#213 – Uric acid: A KEY cause of weight gain, diabetes, heart disease, and dementia (and simple steps to lower it) (Dr. David Perlmutter & Dr. Casey Means)

Glucose isn’t alone in causing insulin resistance and metabolic syndrome. Uric acid is another critical player that determines your metabolic health. Levels Chief Medical Officer, Dr. Casey Means, sat down with our advisor, Dr. David Perlmutter on the discovery of how the elevation of uric acid in the body is a causative mechanism in the development of metabolic diseases. They also talked about how uric acid is one of the key links between obesity, diabetes, heart disease, and other chronic degenerative diseases.

04:23 – More than just gout

Gout isn’t the only outcome of high uric acid we need to look out for, even though that’s what’s traditionally taught in medicine.

Uric acid has been 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 high uric acid, other components lead to gout. So it’s been, when you’d get your annual blood work, if 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.

06:17 – A causative role

Uric acid has a clear causative role in metabolic syndrome instead of its ever-present role as an innocent bystander like we once thought.

We don’t have to even unpack an article. A study, a paper, was in 2016, a collaborative study from researchers in both Japan and Turkey. The title was “Uric acid in metabolic syndrome: From innocent bystander to a central player.” And what has happened in the past two decades with respect to uric acid is it has gone from simply kind of being there with obesity and diabetes and hypertension. Yeah, we notice that those people tended to have higher uric acid, and now we recognize that it doesn’t happen to be just there, it’s playing a causative role. It’s something that’s actually leading to those problems. And in the world of blood sugar and insulin sensitivity, et cetera, to have a new tool that was previously unrecognized opens the door for us to really gain more control, which is what we want. I mean, keeping our blood sugar under control, why that has become so central in so many discussions these days, and now we know that uric acid’s actually deeply entrenched in that whole process.

08:54 – The number one cause of death

Elevated levels of uric acid can lead to numerous chronic degenerative conditions.

It matters because here in America, 88% of adults has at least one component of the 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 consequences, the downstream effects, the cardiovascular disease, the senile dementia of the Alzheimer’s type, the strokes, et cetera, various forms of cancer, colon, 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 number one causes of death on planet earth, not COVID, are the metabolic downstream issues, the chronic degenerative conditions that are beyond epidemic.

16:35 – Evolutionary environmental mismatch

Our genes are wired to listen to the food we consume as information for how to live, and to help us survive during periods of drought or food shortages, which we rarely face in today’s modern world.

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 is 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, isn’t just overweight, but obese. And in the distant future, in the year 2030, that’s way in the future, right, eight years from now that number’s going to be 50% of Americans, adults will be considered obese, basically, because they’re preparing for food scarcity and they’re not likely going to happen. So we call this then an evolutionary environmental mismatch.

18:08 – High fructose corn syrup

The cheaper, faster sugar to produce, called high fructose corn syrup, took over markets to deliver four times the amount of sugar to most American households.

The rise in uric acid from 1920, at 3.5 to the average today at six milligrams per deciliter, perfectly parallels our consumption of sugar and more recently the higher levels of fructose because of the development of the technology to extract fructose and create high fructose corn syrup, which is very sweet and very inexpensive, and as such is seen in about 60% of packaged grocery store foods. So to reduce it again, this is a mechanism in our bodies that allowed us to survive, but in a different context.

23:39 – The dangers of uric acid

The increased risk associated with uric acid is undeniable with a large proportion of mortality connected to cardiovascular issues and stroke.

A uric acid level of seven is dangerous. One study in Annals of Rheumatism 2018 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 seven 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 — that’s this gout thing, uric acid — a 38% increased risk of cardiovascular mortality. A 32% increased risk of dying from stroke. And interestingly for every point elevation above seven and we see it every day, there’s an additional additive, eight to 13% increased risk of what’s called all-cause mortality, meaning dying from anything whatsoever.

24:49 – Uric acid and dementia

Uric acid also affects nitric oxide, which relates to vascular health and the propensity for developing vascular dementia.

A similar study followed individuals for 12 years and showed that those individuals with the highest or above seven, they 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.

31:44 – Too much fructose

The amount of fructose in a carton of fruit juice is well beyond what is biologically necessary or manageable based on our genetics.

The big issue is the fructose like in a glass of apple juice or orange juice. And 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 and you are signaling it through the production of uric acid, that lights up fat production.

42:43 – Erectile dysfunction and cardiovascular risk

Nitric oxide connects erectile dysfunction to uric acid through its ability to relax arteries and improve blood flow, which also happens to relieve cardiovascular issues.

My point is that we now have this really new, and for those of us who enjoy this stuff, exciting and valuable tool in our understanding, and that is 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. So it opens up the door for us to target uric acid as a way of improving blood supply. It’s noted that people, 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. So this is really starting to tie up some loose ends.

01:04:29 – No need to eat sugar

Based on our genetics, there is no reason to voluntarily consume excess sugar in our daily diets.

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 but to get you to buy them is absurd. Then when you see this happening, then you look around at what people look like these days, we talked to statistics earlier, everything fits in. You totally get it. And our mission is then to interrupt this, is to identify i

Dr. David Perlmutter (00:00:06):

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 of Coke or any of these 60% of the foods in the grocery store that have added sugar for no other reason, but 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 in. You totally get it.

Ben Grynol (00:00:39):

I’m Ben Grynol, part of the early startup team here at Levels. We’re building tech that helps people to understand their metabolic health. And this is your front row seat to everything we do. This is A Whole New Level. When thinking about things like obesity, insulin resistance, diabetes, fatty liver disease, hypertension, cardiovascular disease, stroke, neurological disorders, premature death, what do they have in common?

Ben Grynol (00:01:17):

Well, poor metabolic help. More specifically, a lot of them are linked to high uric acid levels. Dr. David Perlmutter, New York Times bestselling author, also one of the advisors of Levels, he recently came out with a book called Drop Acid. And so he and Dr. Casey Means, chief medical officer for Levels, the two of them sat down and they deconstructed the idea of uric acid and how it ties into metabolic health. No need to wait. Here’s Casey.

