Keto Works… But Not the Way You Think | Dr. Andrew Koutnik

A very low carbohydrate and very high-fat diet, known as the ketogenic diet, has been known to have powerful metabolic changes.

When people utilize these high-carbohydrate diets since the 1970s as the one optimal form of diet, it is foregoing the knowledge for over 200 years that lower carbohydrate strategies are actually one of the most effective ways to reverse obesity and diabetes and other major conditions that now plague the vast majority of adults in the United States of America.

For that first meal, when you first consume it and it's lower in carbohydrates, instantly, glucose is going to drop. Once the body senses less glucose in the blood, it's going to detect that in the pancreas, and the pancreas is now going to lower its insulin secretion. Insulin is a fat storage hormone, and it actually blocks fat from being broken down to be utilized and metabolized for fuel. So, when insulin lowers, it removes this blockade on fat breakdown and allows for your own body fat to now be broken down, taken to the liver, go through fatty acid oxidation, and also goes to other tissues to be starting to utilize as a more predominant form of fuel. And the liver will take that fat and convert some of it to ketone bodies.

I think there's a misnomer in the low-carbohydrate ketogenic community that says, "Oh, fat won't spike insulin and calories don't matter." Fat does matter, and it does contribute to calories, and calories are 100% important. But if you kept calories identical in two different diets, and you just start pouring fat on top of one of the diets, you will gain weight, probably fat.

Andrew, as a metabolic health scientist, somebody who has been on a keto diet for over 10 years, you're somebody that can go deep on the nuances of keto, and that's exactly what we're going to do today. Are you with me?

I'm ready, Jesse. Appreciate it, man.

All right, let's take it from the top. For people who aren't so familiar, what is the ketogenic diet and what is the history there?

So, the ketogenic diet has been around for around 200 years, and this is a diet where most well-known for its to lower carbohydrates in the diet. Lowering carbohydrates in the diet shifts the body away from sugar and carbohydrate dominance as a form of fuel for the body towards more fat and ketogenic or ketone-related fuels. That's the kind of main switch between these two forms of diets, and that's how most people can appreciate them.

Now, when people think about these diets, they're typically composed of some form of protein. Um, you can think salmon, eggs, chicken, um, dairy can be included on this, nuts can be included on this with some type of fibrous vegetable, typically consuming less than 50, less than 50 net grams of carbohydrates per day. And that means total amount of carbohydrates minus fiber. And then you have fat making up the remaining more form of calories. So, this typically breaks down to around 10, less than 10% of total calories coming from carbohydrates in the form of green leafy vegetables, around 20 to 25% coming from protein, and the remaining calories making up from fat. And obviously, you can shift these around in any particular fashion someone chooses to, but that's what mostly makes up the diet.

Now, I mentioned that this diet has been around for 100 years, or sorry, for over 200 years, but it was originally cited in 1796 by John R. as a physician who used this to, or used this nutritional strategy, a nutritional strategy of very low carbohydrate as a tool to medically treat patients with type two diabetes. In fact, it was standard of care for type two and type 1 diabetes for 200 years, or going back 200 years. It was known since 1920, so over 100 years, that it was utilized for neurological disorders. It's been known for 150 years that it's been utilized in Banting where it was a gravedigger who reported his ability to utilize this diet to address obesity. So, it's really been around for quite a long period of time as a therapeutic medicinal tool to address some of the most common forms of metabolic dysfunction observed in the developing world, including obesity, multiple forms of diabetes, as well as the emergence of neurological-based conditions. And now more recently, it has been utilized in a number of emerging trials looking at even things such as anxiety as a mental health condition, bipolar, schizophrenia, and initial pilot analysis and observational studies show it can be quite promising for these conditions. But now there's actually randomized control trials and meta-analyses out of JAMA Psychiatry showing its ability to be utilized as a tool to assist in helping treat anxiety as a mental health condition. So, it's, uh, uh, sorry, depression as a mental health condition. So, it's a very promising and emerging tool as a medicinal tool and has a lot of therapeutic promise.

Okay. With this long history, different benefits that you've named, why in modern-day society is it still so controversial?

So, in the 1970s, the dietary guidelines first came out, and these were issued by the US Senate, and the goal of these were to develop the idealistic diet for the American people. And when they did, they developed a diet that was focused predominantly around higher carbohydrate intake with lower fat. Now, the question is, why would they do this? Well, there was emergent evidence that fat may be of concern because it can raise certain blood lipid levels, in this case, LDL cholesterol, which had been starting to emerge as in a link between that and cardiovascular disease. And obviously, at this time, there was an more rudimentary, reductionist mindset towards, "Okay, if you consume more fat, you will get fatter. If you consume fat, you will displace fat in various tissues." And so, and obviously, it's more calorically dense. For every gram of fat, there's nine calories, and for every gram of carbohydrates, there's four calories. And so, there was a shift towards this logical approach of reducing fat. This should, in theory, at this time, improve blood lipid levels. It should also assist in lowering calories in the diet. And this was thought to be healthy because typically the carbohydrates they were recommending at this time were vegetable-based carbohydrates, not typically what eventually emerged in due time.

So, as this became the predominant diet, and over time, obviously, fat had been getting a worse and worse rap as the emergence that higher fat diets were associated with worse and worse outcomes. What was not being addressed is a particular nuance in that conversation, and that yes, if you eat very high-carbohydrate diets and include high fat on top of that, it develops something called the Western diet or the standard American diet, which is an obesogenic diet, which is known to associate with overconsumption, driving obesity, insulin resistance, and most of the major metabolic issues that we observe in the United States and many of the Western developed world.

Now, one difference between just a higher fat diet on top of high carbohydrates versus a high-fat, very low-carbohydrate diet is a very distinct metabolic phenotype, where that a very low-carbohydrate and very high-fat diet, known as the ketogenic diet, has been known to have powerful metabolic changes again, where you're switching from carbohydrate and sugar dominance towards a fat-based metabolism through metabolic changes in glucose and insulin, which drives this whole shift in the body towards fat and glucose or ketone-based metabolism. That shift is quite critical and associated with many metabolic benefits. However, just the elevation of fat on top of an already high-carbohydrate-based diet has been associated with many negative consequences. So, for a long time, there was this misconception mixing just higher fat diets on top of high-carb diets with this other form of diet, which was a low-carbohydrate high-fat diet, which is a distinct metabolic difference. And that misnomer or mischaracterization of these two completely different diets as one and the same led to a misconception around the ketogenic diet that persisted for multiple decades.

On top of that, we've also known that much emerging evidence has risen on the ability to utilize ketogenic diets over long periods of time, of which our group has reported in the context of metabolic diseases such as type 1 diabetes. And we've shown that over a 10-year longitudinal study that in type 1 diabetes, that this diet can actually have powerful therapeutic benefits, be sustainable without any major adverse consequences. In fact, it had powerful therapeutic effects on glucose, insulin, and in our particular report in AJP Cell Physiology, it also showed the ability to have remarkable cardiovascular health in a disease with 10-fold higher cardiovascular risk.

So, there's a lot of reasons why there was a push for higher carbohydrate intake in the form of more plant-based foods, higher fiber intake because of all the evidence supporting that that may be beneficial for health. But there was a lot of mischaracterizations and misconceptions around higher fat intake that was mixing two distinct forms of diet, which actually were distinct from one another. And so, in many ways, this drove a push away from lower carbohydrate intake. And since the 1970s, in these original guidelines, essentially the dietary guidelines have remained remarkably similar all the way up until this last year, where the vast majority of calories come from fruit, grains, vegetables, the remaining come from and smaller quantities than protein. And then you're allowed to have up to 10% of your diet from sugar.

Now, there's a complete reversal of this approach because what has also happened, Jesse, alongside this belief structure that higher carbohydrate diets were superior, and which they are not, they're just one of the many tools in the toolbox that people can utilize on their journey towards health, as alongside a ketogenic diet, is that these dietary strategies, such as higher carbohydrate diets or ketogenic diets, have for a very, very long time been pitted as one or the other or enemies amongst one another, when in reality, if done correctly, they can be beneficial for some people, whereas other people may benefit from a different approach. But dietary guidelines have almost exclusively focused on one type of diet. And that's a major problem because nine out of 10 individuals in the United States of America, according to multiple studies, have some form of metabolic dysfunction. Meaning their waistline is enlarging, their fasting glucose levels are above normal levels, their triglycerides are elevating, or one other metabolic biomarker has categorized nine out of 10 adults in the United States of America across multiple studies to have suboptimal metabolic health. So, when people utilize these high-carbohydrate diets since the 1970s as the one optimal form of diet that we should be advising for all Americans, it is foregoing the knowledge for over 200 years that lower carbohydrate ketogenic-style strategies are actually one of the most effective ways to reverse things like obesity and diabetes and other major conditions that now plague the vast majority of adults in the United States of America.

Okay. Given what you just said there, nine out of 10 Americans have metabolic syndrome. You're knee-deep in the research. Somebody who wants to walk their way out of that, looking just at the science, is the ketogenic diet the best way to do that?

Well, it depends on the person. So, this is a very individualized situation. If we were to just look at the evidence at large, and the American Diabetes Association in their 2019 consensus acknowledges this, the most evidence-based way to lose weight, lower blood pressure, reduce HbA1c, which is a two to three-month average of glucose control, is a very low-carbohydrate-based diet for diabetes specifically. But if it's optimal, it really depends on the individual person. Every person has different lifestyle, cultural, um, uh, kids, work, when they can exercise or can't, or maybe they can't exercise at all, the foods they're going to get access to. All these different variables play into whether it's going to be optimal or not for an individual person, because I can tell you what the optimal diet is, Jesse, but if you can't follow it, it's irrelevant to you. Right?

