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Dominic D'Agostino: Metabolism, Fat, Carbs, Protein, Ketogenic Diet, Nutrition, Blood Sugar & Health

Updated: Jul 6, 2022

Full episode transcript below. Beware of typos!

Nick Jikomes

Dr. Dominic D'Agostino, thank you for joining

Dominic D'Agostino 4:23

me. Great to have you. Great to be here, Nick. Thanks for having me on. Call me down.

Nick Jikomes 4:29

All right, thanks, Tom. Can you start off by just telling everyone a little bit about who you are and what your scientific background and research focuses?

Dominic D'Agostino 4:37

Sure. Well, undergrad biology and nutrition, and then I did PhD in neuroscience and physiology. For neuroscience. I was doing patch clamp electrophysiology for most of my PhD, single channel wholesale perforated patch and you probably knew what that is, and then got really interested in, in imaging technologies. So, in the process of my postdoctoral training, I became very interested in undersea medicine program and extreme environments. And that includes the undersea environment, hypoxia, hyperoxia, space, environment, all that stuff. So we actually build environmental chambers. And we put technologies inside like atomic force microscopy, laser scanning, confocal microscopy, these are things we have sort of developed and patented. And in the process of looking at what brains were animals, mitochondria and cells do in these environments, it became very clear to me that changing metabolism and changing the fuel systems and by virtue of changing metabolic physiology, we can change brain energy metabolism, and neuropharmacology that I could leverage nutrition and nutritional supplementation to basically alter and create neuro protective strategies for the things that the government is funding me to do, which is basically protect the warfighter in extreme environments. So we've done basic science research, and also now clinical studies on these things.

Nick Jikomes 6:19

Interesting. Yeah, I want to get into a lot of that stuff. But I thought we'd start by maybe sort of building a relatively basic base for people just in terms of, you know, calories, energy in general metabolism stuff. So can I get you talking a little bit about like, what exactly is a calorie? And how does our body translate calories into usable energy?

Dominic D'Agostino 6:41

Yeah, well, a calorie is a unit of energy, from a physics perspective, but from the context of, you know, when we talk about calories, we're really talking about kilocalories in the context of nutrition, right? So my caloric if I track my calories, on a ketogenic diet, which I follow, I'm getting about almost 4000 kilocalories per day. And then the calories that we consume through our nutrition, which is macronutrients, which include proteins, carbohydrates, and lipids, they, you know, proteins and carbohydrates contain four calories per gram and fat quite a bit higher. So the energy density of fat is nine calories per gram. So that makes it kind of interesting, from a logistical point of view from some of the things that we study like military and space travel, because you can get more energy in a smaller amount of space. And space is at a premium. And weight is at a premium when you're sending things up into space. So So, for example, a ketogenic diet is much more calorically dense. So you would think that the energy density is quite higher. So you would think that eating this would cause you to gain weight. But in the context of carbohydrate restriction, and this is quite, quite, I'd stay out of the conversations and debate online. But there's quite a lot of discussion about is a calorie, a calorie in the context of nutrition and dietary interventions. In for all, intensive purposes, it is it's the main driver for whether we gain weight or lose weight. So that's important. But with things like protein, where you have the thermic effect of food, there is energy that you expend to mechanically and enzymatically digested protein to its constituent amino acids, which are used for rebuilding but also some part for energy too. So if we kind of dissect diets, diets that are higher in protein, and perhaps we can go down that path fiber, too, because some of the fiber is excreted, insoluble, but some like soluble fiber is broken down into short chain fatty acids like butyrate, and that has interesting effects. So but I think that the main thing maybe your listeners are kind of interested in is that that calories in calories out absolutely matter in the context of the diet. If you want to gain weight or lose weight, there may be a slight advantage for higher protein diets. And there may be an advantage on a ketogenic diet, although I think it's kind of minimal. We regulate ketosis through some parts ketone urea, so in a high state of ketosis, we will urine out will will find ketones in our urine acetyl acetate and beta hydroxy butyrate. And it could be up to 100 to 200 calories if you're in a very high state of ketosis. So Atkins was kind of right in that you are sort of wasting calories, but it's pretty, pretty negligible. I think but for the most Part. Yeah, calories kilocalories are what we talked about in nutrition. And they came come from macronutrients. And they're very, very distinct effects that we can get from shifting the macronutrient profile of a diet. And that is that is what drove a lot of my research interest in the ketogenic diet.

Nick Jikomes 10:18

Yeah. So when we think about, you know, consuming calories, as you mentioned, sort of the simplest equation, you can think of, in your mind, it's just, you know, are you are you eating more calories than you're burning or not. And that in general is going to tell you whether or not you're going to gain weight or lose weight. But you also said something that was pretty interesting. You said, the density, the caloric density of these different nutrient classes varies, so fats have more, more energy in them, essentially, per unit weight than carbs or proteins. You also said something about like a thermic effect, I think, basically, what you were talking about was, it also costs your body something in your body has to expend some kind of metabolic energy to actually process these things. And that's going to be different for different fats and proteins, and carbs. So can you expand on that a little bit more? What were you talking about? There started to sound like you were saying that your body has to expend a little bit more when it processes things like proteins and fibers compared to maybe carbs and fats? Is that what you were saying? Yeah,

Dominic D'Agostino 11:16

yeah. In twin add nutrition, I think we call this the specific dynamic action. And another analogous term would be the thermic effect of food. Essentially, if when you're digesting, assimilating and using macronutrients, fat is relatively easy. Although it gets absorbed quite differently through the lymphatic system and carbohydrates are broken down in and used as energy. The pathway to create to break down a carbohydrate or fat for use of energy is more simple, and less complex than breaking down protein, for example, in a steak, where you have to hydrolyze, the protein and the gut, and you have a whole host of proteolytic enzymes, and on top of that, you have a pretty intense mechanical digestion that happens in the stomach, right before it moves to the duodenum. And then enzymes, pancreatic enzymes start to work on it. And most of that is absorbed quite quite efficiently in the duodenum, the jejunum and ileum. And pretty much all the protein is absorbed by the time you get to the ileum unless you have some kind of protein malnutrition absorption issue. And then those huge polypeptide chains that are found in the protein, and then you have you know, it requires a lot of enzymes are a lot of mechanical energy, and it has to be broken down to dye peptides, constituent amino acids, some tripeptides. But you know, larger peptides are not making it into circulation, which is, which is why we need to inject peptide drugs like insulin, for example, like, we cannot, you know, take a dose an oral dose of insulin expected to work, although, interestingly, if you consume enough insulin orally, it will lower your blood glucose and you could potentially die. So some of it's kind of getting in there. So we think, perhaps maybe fragments of insulin or have and this is always very mysterious for people who study the GI tract where I teach gi physiology at the med school, and we we are taught very specifically. But for protein, you have luminal digestion. And then you have actually, you know, once the peptides are absorbed, you have the breakdown of these things in the cell. So you have actually cellular digestion to that happens. And I think the point is for the listener is that it's much more energy costly, to break down protein, probably more costly to break down something like a steak than a whey protein. So I think that you could get 50 grams of protein from steak and 50 grams from whey. And the metabolic response is quite different even on insulin. So I think that's like an important thing to consider too. Although that's not really recognized so much in the field of nutrition, but the form of the macronutrients that we're absorbing, and also the combination. So if you consume whey protein with no fat that's going to have it's going to be like a bolus of amino acids hitting your bloodstream as opposed to an egg, or steak. And these are things that need to be appreciated, too, that are often not appreciated. If you're not doing a lot of blood work on yourself, which I do. I measure insulin. I take hundreds of insulin tests on myself and I wear a continuous glucose monitor on the back of my arm. I use an app called level's health app that actually will give you predictive information on the food that you eat. So it uses the Dexcom G six, or the Abbott libre device, it syncs with those devices. And that gives you incredible insight into how calories affect your metabolism, and also your glycemic response. And if you, you have a continuous glucose measurement, and you couple that, with blood measurements of things like insulin, you know, and other other things we measure in the lab or in our studies, it can be incredibly insightful. And I guess what's also very interesting is that my wife is a very good car burner. And her glycemic response to a given amount of carbohydrates would be less than mine, and I'm quite larger than her. And since there's a lot of personal variation and individual variation, that we're not, we didn't really fully appreciate until we start using continuous glucose monitoring and start looking at some of these metabolic profiles in patients.

Nick Jikomes 16:09

I see, you know, on the subject of blood glucose, blood sugar dynamics, you know, if you're consuming if you're consuming a given amount, you know, let's just say 100 100 calories worth of carbs versus fats versus proteins, are they going to I'm guessing that they will have a different pattern of effects on your blood glucose levels, that the that what you see in terms of sort of peak rises and falls, but also the time course is going to vary? Is that true? And are there any just sort of general general principles for how to think about how these different macronutrients will affect blood glucose levels?

Dominic D'Agostino 16:46

Yeah, that's a really good point. And it's under, it's being studied now has been studied in diabetic patients and disease patients, but it has been studied more, we're working on a scoping review, but the use of continuous glucose monitoring and non diabetics like we actually don't have we have very little data on what normal glucose is or normal glucose response because only diabetics have been studied. And I didn't fully appreciate how little data we have until I tried to write a systematic review and realize that I need to write a scoping review, because the data is so nascent in this area, you know, of understanding what normal glucose is. What we can say is that the postprandial rise in glucose and insulin is significantly attenuated, if not abolished with a very low carbohydrate diet or ketogenic diet when compared to a standard mixed diet. And if you equate for calories, if you equate for protein, and you eat a low, very low carbohydrate diet, and you have a CGM response, and you measure insulin, and you control for calories, and you eat a mixed diet, the hormonal response is remarkably different. And I am not there's a lot of debate about this. And I feel that was such such diversity in the glycemic variability and hormonal response. You know, insulin, ghrelin, leptin glucagon, many things that we measure, that it's going to have real world effects for people trying to enhance, you know, their longevity, their glycemic control, obviously, exercise performance, but if you suppress the hormone insulin or you prevent it from being released, by regulating glycemic variability, you will promote greater fatty acid oxidation and in the muscle, and I think that's important skeletal muscle is like the biggest glucose sink or energetic sink, so you enhance fatty acid oxidation in the muscle. And if the carbohydrates are low enough, you also enhance fatty ox fatty acid oxidation in the liver, beta oxidation of fatty acids will contribute to the production of ketones, beta hydroxy, butyrate, and acetyl. acetate. The liver cannot use ketones because it lacks an enzyme succinylcholine a trans race. So those ketones actually enter circulation, and then they become an energy a primary energy source for your brain and your heart. And if it's, you know, if you fasted for a week or more, more than 50% of energy is coming from ketones, and this was nobody knew this until 1967 When George Cahill and Oliver Owen facet subjects for 40 days. And then they did you know AV differences in in metabolism in the brain. And they also injected patients with insulin and push their glucose down into one millimolar range and it didn't kill them. It didn't even produce like a coma or brain damage. Actually, they were asymptomatic for hyperglycemia This is published like we can't reproduce this now because IRB is actually an IACUC would not even I tried not to cook would not even approve this Animal Care and Use Committee. So it's it gave us a lot of insight. And it actually ended up in rewriting the textbooks that the brain can use other fuels and glucose.