Dr. Casey Means (00:01:50):

Hello, everyone. Welcome to A Whole New Level. This is Dr. Casey Means, co-founder and chief medical officer of Levels. And I could not be more excited about this conversation. It’s a long time coming and it’s about the new and amazing book Drop Acid, all about uric acid. And we are here today with Dr. David Perlmutter. So a little bit about Dr. Perlmutter.

Dr. Casey Means (00:02:12):

He is a board certified neurologist, five times New York Times bestselling author. And I’m so fortunate to say he’s also a Levels advisor. He serves on the board of directors and as a fellow of the American College of Nutrition, something that he talks about in the book that he was inspired to do after being somewhat dismayed about how little nutrition was actually taught in medical school. He serves as a member of the Editorial Board of the Journal of Alzheimer’s Disease and has published extensively and peer reviewed scientific journals.

Dr. Casey Means (00:02:37):

His books have been published in 32 languages and include some of my favorites, the number one New York Times bestselling Grain Brain, Brain maker, and Brain Wash amongst others. And it’s really an understatement to say that these books have contributed to a tectonic cultural shift in understanding the impact of diet, microbiome and lifestyle factors on our risk for so many of the symptoms and diseases Americans are plagued with today.

Dr. Casey Means (00:03:01):

And in particular, our growing epidemic of issues with brain health, everything from dementia to neuro degeneration to depression, to brain fog. His most recent book that we’re going to be talking about today, Drop Acid was published in February, and it introduces really a revolutionary concept that uric acid is a key driver of metabolic dysfunction, and that by controlling uric acid, we can unlock optimal health.

Dr. Casey Means (00:03:22):

And this is really such a huge addition to the field. It’s backed by hoards of research, but has not until now, until really this year been a part of the mainstream metabolic health conversation. So we’re going to talk all about today, how it contributes to insulin resistance and metabolic disease and how we can get on top of it. Welcome Dr. Perlmutter.

Dr. David Perlmutter (00:03:40):

Oh, Casey. So good to see you again.

Dr. Casey Means (00:03:44):

Yes. The last time we saw each other, we were in Miami, which was quite lovely. And hopefully we’ll be able to do that again sometime soon, but so let’s jump right in. So I think most people have never heard the words uric acid before, and I actually was reflecting back on it.

Dr. Casey Means (00:04:02):

And I don’t think that I ever ordered uric acid 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 also haven’t heard of uric acid, what it is, why we should care about it and how this blood biomarker is affecting the average person?

Dr. David Perlmutter (00:04:23):

Certainly. So uric acid has been 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, other components lead to gout. So it’s been, when you’d get your annual blood work, if 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.

Dr. David Perlmutter (00:04:48):

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 Hague wrote a book describing how elevated uric acid causes high blood pressure, can be related to headaches, cognitive issues and even depression.

Dr. David Perlmutter (00:05:19):

So, there’s been a precedent for looking at uric acid through a different lens for an awful long time, but by and large, what we were taught, 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.

Dr. David Perlmutter (00:05:41):

Gout is caused by high uric acid, give them a drug and move on. It’s much more important than just, I’m not saying gout is 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-O-man, it becomes very interesting and a very powerful new tool in our metabolic toolkit.

Dr. David Perlmutter (00:06:16):

And I think the title, we don’t have to even unpack an article, a study, a paper was in 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. And what has happened in the past two decades with respect to uric acid is it has gone from simply kind of being there with obesity and diabetes and hypertension.

Dr. David Perlmutter (00:06:48):

Yeah, we notice that those people tended to have higher uric acid, and now we recognize that it doesn’t happen to be just there, it’s playing a causative role. It’s something that’s actually leading to those problems. And in the world of blood sugar and insulin sensitivity, et cetera, to have a new tool that was previously unrecognized opens the door for us to really, gain more control, which is what we want. I mean, keeping our blood sugar under control, why that has become so central in so many discussions these days, and now we know that uric acid’s actually deeply entrenched in that whole process.

Dr. Casey Means (00:07:33):

Amazing. And, I think it is so interesting. You talk a lot in the book about how Alexander Hague was writing about this almost, what was it? 200 years ago? Was it 1820 around that, that he was-

Dr. David Perlmutter (00:07:44):

No, it was in the late 1800s, around 1888 is when he published.

Dr. Casey Means (00:07:48):

I mean, it’s amazing. And he was seeing this as this link between several different diseases. And I think that was so interesting to me that, like you said, we’re really only thinking about it in the context of gout, even now, until now, no longer after all the work that you’ve published about this. And I think that certainly 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, I mean that wasn’t something that we would necessarily zero in on or focus on.

Dr. Casey Means (00:08:16):

And so it’s just so interesting to see now that this is actually something that we see elevated and mechanistically contributing to all of the conditions and diseases we often talk about in relation to glucose and metabolic dysfunction from Alzheimer’s dementia to heart disease, to diabetes. So, what I would love for you to talk through a little bit is maybe some of the mechanisms of how uric acid is actually causing metabolic problems and is no longer just this biomarker that we think might be elevated, but actually is causing some of these issues.

Dr. David Perlmutter (00:08:50):

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 the 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 consequences that really … the downstream effects, the cardiovascular disease, the senile dementia of the Alzheimer’s type, the strokes, et cetera, various forms of cancer, colon, breast, and pancreatic cancer that are related to metabolic dysfunction in many cases.

Dr. David Perlmutter (00:09:36):

So it’s not just that we happen to be metabolically dysfunctional, but the biggies, the number one causes of death on planet earth, not COVID are the metabolic downstream issues, the chronic degenerative conditions that are beyond epidemic. This is affecting, as I mentioned, 88% of Americans right now, and we’ll get to this notion of evolutionary environmental mismatch at some point later on when we talk about uric acid.

