A Sugar Substitute That’s Good For You? The Science Behind Allulose - with Dr. Bikman | EP 169

The degree to which allulose can be used as a replacement for fructose-containing sugar, um, is an ex— a direct— that direct swap will result in an immediate reduction in uric acid production. And I've, I've seen this as well.

Hello, everyone. I'm Dr. David Perlmutter. Welcome back to the program. There's been a lot of talk lately about a sugar called allulose, indicating that in fact consuming this allulose sugar might actually be good for you, might help you with things like your body weight, with controlling your blood sugar, other markers of metabolism. And I've asked Dr. Benjamin Bikman to come on the program today to walk us through latest in the science as it relates to allulose. Dr. Bikman is really a leader out there right now in terms of bioenergetics, in terms of insulin sensitivity, insulin resistance, and that whole paradigm. And let me tell you a little bit more about him. Dr. Benjamin Bikman earned his PhD in bioenergetics and was a postdoctoral fellow with the Duke National University of Singapore in metabolic disorders. Currently, his professional focus as a scientist and professor at Brigham Young University is to better understand the role of elevated insulin and nutrient metabolism in regulating obesity, diabetes, and dementia. So we're going to jump right in and learn all we can about allulose, a very, very exciting new development in the world of sweeteners. Here we go. Hello, Dr. Bikman. Welcome to our program.

Hey, Dr. Perlmutter, nice to see you again.

Nice to see you too. We in fact just saw each other, uh, on a scientific advisory board meeting for RxSugar, a form of allulose. So I wanted to mention that on our time together today, and who knows, it just happened. But before we jump into allulose, I know there's a lot of interest in that, I want to explore you a little bit. And, uh, because your interest is deeply rooted in metabolism. Bioenergetics, I would say, pretty much one and the same. So what does it mean that you study metabolism and why is that important?

Right. Yeah, I appreciate the question simply because there are so many ways to define metabolism, so much understanding of it. Yeah, my— I like that you mentioned my actual academic credentials, which is bioenergetics. Bioenergetics is the study of energy in living organisms, which is Metabolism in some where you are familiar with the building up and the breaking down and the the energetic expense or the molecules that have to get broken apart to pay for that work, if you will. So my focus in metabolism, which more and more I guess to define that a little deeper, is I study metabolic health. And I define that based on the efficacy of the hormone insulin. And someone may think that's a strange step to take. How do we go from metabolic health to the hormone insulin? Uh, it's because insulin is the, it, it, it is the, the, the gatekeeper, um, to all, uh, reactions that I care about as a scientist who studies muscle and neurons and fat cells. That's the, the primary tissues of interest for my lab. Insulin has a thematic effect throughout the body, which is to, uh, it tells cells of the body what to do with the energy that it has. Um, and in that role, it has a powerful influence, potentially influencing whole body metabolic rate, for example, getting back to bioenergetics and measuring metabolic rate. So my focus as a metabolic scientist is really studying the effects of insulin and the consequences of having too much insulin, to be really precise.

Well, you know, in my world, the role of insulin is, as you described, so fundamental in terms of brain health. And beyond that, you know, the notion that insulin is a trophic hormone, that it actually stimulates the growth of neurons, it stimulates the connection of neurons in terms of synaptogenesis, and even nurtures these connections, you know, as another very minimally talked about Side light in terms of the incredible role of insulin. But, you know, what you're talking about is at the, the central core of not just our metabolism, but by default, therefore, our health, resistance to disease, our longevity, and really the whole experience based upon metabolism with insulin being the central player. So what do you do day to day in terms of looking at insulin? What are you involved in in terms of your research?

Right. Yeah. My research, uh, with the big theme being, uh, better understanding insulin and the pathogenicity of living a life where insulin levels are too high too often. Um, an average day will be a mix insofar as I am, yes, both research scientist and professor. I will have a mix of teaching a class. Um, and this semester it just happens to be my teaching assignment is a class called pathophysiology. So any, any Uh, you know, pathophysiology is a course that nursing students will take, and a lot of pre-med students take it. Um, just if you'll allow me a brief aside, um, it's been a very gratifying class to teach because it has helped hone my— and perfect my view of the relevance of insulin resistance in chronic diseases of virtually every tissue, whether we're talking about heart problems or, or liver problems or brain problems or reproductive problems. It's been a fun exercise for me over the years as being a teaching professor to just as an act of personal curiosity, look to determine the influence of insulin resistance in those and more problems. But then other than the classroom, of course, I have a considerable interest in what goes on in my laboratory here on campus where we have multiple projects going on. For example, today we have a lab meeting to discuss a uric acid project that we're doing with Dr. Rick Johnson at Colorado. And just to shed a brief moment of light on that, it's— we're trying to determine the degree to which ketones are sufficient to offset the inflammation that is turned on in response to uric acid. So what happens if uric acid levels are up, but also ketone levels are up within a body? So that's one of a handful of experimental designs and projects that we have working on. So that's the average day in the life of a research professor.

