Click Here for Richard Johnson, MD : Role of Sugar in Obesity, Diabetes, and Alzheimer

Title of my talk is Sugar and its potential role in Obesity, Diabetes and Alzheimer's Disease. My disclosures I'm a professor of medicine at the University of Colorado. My research has been funded by the National Institute of Health. I'm also the chief scientific officer of Rx sugar that markets a low calorie sugar called allulose. I also have equity in Colorado Research Partners where we're trying to develop inhibitors of fructose metabolism. I've received honorarium from Horizon, and I have a book called Nature Wants Us to be Fat. Okay, so I think everyone is aware that we are in a epidemic of both obesity and diabetes, and that there was a time not so long ago when these diseases were actually quite rare. Around 1900, there was only about 1 in 50,000 people who were a diabetic. And today it's like 1 in 8 to 1 in 12. So there's a huge difference in the rate of diabetes. And obesity as well is really declined from being about 3% of the population to being over a third of the population. So the question is, what's driving these epidemics? And the classic hypothesis was presented by Elliot Joslin in the 1920s. And what he suggested is that obesity really is a thermodynamic problem. We're taking in too many calories because we're just asking for more and more food, and we're eating more and more. And so we're taking in too many calories, we're exercising too little because of the car and elevators and escalators and Internet and all these things where we don't have to move. And so the result is that we're spending too little energy, we're taking in too much, and the excess gets stored as fat. Well, that theory has been so popular that it just suggests that it should be relatively easy to treat obesity. We just have to eat less and have to exercise more. But we all know how hard that is. And it really raises questions as to really, is it just that simple, or could there be other possibly biologic mechanisms that are making us fat, that are. Are causing us to eat more? So our insights actually began different places, but one of them was through our work on hibernating animals. And we, we began by thinking, you know, well, obesity we considered a kind of a problem, a medical problem. Insulin resistance is almost like a disease. But there are animals in the wild that purposely get obese and purposely become insulin resistant. And for example, hibernating bears, they'll stay. They'll keep their weight completely normal during the summer, and Then some point late fall, they just change their behavior. They become hungry, very hungry, and they start eating a lot more food, they start putting on a lot more weight, they become fat, they become insulin resistant, they get fatty liver and then and high fats in their blood. And then when they're really, really fat, they'll hibernate in a den. They won't pee, they won't eat. They can go for four to six months without eating. And during that time they live off their fat. And when they burn the fat, they're also producing water, because when you break down fat, you generate water. So they're really living off the fat from both their calories and their water. So we were wondering what triggers the switch in the bear. And one of the things that's very notable is that in the fall they start eating huge amounts of fruit, especially berries. And as the first frost comes, the berries will sweeten up and the sugar content goes up in the fruit and they'll eat thousands of fruits, thousands of grapes in a single 24 hour period. And so over course of weeks they're eating so much fruit that they eat, get really a lot of fruit sugar. Now fruit sugar is known as fructose and it's different from glucose, which is the main sugar in our body. But it's important to note that two of the most common added sugars that we add to food have both fructose and glucose in them. So table sugar is sucrose. It's actually glucose and fructose bonded, bonded together to form a disaccharide. And then there's high fructose corn syrup, which has really a mixture of fructose and glucose so that you can alter the ratio. And typically high fructose corn syrup, when it's used in drinks, for example, like soft drinks, will be a little bit higher in fructose than glucose because people like the sweetness of the fructose. So we wondered, could the fructose be playing a role in this metabolic switch that the bear undergoes? And we put fructose in the drinking water, and when we put it in the drinking water, very amazing thing happens. In the first couple of weeks the mice will love the, the fructose water and they'll drink it a lot, but they'll regulate their weight, their weight. They get more calories from the drink, but then they'll eat less. And the consequences, they don't gain weight, but after several weeks that that system breaks down and suddenly the fructose fed mice will, will not only drink a lot, but they'll eat more than they should so that their calorie intake goes up. And in addition, their resting energy metabolism falls so that when they're actively running around, there's no problem. But when they go into rest, they kind of really go into rest. They become a couch potato and they, they, they're resting, energy metabolism falls and they start gaining weight. The excess energy is turned into fat and their glucose levels go up. They become insulin resistant, their liver fat goes up. This is shown in the