So, but if we only focus on the literature, we can see that there is evidence that says that if you were to follow an extremely healthy form of a low-fat, high-carbohydrate diet, kind of more similar to what would be a vegetarian diet, that yes, that can lower insulin quantities in the blood. And there are some health benefits from shifting from a Western diet to a diet such as a vegetarian diet. A lot of evidence that suggests that. But we also know there's a ton of evidence for over 200 years that shifting towards a lower-carbohydrate ketogenic-style diet has also profound health benefits alongside it. So, when actually looking at the ability to address or even actually put type 2 diabetes into remission, we know that both diets can help assist in this. The most evidence-based of these diets is the low-carbohydrate ketogenic-style diet, according to the American Diabetes Association.

Now, another thing to consider is adherence. So, one of the struggles that many people find on their journey to let's say reduce their body fat, reduce their glucose levels or insulin levels in their blood, maybe assist with their diabetes management or reversing it altogether, is the ability to sustain the dietary approach that is most likely to help them achieve that goal. And in the context of something like obesity and type two diabetes, weight loss is incredibly important. Well, how are you going to lose weight? You have to change your diet. Now, what is one of the main reasons someone fails, Jesse, to actually adhere to a diet and see weight loss over time? Hunger. And so that's the emergence of GLP-1 receptor agonists, semaglutide, Ozempic, Wegovy, tirzepatide, all these various weight loss drugs. And what they primarily do is elevate GLP-1 in the brain, leading to a dramatic reduction in hunger, which allows people to adhere to much lower calorie diets of any form. So, people lose weight. Okay, but how do you do that without these various tools? Well, you have to find a diet that allows you to not feel as hungry. Well, one of the most well-known forms of food in the American diet that often drives hunger with low nutritional value is refined carbohydrates. In fact, if you look at the grocery store, typically the 70% in the center of the grocery store is this processed, sometimes ultra-processed forms of carbohydrates, which often are either reduced or absent in nutrient quality and have obviously an abundance in caloric density because these diet, or the people often overconsume these styles of foods. They're actually very prevalent, make up a huge percentage of many American diets. So, simply removing those as barriers allows people to often voluntarily reduce their caloric intake, which is why so many people, including multiple bodies of evidence, suggest that when people just reduce these forms of carbohydrates in the diet, they reduce their struggle with reducing the calories required to reduce body weight.

So, it's one of many tools in the toolbox. Is it superior than others? Well, in type two diabetes, it appears that it might be for at least weight loss, HbA1c, or glucose control in blood pressure. But, you know, everyone's got to find what works best for them because if you lost even more weight on a different diet, then I would say that's best for you. So, it comes down to the person.

Okay. Let's talk to that person right now who is metabolically unhealthy, overweight. They've tried the classical cut back on calories, move the body more, they're ready to try keto, but we want to not overwhelm them. So, what's the simplest way into this diet? And then let's talk about over that first day all the way through the first year and really take our time here and talk about the physiological changes as somebody changes that fuel source.

Sure. So, the best way to do this is to think about what are you eating today? Because the best way to help transition someone to a lower carbohydrate or ketogenic diet is to find out what they're already consuming that they enjoy that already fits that dietary pattern. Okay? And so, maybe they're already eating chicken, maybe they enjoy that they're eating eggs, maybe they like salads, maybe they like asparagus or broccoli or cauliflower. Okay? Well, we're going to keep all those things, but they were consuming a lot of bread and let's say a lot of sweet potatoes or white potatoes, rice. Well, we're going to remove those, okay? And then we're going to find out, okay, how much of those forms of foods, starchy, starchy, sugary forms of carbohydrates, do they really miss in their diet? Do they really miss rice? Okay, well, let's find a substitute for that that's lower carbohydrate. It may not replicate it entirely, particularly rice. That's a hard one to replicate, but there are things like cauliflower rice. It's not exactly the same, but it gives you an alternative that you can supplement in so you don't feel like you're entirely deplete of the foods you were eating before. If you're thinking about, okay, well, I'm So, that's that's an easy guide at first.

Now, for a lot of people, there's amazing tracking tools online that allow them to just input the foods they're consuming, sometimes simply with just pictures, and it will tell them the composition of that diet. Now, what people want to shoot for is green leafy vegetables, a protein source with each food, typically broken down in equal quantities across all meals. So, let's say Jesse, you're 180 lbs give or take, and you wanted to eat the optimal form of protein for you and you exercise. I would say, okay, you could go up to 180 grams of protein, split that over, let's say, if it's three meals, 60 grams per meal. If it's four meals, maybe you're obviously less than that. So, you'd break it up proportionally equally across these meals, you would choose a high-quality protein source, typically from a whole food source, and that would make up your protein source.

Now, if you were to put this into, let's say, Cronometer, MyFitnessPal, this is just going to tell you the amount of fiber, net carbohydrates in that meal from the fiber specials you're consuming, and the protein source. Well, a lot of these protein sources, Jesse, including eggs, salmon, beef, some forms of chicken, like chicken thighs, chicken breasts, are very low in fat, or even the dressing that you put onto your salad are probably going to come with fat, natural forms of fat. And as a result, those natural forms of fat are going to make a a decent amount of calories in that meal. And you also want to account for those within the diet. But ultimately, you're shooting for more of a ratio of lower carbohydrate, ensuring you're getting adequate protein, and allowing the fat to come along for the ride. That's typically a how-to guide in how to implement this in a functional capacity. If you're like an elite low athlete, another level consideration would be, okay, now you need to actually make sure you're getting sufficient calories. You want to split this up strategically around meals, but we're not going to go into that right now. But for the average person, fibrous carbohydrates, net carbohydrates per meal, probably less than 15 or so. It's good to get that fiber in the diet in my opinion. And you want to focus on a high-quality protein source. Again, trying to get as many whole foods in as you can. And just allowing the fat to come on for the ride. Again, avoiding starchy, sugary carbohydrates or hidden sugars that are often in many foods. So, you want to check the back of a label. Sometimes people will pick up some bacon and not realize that a lot of times they add sugar to bacon. They add sugar to beef jerky. They add sugar to peanut butters. And so they do that on purpose because it gives it a higher flavor profile. And then people tend to overconsume them. It also adds more calories. It also reduces the metabolic health of that food in my opinion. So, you have to be conscious of what you're consuming. But if you consume whole foods, you can typically forego a lot of the tricks that food companies will do in packaged foods products. Again, not all companies are trying to trick people, but unfortunately, many do things that may be suboptimal to the food in order for you to overconsume them or consume as much as possible and may not be to your benefit. And that's really making up the diet, okay? Okay, lower carbohydrates, higher protein source, and allowing fat to come along for the ride.

Now, what are the metabolic changes that will transpire? Let's say at the very first meal. So, let's say that you were eating oatmeal in the morning with some egg whites and some fruit, and then your second meal was let's say chicken breast with a some sweet or like a let's say a sandwich like say with some deli meat. And then for dinner, maybe you had some chicken with some potatoes or and maybe a side some side greens. All right. Well, then how would you switch this around? Let's say you switched to a ketogenic style diet. For the first meal of the day, you switched away from the oats and the higher forms of sugary-based fruits towards let's say you're going to do eggs. You're going to do some forms of like let's say chia seeds or some other form of high-fiber low-carbohydrate quantity form of fiber source that may be applicable for say a breakfast style meal. Let's say for that first meal when you first consume it and it's lower in carbohydrates. Maybe you add a little bit of raspberry and blueberries because those are higher fiber content fruits and can be in smaller quantities, let's say a quarter of a cup applicable on this diet. You consume at the first meal, instantly glucose is going to drop. So, the amount of glucose your body is exposed to at that first meal is going to go down. That means the body is now going to sense less glucose in the blood. Once the body senses less glucose in the blood, it's going to detect that in the pancreas, and the pancreas is now going to lower its insulin secretion at the very first meal.

Then, over the next hours up to around hour 18 after that first meal, you're going to see an elevation in something called ketone bodies, which is a byproduct of fat metabolism. What has happened is when the insulin lowers, it removes the blockade on fat breakdown. Insulin is a fat storage hormone, and it actually blocks fat from being broken down to be utilized and metabolized for fuel. So, when insulin lowers, it removes this blockade on fat breakdown and allows for your own body fat to now be broken down, taken to the liver, go through fatty acid oxidation, and also goes to other tissues to be starting to utilize as a more predominant form of fuel, and the liver will take that fat and convert some of it to ketone bodies. The reason your body's converting some of that to ketone bodies, and you actually see a noticeable elevation at hour 18, post the first meal of a ketogenic diet, is because the body is starting to replace what was the sugar for brain energy metabolism towards more ketones as a form of brain energy metabolism to ensure your brain always has sufficient amount of energetic substrates, and any combination of glucose, ketones, or lactate, all three of which are readily utilizable by the brain.

Now, after hour 18, you're going into the next day to next week. Over this next week, the lower insulin quantity within the body is going to now stop the body from retaining as much sodium and water. Why? Because for every gram of glucose that goes into the cell with insulin, three grams of water go in as well. And along with that comes sodium. So, when insulin goes lower, you're not going to hold as much water, which is why it's such an effective tool for many people who have high blood pressure, because you're holding less water. So, as a result, you're starting to excrete more water. You're starting to hold less sodium over this period of time. And that can last for up to two to four weeks. At least some evidence suggests that that's the average period of time for some individuals.