Well, please give Dr. Johnston my regards. I'm— we've not met personally, but we've spent an awful lot of time together in conversations on the phone, uh, and I look forward to meeting with him. We, we actually, I think, began our, our friendship during COVID so we, we've been virtual since. Um, but let's get back to this notion of insulin resistance, which I think is, as you mentioned, so, uh, fundamental to all of our chronic degenerative conditions, which The World Health Organization would characterize as being the number one cause of death on our planet. That said, if insulin functionality is playing such a pivotal role and these diseases are increasing aggressively, why is it that more and more people are becoming less able to use their insulin effectively?

Right. Yeah, that's a great way of framing the question. And just so that the audience appreciates why I would even devote my career to this, insulin resistance affects Up to 88% of all adults within the United States based on recent data. This is the most common health problem. And if it, uh, if that were all and it was a health problem that was benign, then who would care? But the fact that it is not only the most common health problem but also contributes to every non-communicable chronic disease, it means it's also— not only is it very prevalent but also very relevant. So how does it start? Firstly, let me just— Provide my own very brief definition of what insulin resistance is. And I will invoke this, the metaphor of a coin that imagine this coin that I'm holding is insulin resistance. On one side of the coin is the phenomenon that you just described, which is insulin isn't working as well as it used to. At some cells, I will add that as a provision here. So some of the cells of the body, indeed big ones and dominant ones like muscle cells and fat cells, aren't responding to insulin as well as they used to. Now, however, some cells are responding well to insulin, and that becomes a problem when we flip the coin over, because the other side of the coin that we call insulin resistance is an obligatory hyperinsulinemia or chronically elevated insulin. And that's a good place to start. Um, because of the handful of causes of insulin resistance, I firmly believe that chronically elevated insulin is the most relevant of the causes. In other words, if a person is living a lifestyle Which is chronically keeping their insulin at an elevated state, they become they become progressively more and more resistant to that insulin. At least some of the cells of the body do, and this then is the insulin resistance in that coin metaphor. So chronically elevated insulin is a key cause. Now, of course, as the body becomes more resistant to insulin, it needs more insulin in order to get the same signal that. Once upon a time was realized with a more modest amount of insulin. And thus we start to see this very vicious cycle where yes, on one hand, too much insulin is driving insulin resistance, but a failure of the body to respond to the insulin is in turn promoting a greater need for insulin. And so we end up with this scenario in which hyperinsulinemia is both cause and consequence of insulin resistance.

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Right. Uh, it is, it becomes obvious when we consider the insulin effect of the 3 macronutrients within the human diet. So the macronutrients, and your audience knows this, carbohydrates, proteins, and fats. If a person eats pure fat, there is no insulin spike at all. The body, the, the beta cells of the pancreas don't respond to dietary fat. When someone eats pure protein, there can be a modest effect. Um, but it sort of depends on the individual. For example, type 2 diabetics may have a higher response to protein than a non-diabetic. In fact, most certainly does, but generally it's little to no effect. When someone eats pure carbohydrate, there is a substantial effect where even in an insulin-sensitive person, insulin will easily spike 10 times over normal, over fasting levels, and take up to 3 hours before it comes back down to normal.

And that's a normal, good response. That's, that's exactly right.

That is a response in an insulin-sensitive person. Now, If we were to look at that same response to pure carbohydrate in an insulin-resistant person, it could go up twice as high as that. So up to 20 times higher than normal and stay elevated for up to 5 hours.

Now, in an attempt to bring down the blood sugar.

That's right. Insulin's just having to work so much harder and stick around so much longer to, in order to correct the blood sugar, all the while creating havoc throughout the body at the liver cells or the gonads, um, partic— you know, the ovaries in women or the blood vessels creating metabolic Havoc in the meantime. Now, that phenomenon, that response to carbohydrate, is relevant in and of itself, but it becomes doubly relevant when we look at it through the lens of what the average person is doing. So an uncommon person will eat only three meals a day and be insulin sensitive. And so if they eat three meals a day with about four hours in between each meal, there has probably been some some period of time about an hour or so. Before the next meal, when insulin has been able to come back down to fasting conditions. So they have most of their day is spent with normal insulin, or at least a decent part of it of their waking day, a decent part of it. Now, however, when we consider two things, it becomes problematic. Well, three actually. One, which is that most people don't eat three times a day. Most people eat six times a day or so. They will have a big 3 big meals and then 3 snacks in between that we call it a snack, but it might actually be as big as the meal itself was, particularly into the evening when most people really start to indulge. Um, and second, most people are eating primarily carbohydrate. Globally, about 70% of all calories consumed are carbohydrates. So we're eating not only most of the greatest insulin-spiking macronutrient, but we're eating them. Every hour and a half or so, so insulin never has time to come down. But the third aspect to this that's still relevant is that the average person is in fact insulin resistant, and so there is not even a hint of moment every where where in every waking moment insulin levels are are elevated. I'll say it that way. So the average individual is living a life where every waking moment is spent with elevated insulin, and frankly, depending on Their metabolic health, and when they eat in the evening, this may be even spilling into several hours of their non-waking moments. And this is why I believe firmly that we need to, of all the various noxious stimuli that can contribute to insulin resistance, and there are others, and I believe they are relevant, but the most relevant is just give your body a break from the hyperinsulinemia. Give it a chance to have insulin come down, and now you can resensitize the body. and your risk of, risk of all of these chronic diseases goes away, if not the disease itself disappearing.

