Transcription
Obesity is really a survival response. The story is not that well known about how there is a switch that drives obesity. This switch doesn't just increase fat; it makes you insulin resistant.
Meet Dr. Rick Johnson, board certified in Internal Medicine, infectious diseases, and kidney disease, professor at the University of Colorado, and author of "Nature Wants Us to Be Fat." It's also been linked with the MEA. There are different kinds of dementia, but the one that I'm most concerned about is Alzheimer's disease. The brain shrinks and atrophies; there's formation of things called amyloid plaques. But it seems like it's already too late when those things form.
There are three big things that happen: the brain becomes insulin resistant, you get mitochondrial problems, and you get that low ATP. You get insulin resistance. I mean, it's the same formula, it's just in the brain. There is a biologic switch that allows animals to suddenly gain weight. The main thing that turns on this switch is [Music].
I want to start with a couple of questions that really give you the reins. First of all, why did you, yeah, it's marked up, why did you write this book?
Well, for several reasons. First is because the story is not that well known about how there is a switch that drives obesity, how it was important in nature, and how we've kind of inadvertently activated this switch. So, you know, I felt like there was a need to communicate to the community about the work that we've been doing in the scientific field. We've been publishing for doctors and scientists, but it seemed like it was important to carry this message to the people who care about this and who are living through the problems and trying to fight obesity. So that was number one.
Number two, it was sort of a desire to summarize the work that we've done because we've done a lot of work in this field that not many people knew about. So there was also a self-serving aspect of trying to let people know a little bit about the work that we've devoted to over the last several decades. But I think the main reason was to communicate to the community about this important switch.
Honestly, you hit the mark. As much as I try to keep up with what is the chatter about obesity and metabolic disease, this book summarized more of the curiosities into the punchlines that I couldn't state before I read your book. After reading the book, I'm going to make you state a few of them out loud because I think they're so important. It really does—it’s not a whimsical thought; it's really backed by all the work you've been doing for years.
Yet you put a pin on it. Tell us the summary about why do people get fat? If you had to tell your grandkids, why do they get fat?
Well, I think I would begin by saying that nature is very wise, and usually things like diseases, and so forth, can be related to something in nature that triggers. When it comes to obesity, the big understanding—the big breakthrough—was to realize that obesity is actually desired by some animals to help them survive. Obesity is really a survival response.
Obviously, if you're an animal, you don't want to just get fat because it will be hard to run and escape from predators. But there are times when one has to have a little bit of extra fat stores. A great example is the animal that has to survive through winter. If there's no food around, you need to actually store fat because it becomes a source of energy. When you break down fat, you produce calories. So fat is really a survival mechanism. Not only does fat break down to provide calories, it also generates water when it's broken down.
For example, when a bear stores fat before it hibernates, it gets really, really fat. Then it sleeps, and during that time, it doesn’t eat or drink, and it can go six months without eating or drinking. What it does is it breaks down its fat to generate the calories it needs. Then it also drops its metabolism, so it doesn’t need that many calories.
As we started studying this, we realized that the trick to figuring out obesity is to figure out how animals purposely become fat. It turns out that normally, if an animal eats a lot one day, it will eat less the next. We regulate our weight. So, we realized that animals that are getting fat are triggering some kind of switch—whether it's a bird that has to migrate 10,000 kilometers or whatever, they have to trigger a switch so that they actually store fat.
Our work led to the discovery that there is a biologic switch that allows animals to suddenly gain weight. This switch is all about your energy levels inside your body. If you can sort of trick the body and drop your energy in your cells, it makes the animal want to eat more, want to store fat, because it’s a warning sign that you don’t have enough energy.
The big trick was to realize that if animals are starving, they have very little energy and you're going to break down anything to create energy and survive. But if you drop energy just a little bit, then what happens is it's like a warning sign—it's like saying the gas tank is low; it means that you need to get gas to fill up the tank again.
What this switch does is tell you that, but because it can't break down the fat you have, the switch turns off your ability to break down the fat into energy and drops the active energy in the cells. The energy goes down in the cells even though this fat is there that could normally provide it. So when you block the fat's ability to break down and the energy starts to fall in your cells, it makes you hungry.
Then, what this switch does is, as the energy comes in from food, it preferentially shuts it to the fat. One of my favorite metaphors from your book was if you were at empty, you'd be doing what you think you're doing when you're dieting, which is, we're emptying fat cells. But you're not empty; you're low. And low means “he who will survive the low” is who stores the best and shuts down metabolism the best.
Thousands of our patients, our family members, are low. We need to get you out of low. You can go to empty—that's kind of a scary place to go because of survival. But there are other places that we could help you undo this obesity problem.
It's not a great place to be, and patients feel terrible. But it answered a lot of questions like, “Oh, now they're in this place of creating that camel’s hump right on their big tummy.” If you are in a place where there's no food and you have very little energy stores left, you're going to break down everything in your body to try to create energy and survive. You are dying.
The animal doesn't want to get into that situation, so it will find a way to activate this switch. The switch actually drops the energy in the cell just a little, which makes you want to eat. At this point, there's still food around; this is a switch that's supposed to be turned on when there's food around.
It just tricks you into thinking that you're kind of low energy, and your ATP levels are low, but your whole body is filled with fat and you continue to add to the fat in preparation. It's a signal to prepare you for a crisis as opposed to being in a crisis, and animals much prefer not to be starving. They would much rather activate a switch to store fat to help them through a dark time before it happens.
A lot of people knew that when you're starving, it's a crisis, right? But being active—when they're still—that's really a kind of a cool aspect of this.