Now, for that period of time, people are often recommended to supplement with some sodium to help balance out this shift in mineral quantities within the blood because some people get this concept called the keto flu, where they feel fatigued or tired. Well, one, the body is shifting from its lifelong predominant reliance on fat or carbohydrates as a fuel source towards this new form of fuel as its new predominant form in the form of fat. That will require the body to make some adjustments and shifts, but also in order to offset what is oftentimes people can experience fatigue or headaches or irritability during this transition. A lot of times, yes, that in part might be due to this major shift the body's going through, but also because you're actually have insufficient amounts of mineral, typically sodium. So, it's often recommended to supplement, increase your sodium intake at your meals, and if that is not able to resolve any of these issues, if they do arise, to add somewhere between one to three grams in addition until those issues begin to reside or resolve until you're fully adapted. Okay? But that's typically within the first seven days. So, you're losing weight typically in the form of water weight. Your glucose is coming down. Your insulin is already coming down, and you're starting to see elevations in signs that your body is now starting to burn more fat.

Now, up to the next two to three weeks, Jesse, your body is going to start progressively shifting to higher levels of fat burning, what we call fat oxidation. And typically within two to up to three weeks, almost all of that has occurred, at least on measurements during exercise that we've done and other people have done, where the body is shifting towards glucose as its predominant form of fuel, towards ramping up its use of your own endogenous forms or own body fat as its new form of fuel or predominant form of fuel. And by week two or three, your body's really ramping it up almost in its entirety, or at least start to get to a place of normalization with those higher fat burning values. Okay? Now, that's going to last up to week two or three. Even up to the first two to three weeks, we also know the body is undergoing changes in its perception towards food. Okay? Okay. So, your reliance on certain forms of food, your dependency, and your your kind of like attachment toward certain foods, in in your your basically your psychological relationship with some of the foods you consumed, and your your new psychological relationship, your new diet is starting to transition and transform over that period of time. And we know that around week four is when we start to see normalization typically of blood glucose levels. And around just after week three, ketone levels start to peak and plateau. So, we're starting to see that brain energy metabolites begin to hit a level of normalization after the three-week window.

Now, that's why we see at the four-week window that most athletes who transition to these lower carbohydrate ketogenic diets begin to see normalization of their performance, where what they were doing on a high-carbohydrate diet, they have now matched and or are equivalent to on a ketogenic diet. So, they're no longer seeing any time of functional decline with a much higher level of fat as their predominant form of fuel or burning during that exercise. And the reliance on fat and ketone bodies as a new form of fuel for many tissues, particularly the brain, is now at a much higher level.

Now, there's other changes that extend beyond that. Some of those appear to potentially be renal changes, glycogen changes, and an array of others that maybe have yet to be detected, like specific muscle fiber type changes, or receptor changes, or otherwise. We don't know all the answers at this point. What happens over this period of time, but we do know that most of the major changes appear to occur within the first four weeks, but some do persist for longer. And ultimately, what we're talking about beyond that point is a stabilization of this new style of diet where your body is now mostly burning fat as fuel, both your endogenous or stored fat on your body, but also the fats that you're consuming from your food. And over time, and as this persists for longer, one would expect that most of the enzymatic changes, the molecules in the body that process metabolites and break them down, most of the stable functional forms of fuel in the blood, glucose, ketones, begin to normalize, and then we start to see changes up to muscle glycogen that may persist for months. In fact, the only study we know of where the muscle glycogen levels begin to fully normalize is 9 to 36 months in duration in high elite athletes, whereas studies for 3 months or less in duration have largely shown initial drops in muscle glycogen levels that start to be restored over time. So, again, these some of these changes appear to be very rapid. Most actually are within the first two weeks. There's some that last up to four weeks, particularly the functional performance-based changes, and then there's some changes that clearly linger for longer than that. And there may be even things beyond that that we don't fully understand. But that's the physiological and metabolic changes that transition when someone shifts towards the standard higher carbohydrate-based approach to a lower carbohydrate diet, where your body is now less reliant on glucose and sugar as a fuel source, insulin is now lower, and your body has now shifted towards more of a fat and ketone-based metabolism.

All right, that was a great overview. A lot of questions popping into my head as you're going over all that. I want to take it back to the beginning. You mentioned lowering carbs. It sounded like protein was around one gram per pound of body weight you recommended. And then fat. I want to zoom in on this aspect because you made it clear we just want to let that take care of itself as we're switching to this lower carb diet. There seems to be this divide in the keto world where some people say we want to up the fat. Let's talk about how you see people in that camp versus how you explained it.

Sure. So, specifically focusing on the protein first, I had mentioned 1 gram per pound of body weight. That's that's a quote-unquote optimal number, especially for athletes or people who are doing any type of exercise training. Higher protein quantities seem to be very beneficial for supporting muscle mass, muscle recovery from exercise, and those benefits seem to be maximized at that amount. You don't need to consume that amount. The RDA used to be 0.8 grams per kg, which was dramatically lower. Okay, what I'm talking about here is 2.2 grams per kg, which is quite a bit higher, over twofold higher, but again, that's mainly due to a lot of evidence supporting its role in muscle function, but also because protein also helps reduce hunger. So, if you say set the calories at a set amount and you start replacing some fat and forms of carbohydrates for protein, your body can actually begin to benefit from higher satiation or lower hunger from just having higher protein within that diet. It seems to be a unique molecule. It's also an essential form of our diet because you need to get essential amino acids from protein. But that addresses the protein quantity. You don't need one gram per pound of body weight or 2.2 grams per kilogram of body weight. But that's really the threshold for maximizing its benefits, particularly if you're an athlete or exercising in some form.

Okay, let me jump in before we go to fat because protein was another thing I want to make sure we hit on. It seems like in the keto world, maybe 5-10 years ago, this was more of a thing, but a lot of people in keto would recommend lowering protein because of gluconeogenesis. So, talk about it from that angle and how you think about that.

Sure. So, that's really a question of what's your priority? Is your priority to maximize body composition on this diet, or is your priority to elevate ketone levels on this diet? They're not necessarily mutually exclusive, but they typically go antagonistic to one another. Meaning, if you have very high protein quantities in the diet, protein does require insulin. Okay? It's nowhere near as much insulin as carbohydrates. 1983 analysis by Odal and Calura actually explicitly showed this. So, you can take 50 grams of a potato versus 50 grams of chicken breast. 50 grams of carbohydrates from a potato is going to require 2.5 times more insulin than 50 grams of a chicken breast, at least protein. So, gram for gram, protein requires 2.5 times less insulin. It's a much slower elevation in glucose, much more persistent over time. Most people will never see the glucose elevation from this because they're not tracking the insulin response or glucose response from this. People with type 1 diabetes, which the disease I live with, you can see these changes because you see 24/7 glucose and insulin, but for the average person, they're never going to see a meaningful glucose elevation or insulin because they're not quantifying it from protein.

But protein does require some insulin. So, the higher the protein quantity, the more insulin. Again, nowhere near as much that would be the case on a higher carbohydrate approach, but it still requires more insulin, even though it's less. And the higher the insulin, the less fat breakdown and the less ketogenesis that's going to occur. If your priority is exercise training and adaptation, then getting protein is almost certainly more important than the level of ketone bodies in the blood. Okay? And particularly so for athletes. But if you have a neurological condition where ketone bodies play a particularly important role for brain energy metabolism or normalization of key symptoms within the brain, then you do want to prioritize ensuring that you are getting higher ketone levels, which means you need to be cautious of how high you put protein. Maybe you don't put protein as high. Maybe you back it off to ensure your ketone levels are sufficiently high for your set outcome. So, it isn't one or the other. It's about the main goal. The majority of people listening to this, Jesse, right now are people who probably want to improve their health as a number one goal. And two, maybe they want to lose weight because seven out of 10 Americans have some form of obesity in the United States. So, they're probably focused more so on their body composition. For the average person, which is why the priority is typically, hey, focus on a protein-dominant diet, lower fiber, or sorry, high green leafy vegetables with higher fiber content, and allow for fat to just come along for the ride. Because if you just allow it to come along for the ride, you're not adding it on top of what you're already doing. If you add a ton of extra fat on top of the food you're already consuming, let's say you kept everything controlled and you just add fat on top of it, it adds a ton of calories, and a ton of calories is going to contribute to excess energy intake. Do you think that energy intake is going to magically evaporate into thin air? No. It's going to be processed by the body to either be stored, or it's going to be put somewhere. It doesn't disappear. And so calories matter.

