Dr. David Perlmutter is a board certified neurologist, five-time New York Times bestselling author of books like Grain Brain and Brain Wash, and is a Levels advisor. He serves on the board of directors and as a fellow of the American College of Nutrition, and as a member of the editorial board of the Journal of Alzheimer’s Disease. He has been published extensively in peer-reviewed scientific journals.
Dr. Perlmutter joined Levels chief medical officer Dr. Casey Means recently on A Whole New Levels to discuss his most recent book, Drop Acid, published in February. It introduces a revolutionary concept that uric acid is a key driver of metabolic dysfunction, and that by controlling uric acid, we can unlock optimal health. Here’s a lightly edited version of that conversation and you can watch the full episode below.
Dr. Casey Means: I think most people have never heard the words uric acid before. I was reflecting back on it and I don’t think that I ever ordered a uric acid test in five years of residency or in clinical practice until this year, when I’ve learned about it from you and Rick Johnson. So can you just describe for people who probably haven’t heard of uric acid, what it is, why we should care about it, and how this blood biomarker affects the average person?
Dr. David Perlmutter: Certainly. Uric acid is something people have had checked over the years, but it’s only traditionally been in the context of a disease called gout. Gout is characterized by a high uric acid. When you’d get your annual blood work, if your uric acid was there, and if it was elevated, the doctor might say, “well, you have to change your diet because if you don’t, you might get gout.” But the reality is that uric acid throws a much bigger net and it throws a huge metabolic net. It’s deeply involved in regulating our metabolism and, in fact, taking uric acid away from just being involved in gout is something that happened in the late 1800s. Dr. Alexander Haig wrote a book describing how elevated uric acid causes high blood pressure, and can be related to headaches, cognitive issues and even depression.
There’s a precedent for looking at uric acid through a different lens for a long time, but by and large, what you and I were taught and people are taught in medical school is if somebody has gout and has a high uric acid, give them allopurinol and then see your next patient. It fits together really well. Gout is caused by high uric acid, give them a drug and move on. I’m not saying gout isn’t an important disease, but as we look at uric acid’s relationship to high blood sugar, insulin resistance, high blood pressure, the creation and storage of fat, then thinking about uric acid with all the problems that plague our modern society, man, oh man, it becomes very, very interesting and a very powerful new tool in our metabolic toolkit.
In a 2016 collaborative study from researchers in both Japan and Turkey, the title was Uric Acid in Metabolic Syndrome: From Innocent Bystander to a Central Player. In the past two decades, uric acid has gone from simply being there with obesity and diabetes and hypertension to now we recognize that it’s playing a causative role. It’s leading to those problems. In the world of blood sugar and insulin sensitivity, to have a new tool that was previously unrecognized opens the door for us to really gain more control, which is what we want. Keeping our blood sugar under control has become so central, and now we know that uric acid is deeply entrenched in that process.
On the function of uric acid in our evolution …
Dr. Casey Means: I think it is so interesting you talk a lot in the book about how Alexander Haig was writing about this almost 200 years ago?
Dr. David Perlmutter: 1888 is when he published.
Dr. Casey Means: He was seeing this link between several different diseases. We’re really only thinking about it in the context of gout, even now. For me, training as an ear, nose and throat doctor, this was not something that was on our radar because if a patient had gout, that wasn’t something that we would necessarily zero in on.
So what I would love for you to talk through a little bit is some of the mechanisms of how uric acid is actually causing metabolic problems.
Dr. David Perlmutter: Let me lay a little groundwork ahead of that and first why it matters. It matters because here in America, 88% of adults has at least one component of metabolic syndrome and it’s important that we talk about people and their blood pressure and their body, their BMI, and their blood sugars, their insulin sensitivity (or not), their blood lipids and triglycerides. Those are all interesting and important things, but it’s the downstream effects—the cardiovascular disease, the senile dementia of the Alzheimer’s type, the strokes, various forms of cancer, colon and breast and pancreatic cancer—that are related to metabolic dysfunction in many cases. So it’s not just that we happen to be metabolically dysfunctional, but the biggies, the leading causes of death on planet earth, are the metabolic downstream issues, the chronic degenerative conditions that are beyond epidemic.
It’s exceedingly valuable to look at it through that perspective and think about anything we can do to right that wrong, to bring people back into metabolic balance. The other thing is that this provides now a mechanistic understanding to some of our long-time unanswered questions, like the relationship between salt and obesity, between salt and diabetes, between salt and hypertension. We knew there were relationships. Of course, we did. That’s been published for decades, but now we know why. Now that dots finally got connected and we sit back, we go, “Oh, I get that.”
And one last point I want to make: I want to play upon the earlier discussion about how we looked at uric acid in the context of gout. In our medical training, we were given the notion that uric acid deals with gout and here’s the medicine, much as we were instructed about insulin. Insulin deals with blood sugar, packs it into the cell, end of story. Where did we really flesh out the role of insulin as a trophic hormone in the brain, the role of insulin in regulating protein metabolism, for example. We tend to pigeonhole things. We tend to look at testosterone as a male hormone, not recognizing how valuable it is in women. Why do men have estrogen, a female hormone? Why is there cholecystitis, the kind of receptors in the brain for crying out loud, in the gallbladder hormone? Why would we have receptors in the brain? And so it is with uric acid that it has this manifold opportunity in the body to do various things.