So, when you look at the American obesity problem, it has hit you, your family, my family, your patients, my patients, and your kidney disease. I’ve watched several of your interviews, kind of anticipating this. I've really studied you and your work. I love how many interviewers get to this question and then they run out of time.
So, I'm going to skip ahead and ask you some questions about the work you've done. But also, you've come to some really great conclusions that I have some patients that I'm going to ask you about in a minute.
But I want your opinion on what you think is the cause of most of the dementia that's around our world?
Think: sugar. Let me try to explain how this works. When we were studying this, we realized that there was a switch, and the main thing that turns on the switch is fructose, which is a specific sugar. It's in fruit and honey, which we think of as healthy, right?
But if an animal eats a large amount of it, it will drop the energy in the cell and trigger the switch. That's how it works. Glucose is actually a fuel that tends to raise energy, whereas fructose tends to drop energy. So there are these two sugars, right?
If you inject glucose in the brain, actually, energy acutely goes up in animals. If you inject fructose in the brain, energy acutely falls. That energy is called ATP. If you keep eating glucose, though, if your glucose levels get high, the body converts the glucose to fructose. It turns out that carbs can generate fructose even if there's no fructose in it.
Dirty trick, yeah, it’s a dirty trick. So if you eat pancakes and bread and rice, these high-glycemic carbs, when the glucose goes up in the blood, it gets converted to fructose. It was shown by a group at Yale that it actually converts to fructose in the brain as well as the liver.
So in people, if they raise their blood glucose, your brain starts making fructose. Now, fructose doesn’t cross the blood-brain barrier, right? Well, it does, but here’s the scoop: when you eat a large amount of fructose, the liver sucks up most of it, and so does the intestine. So not so much fructose gets to the brain from the fructose you eat, but fructose signals production of fructose in the brain.
So dietary fructose and dietary sugar—if I eat sugar, my brain starts making fructose. Some of the sugar I actually eat—some of the fructose does get to the brain, but the brain will start making fructose on top of it. One reason is like when you eat sugar, your blood glucose goes up. After you eat a meal, especially with high-glycemic carbs like sugar and bread, the blood glucose goes up.
The guys at Yale showed that when the blood glucose goes up, the brain starts making fructose—boom! So the brain is making fructose from the rise in blood glucose and other mechanisms too.
The bottom line is when fructose is made or you start eating fructose, you activate the switch. The way the switch works is energy consists of two forms: the active energy we call ATP and the stored energy, which is fat. What fructose does is it works on those little mitochondria that make ATP and drops the ATP production.
The ATP goes down, and that’s the signal for the switch. The switch doesn’t just increase fat; it makes you insulin resistant, which is actually a protective mechanism when there’s not a lot of food around because your blood glucose levels stay high for the brain and other sites that need fuel.
Also, it raises fat in other sites like in the liver and tissues, and raises blood pressure to maintain circulation. It increases pressure in the kidneys to force excretion. There are all these effects occurring. But one of the big effects is its effects on the brain, and this is what we didn't realize.
Originally, when we looked at it, we said, “Oh, it's the metabolic syndrome.” This is what fructose is—basically acts as the cause of the metabolic syndrome, because the metabolic syndrome affects a quarter of everybody of all the people you know, and fructose absolutely does.
All the metabolic syndrome—anything with a metabolic syndrome, fructose does it: it drops HDL, raises triglycerides, causes visceral obesity. It is exactly what fructose does. Originally I said, “Hey, metabolic syndrome is really a fat storage syndrome; it's really a survival mechanism.” It’s not necessarily a bad thing if you're an animal. It’s bad for us.
But it's not necessarily bad for an animal who wants to survive in a difficult situation.
Then we realize, "Oh my God, there's a lot of other things that this switch does." There’s this entire effect on the brain. If you give fructose to an animal or to a human, you know what it does? It activates the back of the brain, the occipital lobe, to actually be able to see foods like sugar, like cakes. It heightens the ability to see food.
We don’t need any help with that! But if you're foraging, it stimulates the desire to find food. So it makes you hungry; it makes you thirsty. Fructose makes you both hungry and thirsty. We want to tank up the water too!
It makes you want to look for food—not just be hungry but we call it a foraging response, where you're willing to get up and start looking around for food. You know little kids who eat a lot of sugar? You can kind of see this hyperactive response.
If you give fructose to animals or uric acid and raise it in animals, the animal will start to become hyperactive. The mice will jump a little bit, and they’ll start searching, looking for food. They'll also become impulsive because you have to make decisions quickly.
You can't really take too long because if you're foraging, you’ve got to get that food. If you’re going into an area where you don’t know what’s in there, you want to get in and get out. So you’re going to move fast; you're going to look around quickly; you’re going to make quick assessments.
It can be a very good thing. I mean, it sort of starts off like an adventurer. But if you keep activating this pathway where you're doing it all the time, pretty soon you can’t concentrate because you’re really just trying to find your way.
You’re trying to find that food, and you’re looking around so quickly you don’t ever have time to really think. So your deliberation has to be very quick, and you have to be brave and potentially aggressive if you need to fight for food.
We look at folks in today's world, and those things sound like impulsive; we can make it a negative connotation—aggressive—but that's survival. When you reframe these adjectives and efforts, foraging is survival; aggressive is survival.
Especially when you start to say, “Well, now it's on all the time.” I didn't mean to interrupt your process, but those are the connections!
No, no, I like what you're saying—you're saying exactly right. One of the interesting things: initially, you're kind of like the one who's willing to go out and risk it for everybody else. You're like the scout, the adventurer, the hero.
It starts like that, but then if you keep activating it, pretty soon you've got... Some of the dark side of it is, if you look at what they've discovered in the last few years, ADHD, or Attention Deficit Hyperactivity Disorder, which is so common, really has a lot of linkage with sugar.