I think there's a bit of a misnomer in the low-carbohydrate ketogenic community that says, "Oh, fat won't spike insulin and calories don't matter." Fat does matter, and it does contribute to calories, and calories are 100% important in my opinion. Now, what is the controversy and often I think miscommunicated out in the conversation around this is that if people focus on higher fat diets, low carbohydrate, and you know, having sufficient amounts of protein, then people inadvertently voluntarily often caloric restrict. And so calories do become less relevant from a practical perspective because you often didn't see a lot of literature that shows that people just foolishly reduce their caloric intake. So, yes, by default, it's becoming less relevant. And so from that perspective, people say, "Okay, it doesn't matter." And that's more of a practical mindset within that context. But if you kept calories identical in two different diets and you just start pouring fat on top of one of the diets, you will gain weight, probably fat. So, you don't just want to add it on top on purpose. This was something that was pushed by a guy named Jimmy Moore like 10 to 15 years ago. And I don't think it's going to produce optimal outcomes for most people, but it's more about the balance and composition of the diet over the entire diet based on your goals. Again, talking about, okay, is your goal to optimize body composition, or is your goal to optimize, let's say, neurological benefits for a specific condition by elevating ketone bodies to a certain particular level, or do you want to balance the two? So, you find kind of an in-between period. So, for myself, I have probably around 1 gram per pound of body weight of protein. I also exercise quite a bit, typically an hour and a half per day. And my ketone levels range anywhere from 0.3 to 1.5 per day. Okay? So, I'm pretty much well in ketosis most of the day. I have, I hit those protein thresholds. I exercise a lot. I'm very active. And I follow those guidelines and I'm doing just fine. I compete in sport. I am a father, a husband. I am a researcher. A whole, a whole, whole lot of things, and I'm trying to balance myself. Sometimes I lose my mind trying to do these things, admittedly. But either way, at the same time, it's doable, and it's all within the context of the overarching goal. So, you can, it's all along the spectrum, maybe is a better way to describe it. You can push high protein, high, high. Maybe you reduce ketone bodies a little, and you reduce ketone bodies a little or protein a little bit over here, and maybe you up, up, up ketone levels. It really depends on what the actual goal is for the person. Um, and this is where it's important to understand when let's say higher protein is more important, again, body composition, or maybe higher ketones is more important, again, for neurological conditions and maybe mental health disorders.

Really important you went there with the calories because there is this camp out there, and I feel like I've been part of it in the past, who assumes that as long as insulin's low, you can have as much fat as you want and the body won't go into storage mode. So, I think it's important that you highlighted that and any other insight in that realm I'd love you to bring forth.

Sure. So, let's let's talk about that. So, one of the primary examples that's often utilized that said, "Okay, if you reduce insulin almost completely in type 1 diabetes, no matter how much fat you consume, how many carbs you consume, how much protein you consume, you can't gain weight." 100% true. That's a great example of how important insulin is. Well, let's say you don't have type 1 diabetes and you don't completely forget to take your insulin, which is a normal metabolic system where insulin is always present, but it's going to be regulated by everything that's going on. Okay? Well, carbs take the most potent impact on insulin at each meal. So, the higher the carbohydrates, the higher glucose, the higher the glucose, the higher the insulin. Protein is 2.5 times less glucose and insulin impact. As a result, not as much insulin, but still requires insulin. People often talk about you can consume more fat and you see no meaningful impact on insulin. There are studies that show this. However, it's all within context. Fat does not require the same insulin spike that carbohydrates do to be permissive of fat storage. That's important. So, if you consume an unbelievable amount of fat, and I don't recommend anyone trying this, but I know people who have done this, who have said, "Okay, I'm just going to up more fat." In fact, there's actually examples of people who actually, crazy examples. There's people who go on these survival shows, okay, who actually try to survive for 100 plus days out in the wilderness, and usually most of those days they're starving, okay? They're fasting. Alone is a great example of this. There's actually a character on one of those shows who drank a bottle of olive oil every single day on top of what he was already doing to gain 50 lbs before he entered the competition, and he ended up winning it. It will cause you to gain weight. Okay. Um, but if you up your fat intake and you proportionally reduce other forms of food in the diet like carbohydrates, then maybe you find yourself less hungry, and then maybe you find yourself not eating as many overarching calories, and then maybe as a result, you actually find yourself in a caloric restriction. What's important to realize is that calories are not the only factor that matter in weight loss. They're just the one factor that most reliably has consistency consistently across almost virtually every trial ever conducted. It has been demonstrated to impact weight loss. That is different than the practical considerations of how you compose a diet while choosing foods that may have more or less insulinogenic impacts in order to optimize a ratio that one you can adhere to, sustain to, that will also be something that will voluntarily reduce your hunger cues so that you eat less calories by default. But calories are still important. I think virtually everyone who would at one point have said they don't matter is acknowledging they do matter, but it's always within the context in which they speak it. So, pay particular attention to that. They're not saying calories don't matter, although they may actually state that statement. But then they'll also say, "But by the way, here's the here's the nuance of that, which I'm trying to describe here is that yes, there's plenty of nuance to this conversation. But one thing is abundantly clear that if you load up the fat in the blood at high enough levels, and you actually see this in type 1 diabetes, type 1 diabetes, in my opinion, gives one of the best examples of actually trying to elucidate this effect. And there's clear evidence that shows that dose-dependent elevations of fat in type 1 diabetes require dose-dependent elevations in insulin. Nowhere near as much as it would be the case for carbohydrates, but a meaningful elevation nonetheless. Okay. Now, there's a lot of nuance there, but it's just one of many illustrations that fat quantity does matter, calories do matter, and you just want to find a balance. So, it's about finding the again, it's not trying to do like biohacks here or there. It's about designing the diet to optimize the outcome so that you're not always working against yourself to achieve your goal. Again, it's about the design of the diet that allows you to get there. That's the ecological mindset. That's the mindset of what's practical and what can people actually do. But if I say calories are all that matter, someone may just go start counting calories and try to reduce their calories, and that almost always fails people. Always fails people. So, if you just follow that mindset, this is where a lot of people say, "Well, calories don't matter." Okay, well, they do matter, but maybe if you only thing you think about is counting calories, it will fail you. And that's obviously, there's some evidence that suggests that if you just focus on a practical perspective of reducing calories, it can be difficult to adhere to.

Okay. But one other area in the fat realm I want to make sure we hit on is this belief I know I had in the past where it's not just about lowering carbs. You need a certain amount of fat in the diet to actually produce ketones. Tie that bit in. If you reduce your goal is to lower body fat and you're able to lower your calories sufficiently by just consuming let's say fibrous forms of carbohydrates, green leafy vegetables, prioritizing protein, and you're in a caloric deficit and you find you're losing weight. Some people would say, "Okay, well it might be good to consume fat so you're you're producing more ketones." You're no, no. Your body is going to strip the fat off your body to make up for the deficit. So, it's so you don't have to consume fat to produce ketones. Your body will reliably do this on its own. And the best example of that is fasting, where the body will reliably shift towards stripping the predominant form of energy from fat that is stored to make up energy needs for the body, and it'll rapidly elevate ketone.

levels. So if you're in a caloric deficit and you don't get enough fat, your body is just going to take it from your own indigenous fat stores, which for many people is a desired outcome.

Okay. For people that still have the belief that we need to include this extra fat to produce ketones, would that actually block fat from being released from the body to produce ketones?

Yes. Important nuance there. Again, coming back to our metabolic health, people that are obese wanting to lose weight on this diet, if they have that assumption and they're stacking on the fat, they could be working against themselves. And you're saying they are.

Absolutely. Well, if they're trying to lose weight, they are. Okay. But keep in mind, if a little bit of extra fat helps you adhere to the diet more and you remain in a deficit and you're making progress towards your goal, then maybe that's more um sustainable than someone who's trying to cut all the fat out and then they find that they're too ravenously hungry. They can't sustain the diet. Well, that's not a net benefit. So, again, it's about this complex nuance of interactive factors that you work together to get the desired outcome.

Okay. Bottom line, your body's going to find the fat either through the diet or the body. If you want to prioritize the body fat making the ketones, you actually don't want to include that extra fat in the diet.

You want to minimize including excess calories that are not necessary to sustain the diet. Let me let me say it that way because sustainability is the most important part. So if you're able to sustain the diet while not including those excess calories and you're trying to lose weight, then yes, you want to avoid those things. But if those extra calories are important to sustaining the diet, then that might be more important than not doing the diet at all.

Okay. But looking at fat specifically to make those ketones, it's going to want fat either through the diet or from the body. Correct.

Correct. And the best example of this is fasting. If you don't eat anything at all, no protein, no carbohydrates, no fat, the body is going to break down what it needs to from its own storage to ensure you have sufficient energy for your brain and various other tissues. So the body will always make sure that it has what it needs. And for most of us, we all almost universally, even the leanest of us, retain around 2 to 3 months at least of fat stores. And for some people, well over a year of fat stores. So that's just the best example to give as saying, okay, well, if you go into a deficit, will you be able to survive that? Absolutely. You can go into complete absence of any nutrients whatsoever and survive that. Not saying that's necessarily optimal, but it's just an example of how your body will work to ensure your survival using its own stored energy substrates, which is also why the body strategically stores fat. Because the body wants to store as much energy because evolutionarily speaking we would go through periods of feast and famine and you'd want to have something you could reliably tap into for extended periods of time to ensure your survival. So as a result, we have built a machinery that allows for that, particularly for fat, which is the easiest to store and the hardest to lose.

All right, I want to come back to protein, make sure I fully understand the nuances there. We know that protein, independently of the amount, does stimulate insulin less than carbs. But coming back to that bit I was talking about before where 5, 10 years ago, it seemed like more people were worried about taking in too much protein, having that bolus and then creating glucose through gluconeogenesis. Somebody who isn't, say, having copious amounts of protein powder, they're having a healthy mixed diet, omnivore diet. Is that ever a concern?

