#243 – Why sugary drinks can cause weight gain and low energy | Dr. Richard Johnson & Dr. Dominic D’Agostino

Traditional soft drinks, juice boxes, and energy and sports drinks are loaded with high fructose corn syrup, an ingredient also found in many processed foods. The body processes fructose differently than other sugars, and fructose can lead to weight gain by encouraging the body to store energy. Dr. Richard Johnson and Dr. Dominic D’Agostino discuss the issues with fructose, how fructose can drive food cravings and overeating, how fructose might be an Alzheimer’s contributor, and the potential benefits of a different sugar that might promote the release of GLP-1, the hormone that Ozempic and Wegovy help increase.

Helpful links:

Richard Johnson, MD: https://drrichardjohnson.com

Richard Johnson, MD, on Instagram: https://www.instagram.com/drrichardjjohnson/

Richard Johnson, MD, on Twitter/X: https://twitter.com/richardjjohns11

Nature Wants Us To Be Fat: The Surprising Science Behind Why We Gain Weight and How We Can Prevent—And Reverse—It: https://drrichardjohnson.com/books/

Study in the journal Nature on allulose: https://doi.org/10.1038/s41467-017-02488-y

Dominic D’Agostino, PhD: https://www.dominicdagostino.org

Dominic D’Agostino, PhD, on Instagram: https://www.instagram.com/dominic.dagostino.kt/

Dominic D’Agostino, PhD, on Twitter/X: https://twitter.com/DominicDAgosti2

1:59 — Richard Johnson, MD, is a prolific researcher regarding sugar’s effects

Dr. Johnson shares a bit about himself and his career.

I’m Dr. Richard Johnson. As you mentioned, I’m a professor of medicine at the University of Colorado. I’ve been doing research for more than I want to admit—for many decades. I’ve been involved in trying to understand the cause of obesity and diabetes since the 1990s. Much of my research is focused on sugar, the role of fructose, which is a component of sugar, and of uric acid, which is a metabolite of fructose. Just a disclosure: recently, I joined a company called RxSugar, which has a fructose-like sugar that does not seem to activate the switch. It’s called allulose. And the reason I joined the company as their scientific officer is because I’m intrigued by this really interesting sugar that looks like fructose but doesn’t seem to have the injurious effects.

6:38 — Soft drinks are a major source of added sugar, which has negative effects on metabolic health

Soft drinks and other sugary beverages lack nutritional value and cause blood sugar spikes.

Yes, there is fructose in fruit. But the major source of fructose we get is not from the occasional fruit; It’s from the huge amount of added sugars we’re eating. So the average person’s eating like 150 pounds of sugar a year. That’s a lot of sugar. And probably about 15% of our diet comes from these added sugars. And as you say, the killer source is where it’s basically just sugary beverages, really just water and either fruit, sucrose or table sugar, or high fructose corn syrup as the main calories. And you can get a lot of sugar and calories from soft drinks. And it’s been known for decades that sugary beverages are a dramatic risk factor for obesity and diabetes and dementia and fatty liver. The world has known that soft drinks are bad, and it turns out that it’s that combination of fructose and glucose. Now, my research tried to distinguish between fructose and glucose and what was actually the bad guy. The truth is both are bad guys the way we eat them. And when you eat fructose, it’s bad from the first mouthful. If you take a large amount of fructose, it’s different from all other calories. It’s a nutrient that does a trick to the body.

8:31 — Fructose lowers energy in the body, driving hunger

Dr. Johnson explains how fructose typically becomes stored energy, leading to weight gain.

We run on energy. The energy is called ATP, adenosine triphosphate. Basically, we run on energy, and we eat calories to make that energy, and that energy can either be active energy, which is the ATP, or it can be a stored energy, which goes into fat. And the great thing about fat—there is a good thing—is that if you don’t have any food around, the fat can be broken down into calories. And so animals get fat to protect themselves when there’s no food around, like the hibernating bear. So fat can be good as a stored energy, but when you eat fructose, it tries to take the calories we eat and put it into the stored energy, not into the active energy. And when you eat glucose, it does the reverse. It tries to make active energy. and then secondarily, stored energy. And so they work slightly differently. Fructose actively lowers the ATP in the cell through effects on the energy factories. It suppresses the energy factories, which are called mitochondria. And by doing that, it drops the ATP levels. And at the same time, it blocks the fat from being broken down to replace that energy. So what happens is when you eat a lot of fructose, you set your energy to a lower level. And that is the trigger to tell the body, “Hey, I’m running on low power. It’s low power mode. My battery’s going to run out. I need to recharge my phone. In this case, I need to eat more. I need to bring in more calories, and I need to do this to bring my energy levels up. But the truth is, your total energy isn’t low, because although the ATP is low, the stored energy is high.

14:16 — Fructose can drive insulin resistance and increase fat

Your body can make fructose from glucose, both of which stimulate insulin release.

When you eat fructose, it does all these things to make you hungry and eat more. And at the same time, it’s also working in your body. It’s making you insulin resistant. So fructose is what causes insulin resistance. And that means that your tissues become less sensitive to insulin. So you’re getting less energy into the muscle, which isn’t good, right? And at the same time, the glucose levels are going up in the blood. Now the glucose levels, when they go up in the blood, guess what happens? You make fructose from the glucose. And the glucose also stimulates insulin. So you’re insulin resistant. Insulin levels are going up from the rise in the glucose and also from the glucose you’re drinking in the soft drink. So it’s a double whammy, right? The insulin resistance makes the glucose goes up, but the glucose levels are going up as well from the soft drink. Then that stimulates insulin, which in the setting of insulin resistance, is not going to do you good. It’s going to increase fat.

21: 44 — A small amount of fructose can be beneficial to the body

Small quantities of fructose may help with exercise performance, but larger quantities can hinder it.

Very small amounts of fructose, like 1%, 2%, or 3%, not like 6%, but 2%, can actually accelerate glucose oxidation. And it does it by facilitating glucose absorption. There were studies done at the Gatorade Institute, suggesting that what we call catalytic amounts of fructose may actually accelerate glucose absorption and may improve performance. So it’s not like fructose is always evil, right? Natural fruits have small amounts of fructose. But there are so many good things in the fruit, and the fructose quantity is relatively low. It’s not the same issue as drinking a soft drink.

29:11 — Fructose consumption may be a culprit of Alzheimer’s disease

Researchers theorize that Alzheimer’s is a maladaptation of an evolutionary survival mechanism.

Many patients with Alzheimer’s start craving sweets. Well, they usually have a history of craving sweets, but they often will enhance their craving of sweets. And many of them do this thing called the wandering syndrome, where they kind of wander off. This wandering syndrome is sort of like a foraging response. And I think it’s a carryover from this fructose pathway.

48:21 — Low-calorie sugars can still make you crave more sugar

Although, they may be the lesser evil when compared to high fructose corn syrup, low-calorie sweeteners still drive cravings for sweets.

