Understanding Therapeutic Ketosis with Dr Dominic D'Agostino

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Understanding Therapeutic Ketosis with Dominic D'Agostino

Is the ketogenic diet suitable for everyone? Today we are joined by Dr Dominic D'Agostino who is an associate professor and research scientist with interests in neuropharmacology, medical biochemistry, physiology, neuroscience, and neuropharmacology.

Dr D'Agostino is a world leading expert in the scientific applications of keto nutrition, his laboratory develops and tests nutritional strategies and metabolic-based supplements for neurological disorders, seizures, cancer and metabolic wellness. Dr D'Agostino's expertise in ketosis has led to him working with astronauts, athletes and the military. In today's episode Dr D'Agostino shares how the body uses ketones, the difference between pathological and therapeutic ketosis and the reasons why not everyone may be bio-compatible with a ketogenic diet. 

Covered in this episode

[00:30] Welcoming Dominic D'Agostino
[01:08] How is the body using ketones for fuel?
[06:09] Adaptation: pathological ketosis vs. therapeutic ketosis
[11:45] Is self measurement of ketosis reliable?
[13:28] Getting into the ketogenic state
[18:23] Enzymes: why the ketogenic diet may not be suitable for everyone
[22:04] Overcoming the "ketone flu"
[26:23] The utility of ketone supplements
[32:48] Genetics and evolution
[43:47] Is keto the 'easy way' to lose weight?
[48:09] Paediatric ketosis
[52:40] Are there any downsides to the keto diet?


Mark: Hi, everyone, and welcome. Today, we're talking with Dr Dominic D'Agostino. Dominic is a tenured associate professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine. He's also a research scientist at the Institute for Human and Machine Cognition and most interestingly, of course, has worked with NASA's extreme environment mission operation. Hi, Dominic. How are you going?

Dominic: I'm doing great. How are you?

Mark: I'm great. Early mornings over here are always good for a start, you know, especially when we're just trying out the ketogenic diets for the first time. 

So, I'm here to ask you some practical questions, but I've got to ask you the first question that's burned ever since I heard of the ketogenic diet is in 1979 at university, what we learned was the brain can only run on glucose and oxygen. They're the only fuel supplies that work for the brain. The heart is different, muscles may be different, but lactate can’t be used and it was all about glucose, lactate and how the brain runs. When did that change? When did the idea of the fuel supply being only glucose and oxygen or lactate, when did that change?

Dominic: Yeah. It's a pretty interesting story. Like prior to, I would say, 1967, when a seminal paper was published, first author was Oliver Olin and George Cahill Flat at Harvard Medical School. Where they did an elegant study measuring the A/B difference in substrate utilisation of the brain in subjects that had fasted actually for 40 days. 

 The keto diet for weight loss by Christine Valenzuela - Read Article

Mark: Wow. 

Dominic: You know, this would be hard to replicate today because ethics boards would never approve subjects fasting for 40 days, at least here in the United States. And they showed very conclusively that about 60%, upwards of around 70% of brain energy metabolism, cerebral metabolism was derived from ketone bodies, beta-hydroxybutyrate, and acetoacetate. 

So, that kind of revolutionised how we thought about brain energy metabolism in the context of fasting or starvation. And it was also recognised at the time that the ketogenic diet elevates these substrates. So, subjects that were not necessarily calorie-restricted or fasting could also be utilising ketones as an energy source.

Mark: I mean, that may be a useful study for understanding fasting. But when it comes to the options of two fuels, that's an extreme case of remaining alive. So, I do understand, in evolutionary terms, it's always good to have a fallback system, however damaging it may be better than dying. But 40-day fasting doesn't replicate what most humans do. Although it quite possibly could have in times of winter and starvation, in evolutionary terms, how does that system, that fuel system make it through?

Dominic: Yeah, well, we've got to keep in mind that's a very extreme system where you have limited calories and, obviously, limited carbohydrate...

Together: Availability.

Dominic: You know, because you're depleting your liver glycogen. And through the process of gluconeogenesis, we do break down...we catabolise gluconeogenic amino acids from skeletal muscle. But the generation of ketone bodies is a very elegant and controlled process. And one of the evolutionary functions of ketone bodies are a protein-sparing effect, and that's probably a major reason why mammals and humans, in particular, can go long periods without food, you know, while fasting. 