It's all in the context of the goal. So, if the person wants to optimize body composition, they're lifting weights, they're an athlete, or they want to shift their calories towards more forms of calories that may help reduce their hunger so they're not tempted to overconsume on their diet, then protein is an idealistic way to prioritize as a macronutrient within the calories you're consuming within your diet. But I think there's grains of truth in every single one of these arguments. So this idea that if you consume too much that it may cause an abundance of more glucose, it does. It does produce more. But again, your body's always been doing that. This is not some new revelation, by the way. This has been known for decades that if you consume more protein, you're going to release more glucose and then have more insulin. But people have been doing these ketogenic diets that have been highly protein-focused and they've been seeing huge remarks of benefit. This idea that protein is going to circumvent those benefits is not consistent with 200 years of data showing that just reducing the carbohydrates is the primary form of modification in the diet is the most powerful way to induce some medicinal therapeutic benefit from that dietary strategy. So again, keep in mind this has been done for 200 years in this way. In fact, mostly what was done over 200 years ago was just reducing carbs. That was what was done. It wasn't necessarily a focus around more or less fat, more or less protein. It was just reducing carbs of any form in the diet, and then they were seeing these profound benefits for people who had obesity and diabetes and otherwise. So, it's only now the conversation has got into this like optimization discussion, but keep in mind for most people, they're the farthest from optimized. They're struggling with metabolic health issues. They're not anywhere close to optimal. So simply shifting towards a tool that reliably works and doing it in a consistent way is one of the most powerful steps they can take on their health journey and not get too bogged down in the nitty-gritty detail of, "Okay, will this stimulate more gluconeogenesis and insulin?" Well, yeah, it does. But guess what? It doesn't really matter, does it? Because for 200 years, they've been doing that just fine. So, again, it is not like people are wrong when they state that it's accurate, but to be overly concerned about it as it's going to forego their benefits from the diet is, I think, misguided.

Okay, let's stick with that old-school mentality of just lower the carbs. And somebody coming into this, just applying that, they're obese, they're metabolically unhealthy, they're not really exercising, but they want to lose the weight, they want to get healthy. Are ketones, if protein isn't being prioritized, protective of lean mass tissue?

So, this is exactly what I studied in graduate school. I've actually, there's very few people who have actually done research on this. I'm one of them. Um, and yes, it does appear that ketones help lower the breakdown of muscle tissue and do have a muscle-sparing effect. That does seem to be a real effect. Uh, there's also work back in the day looking at some clinical physiology studies where they infused ketone bodies and also seemed to help assist in stimulating muscle protein synthesis. So yes, ketone bodies can be supportive of muscle mass retention by preventing catabolic processes within the muscle. That said, I question how important that is related to things like exercise.

Okay. So if someone wants to practically improve their muscle mass composition, dietary components are much less important than the exercise-induced anabolic processes that we know occur from things like resistance exercise, particularly progressive resistance exercise, which challenge the muscle to become bigger and stronger. So, but to your point, yes, ketones have anti-catabolic effects. We showed this in cancer models of one of the most aggressive forms of muscle wasting in cancer cachexia. Um, we know that there's multiple studies that have actually infused ketone bodies or applied them through exogenous ketone administration and it lowers catabolic processes within the muscle. Um, but I, people have to be careful in getting too bogged down in any one nutrient here as being the way to forego something like muscle loss. The most powerful way in lifestyle to improve muscle loss, prevent muscle loss is resistance exercise training, then protein to support the muscle mass and recovery from that training. And then ketone bodies may also be a supportive tool even beyond that to help attenuate the muscle breakdown process. So again, it's all context-dependent here, but for most people who don't have a disease where muscle breakdown is accelerated, which is where ketones may be most applicable, um, resistance exercise and prioritizing protein as a new treatment within their diet is probably going to be the most effective strategy. And this is coming from someone who has actually studied this specifically for this purpose and has also tried to apply these tools to optimize muscle mass myself. So, um, they're all important, but some are more important than others.

And where I think this is really important to understand the physiology is somebody coming to this, say they're 300 pounds, they have sore joints, they can't really move their body, and they need to lose 100 pounds before they get to that point where they can start thinking about exercise. Or maybe it's just too many changes at once, and they want to go for the diet realm as the foundation, which personally I think would be the best first step. Knowing that their muscle, because of ketones, will be preserved, I think is important.

That's a very fair point. Okay. So that is a very unique situ I won't say unique, it's actually becoming much more common. Uh, but that is a very important and nuanced situation where that might be more applicable. No doubt about it. Uh, and and truthfully, when your body goes into a caloric restriction or catabolic breakdown of its own tissues because you're in a deficit, you're probably going to have some ketone elevation even if you're on a higher carbohydrate approach, okay? Because your body is breaking down fat along with that process. But most people who are that heavy tend to hold more muscle mass to begin with. And so as a result, just losing weight in general, they're probably going to start with a surplus. And the second they can start engaging in any form of resistance exercise, even if it's doing push-ups from a wall, okay, maybe they're not doing push-ups from a floor anytime soon, but even if they're almost vertical and doing push-ups and they build up a tolerance over time to be able to handle more and more of that, that's going to be one step on the journey to being able to do a full push-up, to be able to then bench press weight, to be able to bench press even more and more weight. Um, and it's just a step-by-step journey. But yes, you're right that a lot of people struggle to even function at all, and losing weight is a required first step. So, yes, I think that's a really interesting example.

Let's bring exercise into this whole ketogenic diet piece right now and how that could be used as a tool to help produce ketones. Say somebody is able to move, whether it be going for walks, burning up glycogen in the muscles that way, doing resistance training. How can they use exercise to accentuate being in ketosis?

Sure. So, we've known that prolonged forms of exercise can actually increase ketone production. Mainly because as you get to longer, longer duration forms of exercise, your body tends to shift away from carbohydrates and more for fat as a fuel substrate. And anytime you're starting to burn more fat, you by default are increasing ketogenesis. They kind of go hand in hand. You typically don't see noticeable levels of them though until ketone or fat breakdown becomes a meaningful portion of the body's total caloric needs. Uh, but yes, you start to see a shift towards ketone production with exercise. And one would expect that that would only amplify when someone is actually on a ketogenic diet and also exercising at the same time. But I want to throw an important nuance in here because a lot of people who are athletes with higher muscle mass who go on a ketogenic diet don't seem to have very high ketone levels and they may misconceive what I'm saying and say, "Well, hold on. I am the example of what you're saying and my ketone levels are not very high." Yeah. You know why? Because you tend to actually be more metabolically, those tissues, those muscles that you have are more metabolically demanding. You've also probably have the machinery within your body to be more efficient in utilizing those ketone bodies because you have been utilizing them previously. And as a result, you're utilizing them more. You're not just producing them and they're lingering within the blood. Which is why we see that obese individuals actually tend to have higher ketone levels on a ketogenic diet than a normal healthy lean individual. And we see even lower levels in athletes for many reasons. One of those being increased utilization.

Okay. Interesting. So what you're saying there is athletes can utilize that substrate, the ketone, better than somebody who is obese and coming into this.

That's what the data appears to suggest. Yeah.

Let's bring in exogenous ketones then for the athlete who has the metabolic machinery to utilize those versus somebody that might bring those in along the journey of getting metabolically healthy and what we know about the differences there. machinery of the body and utilizing.