The context of uric acid increasing our metabolic dysfunction is one that looks upon it initially as being something very favorable, that it’s very favorable for our survival to become insulin resistant, to make and store body fat, to raise our blood pressure and profuse our organs when we don’t have water and we face dehydration.
Many of the viewers right now are questioning what I just said: did Dr. Perlmutter just said that having insulin resistance and raising your blood sugar is a good thing? Yeah, I did say that. That making and storing body fat is a good thing for survival? You bet, I said that. In the context of our genome and our ancestors, when we didn’t know where our next meal was coming from, or if there will even be a next meal or we would find water to drink.
Uric acid is elevated in humans about four to five times higher than the uric acid in other mammals. It’s also elevated in the great apes. And if I may digress for just a moment, because I think the story is fascinating. It was actually in Scientific American—our ancestors, our primate ancestors about 15 million years ago, faced a time of food scarcity during what was called the Middle Miocene period when the earth became cooler. When the earth became cooler, various tropical fruits, like figs were less abundant. It was a survival pressure on our primate ancestors but a small group of them had a superpower. And what was that superpower? They were able to store and make more body fat and raise their blood sugar so they could power their brains. And the signal that made their bodies do that was something called uric acid. Who knew?
What they developed over a period of a million years was a defect in the enzyme called uricase that would’ve broken down their uric acid and allowed them to excrete it. They became basically without uricase because of genetic selection and that gave them this superpower. They didn’t become fat and obese. They became just a little bit heavier than the ones who didn’t have the uricase mutations. So they survived and passed it on to Dr. Casey Means and Dr. David Perlmutter and to everybody walking the planet today.
We inherited this legacy as a survival mechanism by having elevated uric acid, such that in the late summer, early fall when the fruit ripens and we might hunter gather, find some blueberries, it would be a signal to our bodies get ready for food scarcity, why? Winter’s coming. So that small amount of fructose, which is directly metabolized into uric acid, lights up your physiology. Whoa, warning sign goes off, make fat, store fat, raise your blood pressure, raise your blood sugar, become insulin resistant as a wonderful, terrific survival mechanism.
We needed elevated blood sugar to power our brains when we couldn’t find food. Why? To avoid two things: starvation and predation. We’d be clever enough where our brain’s still working and we’d be clever enough to avoid getting eaten by some other animal that was also feeling hungry. That was our environment and our evolution, our genes, our physiology, that is the byproduct of our evolution, of our genetic expression. Worked beautifully in that environment. Now, genetically, we haven’t changed. We haven’t had any significant metabolic changes in our genes for at least 70,000 years, but what did change were the environmental signals that we send to our bodies—primarily, the abundance of sugar in the diet, mainly fructose.
We’ll talk about the relationship to glucose a little bit later on, but we started just pounding our bodies with ever increasing amounts of this signal. We talk about food as the macronutrients of protein, carbohydrates and fat and the micronutrients of minerals and vitamins, but we tend to neglect the discussion of food as information. Food is informing us as to the environment. Fructose tells our body winter is coming and the signaling mechanism is uric acid. Uric acid is screaming in the body, “Get ready!” If you want to survive, we’re going to help you make fat, store fat, raise blood sugar, raise blood pressure. Suddenly that signal’s on 24/7 for the winter that never comes. That’s the nature of our world today is we are constantly telling our bodies prepare for food scarcity and now a third of American adults aren’t just overweight but obese. And by 2030, that number’s going to be 50% of American adults will be considered obese, basically because they’re preparing for food scarcity and they’re not likely going to happen.
We call this then an evolutionary environmental mismatch. We can’t fix the evolutionary part, nor should we. But the relationship with the environment we can definitely work on because we can change the signals, stop telling our physiology prepare for winter, raise your blood sugar. How do we do that? We turn off the signaling pathway. That’s what uric acid does and that’s why the book is about doing the best we can to bring uric acid under control. Certainly fructose is a major player these days. The rise in uric acid from 3.5 mg/dL in 1920 to the average today of 6 mg/dL perfectly parallels our consumption of sugar, and, more recently, the higher levels of fructose due to the ability to extract fructose and create high fructose corn syrup. It’s very, very sweet and very inexpensive and is seen in about 60% of packaged grocery store foods.
This is a mechanism in our bodies that allowed us to survive, but in a different context. I’ve been thinking about this environmental evolutionary mismatch for a long, long time. I wrote about it 50 years ago, half a century ago, in the Miami Herald and I asked the question in that publication at the end: What about those of us living today with the outdated machinery? It’s outdated machinery because we don’t have time to adapt to the new environment, the new diet, the new world that we live in.
That’s the information that people need to get. We’ve identified the signaling pathway. Now we’ve got to understand uric acid. How do we measure it? How do we lower it? How do we monitor it moving forward?
Why fructose is bad for metabolic health
Fructose is a natural sugar but as an added sweetener its metabolic impact can be severe. Here’s what it does to your body and how to avoid it.Read the Article
On the optimal levels of uric acid and how to test it …
Dr. Casey Means: I was struck in the book by one of the statistics that you mentioned: about a hundred years ago, we were eating about 15 grams of fructose per day; maybe what you might find in a small piece of fruit. That has since quadrupled for the average person—eoinciding with the production of high fructose corn syrup, which was a cheaper version of sugar than sucrose. So table sugar was replaced with high fructose corn syrup and then we see this monumental rise in the amount of fructose. It really is “the dose makes the poison.”