We’ve written about how fructose can activate some of these same processes, and people with ADHD often have a history of sugar intake, elevated uric acid, and show changes in the brain similar to what sugar does.
We realize that ADHD is probably linked, at least in some cases, to sugar intake. The same thing has been shown with bipolar disease—kind of manic and then a kind of depressive episodes are very strongly linked with sugar.
People with bipolar disease have high fructose levels in their brain, but it’s also been linked with dementia. This is my big... actually, I think it's one of our bigger discoveries, the importance of this.
There are different kinds of dementia, but the one that I'm most concerned about is Alzheimer's disease. This is a disease where the brain shrinks and atrophies, and there's formation of things called amyloid plaques, which are kind of these little protein plaques that get in between cells.
And there's accumulation of a protein called tau protein. For years, Alzheimer's disease is a horrible disease because dementia, in general, is just a horrible disease. It really can end one’s health span, basically. We want to live long, but we want to live healthy, and dementia is the one thing we don’t want.
When you look at this disease, it's so important to try to find ways to treat it. A lot of people were thinking it was, “If we block the amyloid plaques and if we block that tau protein, maybe we can stop Alzheimer’s.” But it seems like it's already too late when those things form. You can get a little bit of improvement, but, you know, it would be wonderful if we could figure out how to treat this disease early because once the brain has shrunk and atrophied, it's hard to bring it back.
What they discovered is that early on, there are three big findings. The brain becomes insulin resistant—wow—the brain becomes insulin resistant! Some people call it brain diabetes.
Another problem is that the brain's mitochondria get inhibited and don’t make as much ATP. Now think about fructose: when you give fructose to animals, you get mitochondrial problems. You get that low ATP; you get insulin resistance. I mean, it’s the same formula; it’s just in the brain.
So the big discovery was this group found that fructose levels are very high in the brains of Alzheimer's patients—like five to sevenfold. Then they found evidence for the production of fructose in the brain, this activation of this pathway.
Then they found the enzymes involved in suppressing ATP. They’re the fructose pathway. People started giving fructose to animals. They had trouble getting through mazes, they had trouble swimming, and they started showing real cognitive decline. Then they get insulin resistance in their brain, they get that mitochondrial problem, they get that inflammation, they get the fallen ATP, and over time, they even get the tau protein and the amyloid plaques.
This is the whole story. Now we know that it's like a perfect fit. The risk factors for Alzheimer's include obesity, diabetes, sugar intake, and all those things: high-glycemic carbs, elevated blood glucose. These are all the things that drive fructose, and then you see the same findings as what I mentioned: the insulin resistance, the plaques—the whole story is there.
I think we could have a major impact. We could make so much impact by trying to reduce our diets rich in glycemic carbs and also sugar and fructose. I think this is the way to go.
There is some evidence that keto diets are helpful in Alzheimer's, and there’s also now data that GLP-1 agonists can be protective to some extent. There are some papers showing that GLP-1 may work by blocking fructose.
Oh wow! Really? I haven't seen that yet. Yes, there's a beautiful paper I’m happy to send to you. We're actually investigating this ourselves. I think that the GLP-1 agents are working probably in part—maybe mostly—through this pathway.
But we need to do more studies. There’s one really nice study out there that shows this. Anyway, the bottom line is that I think we can do a lot of good things.
Now, the question is, why would a survival pathway cause Alzheimer's? You have to understand how fructose is stimulated in the brain. The cortex is the thinking area, but it’s also involved in self-control.
When you’re foraging, you want to inhibit those areas. You're willing to do things that are a little bit more dangerous because it’s a dangerous thing.
You’re in your gas tank low and you need to do something. It turns out that when you give fructose to a human, you can see that drop in blood flow to the cortex, and you can see a block in blood flow to the areas involved in recent memory.
You don’t really want to remember that tiger you ran into or that you saw in the distance if you’re going to have to go back to that area, right?
So it turns out that the way fructose works is it inhibits blood flow and glucose uptake, which is fuel, to those areas of the brain that are involved in self-control and recent memory and so forth. This causes insulin resistance—this does it—by causing insulin resistance to those areas.
When it's done repeatedly, the little neurons become starved. They don’t have enough ATP, they can't get the fuel they need, so they start going through changes. Their mitochondria start getting disregulated; they get inflammation.
There’s a fantastic paper that just got published, in which they were looking at diabetes. In diabetes, blood glucose levels are high, and over time it can lead to fructose generation in the brain and cognitive problems.
Diabetes is a risk factor for Alzheimer's, so if you do have diabetes, try to keep your blood sugars under the best control you can, because that can help you.
In this study, which was done in animals, they showed that over time, these animals started having trouble with their cognition, and they were making fructose in their brain, and they proved it.
They even found what cell type was doing it—called monocyte, which is like the white blood cells in the brain. When they inhibited fructose metabolism in those cells through a specific targeting, they were able to rescue the cognitive defect. So I think the whole story is there.
Actually, there was just a very comprehensive paper published in The Lancet just a few days ago that talked about risk factors for Alzheimer's, but they didn't really focus on sugar.
I've written a letter with David Perlmutter and Rob Lustig that we're going to submit to talk about the three key points about this evidence. I mean, it's pretty significant evidence.
Well, and again, leaders in the space—you don’t have to have a contest when you have those three names saying, “Hey, you forgot about something.”
I really want to share how much I appreciate the connection—not just saying, “Okay, wait a minute.” I went back and looked at my 1998 physiology book when I took human physiology in med school and looked for this switch thing called the polyol pathway.