Nick Jikomes 20:15

Yeah, so a couple things here, there was a lot to chew on. Two things, two things I want to circle back to and unpack a little bit. So one, you basically said, if I'm hearing you, right, if you're eating, let's just say, a normal diet, meaning you've got somewhat comparable levels of fats, carbs and proteins, compared to if you're eating a diet that is lower in carbs, the blood glucose rise you get, after you eat a meal is going to be lower, if you have that diet that is lower in carbs, and the blood glucose rise after a meal will be higher. If you've got, you know, a normal amount of carbs in your diet.

Dominic D'Agostino 20:54

That's correct. Yeah, the acute postprandial response, okay. And then the insulin response to what happens long term with baseline insulin, that's another story, but the acute insulin response is going to be quite higher.

Nick Jikomes 21:07

Okay, so the takeaway there is, you know, if you eat 100 calories of this, and 100 calories of that, it's not necessarily gonna have the same impact on your blood glucose dynamics, it can really, really depend on the composition of the diet and where those calories are coming from. You also mentioned that there are these hormonal effects and you said things like ghrelin and leptin. Can you explain for everyone what those are and why that's important and important consideration in terms of what kind of calories you're consuming?

Dominic D'Agostino 21:35

Yeah, okay, so this is like a subject of debate. And most of what we do is animal model systems, although we are doing a registered clinical trial on this now, and I'm looking at the data. So I can speculate a little bit. leptons a little bit more variable. But I'll talk about insulin, ghrelin, glucagon, a few other hormones. So yeah, in the context of a higher protein diet and a high fat diet with carbohydrate restriction, ghrelin tends to well, and we think this is in part due to ketones. So being in restricting carbohydrate to the degree that you produce metabolic ketosis can suppress the hormone ghrelin, which is a driver for our appetite has interesting effects on the brain. And only recently really have you know, we've been been studying this, and it seems to be independent of calorie restriction, and independent of weight loss. And further validation of that is that if you integrate ketone Ester or ketone, electrolytes or ketogenic agents into a standard diet, and that standard diet is fed to like Sprague Dawley rats, it also suppresses groan. And it also it seems to be some part perhaps linked to insulin sensitivity. So insulin sensitivity, even independent of calories are independent of weight loss, if you have elevated ketones will be enhanced with with a ketogenic diet. There is There's Dr. David Ludwig and I respect him very much. And he put out a very compelling model, the carbohydrate insulin model of weight loss. And I am I believe that that model has a lot of validity and is very much in line with what we're talking about now. But I don't think it necessarily applies to everyone. And I think he may say that too. And I met with him last weekend. But I, I have, I'm very compelled by the idea that people who need to lose weight or people who have type two diabetes are insulin resistant, that their their hormonal response, leptin, ghrelin, insulin sensitivity. Glucagon, Will, those parameters will be optimized for weight loss in patients that follow a carbohydrate restricted diet. So I know there's quite a bit of debate back and forth. I don't get into debates, but I read into the science as much as possible. So I think for the listeners that and I think I'm a big believer, I don't know why insulin is not on a CBC or CMP. But it should be we should know what our fasting insulin is. If your hyperglycaemic are pre diabetic, or your insulin levels are elevated, I the data at this point in time is compelling in the context of those conditions that a carbohydrate restriction would be a more favorable way to improve, you know, your body composition, and for fat loss. Many people would argue that statement, but I think the data in that context is supportive of that.

Nick Jikomes 24:59

So One of the one of the overarching things here is that the kind of calories you're consuming will have an effect on everything from insulin to these hunger and satiety hormones, hormones that your body releases that tend to make you want to seek out food or tend to make you feel like you don't want to do that. So if you eat 100 calories of Diet A and 100 calories diet B, there could be a difference in how hungry you subsequently feel. Is that a general takeaway?

Dominic D'Agostino 25:30

Yeah, absolutely. And I think this is generally appreciated. And the general consensus is that we know this. My early lectures 10 years ago on the GI system talked about fat affecting py, which is a hormone associated with satiety. Py receptors, thinking early on. But then some studies came out on protein, and protein combined with fat seems to have a higher satiating value. So both protein and fat, have a greater satiety effect than carbohydrates. And I think even people that are proponents of a high carb approach would probably agree with that. But most people promoting high carb approach are also promoters of flexible dieting where you should have a balance of macronutrients. The thing that I study, the ketogenic diet is completely in the other direction, where it's, it's very, you know, unbalanced. And I think there's potential, there's great applications for this. Maybe not for everyone. But I think that it's distant lends to the idea that perhaps a ketogenic diet could maximize satiety, through suppression of ghrelin through hyper keto anemia, and activating, you know, PY and N altering. But this research is still ongoing. Yeah, I think even our own research is more variable than I expected. And things tend to fall on if people lost weight or not, even more so than I expected.

Nick Jikomes 27:07

I see. But it sounds it sounds like there is, in general, on average, probably some broad agreement among researchers that if, you know, if, if you're consuming a given amount of calories to people consuming the same amount of calories, one is much higher in those calories coming from proteins and fats. One is much higher in this protein is coming from carbs, the higher fat protein diet will probably lead to higher satiety levels, lower levels of hunger overall.

Dominic D'Agostino 27:35

Yeah, absolutely. And I mean, if the other end of the spectrum and it's also pretty, the general consensus is that foods that are hyper palatable, so sugar processed, you know, carbohydrates, sugar, fat, and salt will create hedonic response in the brain and even increased dopamine levels. I went through, saw two very compelling lectures at a conference this weekend on food addiction, and I didn't know that the research has advanced that far. Where, you know, brain scans are clearly showing that you know, one proponent is saying that it's about 50% of the population, but I think it's more like 10 or 20% of the population that's obese aside, I think it's a small subset that actually have the DSM like criteria for addiction but there's there's absolutely no doubt that spiking glucose, you know, sugar, sugar in the in the context of fat and salt triggers, changes in brain, brain energy and and energetic systems in the brain and also affects the neuropharmacology and areas linked to reward the ventral tegmental area, that nucleus to show the nucleus accumbens sort of lights up, you know, like, there's, there's good data to show this now. So I think that's important when you're constructing a diet, a lifestyle that we're trying to get people to lose weight, I think we need to acknowledge that macaroni macronutrient composition matters. And, you know, I went through a dietetics program where really didn't matter. And I think the data is showing that it's matters.

Nick Jikomes 29:21

Yeah, I mean, it's it's super intriguing to think about, like, if you if you think about a highly palatable food, you know, something high in sugar, not only is it palatable in the sense that it tastes good, and we want to eat it because we like the taste, but we're basically saying is, there can be physiological effects in your brain and elsewhere that actually influence and alter circuits in the brain so that, you know, if you're, if you're eating a lot of sugar over a long period of time, you might even become more sensitive and more. You want to find highly palatable foods and highly palatable, things that have this hedonic effect even more. So you can imagine there's sort of a sort of a chronic effect here as If you're consuming such a food over long periods of time, you may be increasingly predisposed to want to seek out those things even more.

Dominic D'Agostino 30:09

Yeah, and listen, I think that and there's a lot of debate on what diet is best for weight loss. And I would be the first to say, although I follow a very low carb ketogenic diet that a ketogenic diet is hypo palatable, it does feel like you're restricting yourself and it's hyper satiating. So I think you're not going to overeat on typically don't overeat on on the macronutrient of a meal plan as a macronutrient profile, something like a ketogenic diet, and that's why it's easy to lose weight. There's no what was the term used metabolic superiority, like Dr. Atkins, and I appreciate he he, he changed our thinking, you know, on this, but I don't think there's any metabolic advantage to a ketogenic diet. If there is I think it's small, I think the advantage is that it changes metabolic physiology, which changes brain energy metabolism and the neuropharmacology of the brain. And then the hedonic response to eating coupled that with a hedonic response to eating as attenuated.

Nick Jikomes 31:14

I see Yeah, I do want to get into some of that, because it is your wheelhouse, and we've already been talking about keto stuff. Can you start off by just giving everyone you know, who isn't aware, a very basic picture, what is the ketogenic diet, and what is this metabolic state that it induces?

Dominic D'Agostino 31:30

Yeah, the ketogenic diet, I think it's really important to understand because even practitioners don't fully know that a ketogenic diet is the only diet defined quite explicitly by the elevation of blood, urine or breath ketones. And if you're not in a state of elevated ketones, by definition, 0.5 millimolar, beta hydroxy, butyrate, or acetyl acetate, would be 15 milligrams per deciliter. If you're not in a hyperkeratotic state or hypercube to anemia, you are not on a ketogenic diet. So this typically requires you to restrict carbs have trace amounts of carbohydrates, adequate protein, enough to prevent protein malnutrition. early forms of the ketogenic diet are like eight to 10% kids, it stunted some of their growth. So now we know a little bit more that we can be more liberal with the protein. And then the balance of the energy is actually coming with a classical conventional ketogenic diets about 88 to 90%. Fat, the diet, the diet is in percentages. And then eating that will produce a physiological state that is in in many ways analogous to fasting. So if if someone's on the diet, and you pull blood, and you do a metabolic profile metabolomics, it would look like they're fasting, actually, especially if it's you caloric or slightly calorie restricted, it would look like you know, they're fasting even during meals,

Nick Jikomes 33:08

I see. And when you say fat, so the metabolic profile that you would see is for to draw blood from someone who's in ketosis looks like someone who's fasting is that and does fasting, they're mean like has not eaten for 24 hours, or what does that mean? Exactly?