And get a good night's sleep.

Absolutely. And that's much easier to do, David, if they go to bed without having hyperglycemia. As much as we always focus on blue light, and I think that matters, I'm not saying it doesn't, what we overlook, what too many people overlook, is what did you eat before you went to bed? And we know very well that if someone goes to bed with hyperglycemia, They will have activated the sympathetic nervous system. Good luck trying to sleep if you are in your fight or flight response mode where your, your, your blood pressure is going to be higher, your heart is beating harder, and your body temperature is going to be elevated. That is a perfect storm to ensure it takes you a long time to fall asleep and you're going to sleep poorly. And most people will say, I'm a bad sleeper because I just start to feel anxious. Anxiety has nothing to do with it.

You've simply activated—

that's the consequence.

If this is so central to health and disease resistance and plays such an important role in all of the chronic degenerative conditions that are globally so pervasive, how does that— since it's that important, how do you square that with the fasting blood sugar test that most people get once a year At their doctor's office as an indicator of their glucose homeostasis.

Right, right. I, I very much rail against our glucose-centric paradigm of metabolic health. Um, but you teed this up well, and I— it is important for people to appreciate the fact that our conventional clinical care really does peg almost all markers of metabolic health on glucose. And, and for a problem called insulin resistance, there is one aspect that is conspicuously absent. And just to really illustrate the problem with this insulin resistance, which is you know before it's become type two diabetes, and we define type two diabetes based on the glucose level. Unfortunately, this means by having such a glucocentric paradigm, we're missing what's happening over here, if you will, on the other side of this formula. Because insulin resistance in this pre-diabetic state is a state where glucose levels are normal. But in order to keep the glucose levels normal, insulin has been steadily multiplying up over the years. And so by the time glucose levels change in in an individual, it's very very likely that their insulin has been elevated in a fasted state for up to ten or twenty years. Of course, nowadays this is happening in kids that are under ten, so we are condensing this timeline significantly. But even still, the individual as I'm kind of acting this out and those who can't hear. Or aren't watching us but just listening, insulin resistance is a state where insulin is elevated but glucose is normal. Thus, the glucocentric paradigm fails to detect the problem. There's another canary in the coal mine that's whistling, and that's insulin.

Right. In other words, if you're having a fasting blood sugar, uh, once a year, which I think is, is ridiculous, a snapshot when you should be looking at a video, why not at least ask your doctor to do a fasting insulin at that time as well? A better test would be a glucose tolerance test with insulin measurements each time. And then what is your feeling of the merits of a continuous glucose monitor?

Yeah, I am an enormous advocate. Um, I, I've seen— I've looked with some wonder at this debate where many people are, are very animated in their opposition, and I can't, I can't understand that.

To me, I know that— I know what the argument is, and I— and it's puzzling. But the biggest argument as published in the debate, which was an op-ed actually in the Journal of the American Medical Association, was giving people this data is going to make them neurotic. Oh my gosh. Therefore, we shouldn't allow people to buy scales so they can't— That's right. So they don't have to know how much they weigh.

Yeah, heaven forbid.

This is a metric that you can use.

Yeah, heaven forbid. Don't let anyone have an at-home blood pressure monitoring device.

Right. The doctor knows best and we'll take the pressure.

Yeah. And what good is a speedometer on your car? You don't need to know how fast you're going.

Yeah, it's true.

It's crazy. I think that there is— I mean, would— I mean, would— wouldn't it be wonderful if more people were a little neurotic about what they ate? Perhaps we wouldn't be in the problem we're in. But I think that's a silly premise. I do firmly believe in the democratization of CGMs. I have seen so many people's lives changed and the power of it. Is that they change it themselves. Once they see what's happening in their body, they don't need someone to be telling them what to do.

Exactly.

It ends up becoming a self-correcting behavior because they look at what happens when they eat these foods that they, they, they are told they should, and they see their glucose levels go up to 300 milligrams per deciliter, and it takes 4 hours to come back down. Or they eat something simple like scrambled eggs, and then they see that there's no response whatsoever. Uh, to the, to the glucose. And that to me is the power.

We could talk about those venues whereby people are told what they should eat to keep their blood sugars under control. And, uh, you know, as we see the fruit juices, etc., and high fructose corn syrup being used in recipes. But that said, uh, I think we'll have to do that another time. It's a bit cynical too, and I don't necessarily want to go there. We are going to talk today about a new player in the world of sugar, and that is allulose. And I think both you and I and Dr. Johnson and many of us are really rewriting our books a little bit about embracing the notion that there's a sweetener out there that looks and feels like sugar that may actually have some positive aspects on metabolism. So how did the allulose door get opened for you? Let's start there.