picture on the right, where those red, red dots, those big red dots are fat globules in the liver tissue of the, of the mouse. And so the question is, you know, how does this happen? Why does fructose do that? And the interesting part is that fructose is really a different kind of nutrient. So normally when you eat food or nutrients, you're using them for their calories. And when you eat those calories, the calories are converted to energy. The energy can be one of two forms. It can be immediate energy, the energy that we use, you know, to move and talk and walk and dance and sing, or it can be stored. And when the energy is stored, the main way you do that is to make fat, which is really a type of stored energy that you can then break down the fat when you need it to get the energy if there's no food around. So what, so really what happens is when you eat nutrients, you use that to kind of keep your ATP levels high. And then if the ATP levels fall, then the fat can break down to provide the ATP you need. But what's interesting about fructose is that it actually drops the ATP or active energy in the cell. So when it's metabolized, there's an enzyme called fructokinase, which is shown here is khk, because its other name is ketohexokinase. And this enzyme initiates the metabolism of fructose, but it uses ATP to help break down the fructose. And so with the ATP, levels initially drop, and there's no negative feedback system, there's no feedback system to protect it. So if you get a big slug of fructose, the ATP levels fall. But then there's a trick where the amp, which is generated when the ATP is degraded, is removed to make uric acid, and then the uric acid then has effects on the energy factories to help block further ATP production and to block the regeneration of ATP. So what happens is when you eat fructose, you actually reset the. The ATP levels to a lower level. So, like, if you have your ATP, like a full tank, when you eat fructose, it will drop that ATP down to like 70%. So kind of say you have a low tank of gas, and then what happens is those the calories end up going into fat because energy balance has to be maintained. So if you're making less ATP, then the calories have to go somewhere else and they go into fat. So this is sort of how it works. Shown here, the way we used to think about it is that we eat too much, we exercise too little, and those excess calories kind of top off the tank for the ATP levels. It's like filling up the gas tank to full and then the extra energy gets turned into fat. This way we're kind of in a high ATP state. But that's not how it works, because what actually happens in obesity is that the ATP levels fall and fructose seems to be the only nutrient that does this, you know, on a regular basis. It lowers the ATP and at the same time it prevents the fat from breaking down to replace it. And that low ATP level acts as a signal to the organism to say, hey, my gas tank is half full, I'm in trouble, and so I need to get more food to help keep my energy, you know, my gas tank full. And so it stimulates hunger, it stimulates thirst, it stimulates foraging for food. It makes you lose your control of appetite, you lose that satiety response, and that's because you become resistant to, to this hormone called leptin, which normally tells us that we're full and it drops energy metabolism, but only at rest, because it wants you to have good energy to forage for food. It just doesn't want you to use up energy when you're resting. Makes you insulin resistant so that the glucose levels go up in your blood to make sure there's enough fuel. For the brain, which prefers glucose, it raises blood pressure to help maintain circulation, and it maintains blood pressure in the kidney by increasing glomerular pressures or the filtration pressure, which, you know, is to help maintain excretion. It blocks the mitochondria, which normally uses oxygen, so it decreases our oxygen needs and it increases an inflammatory response to help the organism in case it runs and gets an infection and so forth. So it's really was meant to be a survival response. Basically, if we drop our ATP levels a little bit, not a huge amount, but if you drop them a little bit, the animal gets activated and wants to store more food. If you drop energy a huge amount like if the ATP levels go down to zero, it goes into a complete starvation mode where it tries to break down everything we have to make ATP, but this is only dropping it a little ways, like 25, 30%. And that is a signal to eat more. So basically, when you give fructose, it's really the only nutrient that lowers ATP and that stimulates all these things that we would call a survival response. And what supports this is like if you take a person who's obese and you biopsy their muscle or their liver, you'll find that the ATP levels are low, even though the person's eating more food than you are, and, you know, and so forth. What's happening is they, they're eating because their ATP levels are low and they're trying to, to bring the ATP levels back up. And eventually it will come up, but at the expense that you now have extra calories on board. So the formula turns out to be the same. You are eating too much and you are exercising too little, or actually your resting energy metabolism is decreased. And the consequence, though, is that it's being driven by biology, not by choice, and it's being triggered specifically by one nutrient. So fructose is in fruits. And I told