The body may be able to handle and process a certain amount of fructose, especially in its whole food form. You explicitly mention in the book that we’re not talking about whole fruit in terms of the big problem here. Rather, it is the refined, processed fructose; when you overwhelm the body’s machinery with processing this huge load of fructose, you get this big surge of this byproduct, uric acid. That’s going to damage the cells. You talk about how that’s useful in a certain context, like if it’s autumn and we’re a bear about to hibernate and that signal tells our body to store fat.
But now it’s 24 hours a day, seven days a week, 365 days a year. It’s interesting to think of obesity as a flashing sign saying, this body is preparing for winter. That’s just not coming, because we’re never actually going to get to the hibernation phase where we’re away from food and using that stored fat.
So could you talk a little bit about what’s happening in the cell and how uric acid is generating fat? What is it doing in the mitochondria? And maybe touch on things other than fructose that can stimulate uric acid production.
Dr. David Perlmutter: Let me take the second question first because I think people are probably on the edge of their seats want to know. Step one is to certainly have your uric acid level measured. Go to your doctor or have that doctor send you to the laboratory. You can also check your uric acid level at home, with a little finger stick. Here’s my most recent level, 4.7 mg/dL.
We want to keep our uric acid levels below 5.5 mg/dL. I mention that because when you have a uric acid level done at the doctor’s office, the report you’re going to get is, “Hey, don’t worry. Your uric acid is in the normal range.” Anybody watching this podcast, they don’t want to hear that. Why? Because they want to be in optimal health. They want their labs in the optimal range, number one. In the normal range according to most laboratories is 7 mg/dL or lower.
But please understand a couple things. That’s not ideal. That’s not optimal, number one. Number two, that number was derived because it relates to gout. Of course the only thing that is important in uric acid, right? So it’s above7 mg/dL where uric acid begins to precipitate in the blood and that can lead to the formation of crystals in the joints, in the coronary arteries and even in the prostate gland.
The cardiometabolic issues begin at 5.5 mg/dL. We talk about in the book times to check it, why you don’t want to check it when you’re fasting, why you don’t want to check it after a vigorous workout.
A uric acid level of 7 mg/dL is dangerous. One 2018 study in Annals of Rheumatism looked at 90,000 adults—42,000 men, 48,000 women—followed them over an eight year period. They found that those individuals who had a uric acid level of 7 mg/dL or greater had a 16% increased risk of what we call all cause mortality, meaning they died from anything under the sun, they had a 38% increased risk of cardiovascular mortality, and a 32% increased risk of dying from stroke. Interestingly, for every point elevation above 7 mg/dL, there’s an additional 8–13% increased risk of all cause mortality.
A similar study followed individuals for 12 years and showed that those individuals with the highest or above 7 mg/dL, had about 155% increased risk of any form of dementia, a 55% increased risk of Alzheimer’s and about an 80% increased risk of what is called vascular dementia. There’s a very powerful relationship between elevation of the uric acid and vascular problems because it affects something called nitric oxide.
On the sources of uric acid …
Dr. David Perlmutter: Now let me get back to the question about the sources of uric acid. When you go online, if you have gout or want to know why you have an elevated uric acid, go onto one of the major clinics. I won’t mention any of them, but the big clinic names, you go onto their website, what diet should be on? It’s all about lowering your purines. That’s been the big messaging in gout medicine for such a long time. Purines are the breakdown products of the DNA and the RNA that you would find in food. So foods that are very cellular, like organ meats, liver and kidney and small fish like anchovies and macro, very dense foods, and even some vegetables are high in purines. When we break down those purines, ultimately we form uric acid. But two things are relevant. First, two thirds of the purines in our bodies are generated from our own day-to-day activity, breaking down our own muscle, our own tissue, creating these purines that can become uric acid or that can be recycled to form nucleic acids. The biggest issue by far is the fructose. Who knew?
Fructose isn’t really talked about in the major clinics in terms of the diets to lower uric acid. They talk about purines, but what is this reluctance to talk about sugar? You and I wrote an op-ed in MedPage Today in February 2021 about sugar in the American diet and the USDA recommendations. You know and I know there’s a lot going on behind the scenes that keeps people eating their sugar and it’s preposterous because we now know what it’s doing.
Fructose was sort of on the back burner all these years. It was actually the recommended sugar for diabetics because it doesn’t induce directly insulin response for its metabolism, so until quite recently, the diabetic websites were saying eat more fructose! The relationship between fructose consumption and metabolic issues was first described in 1970 in The Lancet. But that information just wasn’t forthcoming for us medical practitioners.
The third source of uric acid is the metabolism of alcohol. The metabolism of fructose and alcohol are almost identical. Interestingly, we know that in large studies like the NHANES study, that use food frequency questionnaires, we see that it matters what kind of alcohol people consume. Gender plays a role as well. As an example, men who drink wine, there’s no real effect on uric acid. Women who drink wine actually are observed to have a slightly lower uric acid in comparison to women who do not. Both men and women who consume hard liquor show an association with a fairly prominent elevation of their uric acid, but the worst player by far is beer. Why? Because it contains alcohol, but it’s also loaded with purines. Why would beer have purines? Because it’s made from yeast and yeast is highly cellular. So brewer’s yeast loads that beer up with purines, hence the uric acid level goes way up and tells the body make a beer belly, right? Who knew? Who could explain that in the past?
I will say that Japanese researchers and public health individuals have been dialed into this for quite some time. Much of the research in the book comes from the Japanese literature. And in Japan you can buy purine free beer and beer doesn’t have a lot of alcohol compared to spirits and wine. So there’s purine free beer because they get it. They get the fact that people drinking beer are going to have metabolic issues.