I found one little paragraph that said it’s only in diabetics—it’s a rare thing you turn on. I don’t ever remember learning it. As I was reading your book, I was like, “Huh!”
Not only did it turn that on, but there was, as you talk about this dementia and how it’s getting that poor energy development and poor energy delivery inside a cell, the rapid aging process—those little things you were talking about to me were like, “Uh-oh—danger!"
You’re going in the wrong direction. And then the final caveat of landing at uric acid—so can you link uric acid to dementia?
Yes, yes, I can. So before I do that, just real quick, there is a gentleman named Peter Denoia. He’s a biochemist; he runs a podcast too, and he has gout.
I’ve been on his podcast a lot. He just wrote a paper that I’m an author on. He did very nice work showing that this polyol pathway is very rarely activated.
In a person, when you’re born, for example, this polyol pathway is not really turned on and makes up only about 3% of the glucose we eat to fructose.
If it gets activated, like in the switch, 30% of the glucose we eat can get converted to fructose. That is huge—that is terrible!
So when I went to medical school, it was just supposed to be important in diabetes. This is where all the discussion was, and the polyol pathway makes fructose and it also makes sorbitol.
The focus was on sorbitol, not on fructose—but now the world is waking up, and we’re seeing that fructose production through the polyol pathway is important in diabetic kidney disease.
There’s a Nature paper by a group from Germany showing that when you have a heart attack, the polyol pathway is turned down in the heart and starts to make it.
Now we know the polyol pathway is also important in cancer and there are cancers where that love fructose. If you can inhibit the fructose pathways, you can actually have an impact. So it’s a bigger deal.
So now you’ve asked the question because uric acid has been linked with dementia. There are papers that show that if you have a high uric acid, it increases your risk for dementia.
But there's also this funny epidemiology work that shows that if you present at the time with dementia, usually you're not obese, you're not diabetic, and you don't have gout. Even though 20 years prior, if you have gout, diabetes, and obesity midlife, it predicts dementia later in life.
But at the time of dementia, it doesn’t. So you get all these people saying, “Hey, you know, gout actually protects against dementia.”
If you look at people who present with dementia, fewer people have gout than the reverse. So how can it be a risk factor?
Here’s the trick: what they’ve shown is that people who develop dementia often, for several months before, start losing weight. It’s actually quite substantial; there are quite a few papers on this.
It sort of presages the discovery of dementia. As people start developing cognitive decline, they don’t eat as well, and it’s initially not clear that they have dementia, so there are mild memory problems.
But there’s this thing that happens where a lot of people start to lose weight before. At the time they present with dementia, they’re no longer fully obese, and so forth, or their diabetes is less severe—and their gout has gone, too.
Part of the reason a person has gout is that they continue to eat a lot of foods that raise uric acid and keep it high. If you’re not eating a lot of these bad foods, the uric acid comes down.
So that was it. But here's the punchline: in the last two years, there have been two incredible papers that have done a thing called Mendelian randomization.
One of them took 376 metabolites that were thought to be important in dementia—376—and they did this huge thing called GWAS, genetic studies, and Mendelian randomization.
This is a way of kind of determining if there’s a genetic link between high uric acid and the development of Alzheimer's. It’s a clean way of looking at causality. It’s a way that’s supposed to be interesting to watch how they’re using it.
So they took one paper, took these 376 metabolites, and only one was strongly associated with Alzheimer's. With every test they did, it was uric acid.
Whoa, pretty good! Then there was the second one that took 46 classic risk factors, did their genetic linkage, and came up with two. One was uric acid, and the other one was actually—I don’t know if you know this—linked with education.
The higher the level of education, the less chance you have of developing dementia. When you do more educational work, you keep those neuron synapses active; maybe it’s just that.
But in terms of disease process, uric acid is emerging as the king driver in these two Mendelian studies that were very, very extensive and had backup GWAS studies.
Well, oh yes, that’s impressive!
Honestly, in several of your other interviews, you kept getting close to this, and then nobody would ask the question: “Uric acid and dementia—connect them.”
Yes, yes, we did it! They are connected. There’s also interesting studies done with mild cognitive impairment—this is kind of the early stages where people are beginning to have trouble, but they don’t have frank dementia.
At that stage, uric acid is clearly linked, but when you become—at the time you’re diagnosed with it, your uric acid tends to have fallen at that time.
This is an interesting thing when the polyol pathway gets activated in the kidney: it causes uric acid to be excreted in the urine and can drop your uric acid.
A lot of these people probably have the whole body having polyol pathway activation. Various, so some people with dementia will actually have a fall in their uric acid because they’re suddenly excreting large amounts, and that could also play a role.
But in terms of causality, we believe that fructose and uric acid are driving a lot of this disease. It looks very strong in animal studies; it looks strong when you study people with autopsies.
You can show the fructose levels are five to eightfold higher in an age-matched person.
I’ll tell you, your research into this really helped me solve a couple of—I mean, your book is not one of the books where I could read it in a weekend and apply it.
I must have gone back to it like seven or eight times, went to the studies you were talking about, and really helped consume information in a way, because I was trying to apply it in a couple of strange cases.
So I’m going to tell you about the cases and tell you what I did.
Great!
Here’s the case: I met the patient probably the first year—that year my kids told me I became YouTube famous. I had 100,000 followers, but this man writes in. He had been in a hospital; he read the book that I wrote about how metabolism changes, and you need to do these things.
He was following along, lost like 70 pounds, but was in the hospital from kidney stones made from uric acid crystals, as well as several other health problems, including diabetes and such.
He has since gotten off his medications for diabetes; his blood sugars were controlled. He is probably the best patient I’ve ever had in 25 years for following through with what I tell them to do.
Right?
I know, right? You want a crop of those. That was like WOW!