If you do a comparative study and you have one group take high fructose corn syrup and the other group take one of these low-calorie sugars, you will show a benefit because you’re comparing it to something that we know is bad, but it doesn’t mean that those sugars are actually doing anything good. Rather they’re superior and preferential compared to high fructose corn syrup.  Now, having said that—because they’re sweet—they still stimulate dopamine in the brain through the sweet taste buds. But a very interesting thing is they only stimulate it to a smaller degree than sugar. And the other really interesting thing is, if you knock out the taste buds, you lose your liking of these low-calorie sugars. But even though the taste buds are not working, you’ll still get that dopamine response with fructose because it’s stimulating dopamine through the metabolism of fructose anyway.

53:59 — A low-calorie sugar called allulose has potential health benefits

Allulose may have a blunting effect on rising blood sugar.

I became aware from Dr. Peter Attia of a sugar called allulose, and I started reading about it. It looks just like fructose. It’s a natural sugar. It’s present in small amounts in fruit and in foods that we’re all eating, but just in small amounts, so we don’t really know that we’re eating it. But when you make a lot of it, it turns out to be a sugar that’s not as sweet as table sugar, but it’s like a sweet sugar that has very few calories. It has about 0.2 calories per gram. So it’s very low in calories. When you take it, it can substitute as another type of low-calorie sugar. But what was interesting is their report is saying that it’s actually beneficial. It’s actually positive, and the most impressive is that it lowers blood glucose. It blunts the rise in glucose with a meal. So if you take a little bit of allulose and then you eat bread, instead of your blood sugar shooting way up and stimulating insulin and driving fructose production, it won’t go up as much.

55:59 — Allulose may stimulate GLP-1

Glucagon-like peptide 1 receptor agonists work by increasing the hormone GLP-1. Allulose may also stimulate this hormone. Researchers, including Dr. Johnson, are hoping to investigate the potential for allulose to help with weight management. I want to do a big clinical trial on this. There are small studies that are published, but they’re pretty convincing, and they’re all generally positive. It suggests that allulose can stimulate GLP 1, which is that hormone that the semaglutide (Wegovy) and (Ozempic) are working on.

59:39 — A low-carb diet helps reduce sugar cravings

More research is needed, but allulose may help, as well.

It’s really hard to get rid of that craving and addiction. And it’s true that when people go on a low-carb diet or a keto diet, their craving for sugar tends to decrease after some time. There is this thing with fruit, for example. As we mentioned, consuming one or two servings of natural fruits is really healthy because they contain all these other things that counter the fructose. You don’t want to be eating 10 servings of fruit at a time, but fruit can be an alternative that’s sweet, with satiety from all the fiber. But allulose might be a candidate.

Rick (00:00:04):

Fructose is the fire. It ignites the fire that makes you hungry. High-fat diet is the firewood. You put that on and you get a big blaze. If you’re on a low-carb diet, if you’re on your keto diet, you can eat a lot of fat. You’re going to control your weight, you’re not going to be hungry, and so you’re not going to really gain weight even though you’re on a super high-fat diet, because you need the carbs to make you hungry, to gain the weight from the fat. Even having said that, the carbs themselves will fructose, even on a low-fat diet, will still make you diabetic.

Ben Grinnell (00:00:52):

I’m Ben Grinnell, part of the early startup team here at Levels. We’re building tech that helps people to understand their metabolic health, and along the way we have conversations with thought leaders about research-backed information so you can take your health into your own hands. This is a whole new level.

(00:01:21):

As we move into the new year, it’s no surprise that many people have New Year’s resolutions. What tops the list? Well, weight loss. Another one is also eating less sugar. When this is the case, giving up sugar can be challenging for some people as they start to think about alternatives. What can they consume that will feed their sweet tooth, no pun intended? Well, avoiding things like sucrose, table sugar and fructose, which is found in many sodas, juices, and candies, it’s pretty hard to avoid. It’s prevalent and it’s everywhere.

(00:01:53):

We know that excess sugar isn’t good for us, but to what effect? Well, excess fructose, when added to these things like juices and sodas, it is detrimental for our metabolic health. Leads to insulin resistance, has an effect on our mitochondria by lowering ATP levels, leads to increases in uric acid, and impacts our kidneys. It can even lead to increases in cancer, because the body cannot absorb fructose in liquid form as quickly as it’s consumed.

(00:02:23):

Fructose is everywhere and it must be avoided. Same with sucrose. But what about other artificial sweeteners? Can they cause insulin resistance when consumed in excess? Things like aspartame and sucralose, which is found in Prime Energy drink? Well, yes, they are not good for our metabolic health. They can lead to insulin resistance through effects on our microbiome.

(00:02:46):

Are there other sweeteners which people can consume that will satisfy those cravings? Well, the answer is yes: allulose, monk fruit. These are things that Dr. Rick Johnson and Dom D’Agostino discuss in this episode. How can these sweeteners be consumed in moderation, based on the current research and what we understand about them, without leading to negative downstream implications for our metabolic health? In this episode, Rick and Dom discuss what does excess fructose do to our metabolic health, and how does it impact things like uric acid, and why is uric acid bad for our bodies?

(00:03:20):

Rick Johnson is an author of The Sugar Fix and the Fat Switch. He’s a professor of medicine at the University of Colorado and one of the leading experts in the world on fructose and uric acid. He spent his career focused on research in nephrology to understand the kidneys and how things like sugar and uric acid can impact our metabolic health as it relates to diabetes and obesity.

(00:03:43):

Dom D’Agostino needs no introduction. As many of you who listen regularly know, he’s a Levels friend and advisor and a researcher and professor with a very diverse background in neuroscience, molecular pharmacology, nutrition and physiology. Dom is an associate professor in the Department of Molecular, Pharmacology and Physiology at the University of South Florida Morsani College of Medicine. He continues to explore metabolic-based research studies to better understand the complex orchestra of our physiology and biochemistry.

(00:04:16):

Anyway, no need to wait. This is a great episode with Rick and Dom, going deep into everything related to fructose, alternative sweeteners and what people can do to start consuming things that are better for their metabolic health.

Dom (00:04:36):

Dr. Rick Johnson, it is so great to connect with you on a whole new Levels podcast. I have been looking forward to interviewing you, or just more of a conversation about the research that you’ve done, taking a deep dive into fructose, into sugars, artificial sugars, sugar alternatives, and some of the implications of these compounds in our food system. And I really enjoyed your Levels podcast with Dr. Rob Lustig, that was a favorite of mine.

(00:05:07):

I’ve also, in preparation for this podcast, I reviewed your podcast with Dr. Peter Attia and the show notes for that. I don’t think we’re going to go into as much of a deep dive into the biochemistry, but I’d like to direct people to the Peter Attia podcast, which was fantastic. And also the podcast with Simon Hill, which was very engaging. And that led me to come up with a number of questions, follow-up questions to ask you. And I know our Levels subscribers have a number of podcasts too, relating to table sugar and alternatives, and we’ll take a deep dive into that. Before we begin, if you could give a brief introduction to yourself, and I’ll do the same before we start.