Dominic D'Agostino 33:23

Yeah, it would, it would mean quite that, well, looking at blood glucose and insulin, too. So these are things that you look at. There's like, there's four, five ways, I guess, to enter ketosis, and that could be fasting, you know, that's fasting ketosis, which we knew that fasting was a very powerful way to control seizures, even in millennia, right? Like, Hippocrates talked about it. There's ancient texts that talked about it. In the Bible, Matthew and Mark, you know, talk about fasting. So you can enter a state of ketosis with just not eating and after about 24 hours, your ketones become elevated through the suppression of the hormone insulin. But you can also do the ketogenic diet. You could take ketogenic fats like medium chain triglycerides, you could use a drug like to deoxy glucose to block glycolysis. Or you could take exogenous ketones. So these are five ways that you can enter ketosis and they all have different therapeutic applications we can talk about, but yeah, I think from the seizure point of view, the Mayo Clinic in 1921, so over 100 years, the ketogenic diet has been used clinically for seizures. And it was observed that in patients at fasted that they would have elevated ketones and under high hyper ketone EMIA. That's when the seizures were controlled. So at Mayo Clinic, they designed a diet that was very high in fat that would produce ketones and just enough protein to prevent protein malnutrition and And then this actually became the standard of care for epilepsy. Back then, until drugs came on the scene. And then they were used and now ketogenic diets got a resurgence in 1994, when Jim Abrams went on Dateline NBC and talked about a story that Charlie, Jim Abrams, the Hollywood producer, talked about his son, Charlie. And then you can actually look at PubMed, where there's a huge spike up in trials. And now there's 294 clinical trials, as of last week on the ketogenic diet, registered clinical trials.

Nick Jikomes 35:33

Yes. So we've known for millennia that that fasting has potent physiological effects. We know that, you know, if you look at the blood from someone in ketosis, it looks a lot like the blood from someone who's fasting. So let's say you're just starting the ketogenic diet. So you're getting most of your calories from fat, you're getting enough protein, you know, the minimum requirements, protein that your body needs, very, very low levels of carbs, walk us through sort of what starts to happen to create that, that that protein, that metabolic profile that looks like your fasted, what, what's happening in the body in the GI tract in the liver, to get you from where you were to producing these things called ketone bodies and creating that like fasted type state.

Dominic D'Agostino 36:16

Yeah, so you're altering metabolic physiology to essentially restrict glycolytic metabolism and glycolytic flux, and augmenting and enhancing fatty acid oxidation, beta oxidation of fatty acids in the liver, and then in the muscles and things so. So, okay, if you start a ketogenic diet, there, it becomes very difficult for many people to start a ketogenic diet in our in our clinical trial, we titrate it over the course of a month to six weeks. So what happens is that you start to metabolize all the stored sugar that you have in the form of liver glycogen. And, and muscle glycogen doesn't get used unless you're exercising, you know, that's, but liver glycogen gets depleted and delivers more or less like an energetic sensor. And once the liver gets depleted to a certain point of glycogen, and it's not like it's on or off, and people often talk about like you're in ketosis, you're not your own. No, it's kind of like a rheostat. Right. So you restrict carbohydrates, you're eating just fat and adequate protein, you caloric ideally, if it's a little bit calorie restricted, that can promote faster ketosis. In, in epilepsy clinics, they would fast subjects for a day or two to get them into ketosis, but independent of that, so you glycogen in the liver is like 2000 calories, but we have like, you know, 30,000 calories of stored body fat, right? So we have endless amount of fat in our subcutaneous and intro mental fat and things like that. So we start to liberate that as a source of energy, that fat gets used by our peripheral tissues, but the brain then becomes deficient in energy. And because the brain is a massive glucose sink, so and, you know, the brain going through glucose withdrawal is to some extent where people call the Keto flu. And that's part of it that you get a headache, you get brain fog, when you start a ketogenic diet. It also suppresses the hormone. I mean, it does this by suppressing the hormone, insulin, that's how you start making ketones in the liver. And when you suppress the hormone insulin, you tend it has a diuretic effect and a naturalistic effect. What that means is that you excrete excess water and you excrete excess sodium. And that will cause a relatively significant change in the plasma volume. So there'll be a contraction of the plasma volume, even if you're drinking water, if you don't get enough sodium, everything. And a decrease in plasma volume will decrease your blood pressure and that'll create that can create the brain fog and you get orthostatic hypotension, like many patients see this when they're fasting or follow the ketogenic diet. So there's a period of adaptation in most exercise studies. Like when I was reading the other day someone sent me they did the ketogenic diet for four days and then push them on a robic exercise. Another study was like four days to a week and they did an anaerobic exercise. And there's no doubt that you'll have tremendous performance detriments on a ketogenic diet and probably cognitive deficits until you adapt to your body will adapt to a lower level of glucose. So we know this with like a type like I have a PhD student who was a type one diabetic, and once he got his glucose under control, he could maintain it at like 80 but when was like maintained at 150. If it would drop down to 100, he would have a reactive hypoglycemic event. So over time, there are metabolic and physiological changes in you know, the transport of glucose is upregulated. Like in the brain, the blood brain barrier, that's a glut one transporter, there's an increase in ketone production and also a key increase in ketone transport and catalytic activity within the mitochondria. And then you can, you know, in rats, you can take out, you know, the tissues, and you can do a PCR and see the protein levels increase almost 50% in the transporter in just two weeks, you know, things happen faster in rats and mice. But the point is that the more you follow a ketogenic diet, the easier it gets, you get through the adaptations over time, and it could take weeks to months, okay, to adapt and feel normal. And that's important point.

Nick Jikomes 40:55

I see. Yeah, I was actually just about to ask that. So let's say you go on the ketogenic diet tomorrow, for the typical person, you know, what's, what's the approximate timeframe you have, where you have this brain fog and this effect before you adapt? And what's actually what's actually happening and changing in the body when that adaptation is occurring?

Dominic D'Agostino 41:17

Yeah, good question. Even in subjects like to go back to the Cahill studies, it actually took about three weeks to reach steady state ketone levels, you know, steady ketone levels in the blood. So there's a lot of things happening metabolic physiology is, is quite complex, you know, even hormonal II. So, just from the context of, you know, you can kind of relate it back to fasting too, because many of the same adaptations happen, but you are suppressing by virtue of suppressing the hormone insulin, you are suppressing glycolysis through glycolytic enzymes and glucose transporters, so, and also an enzyme in the mitochondria called pyruvate dehydrogenase complex. And if you follow a very low carbohydrate diet in a lot of carbohydrate restriction, you can significantly inhibit glycolytic activity even in the muscle. And that's why in athletes who are engaging in like high high intensity exercise, or weightlifting and things like that, they could have impair performance. Because if you if, as these adaptations occur, that it is favoring fatty acid oxidation and ketone metabolism at the expense of glycolytic energy production, and I think that's important, not so much important for the epilepsy patient or other patients using the diet therapeutically. But it could be something to consider if you're an athlete, engaging in high intensity exercise. So I'm of the opinion to sort of stay more moderate a low carb and if you aren't ketogenic incorporate carbohydrates and a few times a week, and then that can actually prevent the inhibition of pyruvate dehydrogenase complex you have, there's less actually, proteins being made. So there's actually a decrease in the amount of PDH that we have, and a decrease in the catalytic activity of that enzyme. With with with, you know, significant carbohydrate restriction. You know, there's actually a disorder card called pyruvate dehydrogenase deficiency syndrome, and glucose transporter type one Deficiency Syndrome. And the standard of care for those conditions is the ketogenic diet, people stay alive when they have these inborn errors of metabolism by being in a state of ketosis when they when their glycolytic flux is decreased. That's actually how they stay alive. But you don't, you know, this has tremendous therapeutic applications, but it's quite a lot of people following the ketogenic diet and athletics and sports and things like that. And I think it can work because if we keep the body hungry for glucose, but give just enough us enough, it can actually increase insulin sensitivity, enhance glucose transport. And then of course, if you're chugging Gatorade all the time, it can have the opposite effect, right? You can have glycation, you can have a lot of consequences. inflammation, which could inhibit glucose transport over time. So you want to keep your body hungry for glucose. And you want to keep insulin low, but not fully suppressed. Like on a ketogenic diet. I'm speaking about, you know, the lay person wanting to tinker with these things.

Nick Jikomes 44:40

So so it sounds like when you go to a ketogenic diet, there's going to be this transition period where you get brain fog and your body's metabolism is shifting and changing and there's like a time lag there it takes time for for things to switch. You can sort of decrease the magnitude of this intermediate adaptation period and some of the negative effects by being extreme Be mindful about getting, you know, just the right amount of carbs. But I guess Long story short, if you're going on to keto genic diet, there's gonna be some kind of transition period, it probably doesn't make sense to try it for a month or less is what you're saying.

Dominic D'Agostino 45:11

Yeah, and you might one way to sort of adapt your body to follow a ketogenic diet is simply to do some form of intermittent fasting, you know, 12 hours per day on a standard diet, mixed diet, and that period of fasting will produce low levels of ketones and will get your body used to functioning in a lower glucose, lower insulin state. And you'll start to have these adaptations before even changing the macronutrient profile of the diet. And one way to fully get the most out of the ketogenic diet to quickly get into ketosis is to do time restricted feeding with a ketogenic diet. And then you could add, like exogenous ketones, that could fill the gap because it's going to take a while for your liver to start pumping out ketones. So it's a process there's a number of enzymes that need to be up regulated over time. You can also incorporate ketogenic fats, like medium chain triglyceride, that are the eight carbon Caprylic, triglyceride capric, to some extent, can be helpful, but yeah, there there are ways to construct it and optimize it where you don't feel anything. You could go on a ketogenic diet. And if you do it right, you can just transition seamlessly into it. It takes some knowledge to do that. But you can do it.

