyme called econotase with oxidative stress to the

mitochondria and that increases citrate which drives fat generation and so you end up with fatty liver that's driven by both increased fat synthesis and a blocking fat

burning the mitochondrial oxidative stress also is very much linked with the development of insulin resistance and then uric acid is also degenerated

uric acids also causing oxidative stress to the eyelids to the pancreatic eyelids as well uric acid is actually harmful to the eyelid cells of the pancreas uh-huh in fact if you give

sugar we did a study where we gave sugar to animals where we we actually restricted the amount of calories the rats were getting they were on a diet basically they were

on a diet they're on a high sugar low calorie diet right and then we had as a control rats that got the same number of calories but they weren't getting the sugar right so just a low calorie low sugar diet yeah

and when we gave the high sugar low calorie diet all the animals developed fatty liver hypertension insulin resistance did they

actually gain weight no no this is a trick weight gain really requires increased calories really to show it you know long term maybe just decreasing metabolism will do it but this is

interesting you're saying both animals lost weight did they lose about the same amount of weight no they maintained their weight even though they were eating 90 percent of what they normally eat they were able to maintain so both groups slowed their

metabolism enough to maintain weight at a 10 reduction of calories so on the outside they look the same but the high sugar group still developed fatty liver severe and they all became diabetic do you

recall in the study rick what the actual percentage of their macros that came from fructose 20 right so the critic will say well that's highly unnatural although in reality it's not that unnatural there are lots of people unfortunately walking around

getting 20 of their energy input from that so it's not physiologically completely out of whack but as a proof of concept these animals got diabetes without gaining weight they got fatty liver

disease without gaining weight they were by definition insulin resistant right and when we measured their insulin levels they first became insulin resistant with high serum insulin levels which is what

we see early diabetes early type 2 diabetes but over time the serum insulin levels started to fall so they almost developed a type 1 diabetes

well just like humans do and what we saw is that the eyelids used to be the phrase was called islet exhaustion because long-standing type 2 diabetes we see the same thing but it's actually

low-grade inflammation in the eyelids we could show that there was low-grade inflammation and it was associated with big time up regulation of urate transport proteins

on the island and when we took isolated islets and we put uric acid on them it induced oxidative stress and over time caused a drop in insulin level so what

we think is going on is that sugar causes diabetes through this pathway that we've been talking about and it involves initially insulin resistance

but over time it will cause eyelid cell dysfunction as well and this has been confirmed by other groups now that sort of comes to the triglyceride story right if you have a net accumulation of fat

in the liver you're going to have to export some of that in the form of vldl a very low density lipoprotein so that would drive up the serum triglyceride what's driving down the hdl cholesterol

you know i haven't studied that personally i don't really know but i did see that there are reports that fructose can lower hdl like in animals and stuff but i don't really know the mechanism when you sort of

pause for a moment rick do you ever worry that talking about fructose this way just seems i don't know what the word is i don't think it's necessarily being too much of a reductionist but

it almost seems too simple that this one molecule could simultaneously have probably allowed our species to survive

during this very cold spell 6 to 12 million years ago and obviously evolution wasn't thinking 12 million years into the future

that we'd be flush with fructose and yet here we are today one could interpret what you're saying to mean if you simply had no fructose in your diet

most of the bad things we think about metabolically would go away is that a fair assessment yeah i think that's true so let me give you another one where we've really learned a lot i don't know if you

are aware of the relationship with cancer but what we've learned is that fructose was a incredible survival nutrient in the setting of near starvation

so as i mentioned what we're learning is all these animals use fructose they either get it from their diet or they make it in their body and they use that to help them survive and

we can talk about it but it involves not just storing energy but they use fructose to store water and we can talk about that and they use it to become insulin resistant insulin resistance is a survival

mechanism whereby increasing blood glucose and preventing glucose from taking up in the skeletal muscle it preserves it for the brain which is what you want to do if you don't have enough food around you want

to be able to think so you can escape predators and so forth so it was a survival tool to increase energy

and it actually also protected animals from a low oxygen state so by switching by reducing mitochondrial function and

stimulating this thing called glycolysis it allowed the animal to survive with a lower oxygen state and so we know for example that the naked mole rat

which lives in burrows very low oxygen bureaus they make fructose to survive when they're in those bureaus so suddenly the fructose goes up in their blood and they use it to survive

the low oxygen tension there because they switch from mitochondrial metabolism to glycolysis but why can't they just rely more on glucose for which we have

such an abundant apparatus to store it at large amounts is there an energetic reason for fructose a lot of the fructose is converted to glucose into lactate which can be converted to

glucose and then it's driven through this glycolysis pathway so it turns out though that what happens is when you metabolize glucose a lot of it will go through mitochondrial metabolism