Dr. David Perlmutter (00:10:05):

So, it’s exceedingly valuable to look at it through that perspective. And again, makes us again, think about how anything we can do to right that wrong, to bring people back into metabolic balance, I think is going to be very important. The other thing is that this provides now a mechanistic understanding as we break it down, as we will now do as to some of our unanswered questions for an awful long time, like the relationship, and we’ll talk about salt later on, the relationship between salt and obesity, between salt and diabetes, between salt and hypertension. We knew there were relationships, of course we did.

Dr. David Perlmutter (00:10:45):

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 and that is that 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 kind of were given the notion that uric acid deals with gout and here’s the medicine, much as we were instructed about insulin.

Dr. David Perlmutter (00:11:15):

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.

Dr. David Perlmutter (00:11:39):

Why do men have estrogen, a female hormone? Why is there cholecystic to kind of receptors in the brain for crying out now, 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. So 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.

Dr. David Perlmutter (00:12:29):

So, I think 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. It’s in the context of our genome and our ancestors when we didn’t know when our next meal, where it was coming from, or if there would even be a next meal or we would find water to drink.

Dr. David Perlmutter (00:12:57):

So uric acid is elevated in humans to the extent that it’s 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, et cetera, figs were less abundant. And it was a pressure, a survival pressure on our primate ancestors and a small group of them had a superpower.

Dr. David Perlmutter (00:13:45):

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? And 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.

Dr. David Perlmutter (00:14:14):

So 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 mutation. So they survived and passed it on to Dr. Casey Means and Dr. David Perlmutter and to everybody walking the planet today. So 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.

Dr. David Perlmutter (00:15:00):

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?

Dr. David Perlmutter (00:15:25):

To avoid two things, starvation and predation so that we would not starve. 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 kind of hungry. So 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.

Dr. David Perlmutter (00:15:52):

Now, genetically, we haven’t changed. We haven’t had any significant metabolic changes in our genes for at least 70000 years, but what did change were the environmental signals that we send to our bodies and primarily the abundance of sugar in the diet, primarily fructose. And we’ll talk about the relationship to glucose a little bit later on, but when we started just pounding our bodies with ever increasing amounts of this signal, and 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.

Dr. David Perlmutter (00:16:35):

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 is 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, isn’t just overweight, but obese.

Dr. David Perlmutter (00:17:10):

And in the distant future, in the year 2030, that’s way in the future, right, eight years from now that number’s going to be 50% of Americans, adults will be considered obese, basically, because they’re preparing for food scarcity and they’re not likely going to happen. So we call this then an evolutionary environmental mismatch.

Dr. David Perlmutter (00:17:36):

We can’t really fix the evolutionary part, the gene part, and nor really should we, but the relationship with the environment, we can definitely work on because we can change the signals to our physiology and 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 written about doing the best we can to bring uric acid under control.

Dr. David Perlmutter (00:18:05):

Certainly for fructose is a major player these days. The rise in uric acid from 1920, at 3.5 to the average today at six milligrams per deciliter, perfectly parallels our consumption of sugar and more recently the higher levels of fructose because of the development of the technology to extract fructose and create high fructose corn syrup, which is very sweet and very inexpensive, and as such is seen in about 60% of packaged grocery store foods.

Dr. David Perlmutter (00:18:41):

So to reduce it again, this is a mechanism in our bodies that allowed us to survive, but in a different context. And I have to say, I’ve been thinking about this environmental evolutionary mismatch for a long time. I wrote about it 50 years ago, half a century ago, gosh, 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?

Dr. David Perlmutter (00:19:14):

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. And so 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?

Dr. Casey Means (00:19:35):

That’s such an amazing overview. And I was struck in the book by one of the statistics that you mentioned, which I think was that back about 100 years ago, we were eating about 15 grams of fructose per day. Maybe what you might find in a small piece of fruit. And that has quadrupled since then for the average person. And again, coinciding with things that happened in the 1970s around the production of high fructose corn syrup, which was a cheaper version of sugar than sucrose.

Dr. Casey Means (00:20:03):

And so table sugar was replaced with high fructose corn syrup. And then we see this monumental rise in the amount of fructose. And so I think that was such an interesting concept that, 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.

Dr. Casey Means (00:20:20):

You explicitly mentioned in the book that we’re not talking about whole fruit in terms of the big problem here, which is more the refined processed fructose and that, but 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 cause damage to the cells. And maybe, and like you talk about that in a certain context, if it’s autumn and we’re a bear and that signal may actually be useful to us because it’s going to tell our body to store fat, but now it’s 24 hours a day, seven days a week, 365 days a year.

Dr. Casey Means (00:21:01):

So it’s interesting to think of obesity as literally 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 actually using that stored fat. So could you talk a little bit about that process of what’s happening in the cell of how uric acid is actually generating fat? What it’s doing in the mitochondria and I’d love for you to just touch on that and then also maybe touch on what are the other things other than fructose that can stimulate uric acid production and feed into that pathway.

Dr. David Perlmutter (00:21:41):

All right. Let me take the second question first because I think, people are probably on the edge of their seats wanting to know-

Dr. Casey Means (00:21:48):

Like, where is this come from?

Dr. David Perlmutter (00:21:50):

So step one is to certainly have your uric acid level measured, go to your doctor or have that doctor send you to the laboratory or call the doctor, say by the way, did you do that with last year’s blood work? Maybe it was already done, but you can check your uric acid level at home much as we used to do before we had CGM, you can check it at home with a little finger stick. And here’s my most recent level is, I don’t know if you can see that, 4.7.

Dr. Casey Means (00:22:17):

Nice.

Dr. David Perlmutter (00:22:17):

There you go. We want to keep our uric acid levels below 5.5. And the reason that’s important is because, and why I mention it because when you have a uric acid level done at the doctor’s office, where they send you to a laboratory, the report you’re going to get, or the telephone call you’re going to get is, hey, don’t worry, your uric acid is in the normal range and anybody watching this podcast, they don’t want to hear that. Why, because they want to be in optimal health.

Dr. David Perlmutter (00:22:47):

They want their labs in the optimal range, number one. In the normal range, according to the most laboratories is seven milligrams per deciliter 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?

