Allulose: Nature's Sweet Ozempic?

Hey everyone, I want to go over a paper that was published in 2018 but I think is particularly pertinent now because it blends two topics that seem to be consistently sexy and provocative right now with respect to obesity and nutrition. Those two topics are GLP-1 and non-nutritive sweeteners. GLP-1 is the hormone, the incretin hormone in the gut which is the mechanism of action of a lot of these drugs you hear about, the weight loss drugs, Ozempic, Wegovy. Those are GLP-1 receptor agonists. They act on the GLP-1 pathway. And then non-nutritive sweeteners, which become a confusing mess for people. What's healthy? What's not healthy? What are the dangers? And what are the different types of non-natural, then natural non-nutritive, meaning no calories. So this in particular, this paper in particular focuses on allulose, which in my current opinion, if you were to rank all the non-nutritive sweeteners, things like allulose, erythritol, saccharin, sucralose, aspartame, et cetera, et cetera. Allulose, in my opinion, seems to be the safest and potentially even most beneficial. So there's research going on with respect to allulose. Chemically, just so you know what it is, it's an epimer, um, C3 epimer if I'm correct, of fructose. So it tastes a lot like fructose. It has about 70% of the sweetness of pure table sugar, but it's not really processed by the body. It's absorbed and then urinated out because our body's enzymes aren't very good at acting on it. But it has interesting potential benefits, maybe even. So when you think about things like aspartame and saccharin, um, you know, these non-nutritive sweeteners, I think there are actually some data that suggests they're harmful. Um, that's topic for another video, or I've had videos on this already. Um, but then you have something like allulose, which, you know, there are different ways in which it might cause benefits. But I said these are blending two worlds, two topics, right? So this paper, I'll read the title, It's GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose. That's a mouthful, I know. But basically what it's saying in this title is that allulose might actually have a beneficial effect via acting just like these weight loss drugs, these GLP-1 receptor agonists. And what this paper shows is that allulose actually causes at least in a mouse model, the release of the GLP-1 hormone that acts through the 10th cranial nerve, the wandering nerve, um, the vagal nerve, to signal from the gut to the brain with potential therapeutic benefits, which I'm going to go over in this paper. And it actually interacts with chronotherapeutics, so timing of eating as well. So it gets a little bit complicated, but I'm going to try to give you the money shots so you can take away from these data what you will and kind of contemplate, because I found them very interesting. But, um, let's start with the, the first figure. So the first thing they wanted to show is that allulose, as maybe been suggested by other literature, can actually decrease food intake in a mouse model. So that's in fact what they did. So they just fed mice allulose orally and looked at cumulative food intake over a period of time. So the figure I'm going to show you, Figure 1A, shows different doses of allulose and food intake over time. Let's just focus on that figure 1A. And what you see is you're going from white to yellow to orange to red, is the bars are getting smaller over the 1 to 6 hour time frame because higher doses of allulose decrease food intake. So there's a dose-dependent increase on— dose-dependent effect on decreasing food intake. Now the money shot, if you're gonna take one figure away from this paper, it would be Figure 1D. And so what they do is they can look for GLP-1 levels. Now, whereas in humans it would be easiest to kind of access a peripheral vein, you know, when you go to get your blood drawn, you get a little needle right here and they take some blood. Because GLP-1 is an incretin hormone released by the gut, the best place to measure it is actually in the portal vein. So when you eat food and nutrients are absorbed, they actually go through a portal vein from your GI system to your liver, but before going to circulation. So your liver kind of acts like a filter, but that means the portal vein could have much higher concentrations of certain hormones like GLP-1. So that's the best place to look. So what they would hypothesize is if GLP-1 is, um, induced to be released by allulose, you should see an increase in GLP-1 after you give allulose. Do you see that? Well, you can tell me. 1D, Do you see that? The red line is allulose, the black line is control. What you can very clearly see is at the 1 to 2 hour mark, there's a big spike in GLP-1. And what this is showing is that the allulose actually does cause a release of this GLP-1 hormone. Again, the same hormone system that is being acted upon by Ozempic, Wegovy, these expensive new weight loss drugs. That the allulose, allulose, might actually have an analogous effect, which is quite interesting. And I will just note what the dose was. Um, the therapeutic doses they were looking at were 1 gram per kilogram or 3 grams per kilogram allulose. The 1 gram per kilogram, which they use a lot in this study, is— you could eat that as a human. It would be a pretty high dose. If I ate that much, I get GI upset. Um, it could be done, but, um, point being, I think, for this paper is it's not supraphysiologic, as in it's not unrealistic to get in