and so if we can inhibit mitochondrial metabolism which uses oxygen we can live off glycolysis which doesn't require oxygen so what happens is in a low oxygen state like the naked

mole rat will use fructose to survive but cancers but wait i'm still confused about this rick because wouldn't that fructose but they're not

storing that fructose as fat then because that would be the worst fuel they could have around in a low oxygen environment right well so fructose is increasing glycogen

and lipid but it's also reducing mitochondrial use when you're eating fructose you actually are are not burning the fat you are storing the fat

and then so what it's doing is it's putting you into a glycolytic state so animals use it to store fat and then they they fast and then they burn the fat so

they hibernate or they go flying long distances where they have no food and then they switch and then the fat that they store it suddenly becomes their survival

but during the time that they're in a low oxygen state they want to have fructose on board because the fructose is helping them to survive low oxygen by switching their metabolism

but unfortunately like cancers also live in a low oxygen state and so these cancers love fructose as their fuel because it helps support them surviving

in the low oxygen state so recently it's been shown that many cancers colon liver kidney breasts brain all these cancer cells intestinal they

all tend to like fructoses as their preferential fuel there was just a paper in science a few weeks ago and if you block that fructose pathway the cancers don't do as well

and when you say block it do you mean block fructokinase yeah which pathway specifically fructokinase so if you take intestinal colon cancer you put high fructose corn syrup on it they love it

they grow they metastasize and if you block fructokinase and block fructose metabolism you can block a lot of the growth of those cancers give a sense of how much you're blocking it it's pretty

remarkable it's like 50 or more and we know it's the fructose not the glucose presumably because we don't impair glucose metabolism at all in that experiment that's correct and also they

were able to show that this was driven by that shift from a mitochondrial based metabolism to a glycolytic metabolism and what happens to lactate levels in that sense oh very high

like meaning the more fructose they have the higher the lactate level yes again very counter-intuitive because aren't we sort of taught that the liver is the only organ that can really process

fructose and that it all sort of accumulates there and i mean conventional thinking is that fructose really doesn't have much of an interaction outside of the liver unless converted to glucose correct that

was said by a lot of people but the findings show that about 20 percent of fructose is used by the intestine and maybe 40 percent by the liver

and at least 10 to 20 percent can escape into the circulation and of course if the larger the dose the more that will pass and the kidney is a big target

there's fructokinase in the brain there's fructokinase in the eyelids there's fructokinase in the adipose tissue does the muscle have fructokinase there's some thought that fructokinase

may be in the muscle it's got to be very low but there's some thought that fructose is being metabolized in the scala muscle and one of the things that's interesting is there was a paper in

nature that showed that the heart normally doesn't have fructokinase but when you have a heart attack the low oxygen state there

induces the fructokinase and there's probably production endogenous production of fructose and it seems to be involved in cardiac remodeling so it's probably involved in more things than we think of and

certainly it's in the brain which means that in theory the brain could actually use free molecules of fructose to make atp

in addition to the mainstay of its energy metabolism which is glucose driven and lactate i think we're now seeing lactate there's actually some evidence that first off we know that fructokinase

is in the brain we know the brain can make fructose and there's increasing evidence that insulin resistances can occur in just in the brain and may be a forerunner for the development of

alzheimer's and there are actually reports that amp deaminase is high in the brains of alzheimer's patients and it raises the possibility that local

fructose metabolism could be involved in disorders like that are there any people with naturally occurring mutations in fructokinase that render it less capable yeah so there are people with a condition called the essential

fructosyria where they are born without active fructokinase and they live normally no one's ever been reported to have type 2 diabetes or obesity so these people if i'm understanding you

correctly are genetically immune to the harm of sugar yes and they pee out all the fructose yes okay so that seems to be an interesting topic this must be very rare i've never heard

of it it's a rare condition they actually don't pee out all the fructose some fructose can be metabolized by an enzyme called hexokinase which is

normally metabolized as glucose but fructose is preferentially metabolized by fructokinase so these people have very sweet urine going back to osler had he tasted their urine he

would have confused them potentially with an even sweeter version than the people with ultimately type 2 diabetes that's how they were discovered because they would have reducing sugars which

was fructose in their urine that was picked up with the old tests they used to use for diabetes but then they didn't have diabetes when they tested them and these people could literally just consume

all the sugar they wanted and their uric acid is not going to go up their blood pressure is not going to go up their trigs don't go up they don't gain weight they don't become insulin resistant that's right so is there any benefit to having fructokinase if you're not

hibernating or in a world where famine is potentially coming your way it's really a survival enzyme that was meant to help in situations where

there was food shortage if you live in the western world and you just have to go down to the grocery store no i think living without fructokinase would probably solve a lot of

the world's health problems i mean and there are fructokinase inhibitors that are being developed pfizer has one that's now in a finish to phase two trial it was quite successful at treating