you that the bear becomes leptin resistant and fat because it's eating fruit, but it's eating thousands of fruits. We don't eat thousands of fruits. And if you look at the relative amount of sugar we're eating and the relative amount of fructose we're eating, we're getting much less fructose from fruit than we are from soft drinks and from cakes and desserts. And when you eat a fruit, most of the fruit we eat tends to be tart. And there's a lot of good things in tart fruit, like vitamin C and flavonols and fiber and potassium. And fruit is actually good. So you should go ahead and eat natural fruits, but remember that if you eat a lot of them, you could overcome the benefits. So, like, if you eat a bowl of grapes or if you eat, you know, several apples at once, it's going to actually add up. And, and that's the problem with fruit juice, because you actually, you know, put several fruit into a blender and then you make a juice, and the juice actually has a fair amount of fructose in it. So is it that simple? Is it. Is fruit fructose just working to make us hungry and eat more, or is the fructose doing something independently of calories? And it turns out that work we did was able to show that there's two ways fructose works. The way it causes weight gain is by making you leptin resistant. And once you're leptin resistant, you become hungry. Hungry. You can't control your appetite. You actually start craving fat. So the craving of fat is driven by this fructose induced leptin resistance. And so you eat excess of fat which is high in calories and that helps drive the weight gain. So fructose is directly linked with eating too much and putting on extra weight. But if you prevent a person from eating the extra calories and they get fructose but you everyone's getting the same amount of calories or even you re reduce caloric intake. Fructose still has metabolic effects because it raises uric acid and that uric acid affects the energy factories or mitochondria. And, and it can drive insulin resistance, high blood pressure, fatty liver, independently of excessive calories. So for example, this is a study we did where we calorically restricted rats. These are laboratory rats. They're normally eating a certain amount of food. We actually reduced their food intake. But one group had had a high sugar content and the other did not. And because they're all eating the same number of calories, there was no change in weight. Actually there was a little bit change difference in resting energy metabolism. So the sugar fed animals did gain a little weight, but it was very little really. There was minimal weight difference, but there was a huge difference in metabolic effects. So the animals on the high sugar diet, even though they were on a caloric restriction, they became diabetic, they developed fatty livers shown by the red stain, they developed hypertension, they developed hyperlipidemia and even their visceral composition. They increased their relative fat content even though their weight didn't go up. So there's, it isn't just about weight gain, it's really about the metabolic effects as well. So when we were doing these studies, it really suggested to us that fructose was the king, that it was going to be the problem that was driving the metabolic syndrome, that it was this high sugar intake that people are have that's driving obesity and that we should be able to cure the problem by just blocking reducing sugar intake. But I was always worried about things like french fries. French fries are potatoes that are starchy and don't really have sugar or fructose in them. But I knew that they weren't healthy and I knew that they could cause obesity. So the question is what about glucose or starchy that you get from starch? Well, as you probably know, there's a huge theory out there that insulin is the driver of obesity. And if you're eating a lot of starchy foods that that can, they contain glucose, they stimulate insulin, the insulin drives obesity. And so it might be something as simple as that. And great authors such as Gary Taubes has, has really promoted the idea that it's the glucose that's the problem. But our story suggested that it's fructose and it's going through this low energy, that it creates a low energy state and that's what drives fat. So which one's correct or could they both be correct? Well, we did is we put animals on glucose in their drinking water and they had the same thing happen to them after the first week or so. Suddenly they became leptin resistant and then they started gaining weight, they became fat, they became diabetic. It was just like giving fructose. And, and it seemed to be evidence to us that it isn't just fructose. There must be, you know, must also. Glucose might, must also be driving obesity. But then we realized that it wasn't just didn't have to just be through insulin because glucose can be converted to fructose in the body. In fact, the body can make a lot of fructose. It isn't just the fructose we eat, it's the fructose we make. And the main source of fructose. And the only source are carbs. And fructose can only be made from glucose. And under the setting of a high carb diet or high glycemic carbs, starchy foods, and even in diabetes, fructose starts to be made. And this has now been shown in people that fructose is produced when you eat starchy foods. And in fact, when we looked at our animals, we found that the fructose levels went up in the liver and in other sites when