Dr. D'Agostino: So, a ketogenic diet is unique from a dietary therapy point of view in that it's the only diet that we know of that is defined by an objective biomarker. So, that's ketones, and you measure that in your blood, in your urine, and also in your breath, right? So there's different ways to do that.

If you are not in a state of hyperketonemia, elevated ketones, you're technically not on a ketogenic diet. And what most people don't really appreciate is that to really get higher levels of ketones that are therapeutically linked to what it's used to treat, which is like neurological disorder, seizures, and things like that, you really have to increase the fat...drop the carbohydrates especially but moderate the protein and really consume a really high-fat diet. And that's not always sort of appreciated in the mainstream.

And a clinical diet is probably not the best choice for a lot of people, a clinical ketogenic diet. But there are variations of the diet from a four to one, which is a classical ketogenic diet, which is 90% fat and one part protein and carbohydrates. And then, all the way on the other end of the spectrum, there's the modified ketogenic diet or modified Atkins, or low glycemic index therapy or LGIT. And that's more of a one-to-one ketogenic diet. It's personally kind of what I follow, and I think you can construct the diet in a way that produces a mild state of ketosis. I think that could be a good lifestyle diet, but it's far different than the classical ketogenic diet, which was used for pediatric epilepsy. But they both have, you know, therapeutic effects that we can delve into.

Dr. Patrick: Can you give us an example of that type of diet and also what is defined as being in either mild ketosis to actually, you know, basically identify you as being in a state of ketosis from a ketogenic diet or even from other...we can talk about other ways. Obviously, we've had a lot of people in the podcast talking about fasting.

Dr. D'Agostino: Yeah. So, a ketogenic diet produces ketosis by suppressing insulin, right? And I think of it as almost like insulin suppression therapy. So, when you fast, you suppress the hormone insulin, you deplete liver glycogen, and then that accelerates beta-oxidation of fatty acids. And it's the oxidation of fatty acids in the liver or the over-oxidation of fatty acids that accelerates production of acetyl-CoA, and then that condenses to acetoacetate and beta-hydroxybutyrate. So that's accelerated at a maximal state with fasting, and you can mimic that state of fasting with a classical ketogenic diet, which is like 90% to 80% fat with a level of carbohydrate that almost has no effect on insulin, really. So in many ways, it mimics fasting in that you have a low insulin, low IGF-1, a little bit...suppression of the mTOR because protein is moderated too.

And then that diet is used classically for epilepsy. That's the four to one ketogenic diet. In extreme cases, they use a five to one ketogenic diet. And then if you move down the spectrum, it's 3 to 1, 2 to 1, and then modified Atkins, which is like a 1.5 to 1 ketogenic diet to a low glycemic index diet. So what that would mean as far as to give an example for me. So yesterday I counted my macros and I had 200 grams of protein, 150 grams of fat, and 50 grams of carbohydrates. So, 200 grams of protein compared to a combination of 150 grams of fat and 50 grams or 150 grams of protein, sorry, and 50 grams of carbohydrates. So that would be a one-to-one. So I have 200 grams of fat, 150 grams of protein, and 50 grams of carbs, right? So it's 200 grams and 200 grams. You know, that's how it's constructed in the world of epilepsy or dietary therapies by grams, not percentages. So, that's a one-to-one ketogenic diet, and that sounds extremely high in fat, right, 200 grams of fat and 150 grams of protein. But that's actually the very liberal, more loose version of the ketogenic diet that produces a very mild state of elevated ketones. Whereas a 4 to 1 ketogenic diet would be like 400 grams of fat to like, you know, 90 grams of protein and 10 grams of carbohydrates, right? So that would be very high in fat.

Interestingly, the research over the years have shown that they both have anti-seizure effects, and we're getting a better appreciation for a more liberal version of the ketogenic diet that is not so protein-restricted and not so extremely carbohydrate-restricted than something like a low glycemic index diet, which can produce little or no ketones, it can still have an anti-seizure effect and still have benefits, even independent of high ketones. So that's kind of interesting to me because it was always thought of that you needed to get really high ketones to achieve a therapeutic effect, but it looks like you could probably get many benefits from low ketones. But you're also suppressing insulin and suppressing a lot of other pathways that are, you know, therapeutic in some way, they're altering, I should say, different pathways. I don't know if I answered your question. I'm just trying to...

There's variations of the ketogenic diet, and I think that over the last 10 years...I guess it's longer than that. I think in 2008, Dr. Eric Kossoff from Johns Hopkins, he worked with Dr. John Freeman, the late John Freeman, and developed a modified Atkins diet or modified ketogenic diet for adult epilepsy. And then it was published that the diet can work for adults too back in 2007 or '08, I think around that time. So, we have many variations of the ketogenic diet even used clinically. And then when people talk about the ketogenic diet in the mainstream, that could be anything. I mean, typically, it means carbohydrate, you know, restriction, and it could be a carnivore diet. And we can talk about that. And there are many different variations.

But clinically, what you have is a five to one, which is very extreme high fat, four to one, three to one, two to one, and then a modified ketogenic diet or low glycemic index diet. And all of them are therapeutic in one way or another, and they're used for a variety of different neurological disorders, seizure disorders, metabolic disorders. Some are more efficacious for others, it depends on the individual, it depends on compliance, on the family, there's a lot to be considered when it comes to implementing these approaches.

Dr. Patrick: For a person who has not done the ketogenic diet before, what would be a good starting point? Like, you know, would you want to start with something that's one of the more like four or five to one? You know, because, from my own personal experience, and, you know, I'm going to be doing another ketogenic diet very soon, I just haven't gotten my biomarkers measured, it was very challenging for me, even someone that does a lot of intermittent fasting, to get into ketosis and to really stay in it. And also what levels if someone's measuring. And we can talk about, you know, biomarkers and measuring things but like, you know, what would be considered a mild state of ketosis if you're wanting to go by ketone levels, for example.

Dr. D'Agostino: So, very good question. It's very context-dependent. So, if you are using the ketogenic diet to manage a metabolic or a metabolically linked disorder or a brain disorder like epilepsy, right, you probably want to start with a clinical ketogenic diet and be under the supervision of a registered dietitian and a neurological team. So this is what they use in epilepsy. And there used to be an induction phase where they would fast you, and that actually helps facilitate metabolic switching, which is the transition into ketosis from being primarily a glucose oxidizer to a fat and ketone utilizer. So you can speed that with fasting. But then you have...most people are doing it as a lifestyle approach.

So, in our clinical trial that we're doing using... In non-diabetic people, they tend to be a little bit on the heavier side, but they don't have type 2 diabetes, they're using it to optimize their metabolic parameters and glycemic variability. We transition them into a ketogenic diet over four to six weeks. So, we titrate the carbohydrates down. And what we have found or my colleague has found, Dr. Allison Hull, she's at the Florida Medical Clinic and has a wellness program, that compliance and adherence to the diet and ultimately the results are better. If you take someone who's eating 300 grams of carbohydrates a day, that's standard, you know, American diet, and you drop them down to, you know, 100, and then the 75, and then 50 at about the four to six-week point, and you get a very nice improvement in many different subjective and objective, you know, biomarkers, they feel better, signs of mood are increased, anxiety using the GAD-7 test, the PHQ-9, SSQ. Sleep actually improves.