fatty liver and so now they're taking that drug to phase three wow that's a potential blockbuster actually of course it begs an interesting question which is

how will that drug be treated will it be only used as a way to treat an active condition such as fatty liver in which case it's going to have a smaller on label market versus what will

likely happen which is people who just want to be able to have more sugar without the consequences of it would take it correct yeah although it's probably priced to avoid that i'm guessing anyway yeah there's a lot of interest in

fructokinase inhibitors there's other big pharma that are working on it now and so we'll have to see if it turns out to be as powerful as we think it might be so the work that we've just discussed has sort

of been you've been at this since 2002 basically specifically with respect to this let's go back to allopurinol and uric acid in your clinical practice because you're

still you've spent 17 years as the division head of nephrology across three world-class medical centers most currently the university of colorado and yet i was surprised to learn over

dinner the other day that you still have a very pretty heavy clinical practice you still actually take care of patients in the inpatient ward and you probably spend a quarter of your time in clinic so how do you put some of this

stuff into practice do you liberally use allopurinol even for patients who have high uric acid but have not developed gout yet i do

so our data strongly suggests that lowering uric acid could be beneficial so what i do is the following so it turns out that allopurinol is not

totally safe there is some people who can develop reactions to allopurinal drug reactions especially asians about three to four percent of people who are asian

can develop an allergic reaction to allopurinol where they can get rashes and it can be pretty severe and it's about two percent in african americans and it's about point five percent in

caucasians you can test for it there's a test called the hla b58 test but the point of the matter is that no drug is fully safe every drug has side effects so ideally

you'd want to really be certain that your drug is going to provide the benefit that you want and you have to consider the risk versus benefits now although in animals allopurinol is

totally protective or protects a lot against sugar-induced metabolic syndrome the data in humans is suggestive so there's been for example four pilot studies showing

an improvement in insulin resistance with lowering uric acid in humans all four are positive there's a lot of trials in kidney disease showing that lowering uric acid

may benefit kidney disease there's data on blood pressure we had a paper in the jama showing that oil and uric acid could improve blood pressure control in adolescence with hyperuricemia so

there's a lot of supporting data there are some negative studies too but the overall weight is now in favor of lowering uric acid to benefit what

would the target be so what i do is when i see a patient in clinic i measure the uric acid and currently we know that the risks

start to go up when the serum uric acid is over 5.5 so once the serum urecast is over 5.5 they really start to have increased risk for pre-diabetes insulin resistance

hypertension kidney disease etc and what's interesting is most labs like my lab for example doesn't even flag it until it hits about 6.5 as a sort of intermediate risk

and it's really not until about 7.5 that it says well this is high risk but of course that's only through the lens of gout i assume yes that's right so if a uric acid comes back really high like 9 or 10

i have no doubt that that based on everything i've done i have no doubt that that's not good not only does it increase the risk for gout but it increases the risk of kidney disease and all these things

and i talk to the patient about the pros and cons of treatment i talk about the rash i tell them to stop the drug if they get a rash and then call me but i always

start aloperinal when the uric acid is like eight or higher and certainly when it's nine or higher when it's between five point five and eight i'll talk to

them about the pros and cons but we don't have full proof yet but i tend to do it especially with patients with kidney disease where the data is probably the strongest to start treating

i'll even do it with uric acid of six and a half for example with chronic kidney disease but anyway it's worthwhile discussing it with the patient but outsides of that sort of the risk of stephens johnson syndrome which you've

alluded to what are the other potential risks of allopurinol that's by far the big one some people will get just a mild rash without true stevens johnson syndrome

they're rare cases where liver function tests may be elevated but it seems to be rare if you start it a huge dose right away it can increase xanthine levels in the urine

theoretically there could be risk for xanthine stones but i've never seen it so it's really the risk of stevens johnson that and do you have to use allopurinol or can you use

euleric or other drugs that also lower uric acid well the xanthine oxidase inhibitors are the best because the way uric acid works to cause cardiovascular disease

and kidney disease and all these things appear to be through its actions inside the cell as we said works on mitochondria and it does all these things it's not it's work outside the cell so

gout is really an extracellular deposition but when you're thinking about uric acid and its biologic effects that's an intracellular action so

xanthine oxidase makes uric acid inside the cell so one of the best ways to reduce intracellular uric acid is to give us

antioxidants inhibitory like allopurinol or phi boxes that now for boxes that i think it's probably just as good as alpinal but there was a big clinical trial that was published in the new england journal

that showed that alpina was associated with less cardiovascular risk than for boxes that there seemed to be an increased cardiovascular events in the boxes stack

group meaning less of a reduction or more events well see the problem was there was no placebo group oh yeah that's a disaster yeah that's a disaster this is the vioxx problem yeah with naproxen