Those are the exclusively where uric acid comes from: fructose, alcohol and purines.
On uric acid and fruit …
Dr. David Perlmutter: The question of fruit consumption always comes up. Fruit sugar is where the word fructose comes from. Should I eat fruit? And the answer is yes, in moderation. Why? And you alluded to it before, your typical apple might have five grams of fructose and we can live with that. As long as you don’t drink an apple, so it’s going to take you a little time to consume it. That will be metabolized by the small intestine and pretty much dealt with at that level and won’t make its way to the liver where all the problems really begin. The other thing is that fruit has fiber, which slows fructose release in the body. Fruit contains bioflavonoids like quercetin that target one of the important enzymes in making uric acid, which is called xanthine oxidase—happens to be where the gout drugs like allopurinol and febuxostat work, they target that very same enzyme like quercetin and luteolin.
Finally, fruit contains vitamin C and vitamin C aids in uric acid excretion. Can you go overboard? Yes. An apple a day keeps to the doctor away. Five apples a day the doctor you will pay.
It’s valuable to note that there are high purine vegetables, like the cruciferous vegetables, and their consumption is associated with a lower uric acid. The same mechanisms are involved. I think you can eat the organ meat if you choose in moderation and have the anchovies and sardines and scallops, though they have high levels of purine. The big issue is the fructose like in a glass of apple juice or orange juice. I love looking at the carton in the health food store, it says all natural orange juice. It has 36 grams of sugar in a glass. And there’s nothing natural about that. Our ancestors didn’t find cartons of orange juice on trees. Our bodies are not set up to deal with that bombardment of fructose. Why?
Because when it happens, you’re telling your body, winter’s coming. You are signaling it through the production of uric acid that lights up fat production. This was your second question: How does it do so?
On the cellular mechanisms of uric acid …
Dr. David Perlmutter: In the mitochondria, it does a couple of things through its inhibition of an enzyme called cis-aconitase. Cis-aconitase is one of the enzyme that’s inhibited. NADP oxidase is another. When inhibited by uric acid, both compromise our ability to burn fat as a survival mechanism and increase our production of fat as a survival mechanism. The third thing is there’s a general downregulation of mitochondrial function as a way of conserving energy. There’s a physiological pathway that we like to stimulate because it tells the body: Don’t make fat, burn fat, turn up energy utilization, keep the blood sugar low. We talk about something called AMP kinase or AMPK. That’s what we’re doing our best day in and day out to stimulate because it’s basically telling your body the hunting is good. It means you’re in great shape. We don’t need to pack it away. Everything is good. We’re going to use our fat for energy. Who wouldn’t want that? We’re going to keep the blood sugar where it needs to be. We don’t need to generate new blood sugar glucose from the liver because we’re doing just fine.
We want to do whatever we can to keep AMP kinase lit up, doing its job. How do you stimulate your AMP kinase? Exercise is one of the most powerful things you can do for your health. How so? It stimulates AMP kinase. Quercetin—now that’s the second time I’ve mentioned it—first, because it inhibits the enzyme called xanthine oxidase that makes uric acid and second, it stimulates AMP kinase. Who wouldn’t want that? Third, you could take a pharmaceutical called metformin as well. That’s not what we’re necessarily about. If a person needs metformin for their diabetes to inhibit their production of sugar in their body, that’s between them and their doctor, but I’m simply describing this mechanism. Now the evil twin of AMP kinase is AMP deaminase—it’s almost the same, but does exactly the opposite. It says winter’s coming. It says ratchet down the metabolism, power the brain with glucose, make more fat and store more fat.
It’s this AMP deaminase that’s really active. You alluded to it earlier: When a bear is getting ready to hibernate, he needs to make as much fat as he possibly can and keep that fat locked up. How does the bear get ready to hibernate in the winter? It eats pounds and pounds of berries every day. And what does that do? Fructose, uric acid shuts down AMP kinase, lights up its evil twin AMP deaminase. Uric acid directly works against us by taking AMP kinase offline.
So as your viewers have heard about AMP kinase before and all the things that we try to do to stay healthy and keep AMP kinase doing its job, the worst thing you can do is have a high uric acid because that’s totally working against you. It’s knocking down AMP kinase. You can’t help but make more body fat, raise your blood sugar, become insulin resistant, raise your blood pressure as a survival mechanism against dehydration (to take us to our next topic). It’s a losing battle.
So for people who not making the grade, they’re monitoring their blood sugars, they’re trying to be as low-carb as possible, doing their best to exercise. Something’s missing. Check your uric acid because that could be the monkey wrench in the whole system that’s keeping you in metabolic mayhem.
On uric acid and insulin resistance …
Dr. Casey Means: I want to drill in a little bit more on insulin resistance and the development of insulin resistance from uric acid because our listeners, of course, at Levels really care about insulin resistance. One of the things that has been drilled into everyone’s mind is that repeated glucose spikes cause repeated insulin spikes and then the cell becomes numb to insulin and we develop insulin resistance and we have to produce more insulin to drive glucose into the cell. That’s one prototypical pathway we’ve heard for the development of insulin resistance. But what uric acid does and why I think it’s one of the most interesting things I’ve learned about in the past 10 years, is that it’s like a whole other way of looking at how insulin resistance develops in concert with that. We’re storing fat, including in the liver, and then that fatty liver essentially creates an issue where the pancreas is needing to produce more insulin. It’s becoming insulin resistant.