We have very limited carbohydrate stores, but even a lean subject has, at least, 20,000 calories of fat and our peripheral tissues can use fat very, very efficiently for fuel. Our heart runs very efficiently on fat. 

Mark: Yep. 

Dominic: And then our brain cannot readily use fats, long-chain fats, so we convert them through beta-oxidation in the liver to these ketone bodies. Which are, think of them as water-soluble forms of fat that can cross the blood-brain barrier and then provide that energy source to the brain. And the brain will use ketones if it's in the bloodstream. Meaning that you really don't even have to reach a certain threshold. If your ketone levels are elevated 0.5, that gives the brain about a 5% boost in energy or substrate availability. If you get your ketone levels up to 5 millimolar, that is actually giving the brain about a 50% fuel availability.

Mark: Right. 

Dominic: Meaning that, you know, your brain is basically running and it's, you know, if you have a glucose level of 30 or 3 millimolar and a ketone level of 3 millimolar, your brain is using about 50% of each fuel. So, you can kind of think about it like that. 

It will use what's available and the transporters are there. They’re present in the cells, they are present in the blood-brain barrier, and we have ketolytic enzymes throughout, you know, all regions of the brain to use these at the level of the mitochondria.

Mark: Okay. So, if you're doing that swap of the fuels, generally, the kind of glycogen stores drop relatively slowly and there's time to adapt. How quickly can that change occur? Can that change cover, say, hypoglycaemia failure? Some people kind of turn their glycogen to glucose fairly slowly and we talk of that as a hypoglycaemic effect. Does the body kick in within, say, minutes, hours, or days, or is this a longer term adaptation that we're talking about to utilise the ketone bodies?

Dominic: Yeah, it's a process that's really dependent upon fat oxidation in the liver. And it generally occurs efficiently in the context of low insulin. 

If you were to inject someone with insulin and that would lower their blood glucose levels but the insulin also stops the breakdown of fat in the liver, that person would die of a hypoglycaemic...could go into a hypoglycaemic coma, that's called insulin shock. 

Mark: Right. 

Dominic: But if a subject is fasting and their insulin goes low and their blood glucose starts to drop too, what happens is the low insulin stimulates fat oxidation in the liver. And even though the blood glucose may be dropping due to the fasted state, the ketones kind of fill that gap. And that occurs over the course of...it starts to happen after about 18 to 24 hours of fasting. 

Mark: Right. 

Dominic: So, there is a time delay there. And I think, you know, that's important to understand, it also kind of gives, you know, this idea of exogenous ketones where if someone goes into insulin shock…

Mark: Yes. 

Dominic: You know, maybe they could be rescued with the administration of exogenous ketones to kind of ensure that the brain and the heart have a steady fuel flow. But it's a very dynamically regulated.

Mark: Okay. So, the brain is ready to utilise the fuel. There's no stepping up enzymatic-type responses needed…

Dominic: Yes, yeah. 

Mark: It's all about delivery of the ketones, which doesn't happen if the insulin is high and the glucose rapidly drops. Is that fair to say?

Dominic: Yeah, yeah. That could be the case. Yep. But the body is sort of set up to use ketones at any time. And there's something called post-exercise ketosis where if an athlete depletes their glycogen stores through extended exercise, by the time they're finishing up their exercise, if it's three or four hours long or more, they're already in a state of Ketosis…

Mark: Right. 

Dominic: A state of mild ketosis. But in the context...medical... Doctors, generally, and this applies to the medical students that I teach, is that they basically have heard of ketosis in the context of diabetic ketoacidosis. 

Mark: Yes. 

Dominic: And that's a situation where insulin insufficiency, if you don't have insulin present and you don't inject insulin, what happens is you have runaway ketogenesis, right? Because the body is starved of glucose because it can't transport it into the cell, so it stays in circulation and the glucose levels actually go very high. And then you also have the acidosis, is actually, you know, more associated with the high glucose. And then your body goes into an emergency mode and basically starts producing these ketone bodies through runaway ketogenesis because the liver is sensing that there's very low insulin. 