we fed them glucose. And when we block the fructose metabolism by using mice that had had their fructokinase knocked out. Remember, that's the enzyme that metabolizes fructose. But when you block that, they got less fat, they got less insulin resistance, they got less fatty liver, they still got a little bit of fat. So it turns out like about half of the effects of, of glucose go through insulin and half go through fructose. And that's really a nice way to look at it. And so both mechanisms are important in how carbs cause obesity. So now we actually have two big mechanisms, sugar and High fructose corn syrup contain fructose that obviously can activate this pathway. But also there's starchy foods and they can be converted to glucose and then to fructose. And so you can get there this way as well. Well, now we knew that, you know, low carb diets, why they work so well, if you go on a low carb diet, you can't make fructose very well because you make fructose from carbs. So if you're on a low carb diet, you can't make fructose and people lose weight. You can be on a high fat diet and a low carb diet and you won't gain weight. It's because you don't get leptin resistant, because it's the fructose that makes you leptin resistant. So this could explain this whole low carb story pretty well. But then we started getting interested in other ways that this glucose path or this conversion of glucose to fructose can happen. And we realize that salt is actually known to be a mechanism for activating the enzyme that converts glucose to sorbitol into fructose, fructose. And animals, you know, love salt licks. And when they find a salt lick, it's, they, it's been shown to help help them gain weight. And we think that it's working through this mechanism that the salt is activating this enzyme to help convert the glucose carbs to fructose. To look at that, we actually gave animals salty diet. And when we gave them a salty diet, they started making a lot of fructose just like, like they did when they were given glucose. And after several months that it took longer. But after several months, these animals actually became fat, diabetic and the whole bit. And actually in the literature, we went back and found that, my God, a high salt diet also predicts obesity and diabetes in humans. And there's even studies that show that if you go on a high salt diet, you can become insulin resistant within five days. So it turns out that when we looked at this, we found that we could block the obesity and block the diabetes by blocking fructose metabolism. So the way salt works, even high blood pressure, all these things are driven through the ability of salt to stimulate fructose production. And when you block fructose, you end up blocking the effects of salt. So now we're going to move on to dementia and we're going to talk about Alzheimer's disease, which is one of the scariest disease of all. No one in the, you know, it's one of the most frightening diseases because there's not really good treatments and it's really a horrible disease to get from both the patient as well as for the family. Well, Alzheimer's disease is a type of dementia in which the brain shrinks and there's a loss of brain cells or neurons. And so the question is, what causes that loss of the brain? And when they look in the tissues of the brain, they see these things called amyloid plaques, which is this accumulation of a kind of a protein like material. And so when they saw that, they go, oh my gosh, maybe that's the cause of Alzheimer's. And if we can block those plaques, we might be able to block the disease. So there's been all this work done over the last 20 years and many, many drugs have been developed to block those plaques. But the trouble is they don't really work. So it suggests that there's something more, there's something, you know, besides the plaque that is driving this horrible disease. So people are beginning to say, well, what happens before the plaques? Can we pick up the disease? You know, maybe the plaques are a late stage of this disease. And when they start looking, some of the earliest changes they see in people who develop Alzheimer's is that they develop insulin resistance, but in the brain, not in the circulation. And they get problems with their energy factories with low ATP production and they get inflammation. And if you look at these three findings, it's striking to me that these are the three main findings of that. What fructose does. Fructose causes insulin resistance. Fructose causes mitochondrial, you know, the dysfunction and poor ATP production. And fructose stimulates inflammation. It actually could fit. But is there evidence that fructose is involved in Alzheimer's? Well, remember, the main source of fructose is sugar and sugar or sucrose. And if you look at sugary beverage intake, you can see that there's a direct relationship between, between the more sugar you eat and the worse your memory is, both short term and long term memory. It also correlates with brain volume. This horrible study in which they did a CT scans and measured brain volume. If you're drinking more than two soft drinks a day, it's very likely that your brain volume is going to be smaller than your friends. That's that. When you think about it, that's a horrible finding. And the main area of the brain that is involved in memory, recent memory, is called the hippocampus. And that's one of the first sites hit in Alzheimer's. And by gosh, it also tends to