yeah yeah i mean so the problem is allopurinol is less than pheboxystate but there's no placebo groups theoretically the placebo group would be could be higher than both of them yeah it could be higher than both of them and

there's actually evidence that that's probably true but because of the care study the way it was designed we don't know so the fda is worried about giving for boxes that

to people with cardiovascular problems because they would prefer you to give allopurinol but the trouble is it's not necessarily that fabulous that is bad it's just that it's not as good as alpine

and it's like a hundred thousand times more expensive too i mean it's a although it's i think becoming generic now so we may see a change in that i believe it when i see it and of course well you trust the generics but that's a

whole separate issue exactly so what about uh sodium restriction going back to how we started the discussion i'll tell you a story from i may have even told this on the podcast once before but in medical school i remember

when we were doing renal physiology we had a great nephrology professor who was teaching something and i think he was quite ahead of his time because this was more than 20 years ago and he was not

sort of part of this salt is bad bandwagon even though he was a nephrologist and and i won't do it because i won't do it justice but in a beautiful southern accent he made the point that

if you lined up all of the nephrons in the world all the functional units of the kidneys in the world from dumbest to smartest and then all of the nephrologists in the world from dumbest to smartest

and you took that dumbest nephron and put it next to the smartest nephrologist it's still smarter his point being of course like the kidney is a brilliant organ that is exceptional at

autoregulation of everything from flow to osmolarity to anion cation exchange again his point being he didn't buy this argument that salt is the problem

you're saying something much more nuanced and i want to kind of go back to it because i think there are important clinical implications of it you're saying no no salt does play a role

but it's dose timing bolus concentration that matters it can also be amplified or mitigated by the state of inflammation so how do you

then translate that information to your patients acknowledging that they're a very select group of people by definition they have kidney disease or they wouldn't be seeing you so it's the combination of salt and water so if you

don't drink any water as you eat salt you're going to raise your serum sodium you're going to get thirsty and as soon as you're thirsty you've triggered that in itself is a sign that you're already making fructose from the

salt so when you eat salt you're making fructose in your body and the fructose is then driving a lot of effects now we know that high salt diets are associated

with obesity not just high blood pressure they're associated with the development of diabetes there's many studies now but high salt looks like it works by producing fructose so if you drink

water with salt the danger of the salt is much less if you drink water and then your pretzel you would be safer than if you ate your pretzel and then drink the water

because what triggers it is the rise in salt and so when you see someone in the clinic what we try to do is to tell them to drink a lot of water and to reduce their salt but it isn't

the amount of salt it's the balance of salt and water now that can be sometimes challenging for patients in a kidney clinic because that would be one population in which you do have to be mindful of volume

right but most patients with chronic kidney disease they will excrete water normally or just minimally abnormal and so there's actually clinical trials looking at the evidence that water may slow

the progression of kidney disease it might be working in part by blocking the effects of salt and so forth on the kidney and we experimentally can show that giving water can

slow kidney disease progression so drinking water turns out to be good here's another thing it turns out that many animals use fructose to make fat as a means for making water

so when you make fat although there's no water stored in the fat when they burn the fat they make water so whales don't drink salt water they are fat because when they break down the fat they're making the water

we call it metabolic water so it turns out that fructose dries fat production and in part to preserve water not just energy

so animals will use that fat to provide an energy source but also to provide water so it turns out that if you take an animal on fructose and you give it a lot of

water you can suppress some of the obesity you can suppress some of the effects of metabolic syndrome and so the old wives tale that drinking

six glasses of water a day is good to help keep you skinny is true it turns out that water suppresses some of the effects of fructose and does it need to be water could it be tea or

coffee or something that's equally the osmolarity of water is what serum is about 280 yep okay so anything with the zero osmolarity is good enough yes technically a diet soda should have a zero osmolarity as well diet soda

would work actually for the record you and i are sitting here drinking just plain water right and diet sugars have their own issues so we'll come back to that in a few seconds because that's super interesting so

rick you sort of you toss these little nuggets out there like they're nothing but they sound i mean again just based on the sort of breadth of research you've put into this it almost just seems too good to be true and so profound

yet you sort of throw it out there like an after the fact well look as long as you drink enough water and don't eat fructose and god forbid don't drink fructose manage your uric acid levels etc etc you

make it seem like a lot of problems could go away from these things how would you shape that advice for someone with normal kidney disease uh pregnancy with normal kidneys would you basically just say the same

thing or can you be less restrictive with sodium for example if we could reduce our fructose intake i think it would have a huge huge effect but the problem that most people face is that sugar and high fructose

corn syrup are in almost everything so if you go to the supermarket like 70 percent of processed foods have sugar in it and packaged foods

actually 70 percent of packaged foods have sugar or high fructose corn syrup so it's very hard to avoid it and here's another problem our bodies can make fructose