Rick (00:05:49):

Yeah, thank you. Well, first off, Dom, it’s just a total pleasure to be on this show with you, and it’s really great to speak to another expert, and hopefully we’ll have some really interesting insights together as we work through all these questions that people have been preparing for us on this topic.

(00:06:09):

I’m Dr. Richard Johnson. As you mentioned, I’m a professor of medicine at the University of Colorado. I’ve been doing research for more than I want to admit. For many decades, I’ve been involved in trying to understand the cause of obesity and diabetes, since the 1990s. Much of my research is focused on sugar; the role of fructose, which is a component of sugar, and of uric acid, which is a metabolite of fructose.

(00:06:38):

And a disclosure, recently I also part-time joined a company called RX Sugar, which has a fructose-like sugar that does not seem to activate the switch. It’s called allulose. And the reason I joined the company as their scientific officer is because I’m intrigued by this really interesting sugar that looks like fructose but doesn’t seem to have the injurious effects. So that’s my disclosure, and Dom, looking forward to it.

Dom (00:07:06):

And I should also disclose that I’m an advisor for Levels Health and have been for a number of years and also more recently, RX Sugar, just because the science behind allulose has really captivated me. I do research about 50% and I also teach PhD students, master’s students, and quite a few medical students and directing them to the literature on fructose and allulose, some of your literature, Rick. This topic has become integrated into my education, and nutrition has become a mandatory course for our medical school, so I’m excited about that.

Rick (00:07:41):

There’s a focus on nutrition in the medical schools because when I went to medical school, we got very little information on it. We got very little teaching on it.

Dom (00:07:51):

Yeah. I have a lot of questions here. In general, people are moving away from table sugar because the science is implicating added sugar, especially sugar sweetened beverages, which is basically… You know, sugar is hidden everywhere in processed food. And there are many different types of sugar alternatives out there today, and people want to know how these compare to what was available 50 to a hundred years ago. So maybe we could start out by talking about the elephant in the room, really, which is fructose. So fructose has permeated our food system. It’s in our bread, it’s in processed foods, it’s saturated into our drinks. And maybe give your perspective, sort of in a nutshell, of the research that you’ve done on fructose and why that could be problematic.

Rick (00:08:49):

Well, there are two major carbohydrates that are called monosaccharides or simple sugars, and one is glucose, which we all know about, right? It’s the main sugar that is in our blood, and it’s when it becomes chronically high that can lead to the condition diabetes. We have these glucose monitors that probably some of you are carrying to understand our blood glucose. And glucose is the main fuel our body uses, the main carbohydrate fuel.

(00:09:21):

There’s another sugar called fructose, and we do have fructose in our blood, but it’s much lower concentrations. And fructose is, we think of it as being healthy because it’s in natural fruit, but it turns out that fructose is also a major component of sugar, of table sugar and high fructose corn syrup. Fructose is quite sweet, it’s sweeter than glucose. And when you mix glucose and fructose together, you get a really tasty sweet substance called table sugar, or high fructose corn syrup. And these are commonly referred to as added sugars because they’re often added to foods. And so sucrose is officially table sugar, but it’s a molecule of glucose and fructose bound together.

(00:10:12):

So what I’m trying to tell you is that yes, there is fructose in fruit, but the major source of fructose we get is not from the occasional fruit. It’s from the huge amount of added sugars we’re eating. So the average person’s eating like 150 pounds of sugar a year. That’s a lot of sugar. And probably about 15% of our diet comes from these added sugars. And as you say, the killer source where it’s basically just sugary beverages, is really just water and either sucrose or table sugar or high fructose corn syrup been added as the main calories. And you can get a lot of sugar and calories from soft drinks. And it’s been known for decades that sugary beverages are a dramatic risk factor for obesity and diabetes and dementia and everything bad. The world has known that soft drinks are bad, and it turns out that it’s that combination of fructose and glucose that are doing it.

(00:11:19):

Now, my research tried to distinguish between fructose and glucose and what was actually the bad guy. And the truth is, both are bad guys. When you eat fructose, it’s bad from the very first mouthful. If you take a large amount of fructose, it’s different from all other calories. That does a trick to the body. In our cells, we have energy, we run on energy. The energy is called ATP, adenosine triphosphate if you want to know. But basically we run on energy, and we eat calories to make that energy. And that energy can either be active energy, which is the ATP, or it can be a stored energy, which goes into fat. And the great thing about fat… There is a good thing about fat, is that is if you don’t have any food around, the fat can be broken down to calories. And so animals get fat to protect themselves when there’s no food around, like the hibernating bear and things like that. So fat can be good as the stored energy.

(00:12:25):

But when you eat fructose, it tries to take the calories we eat and put it into the stored energy, not into the active energy. And when you eat glucose, it does the reverse. It tries to make active energy and then secondarily stored energy. And so they work slightly differently. Fructose actually actively lowers, actively lowers the ATP in the cell through effects on the energy factories. It suppresses the energy factories, which are called mitochondria. And by doing that, it drops the ATP levels and at the same time, it blocks the fat from being broken down to replace that energy.

(00:13:05):

So what happens is, when you eat a lot of fructose, you set your intracellular or you set your energy in your cells to a lower level than normal, and that is the trigger to tell the body and say, “Hey, I’m running on low power, it’s low power mode. My battery’s going to run out. I need to recharge my phone. In this case, I need to eat more. I need to bring in more calories and I need to do this to bring my energy levels up.” But the truth is your energy, your total energy isn’t low, because although the ATP is low, the stored energy is high. So the calories, it sort of tricks the body into thinking that you’re in a low energy state even though you have fat that can provide that energy.

Dom (00:13:54):

Okay, I have a couple questions there. So that was a fantastic overview. So you’re saying independent of caloric surplus, the consumption of fructose will, via various mechanisms, lower ATP levels, not only in the liver, but also potentially in peripheral tissues like maybe muscle too through… I think you had talked about aconitase being a mitochondrial inhibitor. So if fructose is de-energizing the cells, so to speak, if someone was to consume fructose prior to athletic performance or measuring, would an acute dose of fructose reduce athletic performance via this de-energizing or reducing ATP? Has that been shown?

Rick (00:14:46):

Yeah, there was work done at the Gatorade Institute. I once was the Gatorade professor. I don’t know if you know that. I was down in Florida myself at Gainesville. I was the Cade professor. And I’d love to talk to you about sports drinks because there are some really good things about sports drinks, and sometimes a tiny bit of fructose is good. We can talk about that.

(00:15:05):

If you just drink pure fructose, on an exercise bicycle or any type of exercise, it will cause problems. It will actually decrease exercise performance. It can cause lactate build up very rapidly. So the way fructose works is, it lowers the ATP, only by 20 or 30%. Sometimes a little bit more if you take a big slug. It’s kind of like a dimmer switch. If you take a little bit, it may not lower it at all. So if you sip a coke and just drink a tiny bit of fructose per hour, you may not drop that ATP level. But if you take a big slug of it, boom, you’re going to knock it down.