Dr. David Perlmutter (00:23:10):

So it’s above seven milligrams per deciliter 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 for that matter. But the cardio metabolic issues begin at 5.5. That’s the level that we want to keep our uric acid at or below.

Dr. David Perlmutter (00:23:33):

And we talk about it 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, et cetera. If we have time, we’ll get into that. But a uric acid level of seven is dangerous. One study in [inaudible 00:23:51] of rheumatism 2018 looked at 90000 adults, 42000 men, 48000 women, followed them over an eight year period. They found that those individuals who had a uric acid level of seven or greater had a 16% increased risk of what we call all cause mortality, meaning they died from anything under the sun.

Dr. David Perlmutter (00:24:14):

They had a 38% increased risk of cardiovascular mortality. That’s this gout thing, uric acid, a 38% increased risk of cardiovascular mortality. A 32% increased risk of dying from stroke. And interestingly for every point elevation above seven and we see it every day, there’s an additional additive, eight to 13% increased risk of what’s called all cause mortality, meaning dying from anything whatsoever.

Dr. David Perlmutter (00:24:47):

So these numbers become very real. A similar study followed individuals for 12 years and showed that those individuals with the highest or above seven, they 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. I’m hoping we can circle back to that.

Dr. David Perlmutter (00:25:25):

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.

Dr. David Perlmutter (00:25:53):

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 periods, 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.

Dr. David Perlmutter (00:26:36):

The biggest issue by far is the fructose. Who knew? And it’s interesting because fructose isn’t really talked about in the major clinics in terms of their websites, about the diets to lower uric acid. They talk about alcohol, we’ll get there in a minute and they talk about purines, but what is this reluctance to talk about sugar and you and I, when we wrote, in February of ’21 wrote that op-ed in Medpage Today about sugar in the American diet and the USDA recommendations, et cetera, 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.

Dr. David Perlmutter (00:27:25):

Fructose was sort of maybe 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. Caramba, you have to just wonder, I mean, the relationship between fructose consumption and metabolic issues was first described in 1970 in the Lancet.

Dr. David Perlmutter (00:27:56):

But for reasons that I would say are unclear, but you and I know very well are clear, that information just wasn’t forthcoming for we medical practitioners. The third source of uric acid is the metabolism of alcohol. The metabolism of fructose and alcohol are really almost identical. But interestingly, what we know is that in large studies that use, like the NHANES study using food frequency questionnaires, we see that it matters what kind of alcohol people consume.

Dr. David Perlmutter (00:28:30):

And 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 are show an association with a fairly prominent elevation of their uric acid.

Dr. David Perlmutter (00:28:52):

But the worst player by far is beer. Why? Because it contains alcohol, but it’s 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?

Dr. David Perlmutter (00:29:17):

I will say that Japanese researchers and public health as well 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 that in 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.

Dr. David Perlmutter (00:29:46):

So, those are the exclusively where a uric acid comes from fructose, alcohol and purines. Now, let me digress because it’s important. And that is that the question of fruit consumption always comes up, if fruit, sugar is where 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.

Dr. David Perlmutter (00:30:17):

And so we can live with that. Five grams of fructose when you consume it, 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 that is that fruit has fiber, which slows it 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 work like allopurinol and febuxostat, they target that very same enzyme like quercetin and luteolin.

Dr. David Perlmutter (00:30:59):

And finally, fruit contains vitamin C and vitamin C aids in uric acid excretion. Can you go overboard? Yes. An apple a day keeps the doctor away. Five apples a day, the doctor you will pay. But I do think 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. So the same mechanisms are involved. So we get away with eating a lot of those fruits, not a lot of them, but eating those fruits and vegetables. And I think you could eat the organ meat if you choose in moderation and have the anchovies and sardines and scallops, though they have high levels of purines.

Dr. David Perlmutter (00:31:44):

The big issue is the fructose like in a glass of apple juice or orange juice. And I love looking at the carton in the health food store. It says all natural orange juice. It has what, 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 and you are signaling it through the production of uric acid, that lights up fat production, which is your second question. How does it do so?

Dr. David Perlmutter (00:32:28):

The main thing it does is acting in the mitochondria does a couple of things through its inhibition of an enzyme. If your listeners want to know this, if it’s going to be on the quiz, it’s called cis-aconitase.

Dr. David Perlmutter (00:32:43):

So cis-aconitase is the enzyme that’s inhibited, one of the enzymes, NADP, oxidase is another, but nonetheless, they 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. And the third thing is there’s a general down regulation in mitochondrial function as a way of conserving energy.

Dr. David Perlmutter (00:33:14):

So, this starts to ring a bell for many people that there’s a pathway, 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. And 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.

Dr. David Perlmutter (00:33:49):

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, gluco neogenesis from the liver because we’re doing just fine. So we want to do whatever we can to keep AMP kinase lit up doing its job. And that means what, how do you stimulate your AMP kinase?

Dr. David Perlmutter (00:34:16):

Exercise is one of the most powerful things you can do for your health. How so? It stimulates AMP kinase. [inaudible 00:34:23], now that’s the second time I’ve mentioned it first because it inhibits the enzyme that makes uric acid called xanthine oxidase. 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.

Dr. David Perlmutter (00:34:52):

But I’m simply describing this mechanism. Now the evil twin of AMP kinase is AMP deaminase. Almost the same, but does exactly the opposite. It’s the evil twin. It says winter’s coming. It says ratchet down the metabolism, power the brain with glucose, make more fat and store more fat. And it’s this AMP deaminase that’s really active. You alluded to it earlier when a bear is getting ready to hibernate and needs to make as much fat as he or she possibly can. And keep that fat locked up.

Dr. David Perlmutter (00:35:30):

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, I might add as a survival mechanism against dehydration to take us to our next topic, and it’s a losing battle.

Dr. David Perlmutter (00:36:26):

So for people who are not making the grade, they’re monitoring their blood sugars, they’re trying to be low carb as possible, doing their best to exercise, something’s missing. I don’t know what it is. There’s got to be a missing a link here. I don’t know what it is. Got to check your uric acid because that could be the monkey wrench in the whole system that’s keeping you in metabolic mayhem.