Right. Yeah. So let me— I'll preface this just by briefly saying I do think there is value in having sweet alternatives to sugar. I know some people will just say don't eat anything sweet. I personally don't love that idea because I simply enjoy having sweet-tasting things. And so I think there is value—

Every human walking the planet, it's a survival mechanism. So

yep,

get over it. We all have a sweet tooth.

Yep, that's right.

You know, how aggressive can you be with yourself and, and at times miserable by not Participating when others do.

Yeah, that's— yeah, well said. Right. So for me, allulose got on my radar, um, intellectually when I saw data that suggests, uh, that, that shows that allulose as a rare sugar, um, increases GLP-1. Now, GLP-1 will sound a little familiar, um, to the audience because that is the drug mechanism of the most famous weight loss drugs on the planet right now. um, in the form of semaglutide and then in the form of, um, Wegovy is the weight loss version, or Ozempic, which was the earlier lower dose diabetes version. Yeah. The anti-diabetic version. Um, frankly, when it was at the lower levels, when in my PhD work in bioenergetics, it was actually at a lab that was among the first labs ever funded by Johnson& Johnson to study the effects of the incretins. So I have kept my finger on the pulse of this work for almost 20 years, um, at the very, very beginning. So that has left me with a pretty strong appreciation for the drug and increasingly a wariness, to be frank, where at, at its original lower dose, um, and I will mention some of those effects because I think it becomes a little relevant with aldolose, I, I could look at it and give it a passing grade. As, as much as I, um, am very reluctant to embrace drugs as a therapy for metabolic health. Indeed I am. But even still, I could look at it and say, all right, the, the benefits may be worth the negative consequences because every drug we take is a matter of balancing consequences. Are those the ones— are the ones we want worth the ones we don't want? So again, to answer the question succinctly, I was interested in allulose when I saw that it had a substantial effect at increasing GLP-1. Now, so what? Well, There are benefits to increasing GLP-1, one of which is, um, to delay gastric emptying. So it helps you feel a little more full. Um, so if someone were to take allulose before their biggest meal of the day, for example, it's very, very likely that they will control their appetite a little better during that meal or in the evening when they're at their weakest and they typically indulge more. Perhaps a little allulose is going to be sufficient to take the edge off those cravings and help them just feel full a little better. So it delays gastric emptying. It slows the rate at which the food is moving and helps you feel full longer. Another benefit of GLP-1 activation that we can see with allulose is that it inhibits the hormone glucagon. And as much as we've been talking about insulin, um, glucagon is insulin's opposite, um, with a few different metabolic pathways or metabolic processes, most especially being blood glucose levels, whereas insulin wants to Lower blood glucose levels. Glucagon wants to increase blood glucose levels, and so if GLP-1 is increased and it's inhibiting glucagon, we can see that that's another mechanism whereby allulose allulose may be helping correct blood glucose. And this, I suspect, is one of the main reasons why the evidence that we see—a lot of it's anecdotal at the moment—of people with type one diabetes who take an allulose product like Rx Sugar. They will have a significantly easier time controlling their blood glucose levels, even after they eat something that is starchy or sugary. And it's probably due to the inhibition of glucagon, which is chronically elevated in states of diabetes, type 1 or type 2. So these 2 phenomenon, the delayed gastric emptying and the reduced glucagon, I believe are mechanisms that help control blood sugar because it's controlling the amount of of glucose coming into the blood, which is helping insulin be a little lower. But also there's substantial evidence to suggest that allulose helps on the backside as well, which is the glucose clearance or removing the glucose from the blood. So not only controlling the amount coming in, but also the amount going out, namely increasing it by activating an enzyme called AMPK. And everyone by now has heard of mTOR. And that's a topic for another time. Um, but mTOR is this now famous protein that wants to build things up. Um, AMPK wants to break things down, including accelerating the rate at which we're burning through glucose, um, just to start increasing the catabolic side of the metabolic equation, breaking things down for the production of energy. So collectively, this really does become a pretty metabolically favorable milieu. where the GLP-1 increase, um, is delaying gastric emptying and it is affecting glucagon levels, helping reduce the amount of glucose coming into the blood. And then the allulose is directly increasing AMPK at tissues like the muscle, which is accelerating the weight at which— the rate at which we're pulling the glucose out and burning it for energy.

Well, these are really fundamental biochemical, uh, areas of, uh, interest for so many of us that are involved in looking at metabolism. You know, this notion of AMP kinase, I think, you know, we've talked with our audience quite a bit about it. We want to activate AMP kinase, as you mentioned. One of the best ways is physical exercise.

Mm-hmm.