so our bodies as i mentioned we can make fructose from a high salt diet we can make fructose if we get dehydrated we can make fructose high uric acid stimulates fructose production and we're making the fructose

out of glucose in all of these situations high glycemic diets normally if you take an animal and you give it starch they will not really get fat but we all know

that french fries which don't have sugar in it they don't have fructose they are fattening but you've got potatoes which raise your glucose and what we showed is that if you just give glucose to an

animal the high glucose as it hits the liver induces this enzyme to convert glucose to fructose which enzyme is that that converts glucose into protein aldost reductase so

when we took mice and we gave them glucose and we were thinking we might not see much because we were believing that fructose is the culprit but over

time these animals got really fat they got insulin resistant everything but you had to over feed them glucose they we put the glucose in their drinking water so they were drinking a lot of glucose but they would

eat less chow so we gave them chao and glucose in their drinking water and their chow had it was normal chow it wasn't the high fat high sugar chow no just regular chop and these animals

started getting really really fat and when we looked at the portal vein which goes into the liver the glucose levels were high and when we looked in the liver

we found that this enzyme was activated it's also activated in diabetics for example because of the high glucose in the blood and when that enzyme got activated it started to make fructose

so even though these animals were eating no fructose they were producing fructose in their liver and then when we blocked their fructose metabolism they're eating the same

amount of glucose no change exactly suddenly they're not getting as fat they have no fatty liver they're not insulin resistant

but this suggests rick that a diet an excess carbohydrate even if it's not high in sugar could lead to fatty liver disease yes yeah absolutely if you have that enzyme induced

but let's say that you are a young person when you're young this enzyme is really not present in the liver once you're eating sugar though if you eat a lot of sugar it will induce that

enzyme for how long i don't fully know but let's say that you eat a lot of sugar and you get obese so sugar itself it looks like the induction of this enzyme probably would

be reversible within a few weeks but once your uric acid goes up that will keep it elevated so that's another reason potentially to use allopurinol if necessary

in addition to fructose restriction to keep uric acid low is to prevent or mitigate the induction of this enzyme oh yeah right so it turns out that if you give

starch or potatoes to a skinny person who does not have all this reductase induced they can eat the potatoes they want in ireland back in the 1700s where potato was basically the

main thing they were eating there wasn't a lot of obesity but you wait until you eat sugar and then develop the metabolic syndrome now you stop eating sugar but you continue to eat

carbs and the carbs are going to continue to activate through the same pathway so a low-carb diet is really great because it's necessary if you're

overweight or fasting but that's basically reducing carbs too but a low-carb diet when you're overweight is removing the high glycemic carbs that are also driving the disease but it's through

fructose so it seems that fructose reduction obviously comes with its own benefits do you have a sense of how much fructose can be produced in a fructose

free intake environment just from glucose is it a meaningful amount well we did our study by putting glucose in the drinking water they're getting a lot of glucose we haven't done the study

is the one that you're talking about trying to figure out what the range is i do think that if you just give high glucose alone you probably have to give a lot but if you've already triggered

the production of this enzyme aldost reductase you probably don't have to give a lot what about fat what if you did that same experiment with rats or mice which would be hard because to eat pure fat is difficult

but if there was a way that somehow you could make it palatable enough that they could you could over feed them to the same extent using fat and protein let's say they're getting a normal amount of glucose but the over feed was

coming through the fat would that induce any of these properties in other words is part of this due to an absolute sense of total energy being too high or is this really about a

particular carbohydrate it's definitely about a particular carbohydrate because we've actually done what's called pear feeding where you control how much they eat and you can have your control group those fructose effects will still as i

mentioned cause fatty liver yeah explain what para feeding is for people because it's a clever little tool done in this type of research so the way fructose works is it works by making you eat more and

that's how you gain weight but even when you control so that you don't eat more fructose will not cause weight gain but it will cause fatty liver insulin resistance and diabetes and so forth and the way we can

show that is by pear feeding in pear feeding we give each animal eats the same amount of food so if you give one animal sugar which normally makes it want to eat

more because it causes this thing called leptin resistance where they want to eat more but if we don't give them any more food we only give them the same amount as the control then there will be no

difference in weight but there will be differences in fatty liver metabolic syndrome and so forth the sugar industry has used this to their advantage so what they say is

okay we're going to look at clinical trials where we've given sugar and we're going to see if sugar causes weight gain but it's only fair to do that if we have it controlled where we control the energy intake to be equal

among groups so they have a control group where they've restricted there's a caloric restriction on both sides so you have a high sugar in a non-high sugar group

but it's not where you get the people get to eat as much as they want basically is this problem of not having ad libitum feeding so it's sort of like what the sugar industry is saying is look a calorie is a calorie if i give