Dr. Casey Means (00:36:52):

Amazing. Such an incredible description of all that, Dr. Perlmutter and 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. And I think one of the things that has kind of been drilled into everyone’s mind is that repeated glucose spikes cause repeated insulin spikes.

Dr. Casey Means (00:37:18):

And then the cell becomes numb to insulin and we develop insulin resistance. And then of course we have to produce more insulin to drive glucose into the cell. And that’s kind of one prototypical pathway that we’ve heard a lot for 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 a whole nother way of looking at how insulin resistance develops in concert with that, which is, that basically what you just talked about, we’re storing fat, including in the liver.

Dr. Casey Means (00:37:46):

And then that fatty liver essentially creates an issue where the pancreas is needing to produce more insulin and it’s becoming insulin resistant. The fat in the liver actually is blocking that signal. And that’s a problem, but there’s other mechanisms involved too, inflammation from uric acid generating insulin resistance and there’s a lot going on. So I think the question I have for you is one, can you describe a little bit the relationship between uric acid and the development of insulin resistance?

Dr. Casey Means (00:38:14):

Maybe speak to, given that most people are more familiar with that former framework that I talked about how those two are related and I think just paint this expanded picture of insulin resistance that we’re now understanding in the context of uric acid, that’s somewhat separate, but interrelated than just the glucose stimulation.

Dr. David Perlmutter (00:38:37):

Sure. I will say Dr. Means, for those weenies of us who really enjoy this stuff, it’s an incredible story because, frankly, our job is to connect dots, is to really try to figure it out. And you had just asked a question, well, we know that the cell gets kind of tired of answering the door when insulin’s knocking and that’s sort of what happens. And then the insulin doesn’t do its job.

Dr. David Perlmutter (00:39:03):

The pancreas has to make more and more insulin to get through and get the glucose into the cell. And it’s an interesting mechanism. It works for understanding, but now we have another … an issue that when we look at becoming insulin resistant as a survival mechanism, and it is how does that work vis-a-vis the whole uric acid fructose relationship and fructose is involved?

Dr. David Perlmutter (00:39:31):

Let me first focus on a mechanism. Now there are several, but let’s first focus on a really kind of exciting mechanism. And that is uric acid directly inhibits nitric oxide functionality, nitric oxide generation within the blood supply within the actual arteries themselves and the vasculature. Now what does nitric oxide do? And why would its inhibition be problematic for us?

Dr. David Perlmutter (00:39:58):

Nitric oxide, we know is important to allow 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. And I quoted to you a statistic earlier that showed about a 32 to 33% increased risk of stroke, death from stroke in individuals with high uric acid. Now it starts to make sense, and Alzheimer’s, which is certainly a vascular component to that.

Dr. David Perlmutter (00:40:32):

So we understand that and that’s certainly very important. And yet we tend to overlook another important role of nitric oxide and that’s for insulin functionality. So for insulin to get out of the artery and then to allow to facilitate how insulin, the entry of glucose into the cell requires the functionality of nitric oxide.

Dr. David Perlmutter (00:40:59):

It becomes 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. And let me break that down just a little bit. So, there are several drugs that people have heard of that are involved in increasing nitric oxide and as such 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.

Dr. David Perlmutter (00:41:41):

So these drugs were developed to enhance nitric oxide functionality to allow erectile function. And that’s an important role then as we see of nitric oxide. So an interesting study was published earlier this year, looking at several million individuals and found that those men, primarily, the women do take some of these drugs as well, those men who took these drugs Viagra had a 70% reduced risk of developing Alzheimer’s disease.

Dr. David Perlmutter (00:42:17):

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.

Dr. David Perlmutter (00:42:43):

My point is that we now, this really new and for those of us who enjoy this stuff exciting and valuable tool in our understanding, and that is this relationship between elevation of uric acid and its compromise of the functionality of nitric oxide, which has two downstream, very significant effects.

Dr. David Perlmutter (00:43:04):

Number one, a vascular effect, number two, an insulin resistance effect as well. So it opens up the door for us to target uric acid as a way of improving blood supply. It’s noted that people, 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.

Dr. David Perlmutter (00:43:31):

Men with erectile dysfunction have a dramatically increased risk of cardiovascular death for that matter. So this is really starting to tie up some loose ends. 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.

Dr. David Perlmutter (00:44:02):

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. And that’s where we’ll go next. How does this whole pathway relate to our survival during times of water scarcity?

Dr. David Perlmutter (00:44:29):

I mean, you can understand the food scarcity, make more body fat as a reservoir of calories, you’ll survive. But there’s a powerful mechanism that allows this pathway to allow our survival during times of water scarcity. How incredible? And it gets to another pathway that will be on the quiz. It’s called the polyol pathway and the polyol pathway, write it down, it’s going to be question 34, the polyol pathway is how our bodies endogenously create fructose.

Dr. David Perlmutter (00:45:01):

Can you imagine, you don’t need 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?

Dr. David Perlmutter (00:45:25):

And it’s various types of stresses. One primarily is when the body thinks that it’s dehydrated and when you can’t find water, you’re a hunter gather, you can’t find any water, what is … Somebody goes to the hospital with dehydration, you look at their blood work, their sodium is elevated, right? You have a high sodium. And what does that high sodium do?

Dr. David Perlmutter (00:45:49):

Well, vasopressin is activated, et cetera, but it stimulates an enzyme called aldose reductase. And 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. Well, why in the world would you want to make fat? So we turn to our friend, the camel. The camel has this huge hump on his back or her back, walks across the desert. Doesn’t get dehydrated, doesn’t drink any water and yet manages to survive.

Dr. David Perlmutter (00:46:26):

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. So 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 or whatever you call it, thousands of miles stores up to 40% of its body weight as fat, a fat hummingbird. Who knew?

Dr. David Perlmutter (00:47:05):

But if you want hummingbirds in your backyard, you put out sugar water, right? And 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 all this reductase. You convert glucose into fructose, alarm signals, uric acid, make fat, metabolic water. That’s kind of interesting.