We know that a drug activates AMP kinase called metformin, and as such, one of the things that's able to do when AMP kinase is activated is reduce the formation of blood sugar from de novo creation of blood sugar in the liver. We call that gluconeogenesis. So this is a pretty handy thing to have on board, and using this in our coffee or whatever, or cooking, that this is yet another way, along with something else I think I'm very fond of, that is quercetin as a nutritional supplement. So these are some of the mechanisms of allulose, and so we're really getting benefits. It's not just that it's Carbon neutral. It actually looks like there's some positive aspects to using this in our foods, using it as a sweetener.

Yeah, yeah. I I can tell you now we're firmly in the realm of anecdote now. But if if the the audience may find this amusing, one of my great struggles with regards to my health is my cravings in the evening. I've I've made no secret about this, but I think that

I've heard you

on podcast. Well, it's it's an embarrassing it's an embarrassing confession. confession where I think it's a consequence of my college days where, you know, as a college student, uh, in the late '90s, early 2000s, I, I would— I ate a lot of cereal, of cold cereal, a lot, like all of my roommates did. It was just sort of the college male diet.

It was handy.

Very, very handy and always delicious. And you, you've— because it's, it's supplemented and has all these vitamins and minerals, you've convinced yourself somehow that it might be healthy for you. But nevertheless, To this day, when I have cleaned the house, got the kids in bed, and I'm sitting down to enjoy some quiet time with my wife, if we have cereal in the house, um, and we don't— I make breakfast from scratch for my kids every morning, in part because I don't want it in the house— if there is any cereal in the house, it is just whispering my name in these seductive tones all evening. And like a true addict, I will tell myself I'm just going to have one little bowl. And I start to justify this, knowing that a little part of me knowing I can never stop at just one bowl. This—

I heard you on somebody's podcast talking about this.

Well, but now I resolve it with allulose. Um, truly, I, I have, I have actually developed this little strategy where I will take a sachet of RX Sugar and I get that delicious sweet hit. And then I make my own kefir. I say it sort of the Russian way because of my time living in Russia, but it's just this fermented milk. That I ferment on my own. I have a little corner of the kitchen counter that's devoted to my little milk, my little dairy brewery, but then I will drink a pint or so of this kefir and, and to have the sweet followed with this little bit of tart from the fermented milk, it, for this kefir, it absolutely takes the edge off my appetite. And so I unabashedly credit allulose and arctic sugar for really becoming part of my strategy for improving my cravings.

Well, in the interest of transparency, I will say that as I started using allulose, I didn't then ask myself, well, how am I feeling? But after a week or so, I noticed that my appetite was reduced. And I mentioned it to my wife, and I didn't put it together at first because I just started using allulose. And then I realized that, in fact, my appetite is has declined a little bit. And I have a voracious appetite. I exercise a lot, and I, I have too good of an appetite. Can get me into trouble, uh, and even if it's too late in the day. But that said, um, you know, I, I hear you loud and clear. Let me move on to, um, something that's been talked about quite a bit lately, and that is the notion that allulose helps to bring down uric acid. So why might that be important? Well, hi everyone, Dr. David Perlmutter here. We hope you're enjoying this content, and if you would do so, go ahead and hit the like button. And if you're not already a subscriber to our channel, please consider doing so. Uh, we're really grateful to have you as part of our community. So let's get right back to the presentation.

Right. Yes. In fact, you, you're one of the authorities on this, and it's very appropriate that we've discussed Rick Johnson, who I credit him with really helping me be aware of uric acid. And then I give you credit as well for the excellent book that you produced on the topic. Um, so most people don't appreciate the origins of uric acid, where we have this very— not your audience, but average individual, if they know anything about uric acid and gout, they're going to repeat the same old line, which is avoid meat. Um, and, and beer, maybe, maybe if they're thinking a little further, they may invoke, you know, beer as well. Um, and They those may especially beer. Well, I would say much much less meat. While that may be a source of uric acid, by far the greater source is fructose metabolism. And again, a topic you're more familiar with than me. My answer to the question then is simply: the degree to which allulose can be used as a replacement for fructose-containing sugar is an a direct that direct swap will result in an immediate reduction in uric acid production. And I've I've seen this as well in time. Time will test this out, um, with, with more peer-reviewed randomized trials. But, um, I strongly suspect as those trials begin to come out, we will see as allulose is used to swap out sugar and other fructose-containing sweets, um, we will produce less uric acid and gout symptoms will improve. Um, that's— it seems inevitable.

Yeah. And beyond gout, of course, you know, what, what we had written about was the notion that uric acid is playing a really important role in metabolism, that as a survival mechanism, it would increase blood sugar, increase sequestration of fat, reduce energy burn, so we stored fat for— as a hedge against starvation, helped to raise the blood pressure. So for these reasons well beyond gout, getting the uric acid level down is what we were talking about, what people continue to recommend, and You know, if allulose can help us with that goal by helping us reduce fructose input, that's a big positive. Let's circle back around to insulin resistance because we opened with that. You know, it's certainly an area of your primary focus. How does allulose factor into that?