the order of magnitude of this intake, um, as a human. If you have, you know, like an RX Sure, like, swelthy stick bar, that's like 10 grams right there. So, you know, for some of my size, it would be like 6 of those, which would be a lot. I get diarrhea, to be perfectly honest. But, um, because mouse metabolism, human metabolism is a little different— humans have slower metabolisms relative to mice— maybe you're actually just going to get a therapeutic effect having a normal dose in a diet that includes an allulose sweetener. That aside, that's the dosing. I just wanted to mention that. Now I just wanna, you know, before I go on with the data, I want you to put your scientist hat on with me and ask the question, you know, if I wanted to prove that the mechanism of allulose reducing food intake was by causing GLP-1 release, and that signaling to the vagus nerve to the brain, how would I prove that? What are the techniques I could use? And if you want to pause the video and just have a little thought problem there, um, I will reveal the answer now, which is generally what you want to do in science is, you know, block different parts in the pathway. And if you abolish the effect, then you know that that pathway was relevant to the effect. So if In this case, what would you expect if allulose is causing GLP-1 release, GLP-1's acting on the vagus, and it's signaling to the brain? Well, you'd expect if I block GLP-1 with a GLP-1 receptor antagonist, so it blocks the receptor, or if I have mutant mice that have a loss of the GLP-1 receptor, then the effects should go away. And that's indeed what they show in multiple studies. Um, so here's one. In Figure 2, you're gonna see D and G. And you're gonna look at food intake, where the red bar is food intake. And if you look at D, what you see is allulose treatment does decrease food intake. The red bar is smaller than the white bar, right? But then if you look below, what you see here is it says GLP-1 receptor KO, that's knockout. So when they knock out the receptor, the blue, sorry, there's no blue, the red bar and the white bar look the same. And that's because you can abolish the effect by knocking out the GLP-1 receptor. Receptor, suggesting that the mechanism has to do with increasing allulose, and that allulose is signaling through the GLP-1 receptor. And to kind of cut to the point and not to show you a million graphs, they are able to also confirm this effect is mediated by GLP-1 by cutting the vagal nerve, selectively knocking down GLP-1 in the vagal nerve, and using receptor antagonists. Where you just straight up block the receptor. And all these data collectively show that the effect of allulose is to release GLP-1, endogenous produced by the mice GLP-1, and that reduces food intake. Um, also, I'll also point out that the effect isn't just on reduced food intake, but there's improvements in glucose tolerance. So you can do an oral glucose tolerance test where you give a glucose bolus and the area under the curve will tell you how responsive the organism is to glucose. So lower area under the curve suggests better response to glucose. And you can see that here where the allulose group, the lower bar is smaller, the curve is lower down when you treat with allulose showing a better glucose response when allulose is given. And again, when you do the knockout there, the effect is abolished. So you You know, I'm, I'm really hammering this point home, but I think it's a good science teaching point is a way to demonstrate a pathway is by knocking out a component on that pathway and seeing if the effect goes away. And here indeed it does. So again, allulose is causing GLP-1 release. We saw that in Figure 1D, and that's acting on receptors, in this case on the vagal nerve, to signal to the brain, um, in order to regulate food intake. And just as a way to show that it actually is signaling to the brain, I'm gonna to the end, which I think is Figure 10, but you can do staining for areas in the brain to see if there's activation of neuron groups. And in this case, the vagal nerve is communicating to an area of the brain called the nucleus solitary tract. NTS, I believe, is the abbreviation they use. Yeah. And so once the mice are dead, or you kill them— sorry, mice, this is science— you can stain the brain for activation of pathways. In this case, like a pERK1/2 stain. And what you'd expect to see if allulose is causing activation of the vagal nerve communicating to this area of the brain is this area of the brain lights up. Now, do we see that? Again, we do. So I want you to see, you know, it's, um, let's just check up, uh, A, B, and C, and D. And what you're seeing there is you have a control, which is A, and there's not much signal. Then you go to B, and what you see is there's a lot of green, right? Because that's the marker in the brain lighting up after the allulose treatment. In the nucleus of the solitary tract. But then again, you use the GLP-1 receptor knockout mice and the signal goes away. So this is all consistent with the idea that, yeah, allulose is causing GLP-1 release, that's signaling to the brain, causing activation in certain neuron groups in this area of the brain that is, um, important for regulating food intake. And you can actually see that quantified here where the activity, you can see the red bar is very high for the allulose treatment, but the then you knock out the GLP-1 and it goes to nil. So again, I know I keep saying the same thing over and over again, but the mechanism they're