Dr. David Perlmutter (00:47:30):

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 or the final four, whatever it is. And sit there, munching chips, not only the carbohydrates that are … the process carbs that you’re going to raise your blood sugar, which also activate this pathway, but it’s the salt. Your serum sodium goes up and the next thing you know, you’re getting fat and why are you getting fat?

Dr. David Perlmutter (00:47:57):

Because you’ve stimulated the survival pathway. So again, I alluded to that 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 raised blood pressure. And now we know why. Uric acid is sending this signal and does a couple of things that are so incredibly important here.

Dr. David Perlmutter (00:48:24):

Exciting is the fact that when fructose, the first step in the metabolism of fructose is characterized … utilizes an enzyme called fructokinase. So fructokinase uses energy, ATP, unlike glucose metabolism, uses ATP and creates ultimately a DP and then AMP adenosine, which becomes uric acid monophosphate. It’s that adenine that has to be dealt with by AMP adenosine monophosphate kinase, or ADP, AMP deaminase.

Dr. David Perlmutter (00:49:03):

That’s where the adenosine has to go, either recycled back up to make more ATP or it’s broken down further or converted into pneumonia. But that said, uric acid stimulates fructokinase. It stimulates the metabolism of the very thing that created it in the first place. So 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 inhibit fructose metabolism.

Dr. David Perlmutter (00:49:39):

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. It’s so cool to keep us alive that, that whole pathway is lit up. And it turns out, where the story gets really interesting that this fructokinase enzyme is really very important because in the laboratory animal … We talk about what happens when we eat a lot of fructose, you develop something called non-alcoholic fatty liver disease, and by its name it’s developing, as you talked about earlier, fat in the liver, and then in the body unrelated to your consumption of alcohol, right?

Dr. David Perlmutter (00:50:22):

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 is not alcohol related, but 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.

Dr. David Perlmutter (00:50:50):

It’s the same thing. And 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. 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.

Dr. David Perlmutter (00:51:23):

So the notion of inhibition of fructokinase as a treatment for non-alcoholic fatty liver disease and even alcoholic liver disease, fatty 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 (00:51:55):

Oh my gosh. I could listen to talk all day, Dr. Perlmutter. That was amazing. I’ve been literally on the edge of my seat, because it’s such awe for the body. I mean, here we have this molecule and like you described back in this conversation about blood pressure, it has dual effects. It has so many effects, but one is to literally change nitric oxide functionality, constrict blood vessels. And then on the flip side 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 just, it’s really mind blowing that it’s doing all of that.

Dr. David Perlmutter (00:52:30):

It’s so interconnected. As the insulin resistant person develops higher and higher insulin levels as is the case, 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.

Dr. Casey Means (00:53:00):

So this was going to be my next question, actually that I do want to set up because this is something that I think is going to be mind blowing to everyone listening and everyone who reads your book is that again, we’ve really focused on this paradigm of glucose causes insulin resistance because glucose stimulates insulin repeatedly, which then causes salt to become numb to it. And then we get insulin resistant, but this is bringing in a whole nother lens, which is actually that, like you said, there’s multiple things that can activate the polyol pathway, but one of them is glucose.

Dr. Casey Means (00:53:32):

And it actually could be the glucose to fructose conversion and then the subsequent uric acid and lipogenesis in the liver, that’s actually causing insulin resistance and then feeding into more glucose instability. So what I’d love for you to do is maybe talk about that a little bit and maybe given an assessment, because this is a question I actually still have of what’s the weight of these relatively in the body in terms of what glucose is doing on its own, and then what glucose is doing by nature of it being converted to fructose at high levels?

Dr. Casey Means (00:54:08):

Because we also know glucose has lots of its own effects on the body as well like inflammation, oxidative stress, and things like that, which can feed into these processes.

Dr. David Perlmutter (00:54:16):

Glycation.

Dr. Casey Means (00:54:18):

Glycation. How do you see these two different mechanisms relatively contributing to the problem of insulin resistance?

Dr. David Perlmutter (00:54:28):

I think importantly, I mean, one of the factors involved here that really resonates is the fact that it’s a feed forward, no pun intended to 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.

Dr. David Perlmutter (00:54:53):

I think that 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 as the case may be, this is a new sidelight. I think it’s very important. I think the glucose to fructose conversion and then the activation, these pathways, again, that self stimulate I think is really very important. And we know that based upon interventional trials that can inhibit this pathway at multiple places like inhibiting fructokinase, like inhibiting uric acid production by giving people allopurinol in research setting and seeing improvement in their metabolic parameters quickly.

Dr. David Perlmutter (00:55:38):

So these studies involve humans, first animals, then humans, where they’d give them 180, 200 grams of fructose in a day, within a couple weeks, they would have many metabolic issues, which would not happen when these individuals received that level of fructose, but had its metabolism as it relates to uric acid production blocked by simply giving them a gout pill called allopurinol.

Dr. David Perlmutter (00:56:04):

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. And the point is you break the cycle and there are many opportunities to break the cycle along the way.

Dr. David Perlmutter (00:56:43):

As I mentioned earlier, 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, but you can inhibit your xanthine oxidase right now and you can do it by taking quercetin 500 milligrams a day or taking luteolin 100 milligrams a day, aid yourself in the excretion of uric acid by taking 500 milligrams a day of vitamin C.

Dr. David Perlmutter (00:57:11):

And certainly on the front end, limiting your consumption of the fructose that we talked about and limiting the production of fructose by the activation of this polyol pathway. The relative weights I think you were getting at, I think has yet to be determined, because we’re just beginning to see the interventional trials. And 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.

Dr. David Perlmutter (00:57:52):

If we can see what is 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-O-man, that’s going to be a really exciting time because then we’re cutting down the fructose, which is very difficult to measure, production. And 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, HOMA testing, as well as lipogenesis.