So, we're actually in some ongoing studies to really tease apart the nuance of how age, sex, body composition, metabolic health status, all seems to cause distinct effects in how people do metabolize ketone bodies. But based on the precedence of literature that we have today, it appears that exogenous ketone bodies will, let's say from sports performance first. Let's start category by category. Exogenous ketone bodies, number one. Um, are known well, actually, let's back up for a second. Why would someone even consider exogenous ketones? Let's start there because many people may wonder, well, why would you even talk about exogenous ketones right now? They're just a byproduct of fat metabolism. I would just do a ketogenic diet. Well, someone may struggle with adhering to a ketogenic diet. Maybe they do really well with their high carbohydrate diet, but they won't experience some of the benefits of ketones. So the question is, what are those benefits? Well, there's been evidence that suggests just administering ketones in and of themselves can cause shifts and lowering glucose levels, causing kind of widespread shifts in metabolism. Uh, they're also signaling molecules. We know that these molecules signal various effects within the body. Uh, we know that it also can block certain inflammatory processes like NLRP3 inflammasome, which is a known inflammatory driver. We know that it can also change your epigenetics. So the things that regulate how your genes actually express or turn your genes on and off. Um, so you have all this gene machinery, but you only utilize some of it. Well, how does your body determine which part of the genes to utilize at any one moment? Well, um, maybe it's the actual epigenetic regulation of those. And so we know ketone bodies actually regulate how your genes are expressed. And one of those ways it does that is it increases antioxidant signaling through FOXO. And so that antioxidant signaling also has been shown in a science paper to demonstrate that ketone bodies have antioxidant effects in and of themselves. Uh, there's multiple studies that show just adhering to a ketosis-based dietary pattern has anti-inflammatory effects in general. We, there's a lot of signaling, a lot of effects from an energetic perspective, neurologically speaking, that come along with ketone bodies. Obviously, we talked about the muscle effects, the anti-catabolic effects, and so there's a lot, a lot of things going on here with ketone bodies. So there was this emergence of the utilization of exogenous ketone bodies, and this actually was once thought to emerge over the last 10 to 15 years, but actually goes back to the 1950s. So in the 1950s and 1960s, medium chain triglycerides, which is a form of fat that readily converts through exogenous consumption into ketone bodies. So some people would define them as exogenous ketone bodies. MCTs are found in butter. They're found in coconuts. They're found in breast milk. And when consumed, they rapidly convert to ketone bodies in the liver. And they were actually used in the 1950s and 60s to help children who had malnutrition disorders. They weren't able to readily digest certain foods. And so they applied ketone bodies as an alternative form of fuel substrate, and it actually helped these kids gain weight. So that's actually the first medicinal administration of exogenous ketones that I'm ever known to be discovered back in the 1950s and 60s in children. Now, fast forward to the 1960s, 1,3-butanediol, which is actually a biochemical structural alcohol, but actually when converted turns into ketone bodies in the liver. This was actually used in the 1960s by MIT to be looked at as an aerospace fuel substrate. One, it's extremely shelf-stable. Number two, it readily converts to ketone bodies. And number three, it's nutrient-dense. It's a form of fat, right? So, where it can be converted to a ketone body, which is more nutrient-dense than carbohydrates and other fuel substrates. So, that was actually the second form of looking at ketone bodies and actually been explored in many different models like dogs and other model systems as a potential tool. Fast forward to the last, let's say 15 to 20 years. Uh, there was a project by the US Department of Defense called DARPA where they looked at something called the novel formulation from they funded the National Institute of Health and also Oxford to develop a novel ketone formulation that could be used as a tool to optimize metabolism and potentially performance. And they developed 1,3-butanediol attached to beta-hydroxybutyrate. This combination when ingested cleaves off beta-hydroxybutyrate, and then the 1,3-butanediol readily converts to ketone bodies after liver processing. As a result, it elevates ketone bodies to levels that you'd only achieve with days and days, maybe even weeks of fasting within 15 to 30 minutes. And so what they found is that administration dramatically shifted almost all of metabolism through various tissues. It's quite remarkable how powerful the exogenous administration of these substrates were. What was most interesting in that study is that they actually showed at the end of it in a cell metabolism paper that it actually improved high-level athletic performance in a cyclist trial by 2%. Now, someone may say 2%, who cares? Okay, well, I would agree for most people, 2% is probably not that relevant, but for a high-level athlete, 2% may be first or second place, and now it becomes highly relevant, right? Especially when you control it for athletes where margins are often hard to grab. So that really caused this explosion of interest of exogenous ketones in the sports performance space. We've done a lot of studies in various ketone formulations on their ability to regulate performance, sports performance. And we published a really kind of systematic review in 2022 in Sports Medicine by Brennan Egan, actually looking at the evidence on sports performance, and you see that some exogenous ketones in certain contexts improve sports performance, some other contexts maybe not so much. It really depends on the type and when they seem to be maybe most applicable is based on the type of ketone and also when they are administered over prolonged strenuous forms of exercise, and that seems to harken back to a recent review we published looking at what's the key determinant of exercise performance, and it appears that the sustainment of brain energy metabolism is a particularly important way to maintain performance. And so this really emerged this field of sports performance, but there's a lot of nuance there, and we're in early days in understanding when and where to apply them. In fact, we just completed the largest ever dose of exogenous ketone administered over the longest period of time in a randomized control trial. Just got published two days ago. Actually, not two days ago, but some period of time recently. Um, and what people will see is that over 31 days, consuming 90 grams of ketones per day, again, this is the highest dose ever administered over any period of time. We found that it was safe and tolerable, which is encouraging. It shows that people can tolerate these molecules at high dosage. And this is a 1,3-butanediol component attached to a BHB molecule. And we also showed that it improved cognition. So individuals who were already runners, who were healthy and young, so they already are pretty much at what you'd expect to be peak level performance physically and mentally, they actually saw a performance boost. They had better executive function. They were able to engage in better cognitive switching tasks when two different tasks were presented to them in congruent and incongruent manners, meaning they were challenged with kind of inconsistent information, they were able to look through that and actually choose the correct response. It's a very mentally engaging and difficult task that they were asked to endure, and they were seeing performance improvements or had resilience against performance decline. And so this is a very consistent effect. We see that exogenous ketones appear to improve, sometimes even the well person's cognitive performance. Some other things that we found quite interesting is because it, again, in this particular study, we only did a 5k time trial, and we didn't see any performance differences. You know, there were no improvement or decline. What we did see that we found very, very interesting is that the application of exogenous ketones over 31 days is what happened after we stopped administering exogenous ketones. So even when sustaining ketones over a 31-day period at these dosages, we saw that after you stop taking them altogether, that you, during a graded exercise test, which is this incremental increase in exercise intensity over a period of time, we saw that the placebo group saw a reduction in oxygen either uptake and or utilization. Whereas the ketone group sustained a higher level of oxygen uptake or utilization in VO2, absolute VO2, which is the volume of oxygen consumed. This is an indication that ketone bodies are causing permanent or semi-permanent changes in the way the body is either uptaking oxygen, utilizing oxygen, or how the muscle was actually delivering it. There was an analysis around five, five or six years ago looking at just utilizing one dose of ketone bodies after exercise. And what they found is just over three weeks of period of time that the administration of exogenous ketones allowed for athletes to have resilience against overtraining. So they were able to do higher volumes over extended periods of time. And they increased the amount of vascularization and capillarization in the muscle, which means that they were actually able to increase blood flow and vascular changes within the muscle that would in theory improve their performance. Again, they did improve their performance consistent with the study outcome. But this is also consistent with emerging evidence that shows that a single dose of exogenous ketones increase erythropoietin or EPO, which is the drug that was abused by many Tour de France athletes to increase red blood cell count. Well, if you have increased red blood cell count and you have increased oxygen delivery to the muscle, this is all making sense, especially if they're administered over chronic periods of time. So, our data is just the first to ever show that even after you stop taking them, you have persistent and permanent or maybe semi-permanent changes to how your physiology works. But we've done a number of other studies, Jesse, in other environments, including some work funded by Special Operations Command, administering exogenous ketones. That was actually a project utilizing HVMER Ketone IQ, which is a 1,3-butanediol-based product, and at that time, they had it linked to BHB. And when we administered that, we actually saw that when exposing individuals to either 15 or 20,000 foot altitude almost instantly, not quite Everest, but pretty close to it, that that reliably reduces cognition, executive function, and other key parameters, which obviously are highly relevant for individuals exposed to high altitude exposure and need to perform at optimal levels, athletes going into altitude or special operations forces who are going to be flown into environments of high altitude and have to perform immediately both physically and cognitively. What we saw is that ketone bodies actually not only increase SpO2 levels, so the amount of oxygen within the blood, again, also showing that ketones regulate the amount of oxygen the body is able to absorb and increase cognition. Again, consistent with other literature even outside of extreme environmental settings, that ketones seem to support brain energy function and metabolism. So, exogenous ketones are quite a unique field that is being now applied not just to the well person or high-performing individuals, but now to disease populations who are experiencing cognitive decline or mental health conditions where they're trying to understand, can these improve conditions like anxiety, depression, or otherwise?

Okay, so we know they're working. My question, do we know if there's any difference between somebody who is ketogenic versus somebody who's on a more standard type diet using them in the latter to hack ketosis?

That's a great question that we really don't have a whole lot of research on. So, we can speculate here. I'm going to be very clear to the audience that this is what I'm talking about now is very much speculation with very little evidence to know which way is going to happen. There's only been one study by Jeff Volek's group at Ohio State University that actually looked at the co-administration of ketone components. I think it was a ketone salt that also had caffeine in it, intake on top of a ketogenic diet. But it's really hard to tease apart from that study what the implications of ketone supplements will be on top of a ketogenic diet. But one would suspect that the body is always going to work to balance itself. So, if you're on a ketogenic diet, you have low insulin levels, you have low glucose levels, you're producing higher ketone levels from higher fat breakdown and higher utilization of fat as an energy source, that if you now infuse higher levels of ketones on top of that, yes, you would have in theory the machinery to more readily utilize those fuel substrates and maybe do so more efficiently, but you also might to a partial degree dampen the amount of ketone production because we know that ketones in and of themselves are self-regulating. We know that ketones can also stimulate a very small but non-negligible amount of insulin. And the reason it does that, it also stimulates and attenuates fat breakdown. And why does that happen, Jesse? You think, okay, a ketone body, why would it try to blunt fat breakdown? Well, when ketone bodies are extremely high, Jesse, the body needs a way to know to not cause them to just continuously be broken down in uncontrolled manners. So the body has built-in mechanisms to self-regulate. So when ketones are extremely high, they actually stimulate GPR109A receptors on the fat cells, which actually temporarily attenuate some of the fat breakdown. This is a way of when ketones are high, it's preventing ketone bodies from coming higher than are necessary. Additionally, when ketones are high enough, we also know there's evidence in cell culture models by Jim Johnson's group that ketone bodies can actually help stimulate just a little bit of an insulin response at certain levels. And again, that's another way of having self-regulation. It's a way of preventing ketone bodies becoming completely unregulated. Why is that important? I'll use an example. My disease, type 1 diabetes, where in the complete absence of insulin, ketone bodies go so high, so rapidly that it's not the ketone bodies that cause a problem. It's actually the acid load that comes from the production of ketone bodies that is so rapidly elevating that can't be controlled by the body's blood buffering capacity through bicarbonate. And as a result, acid levels get too high, and they have something called diabetic ketoacidosis. So the body, when it's functional and doesn't have a complete or a tissue system not working, like in the context of type 1 diabetes, it's working to self-regulate. So if you're on a ketogenic diet and you take exogenous ketones, you almost certainly would be able to utilize them potentially more efficiently because you've developed the machinery to rapidly metabolize exposure to ketone bodies. But you're probably also going to dampen to a degree some of your own ketone production, at least for a window of time, simply because that's how the body is self-regulating to keep you in balance.