(00:15:47):

When that ATP goes down, the body senses it as a low energy. If it goes down really low, you activate a different process. If it goes down really low where you think, the organism thinks it’s going to die, it will start breaking down muscle and all these things to find whatever energy it can, because it’s desperate. But if you bring the energy down 20 or 30%, it’s kind of like saying, “Hey, it’s time to go get some gas. It’s time to go eat a little bit more.” And what it does is it stimulates hunger, it stimulates craving, it stimulates food intake, it stimulates foraging. So you actually become active even though your energy’s low, but only while you’re looking for the food. It’s like a foraging response. But as soon as you quit, your resting energy metabolism actually drops, because you’re in a low ATP state. When we give it to our little mice, the mice will be, when they’re not actively trying to get food, they actually huddle. They actually go into kind of a, almost like torpor, like a low energy state.

(00:17:02):

So anyway, so when you eat fructose, it does all these things to make you hungry and eat more. And at the same time, it’s also working in your body. It’s making you insulin resistant. So fructose is what causes insulin resistance, and that means that your tissues become less sensitive to insulin. So you’re getting less energy into the muscle, which isn’t good, right? And at the same time, the glucose levels are going up in the blood.

(00:17:31):

Now the glucose levels, turn out that when they go up in the blood, guess what happens? You make fructose from the glucose and the glucose also stimulates insulin. So your resistant insulin levels are going up from the rise in the glucose and also from the glucose you’re drinking in the soft drink. So it’s a double whammy, right? The insulin resistance make the glucose goes up, but the glucose levels are going up as well from the soft drink. And then that stimulates insulin, which in the setting of insulin resistance is not going to do you good. It’s going to increase fat.

(00:18:08):

And the high glucose gets converted to fructose. So fructose is a carb, right, and glucose can make fructose, and fructose can be used to make glucose. They can go both ways in the body. But when the glucose levels are high, we have shown, and now it’s been shown in many other situations, that the glucose starts getting converted to fructose. I love Levels by the way, and I have a CGM, and I always want to know what to avoid foods that raise my glucose, not only because I don’t want to stimulate insulin, but because when the glucose goes up, it gets converted to fructose.

(00:18:47):

And that’s been shown in the brain, in the Alzheimer’s patients. They have high fructose levels in the brain. And it’s been shown that when blood glucose goes up, guess what happens? You start making fructose in the brain. So both are important. When you drink a soft drink, the fructose is the evil guy that lowers the energy, sets the stage, and then the glucose is actually driving the insulin response, which you don’t want in this setting. And at the same time, it’s also being converted to fructose. So both sugars are bad, but in general, glucose, when it doesn’t get converted to fructose, is there to make instant energy. And fructose was really designed to make stored energy. Together, they create havoc.

Casey Means (00:19:41):

This is Dr. Casey Means, co-founder and Chief Medical Officer of Levels. If you’ve heard me talk on other podcasts before, you know that I believe that tracking your glucose and optimizing your metabolic health is really the ultimate life hack. We know that cravings, mood instability, and energy levels and weight are all tied to our blood sugar levels. And of course, all the downstream chronic diseases that are related to blood sugar are things that we can really greatly improve our chances of avoiding if we keep our blood sugar in a healthy and stable level throughout our lifetime.

(00:20:18):

So I’ve been using CGM now on and off for the past four years since we started Levels, and I have learned so much about my diet and my health. I’ve learned the simple swaps that keep my blood sugar stable, like flax crackers instead of wheat-based crackers. I’ve learned which fruits work best for my blood sugar, like I do really well with pears and apples and oranges and berries, but grapes seem to spike my blood sugar off the chart.

(00:20:42):

I’m also a notorious night owl, and I’ve really learned with using Levels, if I get to bed at a reasonable hour and get good quality sleep, my blood sugar levels are so much better. And that has been so motivating for me on my health journey. It’s also been helpful for me in terms of keeping my weight at a stable level much more effortlessly than it has been in the past. So you can sign up for Levels at levels.link/podcast. Now, let’s get back to this episode.

Dom (00:21:17):

So it’s a dose response type of thing, and I wanted to study this with my CGM. So I went on Amazon and just typed in high fructose corn syrup. I went to the store and looked for high fructose corn syrup, and you cannot seem to buy at least something labeled high fructose corn syrup. It’s integrated into everything. But I think there’s reasons why, and I kind of looked into that, but you can buy crystalline fructose. So crystalline fructose is a hundred percent fructose with no glucose. So that would be if I was to bolus 30 grams of crystalline fructose, which I think you can buy on Amazon. So I’ve been wanting to do some studies with this. What would I see on my CGM if I consumed, took crystalline fructose, dissolved it in water and drank it, what would my CGM response be? This is like one of the experiments that I have in my queue to do, but I haven’t done it yet.

Rick (00:22:16):

So some of that fructose can be turned into glucose. So when you take a big bolus, some people will see a rise in glucose because some of the fructose is being converted to glucose, and some people will not have that much converted and they can actually see their serum glucose maybe stay normal or go down. And this may, people think it was safe, that this was the safe sugar. And way, way back, like 30 years ago, there were groups that were giving fructose to diabetics because it doesn’t raise blood glucose so much. What they didn’t understand is that the way fructose works is that it lowers the energy in the cell, which then causes insulin resistance. And it is true that if you just take fructose immediately, it doesn’t cause insulin resistance on the first go. If you put an animal on fructose, it takes about two to three weeks before they become insulin resistant.

(00:23:16):

So it’s a gradual thing. It’s suppressing the mitochondria and activating pathways. And the more athletic you are, and Dom, you’re athletic. You’re like an aquanaut, right? Well, no, you are. But when you’re really, if you’re young and athletic and you have great mitochondrial function and you have great endothelial function, it takes more work to knock down the mitochondria because you’re starting with a super mitochondria. And if you are a elite athlete in the Tour de France, you can drink soft drinks and you cannot really show that much damage to the mitochondria acutely.

(00:24:00):

But actually, there’s now data showing that even in the elite athlete, if you keep hammering with high fructose corn syrup, you can absolutely start damaging mitochondria. In a young athlete, if you’re drinking soft drinks all the time, you will get into trouble. So if I’m working for the industry, high fructose corn syrup industry, and I want to try to show that high fructose corn syrup doesn’t do much, I’ll pick an 18-year-old thin athletic person who’s super active, and it’s very hard to show an effective fructose or of high fructose corn syrup in that individual with one go. You usually see the triglycerides go up, you’ll see lactate going up, and the glucose could go up, normal or down, depending upon the situation.

(00:24:52):

But if you keep hammering them with fructose, I can guarantee you’re going to get into trouble. High doses of fructose are clearly bad. Very small amounts of fructose are used in sports drinks, including in things like Gatorade, and there is a reason for that. And that reason is that very small amounts of fructose, like one to two or 3%, not like the 6%, but when we 2%, can actually accelerate glucose oxidation, and it does it by facilitating glucose absorption.