Nick Jikomes 46:36

Yeah. So yeah, okay. So you can you can, instead of diving right in, and you know, starting full blown 90% high fat diet tomorrow, you can start doing intermittent fasting for, you know, 12 hours or so if not eating, you can start taking exogenous ketones, so basically ketone supplements, I want to talk about that stuff more. But let's talk a little bit about, like, what the ketones are. And what they do. My understanding is that the main one or one of the main ones is BHB. So what is BHB? And what does it actually doing in the brain and body?

Dominic D'Agostino 47:09

Yeah, BHB is a molecule of energy. And for one thing it's like, so you know, when we enter a state of ketosis, if we go if we fast or do the ketogenic diet, then we're metabolizing fat for energy, but fats do not cross the blood brain barrier. So long chain fats don't. So that's why we make ketones. So I think of ketones is like water soluble fat molecules kind of like throwing fat into a wood chipper, and it's making it small enough that the mono carboxylic acid transporter gets it in there. So they're water soluble. That's generally not water soluble, but ketones are, so they need a lipid protein. So ketones are water soluble fat molecules that enter circulation, and they are a superior fuel for the heart. That's pretty well established. And and probably the brain to emerging data is good enough to say I think ketones are a superior source of energy for preserving and enhancing brain energy metabolism.

Nick Jikomes 48:12

What do you mean by superior?

Dominic D'Agostino 48:14

So it's superior for a number of reasons. From an energetic point of view, the delta G of ATP hydrolysis is higher per carbon if you're metabolizing, ketones relative to glucose, so

Nick Jikomes 48:34

we more efficiently metabolize each unit. Yep,

Dominic D'Agostino 48:39

so I observed some of this back in like 2008. I was using a laser scan, a laser scanning confocal microscope and changing the metabolic fuel substrates. And when I when I give glucose, right, and I'm measuring superoxide production with like dihydrate with videos or different superoxide dyes, I would see a certain rate of superoxide production from the mitochondria. When it's metabolizing glucose as an energy source. If you restrict glucose that goes down, if you maintain that level of glucose and add ketones, it goes down. If you restrict glucose and actually eliminate glucose altogether and just give ketones, the slope of the rise of superoxide production is significantly decreased. So this is like very significant reduction. So there's the ketone bodies will there's an oxidation of q in the electron transport chain, and this increases the risk makes more reduced NAD and then that actually makes the super ubiquinone On is the semi ubiquinone radical is not oxidize. So there's less oxidation at the semi ubiquinone site, where if Q is oxidized, the semi ubiquinone site cannot be oxidized and turned into superoxide productive production. So that's where most of our superoxide comes from the semi ubiquinone site

Nick Jikomes 50:24

and because what it hydroxy what is superoxide?

Dominic D'Agostino 50:28

So, superoxide is the precursor, we talk about oxygen free radicals reactive oxygen species, super superoxide is I consider it as the precursor reactive oxygen species that is produced primarily by the mitochondria by this semi quinolone radical, but also NADPH oxidase like xanthine oxidase so we have various ways that we can produce reactive oxygen species. And most of what we heard we hear is that reactive oxygen species are bad. And they, but we actually study reactive oxygen species as signaling molecules. So, in that context are kind of good. But, uh, but I also studied them in the context of hyperbaric oxygen toxicity and things like that, where an overproduction of oxygen free radicals in the form of superoxide can be toxic because superoxide then can be converted to hydrogen peroxide through superoxide dismutase. And catalase converts that you know, to water but what can happen in the context of too much oxygen, metabolic stress? You know, pretty much every neurodegenerative disease is patho, physiologically linked to an overproduction of oxygen free radicals. So the superoxide can go to hydrogen peroxide. And in the context of certain in micro environments, for example, if there's like high iron, it can drive the Fenton reaction. And with the Fenton reaction, you could produce a hydroxyl radical, then that's very reactive, so that can oxidize membrane lipids, proteins, nucleic acids, if we're doing confocal, or atomic force microscopy, we can actually see membrane Blooding and membrane lipid oxidation. And we can correlate this membrane damage and roughness with Malin dialdehyde, which is like an oxygen a reactive oxygen species. So yeah, superoxide is the precursor oxygen free radical that can then go on do a lot of damage, and you get much less of it. When you metabolize ketones relative to glucose,

Nick Jikomes 52:45

I see. So in general, when when ketones are higher when BHB is higher, and or when glucose is lower, you're gonna get less of at least certain types of free radicals.

Dominic D'Agostino 52:56

Yeah, yep, for sure. So I mean, this is kind of universally accepted. It's also demonstrated the late Dr. Richard Veatch, who did a lot of he was a student of Hans Krebs, the Krebs cycle, he did a lot of very innovative work at the time, very innovative using the perfused heart preparation. And he demonstrated, and this was quite some time ago that the hydraulic efficiency of the heart is increased about 25 to 28%. If it's metabolizing, ketones for energy, and you know, when I read the these papers a long time ago, as a neuroscientist, I became very compelled with the idea of, you know, fueling the brain of ketones and then, you know, the ketogenic diet showed tremendous efficacy for a wide variety of seizure types independent of the etiology, meaning that you could have temporal lobe epilepsy, absence epilepsy, you could have a neuro metabolic disease like glucose transporter, which causes seizures, and then the ketogenic diet worked for all of them. So it was definitely supplying by elevating ketones, you're supplying an important form of brain energy. And this becomes really important for diseases like Alzheimer's disease where a hallmark characteristic is glucose hypometabolism, you can do an FDG PET scan on a person with depression. And there's, you know, significantly less glucose metabolism in a person that has depression relative to a normal person. So if we elevate ketones in the blood, those ketones freely cross the blood brain barrier, and they can restore not only brain energy metabolism, but it impacts significantly the neuropharmacology of the brain. So by stimulating the TCA cycle, you create data that can create the reduced intermediates to drive the electron transport chain. So that's one thing, but the TCA cycle many of our neurotransmitters come from the TCA cycle even, you know, neurotransmitters are produced in the mitochondria like monoamine oxidase, for example. So, so that becomes that got me super interested in a lot of my research is on the neuropharmacology.

Nick Jikomes 55:14

Interesting how, before we get to some of the details there? How easy is it for people to alter ketone body levels by not by going into a full ketogenic diet by but by just taking bhp supplements or ketone body supplements? Are those readily absorbed by the body? And will your body use those even if you have, you know, carbs in your diet? And you've got a lot of glucose that can also be used? Or does your body sort of ignore the BHB when it's got this other source?

Dominic D'Agostino 55:45

Yeah, that's a really good question. I had all these questions. You know, early when I started this work, like the teen years ago, I was on the phone with some of the real pioneers. Like I'm just the guy that came in secondary to all these guys that really set the stage. So that was George Cahill from Harvard, Dr. Richard Veatch, from NIH, on recruiting grabber who really helped us develop the ketone Ester, Dr. Theodore Vannelli. I mean, there's so many, it's almost like a certain generation, and they're gone. But so I kind of stepped in and started doing this work kind of early on. And I had the question because the Department of Defense didn't really want to use a ketogenic diet because it was high fat, and they thought it was going to cause some issues. So they're like develop a ketogenic diet and a drug. And so I was interested in things like two deoxy glucose, and then that is that actually inhibits glycolysis through hexokinase, and can produce state of ketosis. But it wasn't really it would produce performance detriments and but I noticed that DARPA was funding a program on warfighter performance enhancement. And I saw that they were using ketone esters, and it was not really much in the public domain. But I had access to some of the databases. And I was like, wow, this is really interesting that I was contracted to develop something to prevent oxygen toxicity seizures, and I saw that they were not they were using a standard diet, just giving a ketone Ester, and the project was showing some compelling data on performance enhancement. Although it was a slight performance enhancement, it was kind of across the board. So yes, so you can consume an exogenous ketone in the form of a ketone ester. You could take beta hydroxy, butyrate. And then ionically, bind that to sodium, potassium, and magnesium and create what we call a ketone salt. And we've probably done about most of our research on ketone esters, but then, maybe about 10 years ago, after we were working with esters, we saw that well, why don't we create a ketone salt, and I saw that the only salt they had was sodium beta hydroxybutyrate. But then if you consume a lot of that, you can get too much sodium. So I was like, Well, why, why can't I take any monovalent or die Vaillant cat ion and then ironically, bind it to beta hydroxy butyrate. So we created some patterns and formulations around that through the university. So So yeah, you can independent of diet, you could follow a high carb standard diet consume a ketone Ester, and there's different ones that we can talk about or a ketone salt. And what will happen is, the ketone Ester needs to be metabolized in the liver through primarily an alcohol dehydrogenase pathway, because you're taking one three butane dial, and that's bound, you do a trans esterification reaction to bind that to beta hydroxy butyrate. We actually take one three butane dial and we put two acetyl acetate molecules on it. There's a huge advantage to that for our applications because one, three butane dial acetyl acetate diaster When ingested, elevates beta hydroxy, butyrate and acetyl acetate and a one to one ratio. And then that particular ketone Ester has very profound neuroprotective effects. And there's different reasons for that. So the GABA glutamate ratios are changing acetyl acetate competes with chloride as an Alice allosteric activator of the glut for so there's actually it reduces glutamate release. So that's one thing that we know acetyl acetate does also it's just seems to have more profound anti seizure effects. So there's a bunch of different ketone esters. We have a library of about 60 of them, but like, I don't know, I'm drinking ketone supplement now. And I consider it like a nootropic. When you drink it even independent of caffeine, you feel an effect feels like you're drinking glucose, but there's no crash or anything because you're not releasing insulin, you're just giving your brain energy without the insulin fluctuations. And you're also giving your body electrolytes that are often depleted with a ketogenic diet. So, so to answer your question, you can consume ketones, they are readily used as a source of energy. And they do not impair, they actually enhance insulin sensitivity. So they can actually help your body,