Early in the conversation when we were talking to the newbie about adopting a keto diet, you mentioned salt and the benefit there for the new person. How do you look at things like MCT oil, exogenous ketones as a tool in that earlier phase?

Sure. So, MCTs can be utilized as a form of fat in the diet. You need to be very careful with MCTs because if you're never exposed to them before, you have to slowly introduce them. Otherwise, that can cause GI discomfort. So, slowly introducing them over time is a very effective way to blunt some of the gastrointestinal issues that when someone consumes at very high levels for the first time may experience. So, just slowly incorporating that's important. But they do increase ketone bodies and in by all intents and purposes, those are not going to do anything to attenuate. Those are only going to be beneficial in my opinion unless they cause gastrointestinal issues on a ketogenic diet. Uh, ketone salt is another form of ketones, ketone bodies. So these can provide mineral loads along with type of ketone levels as well. So they're ketone bodies attached to a salt, whether sodium, magnesium, potassium, calcium, one of these minerals. But you can consume those up to a certain level, but you have to be cautious because again, if you're someone with hypertension or other issues like that, you can't consume, you're not recommended to consume an overabundance of sodium. And for most individuals, it's very hard, you have to be cautious of the amount of mineral load that you're consuming. So to a degree, you can consume these, but they're somewhat self-limiting in that you can only consume so much without maybe consuming too much sodium. So that's always that's the limitation there. So for MCTs, it's gastrointestinal issues that you can only have so much and you can't overconsume MCTs and just get more high ketone low bodies because it's a fat. So it's self-limiting in its digestion rate. Salts are rapidly digested into ketone bodies. They come with a mineral load, but you have to be cautious around how much that mineral load you're consuming because you don't necessarily want to overconsume a mineral. So you want to keep that within balance, but they're very rapidly form, rapid form of ketone elevation. You have something like 1,3-butanediol, which has been used for 60 years. It readily converts over to 1,3-butanediol and are actually commercially available and they're reasonably cost. They don't come with a sodium load, and they're generally well-tolerated within a reasonable dose. And like a product like Ketone IQ, that's a company that sells a product like that. We've done research on that before. Then you have other molecules where it's 1,3-butanediol attached to another molecule. Could be acetoacetate molecules. It could be 1,3-butanediol or sorry, beta-hydroxybutyrate. And these are just other tools of what they call a monoester or pseudoacetate diester that have been used in various contexts. And this is just attempting to further elevate ketone bodies to some degree. And the question is, you know, for a lot of these things, it really comes down to what's the goal? If your goal is to see cognitive benefits, many of these will do that, and we've seen that with many of these iterations. And then it comes down to what's practical and cost-efficient. You know, can you, what can you consume that's reasonable and practical? And, you know, for some individuals, they want to boost the highest levels possible. Okay, when you have to consume something that's going to allow for that. If you want to have a kind of a middle ground and have elevations of ketone bodies to therapeutic levels for whatever your goal is, but be cost-reasonable, then it's a different one. So, there's a lot of different considerations here on what someone may or may not want to use. Um, but a lot of times more may not always be better. Sometimes it's actually about hitting the minimal effective dose with these strategies to maximize their benefit without overconsuming them, which I think is a generally good principle for most scenarios. Typically, there's a point of diminishing returns with overconsumption with anything.

Okay, I want to zoom back now and talk about different substrates used to make energy. We've been primarily focused on the ketone. We also have glucose, which most people were relying heavily on, but there's also fatty acids. And then there's also the nuance of the blood-brain barrier and fat as a medium for making energy. There's a limitation there. So basically, I want to talk about how the body decides when to use fat versus make ketones in the liver endogenously. And then I want to bring in the brain aspect and how the fatty acids don't cross over readily.

Sure. So when someone's regulating between just fat production in general, it's regulated by insulin. So insulin load is really going to predominantly regulate how much fat is being broken down or oxidized. That's the primary determinant. Okay? And the fastest, best way to determine insulin levels is usually through dietary components. And the one that rises insulin the highest is carbohydrates. Reduces at the lowest is when you go to a lower carbohydrate approach. Beyond dietary components, which are the most potent, there is body weight. Excess adipose tissue reduces insulin sensitivity, and you produce more insulin to try to produce the same effect, and as a result, typically you are less capable of actually getting to a fat oxidation state. So a characteristic of type 2 diabetes is a high glycolytic or glucose dominance as a form of energy or metabolism, and less fat oxidation. So again, it's really regulated predominantly in lifestyle through insulin levels. Beyond insulin levels, though, as a way to regulate how much fat the body is burning, typically ketone bodies come along in a dose-dependent manner with higher levels of fat oxidation. So as fat starts to rise as a byproduct of fat breakdown, they typically go hand in hand. So that highest levels of fat oxidation are typically when you have the highest levels of ketone production. Now, I mentioned lifestyle factors like nutrition and then also body weight as a way of dictating insulin sensitivity versus resistance. We also know exercise is a powerful way to increase fat breakdown as well as ketone production as well. So those are the kind of key determinants of how something or how the body through lifestyle interact together to regulate fat oxidation and also ketone utilization. Now, you asked a question about the brain and fat getting to the brain. Well, we know that some fats can get into the brain like medium chain triglycerides, but if you consume medium chain triglycerides, your body tends to convert them in the liver before they even get to the brain. Long-chain fatty acids are the type of fat that you store on your body. They're also the form that are the most predominant in the diet. So when you're consuming olive oils or other forms of oils, typically when you think of fat, they're typically long chain. Now, those fats don't readily cross the blood-brain barrier and provide the brain with energetic substrate. So as a result, when you're consuming a lower carbohydrate-based diet and you consume less glucose, but fat doesn't cross the blood-brain barrier, there is concern. Oh no, the brain's going to become glycopenic, meaning glucose reduction in glucose lower than the brain needs to sustain its optimal energetic needs, and you're going to have a brain energy deficit, and you're going to get into something called hypoglycemia, which causes neurological deficits and cognitive decline reliably. So, how does your body make up for that? Well, it's built this beautiful machinery within the liver where it converts this excess fat over to ketone bodies to then make up the energetic needs in the brain when glucose is reduced. This is the primary way in which ketones are actually necessary in the body. Okay, they obviously have almost hormonal-like components, signaling components, and metabolic components, but they also play the most fundamental role in survival when you're in a fast or famine evolutionarily speaking by ensuring the brain doesn't go into an energetic deficit when you're deprived of the ability to consume food. So deprived of energy, and that's because the fat can't just go to the brain and make up for glucose as a fuel. It had to convert it to something that crosses the blood-brain barrier and can be readily metabolized by brain tissues, and those are ketone bodies. So that's how the body works to regulate that. Um, but another example to that is lactate. So the body, when it goes to extreme forms of exercise, let's say you're evolutionarily speaking having to run miles and miles and miles, maybe in, you know, 20-plus miles to get your fuel, and you're producing more lactate. Well, the body knows that all of a sudden you're producing more lactate. It's going to now utilize that as well as an energy source. So, it's producing more lactate, more ketone bodies for these prolonged forms of exercise. What your body is really trying to do here, Jesse, is trying to ensure the brain is always energetically sufficient. So, when ketones and lactate are present, typically evolutionarily speaking, they are only going to be present, at least ketone bodies, in an energetic deficit environment. Now, we know we can follow a ketogenic diet or apply ketone bodies, but evolutionarily speaking, typically it was an energetic deficit. Lactate produced through high levels of exercise over prolonged periods of time. Um, but when both of those are present, Jesse, they are actually consumed by the brain in a dose-dependent manner. Glucose is only consumed in the brain proportional to the brain's energetic needs. Why is that important? It tells us how the brain or the body self-regulates. It is saying that the body says, okay, if I have ketones or lactate present, I need to utilize those first because I might be in a crisis for brain energy, glucose deficits. So I need to spare glucose and make sure that I'm utilizing these other substrates the bodies have limitless supplies of in the theory of ketones because of fat breakdown or lactate because of conversion of glucose over during exercise. So that's how the body is telling us what it prefers. If you give glucose or ketones, the body will preferentially utilize those over glucose in a dose-dependent manner, and that tells us the body's when those substrates are available are going to prioritize those over glucose. And we see that in MRI scans when you co-administer glucose and ketones in the brain and see that ketones are readily utilized in a dose-dependent manner and glucose is not. So these, this is all explained through an evolutionary lens of self-survival.

As you're sharing all that, it gets me thinking about somebody trying out this diet and maybe missing the mark on getting the carbs low enough to produce ketones. So, they're not bringing in a lot of glucose. They might just be bringing in enough glucose through carbs or sugar to block the fatty acids from being released and used as energy. Then, we also have the blood-brain barrier piece. What I'm getting at with all this, if you're not lowering the carbs, getting the ketones, you're not really getting the glucose through the diet that you were before, I could see how specifically in the brain and the rest of the body, you could have a real energy problem.

Correct. Which is why the body has this machinery in place, which is also why we see that when you exogenously administer things like ketone bodies, there seems to be metabolic benefits to them, at least acutely speaking, as the body tries to utilize those preferentially. So there's ways in which we understand how biology is working, even from a self-survival mechanism, that has elucidated opportunities to optimize the already well person by leveraging these same tools on top of normal standard dietary environments.