(00:25:30):

There’s different mechanisms. But basically there were studies done at the Gatorade Institute, again, I think just outside Chicago, suggesting that what we call catalytic amounts of fructose may actually accelerate glucose absorption and may improve performance. So it’s not like fructose is always evil, right? Natural fruits have small amounts of fructose in it, but there’s so many good things in the fruit, and the fructose quantity is relatively low, that that’s not the same issue as drinking a soft drink. So I just wanted to make that point, because kind of an important one.

Dom (00:26:08):

Yeah, because people will have questions about… A fruitarian, I never met a fruitarian, but I’ve read about them and kind of seen them online where people will subsist completely on fruit, and presumably fructose is representing a very significant portion of their caloric consumption, maybe 20, 30, 40% of their calories. And some of these people are in their 50s, 60s, and 70s, and they’re not overweight.

Rick (00:26:37):

This fructose story is sort of confusing, right? Because there are people who say, “Well, all I do is eat fruit, and I’m not gaining weight and blah, blah, blah.” And it turns out that when it comes to weight gain, there’s two mechanisms associated with weight gain that are really important and often people forget about it. One is there’s a combination effect of carbs and fat, and any one of us who does animal studies know that if you put an animal on carbs or on fat, that you don’t get the same degree of weight gain as if you give them together. And the way it works, and we actually did very careful studies to prove it, the way it works is that the carbs, and particularly the fructose that’s either in the carb or produced from the carb, because remember, you can make fructose from carbs like glucose.

(00:27:34):

So the carbs generate the fructose that drop the ATP, or drop the energy and stimulate hunger. And they also induce a thing called leptin resistance where you don’t fill up, you stay hungry even while you’re eating. And so you don’t really know when to stop. This was all to increase that energy and fill up that tank. So fructose makes you hungry, basically. And then the fat is like the fuel to really drive weight gain. Fat has like nine calories per gram. It’s much more energy dense. And now, there’s now papers coming out. This was actually first noted by a group in London, but more recently it’s been just published in Cell, where they show that fructose or the carbs triggering this leptin resistance is associated with craving of fat.

(00:28:29):

Normally, we don’t have taste receptors for fat, right? We don’t have taste buds for fat. But what’s interesting is when you eat fructose, you activate this switch that I call the low energy switch. And when that happens, suddenly you start craving fat. And so now you’re hungry. You can’t control your appetite, and you like the fried foods. And the [inaudible 00:28:55] combination causes dramatic weight gain.

(00:28:57):

So if you’re a fruitarian, and you may be hungry if you’re not allowing yourself to eat high fatty foods and so forth, you may not show that significant weight gain. We did a study in animals where we put them on fructose, just fructose basically. It was a high fructose diet, no fat, minimal fat. And the animals weren’t gaining much weight, but we could show that they were leptin resistant. Then when we added a high fat diet, they just gained weight dramatically. But if we gave them a high fat diet without the fructose, they didn’t really gain much weight at all.

(00:29:35):

And then we did a real cool trick. We stopped the fructose, but they were still leptin resistant, and they stay that way for about two weeks. And during that two weeks, we put them on a high-fat diet and they gained much more weight than they would on a normal fat diet. So the leptin resistance carries over, at least for a few weeks.

(00:29:54):

So that, sort of complicated, but basically, think of it this way. Fructose is the fire. It ignites the fire that makes you hungry. A high-fat diet is the firewood. You put that on and you get a big blaze. If you’re on a low-carb diet, if you’re on your keto diet, you can eat a lot of fat. You’re going to control your weight, you’re not going to be hungry. And so you’re not going to really gain weight even though you’re on a super high-fat diet, because you need the carbs to make you hungry, to gain the weight from the fat.

(00:30:26):

Even having said that, the carbs themselves with fructose, even on a low-fat diet, will still make you diabetic. It will still give you fatty liver. It will still increase your body fat even if your weight gain doesn’t go up. So the weight gain is tied to the high-fat diet, but becoming fat inside or diabetic inside or get fatty liver inside or develop hypertension, that is driven by this fructose pathway independently of calories.

Dom (00:30:54):

I want to get into some of those pathways. It’s always been a bit hard for me to get my head wrapped around fructose-induced fatty liver disease or hypertension or other, independent of calories, like if it’s isocaloric or even hypocaloric. But some of that, the pathways that you outline in many of the pod, and your papers really, you point to hibernating animals and how that’s part of the starvation pathway. And I kind of think too in regards to, with Alzheimer’s disease, I remember talking with Dr. Mary Newport, and her husband who had Alzheimer’s disease would sit at the sink and he would eat 10 or 12 pieces of fruit. And it was just like a bizarre eating behavioral ritual associated with getting his Alzheimer’s disease, which is probably indicative of the type three diabetes, like in the brain. And you have talked about that and written about that before.

Rick (00:31:50):

Yeah, that’s true that many patients with Alzheimer’s, they often will enhance their craving of sweets. And also many of them do this thing called the wandering syndrome where they kind of wander off. It’s very sad, but they’ll wander off, and it can be dangerous sometimes. They can drive off. And I know many cases of this. And this wandering syndrome is sort of like a foraging response, and I think it’s a carryover from this fructose pathway.

Dom (00:32:21):

And now uric acid is also implicated in the pathogenesis, I guess, of fructose-induced metabolic syndrome. So I’ve been really interested in uric acid. I have a uric acid meter that Dr. Perlmutter sent me. I’ve been experimenting with my uric acid levels and seeing what raises that. I have some questions about uric acid because there’s a lot of… Uric acid blocks aconitase, right? And I know that can cause mitochondrial… But if I look up and do research on uric acid, uric acid is a reducing agent similar to ascorbic acid.

(00:33:00):

And I read that uric acid is, as a reducing agent, it represents one of our major antioxidant pathways, I think, in the body. And I think, I’d written some notes on this. It’s an electron donor. Over half of the antioxidant capacity in the blood comes from hydrogen urate ions. So I have some questions about that. And low uric acid is also associated with Parkinson’s disease. So the etiology of Parkinson’s associated perhaps with low uric acid. And we know that dopaminergic neurons in Parkinson’s are selectively vulnerable to oxidative stress. So could low uric acid be a problem? And I guess what are the beneficial effects of uric acid, because we never hear about that?

Rick (00:33:48):

Yes. Okay, so I have been involved in looking at these studies and doing some studies myself. So let’s just begin. Uric acid is a molecule that can function as an antioxidant, and that’s what you’re basically saying, that it can be an antioxidant. And if you take it and you put it in a test tube and you add oxidants, particularly this one called peroxynitrite… These are oxidants that are produced in the body. It will neutralize those oxidants.