So, that's a very dangerous situation if you cannot make insulin where your glucose is very high and your ketones can get 10-fold higher than they would, for example, on a well-formulated ketogenic diet or even during fasting. So, ketones can get up to 25 millimolar in the pathological state of type one diabetes if it's not managed correctly.

Mark: Right. 

Dominic: Whereas ketogenic diet, I mean, it's challenging for some people to get up to two or three millimolar, which is on the order of, you know, tenfold lower.

Mark: Right. It does explain to me why I and many other doctors have this kind of reflex fear of ketosis. You're putting people into ketosis when we spent our years in medical school and in emergency units trying to combat what we thought of as ketosis associated with acidosis of diabetes. And so, there seems to be a kind of the first move of a doctor, at least, of my generation, is you do not want ketosis. It's just going to cause problems. And this is a different, a pathological approach where both glucose and ketones are rising and the insulin is missing. And that's where the acidosis arises.

Dominic: Yeah, there is pathological ketosis and then there's therapeutic ketosis. 

Mark: Right. 

Dominic: Also called nutritional ketosis, you know, and that's two distinctly different...with therapeutic ketosis you are physiologically managing metabolic control. With pathological ketosis, you have metabolic derangement and out of control ketogenesis and glycaemia too. 

Mark: Right, yeah. 

Dominic: Those are very two distinctly different physiological metabolic states.

Mark: It's a disease process. Just.. I think a practical question for our listeners is a lot of my patients, when they're trying the ketogenic diet, buy the ketone monitors and, you know, just to keep an eye on the level of ketosis. Is that a sensible way of self-monitoring? Are they accurate and is that a reasonable choice for people to make when they're trying it?

Dominic: Yeah, I think so. There are a number of brands on the market. And the urine ketone strips have gotten a bad rap, but you know what? They are cheap and they can be effective for confirming that you are indeed in a state of ketosis…

Mark: Right. 

Dominic: Before you start measuring with the blood meters. And there are these strips out there...I'm sure they're available in Australia too, the multi-stix…

Mark: Yes. 

Dominic: Where it measures 10 different things on a single strip. So, we actually use them for some of the, you know, work that we do with NASA and other...because you can use them out in the field and they have a...it senses the relative changes. It also looks at, you know, it determines if you have an infection or your kidney function. It has biomarkers that are helpful for general health status. 

So, the urine ketone measurement is measuring acetoacetate and the blood ketone monitoring systems that are available here in the United States in most drug food stores measure beta-hydroxybutyrate.

Mark: Right. 

Dominic: And they typically have a certain ratio, a three to one, or four to one ratio beta-hydroxybutyrate to acetoacetate in the blood. And both strategies are okay.

Mark: What's an aim, what should a person who's starting their first ketogenic diet and they're moving along measuring, say, on the blood is a value of three, four, or five? Do we have a goal or is it a step up over time? Is it a progressive entry to a ketogenic diet? Or do you just move to the full diet straight off and then measure and find out where you've landed?

Dominic: Yeah. So clinically-speaking, if the blood levels of beta-hydroxybutyrate are above 0.5 millimolar, you are technically in a state of ketosis. 

Mark: Right. 

Dominic: And that would be very difficult to achieve with fasting, you'd have to like abstain from food for about 18 to 24 hours and some people, you know, you start to reach that. If you exercise you can reach that through intermittent fasting or exercise. 

And at 0.5 millimolar, that's actually… that’s starting to become a significant amount of energy in the blood, you know, that your brain can use. And that becomes, interestingly enough, that becomes sort of the threshold where it starts to have anti-seizure effects too. But typically, to get maximum sort of benefits from the ketogenic diet, you want to be between the one to like three millimolar range, is where we see many of the therapeutic benefits start to be realised.

Mark: Is that a relatively easy level to reach if you stick tightly, closely to the ketogenic diet and don't add glucose, don't add sugar energy sources, is three millimoles relatively easy? And would you be measuring that within, say, two days, three days? Is that kind of measurement time?

Dominic: Yeah. If you do a well-formulated ketogenic diet and by definition, that's really adjusting the macronutrient ratios, right? 