Okay, just to make sure you're clear on what I was getting at there, cuz I was kind of butchering it a bit. We're not taking in a lot of carbs or sugar, but we're taking in enough that we're not producing ketones. So we're kind of at this energy-depleted state. I could see how a person could suffer in that thinking, "Oh, I'm just working my way into ketosis," if they're new to this, having a bit too many carbs and they're not getting to the promised land of producing ketones and feeling good.

Well, this is actually a very important point because most of the benefits that we see from carbohydrate restriction are at the ketogenic threshold. When insulin is sufficiently low to start producing ketone bodies at meaningful levels, again, 0.3 or higher, most people define it as 0.5 or higher, but I typically say 0.3 or higher. And this is the threshold in which we see most of the clinical and metabolic benefits associated with this diet. But there's also, to be fair, evidence that shows that if you just reduce carbohydrates in general down to less than 130 grams per day, somewhere between 51 and 130 grams, that this also has potential therapeutic benefits as well in regulating diseases like diabetes and obesity, where it can assist in helping improve glycemic control. But keep in mind, it's typically shifting, Jesse, from a standard American or Western diet over to a lower carbohydrate diet. So, by default, they're making a shift in a positive direction. But you're right. I mean, you bring up an important point where someone's not actually kind of crossing into that threshold. They may not be maximizing or reaching the full potential of these interventions.

All right. As we wrap up here, I want to talk to the newbie and make sure we give them the tools they need to be successful on this journey if they decide to embark. We mentioned fasting before along with the dietary recommendations that we gave earlier. Do you feel like that's a good tool to include early on or later? Basically, I want to bring that in as a potential tool for people.

Is definitely a potential tool. There's a ton of health benefits. We know that from biblical texts that many, many religious communities would utilize fasting as a religious practice that would describe all these health benefits. And now we're starting to realize that those cellular biological changes are very real. That they do have widespread changes in virtually almost every cell and tissue within the body when you go through a fast. Most of which are maximized around 3 days but extend beyond that even up to seven-plus days. Um, so is it a tool? Yes, it's a tool. The problem with that tool, though, is it's one that requires a lot of understanding of how to implement it effectively. So for most people, just like, "I'm going to fast for 3 days." It can often be something that's not effectively implemented, right? Because people are already struggling to reduce just some of the foods in their diet. If they just go all full bore and consume nothing, is it going to go well? Probably not. But it's also possible that someone just simply can't tow the line between a little bit less of something of something they really love, right? And so they're always going to find themselves on this higher end threshold anytime they're exposed to it. You know, it's kind of like, you know, people hate when you use analogies like this because I'm not drawing an analogy to addiction, but say it's like gambling. You can choose not to gamble again, but if you have a problem with food intake, you can't choose not to eat ever again. You are already always going to be exposed to some degree of food always, even if you have a problem with it. So, it's always going to be a potential challenge in that regard. Um, so in that way, sometimes fasting can be a is a powerful tool for some individuals to just reset themselves on their awareness of hunger, on their awareness, just to kind of I don't want to use this term, Jesus, I was going to say cleanse, because it's the most unscientific term of all times, but in many ways, you are basically scavenging your body of and voiding it of any intake whatsoever, and there is some shown therapeutic benefits to doing things like fasting. But I will acknowledge it's not an easy thing to do, and you have to go into it with a mindset of understanding that you're probably going to need to stick to it for at least 3 days, 72 hours, to really see

any meaningful benefit from doing it other than understanding what it's like to actually truly be hungry. Because when someone says, "Oh, I'm really hungry." They may not be hungry at all. They're just missing they're in the absence of the pleasure response of food that they want to reseek again. Whereas when you fast now, you're going to know what real hunger feels like. Okay? And that's that can be a very powerful experience because it can teach some individuals, hey, wow, all these times I was consuming food. I wasn't even hungry. I thought I was hungry, but really I was just seeking the pleasure response from food. I know what real hunger feels like now. And that alone can be an empowerful realization. I can't tell you the amount of people I've heard who express that. that really the benefit of fasting wasn't some magical therapeutic uh benefit that they observed but more so the realization of what their body actually needs when it needs it.

>> What about just tightening up the eating window with the diet you've been explaining?

>> So I think that that there's a lot of evidence that says the impact of that there's no additional metabolic benefit to doing like say intermittent fasting beyond just consuming regular caloric intake uh of any distributed pattern. But the value I believe of intermittent fasting is not some superior metabolic benefit, but the ability for people to eat when they're actually hungry and not eat when they're not. So a lot of people wake up and they're not even hungry. And they'll eat food anyways because they've been told that breakfast is the healthiest meal of the day. So they ate food when they didn't even need to. And then after that they want to have more food because they realize how fun it is and how good it feels to eat food. And now they're on a roller coaster for the rest of the day seeking food. Whereas they could have woken up, focused on other things, they weren't even hungry, benefited from the fact that they didn't need to consume calories that window and just eat their calories later in the day and maybe find themselves at a better net calorie um um intake compared to otherwise. So I actually do this by in uh by accident. I typically wake up and have coffee and just focus on work for the first part of the day. And it just reduces so many uh other variables in my life and it makes my life easier. And so by default, I find myself intermittent fasting often. Not because I'm doing it for some therapeutic benefit, but because I find it's just easier for my life. And as a result, I tend to not eat a portion of my calories until like 12:00. And then from that point forward, I have the the remainder of my calories spread across meals. I find that to be much more effective. I wake up first thing and eat food and then I'm thinking about food for the rest of the day. Just like when we were talking about longer fasts and the simplicity with that, that brings to my attention the carnivore diet and the simplicity of that type of way of eating which is generally going to be keto again for the newbie just to simplify things and then later on. How do you feel about that?

>> I think that uh a carnivore diet has been incredibly powerful a large number of people. the general scientific and health community bash the diet because it's void of fibers, it's void of plants, it's void of a lot of things that we've known in the scientific literature have been described with health. Um, but you got to understand like when you actually work with people on a one-on-one basis and realize the struggle that some people encounter with with their food intake, it's a this is why GP1 receptor agonists are so popular because just trying to put you on these healthy diets. You don't think these people have been trying to eat healthy their whole life? Of course they have. It hasn't worked. They you you haven't you don't think they picked up a textbook that said eat the the salad? Obviously, you know, and you don't think they know that eating ice cream all day is not a bad idea, but they sometimes still find themselves doing it. Yeah, of course. It's because it's very difficult. But sometimes doing something as radical as a carnivore diet can be eliminating so many other things in their diet that make it a challenge for them to succeed at reducing their calories and can help them be successful. But that same philosophy applies to every dietary strategy. So that's why it always comes down to the individual. Can you find an approach that works for you? And sometimes that may be extreme, but keep in mind extreme may be healthy for you within your context.

I know you got to go soon, but we'll end on this. A good way to wrap up the conversation. We've given people the playbook if they want to try keto and the different benefits. What are a couple of the pitfalls you see people making when they adopt this diet that you can help people avoid?

>> The predictable and preventable pitfalls of these lower carbohydrate or ketogenic diets is not being prepared for their metabolic adaptation. Um, so understanding that yes, sodium load is going to go lower and so you probably want to supplement or increase your sodium intake. We also know that people tend to not have a plan for their food strategy. So making a transitional plan that actually allows for you to consume a lot of the familiar foods that you do already enjoy is I think a surefire way to increase your compliance with the diet. Um and also mapping out what this looks like over a period of not just one day but uh over a month like what does this look like for you over the next month and building in these safeguards and strategies to allow you to to benefit from that. And that could be all the way down to family support and uh getting certain foods out of the house that you know you're going to struggle with. Because I can tell you right now, if I had a pizza in my fridge every single day for a month, the willpower it would take me and the misery it would take me to look at it every single day and think about not doing it would just be unnecessary if I just remove that as a stimulus uh in my my mind. So, it's little things like that along the way that it's more so about preparing yourself for success along the way. So, when people don't prepare themselves ahead of time, they just go Google something online said here's the ketogenic diet and it they just see bacon and beef and they just eat that all day. There's a better way to do this that allows you to have more nuance diversity in your diet that you can incorporate many of the foods you probably were eating before into this new approach and it's completely compatible with health uh diversity in diet, fiber intake and all these other components as long as you put the planning in ahead of time and understand how to do it effectively. So that's what I want people to understand. I'll also say one of the most preventable pitfalls of this is that people will never begin in the first place because they think, "Oh no, I'll never be able to eat pizza again or cake again and I'll never do that." realize that there are web uh websites due to the popularity of ketogenic diet all over the place that allow for people to remake some of their most favorite foods, cookies, cakes, pizzas, bananas, brownies, all these other things in low carbohydrate fashion. Remaking ketchup as a low carbohydrate, barbecue sauce as lower carbohydrate, and oftent times making it healthier, realizing that ketchup is just adding sugar and high fructose corn syrup when you could in fact just make ketchup with stevia, monk fruit or alulose. It makes it basically completely calorically uh neutral and yet you made ketchup instead of consuming gobbles and gobbles of sugar. So a lot of times just the journey alone can be illuminating and how to reformulate a lifestyle for health.

All right, Andrew, we're going to leave it there today. Really appreciate this nuance conversation. We're going to link up your website, social media, YouTube, everything in the show notes. Thank you.

>> Honor.

>> Thanks for watching the episode. I got another great one lined up for you right here. Don't miss it. I'll see you over there.

>> Do you want pleasure now or do you want something far better in the future? So, if you want pleasure now, eat the trifle, eat the cake. But if you want a better future, well, you got to work towards that. Let's put a lot more energy into thinking