Right, well, it's an easy answer insofar as we've mentioned AMPK, where we have found in virtually every experimental model, If you can turn on AMPK, you will improve insulin sensitivity. Now there are other ways I could answer this, but that becomes a pretty convenient answer because we've already discussed it. So AMPK will increase the rate at which a cell is using energy, using nutrients to burn nutrients for the sake of producing energy for the cell to work. Exercise activates AMPK, fasting activates AMPK. That if you— and because one of AMPK's effects is to use more glucose, You want to make the cell more insulin sensitive. For example, a muscle cell or a fat cell is going to have a hard time using glucose if it's not insulin sensitive because it needs insulin in order to get the glucose to be pulled in, except for exercise in the case of muscle. But even then, even in the case of exercise, where when the muscle's exercising, it doesn't need insulin for glucose uptake, but it still needs AMPK. It just has a different way of activating it. So one way or another, we have to go through AMPK in order to open up these insulin-dependent glucose doors and pull in the glucose. So in that sense, AMPK once again becomes a primary solution to improving insulin sensitivity because it will directly activate that pathway.

Yeah, and that does feed back to our discussion moments ago about uric acid. We know that AMP has to be metabolized And generally, we consider the fact that, well, that's what AMP kinase is all about. But it turns out that AMPK has an evil twin, which is AMP deaminase. And what AMP deaminase does is really pretty much the opposite of its twin, AMP kinase. And that is, it fosters increasing blood sugar, increasing gluconeogenesis, the production of blood sugar, the lack of our ability to utilize fat. And even to some degree increases mitochondrial dysfunction so that we don't burn as much energy. And guess what? The lever is pulled by high elevation of uric acid. Uric acid is one of the arbiters of determining which way we go— AMP kinase on the good hand and AMP deaminase on the bad side. And another area that's really relevant to this discussion, I think, and we'll talk about how allulose plays into that, is this production of fatty liver disease, non-alcoholic fatty liver disease. How do you see allulose positioned in terms of even some of the research now as it relates to this really pervasive issue, this NAFLD, non-alcoholic fatty liver disease, or LD rather?

Yeah. So fatty liver disease has 2 origins. I mean, the ultimate— with the ultimate problem being it just has too much fat. Now that sounds more benign than it is because having a fatty liver is just one small step away from it starting to get inflamed, um, and then scarred. And it, it, it really is the gateway problem to further, much more catastrophic liver problems. So we wanna catch it at the fatty liver state because we can still turn it around and we can turn it around quickly. Now, where does the fat come from? There are 2 sources for that fat. One source is insulin-resistant fat cells, where the fat cells that are upstream from the viscera, as they start leaking their fats in a state of high insulin, then it— the liver will readily pull that in and store it. So that's one source. And in that case, if allulose can improve by activating AMPK the insulin sensitivity of the fat cell, then that fat won't be leaking out of the fat cell in a state of high insulin. It's okay for a fat cell to leak fat in a state of low insulin Because then liver will just burn it. But if the liver is seeing a lot of fat and insulin is elevated, it cannot burn it. Fat burning will be stopped. Fat oxidation—it will have to store it. It turns it into triglycerides, and now we have fatty liver disease. But the others—so right there, allulose is once again potentially relevant at the fat cell. But then second, we come back to fructose because the other most common form of the liver accumulating fat, or the most common mechanism, is it—is it? Making its own fat, this process called lipogenesis. And fructose— I'll never forget a manuscript I read probably 20 years ago that described fructose, one of its many ways of describing it, as the most lipogenic molecule in the body. So the liver will so readily take that fructose and turn it into fat very, very easily. And so that becomes a direct contributor where if some— where if someone's eating fructose-heavy sweeteners or sugar Um, or in any other form of it, then that fructose is directly contributing to turning into fat within the liver. But if that fructose-rich sugar has been replaced with a rare sugar like allulose, then you are no longer getting it. And rather than having the, the building block for fat, in contrast, you're activating AMPK in the liver, which will promote fat oxidation or the burning of the fat. So then you begin literally resolving the problem. Rather than contributing to it.

I think Rick Johnson said it very well. He said glucose is the, the sugar of energy utilization and, and fructose is the sugar of energy storage. So, yeah, fits right in with what you're saying. There is some evidence that allulose can be protective as it relates to mitochondria that may be relevant in terms of cardiovascular disease. So where do we— what do we know about that?

Yeah. Yeah. So it could be through, once again, the activation of AMPK, but whether it is through that pathway or not, allulose increases the expression of a master mitochondrial regulator called PGC-1 alpha. And there's lots of acronyms here that you and I are invoking here, but suffice it to say, um, when PGC-1 alpha is turned on, we now have pulled up the lever of the most significant activator of mitochondrial biogenesis. So the synthesis of new mitochondria. So in that sense, allulose continues to contribute to an overall metabolic scenario within the body that is wanting to burn and break down. It wants to take this nutrient, the energy that we have stored, and burn it. So once again, turning on PGC-1 alpha means we're increasing the density or the production, the amount of mitochondria. And where we have more mitochondria, we have a cell that is certainly more inclined and definitely more capable Of burning fat for fuel.