be smaller volume in people who are drinking a lot of sugary drinks. And, and if you give fructose to rats, lab rats, after about eight weeks they actually have trouble really getting through a maze. Normally when you put an animal through a maze, it does have trouble the first time, but then it, it learns its way through. But if you give them a lot of sugar, they, they have that problem learning how to get through the maze. And so they, they takes them a longer time, a longer latency time to get through a maze. And when you look at the effects of fructose, remember it causes insulin resistance or Alzheimer's is associated with insulin resistance. Well, insulin signaling is impaired. So these, in the brain of fructose fed animals there's insulin resistance and there's oxidative stress and there's a fallen ATP production and there's a block in ATP, in ATP regeneration. It's exactly like what you see systemically with fructose. And you can see that happening in the brain. What's more, if you keep giving sugar, you actually start seeing the development of amyloid and tau protein in the brain. The bio signature of AM of Alzheimer's. So it looks to me like sugar can recreate this disease. We also, in laboratory animals, a paper just came out where they took diabetic animals and they showed that they developed problems thinking and cognitive dysfunction and they had all those findings in their brain. They had high fructose levels, that fructokinase enzyme was high, they found mitochondrial dysfunction, they found all the things that we have found with fructose going on in the brains of the diabetic animals. And then they knocked down the fructokinase, they inhibited the fructokinase and they could rescue the ATP levels and they could rescue the phenotype. And it looks like the fructose metabolism is responsible for the cognitive dysfunction diabetics animals develop. So this really suggests that the fructose pathway may be responsible for, for driving Alzheimer's disease. And consistent with that has been studies in patients with Alzheimer's showing that fructose levels are five to six fold higher than in controls. And they're higher in all the different regions of the brain. And you know, all those letters on the bottom are different regions of the brain. And if you give glucose, remember the starchy foods that cause fructose production, like potatoes and french fries, if you give them to people where you can raise their blood sugar, you can show that fructose is being made in the brain using special techniques such as shown here in the right. So it's going on these high glycemic carbs, these salty french fries, you start making fructose in your brain and you're inducing these changes which chronically and at high levels over time can cause brain neuron death. And remember, uric acid is part of this story. And recently there was a paper that came out where they looked at a large number of risk factors and they found that uric acid was a very sensitive and was the most active risk factor for Alzheimer's. And you can show here, this is anything to the right is increased risk. And you know, uric acid really confers an increased risk for Alzheimer's. Linoleic acid, which is from seed oils, was neutral. And if you have a college education and you keep at education, you, you can reduce your risk for Alzheimer's. But it's. Look at here, uric acid a risk factor. Uric acid is produced when you eat fructose. And in fact, when they looked at all the 376 different metabolites, they all fell along the line of what was expected. There was one that stood above where it was supposed to be and it was uric acid. And again, all these studies found that a high uric acid, even genetically driven, is associated with increased risk for Alzheimer's. And ATP levels fall in Alzheimer's just like they do with fructose and ATP levels. When they fall, that's going to be faster fact. It's like starving the neurons, starving the neurons and over time they die. And we don't want that. So here we've identified a pathway. So keto diets are actually a way to reduce carbs and should theoretically be beneficial. And this is a really cool paper where they took patients with Alzheimer's and they were randomized in a crossover double blind study to be on a keto diet or not. And look at what happens. Cognition stayed stable on the keto diet where it started to drift down in the controls activity of daily living. Basically how well you function stable, whereas the control diet actually worsened over the three months and quality of life actually improved. I think keto diets may be a fantastic mechanism, a way to, to help early Alzheimer's. I really recommend people to consider this. I think the fructose pathway really looks very strong as a mechanism. And in fact if we look here at junk food and processed foods filled with sugar, starch and salt, all these have been associated with increased risk for Alzheimer's. And we know that they can stimulate fructose production in the brain, uric acid production, that could cause all these things. So interventions take home messages. Low carb diet, ketogenic diet, those could be good. Limit sugar, limit high fructose corn syrup, limit salt, limit starchy foods, limit alcohol, limit seed oils. You know, all those things would help. I'm not telling you not to eat any, you know, I'm just telling you to reduce it. Stay hydrated, take vitamin C, that actually helps neutralize fructose effects. Omega 3. Omega 3, like