metabolize and utilize glucose. So one of the biggest things and this is published not by our lab, I think at least four or five labs have published that when you ingest exogenous ketones. glucose goes down pretty remarkably. And I was thinking that this was happening because the ketones were causing release of insulin. And that's how we regulate keto anemia. We have ketone, urea, we excrete some ketones. And when we're on a ketogenic diet, and our ketones get elevated, that causes the pancreas to release a little bit of insulin and that insulin decreases beta oxidation of fatty acids in the liver. And that beta oxidation of fatty acids that Acetyl Co A contributes to the ketone production. So we get into a state of ketosis, too much beta hydroxy butyrate causes a release of insulin that decreases hepatic ketogenesis. And it's a very fine to NSS. One, there's like 10 ways that it's regulated, but that's probably the biggest way. So yeah, there's a very fine tune mechanism. And with exogenous ketones, I was thinking that we would get ketones down in rats and mice down into the 30s and 40s. So I was like, this has to be an insulin response. And with a large dose of a ketone Ester it is and also the ketone Ester puts stress on the liver a little bit because the alcohol dehydrogenase pathway, so much like alcoholic ketoacidosis, if you have an alcoholic who's fasted, and then drinks a bunch of alcohol, straight up straight up alcohol, it basically shuts down the livers gluconeogenesis. So glucose goes way down, and then you have runaway ketogenesis. And that's a deadly situation that will kill you. So I was thinking the same thing was happening because the ones retained aisle is a die alcohol, that it was like impairing, and that is the case, but only when ketones get above like two millimolar. So you can have zero ketones. If you're on a standard diet, and take a ketone supplement, drink it, get into that one to two millimolar range, and then you can measure your blood insulin at 3060 and 90 minutes, and there's no change in insulin. If you consume a ketone Ester, and you shoot your ketones up to four or five milli molar, and then measure insulin, insulin is elevated. And that's a very bad situation. And I think maybe we don't talk about it enough. But if you buy a commercially available ketone Ester, and you're thinking you want to like go out running and augment your performance, and you consume a bunch of it, your ketones will get elevated, you'll feel great, but what will happen is the ketones will cause a release of insulin. And two hours later, the ketones are cleared out of your blood and your hypo ketotic and hypoglycemic. And then I noticed the first things we were working with with ketone esters, and I would take a big dose, I get all excited. And it was like, Yeah, I feel it. And, you know, two hours later, I get a headache, and it wouldn't feel too good. And it's like, I just don't, you know, and I was thinking more is better. But the same would apply for glucose. Like, we're not trying to get our glucose levels to like five, you know, 10 millimolar. Right. So I think what I have experienced and what we've seen in our animal models, and now in cell culture, that more is not better and more to be detrimental. And for a person who's not managing a disease process, boosting your ketones with commercially available ketone supplements in that one to two millimolar range offers significant benefits without disrupting your metabolic physiology.

Nick Jikomes 1:04:08

Yeah, so you can increase ketone levels through supplementation, it's pretty easy to do, you can buy these products that are readily available. You don't want to go overboard and too much, which is, you know, I guess a pretty common sense piece of advice. You mentioned these different forms of the ketones, you've got the ester form, you've got these ketones, ionically, bound to different different ions are there. If someone's going to go out and buy, say, a BHB supplement or some kind of exogenous ketone body product? Are most of those products going to contain forms that are readily usable by the body? Or are there products out there where your body's it's not in a form that your body can use very well?

Dominic D'Agostino 1:04:50

Yeah, so good question. There's a lot of variability in the ketone supplements that are on the market. So I think Have a ketone ester is having really good therapeutic potential. But I am not I've seen animal model work and also my own blood work when I consume a large dose, a moderate dose of a ketone Ester for two weeks, I see start to see an elevation of liver enzymes as key hlt. And that's because you're just you know, giving your liver a little bit more work. It's like drinking a couple beers, something you know. So you have a ketone Ester, one is one three butane dial, beta hydroxy butyrate mono Ester, and that's the D enantiomer. So ketones have a D and and an L enantiomer. Or RNs depending upon the chemistry you're talking about. So the D enantiomer is the four beta hydroxy butyrate, that is most abundant and produced naturally, in the liver. There is a wrasse amaze enzyme, at least in the tissues, that will convert it to the L four, which kind of becomes interesting. So one could say that whether you're taking a d beta hydroxy butyrate supplement, or a Simic, which is the DL, both of them are actually found in our body, although it's very, I think the D may be better, maybe for exercise performance, although most of our data is actually with receiving we can use one or another. And when we tested it, we don't see any major differences. And then the receiver it used to be a lot cheaper, but now they're about the same cost. So it's my opinion that a receive MC beta hydroxybutyrate Salt actually has some advantages, right. So if you consume equal mixture of D and L, beta hydroxy butyrate, the D will be used as a source of energy very quickly, whereas the l will stick around in circulation and in the tissues longer, it takes longer to metabolize it. Why that it's almost like a time release form of beta hydroxy butyrate, some of the L converts back to D. And some of the l just goes to acetyl. Co A. But what's important is that both an auntie MERS a beta hydroxy butyrate have signaling effects. So ketones are a source of energy. But ketones have profound they're almost like hormones. So they have a receptor, the GPR window nine a receptor, for example, is a ketone receptor, beta hydroxy butyrate receptor, and also the NL RP three inflammasome. There's these inflammasome complexes that when they're activated, so they have to assemble and then be activated. So beta hydroxybutyrate, D, or L prevents the assembly of the NL RP three inflammasome. And this is a study we published in Nature Medicine. And then it also prevents the activation of that, if the D gets used up quickly as fuel and the L circulates around longer. The L beta hydroxybutyrate has a greater capacity to function as an important signaling molecule. And I think that may explain some of the results we have seen in our studies is that there are Simic seems to have beneficial effects. So suppressing you know, other work showed NF kappa B and L RP three inflammasome. And also now we have a project on epigenetic regulation. So beta hydroxy butyrate, can directly interact with the histone in a process called beta hydroxy butyrate relation, where there's direct interaction of beta hydroxy butyrate with modifying the histones in a way that could be neuroprotective. And that's, that's the big point. We're doing it for Kabuki syndrome, but I think that has real world applications for neuroscience and other areas of science. Okay, so

Nick Jikomes 1:08:57

you can take exogenous BHB in the form of supplement that's the major ketone body in the body. There's two forms of it DNL you know, version one, version two, you know, version one and version two have a little bit of a different time course one of them is sort of like the time released version as you said, they are similar but they probably do have some distinct effects. And when you said the you know, you prefer the racemic mixture you just mean things that contain a mixture of both versions

Dominic D'Agostino 1:09:25

Yeah, similar drugs you know, they're most drugs are received back of course there was that episode with flip flop minimized or the drug that caused fat lid amide Yeah, so it's not like that with you know, ketones so you don't have to worry about a receiving catastrophe actually, I think ringer solution which is lactate is like, you know, receiving too, but uh, but yeah, I was of the opinion.

Nick Jikomes 1:09:55

Can you see this like, oh, you know, if someone goes and buys a bottle of bhp, will will say on the ball. But like d or L or both D and L, will they be able to see that?

Dominic D'Agostino 1:10:06

It depends on the company making it right. So a lot of companies will promote that they have D because that, in theory should offer a greater metabolic advantage. But then what I find is that the D gets metabolized and cleared pretty quick and a receipt back has D in it anyway, so you could deliver D, and then you can deliver L with like a ketone. So I'm using a product called keto start by audacious nutrition. So I'm elevating it the meters interesting that the meter assay only measures the deform so if you take a receipt back and use like, I have different meters Abbott precision extra the Keto Mojo device, I use a breath meter called the the readout biosense. And that goes up significantly, with with receive MC. But the commercially available meters only measure the D. So if you spike it up to point five or point or one milli molar, it's actually probably double that with a receding back because the elbow gets elevated. So yeah, I think, you know, it's also context dependent. And I think much most of the research on exercise has been using the D with the understanding that theoretically, the D will cause greater oxidation of Q and greater mitochondrial enhancement. Although the L gradually gets inter converted about 20 to 30%, or maybe 40, back to D. So it just gets metabolized slower, but the exercise studies have really not panned out. So very few things actually like improved performance. So you have like caffeine and creatine. But what I think the issue is that with the exercise studies is that they dose it acutely. And then they do the exercise experimental paradigm. And if they don't see an effect, or it's a very small effect, it's like, well, it's not that impressive. So the way to use exogenous ketones would not be to consume it acutely. In 1234, I think ketones need to be used as a training aid. So if we stay into ketosis, and appear in a state of ketosis during training, I think you will augment the adaptations to the training that will then translate to performance enhancing less reactive oxygen species, less inflammation. And also when you're training. If you're running an event, and you're in a state of ketosis, you're gonna completely bonk if your body runs out of glucose. If you're on a high fat diet, or ketogenic diet that actually spares glycogen. And by elevating ketones, you're putting more energy to the central nervous system, like your brain is what causes your muscles to fire. So I think that's really an important concept in the context of endurance exercise. And if we can optimize fuel flow to the brain, that's going to give a performance advantage, cognitive and physical performance advantage. So I see

Nick Jikomes 1:13:21

that yeah, that makes a lot of sense. Yeah, your brain is literally driving what your muscles are doing. So optimizing the metabolic efficiency of what's going on in your brain is going to have those downstream effects on what your muscular muscular skeletal system is going to be capable of. So you can take exogenous ketones, even if you're not in ketosis on the ketogenic diet, they will have physiological effects, even if you've got, you know, carbs in your diet, and you've got these other energy sources circulating. And if you do go into ketosis from the ketogenic diet means you're consuming very high fat diet, as we talked about, Can you unpack fats a little bit more for us? Because I'm interested in you know, what, what the fat composition itself needs to look like? Or that matters there? Saturated fats, mono unsaturated polyunsaturated, is that factor into this? And can you maybe just start out by telling people what the difference is between saturated monounsaturated and polyunsaturated fat?