Mark: Yes. 

Dominic: Your fat would be a for a modified ketogenic diet if we're talking about just overall wellness and not a clinical ketogenic diet could be up to 90% fat for paediatric epilepsy. But for adults, even for treating epilepsy in adults, they use the modified ketogenic diet, which is about 65% to 75% fat. A little bit higher in protein than the paediatric upwards of 25%, even 30% protein. And very minimal carbs, 5% to 10% from fibrous carbs, typically, green leafy vegetables, salads, nonstarches, no sugars, no starch, basically just fibrous forms of carbohydrates in the form of vegetables. 

And if that is adhered to, depending on the individual, most individuals, 9 out of 10 people will start registering within that range on the blood ketone meter, the 0.5 millimolar and above range.

Mark: So, that's about, what, two days later or a week later, when do you start the measurement? People get a bit obsessive and they track every single day, three times a day. I'm never sure where to advise them to measure.

Dominic: Yeah. So, for an athlete, I've seen them the next day get into a state of ketosis.

Mark: Right. 

Dominic: And once you've been into ketosis, you tend to enter it a lot quicker. The body knows, it can make ketones, you know, more efficiently if you're kind of going in and out. 

For someone just trying it, that's very insulin...may be insulin resistant and they have maybe, you know, they're overweight and their liver is holding a lot of glycogen and they need to start burning off a lot of sugar for 48 to 72 hours before they really start registering significant ketones in the blood. 

And so, it does kind of vary between individuals. One thing that I really appreciate after studying this, you know, and seeing a lot of data in humans, there's a lot of interindividual sort of variability between people. 

And athletes too, they tend to, at rest, they can produce and have a lot of ketones in their blood, but when they exercise, they tend to clear the ketones from their system kind of quick. And that's an indication that over time, I do think we always have the ability to make ketones and use ketones, but over time, we can ramp up that metabolic machinery to be able to make more ketones but also to transport them and clear them from the blood quicker. So, our bodies become more hungry essentially for ketones.

Mark: In the liver is the ketone production an inducible enzyme system? How are the longer chain fats, how are the ketone's formed, is that an inducible cytochrome enzyme? Is it a very specific enzyme for ketone conversion?

Dominic: Yeah. There's a number of different enzyme systems that play a role in ketogenesis. And, you know, some people may have deficiencies in certain enzymes. For example, HMG-CoA lyase is one that I taught about before in some of my metabolic control classes that I teach. 

And that's an interesting enzyme to sort of discuss because some people actually, genetically, have a genetic basis and are deficient in this ketogenesis enzyme that is found in the liver, HMG-CoA lyase. And if they fast or they go for a period without food or they engage in strenuous exercise, they become extremely lethargic. They can go into a coma, they can have a seizure. And that results from the inability to be able to make ketones in the liver. 

So, they basically have, you know, a block in that metabolic pathway that's associated with beta-oxidation of fatty acids, right? So, those fatty acids are being metabolised, but the ketolytic or the ketogenic pathway is blocked. And that can cause something called hypoketotic hypoglycaemia. So, they burn up their...

Mark: Right. I imagine.

Dominic: Yeah. So, they have low blood glucose and what typically happens in a normal person is that you have compensatory regulation of ketogenesis that fills that gap. 

Mark: Right. 

Dominic: So, you start spilling out ketones into the blood and that offsets that hypoglycaemia, but in patients with HMG-CoA lyase deficiency... And maybe some drugs can do that, and there's genetics. There's a lot of... We're just starting to understand now. It's a very new kind of field looking at these fat oxidation pathways, especially in the liver. 

But it becomes very dangerous. And, you know, not everybody gets tested for these things. So, some people just feel unwell, some people just do not respond well to a ketogenic diet. And there are 30 different, at least, 30 different, you know, fat oxidation enzymes and ketolytic enzymes in the liver and various SNPs. And we're just, you know, we're at the cusp of understanding these things and, or even, you know, testing for them in humans. And, you know, and if you lack, if you're deficient in any number of these fatty acid oxidation enzymes or ketolytic or ketogenic enzymes, enzymes that are responsible for generating ketones or burning ketones in the peripheral tissues, you may not be a good responder to the ketogenic diet. 