What it gave me the privilege of doing is really studying him. So over time, his A1C came down to like 4.8 to 5, very well controlled. His cholesterol kind of went off the charts because he was on a very high-fat diet, but his brain woke up.
He’s an engineer; he got back off of—like, I don’t think it was ever disability, but he was not functioning well at work and came back to the senior position of being able to cognitively perform.
He became a volunteer and helped out with some of the Facebook messages on my channel. I got to keep track of him, and over time, I asked him to do a few things. Like, “I want you to check your uric acid.”
Until April 2024, you could buy uric acid strips and test it yourself. I said, “Let’s get you a hundred of these strips. I want you to check uric acid in several places so that we can learn about this.”
In that, there were some LabCorp checks; there were some checks from the VA hospital. We had several metrics from uric acid, and as he lost his A1C, his uric acid went down.
It was probably down to, like, I think 4.8 to 5—in that range. Lifewas good!
Then he started not doing well. His morning fasting sugars kept sneaking up from that 95, 85 range into triple digits. This is a man who has a two-hour eating window, absolutely no more than 10 carbohydrates a day on an extremely strict ketogenic diet—I can’t be that strict, but he was bound and determined to never end up back in that ICU again.
So here’s this patient with dozens—I mean, at least 70 checks of his uric acid. And the first thing that I found was, when his A1C had gone down, his uric acid went down.
Then, things went wrong; fasting sugars going up; A1C was a little bit higher, but uric acid was significantly higher.
At this kind of transition—about three months into watching this—trying to get him to say, “I think we have a different problem,” and it was a different problem.
His beta cells were dying. Within the next four months, his beta cells died; he made no insulin. The prodrome that showed me this was happening was that the uric acid was rising.
As much as he did not like this, we got him on injectable long-acting insulin. It really controlled the sugars, and he got that A1C back down to about 5.1—4.8, really well controlled.
For way better controlled than most of my patients. In that process, this uric acid—he had done several experiments about what makes uric acid better.
Can it be as volatile as—I mean, I was thinking, “What are the rules I tell patients when I have them on a ketogenic diet?” Very low A1Cs have good control of their blood sugars, and there can be times, like within a 4-hour period, he does this two-hour eating window.
So for seven days, he ate the exact same things and we had him check his uric acid. Right before he ate, it would be somewhere in the five range; he would eat—and this has got some purines in it.
I don’t think there were any sardines in this, but it was high-salty savory foods. You’re like, “Well, there are some purines in there.” Maybe that makes his uric acid go up a little, but it would then drift up by a point or two.
There were several times where it went from like 4 and you know, right around that five to over 10 in a 4-hour period. Some of those confirmed by LabCorp.
You think, “Point-of-care tests, they must not be that accurate.” I cross-checked that. So the first thing I want to hear about is, do you have any insights into what would make the uric acid so volatile?
Yes, I think it can help. Well, first off, wonderful helping this guy. You pointed out a number of really important things.
The very first thing is you start—you pointed out how controlling diabetes helped his cognitive decline and brought him back. This is the first thing everyone should know who’s listening: let’s say you are having some memory issues and so forth—it’s not curtains; you can get it back.
I have seen this—personally, many other doctors have seen this. Controlling blood sugar is a major way to help with that. Because we talked about how when blood sugar goes up, you start making fructose in the brain.
If you block the fructose in the brain of a diabetic animal, they can improve their cognition. Congratulations to this individual if you’re listening, and congratulations to you for bringing the blood sugar, the hemoglobin A1C down to five—to under five—fantastic!
This guy is able to go back and do even very complicated work. The very first thing to talk about is the importance of keto diets, low-carb diets; careful diets, Mediterranean diets, where you really try to reduce the carbs—that's actually really, really important.
The carbs are really what makes the fructose. You don’t make fructose so much from other things; it’s mainly coming from glucose or fructose. If you eat fructose, that’s fructose; but if you eat glucose, that can be converted.
So a low-carb diet really can block fructose production, even if uric acid is around. Now, the second thing that happened is that when you start going on a low-carb diet, the uric acid will come down because a lot of the cause of the uric acid is from fructose.
High purine foods can raise uric acid. Now, purines are kind of like breakdown products of DNA and RNA. There are purines in foods, and we make purines, and they’re kind of nitrogen precursors to uric acid, right?
So a high purine diet can raise uric acid. The food that’s the most rich in purines is beer, and it’s not just beer; it’s actually the brewer’s yeast. Yeast is almost super high in purines.
When you drink beer, it’s like drinking a soft drink. I mean, you’re really going to raise that uric acid. Plus, alcohol can also make uric acid, and of course, alcohol has its own effects too, obviously.
So anyway, you can get a high uric acid from purines in certain types of fish, especially dark meat fish with lots of little nuclei, like sardines. I’m known as the sardine-challenge person.
I tell patients, “If you want to see your blood sugar go down, do sardines only for 72 hours.” I’ve given a few lectures on this. I tell them the volume of food you’re consuming in those sardines, even though they’re high in purines, is so much less than when you were on a 200 to 300 carbohydrate diet converting that glucose into fructose into uric acid.
Yeah, it’s probably low-carb. It’s low-carb, and sardines also have a lot of that kind of stuff, and shellfish can like lobster and crab, and then certain red meats can too—especially processed red meats where they’ve been cured in purines—it’s been cooked for a while and kind of in a rich sauce.
The purines can be released. So anyway, you can get a high uric acid from processed red meats. In the big picture, the carbs are the biggest poison.
In general, high-protein diets are good. High-protein, high-fat is unlikely to make a person fat; it’s really high carbs that activate the switch.