The fat in the liver actually is blocking that signal. There are other mechanisms involved, too, like inflammation from uric acid generating insulin resistance.
Can you describe the relationship between uric acid and the development of insulin resistance? Given that most people are more familiar with that framework I talked about, how those two are related?
Dr. David Perlmutter: We know that the cell gets tired of answering the door when insulin’s knocking and that’s what happens, and then the insulin doesn’t do its job. The pancreas has to make more and more insulin to get through and get the glucose into the cell. It’s an interesting mechanism. Now we have another issue: When we look at becoming insulin resistant as a survival mechanism—and it is a survival mechanism —how does that work vis-a-vis the whole uric acid fructose relationship?
Let me first focus on the mechanism. There are several, but let’s first focus on a really exciting mechanism: uric acid directly inhibits nitric oxide functionality, nitric oxide generation within the blood supply, within the actual arteries themselves and the vasculature. What does nitric oxide do and why would its inhibition be problematic? Nitric oxide allows arteries and smaller vessels to relax. Why is that important? Because then they can carry blood to the organs. When the blood vessels are constricted, we run the risk of not having enough blood supply to our organs. I quoted to you a statistic earlier that showed ~33% increased risk of stroke in individuals with high uric acid. Now it starts to make sense. Alzheimer’s, too—certainly a vascular component to that.
We understand that, yet we tend to overlook another important role of nitric oxide and that’s for insulin functionality. The entry of glucose into the cell requires nitric oxide. It becomes very, very important when we look at some of the clinical relationships to dysregulated nitric oxide and how uric acid then might manifest as clinical disease.
There are several drugs people have heard of that are involved in increasing nitric oxide and allowing better blood supply. What is erectile dysfunction? Erectile dysfunction is lack of blood supply that causes an individual to lose the ability to maintain or achieve or maintain an erection. So these drugs were developed to enhance nitric oxide functionality to allow erectile function. That’s an important role of nitric oxide.
So an interesting study was published earlier this year, looking at several million individuals and found that those men who took drugs like Viagra had a 70% reduced risk of developing Alzheimer’s disease. There is a strong vascular component to Alzheimer’s disease, but make no mistake about it the role of insulin in the brain is fundamental. The elevation of blood sugar in the brain that is not being used is critically important. We’ll get to that in just a minute. As a sneak preview, it leads to elevated fructose, which leads to elevated brain uric acid. My point is that we now have this really new exciting and valuable tool in our understanding: this relationship between elevation of uric acid and its compromise of the functionality of nitric oxide, which has two downstream, very significant effects.
Number one, a vascular effect, number two, an insulin resistance effect as well. It opens up the door for us to target uric acid as a way of improving blood supply. It’s noted that men who have elevated uric acid have about a 38% increased risk of erectile dysfunction and that’s a pretty good marker of vascular functional defect. Men with erectile dysfunction have a dramatically increased risk of cardiovascular death for that matter.
Dr. Richard Johnson on fructose and how we store fat
In this episode of A Whole New Level, Dr. Casey Means sat down to talk with Dr. Richard Johnson about his new book "Nature Wants Us to Be Fat"Read the Article
On uric acid and dehydration …
Dr. David Perlmutter: Now let me segue to another part of this whole mechanistic understanding of the role of uric acid and tie it back to where we just were. First, I’ll summarize: uric acid inhibits nitric oxide, blood vessels can’t relax, insulin doesn’t work as well. And that’s a survival mechanism. That’s one of the tricks of uric acid that allowed us to survive because when we slow blood supply through the body by keeping those blood vessels tight, we can get by when we’re deeply dehydrated. That’s where we’ll go next. How does this whole pathway relate to our survival during times of water scarcity? You can understand that food scarcity makes more body fat as a reservoir of calories so you’ll survive, but there’s also a powerful mechanism that allows this pathway to allow our survival during times of water scarcity.
It’s called the polyol pathway. The polyol pathway is how our bodies endogenously create fructose. Can you imagine you don’t need to consume any fructose whatsoever. You’re reading labels, you’re eating nothing, and yet there’s fructose being produced in your body. Now what triggers your body to activate the enzymes involved in the creation of fructose de novo from the glucose circling around in your body and its various stresses? One is when the body thinks that it’s dehydrated. Somebody goes to the hospital with dehydration, you look at their blood work, their sodium is elevated, right? What does that high sodium do?
Well, vasopressin is activated, but it stimulates an enzyme called aldose reductase. Aldose reductase is fundamental in this polyol pathway to convert your blood sugar into fructose, telling your body to make and store fat because you’re dehydrated. Why would you want to make fat?
Let’s turn to our friend, the camel. The camel has this huge hump on his back or her back, walks across a desert, doesn’t get dehydrated, doesn’t drink any water and yet manages to survive. Why? What’s the superpower here? It’s the hump. What’s in the hump? Fat, up to 80 pounds pure fat. When we burn fat, we produce carbon dioxide and water, metabolic water. Making and storing body fat has been a powerful survival mechanism against dehydration. Who knew? It’s why the hummingbird, when it’s going to make these epic voyages, stores up to 40% of its body weight as fat. A fat hummingbird. Who knew?
If you want hummingbirds in your backyard, you put out sugar water, right? They convert that into body fat. They have a reservoir, yes, for calories, but to make metabolic water, as well.