Dominic D'Agostino 1:14:19

Yeah, well, epidemiologically there's sort of, there's significant effects to these fats. And I do think that saturate I'll say, right off the bat, I think saturated fat has been demonized as an atherogenic risk, and I think it's probably not an ideal fat to, to consume in the context of the high amounts of saturated fat are probably not very good in the context of a carbohydrate based diet. So of course, you know, fats or fats are great and you just need to have certain ratios. There's essential fatty acids And there's essential amino acids, there's no essential carbohydrates. That doesn't mean that that you can't have that's not optimal. So in the context of going back to exercise, I don't think a ketogenic diet is optimal, I think more of a mixed diet. So with a ketogenic diet, the main issue is that it's got a very high percentage of fat. And most of that fat traditionally has come from saturated fat, and saturated fat can elevate can cause pretty profound changes in your lipid profile. And the one thing that kind of stands out is it with high saturated fat is that your LDL can be significantly elevated, although triglycerides tend to be go down on a ketogenic diet. That's if triglycerides go up on a you caloric ketogenic diet, that's not a good sign, that means your body's not metabolizing the fat for energy, it's less likely that it seems like if we have a greater percentage of mono unsaturated fatty acids and some polyunsaturated fatty acids, relative to saturated fat, there's a better conversion. There's less side effects associated with ketogenic diets that have a greater proportion of mono unsaturated fats versus saturated fats. From the context of biomarkers, not so much from the context, there's not a whole lot of clinical data, the best clinical data that we have on the potential negative risk of saturated fat and the ketogenic diet, the best clinical data is from the world of epilepsy, right? Where there's people who've been on the diet for decades, and I communicate with, you know, different practitioners of the ketogenic diet at major institutions that have patients on the ketogenic diet for 20 years and 30 years where they have calcium scores. And you would think that a diet that's like 50%, saturated fat were like the whole macronutrient, you know, you're getting like 80% total fat, and like most of that is saturated fat, you would think if there was an atherogenic risk to this, which is the way it's like way across the spectrum, you know, the cholesterol and saturated fat is like many magnitudes higher than the RDA recommendation, you would think these people will be dropping like flies. But their bloodwork looks fantastic. And they don't have any, any, you know, signs of an atherogenic risk. So I'm that actually gives me when the diet is properly implemented, and calories are controlled. So that's kind of goes back to this thing that we are omnivores, we are incredibly, humans have incredible metabolic flexibility. And that's why they've survived, they can survive off eating almost pure fat. And then you have some groups of people survive and appear to be optimized eating just plants and just basically carbohydrates. So I think that one thing to realize is that we are incredibly adaptable. Although processed foods, sugar, especially liquid, you know, when we consume sugar in the form of liquid, it's like, it's like liquid candy, right? That was a different. Let me

Nick Jikomes 1:18:20

see if I can parse some of this. So it kind of sounds like what you've been saying is you can be on a ketogenic diet, you can, you can be eating a lot of fats, even a lot of saturated fats. And whether or not that's going to have negative effects such as negative cardiovascular effects, actually depends on sort of the greater metabolic context. So someone eating a super high saturated fat, high fat, ketogenic diet, who is eating an appropriate amount of calories and is healthy basically might have a very different effect from that diet than someone who is eating all those saturated fats, but is just over consuming and eating a lot of food generally getting too many calories. Is that the basic idea here?

Dominic D'Agostino 1:18:58

Yeah, exactly. And then there's populations. There's a subset of people who follow ketogenic diets that are term lean mass hyper responders. So these people have low insulin, low glucose, low inflammation, low, low triglycerides, and they have astronomically high LDL levels, and that's the so called bad cholesterol. Yeah, the bad cholesterol and usually, you know, even a little bit elevated HDL. But when your rates of fatty acid oxidation skyrocket, like for example, in the muscle if you're lean and you exercise, we talked about ketones are water soluble fat molecules, long chain fatty acids are not are not soluble, right and water so they need to be packaged into chylomicrons. And then they enter circulation. And ultimately they're packaged in the in triglyceride rich, rich LDL particles or VLDLs. And then they raise the LDL is a transporter for not just cholesterol, it transports triglycerides, it transports phosphate lipids, it plays a big role in growth and repair of tissues. If you damage your muscle, you need lots of LDL to transport phospho lipids and cholesterol to repair the muscle. So in the world of people using low carb diets and ketogenic diets for exercise, or just as a lifestyle, out of that has emerged, a lot of people with astronomically high LDL and in the context of a standard American diet, that level that elevation of LDL would present a very real atherogenic risk, especially if LP little a and a b are also elevated in the context of a ketogenic diet and someone who has otherwise optimized or improved biomarkers of cardio, metabolic health, that astronomically high LDL, I'm talking about five 600. Is, is interesting, but I and doctors would freak out and immediately, you know, emergency write it write a script for a statin. And in the beginning, I thought this was maybe 10% or 15% of the population. But it turns out, it's quite high, you know that most people like almost 50% of people who follow a very high fat ketogenic diet. So that, you know, it has my I had a pretty significant elevation of LDL and I made some changes. So I reduced, I was getting about 200 grams of dairy fat, you know, it's that mostly said it's mostly saturated fat, and increase, decrease my saturated fat increased my motto and saturated fats, and just put more plants and vegetables in my diet. So I'm still doing about 50 to 100 grams of carbs a day, and I still stay in a state of ketosis. That because about a third of the carbohydrate is actually fiber. So lots of leafy vegetables, asparagus. You know, we have avocado trees all over on our property, and just, you know, it's most of most of the carbs in the meeting are pretty high fived or ate some fruits like berries, but you know, kind of high in fiber to

Nick Jikomes 1:22:18

how does one ascertain whether or not they're in a state of ketosis. I've imagined, there's probably a lot of people who think they're on a ketogenic diet, but they're not actually in a state of ketosis. How do you actually measure this?

Dominic D'Agostino 1:22:28

Yeah, urine strips are probably the cheapest and easiest. And that gives you a relative, it's semi quantitative, but they're great devices. Abbott makes the precision extra keto Mojo, my breath ketone meter biosense. Downstairs, I will use that I, what's interesting with a blood ketones is that if you're in a calorie deficit, or you're fasting, I'm sitting at my desk here, my blood, ketones could be two to three millimolar. But if I go walk around the property and come back, it could be down to 0.5. So I know that I have actually increased fat oxidation by doing a brisk walk around my property, and I should be in a higher state of ketosis, but the meter is measuring like way lower. And that's because ketones, you're using them as a source of energy. You're disposing of the ketones in your your muscles in peripheral tissues. So that's why I kind of like for people that are interested in using ketosis as fat loss or fasting intermittent fasting or ketogenic diet for fat loss to breath ketone meter is breath acetone, and the acetone in that meter is basically completely from fat that you've oxidized. So it's kind of rewarding to blow into that meter and see it really high and know all those carbons came from that that. So I think in the context of a calorie deficit, where you have greater uptake of beta hydroxybutyrate, and it's not showing up on the meter, the breath ketones, and you save a ton of money on strips too, because I can blow a balloon into my breath ketone device 1000s of times, and that would have been cost prohibitive with a blood meter. So I'm actually a bit it took me a while took me about a year and a half to warm up to the biosense breath ketone device, but it's FDA approved. It's like a

Nick Jikomes 1:24:22

class one and it works and it's probably cost effective in the long run.

Dominic D'Agostino 1:24:25

Yeah, and if you don't like pricking your fingers, for me, I'm an advocate of this technology for like, for kids that don't want to for kids that had epilepsy and things like that. So I've kind of promoted it or advocated for its use, especially for pediatric epilepsy and things like breath acetone, breath, acetone correlates well with seizure control, but not so much beta hydroxybutyrate. But breath acetone does.

Nick Jikomes 1:24:49

Yeah, one thing I want to talk a little bit about is inflammation, even mentioned a little bit ago, you know, inflammasome, and things like this. In general, those ketosis have have an overall anti inflammatory effect. Is there a clear, clear relationship there?

Dominic D'Agostino 1:25:06

Yeah, I was of the opinion that a ketogenic diet would have an anti inflammatory effect if it was calorie restricted. And I think calorie restriction. Most of the benefits of dietary interventions that you see are associated with calorie restriction. An exception to that, I think would be the ketogenic diet, we know that if we take ketones, and we incorporate it into a standard diet, and we feed it, we see a suppression of inflammatory care cascades. One of them is the NL RP three inflammasome, the GPR 109, a receptor, when that's activated, that causes anti inflammatory effects. So in this context, ketones can function as a hormone like substance that could decrease inflammatory pathways. A lot of this is very context dependent. So, you know, we study extreme environments. And when you give you put an animal or a human into a state of ketosis, in a normal environment, you know, it's not going to enhance their cognition or performance that much, but if you put them in an extreme environment where you know, your hyperoxic are hypoxic, or you know, your environmental extremes, then that's when ketones appear to preserve physiological homeostasis, and it does it through energy, but I think it also does it through some of these anti inflammatory pathways that stabilize cellular machinery. And that and that, that that's an important situation, because, you know, the ketogenic diet is used clinically, when there's some kind of pathology, and then it works. You know, that's not to say that, you know, and cognition is increased in kids with epilepsy on a ketogenic diet, because you're not having seizures, but that doesn't mean that the standard, you know, person could follow a ketogenic diet and have cognitive enhancement.

Nick Jikomes 1:27:03

Yeah, I mean, on the general subject of inflammation, and, and fats, you know, the ketosis is promoted by a high fat diet. We talked a little bit about differences between saturated, unsaturated and things like that. A topic that I've heard a lot of people speak loudly on recently, that I don't have the expertise to really parse that I would love your take on is this idea that, you know, over the past few decades, we've been eating a lot more as a society, poly unsaturated fatty acids, or PUFAs, these things are often very high and things like the seed oils that are in so many foods today, and a lot of people have been on a crusade against these. And I think the basic argument is that polyunsaturated fatty acids, were consuming more of them, they're more readily oxidized, and they more readily promote inflammation in the body. Is that true? And and what's your general take on that subject?