salmon, olive oil and things like that can help as well. And also this sugar that I've been working with, allulose, looks like a promising one as well. A friend of mine, Bill Wilson, who's been on your show, has talked a lot about carb syndrome is what he calls it, but it's basically the effects of carbohydrates on the brain. He picked up on this. He's been working on this for decades. He's author of the Brain Drain. But it's very interesting how he got there from a clinical standpoint, whereas I got there from a research standpoint. But we meet at the, the same crossroad and it looks like to me that carbs are driving Alzheimer's and probably some behavioral disorders as well. So why would fructose do this? It's supposed to be a survival benefit, right? It's supposed to be. Well, we know that fructose stimulates foraging. If you give fructose to animals, they will, you know, increase their, their foraging skills. If you raise uric acid, they'll, they'll jump around and start, they'll, they'll become impulsive, believe it or not. And so there are all these studies that look at this and you know, foraging is a specific behavior. You have to go looking for food. You have to move in, move out, you have to be rapid, you have to be a risk taker, you have to be a bit impulsive. You don't, you don't want a lot of self control. You don't want to remember everything very vividly because you may have to go to a dangerous place. So foraging is a real, it's a real neurologic response. And when you give fructose to animals, you can stimulate foraging. If you give fructose to humans, you'll activate the visual cortex and you'll decrease the areas of the cortex involved in self control. And you'll, you know, stimulate or inhibit blood flow to the hippocampus, which is involved in memory. And if you give glucose, you get the opposite effects for the first 10 minutes. But actually, you know, chronically, we know that if you give glucose a lot, that after about an hour they start making fructose. But at least in the first 10 minutes or so, glucose really is opposite of fructose. So as it turns out, foraging involves the inhibition of activity to some areas of the brain with stimulation of activity in others. And that's exactly what fructose does. But what's really interesting is that the areas where Alzheimer's develops first are the areas where fructose inhibits the activity, reduces the blood flow, impairs the mitochondrial function. So it turns out this the same regions of the brain, whereas the areas where fructose stimulates activity actually are tend to be the areas of the brain that are spared in Alzheimer's. So to me, that's a very strong evidence that what's going on is that fructose was meant to stimulate foraging, and the foraging response involved required us to reduce. Reduce the activity of certain regions of the brain and stimulate others. And when we reduce that activity, we are actually reducing the energy levels in that those areas of the brain. And if we do it chronically, it starts to starve the brain and the brain cells start to die. So we're dying from a hyperactive foraging response. So the brain regions are from stimulating it. And it's interesting, a lot of people with Alzheimer's crave sugar, and a lot of them get a wandering response where they kind of wander off and it's. It may just be a foraging response. So, in summary, we think that the epidemic of obesity and diabetes really relates to the dramatic increase in sugar intake and the rise in uric acid in our population that's occurred over the last hundred years. But it's not just the sugar we're eating. It's also the high glycemic carbs. It's the bread, it's the rice, it's the potatoes, it's the cereal. And these things are also raising blood glucose, especially after meals. And that's stimulating a burst of fructose in our liver, in our brain, and other sites that actually is not good for us. Us. So, in conclusion, we would like to suggest that what was once a survival response can actually be turned into a injurious pathway that's hurting us. And the foraging response is now driving Alzheimer's and behavioral disorders. What was to help us store enough fat to survive starvation is now turning into obesity that's persistent with fatty liver dyslipidemia. What was meant to be insulin resistance to preserve glucose for the brain is now driving diabetes. What was to induce low grade inflammation to help us fight infection may actually be driving things like heart disease. The increase in systemic and glomerular pressure is probably the reason we're at risk for high blood pressure, stroke and chronic kidney disease. And interestingly, this switch away from the mitochondria to a process called glycolysis is actually driving tumor growth. And in the last few years, the amount of papers and we've been involved with some of them showing that fructose can drive cancer growth, it's really enormous and there's a very strong relationship. So this is not our friend. We need to recognize that high sugar diets is not good for our health and we need to cut back on sugar. We need to cut back on carbs. We need, we, we're all eating too many carbs, so we should just cut back. We don't necessarily have to go on a keto diet, but, but we should reduce our carbs. I do have a website. You can check me out. I have a link, bio, I'm on Instagram, I have my book and I have lots of collaborators. I ran lots of papers and I'm very happy to take questions. Thanks.