you 100 calories of sugar and completely control what you can eat in response to that and compare you to another person who's eating the same number of calories

you're really not going to gain weight then the problem with that experiment is it's not the real world in the real world you don't have a clamp on your response exactly so when you

give sugar to animals they become leptin resistant over time and they lose their ability to control their appetite so then they eat more and so then their weight goes up but the

fructose is also doing stuff where even if you control for the weight gain they still get the fatty liver and stuff which the controls don't now a second ago you sort of alluded to artificial sweeteners so comparing i mean i'm sure you get this

question asked all the time by your patients which is i just really love coca-cola is having a diet coke it must be significantly better right i mean there's no fructose in it there's no glucose in it

so is there a downside to it yeah i think there are downsides but first let me just say the positive side we have taste buds that sense sweet and so when we

eat sugar the taste buds are activated and it stimulates this dopamine response in the brain that tells us that we like

this sugar if you actually knock out the sweet taste buds or just knock out the tastes in general animals will still like sugar they will still eat sugar a lot of sugar how hard is

that to do experimentally to knock out the sweet tasting capacity it's been done and we actually have also done it where we not got all taste

can you do it to me no it's like it's like a genetic knockout but anyway these animals will still like sugar but they won't like artificial sugar so the artificial sugar is really driven by

the sweet taste but what makes animal like real sugar is through its metabolism i mean it is true if you knock out taste they will tend to eat a little bit less sugar

but they actually still develop metabolic syndrome that's super interesting so you're saying part of our affinity for sugar is not just in our taste buds and in our brain but also in our periphery where the

metabolism takes place and the elegant way you demonstrate that is you give something of equal sweetness concentration that's non-nutritive and you completely reduce the appetite for it even though it might have the

same central effect it doesn't have the peripheral effect probably the sweet taste bud developed to try to encourage us to eat these foods that at the time

were survival foods but the food itself the sugar itself stimulates dopamine and other effects independently of the sweet taste

whereas an artificial sugar just as activating the sweet taste now if you give a mouse or a rat artificial sugar they don't gain weight

but if you give them regular sugar they do so there is some evidence that artificial sugars are better than sugar and if a person says to me oh doc

i'm afraid to drink this diet coke because it's got chemicals in it i want to drink regular coke because of that that's an error regular coke is more

dangerous than a diet coke however there is truth that things like aspartame and sucralose we don't know

fully the safety of these aspartame when last i checked had been studied more by the fda than any other molecule ingested by humans it's hard to make the case that at the small doses

that people would consume them i'm talking about someone who has a serving of this stuff a day i don't know i've always found that argument that we don't know the full safety profile of these things to be

it's like what else do we need on this one i think aspartame is kind of gross truthfully like i don't really like it that much but i just think it's definitely the lesser of two evils isn't it it's definitely the lesser of two evils

that part's for sure but we don't fully know the safety of some of these like saccharine for example has been associated with little bladder tumors in mice my recollections that aspartame can generate small

tiny concentrations of formaldehyde i think it really comes down to dose yes i think it is i think those studies were really based on rats or rodents consuming doses that simply couldn't be replicated by humans

that's probably true nevertheless water is good yeah that's generally been my take to people as well is look all things equal by certainly consume water tea things like that but yeah there's this

lesser of two evils approach but this point you made this is completely news to me and very interesting because certainly much of the neurobiology today would suggest that the response we have to sugar is mostly centrally mediated

the quote-unquote addictive because everyone loves to talk about functional mri and what happens in your brain when you're eating sugar and all of these other things but i guess i haven't seen this side by side

but presumably the fmri would light up the same for non-nutritive versus like aspartame and sugar correct yeah so let's talk about another taste which is umami i remember we were having sushi

one night when we discussed this what is umami what is that taste so umami is the savory taste and this is different from salt isn't it so there's five taste buds so there's

salt there's sweet and as i mentioned both of these taste buds seem to drive a weight gain sugar is by far the fastest it takes only at two months in a laboratory

animal and salt takes four months five months so high salt generates fructose but it's a much slower process than just eating sugar then you have a mommy which is the savory taste and then you have

bitter and sour and the bitter and sour probably developed to help you avoid eating certain foods so coffee is an example of bitter like a coffee bean or something like a

grain i think so yeah okay anyway so umami is driven by glutamate but it's markedly enhanced by purines like imp

and even uric acid so it turns out that umami is sort of a taste receptor for uric acid type foods foods that raise uric acid now is

msg the purest form of umami that we would eat yes msg is the primary stimulant and people put it in foods to encourage food intake

now there's some link of umami with obesity in epidemiologic studies and there are situations where you can give umami type

foods and especially if you can do it in a liquid form you can induce obesity so umami may not be as safe as we think it is so it's got a lot

of good things written about it in the literature don't most people view msg as evil yeah i think msg is viewed as evil but that seems to be largely unfounded based on my

