Dr. D'Agostino: There's the ketogenic diet and exogenous ketones, and they're not mutually exclusive. But I actually think they're synergistically, you know, when they're combined together. So, if you follow a more liberal version of the ketogenic diet like a modified Atkins diet or modified ketogenic diet or low glycemic index therapy, which is like a one-to-one ketogenic diet, and then supplement ketones on top of that, then I think what you have in my opinion is an optimized ketogenic diet for a lifestyle. This needs to be studied and validated in clinical trials. But I think it would also be optimal for epilepsy, for cancer, for managing type 2 diabetes, and also for weight loss. So the ketones have a satiating effect on the brain.

So the ketones are alternative energy substrate, and when your brain is metabolizing ketones, and it actually experiences low glucose, it doesn't go into an energetic crisis. So it's not signaling that you need to eat. And I think that's really interesting. There have been cases where you could produce a hypoglycemic shock that would be fatal...otherwise fatal. But if your ketones are elevated, you're asymptomatic for hypoglycemia. So that's a remarkable example of the effects of ketones on preserving, maintaining brain energy metabolism, and that has real-world effects in the context of everyday living.

And if you go on a diet, you inadvertently need to go into a calorie deficit. So calories do matter for one thing, and you have to achieve and maintain a protracted calorie deficit to lose weight and to some extent, sustain that weight for a period of time. Then you can go back to a more eucaloric ketogenic diet or eucaloric diet. It will necessitate like low glucose, low insulin, and you're going to get hungry, but if your ketones are elevated, that's where ketones shine. They really shine in the context of calorie restriction or an energy deficit because you have a better fuel flow to the brain in that context, right? So if you're on a low-calorie diet that's producing a state of hypoglycemia, but your ketones are not elevated, that's going to be a painful diet to adhere to and sustain.

Dr. Patrick: Right.

Dr. D'Agostino: Not fun.

Dr. Patrick: No. And it's funny. Like, I absolutely noticed that when I was doing my ketogenic diet. Like I said, I was doing a lot more intermittent fasting, and it was a lot easier to do. I mean, you do feel...I felt satiated. And this kind of gets into another topic, and I did want to kind of ask you about the difference between...you mentioned the diester for ketone esters, but there's also monoester, right? Is there a difference in terms of efficacy, I mean, if you're just kind of wanting to elevate your ketone levels? And again, it seems as though I prefer... I've tried all these different types of ketone supplements, and I personally am not a huge fan of the really quick spike and then like...like to me, it's kind of crashing because my glucose levels get so low, and then when the ketones wear off, it's like, "Where's my energy?"

Dr. D'Agostino: So you have, yeah, hypoglycemia and hypoketonemia, and you might also be kicking yourself out of ketosis. So it could be a dose thing. The 1,3-butanediol beta-hydroxybutyrate monoester, that was developed by...in part by Dr. Richard Veach. That was one of the first ketone esters that we actually...you know, I became interested in, and it did not have anti-seizure effects. I didn't lose enthusiasm because I knew there was so many other molecules that could be developed.

So I think chronic ketosis is probably not ideal for most situations unless you're doing...you're trying to get your insulin managed, you're trying to lose weight and maintain that weight loss over time, and you've had difficulty doing it with other types of diets.

But I think there's so many different factors that need to come into play when you're choosing to do a ketogenic diet, including monitoring. People really need to track nutrients, track calories. Some people put...you know, they eat a ketogenic diet, but they put the same amount of food on the plate. And the caloric density of the ketogenic diet is like 50% higher. So you can't eat...

So, typically, you know, we have auto feedback mechanisms that will tell us when we're satiated full, but for some people, they don't work well. So they do need to count calories and macronutrients and track at least initially so they have some idea of how many calories we're eating. I know, until I started tracking calories, I had no idea how many calories I was eating. So I thought I was eating more like 3,000, but it was more like 4,200 pretty much every day.

And then my breath acetone is off the charts. And I think breath acetone is probably your best ketone to measure if you want to lose fat. So, all the carbons of the acetone you're blowing off essentially are from fat. So, when you look at the device and it's reading like 40, it's like you're just like basically exhaling fat carbons from that.

Breath acetone is great because with beta-hydroxybutyrate I could be at 2 or 3 millimolar and just walk around the house or do some activity, and then I'm back down to like below one. That's because your body is using the beta-hydroxybutyrate as fuel. And if you have a calorie deficit, you have high tissue uptake of beta-hydroxybutyrate, right? Whereas my breath acetone seems to be more stable and a better correlate of fat oxidation. And it's also easier. So if you're blowing into a breath acetone meter five times a day, that's a lot of money in strips and a lot of poking your finger. So I use the Readout Health Biosense device. And I don't know. I've blown into mine like 1000 times, and that would be cost-prohibitive from a ketone monitoring perspective and a lot of finger pricks associated with that. And it has a pretty cool app and also a fasting sort of meter in with it. I think they collaborate with Zero Fasting. So I think there's some collaboration there, but it can show you if you're doing a fasting and using that. Although it's more of a clinical device, but now it's broken into more mainstream. So it's an FDA-approved class 1 or whatever, physical device...medical device for measuring ketones.

And I became interested in acetone because it correlates with seizure control. So, acetone does. So, I recommend it to parents who have kids that are managing and they don't want their fingers pricked and the urine ketone strips are not very accurate. So, to answer your question, I think both blood ketone measurements. If you're just starting the ketogenic diet, it may be good to just use urine to say yes you're in ketosis, you're not. It's like semi-quantitative. And then spend the money to get a ketone meter. Like the Keto-Mojo device is probably one of the best, and then a breath acetone meter is good for people who are doing fasting and for people that are really interested in like weight loss.