Dominic D'Agostino 1:27:56

Yeah, I have a quick answer. So I've looked into this a lot. And, you know, oxidation of polyunsaturated fatty acids or proofers, were a big part of looking at changes in membrane fluidity membrane lipid peroxidation, things like that, which I studied earlier, my postdoc. It is important to get to reduce Omega six fatty acids in our diet. I think that's important. And hey, if you can get a one to one ratio of omega three to omega six, I mean that that's probably unreasonable, but I think would be beneficial, as opposed to, you know, a ratio that has 20 times or 30 times the amount of omega six to Omega three,

Nick Jikomes 1:28:39

Omega six is polyunsaturated, Omega three is Yeah, unsaturated is no

Dominic D'Agostino 1:28:44

Omega three is a polyunsaturated. Yeah, there's n three and N six and omega three fatty acids are generally associated with a profound you know, benefits anti inflammatory benefits. There's docosahexaenoic acid, DHA, EPA, or DHA, and EPA. So these things and EPA has some interesting neurological effects, maybe antidepressant effects, too. So the official supplement is usually a blend of the two in a ratio similar about one to one. So I feel that seed oils I think maybe you're getting to like seed oils and excess seed oil is omega three, which are ubiquitous in processed foods and in the food industry. Many restaurants fast food chains are using the seed oils to cook all their food and in the context of heating, what if you go to the supermarket and pull all these oils off the shelf? They're not really that oxidized. I don't think they're it's that much of a problem consuming them for example, you know, maybe like a salad dressing or something like I don't think they're ideal, and they're just pretty much empty calories. Maybe they make things taste good. But when you take this fat and you cook food in it, then it rapidly oxidizes. And you I mean, it's producing things like that I worked with early on, like AquaLine AquaLine is, is causes a chain reaction of membrane lipid oxidation, that's really cool to look at underneath a microscope that like, basically permeabilized his cell membranes makes them leaky, and causes not only membrane lipid peroxidation, but protein oxidation and things like that. These, you're getting a dose of this stuff, if you're eating food that's cooked in many fast food chains. And they just, you know, the probably the worst offenders are like the mom and pop organizations where there's not like a whole lot of oversight. There's a couple restaurants that I know in Tampa, where you can just you can walk by it and smell. Once you work with these things, you understand what the smell of membrane lipid peroxidation is, and you could just smell, oh, these lipid peroxides like they're like volatile organic compounds that I think for me, I was like, Whoa, like, wow, that is membrane lipid peroxide as you can snap. So

Nick Jikomes 1:31:14

feeding, you're saying that basically, heating polyunsaturated fats caught creates nasty stuff.

Dominic D'Agostino 1:31:21

Very nasty stuff. Yeah. And I think I mean, it should probably be legal to use these things. But if you're just the seed oils, if they're not heated, I don't think they present a huge risk, I'm willing to look at the data. But you know, people been emailing me about this, and I have not seen really good studies have not been done. But I think in the context of heating these oils, and in the context of their consumption in fast food, but then you get have that confounder, right, when you you basically look at fast, you know, consumption of these oils through the fast food industry or when you're heating, there's no doubt in my mind that these things are highly toxic when they're heated. So generally speaking,

Nick Jikomes 1:32:08

they may or may not be polyunsaturated fatty acids, per se, but specifically when they're heated, they're definitely going to cause problems by creating some of these nasty chemicals. And it is probably just, it's just true, right? That a lot of a lot of fast food chains. A lot of food that we create in our society does involve eating these things.

Dominic D'Agostino 1:32:28

Yeah. Or if they're not stored in, you know, in the refrigerator. You know, if you have I consume my omega three pretty quick, but a lot of times they have antioxidants and stabilizers in them. But you know, if you buy omega three fatty acid capsules, and it smells, and if there's an off smell to it, that's basically oxidation of the fats. And you know, that's what fishy smell is a fishy smell. Super fresh fish is. That's what you're smelling. you're smelling the oxidation of omega omega fats. When so when fish

Nick Jikomes 1:33:03

when fish smells fishy, it's because the unsaturated fats in the fish have become oxidized. Yeah,

Dominic D'Agostino 1:33:10

yep. That's isolation. you're smelling?

Nick Jikomes 1:33:12

Interesting. Interesting. So where do you so you also mentioned earlier that you thought saturated fats had sort of been unfairly demonized over the years, I wanted to kind of ask you a very sort of broad set of questions about, you know, metabolism, metabolism is super complicated. Nutrition is super complicated. In my life, just even in my own lifetime, I feel like I've seen so many things where it's like, I grew up and one thing was true. And now people are saying, like, basically, the opposite thing is true. We could talk about the food pyramid and like how that was constructed. What's your general take on like, the official institutional bodies that are responsible for sort of disseminating what the official like healthy way to eat and live is and the quality of the information they're actually disseminating? How does all that tie together and how much should people be listening to you know, the people making the food pyramids and things like that?

Dominic D'Agostino 1:34:08

Yeah, well, that's a loaded question. I could kick the kick the hornet's nest here but uh, you know, I would direct people's attention to the nutrition coalition and also Robert Lustig has a great book, metabolic hull, you know, which really documents all this with a lot of references. The the food pyramid was constructed under policies with an incredible amount of conflict of interest, you know, I have a whole team of conflict of interest people that I have to do you know, paperwork with, you know, if that level of oversight, you know, was maintained in the food industry, we would not see we would see a much different a much different pyramid I grew up farming, you know, wheat and soybeans and Monsanto crops, Roundup Ready crops, all that so I was growing up and running tractors and stuff and we grew up All this stuff and I saw the subsidies and I saw kind of how things worked. I didn't know all the nuts and bolts now I kind of know more. But But yeah, I think it's skewed more towards, you know, grains and processed foods. And that's just the foundation of the food pyramid. And I think I do think that's problematic. And I think that two things that I think we should highlight not so much the seed oils, I do think that's a problem, because there's just an excess amount of these oils, because of all the crops that are subsidized that we grow. But the big problem, and I saw evidence of this at the conference that I attended, was that, you know, a byproduct of, of this industry, industrialized farming is high fructose corn syrup. And that's ubiquitous throughout the food chain. And there's not a whole lot of really good evidence to show that when sugar when sugar is incorporated into a food, beverage, or a food that produces a cardiovascular consequent that the data is starting to be compelling, but what's super compelling is that sugar sweetened beverages, the data on this is super clear. I mean, this is basically liquid candy. And that causes a totally different hormonal glycemic response inflammation, it causes a totally different biological effect than if we're eating the food than if we're drinking sugar. It's a bolus hitting the system. And this is what kids are consuming. And this is what's more, it's cheaper to go and buy a two liter bottle of Pepsi or Coke or Mountain Dew than it is to buy water. And it's having really serious consequences to our kids. And I think that that is part of the problem that needs to be focused on. That's like the low hanging fruit that needs to be corrected. I think kids need to understand parents need parents are the ones that buy food for the kids, you know, if they're not at school, starts with education. And that's, that's probably the biggest problem I see.

Nick Jikomes 1:37:23

Interesting. One of the things that I think I saw scrolling through your Twitter before we started speaking, was that you're I think you said your favorite food is eggs.

Dominic D'Agostino 1:37:34

Yeah, yeah, I guess I would say eggs just because

Nick Jikomes 1:37:37

what, what's what's so good about eggs?

Dominic D'Agostino 1:37:41

Well, I think of eggs and sardines to is kind of like the perfect food. I mean, it has pretty much everything you need for survival. It's got, you know, the protein that you need. It's got fatty acids, of course, it has astronomically high cholesterol, but dietary cholesterol is not that much of a concern anymore, but uh, but I think eggs are pretty economical source of protein relative to meat. I'm of the opinion that you can do a ketogenic diet that's a vegetarian that incorporates eggs and some dairy. And I have quite a few people email me about plant based ketogenic diets. It's possible actually the very first blog on keto nutrition, which is my website, and very first blog ever was a plant based ketogenic because they get so many questions on it. And I was interested in using this form of diet for cancer too. So have just like a personal interest in that. But I think eggs are a perfect food, they have a perfect no glycemic response. And I think you're just loaded with nutrition. I give them to my dogs too.

Nick Jikomes 1:38:42

Yeah. And so you've also mentioned that you know, you do a lot of obviously, compared to the average person, you're doing an incredible amount of measurements and diligence with respect to your own diet and your own glucose monitoring and other things. You mentioned that you were this this device I think all the time you said that measures your blood glucose and perhaps other things. What, what does that like? How does it work? How much does it cost?

Dominic D'Agostino 1:39:09

Yeah, good question. Well, I'm disclose that I'm a consultant for levels health and levels health is an app that gives you real world actionable information from the glucose monitoring system that you're using and I think their app pairs with the dex calm, and it also pairs with the Abbott libre device and wearing a continuous glucose monitor is and they these things are pretty cheap. And if you buy them off the shelf, I think it's like 40 5060 bucks. And I think just wearing them for two to four weeks, can give incredible insight into your food selection and the amount of food that you're eating not only the macronuclear Rent profile that and how to adjust that to optimize glycemic variability. So what I use a CGM for is that I like to keep my glycemic variability between like 60 and 110. And I can stay in 100% of the time eating low carb. If I was on a standard American diet, there's no way that I could stay between 60 and 110, I would be popping up probably to like 141 30. If, if, even with a mixed diet, so you'd see that so the glycemic variability, the standard diet is much much different than a low carb diet or ketogenic diet. And you would not know this if you didn't wear a CGM, having awareness of your glycemic control. And if you eat a meal and say, you know, I feel really good, you can look at your glucose and be like, Okay, that's, that's what I feel like when my this is how I feel like when my glucose is at this level, whereas if you eat something, and you feel terrible, and you want to figure out if it's, you know, histamine response, or it's hypoglycemia, then you have a continuous glucose monitor, and then you can see the postprandial dip arise are dysregulation of glucose. So that insight is incredible. Also, it teaches you that, you know, a 10 minute walk after a big meal can basically cut your glycemic response down to like 50%. Just a walk around the property, eating fiber and protein before eating starch, like a sweet potato or something like that will attenuate that spike, it made a shift the spike to the right, so the area under the curve. Although I've analyzed that, and saw that even my area under the curve is less if I eat like fiber, and protein before eating a starch because I'm on a ketogenic, but I'll experiment with like watermelon popcorn, a lot of berries, sweet potato, these are things that foods I enjoyed prior to going on a ketogenic diet. So sometimes I'll experiment with them. If I'm testing like glucose lowering agents like Berberine, or Metformin or things like that. I'll consume carbohydrates and take a substance to see if I can attenuate that response.