Uric acid is a player in how carbs work, but in the absence of carbs, uric acid is a little bit impotent. It really can’t do that much without the carbs.
In fact, uric acid can do some things by itself, for sure, but it’s a big amplifier in this polyol pathway. When uric acid is high, it stimulates carbs to be converted to fructose.
So you can get into trouble if the uric acid starts getting really high from high-purine foods. There’s this other problem: keto acidosis.
We know that ketones are good; they’re good for the brain. The ketones are good, but ketones block uric acid excretion in the urine, so uric acid can go up.
Now, if you’re on a keto diet, any keto diet expert will know that you can get a gout attack because uric acid can go up high enough to cause a gout attack.
Maybe the uric acid can have other things. We know that uric acid is bad for the islets, for example.
We did a study by giving sugar to animals, and we could show that the islets start becoming insulin resistant. But over time, the islets start to die. We could show that there was uric acid entering these islets.
Here’s a cool experiment: it was in laboratory rats. I’m going to tell you a human story afterwards.
We actually had the animals on a severe caloric restriction; they were on a low-calorie diet. We gave them either high sugar or a control diet.
A high percentage of the food was rich in sugar, and initially, the animals became hypertensive; they developed fatty liver, their fat went up, even though they didn’t gain weight because they were on caloric restriction. But basically, their body composition became very fatty.
They became insulin resistant, and when you’re insulin resistant, what happens is your blood insulin levels go up because the insulin's not working. The islet cells in the pancreas that make insulin have to work harder to make higher levels of insulin to overcome the resistance of the tissues to the insulin.
Initially, the animals maintain their blood glucose because the insulin levels go up to fight that insulin resistance, but then the islets start to… I don’t know the word.
In the experiment, we overcame the resistance, but then the islets start to die.
You’re exactly right; they show evidence of injury, they’re making less insulin, and then they go out. And that’s when…
What’s interesting about type 2 diabetes is that the same thing’s been shown there. Initially, you’re insulin resistant, but over time, a lot of people with type 2 diabetes will start producing less and less insulin, and it makes the diabetes worse.
We know that uric acid can help drive that. What I don’t know is if you’re keto in ketoacidosis. I mean, if you’re on a keto diet, could the high uric acid be playing a negative role on the islets?
It’s possible it could. Most of our work shows that uric acid works with carbs, but the whole keto diet thing is a little mysterious because I don’t know how bad.
We’ve seen a lot of people with high uric acid who are skinny and doing really well, and they’re great because they’re on a keto diet. But we know it can cause gout, and maybe it can still cause other problems like islet problems that we don’t know yet.
It’s certainly a wonderful topic to study—I mean, an important topic to study—because we want to know how safe high uric acid is in a person on a keto diet.
It's interesting because in his case, he was, again, the super patient.
His ketone level was so consistent. I take care of hundreds of these patients; they don’t do that. I mean, they’ll do a nice tsunami wave of ketones when they first join the ketogenic space, and then their body adapts.
We need to flex their metabolism; we need to get their mitochondria in better shape. Those workouts have seasons; sometimes, it's not the right season for the patient to try, and so their ketones are 6.
The other thing that you brought up, which is something that I’m well aware of though many people are not, is that uric acid levels can vary quite a bit even during the day and following a meal.
So let me just give you some examples: If you eat a large amount of sugar, the fructose in it will cause uric acid levels to go up, but the peak is about 32 minutes to an hour after you eat.
You’ll see this rise in uric acid, and it can go up one or two milligrams percent and then come down. By the next day, it’s sort of where it was.
If you eat a high sugar diet all the time, the baseline uric acid will start to rise. But there is this acute effect. Peter H. did these beautiful studies in people in a metabolic lab where he showed that if you give people a high-fructose diet, you get a rise in uric acid after each meal.
The area under the curve—what we call the overall average uric acid for the day—is not necessarily reflected by the morning uric acid.
Because of this rise and fall, interestingly, pureings do the same thing. There was this beautiful paper done in the 80s—I love this paper, and I quote it a lot in some of my papers. They took these people with gout and people without gout, and gave them a high oral purine diet—
You know, a meal like that actually had brewer's yeast, is what they swallowed down, mixed with beer.
You know, just a beer will do this! After you drink a beer or eat the yeast, the uric acid can go up dramatically, especially in people with a history of gout.
It goes up the highest in people with gout, but it goes up in everybody, and it’s quite striking. Instead of peaking at 45 minutes, it tends to peak at two hours, and the urine uric acid takes a big rise as well.
There’s this kind of load: your blood levels go up, you expel it in the urine, and then it will come down. So uric acid is not such a steady measurement.
There are thoughts about doing—just like a CGM—doing one with uric acid. There’s a guy in California, a brilliant scientist, you may have interviewed him—Thomas W.
Not yet. Now, he’s a really interesting guy, and he’s developed a keto drink as well for people with kidney disease.
He has done some really interesting work linking uric acid with chronic kidney disease and showing how it relates to this rise in urine uric acid, where it forms a little bit of crystals that can cause low-grade damage to the kidneys.
He’s really made a very compelling case for this. It’s probably not good to have a high uric acid in the urine because it may increase the risk for kidney disease, and it’s interesting.
You can neutralize that just by taking a little bicarbonate—like a...
Yeah! So just a tiny bit of bicarbonate can make the urine more alkaline, and in alkaline urine, the uric acid can’t form crystals very well.
Goes out—doesn't precipitate, right?
Yeah, yeah!
So answer this question: in the setting of the journey that I help patients with, we try to get them on a low-carb diet. We have them measure numbers like glucose and ketones, we have them take on the next level of their healthcare or their health metabolism repair, and there are seasons where we say, “You know what? If you can’t do exercise, if you can’t find a sauna, we’re going to ask you to abstain from food for 48 hours.