Dr. David Perlmutter (00:58:30):

So that’s where we are right now. And over the next few years, this is going to absolutely explode. Even since the book came out in February 15th of 2022, there’s been such an increased interest amongst people like yourself and people who are deeply involved in understanding human metabolism. So I think it’s exciting. It’s really exciting. And 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.

Dr. David Perlmutter (00:59:14):

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 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 in the podcast. So many people talk about it, but what’s the big thumb on your head keeping you from getting that AMP kinase lit up, that is elevation of the uric acid.

Dr. Casey Means (01:00:00):

Amazing. I think, what you just said about the research, I really do feel like it’s probably going to explode after the publication of your book and Rick Johnson’s book that also talks about uric acid because there’s going to be this amazing … This is what I think is so amazing about books like the books that you’ve written is that they educate, not only the lay population, but physicians as well and researchers to spark this whole new interest.

Dr. Casey Means (01:00:25):

And 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. And then how that’s going to feed into the next 10, 15 years of what PhD students are interested in researching about. It’s an incredible cycle of medical communication and synthesis that I just think that you do so amazingly.

Dr. David Perlmutter (01:00:50):

It’s a hashtag OMG. There’s no question.

Dr. Casey Means (01:00:53):

Yes.

Dr. David Perlmutter (01:00:55):

For anyone who’s puzzled over these things, I know it happens, but actually how and why, well, how does it happen? And why? Why is answered in the context of our ancestors? Why means, why do we have this pathway that’s so bad? Why would it have persisted? As an example, we know that it amplifies inflammation. That’s a good thing when you are injured and have the possibility of an infection, for example.

Dr. David Perlmutter (01:01:26):

Why do we still have the APOE four allele in our population, if it’s so dramatically associated with Alzheimer’s disease, why would it have persisted? Great question. When you look at underdeveloped cultures that live in equatorial areas, those who carry the APOE four allele in the presence of their vast parasitic infections have a much lower risk than non-carriers in terms of Alzheimer’s. That’s our hunter gatherer ancestry. And yet we confront that with our very hygienic environment today, we get this hygiene hypothesis that says, our incredible hygiene might be having some significant counter effects in terms of keeping us healthy.

Dr. Casey Means (01:02:13):

Definitely. I think one of the reasons thinking about the evolutionary aspect of this is so interesting because it makes us realize that really what we’re dealing with here, all the issues we’re dealing with are the result of chemical pathways being hijacked by our modern lifestyle. So if we can understand that and then just work to take the accelerator off a lot of these pathways, it makes more sense why we might have to make some of these hard lifestyle decisions.

Dr. Casey Means (01:02:36):

I think when you don’t necessarily understand these mechanisms or these pathways that you’ve so beautifully described, it can feel a little bit more like, why should I make this really difficult lifestyle choice? But in the context of this, it’s clear, it’s because we want to give different information to our bodies to get off this evolutionary environmental mismatch. Quick question for you, because this is something I was wondering 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 (01:03:11):

My sense is that it’s mild elevation. I mean, 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, all the important parameters, would likely have been pretty low in our paleolithic ancestors based upon their lifestyle activity and certainly based upon their diets.

Dr. David Perlmutter (01:03:38):

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 you see, that we see are absolutely activating that pathway and creating endogenous fructose and therefore explains why we’re seeing such incredible numbers as it relates to the number of people with elevated uric acid, which it’s not necessarily the case in other countries.

Dr. David Perlmutter (01:04:11):

So, why so? Yeah, the purines an 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, sugar be bad. Humans don’t need to eat … The amount of sugar we need to eat is zero grams a day.

Dr. David Perlmutter (01:04:34):

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 but to get you to buy them is absurd. Then when you see this happening, then you look around at what people look like these days, we talked to statistics earlier, everything fits in. You totally get it. And our mission is then to interrupt this, is to identify it, interrupt the pathway and give people the tools to reign in their metabolic health.

Dr. David Perlmutter (01:05:15):

And 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. What will happen then is that 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.

Dr. David Perlmutter (01:05:42):

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 it. 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.

Dr. Casey Means (01:06:10):

Definitely. And then also people can just bring your book to their doctor and share that with them.

Dr. David Perlmutter (01:06:14):

Oh gosh. I can tell you stories about Grain Brain. My gosh, when it got thrown in the garbage by the doctors, because it was based on 500 peer reviewed studies, but back then that was 2013. I was saying that, maybe we shouldn’t be eating oddly enough as much sugar as we are, processed carbohydrates because there’s this relationship between fasting blood sugar as published in the New England Journal of Medicine and risk for developing Alzheimer’s disease.

Dr. David Perlmutter (01:06:47):

Not to mention gluten in some people leading to neurological issues as was described in the early 2000 teens, by Dr. Marius Hajovosulu at Oxford, where actually I’ll be in a couple of weeks, talking about various neurological issues that he had found great success in improving with a gluten free diet in non celiac patients. Who knew? I was on the CBS This Morning show a couple years back.

Dr. David Perlmutter (01:07:18):

And they said, we asked so and so doctor about your book. And he said it was nonsense. And he did say it was nonsense at the time it came out. Now he’s using it at Yale, in the Alzheimer’s prevention program, using Grain Brain as one of the fundamental texts. So, that’s great people admit that, maybe there is some reality out there and who knows what you and I talk about five years from now, it may be completely different, but if we can get so granular as to be able to review these mechanisms in the textbook of biochemistry, it’s right there for you.

Dr. David Perlmutter (01:08:01):

And who would think at my age, I’m buying the latest version of Lehninger textbook of bio … No, Stryer textbook of biochemistry, which has been updated two years ago. It’s great to learn this stuff. That’s the book I have by my bedside right now. How boring am I? But anyway, because you want to understand this stuff because it’s got direct clinical application.

Dr. Casey Means (01:08:26):

It’s amazing. And I think the whole story of how you came to this, which you mentioned in the book is you were listening to a Peter Attia episode, and then you just got, it started to connect some dots for you. And then you went down the rabbit hole. And I think it’s just such a beautiful example of how we can never stop being learners and then this journey, it’s been fun for you. Now, it’s fun for me. Now I hope it’s fun for the people listening. And it’s this feed forward, to go back to feet forward of just this joy in learning and understanding that I think is so exciting and cool.