Nick Jikomes 1:42:17

I see so So is it fair to say that the general as a general rule, if you are consuming something like a starchy food, that's going to cause your blood glucose to spike, Spike less if you are combining that with consumption of fiber or protein, and it will also your your blood glucose will also be impacted significantly by just getting up and moving and doing some light movement after a meal.

Dominic D'Agostino 1:42:41

Yeah, you have non insulin dependent glucose disposal. So the translocation of like the glut for transporter, and also you make best use of the insulin. So you know, if you're going to work out, it might be good to take a little bit of carbohydrates in and going into your workout and you're going to shuttle those, that sugar right into the muscle by insulin, but you're going to attenuate the insulin response and also facilitate when your muscle contracts. That's actually there's an intracellular signaling cascade that signals for the glove for to translocate to the muscle, you know, when your muscles contracting, and this is going to be very helpful for people with type two diabetes, I communicate with a lot of people, I give them two or three tips and then be like, show me your your go implement this and show me your couple of days of your CGM. And it's, it looks like night and day. So they're very simple things that we can do. And I think, you know, when you have diabetes, that's when your blood fasting blood glucose is 126 and over, and then it's like, well, then you have a problem, then you have type two diabetes or whatever. But what about if you're 125? What about if you're fast? Here's 124. Like we ignore these patients, and be like, Oh, no, they're fine. They don't have type two diabetes, and then 126. It's like, okay, well, they need to get a prescription, they need to see a doctor, and then it's a burden to the healthcare system. Why don't we, you know, in people who have type two diabetes, you know, I know some families, entire family after the age of 40 had type two to earner on like medication. Why don't we give, we could pay a little bit now and give these and the doctors could give their patients continuous glucose monitoring, and then it could go to a cloud and they could see what they're doing and make some adjustments there. Why don't we could pay a little bit now and correct the problem and get ahead of the problem and correct it before it starts. Or we can insurance companies could show out a lot later to manage not only the diabetes, but all the comorbidities that come along with it. So I'm of the opinion that we should be using these technologies. That continuous glucose monitor the sensor is one technology that I'm wearing but the app so people are just like telling knew what to eat tells me what I can and can't do. So having an app like levels health that tells you your metabolic score, and say, you know, eat this not that eat less of this not that. So we need an app that gives us actionable information. And we're going in that direction. And I think it's pretty exciting.

Nick Jikomes 1:45:18

Interesting. Well, we've covered a lot of ground. And this is an inherently complex subject. That's, you know, really hard. It's really hard for people to parse what's what, what's good information, what's bad information. Are there any tips, any advice, any sort of overarching things you want to reiterate from what we talked about, that speak to like, what the average person can like one or one or two things they should know, or one or two things they can do that are simple and easy to understand if they want to move in the direction of just having better metabolic health?

Dominic D'Agostino 1:45:51

Yeah, I think Well, one thing I didn't cover that I want to quickly put in is that the ketogenic diet is a medical therapy. You know, I come from the world of epilepsy. You know, I was chair of the American epilepsy society special interest group, and you know, that whole community views the ketogenic diet as a medical therapy that needs to be used very cautiously. And I want to quickly just mentioned that there are real side effects with the ketogenic diet. And you should get a complete blood panel, lipid profile and monitor this. You know, there are many things like if you have carnitine deficiency, or liver disorders, pancreatitis or kidney stones, probably don't want to do the ketogenic diet. So I think that's like important there a greater percentage of it being problematic if you have those things. So and then your body can be depleted of a couple things, too. And I think that's important in kids, we always see carnitine deficiency because you're transporting so much fat into the mitochondria. And that involves carnitine, that you can deplete your body of carnitine. Red meat has carnitine and as part of TJ diet, but so there's many ways. So carnitine is, it's kind of like a B vitamin, it becomes a cofactor for different things. I think at one point in time, I think it was like Vitamin B five or something like that. But carnitine is found in red meat, like liver and meat. So you would think if you eat a lot of meat, you'd be high in it, but I know people who eat me, you know, get tested and carnitine is low. So carnitine plays a role in transporting long chain fatty acids across the mitochondrial membrane for use of fuel. And if you have a if you have carnitine deficiency, which is CPT one or CPT two or carnitine translocase deficiency, then a ketogenic diet could kill you. So you want to be on a higher carb diet because that if you have a genetic disorder with a carnitine deficiency, then you can't metabolize fat for energy. And there's also people and it's the spectrum to the people that have fatty acid oxidation disorders, and a ketogenic good, there's some people you know, we don't test for these things. But some people, they follow it and they get sick when they do a ketogenic diet, they may have one of these disorders. So it's not without side effects. And I think people need to appreciate that. If you have a gallbladder, if your gallbladder is removed, you may have a hard time with the ketogenic diet. So I just kind of want to throw that out there because people advocating online about ketogenic diets, they talked about it as something that's, you know, without side effects, but I think I think I'm a big advocate of doing bloodwork and understanding what this is doing to your body. So that we what was your question prior to me just go I mean,

Nick Jikomes 1:48:39

if there are any overarching things where you know, if people want to move in the direction of improving their metabolic health, and let's assume they're not going to do a full blown ketogenic diet, you know, what are some of the things that they should know that are relatively simple and easy to grok? Are the things that they can do that anyone can do that help at least get you started in that direction?

Dominic D'Agostino 1:49:00

Yeah, well, we talk a lot about biomarkers, right, there's all this discussion about biomarkers and I think one thing that we need to appreciate is that there are blood biomarkers and like urine biomarkers, so things that you want to you want to make sure that you get routine bloodwork at least once a year. And I also do it's getting relatively inexpensive, a cardio metabolic profile which looks at insulin hemoglobin, a one C, HS C reactive protein, or hscrp. And then it also does triglycerides and zrt labs makes it it's a kit you can just buy like online and you don't have to go to a doctor, you could just put spots on a blood card and then you get your cardio metabolic. So, so this is for cardio metabolic health, you know, CBC, chem, CBC CMP, which is complete metabolic panel, a cardio metabolic panel, which you probably get for like 100 bucks. You Do it once or twice a year, I think would be super helpful. For general metabolic health. You know, blood pressure is super important. But I think the low hanging fruit is like your body composition, like I like to talk about physiological biomarkers, right, or physical biomarkers or functional biomarkers, physical biomarkers would be your body composition. So just pay attention don't get too far away from your ideal weight. So, you know, everything improves when you bring your weight down insulin sensitivity. And that would be like a physical biomarkers, and then there's like functional biomarkers, and improving your functional bio, if you can, for some people, walking for 10 minutes may be a struggle. But if you can do 15 minutes, you know it, you know, a couple of weeks after that, and then work up to 20 minutes. For other people, it may be doing 20 or 30, chin ups or something like that. So I think there needs to be an appreciation for like, overall body composition, I think that is like super important. And that is a good marker of metabolic health, you're much less likely to succumb from COVID, or another illness, you know, if you basically pay attention to that and functional biomarkers, be able to do push ups and chin ups with your bodyweight. It's not like you got to go to Gold's Gym or whatever and work out. But these things are really important. And then routine blood work blood pressure, cardio metabolic profile. And I think it's really important to know what your fasting insulin is. Because what we've seen in some individuals is that they may have normal blood glucose, say like their fasting glucose is 95. But in some people, they're their pancreas keeps out, keeps pumping more and more and more insulin over time. So if you plot their their glucose over 10 years, it could be stable, but you see their insulin levels going up. And that's basically their pancreas is working much, much harder to dump all this insulin to control blood glucose. And, and for reasons that I don't know why it's not, I guess, maybe it costs a little bit more, we need to have hyperinsulinemia is a real problem. And it could be a problem because of metabolic health associated with liver function. In our study we're doing now, we had subjects that were non obese, non diabetic, and when we looked for hepatic steatosis, or non alcoholic fatty liver disease, about 80% of them had hepatic steatosis, they had the precursors to non alcoholic fatty liver disease. And there was there's good research to show independent of calories. If you feed liquid high fructose corn syrup, and equate for calories, that you could basically triple or quadruple the amount of liver fat that you have independent of weight gain. So this is kind of scary. So people should and it'll start to creep up in your in your lipid, I mean, in your liver enzymes, your hlt will start to be become a little bit elevated. So

yeah, I think it's really important to get blood work. And, you know, if you can, if you suspect it getting a you don't have to have a CT scan, but you could do an ultrasound of your liver to look at non alcoholic fatty liver. And what happens is that as we get start to progress towards non alcoholic fatty liver, we get insulin resistant, and then the insulin starts to creep up, even if we don't see it in the hemoglobin a one C or fasting glucose. So so the important message is to really measure insulin because it's almost like a silent killer, you know, over time. And once we reach a point where we can't make any more insulin, we max out the pancreatic beta cells and pancreas become essentially burnout. And then then there's a rapid increase and uncontrollable blood glucose. And then it's like we scramble and put the person on type two diabetes meds, but we could avoid that altogether. If we just measured and managed insulin and understood what insulin was doing over time, we could catch type two diabetes before it happens. So I think that's that's an important message. And that would involve actually measuring insulin, which there are commercially available kits out there that you can do that.

Nick Jikomes 1:54:30

Got it. Yeah. So So measure, measure, measure your stuff. Yeah, there's there's relatively cheap and easy ways to do it. Well, Dominic D'Agostino, thank you for your time. You shared a lot of information and I look forward to going back and listening to this one again.

Dominic D'Agostino 1:54:47

Thanks for having me, Nick. I appreciate it. And if people want to learn more about, you know what we're doing, we have a blog keto So all one word keto nutrition dot orgy and we have a blog we have a newsletter. To sign up for that we take a deep dive into many topics discussed here


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