Do a complete 48-hour fast.” Sometimes we ask them to do 72-hour fasts.
As you look at uric acid after that long of a water-salt-only fast, what’s your prediction on what the uric acid would do?
Well, it’s going to relate to the hydration status. If you drink a lot of water, I think you’re going to be okay.
In general, intermittent fasting will tend to make the uric acid go up towards the end—that's what we've seen, you know—but if you keep them well-hydrated, you may not see it. It won’t be as severe; that’s for sure.
It won’t be as severe. Of course, the longer you do the fasting, the more likely the uric acid is going to go up.
It’s sort of like think of it this way: the body is still running on these rules of nature. When you’re fasting and you start dropping energy, you’re burning but, you know, your ATP—especially if most people who are fasting have an underlying issue like obesity.
They probably have—because that’s one of the reasons they’re doing the fasting. The obesity means that they’ve activated the switch a lot.
And the longer you activate the switch, the more little mitochondrial problems there are; so it’s going to be quite likely that there’s going to be activation of this biologic switch from— you know, as the energy starts to drop.
Uric acid can be an initiator of the switch, right?
It’s probably being—it is rising, and it’s sort of like telling the animal it’s trying to get the animal to activate the switch to rescue itself.
You know, there’s this really interesting thing: if you take—there are studies done in the Native Americans in Alaska, like the Inuits, before they—and many of them are on a pure carnivore diet—
Basically, that’s a low-carb diet. There are not a lot of carbs in Alaska, and in these old days especially, what they found was that if they did a glucose tolerance test, they had an exuberant response.
It was as if their system was activated to maximize fat stores. It’s really quite interesting.
I think when you do intermittent fasting, if you go long enough, you’re going to activate things, and things are going to go up in the blood that are going to want to help activate the switch.
But staying well-hydrated and exercising to keep those mitochondria healthy—I mean, intermittent fasting works, and I love intermittent fasting, and I love low-carb diets.
I realize, you know, these, you know, that the body may be trying to react to it a little bit. But it, in essence, if you can keep that fructose away and keep that line of C, you’re healthy.
Exercise is such a wonderful tool as well.
I... but I think we’re kind of fighting the system. The system was built to make sure we had enough fat stores.
If you start fasting, the body's going to want to hold on to those stores and we have to understand the biology, and then we can figure out how to quench it and how to keep ourselves healthy.
Well, that’s very helpful for me. I wasn’t too far off. I’ll say when you’re looking at the equation of how to help a patient that’s in front of you, and they’re 200 pounds overweight—they’ve been insulin resistant, and they can’t exercise.
They really cannot exercise! So we say we’re going to get you there, we’re going to help you. But with the weight loss, you’re fighting insulin resistance, and we use saunas; we do other things to try and help get their metabolism not to be in the lowest mode, but…
I’m sorry to interrupt you, but dark chocolate and this substance called epicaguline is really a wonderful tool.
Do you know much about this?
I don’t know about epicaguline.
Okay, so there was this famous Harvard scientist named Norm Hollenberg. He had learned that there was a little island off the coast of Panama where the Indians there—the Native Americans—were called the Kuna.
They could be eating a ton of salt but never develop high blood pressure, and he got curious about this. He thought, “Well, so he went with a group of investigators and adventurers down to Panama."
It was true: not only did these people have normal blood pressure, but none of them were obese; there was no diabetes. Some of them were eating some foods that you would expect would raise blood pressure, like salt; they were also eating sugar—a fair amount of sugar, in fact.
Yet, they didn’t affect them. He thought it was genetic, that they had some kind of rare gene that might explain this, but then he found that their relatives that went to Panama City were all getting fat and diabetic.
So he was puzzled about this, and then his dietician was the one who figured it out. She realized that these people were drinking a lot of cocoa and they were drinking bitter cocoa—up to 10 to 12 cups a day!
They started studying this. I actually had friends that took over this research for the last 20 years.
They studied it and found that the dark chocolate contains things called flavanols, which are in a lot of foods, right? Flavanols, generally speaking, are really good.
But they found that there was one flavanol that was kind of distinct from most of the others. There’s one that’s kind of related that’s from green tea, which is also a little weaker, but they found this flavanol called epicatechin.
They found that it neutralized that—I mean, it helped mitochondria grow. If you put it on cells, the mitochondria would grow.
When you exercise, mitochondria grow as well, and they also found that it blocked oxidative stress. You know, fructose hurts the mitochondria through a process called oxidative stress, and the epicatechin could block part of that.
I got involved; we gave epicatechin to people, and we could improve aspects of their metabolic syndrome.
These guys formed a company with epicatechin, and they could show that they could help people with heart failure improve their exercise tolerance, and they did these studies with people with muscular dystrophy.
Anyway, long story short, they decided it would be better to make it a nutraceutical, to be more available to more people. Epicatechin is something you can buy through Amazon, I think.
I would say that it looks very promising as another way to help people who exercise in a healthy diet, you know?
Exactly—with things you love!
I’m not trying to sell this, but if you’re looking for additional things to boost, green tea, dark chocolate, pure epicatechin supplements, and pomegranates are very good.
Another one—just stay well-hydrated! Drink a lot of water. Another one is vitamin C. Vitamin C actually has some stimulatory benefits on mitochondria.
There is this concern that vitamin C may interfere with exercise—stimulating mitochondria. If you take vitamin C, don’t take it before you exercise. Take it when you go to bed, and something like 500 mg can do it.
Alright, so there are a couple more questions. I’m worried you’re gonna run out of time and I’m not gonna ask the two questions I’m dying to ask you.