Thank you, Rick. You know, very interesting conversation. Obviously you're not saying don't have, have fructose, you're just saying don't have excess fructose. Is that correct?

Who doesn't have access?

I, I, you're, you're, you're suggesting don't, do not have excess fruit fructose. All right.

Yeah.

You don't want to have, except excess fructose. But, but, but I'm not telling you.

To have no fructose.

For example. Natural fruits have a lot of benefits.

Yeah. And you know, I think you could.

Easily eat 25 grams of fructose a day and be fine. It's really the problem of, of eating too much. Like I think the average sugar intake is, makes up about 15% of our total diet. And some people are eating 25% of their diet is added sugars and that's way too much. And I think soft drinks are particularly bad because you drink them and so you get a very big rapid uptake in a rapid ingestion. And then it's the concentration that hits.

The liver is very high.

And what triggers the depletion of ATP is the concentration of fructose. So if you drink a soft drink very fast, you'll get more ATP depletion than if you sipped it over three hours, where you might not get Any, so in one case it may just be a calorie and the other one is like activating this biologic switch. So, but I, but no one can just sip a drink over three hours. And I, I do not recommend doing that technique because you're going to fail. And, and so I would try to cut out soft drinks.

Rick Rob Lustig also suggests that even if you take soft drinks, like, you know, diet soft drink, it stimulates your insulin, you know, sort of production, and that could be counterproductive. What's your thoughts on that? That, and you know, is it the worst of the two, better of the two evil, or, or worse of the two evil?

So we have done studies with artificial sugars and, and I can say that.

There are papers in the literature that.

Suggest that especially saccharin is the one that tends to cause mild hyperinsulinemia, probably through an effect on the gut. And we've been able to validate that there is a little bit of stimulation of insulin and insulin resistance with saccharin. We've not seen it so much with the other sugars that we tested and our artificial sugars or low calorie sugars. And we've not been able to induce, you know, weight gain with artificial sugars. I know there's a few papers that suggest that it can, but we, we've really tried hard. We, we do not see that, but it does. The artificial sugars and low calorie sugars will stimulate a little bit of dopamine in the brain. So it does stimulate a pleasure response. So it keeps you liking sweets. But if you knock out the taste receptor, which we did, then animals don't care for artificial sugars, but they'll still like fructose because what dries fructose is not really the taste, it's really the metabolism. So anyway, to get back, most artificial sugars and low calorie sugars turn out not to be.

You know, I don't.

Think they cause obesity, but they're not necessarily beneficial. And there's lots of concerns about low calorie sugars and other things like could they cause cancer and things like this. There's some concerns about sucralose and aspartame with different, different kinds of side effects. Now, disclosure, I did join a company called Rx sugar that has allulose and allulose looks just like fructose, but it does not activate the switch. There's a little hydroxy group that goes a different direction. And I, I became interested in it because it looks like not only does it not activate the switch? Fructose does, but it seems to have some benefits like, like stimulating GLP1 naturally. So there, there may be some benefits of allulose. I'm planning to do studies. I was brought in as the scientific officer and I'm. I. I want to understand alulose more.

Well, we certainly will welcome potential collaboration between Emory Farma and your group. We have a lot of expertise in bioanalysis and where we have multiple mass spectrometer and as well as high resolution mass spec. So whatever you think that sounds good. Yeah, we were able to do.

Let's do that.

Yeah. Thank you so much, Anna. Hamid, do you have any questions for Dr. Johnson? Thank you so much. Thank you. Thank you, Rick. Really appreciate it.