Now you’re dehydrated, your sodium is up, you stimulate aldose reductase, you convert glucose into fructose. Alarm signals uric acid to make fat metabolic water. The problem is that you can raise your serum sodium just by eating a bag of chips. So you park yourself in front of the playoffs and sit there munching chips. Not only are the processed carbs going to raise your blood sugar, which activate this pathway, but it’s also the salt. Your serum sodium goes up and the next thing you know you’re getting fat. And why are you getting fat? Because you’ve stimulated the survival pathway.
Again, I alluded earlier that we’ve known that there’s a relationship between eating a lot of salt and getting fat, between eating a lot of salt and becoming insulin resistant, between eating a lot of salt and having high blood pressure. Now we know why. Uric acid is sending this signal and does a couple of things that are so incredibly important. The first step in the metabolism of fructose utilizes an enzyme called fructokinase. So fructokinase uses energy, ATP, unlike glucose metabolism. It uses ATP and creates ADP and then AMP adenosine, which becomes uric acid, monophosphate. It’s that adenosine that has to be dealt with by AMP adenosine monophosphate kinase or AMP deaminase. That’s where the adenosine has to go, either recycled back up to make more ATP or broken down further or converted into ammonia.
Uric acid stimulates fructokinase. It stimulates the metabolism of the very thing that created it in the first place. Normally in the body, we have feedback inhibition, where at the end of metabolic pathway, there’s a signal to shut this off. Not in this case. We don’t want to to inhibit fructose metabolism. We want to keep it going because if it’s not going to keep going, we’ll die when we’re starving or we’re dehydrated. It’s so powerful.
We talk about what happens when we eat a lot of fructose: you develop something called non-alcoholic fatty liver disease. It’s developing fat in the liver, and then in the body, unrelated to your consumption of alcohol, right?
We know that alcohol consumption is going to make you have a fatty liver and ultimately cirrhosis, and who knows what else? Liver cancer, et cetera.
But this mechanisms we’re talking about is not alcohol related. In the laboratory animal, if you block fructokinase, if you block the metabolism of fructose into uric acid, you can give laboratory animals alcohol, and they don’t get alcoholic fatty liver disease. It’s the same thing. The reason is because alcohol similarly stimulates the production of fructose in the body from glucose. So we delineate between alcoholic fatty liver disease and non-alcoholic fatty liver disease. But they’re the same thing. They’re mediated by this pathway of fructose becoming ultimately uric acid and stimulating this lipogenesis, this production of fat in the liver.
The notion of inhibition of fructokinase as a treatment for non-alcoholic fatty liver disease and even alcoholic liver disease is now being vigorously studied. There is research being done at pharmaceutical companies to inhibit fructokinase as a way of helping people stop this whole signaling pathway, keep their blood sugars in check, their blood pressures in check and stop this crazy production of body fat.
Dr. Casey Means: Oh my gosh. It’s such awe for the body. I mean, here we have this molecule and, back in this conversation about blood pressure, it has dual effects. One is to literally change nitric oxide functionality, constrict blood vessels. Then on the flip side, it makes you store fat so that you can have metabolic water, both of which are going to help you in times of dehydration. It’s really mind blowing that it’s doing all of that.
Dr. David Perlmutter: It’s so interconnected. As the insulin resistant person develops higher and higher insulin levels, insulin inhibits uric acid excretion and fans the flames and keeps this whole process going. The other important factor that stimulates the polyol pathway to make fructose in the body, we talked about alcohol, we talked about elevation of serum sodium as a signal that we’re dehydrated, is glucose.
On uric acid and glucose …
Dr. Casey Means: This was going to be my next question. I do want to set this up because it’s something that I think is going to be mind blowing to everyone listening and everyone who reads your book.
We’ve really focused on this paradigm of glucose causing insulin resistance because glucose stimulates insulin repeatedly, which then causes the cell to become numb to it. Then we get insulin resistant. But this is bringing in a whole other lens, which is that there are multiple things that can activate the polyol pathway. One of them is glucose and it could be the glucose to fructose conversion and subsequent uric acid and lipogenesis in the liver that’s actually causing insulin resistance, which then feeds into more glucose instability.
What’s the weight of these, relatively, in the body in terms of what glucose is doing on its own and what glucose is doing by nature of it being converted to fructose at high levels? Because we also know glucose has lots of its own effects on the body as well, like inflammation, oxidative stress, glycation, which can feed into these processes.How do you see that these two different mechanisms relatively contributing to the problem of insulin resistance?
Dr. David Perlmutter: One of the factors involved here that really resonates is the fact that it’s a feed forward, no pun intended. It’s a feed forward mechanism that worked for our ancestors to keep them alive, kept regenerating these signaling molecules to keep the alarm sounded and that’s what’s going on today. I think we have to recognize that every action of glucose is not just either as an energy source, or to be packed away as glycogen, or spilled in the urine—this is a new side. The glucose to fructose conversion and the subsequent activation of these pathways that self stimulate is very important. We know that based upon interventional trials that we can inhibit this pathway at multiple places—like inhibiting fructokinase, inhibiting uric acid production by giving people allopurinol—in research setting and we’ll see improvement in their metabolic parameters quickly.
These studies involve humans where they give them 180, 200 grams of fructose in a day. Within a couple weeks, they would have many metabolic issues. But this would not happen when these individuals received that level of fructose but had its metabolism blocked by simply giving them a gout pill called allopurinol. I want to mention parenthetically that quercetin as a nutritional supplement works almost as effectively as allopurinol. I mentioned earlier, it targets the same enzyme called xanthine oxidase. One study in 22 young men with mild elevation of their uric acid over eight weeks giving them 500 milligrams a day of quercetin dropped their uric acid by about 8%, just in eight weeks. So you’re targeting that enzyme involved in the manufacturing of uric acid. The point is you break the cycle and there are many opportunities to break the cycle along the way.