view of the literature i can't really find evidence that umami is harmful there's this chinese restaurant syndrome where people get warm and headaches and it's thought to be due to excessive msg

but foods that are umami rich are often foods that we love i mean shrimp has umami caesar salad the parmesan and things like that have her mommy

and so in general people like umami foods and it's certainly in the uh websites it is often promoted but if the umami foods have a lot of purines which enhance the

umami flavor it actually may raise uric acid and kind of bypass the sugar pathway and we think that that may turn out to be somewhat of a risk factor too so do you

add this to the list of things that you caution people about we've already got the parry or salt with water idea the restrict fructose and

please god don't ever drink it do you then add the msg containing high umami foods to that playbook for ways to reduce metabolic disease

i think so yeah i think that foods like shrimps and things like that if you eat a lot of them they probably activate this pathway too we're still trying to learn

more about it but it looks like it could be a contributor i think it's if you rank it number one is is sugar and then everything else is less high

glycemic carbs can be converted to sugar what i usually say is the big four are bread potatoes

chips and rice those four are the foods that you should reduce a little bit like chips as in like chips potato chips yeah potato chips you're giving potatoes two votes out of four yeah well corn chips are you know you

gotta got it the kind of things that people put out on their table before you eat dinner and they coat it with salt which isn't good

anyway so high glycemic carbs i think really salty foods drink water i mean that's really important and umami so for example what makes beer

so much more dangerous than other alcohols for inducing obesity is because beer has all this yeast in it brewer's yeast

which basically is activating umami pathways and it's one of the reasons we like beer this is that cellular density issue you spoke about exactly and so a beer raises uric acid more

and there really is this beer belly syndrome and if you look at people who drink a lot of beer it isn't just they get abdominal obesity they get fatty liver they get high blood pressure

their triglycerides go up they basically have metabolic syndrome alcohol especially beer can also mimic sugar and it's probably because of the umami component coupled

with the alcohol those two this is the part that can sometimes drive a person insane when they're trying to think about all of these things is it's very difficult to provide

clear advice to people because there's so many caveats that are required because the dose makes the poison the speed of delivery what it's combined with all of these things i'm using that as a preface to ask a

question that i'm sure you get asked a lot which is really a dose question around fructose so let's ask it in two questions if a person is going to drink something in the form of fructose

whether it be fruit juice or soda or sports drinks which are from a fructose standpoint all basically the same is there a dose of fructose above which you think it really makes no sense under any circumstance

or below which you think once in a while is not the end of the world i mean personally i would not drink any liquids that have sugar in it or fructose or high fructose corn syrup that's fine so we're going to draw a hard line there

and hardline okay now what about eating fructose in the form of fruit because remember there's some big ass fruits out there like you look at a fuji apple which is my favorite apple i mean i like these monster

fuji apples so like half the size of my head or maybe a third the size of my head that's got to have 30 grams of fructose in it i don't think it has that much oh really i really don't most apples and

that would be a big one maybe 10 grams at most i would think no way you think more well think about it these are the really big ones yeah yeah i'm not talking about a little macintosh i'm talking about a

a huge apple and they're so sweet too so you may be right then let's talk about natural fruit so we've actually done trials in patients with low fructose diet with or without

natural fruit supplements and generally speaking natural fruit supplements do not seem to block the benefits of a low fructose diet sorry what does that mean you mean that if you took a patient and

restrict all fructose except fruit that's correct they tend to do okay they did just as well as the low fructose alone and can you quantify how much fruit because here's the problem when you're talking to someone like me rick

i don't do anything in moderation so we have these bowls in my kitchen they're called manly bowls which by definition a manly bowl is a bowl that you can wear on your head like a hat it will come over your head and when i consume

fruit i consume it in that bowl yeah i would be careful so no manly bowls yeah so the data suggests that a single fruit maybe not the giant fuji i don't know the last time i had a

single fruit yeah but a single fruit has like some fruits like kiwi and lime and lemon have almost no fructose and they're totally safe and other fruits pineapple and stuff

you have a fair amount of sugar berries for example blueberries have so many good things in it you can eat a big bowl of blueberries no problem raspberries strawberries they're all oh

the berries in general are very good grapes they have a fair amount of sugar you eat a bowl of grapes you're going to probably raise your uric acid and trigger the activation of this pattern you eat a bowl of grapes you

might as well be eating raisins based on what my blood glucose meter tells you exactly disaster yeah what i would recommend is to try to not eat too many fruit at one time

so for example there was a lady named knotts cheryl knotts i believe is her name and she's an anthropologist and she was studying orangutans and there's a time when the masting

season where all these fruit trees bloom and then fruit at the same time and then these orangutans go in there and they won't eat one fruit they'll eat a hundred fruit at one time