showing quite elegantly is allulose causes GLP-1 release, GLP-1 activates the vagal, vagal signals to the brain, and that alters food intake. Now, they did allude to other data showing that allulose can actually increase energy expenditure. So when you think about the energy balance equation, it can potentially impact both arms of that. But we're gonna put that to rest for now and talk about that in another video. Um, now the last thing I wanted to talk about in this video is the chronotherapeutics. Chrono relating to time, um, because something we do know is when you eat matters. Um, nighttime snacking is generally not a good idea, and that's not just because when you nighttime snack, it tends to be cheesecake and Häagen-Dazs. Nobody really makes healthy food decisions at 11 PM, but they have different metabolic effects because your endocrine system ebbs and flows. And generally, it's not a good idea to eat in a period of low activity. So for humans, that's at night because we're human and we're supposed to sleep at night. For mice, it's flipped. They're nocturnal, so their night is our day, their day is our night. And so what they do in this study is they want to see if treatment with allulose can reduce, um, poorly timed feeding in the mice and thereby ameliorate obesity and signs of, um, poor metabolic health like visceral fat. Now let me find the graph so that when I point to it I'm actually pointing to something. Um, but so what they do is they give a treatment of allulose right before the light period, which is equivalent to the mouse's nighttime. And the idea is they want to decrease intake during the nighttime with hopes that they'll have positive, uh, effects. And what they see is indeed that. So when they treat mice with allulose prior to their sleeping period, their light period, food intake in the light period specifically goes down. So again, equivalent to giving a human allulose before they would otherwise be midnight snacking. It doesn't affect day period intake, but it specifically affects night period intake. And what you then see is over time a, um, a decrease in visceral fat and fat in the liver. So I've circled it here. I'm pretty sure that's visceral fat. Yeah, you can see the visceral fat, and the red bar is smaller than the black bar. The black bar is the fat mice, and then you give them the allulose treatment, and visceral fat goes down. And then here it's showing again fat in the liver, where the red bar is lower than the black bar. Triglycerides, stored fat in the liver, are decreasing with allulose treatment, timed at a particular time to stop the mouse equivalent of nighttime snacking. Timing the allulose in this study at other times, say at the beginning of the dark period, did not have the same beneficial effect. So, you know, that's kind of the cherry on top of this nerd salad, nerd feast, whatever you want to call it, um, that, you know, timing of these exogenous molecules can actually have particular beneficial effects, at least in animal models. So just to summarize, what they show here in this 2018 paper is that allulose um, not just has a GLP-1 mimetic effect, but actually causes the release of endogenous GLP-1. Again, GLP-1 being the hormone system that is acted upon by these new weight loss drugs, um, that signals via the 10th cranial nerve from the gut to the brain to trigger an area in the brain that is important in feeding control. It decreases food intake. It actually also increases energy expenditure. And there's a particular benefit in the mouse model of, um, dosing this at night to reduce poor timed feeding, uh, the mouse equivalent of nighttime snacking. Although again, that's kind of a little bit of an aside and a cherry on top. But, um, I definitely think allulose deserves more study. We've really only hit the tip of the iceberg with respect to it. But I wanted to bring you these data because I find them really interesting. I particularly find the topic of non-nutritive sweeteners interesting because It's very easy to come down on one side or the other of, you know, there is no such thing as a free lunch and sweeteners without calories are going to be bad for you somehow. And, um, or, you know, they're definitely a free lunch and if it doesn't have calories, it doesn't matter. It's not that simple. Non-nutritive sweeteners are a diverse family of molecules. And so when, you know, determining what you want to have in your diet, if you want to use these as tools, I think it's important to look at the data and consider what are the effects of things like aspartame in Diet Coke versus allulose, and how you can make the most informed decision in order to, you know, optimize your life enjoyment if you want to have sweet, or you're baking, um, you like keto baking, whatever, um, and optimize your health as well. So, um, now just, you know, as a personal aside, myself, I don't have much of a sweet tooth, but when I do bake, I like to use allulose for the reasons that it might actually have some beneficial effect as compared to things like saccharin and aspartame, which we know screw up the microbiome and can actually cause glucose intolerance. Whereas we see allulose might actually improve glucose tolerance and can have positive effects on energy expenditure, um, feeding, etc., etc., again via this really cool incretin nervous system interaction. So I've been rambling now for 16 and a half minutes, probably more than I needed to be, but I hope you found this interesting. I find it super cool, and have a lovely day.