(00:34:26):

For example, we have looked in the blood and urine of people with different types of diseases like kidney failure, and a condition called preeclampsia where pregnant women develop really severe syndrome with hypertension. And we can find some evidence that some of the uric acid in the blood is functioning as an antioxidant. So that would sound like uric acid is good. But actually all the studies, every study shows that when your uric acid is high, that it’s associated with bad outcomes.

(00:35:05):

In fact, it’s associated with increased risk for cancer and increased risk for inflammation and increased risk for Alzheimer’s. And even things like Mendelian randomization studies. There are two new ones that just show that uric acid is a predictor of Alzheimer’s. And Mendelians, where you look at people who have a genetically elevated uric acid, and that is associated with increased risk for dementia.

(00:35:32):

So the question is, how can we explain all this? And the way we can explain it is pretty much like this. When uric acid is outside the cell, it has some antioxidant effects, but when it gets inside the cell, that antioxidant effect is totally dwarfed, totally dwarfed by its ability to stimulate the most potent oxidase system inside the cell. That system is called NADPH oxidase. It’s a system that produces oxidative stress. Okay? It’s like the big one. And when uric acid goes in, it activates that big time, within 10 minutes, and that oxidative stress goes to the mitochondria where it absolutely suppresses the energy factories and lowers the ATP.

(00:36:30):

We can show multiple ways it’s working. So the antioxidant effects are totally dwarfed. Now, the antioxidant effects are also not as much as you think because when it’s acting as an antioxidant, it generates radicals, and it generates oxidants in the process of inactivating oxidants. And we’ve actually published them, and it activates white cells and it stimulates inflammatory pathways. So even though it’s acting as a quote antioxidant, when your uric acid is high, you have showing systemic inflammation. There’s activation of monocytes, there’s increases in inflammatory cytokines, and if you lower uric acid, you improve that. In fact, we now know that high uric acid is a major component of systemic inflammation. In fact, inflammation increases the mortality from COVID, and we found that high uric acid is a predictor for death when you get COVID infection.

(00:37:31):

It turns out that this antioxidant pathway was primarily viewed as being important in neurologic diseases. And there was this thought that if you gave compounds that could raise uric acid, that it might help diseases like stroke and Parkinson’s and multiple sclerosis. All those studies were negative. They were all negative, all the big clinical trials. And what they found was that, when they were giving these substances to raise uric acid, they found that there was an effect on the ATP levels. But if they lowered uric acid with those substances, they could actually improve ATP levels.

(00:38:12):

The reason that they couldn’t show any benefit is because when they were raising uric acid, they were lowering the energy in the cell. If they gave their compound with a substance that actually blocked uric acid, they actually did see some potential evidence of some improvement. So it wasn’t the uric acid that in the early pilot studies that was helping. It was something else. And when they did the big clinical trials, they all failed. Uric acid is a bad guy, okay? It’s a real bad guy.

Dom (00:38:46):

I got a question to follow up then. So the association of low uric acid with Parkinson’s disease, there’s not really good support for that. So you’re saying uric acid is more or less a waste product that the body tries to eliminate. If I was to have zero uric acid in my body right now, would there be any negative consequences to that, or would I experience more robust health? Can uric acid be too low? And are there any other pathologies associated with low uric acid?

Rick (00:39:17):

There are animals that carry an enzyme called uricase, and uricase is an enzyme that can degrade uric acid. And even our ancestors used to carry that enzyme. And that enzyme had uric acid levels, the uric acid levels are around one in those animals. What happened in our setting was that our ancestors started to starve during a period of global cooling. This was about 15 million years ago. We actually studied this period of time. And our ancestors had uric acid levels that were very low, one to two, and they were not… When it’s that low, it’s hard to make as much fat from fructose. So if you’re an animal with a uric acid of two and I give you sugar, you will make just a small amount of fat. And so these animals were living on fruit back then, and during the cooler seasons when the fruit wasn’t available, they were starving.

(00:40:23):

And so in that setting with a low uric acid, in a situation where there’s not food around, they start to die. If you raise the uric acid from two to four or five, which is what the mutation did, then what happens is that the animals can survive starvation. So it protected them from death during starvation because it helped them increase their fat stores. And we actually showed this in animals. We resurrected the extinct gene and the whole bit. But now we’re eating huge amounts of sugar and processed foods and carbs that are driving fructose levels high. Our uric acid levels, instead of going from one to three or to four, now they’re going up to six to seven to eight to nine to 10. And that’s being associated with increased risk for obesity, diabetes, hypertension, chronic kidney disease, fatty liver, dementia. All these things are linked with these higher sugar intake and higher uric acid.

(00:41:30):

So the bottom line is, no. If your uric acid is around one or two, yeah. If you get into a situation where there’s no food around, you’re better off to have a higher uric acid. There is a hereditary disease in which you lose uric acid in your urine, and they run around with uric acid levels of one, and they develop kidney failure over time, but it’s from the uric acid being excreted at high levels in the urine. This was proven recently. It’s not because they have a low serum uric acid, it’s because they have a defect in their kidney and there’s so much uric acid going through that it forms crystals and damages the kidney.

Dom (00:42:11):

So then should we be taking drugs to lower uric acid sort of as a preventative? If we’re just running three or four… I forget what my uric acid is, I think somewhere around 2, 2.5 or something. Would there be an advantage to pharmacologically or maybe with natural substances lowering uric acid?

Rick (00:42:30):

This is a very controversial topic, but I will tell you that if your uric acid is over seven, that there’s a dramatically increased risk for you to develop all these bad conditions, like heart disease and so forth. And there’s strong evidence that it’s probably involved, that it could be playing a role in causing heart disease. But currently the guidelines are to treat people only if they have gout where it’s really clear that the gout is from uric acid, and you get these crystals in your joints, you get this terrible pain. And it’s associated with heart disease. And if you control the gout, you can reduce your risk for heart disease and reduce your risk for cardiovascular events.

(00:43:17):

But if you have a high uric acid in the absence of gout, currently there’s no recommendations to treat that group. I personally think that you should. And the way I would recommend it, is first off, review with your doctor what medicines you’re on because there’s some medicines that raise uric acid, so just try to switch them out.

(00:43:38):

A second thing is look at your diet. Are you drinking a lot of alcohol, which can raise uric acid? Are you eating a lot of sugar? That raises uric acid. You should cut that back for sure. And things like certain types of high purine foods. Lots of red meat probably is not as good. It turns out that red meats in particular. But there’s a caveat to that, and that is if you’re on a keto diet, which you’re an expert on, when you’re eating a low-carb diet, the uric acid is not as dangerous. It can still cause gout, but the mechanisms by which it works to cause diabetes and obesity and inflammation are really reduced in the setting of a low-carb diet. So if you’re on a low-carb diet and your uric acid is high, there’s not as much risk. If you’re on a keto diet and your uric acid is super high, you might get gout. And so that, you don’t want that.

Dom (00:44:41):

Liver, like organ meats for example. What if you’re eating paleo and a lot of organ meats and a lot of honey, which is mostly fructose too. So I do eat liver probably about once or twice a week.