The inhibition of fructose metabolism by inhibiting fructokinase is being studied aggressively and I think we’re going to see medications that will do that. And you can aid yourself in the excretion of uric acid by taking 500 milligrams a day of vitamin C and limiting your consumption of fructose, limiting the production of fructose by the activation of this polyol pathway.
The relative weights have yet to be determined, because we’re just beginning to see the interventional trials. I think it’s going to be difficult to determine that. What we are going to soon see is measurement of the actual enzymes involved in the polyol pathway in clinical practice, looking at this aldose reductase—that’s the rate limiting enzyme that is involved in the conversion of glucose into fructose. If we can see your baseline level of aldose reductase in terms of making fructose in your body, do something interesting and then see if that affected the aldose reductase. Man oh man, that’s going to be a really exciting time because then we’re cutting down the fructose, which is very difficult to measure productionof. I truly believe you’ll see that reflected in the uric acid level and we’ll see wonderful clinical benefits from that, I predict, with respect to blood pressure, blood sugar, insulin sensitivity, homer attesting, as well as lipogenesis.
That’s where we are right now. Over the next few years, this is going to absolutely explode. Even since the book came out in February 15, 2022, there’s been such an increased interest amongst people like yourself and people who are deeply involved in understanding human metabolism.
It’s really exciting. The biochemistry is so meaningful in the context of our ancestors, that this is a conserved mechanism in each and every one of us today that worked to keep us from dying. I mean, if you look at it through that lens, then you can begin to appreciate that we live in a time of this genetic environmental mismatch. We’re not going to mess with the genetic just yet. We don’t have that technology—though, who knows what’s the future’s like? But we sure as heck know how to influence these pathways in terms of modulating our environment, modulating our food and our activity, getting back to doing what we can to activate AMP kinase.
That’s been a topic I’m sure you’ve talked about before on the podcast. But what’s the big thumb on the scale keeping you from getting that AMP kinase lit up? Elevation of the uric acid.
Dr. Casey Means: What you just said about the research, I do feel like it’s probably going to explode after the publication of your book and Rick Johnson’s book, which also talks about uric acid. This is what I think is so amazing about the books that you’ve written is that they educate not only the lay population, but physicians as well as researchers to spark this whole new interest. It’s just such a gift that you as such a preeminent medical communicator can take all this science, communicate in a way that people care about and can understand. That’s going to feed into the next 10, 15 years of what PhD students are interested in researching. It’s an incredible cycle of medical communication and synthesis that you do so amazingly.
Another question I wanted to ask, and I couldn’t find anything in the research. Do we have a sense of at what glucose level, the polyol pathway is activated to convert glucose to fructose?
Dr. David Perlmutter: My sense is that it’s mild elevation. And the reason I say that is because I think it’s pretty clear one would anticipate that the general glucose level and area under the curve and excursions would likely have been a pretty low in our paleolithic ancestors based upon their lifestyle activity and their diets. Now, again, all bets are off at certain times of the year when they might have had some access to fructose, found some honey or berries. But I think that these days, typical blood sugar measurements that we see are absolutely activating that pathway and creating endogenous fructose. That explains why we’re seeing such incredible numbers of people with elevated uric acid, which it’s not necessarily the case in other countries.
Why so? Yeah, the purines is interesting story, but look, it’s mostly the sugar. Thank you very much. It’s the reason you wrote and I wrote that op-ed, we’ve got to get our sugar consumption down.
The amount of sugar we need to eat is zero grams a day. Anything else is unnecessary. If it happens to be packaged in blueberries or apples, so be it. But this notion of drinking a Coke or any of these 60% of the foods in the grocery store that have added sugar for no other reason than to get you to buy them is absurd. When you see this happening, then you look around at what people look like these days, everything fits. You totally get it. Our mission is to interrupt this, to identify it, interrupt the pathway and give people the tools to reign in their metabolic health.
Job one is to know your uric acid level. If you don’t want to stick your finger and get a drop of blood on your home uric acid monitor, then by all means go to your healthcare provider and say, I’d like to know my uric acid level. You’ll probably be asked, “Well, why on earth would you want to know that? You don’t have gout?” And I would keep in mind that people tend to be down on what they’re not up on. So again, mainstream medicine is going to say, “You don’t need to know your uric acid. Be a good little patient and go home because you don’t have gout. And I know you might have heard it someplace, but we don’t really need to test this.” So that’s when you have to be your own advocate and maybe get the home monitor or see somebody who will check your uric acid level. I think many integrative healthcare practitioners are dialed in on this now, so it shouldn’t be that difficult.
On uric acid and salt …
Dr. Casey Means: Two questions. Quick ones. So one is back to salt. I want to get a tactical thing here. Something you brought up was really interesting about dehydration being one of these mechanisms that can actually make us generate uric acid and even maybe contribute to weight gain. The body sees dehydration both if we don’t have access to water, but also it sounds like if the salt concentration is high in the body because of stuff you’re eating. So it sounds like we want to stay hydrated and avoid excess salt.
Dr. David Perlmutter: Absolutely. What the research shows is you can give two groups the same amount of salt, but if you give one group water after they do their salt consumption, then this doesn’t happen. They don’t activate the polyol pathways readily and don’t go down that rabbit hole.