i'm descendants of those orangutans me too so anyway when the what she did is she would go up and collect the urine off the trees and show that by measuring things like

ketones and so forth she could show that when they were eating the fruit they were actually impairing fat oxidation and they were storing energy and their weights go way up and it's because they ate so many fruit if you

eat one fruit you're not going to do that but if you eat a huge amount of fruit and get all that fructose it will start to overwhelm the good things in fruit but there's so many good things that fruit there's

vitamin c there's epicatechin and flavonols and potassium and all these things that help fight the effects of fructose so we generally for patients that have

non-alcoholic fatty liver disease we tend to restrict them to 10 grams a day of fructose only in the form of whole fruit do you think that's overly stringent or is that reasonable

i think that's wonderful if they can do it yeah it basically comes down to you can have a bowl of berries no bananas no apples none of the high fructose fruits or even large fruits how do you handle this with your kids

you have two kids they're not that young anymore but they were young during the time in which you were learning all of this stuff how did you balance the knowledge that you have

it sucks when your dad knows more about sugar than almost any human on the planet and you're a kid and we're wired to want sugar how did you balance the sane delivery of this knowledge and to your family

so first of all things like birthdays and stuff i let them have birthday cake but we try to make sugar-free splenda type cakes at home so if we make cookies or

cakes at home we try to use splenda now they're still high carb and there can be chocolate in it occasionally you know so they do get some exposure to sugar we don't give them fruit juice and we don't get them soft

they are not allowed regular soft drinks but they can have a diet soft drink i have a 12 year old and a 15 year old what we try to do is not to be so restrictive that it's disruptive

but we try to be encouraging them to understand that sugar is playing a big role in obesity and diabetes and that's unhealthy to eat a lot what age do you think

kids start to i think that makes sense which is to me it's much more important that you would explain to your kids why you might be putting these rules in place as opposed to just come down as an authoritarian sort of this is the way it's going to be

at what age did your kids start to understand that dad wasn't just being a pain but there's a real reason that he's in the short run asking us to make a sacrifice also i've

been involved in local school programs and there's a foundation called living closer foundation that i've worked with where we've gone into schools and tried to teach children elementary school to learn from

fourth through sixth grade we try to teach them how to look at labels on foods to understand the amount of sugar we do a game where we have someone come up with a cup

of tea and add a spoonful of sugar to it and the person likes it and then we say okay now we're gonna make it like a soft drink and we put in like eight teaspoons of sugar and it's like

you can't drink it but that's the equivalent of what is in a soft drink of the same volume by the way do you think the carbonation masks some of that sugar because when you put it that way which is a great

way to do it i've never thought of that experiment it's almost grotesque it is it's a great way to teach kids but do you think the carbonation makes it a little easier to consume such a high amount of sugar in a soft drink i

suspect so i haven't tested it but i suspect that where the phosphoric acid like there's something else in there that makes it more palatable yeah maybe it's the carbonation probably is what about dried

fruit is that a no-no you know it was so disappointing when i realized that dried fruit was the fructose of fruits without the good things in it so when you make dried fruit a lot of the good things the

natural fruits are lost it's like pure fructose it's disappointing because i love dried fruit but i realize it's

not the best food for you now if you're out hiking the mountains and you're spending a lot of energy maybe it's good yeah exactly that's the thing i've always got a kick out of two things have amused me to no end one is

trail mix the other are sports drinks trail mix probably makes sense when you're mountaineering sports drinks might make sense when you're a professional athlete but paradoxically

most trail mix is consumed off the trail and most sports drinks are not consumed by athletes actively playing sports so again the dose makes the poison context matters absolutely true well

rick this has been awesome i want to be mindful of your time and i know that this is a non-clinical day for you which means every minute we're talking you're not in your lab and i want you to get back to the lab so

i want to thank you very much again not just for this discussion today which for me is super interesting and i think the listeners will agree but much more importantly for the work you've done you've taken a very

different approach to quote unquote the war on sugar you're less involved on the policy side of this and the sort of advocacy side of this but i think what your work has done

is created the strongest scientific foundation to the harm of fructose and you've done it in a largely and i say this in a complementary way but in a largely unceremonious

way which is you've sort of had your head down and a lot of people don't know who you are so i hope that more people become familiar with your work because you're i mean your cv is comical in terms of like it's like every week you seem to

publish something in either gemma the new england journal of medicine the paper we talked about yesterday which we can't talk about today because it's not yet we're not there yet i look forward to seeing that paper in science hopefully

in the next six months but that's an unbelievable tour de force that almost requires us coming back to have a talk about it so well thank you very much those are very kind words

thank you really enjoyable and thank you thank you for listening to this week's episode of the drive if you're interested in diving deeper into any topics we discuss we've created a membership program that allows us to bring you more

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