Rick (00:44:55):

Paleo diets in general are very effective at losing weight because you’re not really eating a lot of carbs and high glycemic carbs like bread and rice and potatoes. And so oftentimes paleo diets are well tolerated. In those diets, your uric acid can be high, but it doesn’t seem to cause as much trouble when the carbs aren’t around. It might be because ketones can block some of the effects of uric acid. And Ben Bikman, for example, is doing some studies on this right now, and others have shown the anti-inflammatory benefits of a keto diet.

(00:45:36):

Honey is a good one. So I’ve not studied honey personally. I haven’t studied it, but this is what I do know. I do know that honey does contain a lot of fructose and fructose, when you eat a lot, it’s going to activate this switch. However, honey can have a lot of other things in it besides, there’s a lot of organic stuff in it. Some of those probably neutralize some of the effects of fructose.

(00:46:05):

Personally, I don’t think it’s probably as bad as pure fructose, or if you took the same amount of fructose from high fructose corn syrup versus honey, my bet is that the high fructose corn syrup would be worse. I think there are good things in the honey. But the truth is, if you’re eating a lot of honey, you can get into trouble. And in the Middle East, I’ve done some consulting over there. And I’ve gone to Kuwait for example, where obesity and diabetes are very high, and it seems to link a lot with the eating of pastries and honey. I personally believe that if you eat a lot of honey, you will get into trouble. But honey is delicious. I recognize that. And small amounts in a low carb diet setting probably is not going to be so significant.

Dom (00:46:58):

Well, people think of honey as a sugar alternative. And maybe let’s pivot a little bit to other sugar alternatives, and getting your take on that. Sweeteners like Equal, which have aspartame. Sucralose, which is in this new drink that has gained a lot of popularity, Prime Sports Energy drinks. So what are your thoughts about, with sugar being the major problem or added sugar, the use of some of these artificial sweeteners, namely aspartame, which is really just two amino acids, right? Phenylalanine and aspartic acid, and I think it’s methylated. It’s a dipeptide that’s methylated. So you get a little bit of methanol as it gets metabolized, and people have talked about that a little bit. And sucralose, I guess, which is chlorinated sucrose, but it’s so, so sweet that you just need a tiny pinch of it to induce the sweet response. So what are your thoughts of these artificial sweeteners?

Rick (00:48:01):

So the first thing is, is that most of these artificial sweeteners do not activate this fructose switch. They don’t lower ATP in the cell. And we’ve studied a lot of them. There’s some that do, like sorbitol actually can get converted to fructose in the body. Not everyone absorbs sorbitol equally. So some people absorb only a small amount of it, but others absorb a lot. So there are these low calorie sugars that can activate the switch and drop the ATP in the cell. Tagatose is one.

(00:48:37):

But most of the sugars do not activate the switch, of these low calorie sugars. So if you compare, if you do a comparative study, and you have one group take high fructose corn syrup and the other group take one of these low calorie sugars, you will show a benefit, because you’re comparing it to something that we know is bad. But it doesn’t mean that those sugars are actually doing anything good, but rather that they’re superior and preferential compared to high fructose corn syrup.

(00:49:10):

Now, having said that, because they’re sweet, they still stimulate dopamine in the brain through the taste buds, but a very interesting thing is they only stimulate it to a smaller degree than sugar. And the other really interesting thing is, if you knock out the taste buds, you lose your liking of these low calorie sugars, but you still love fructoses. Even though the sweet taste buds are not working, you’ll still get that dopamine response with fructose, because it’s stimulating dopamine through the metabolism of fructose.

(00:49:49):

From the energetic point of view, these low calorie sugars do not cause ATP depletion. They do not activate the switch. That is the advantage. The bad news is, they still make you like sweet. And so they do that. And of course, each one of these has questions about their safety profile. There’s questions that people have talked about, and it’s a long list, but I’d be happy to talk about them.

(00:50:13):

But the important thing is that there are some reports that some of these artificial sugars can cause insulin resistance through effects on the microbiome. And we’ve actually tested this, and we can see it with the one called saccharin, and that was the one that was reported in a Nature paper. Saccharin can cause a little bit of insulin resistance, and it seems to be through the microbiome. It doesn’t cause obesity, but it does cause a little insulin resistance.

(00:50:43):

There are epidemiologic studies that link artificial sugars and low-cal sugars with obesity and diabetes. But remember what happens is, the people who take these sugars typically are doing it because they’re trying not to gain weight. They may already have features of metabolic syndrome developing. They already have some evidence of gaining weight and they’re concerned, so they go on these low-calorie sugars. And so it’s not necessarily that the low-calorie sugars predict obesity and diabetes, but rather that the low-calorie sugars are the consequence of people recognizing that they’re beginning to gain weight, they’re beginning to develop metabolic syndrome. And so those are the people who take it. And so those are the people who tend to also progress to getting obesity and diabetes. So I don’t think that the low-calorie sugar epidemiology studies when they say, “Oh, it increases your risk for diabetes,” I don’t think it’s from the low-calorie sugars so much as it is from the general fact that they’re taking low-calorie sugars because they’re concerned about developing obesity.

Dom (00:51:52):

Well, I see two buckets. There’s the artificial sweeteners, which is saccharin, aspartame, and sucralose. And I think we can say, from what you say, these are not inert, so consuming them that the jury’s still out, whether, the health consequences of them. And then you have other things like monk fruit and stevia, and you’re very familiar with allulose. And allulose is very interesting because it seems to not only have many of the benefits of sugar, but it has all these very interesting functional properties, which were brought to my attention after reviewing the literature.

(00:52:28):

You could correct me on this if I’m wrong, but fructose exclusively uses the GLUT5 transporter, and many cancer cells thrive through using fructose for growth and proliferation. And a topic that, actually your review, Blocking Fructose Could Be a Novel Approach Against Cancer, in the Journal of Clinical and Experimental Nephrology, really caught my attention. We actually just did a research review on it for the Metabolic Link podcast, like yesterday. So this idea then of allulose as not only a sugar alternative but potentially having functional properties. So maybe talk a little bit about that.

Rick (00:53:08):

So my take has always been that if you’re trying to lose weight, it’s always better to just try to drink water and avoid dietary or low calorie sugars and try to reduce your intake of sugar, but it’s very hard not to… If you have that crave for sweets, it’s very hard not to try to do something. And so low-calorie sugars was an alternative, but I didn’t view them as having an impact to help you lose weight. It was really just to avoid sugar. It was like they were either neutral or negative, but they’re not really having positive benefits.

(00:53:49):

And then I became aware, actually from Peter Attia, of a sugar called allulose, and I started reading about it. And this sugar looks like fructose. It looks just like fructose. It’s a natural sugar. It’s present in small amounts in fruit and foods that we’re all eating, but it’s just so small amounts that we don’t really know that we’re eating it.