Certainly for people who are deeply into keto or exercising aggressively, there is a place for salt, magnesium, potassium repletion in the context of making sure you’re drinking enough water, which is really a great recommendation. I don’t know if it’s eight glasses a day that your mother told you or whatever it was, but most people are just not drinking enough fresh water and it’s really very important for the simple reason of trying to dilute down the sodium that is so pervasive in our foods today.
Dr. Casey Means: I love the concept of, we’re literally diluting our blood so that we don’t activate the polyol pathway to convert glucose to fructose and make fat. That to me, learning that feels like one of the most motivating things I’ve ever heard about drinking water.
Also just a stat from your book that there was a study done that showed that a high salt diet for just five days in humans can lead to in insulin resistance, which was just mind blowing.
Dr. David Perlmutter: And a very, very low salt diet actually leads to mitochondrial biogenesis, the creation of mitochondria. Who’s not going to want that?
Dr. Casey Means: But too low is also not good of course …
Dr. David Perlmutter: That’s true. There are various products out there. One of them that I use on occasion is called LMNT. It contains a little bit of salt in the context of magnesium and potassium with water, and is reasonable. If you’re in ketosis or you’re exercising aggressively, you should do that. You should have those electrolytes on board. That doesn’t mean drink Gatorade or other sports drinks that are loaded with sugar and much higher levels of sodium. I mean, that was an attempt to replete minerals in high-end athletes, but driving it in with fructose in mortal men like me is not necessarily what you want to be doing.
Dr. Casey Means: It also feels like we don’t want to pair our salt and our sugar because if you’re going to be activating this pathway as well, you don’t want to have a ton of glucose and fructose on board to compound all of that going on.
Dr. David Perlmutter: And yet, what is a bag of chips or pretzels?
Dr. Casey Means: Carbs.
Dr. David Perlmutter: But it’s a refined carbohydrate. And it’s salted. So you’ve got the raw material to make fructose and you’re turning on the pathway with the salt, and off you go and your weight goes up and you wonder why.
Dr. Casey Means: The funny thing is I use LMNT, which I really like. It’s sugar free. Mostly they talk about the fact that this is especially useful on a ketogenic diet or a low carb diet. It’s the context.
On uric acid, leptin, and hunger …
Dr. Casey Means: Last question that I’ll wrap up with is about leptin. One of the most interesting things about this whole story is how uric acid actually drives us to be hungrier, which feeds back into the concept you talked about: if you’re a bear and you get the fructose signal and start generating uric acid, you actually want that bear to become hyper motivated to eat as many berries as possible before winter comes. This is relevant to us now because what’s happening to the human brain is that we’re stimulating hunger. Can you talk a little bit about the effect on drive for hunger and what it’s doing to our satiety signals?
Dr. David Perlmutter: It’s blunting our satiety signals as a survival mechanism. It’s leading to what we call hyperphagia, so that we’ll eat more and we’ll survive. But beyond that, there are some behavioral ideas that are changed as well in the presence of this elevation of the endogenous fructose. We become more likely to be risk takers. Why? Because it’s the risk takers who are going to be more likely to expose themselves to environments where they might find food. Whereas the more conservative individual not taking the risk might not find food and might not survive. So this idea of not learning as much from your environment is sort of an explanation as to why there’s this relationship between high levels of uric acid and risk for Alzheimer’s disease.
Again, as a survival mechanism in the context of today, there’s a powerful survival advantage to not just taking risk and having risky behavior. Sure, there’s a risk of injury, but that’s going to be the individual who may ultimately find the water or find the food.
Dr. Casey Means: It’s so fascinating to think how we’re literally being controlled like little puppets by some of these biomarkers. For those of us who have dealt with cravings or feeling insatiable hunger, this is also so empowering because you can actually change your behavior by taking the gas off some of these pathways.
Dr. David Perlmutter: You are influencing how you see the world based upon your dietary choices. We know that we have two very important decision making areas in the brain—this is going to be somewhat simplified. We have a primitive, impulsive, non forward thinking, I-want-it-now area called the amygdala. And we have the more advanced prefrontal cortex that looks at lot of information, comes up with a really good decision that takes into account how my decision is going to affect other people, how it’s going to affect me, what the impact of this decision may be a year from now, whatever. That’s basically the adult in the room, right? Because that prefrontal cortex exercises top down control over the more impulsive five-year-old, the amygdala. That pathway is fundamental. When we sever that pathway, we disconnect from the top down control. We take the adult out of the room. In Brain Wash, we call that the disconnection syndrome and it turns out that inflammation severs the pathway.
When we become inflamed—as is what happens when uric acid level goes up; that’s what gout is all about—we lock ourselves into a very simplistic decision maker that will further eat the crappy food and further choose to spend time not exercising, but watching TV. It creates really a vicious cycle. We need to bring the adult back in the room, we need to bring that uric acid level down, reduce inflammation. Everybody knows the right thing to do, but we don’t always do the right thing because sometimes we give in and the adult leaves briefly and we take full advantage of it.
It’s all about making better decisions that look at the long term, not just right now. Would I eat a huge chunk of chocolate cake right now if there was no implication for it? Yeah, I would. Who wouldn’t? But my prefrontal cortex says, you know what? You want to get fat and raise your blood sugar and your continuous glucose monitor’s going to probably fry and Casey’s going to see the results and call you? So we don’t do that. That’s because we keep the adults in the room as much as possible.