Dr. David Perlmutter (01:08:56):

And it’s okay to be wrong. People tend to be critical about that, that you said one thing and now you’re saying something else because, I think back 25 years ago, I was telling my patients best bet, low fat diet, right? Because that’s what the literature that was influenced, we now know by whom, but was telling us that’s what we should be recommending.

Dr. David Perlmutter (01:09:19):

And that’s what I did. I mean, there were all the studies, the various heart studies, et cetera, the lower the fat, the better. The Dean Ornish program. And so I changed that messaging for obvious reasons. Now, began saying to people that it’s not just low fat, but let’s welcome fat back to the table, but be careful about what types of fat we are consuming. The real villain here are the refined carbohydrates and the sugars. And it took an awful long time for that message to gain traction though it still hasn’t fully gained traction, which is why, again, we wrote the open letter to president Biden. You and I did that.

Dr. Casey Means (01:09:57):

And the Dean Ornish diet, that’s an interesting one, because it does … That one to me seems the best possible version of that diet in the sense that it’s low fat, but it’s also whole foods based. And so low-ish sugar, but I think the general low fat message that we were getting in the ’90s was literally fill those calories that you’re replacing the fat with carbohydrates of any kind, it’s better than the fat. And that of course was the most disastrous thing that could have happened to the American population.

Dr. David Perlmutter (01:10:31):

We’ve been eating fat for a couple hundred thousand years as a wonderful resource, a wonderful food. But I think the bastardization of dietary fats now is very real and very threatening.

Dr. Casey Means (01:10:45):

Two questions. I just want to wrap up with you the quick ones. So one is back to salt. I just want to get just sort of a tactical thing here. So I think something you brought up really interestingly about dehydration being one of these mechanisms that can actually make us generate uric acid and even maybe contribute to weight gain. So the body sees dehydration both with low, 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. Just to nail this down for people it sounds like staying hydrated and avoiding excess salt.

Dr. David Perlmutter (01:11:26):

Absolutely. What the research shows is, you can give two groups the same amount of salt, but if you give one group water, to drink water after they do their salt consumption, then this doesn’t happen. They don’t activate the polyol pathway as readily. And don’t go down that rabbit hole. And 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.

Dr. David Perlmutter (01:12:02):

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, there are many, but the simple reason of trying to dilute down the sodium that is so pervasive in our foods today.

Dr. Casey Means (01:12:19):

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 that. That to me, learning that feels like one of the most motivating things I’ve ever heard about drinking water. And so I love that. So, that was I just wanted to mention that. And also just that 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 insulin resistance, which was just mind blowing.

Dr. David Perlmutter (01:12:53):

And a very low salt diet actually leads to mitochondrial biogenesis, the creation of mitochondria. Who’s not going to want that?

Dr. Casey Means (01:13:03):

I did not know that. That’s fascinating. But too low is also not good of course, because you can get into a pathologic-

Dr. David Perlmutter (01:13:09):

There are various products out there. One of them that I use on occasion is called Element and it does contain a little bit of salt in the context of magnesium and potassium with water 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 (01:13:51):

It also feels like we don’t want to pair our salt and our sugar because if you’re going to be activating potentially this pathway as well, you don’t want to have a ton of glucose and fructose on board to sort of compound all of that going on.

Dr. David Perlmutter (01:14:02):

And yet what is a bag of chips or pretzels?

Dr. Casey Means (01:14:06):

Carbs and salt.

Dr. David Perlmutter (01:14:07):

It’s sugar, but it’s a refined carbohydrate, may as well be 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 (01:14:21):

The funny thing, I use Element, which I really like, it’s sugar free and mostly they talk about the fact that this is especially useful on a ketogenic diet or a low carb diet. And so, it’s the context and also, the funny thing about it, they’re very concentrated packets. Each one actually only has one gram of sodium and I end up drinking it in three, one liter jars of water over the course of the day. So it actually, I think gets me to drink way more water than I would normally.

Dr. David Perlmutter (01:14:53):

As you should. And now you know why you’re doing that. It’s for all the right reasons.

Dr. Casey Means (01:14:58):

Last question that I’ll wrap up with is about lectin, because I think 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 of 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. So this is actually super relevant, I think to us now, because is that basically what’s happening to the human brain is that we’re stimulating hunger. So can you talk a little bit about the effect on drive for hunger and also what it’s doing to our satiety signals?

Dr. David Perlmutter (01:15:37):

It’s blunting our satiety signals as a survival mechanism. It’s leading to what we call hyperphagia and so that we’ll eat more and we’ll survive. But beyond that, there are some behavioral ideas that are changed as well, that in the presence of this elevation of the endogenous fructose, that 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.

Dr. David Perlmutter (01:16:12):

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 an explanation as to why there’s this relationship between high levels of uric acid and risk for Alzheimer’s disease. So again, as a survival mechanism, in the context of today, there’s a certain powerful survival advantage to being not fixated on certain things and just taking risk and 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 (01:16:55):

It’s so fascinating. It’s so fascinating to think how we’re literally being controlled like little puppets by some of these biologic, these biomarkers. And for those of us who have dealt with cravings or just feeling insatiable hunger, things like that, I think this is also so empowering because you can think I can actually change my behavior by potentially taking the gas off some of these pathways.

Dr. David Perlmutter (01:17:18):

Can you imagine, you are influencing how you see the world based upon your dietary choices. So we know that we have two very important decision making areas in the brain, if you will, and 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 a 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.

Dr. David Perlmutter (01:17:58):

So 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.

Dr. David Perlmutter (01:18:30):

So 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 to choose to spend time not exercising but watching TV. And it creates really a vicious cycle. So we need to bring the adult back in the room. So we need to bring that uric acid level down, reduce inflammation, and 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.

Dr. David Perlmutter (01:19:09):

So, 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? 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 and whatever. So we don’t do that. So that’s because we keep the adults in the room as much as possible.