(00:54:14):

But when you make a lot of it, and you can make it, it turns out to be a sugar that’s not as sweet as table sugar, but it’s like a sweet sugar that has very few calories. It’s like 0.2 calories per gram, so it’s very low in calories. And so when you take it, it can substitute as another type of low-calorie sugar. But what was interesting is that their report’s saying that it’s actually beneficial. Instead of not being negative, it’s actually positive. And the most impressive is that it lowers blood glucose, it blunts the rise in glucose with a meal. So if you’re eating, if you take a little bit of allulose and then you eat bread, instead of your blood sugar shooting way up and stimulating insulin and driving fructose production, it won’t go up as much. And I know that you’ve proved it to yourself as well.

(00:55:17):

And also it competes with a fructose transporter. And fructose has been found to drive cancer through this GLUT5 transporter. And so maybe Allulose can compete with it and get in there and block it. But whatever, we’re seeing positive benefits with allulose. And the most exciting one is that there’s some evidence that you can lose weight with allulose. I want to do a big clinical trial on this. I mean, I would like to, because these are all small studies that are published, but they’re pretty convincing and they’re all generally positive.

(00:55:53):

And it suggests that allulose can stimulate GLP-I, which is that hormone that the semaglutides and the Wegovies and the Ozempics are working on. But there, you’re taking the shots, you’re taking this stuff that you have a lot of side effects. And what’s cool about allulose is that it’s natural. You can take it as a sugar, as a chocolate. I would like to do more studies on that. I’m not telling people to run out and buy allulose right now or anything, but it does look like a promising new sugar that unlike the others may actually have benefits.

Dom (00:56:32):

Yeah, yeah, me too. The science was very compelling. In particular, the paper published in Nature Communications that looked at the effects of allulose on the afferent stimulation. So allulose does not cross the blood brain barrier, but in the gut it stimulates the L cells, I think, and GLP-1 is activated, and then this through activating the brain stem mechanisms in the hypothalamus, activates feeding behavior and has a GLP-1 releasing effect, so releasing your own GLP-1.

(00:57:12):

And they did one, two, I think three grams per kilogram, the human dosing equivalent. I did some calculations, because it came out to about 20 grams of allulose for someone like my size, or 40 grams of allulose, which is achievable with RX sugar bars or something. So this caused an acute increase in GLP-1, 500% in the Nature Communications paper, in the rodent models, and that’s really impressive. So it’s a mouse study, just take away what you want. It’s pretty compelling because they did a very methodical experiment where they inhibited, they blocked the GLP-1 receptor, they had GLP-1 knockout mice, and they concluded that it’s working through that receptor.

Rick (00:58:00):

Yeah, you’re exactly right. The science is very convincing that allulose has the potential to be a sweet that might actually stimulate weight loss and might be an alternative to having to take shots and pay lots of money. But I do think, just like you do, that the ideal thing is to actually run a clinical trial and do a dose response and identify what kind of, how much of allulose do you need to take to get this kind of benefit and to make sure that it’s well tolerated. But yeah, I think that there’s a lot of excitement about that.

Dom (00:58:42):

How do we get off the traditional sugars and cravings associated with it? So the artificial sweeteners could be activating this craving for sweets, and we know sugar does and fructose does. It makes things very hyper palatable. Is allulose part of the solution? And what are some safe options that people can pursue if they’re addicted to sugar, which a large percent of the population really is?

Rick (00:59:08):

The first thing is, it’s really hard to get rid of that craving and addiction. And it’s true that when people go on a low carb diet or a keto diet, their craving for sugar tends to decrease after some time. And I know you probably have talked about that. And there is this thing that fruit, for example… And as we mentioned, one or two natural fruits are really healthy because they contain all these other things that counter the fructose. You don’t want to be eating 10 fruit at a time, but fruit can be an alternative that’s sweet and carry some satiety from all the fiber and everything.

(00:59:53):

But allulose might be a candidate. GLP-1 agonists like semaglutide, there’s some thought that they decrease the craving for sugar. And so there are these potential other ways to go. There’s the actual enzyme that metabolizes fructose. If you make an inhibitor to that, which we’ve done in our lab, if you make an inhibitor, you can actually block sugar craving in an animal. But we don’t have any inhibitors that are currently available for humans. But there are companies, including one that I’m affiliated with, that are trying to make inhibitors for fructose that might actually be able to block craving, but they’re not available.

Dom (01:00:47):

Inhibitor of fructose, like transport or?

Rick (01:00:52):

No, it’s an inhibitor of the fructose metabolism. So it’s been shown, for example, like when you eat fructose, remember the energy levels fall. It’s triggered by an enzymatic reaction. And interestingly, there are people who lack that enzyme. It’s a condition called hereditary or essential fructosuria because they spill fructose in their urine, because they can’t metabolize it. And these people, there’s been no reports of them ever getting obesity or type two diabetes.

(01:01:26):

So it’s a very nice target. And I know Eli Lilly and Pfizer both tried to make inhibitors, and they were not successful actually. But there are other groups trying to make inhibitors that, hopefully at one day will go to clinical trial. And if so, they might really, really help blocking the effects of sugar. But things like allulose, looks like they block the effects of sugar to some extent. And so does things like the GLP-I agonists, like semaglutide. So there are already some things available now that may have some benefit on this.

Dom (01:02:11):

When you talk about blocking fructose metabolism or even GLUT5, I automatically, my mind goes to cancer because we study that. And in your review you talk about the pentose phosphate pathway, the non oxidative, the lipogenesis associated with fructose, and then the fructose transport. But I also think about blocking glucose through, like 2-Deoxy-glucose, for example, something that we studied. Like taking a fructose blocker with a glycolysis blocker and maybe titrating the dose. I don’t know if blocking fructose… Blocking glucose metabolism can be toxic to cardiac, but I think you can titrate it in some ways.

(01:02:58):

Rick, is there any other things that you can think about, or any other topics associated with fructose metabolism? And I think really the main message that we want to get across is strategies to reduce sugar consumption, processed food consumption, and optimizing our glycemic variability and reducing that as much as possible. And allulose has been an incredible tool for that. Because I went back to doing some carbohydrate experiments, if you want to call it that, and eating our sugar bar allulose before, for example, a sweet potato. And I can knock down my glycemic response by 40 to even 50%. So I would not know that if I didn’t have a CGM, using Levels.

Rick (01:03:47):

Still a lot to be done, but the allulose does look like a very exciting sugar. That’s why we’re studying it. But I think that there’s a lot of ways to help beat the obesity epidemic. And the very first one is, reduce your intake of high fructose corn syrup and sugar. Don’t eat a lot of glycemic carbs like bread, rice, potatoes, cereal, because they get converted to fructose, plus they stimulate insulin. So these are still like the basic ones. Stay well hydrated and really look at package labels, and processed foods in general are filled with salt and sugar and you don’t want that. And so try to eat as healthy as you can. But it’s very hard not to eat some. And I’m not telling you never to eat a cake, either. It’s just that we have to reduce these things if we’re going to have an impact on the obesity epidemic.