Yeah. And we have another entree to mitochondria, mitochondrial biogenesis through AMP kinase activation as well.

That's right. Well, and I realize, Dave, sorry, you'd asked this in the context of heart disease, um, where mitochondria matter tremendously in the heart. Um, I, I'm, I'm unaware of direct evidence of allulose in heart mitochondria. Um, so I want to just be careful speculating, but certainly there's this very strong pathway where if you're improving insulin sensitivity, you are removing the leading risk factor for heart disease, where we know that, you know, type 2 diabetes or just insulin resistance is the leading risk factor for heart disease. So any intervention you're, you're embracing that is improving those aspects of metabolic health is reducing cardiovascular risk.

I, I have to stop you right there because people would want to listen to what you just said, that insulin resistance is really the leading contributor to heart disease. And how many years have we been saying, oh no, your cholesterol level is elevated?

I know.

So

in fact, David, did you see the paper that was just published? Was it maybe New England Journal of Medicine, where they looked at the 5 leading risk factors of heart disease contribution, and LDL was the absolute lowest of all of them, and having a history of type 2 diabetes was not only the highest, but nothing else was even close,

right?

It was multiples higher than every other risk factor.

But we love our diabetes because our diabetes is an indication that people are eating more highly processed foods. It's good for growing corn and wheat. And the pharmaceutical— let's not go there. I've already gone there, but I'm gonna pass it back.

Oh no, there's no question. I mean, just to— I'll put my own fine point on the topic. There's no question that the current view of metabolic health, which is a glucocentric paradigm, all with the understanding of eat a lot of carbs and eat them often, it is a wonderful way to sell medications.

Yep, and it works for everybody. Everybody gets a hand in the, uh, in the fructose-sweetened pie. Um, how might allulose be, uh, relevant to cognitive function or cognitive decline? Obviously an area I'm interested in. What are your thoughts on that?

Yeah, well, I'll go back to some, um, answers that we've already discussed here, 2 in particular. One, improving insulin sensitivity, and 2, improving mitochondria. So my lab, I'll start with the latter one, which is my lab's published work, which is building on the work of many other much more prominent dementia Alzheimer's-focused scientists than I am. I'm a mitochondria guy, but it was in there that we made our contribution, where we found that one that the the brain with dementia has a perfectly preserved at the level of its genetic expression ability to use ketones for a fuel, whereas almost every gene involved in glucose metabolism. Metabolism was significantly compromised in brains, in the hippocampus, the memory and learning center of people with Alzheimer's disease. So there's a direct ability of the ketone to fuel the brain. And in that regard, allulose could be therapeutic because ketones are not only made in mitochondria, they're not only made when the mitochondria are burning fat, which you turn on when you activate AMPK, but they're also only made if insulin is low. Which can only happen in a body that has— that is insulin sensitive. And, and so if you're taking normal sugar with the glucose and the fructose, you are spiking insulin and you are inhibiting the production of ketones. So you then begin depriving the brain of a fuel that it may be crying out for. Because just to really make sure people get this, if the, if the brain is insulin resistant, even though blood glucose levels may be very high, It's like, it's like this metabolic version of the Rime of the Ancient Mariner. This, this, this shipwrecked sailor who's starving, who's, um, dying from dehydration, but he's surrounded by water and he's bemoaning the irony of water, water everywhere, nor any drop to drink. But that's the brain saying glucose, glucose everywhere, but none for me. I can't access it at parts of the hippocampus because insulin isn't working to open those glucose doors. So So the ability of improving insulin sensitivity allows the brain to not only use glucose better, but also have some ketones from time to time. But then the second part of this is the induction of new mitochondria. If you can increase the mitochondrial density within neurons, they simply have more powerhouses within the cell, more of a greater ability to burn nutrients for energy, including even burning the ketones that may be coming in. You need mitochondria. to burn ketones?

Well, you know, my world is about prevention, and we know that as things stand, as you and I have our conversation today, there's really no meaningful, effective monotherapy treatment for Alzheimer's disease, though you see the headlines about the new wonder drugs that are now being evaluated and some that are actually being used and sanctioned even by things like Medicare. But having said that, As it relates to prevention, now we can demonstrate these defects that you just referred to, these bioenergetic defects of glucose utilization in the human brain, using radioactive markers, fluorodeoxyglucose PET scans, 2 decades before the onset of clinical manifestation when people begin to have cognitive issues, forgetting their grandchildren's names or whatever it may be. So You know, where things stand right now in the world of dementia is, well, we'll just wait till you're suddenly cognitively at issue and then think that we're going to have some kind of wonderful medicine for you, when the reality is the prevention of that cognitive decline falls right into Dr. Bikman's lap. That is a metabolic issue, it's a bioenergetic issue, it's a mitochondropathy, it's a pathology with the mitochondria, the utilization of energy. Which, uh, for which nature has provided us this wonderful back door to allow the ketones in to be utilized as fuel. And what I've often said during lectures is, because we can show as well using markers of ketone utilization in the very same brains of people who show that they can't utilize glucose, that we can bring those neurons back to function by providing them the fuel. I've said that These are neurons that are functional but not functioning. And so the notion of providing them fuel— and your point is well taken as it relates back to allulose— that here is a nifty way to continue a very normal diet that you like and have various types of foods that you like, but still allow yourself to be in a situation where you can be ketogenic if you want to be. And I, I think that's a good place to be, certainly as it relates to the brain, for the reasons we just talked about.