A couple of things: I’ve seen one of your interviews where you were wearing a continuous glucose monitor.
Yes, I’m going to put it on later today actually. Mine ran out over the weekend too. That’s—and I have lots of patients who’ve learned about themselves through wearing one of these meters.
As soon as I started to talk about how this polyol pathway could be initiated by a level of blood glucose, again, my diabetic profile is a tiny little activation switch.
It's only when there are blood sugars in the high diabetic range; but that’s really not what I'm gleaning from the further research you’ve done.
So if you had to state, now—and I put the framework that all my patients who are wearing a CGM are going to hear this—what level of blood sugar do you think that one-third of the glucose is now being converted to fructose? Where do you think that switch activates?
Well, it’s a dimmer switch, so it’s not on or off. It gets activated the more sugar you eat or the—
You know, it’s graded. So, if you drink a big soft drink and guzzle it down, you’ve got this huge concentration of sugar rapidly ingested, especially on an empty stomach, and it hits the liver, you would get the big switch.
In terms of CGMs, I love CGMs. If you’re wearing one, I think you’re lucky because you can see what foods raise your glucose and what don’t. You can also learn these tricks: like, oh my God!
I have, again, I don’t even know the name of the company, but you can buy these keto tortillas that are really quite good. In the morning, I’ll make eggs—they’re very healthy.
You put them on the tortilla, put a little avocado on top, and you have like a—I mean, it’s delicious and it doesn’t raise glucose at all.
When I put avocado on bread or toast, you can really dampen that rise in glucose. There’s also this—I am affiliated with a company trying to sell allulose, a natural sugar.
It really has an effect on glucose levels too, which is dramatic. One of the last conferences I was at, I donated 50 CGMs to people that were there.
I brought them and my team put them in. I said, “Now the allulose booth is right over there! I want you to get your CGM calibrated, then look at your sugar after you have an allulose bar—an RX sugar bar—and then watch what your sugars do.”
We had, like, oh! Yeah, it was great.
It is amazing! That is the most amazing thing about that sugar: it blunts the glucose effect.
Crazy, it’s crazy! It’s real. We’ve reduced insulin needs with it in diabetics, and it’s great. So you know what you want to do: try to eat healthy.
I think that you are doing a lot of really good things. These low-carb diets, keto diets—even some of these can reduce those carbs; that's the key!
CGMs are wonderful and going to be over-the-counter too. I've been an internist for 20 years, and one of my mottos is that I’d like to try and stop as many prescriptions as I’ve started.
That's great. I should think I should do the same. It takes me a longer time; I’ve written a lot of them. I’m an internist; that’s what we do.
But to undo them—let me tell you the one prescription that I’ve probably written more of in the last couple of years than I’ve ever written, and it has to do with uric acid.
Then I want to show you the observation and see what you think.
This is my final question that you can run away as soon as we’re done, but I’m—I won’t let you off until you answer.
So, in patients who’ve had high uric acid and we are trying to lower their uric acid, they’re on a ketogenic diet. Writing fubstat has been a prescription that’s been an antioxidant inhibitor.
It’s going to lower that, but about two months after they’ve been on it, I have seen a clinical observation: weight loss that I’ve not seen with other drugs.
Do you think that—have you seen anything?
We’ve done several clinical trials with xanoxid and HEC, and they do cause weight loss, which is significant.
So we did a study in Mexico. We also did a study in Houston in adolescents who were actively gaining weight.
These were kids who were actively getting weight, and the allopurinol group, which is like fubstat, really did not show any weight gain compared to the control group.
We had another uric acid drug that was not as effective at lowering uric acid, and it was intermediate. I do believe it’s real, and I have seen it enough.
But I wouldn’t prescribe it for weight loss.
But I have seen it enough that if someone has gout, you can give it, and my gosh, it does have a lot of benefits, too.
There’s evidence that if you’re on it for several years, for example, there are several studies that show it reduces the risk of dementia, fubstat in particular: a 30 to 50% reduction in dementia in epidemiologic studies.
Same with linis, actually, and it reduces the risk of diabetes in several studies or improves blood sugar.
We found that we did a clinical trial where we showed we could improve insulin resistance by giving it. I do think we want to try to keep our uric acids down in general.
If you’re on a keto diet, we don’t really know what the high uric acid is doing fully in that setting because we know a lot of how uric acid works is through carbs.
When you’re on a low-carb diet, it’s a confounding problem issue.
Anyway, but thank you.
Yes, well, I will tell you, your research has been incredibly helpful. Incredibly helpful to me! We’ve been at a couple of the conferences that you’ve spoken at, and I sent all my team to say, “Just make sure you go watch him!”
And I got tied up doing something with an interview, and I missed your talk.
I said, “Yeah, let’s try to meet up at one of these meetings.” I would love that!
I would really love that! Every time I see you, you’re leaner!
I said, “He must be on fubstat!”
No, but just—yeah, no. My whole life, I’ve struggled for the last 20 years with a little bit of weight. I’ve never been officially obese, but I’ve been a little overweight.
It’s very hard. Even when you know what exactly you shouldn’t eat, your foods, you know.
If you're traveling and someone puts a good food in front of you, it can look good, even though you know it's not good, healthy food, right?
It can be very tricky!
So, you know, but yeah, I’ve been losing weight by just following these general rules.
Well, I’m close to being normal weight now.
Well, you look great! I mean, that means you have your brain for several more years, which I'm super thankful for!
That’s a boring thing!
Well, I appreciate the extra time. You have been—I have been counting down to this for a long time, so thank you!
Thank you for blessing My Life by answering those questions for me!
And thank you, too! Have a wonderful afternoon!