Yeah, yeah, I wholeheartedly agree. As much as, uh, throughout my career I have not wanted— I've been careful in that I've not wanted to be viewed as an advocate of a ketogenic diet, but I want to be viewed as a defender of it because there's so much wrong thinking. The one time, however, where I am an advocate of ketones is when it comes to neurological health. The evidence just is growing so rapidly And, and your point about looking at it through a preventative lens is one I agree with wholeheartedly, where the evidence suggesting that ketones are able to preserve neuron health, and even to a degree, albeit perhaps temporarily, reverse failure and dementia in these clinical— these case studies that are getting published more and more, it leaves me so convinced indeed that The primary reason why I want to be personally in ketosis for at least some hours during the day is that I want to make sure my brain is getting fed. Um, I— my fear of Alzheimer's outpaces a fear of any other chronic disease, even cancers. I am more afraid of Alzheimer's disease than I am of getting cancer or even suffering from cancer, even though I have a family history of the latter. Um, it's Alzheimer's disease that worries me. Um, it's just terrifies me. And so I want to make sure my reason, again, for being in ketosis at least for some hours of the day is, um, my respect for Alzheimer's disease and my respect for the robust evidence that continues to accumulate and to which my lab has contributed that suggests ketones are therapeutic for the neurons. Um, it's, uh, it's— it is— it is much easier, of course, when Frankly, if I can control my cravings in the evening, even my philosophy as a middle-aged guy with a young family is I will eat dinner with my family. Whatever my family's eating, I'll have dinner with my family. Now, usually my wife tends to see things in health through the same lens that I do, but even still, I'll be very strict with my breakfast. I'll be very strict with my lunch, which is very controlled carbs, and I may be a little more liberal with carbs for dinner depending on what my family's eating. But if, if I can control my evening snacks, even though I may get out of ketosis for a few hours in the evening because of what I ate for dinner, depending on what we eat, I will absolutely be back in ketosis come the morning. And so then I will have— but that's not the case if I indulge and I eat 3 bowls of cereal. I won't be in ketosis for a full 24 hours. I will have so loaded my body with glucose that it is, it is dealing with that almost for the next full day. Um, and, and so it delays the time I'm in ketosis, which worries me because I want my brain to be sharp.

Well, for our viewers, if, if you're more— if you're interested in the role of the ketogenic diet as a therapeutic related to Alzheimer's, the interview I did with Dr. Matthew Phillips, uh, is one you'll, you'll want to look at. And we've certainly, uh, you know, interviewed a lot of the, the leaders in in this field looking at the role of excessive carbohydrates versus being in ketosis for general health. And, you know, uh, you're right that, um, this really does play out well in brain-related issues. I mean, that's where it began in 1927 with treating children with seizures, and now we're seeing interventional trials even as it relates to Parkinson's, knowing full well that these are energetic issues. These are acquired Mitochondriopathies. And so,

yeah, and even migraines, things that are less, less, um, chronic than Alzheimer's disease and Parkinson's disease. You mentioned 1927. I think the first trial that I've ever seen— I call it a trial study published by a physician for migraines— was 1929, finding that if patients— if he could get his patients into this ketotic state, their migraines would stop. Um, so it just really appears to be that of all the tissues of the body that begin to suffer with chronic disease, The one that appears to respond the most robustly, um, to— in response to dietary changes and an insulin-sensitizing diet is the brain.

Interestingly, Dr. Alexander Haig in the 1890s demonstrated that, uh, going on a diet to lower his uric acid helped his migraines. So, you know,

even older than I thought. There you go.

Yeah, there you go. Well, uh, what a pleasure, and I'm glad we had some time together today. We've talked, uh, Tangentially in various meetings, but it's really great to have some one-on-one time with you, and I hope we can do it again soon.

Yeah, this has been wonderful. Always, always a pleasure to chat with you. Thank you.

Great. We'll talk soon. Bye for now. Interesting, isn't it? After all these years that there's actually a sweetener that looks like it is probably pretty darn good for us to use, uh, as in cooking and in using in our coffee, if that's your desire. I use allulose. I actually always liked my coffee sweet, and now I'm able to do that again. So I hope you find this conversation we had today interesting. I know I sure learned a lot. Thanks for joining me. I'm Dr. David Perlmutter. This is The Empowering Neurologist, and we'll be back soon. Bye for now.