So, I think that's important to understand, and I think it's important for medicine to really, especially if we're going to use the ketogenic diet as a metabolic therapy, as a tool, for patients with like type 2 diabetes or for weight loss, that we understand how their genetics may play a role in their response to the diet.

Mark: So, do we have enough info to do a genetic screen ahead of time as predictive? And I say that because people who hit the ketogenic diet enthusiastically often report this thing of a “keto flu”. A feeling that it's almost like it raises an inflammatory response and they feel that they're doing the wrong thing and the reflex is, "Oh, this is not for me. I better back off." But it's a fairly common effect, commonly reported, what's going on there?

Dominic: Yeah. You know, I never really experienced that. I think... It took me a few months, really, two or three months to really feel the robust effects of being in ketosis…

Mark: Right. 

Dominic: To feel myself, but I wouldn't describe what I had was the keto flu. But it does put quite a bit of stress on your body if you think about, you know, your whole...if you're adapted to a carbohydrate-based diet and you're forcing, stressing your body to switch from burning carbohydrates and glucose for fuel to fatty acids and ketones. Your brain goes through glucose withdrawal. 

Mark: Right. 

Dominic: You know, it's influencing, you know, hormonal regulation, neurotransmitter systems, and you know, it's really forcing an upregulation of the metabolic machinery, you know, in your body to fill that gap. 

So, some people have a problem with that, you know, and they go through periods of glucose withdrawal. And I think things like intermittent fasting, things like supplemental....There's various supplements that you can consume, like medium-chain triglycerides that are ketogenic fats that can elevate your ketones and get your metabolism ramped up to where you're kind of boosting the ketone levels and assisting your body's ability to enter and sustain a state of ketosis. 

So, I think some of these things can be really beneficial. And then there's, you know, the keto flu is kind of a mystery, but I have my own sort of ideas or speculation what might be going on. If you suppress the hormone insulin, it tends to cause a diuretic effect, which some people like because it's a weight loss, but you are losing some water, carbohydrate stores. Carbohydrates retain water, so you're kind of losing that too. But your blood pressure goes down and it has a natriuretic effect, which means you're excreting more sodium and that's part of suppressing the insulin signalling pathway.

And if your blood pressure goes down, you kind of feel tired and lethargic. You might get orthostatic hypotension if you stand up, maybe even feel a little bit dizzy, you might get a headache. So, the two big signs are, you know, orthostatic hypotension, having a headache, and just maybe feeling a little bit lethargic. So, taking in extra fluids, staying hydrated, and adding some additional salt to your diet. I know salt has been demonised too along with fat, but if you boost the level of salt in your diet, that will help maintain your blood volume and kind of offset the diuretic effect that really happens the first two or three weeks. 

Mark: Right. 

Dominic: Your renin-angiotensin system is sort of readjusting to this new diet and that can really help a lot of people out of the keto flu. I've heard people say, "Okay, when I did that, when I re-established...when I just took in some extra sodium" and, you know, that could be in the form of bone broth, that could, you know, there's different ways that you can do that. But I think that's really important to offset that effect. 

And also, MCT oils that I mentioned and also ketone supplements, which are kind of new to the market, but they are beta-hydroxybutyrate in salt form, so they can be combined with sodium, potassium, magnesium. And these things that can be consumed. They're a form of energy and can really pull people out of that keto flu just by, you know, delivering energy to the system in the form of a non-carbohydrate source.

Mark: The ketone supplements really interest me because that seems a very direct way. The medium chain triglycerides, people do adapt to that and they do feel improved energy, and brain energy. Tell me about the keto supplements. So, are they becoming...Is that something that's going to kind of be an easier kick-start to get people to be able to manage ketosis quicker and with less adverse effects or what's the point of them?

Dominic: Yeah. I mean, I consider them a tool in the toolbox, you know, for nutritional ketosis. You know, think of them as a form of energy. Like, we talk about macronutrients, there's fats, and proteins, and carbohydrates, that's the three, and ketones in supplement form are calorie-containing energetic molecules. 

So, you consume them and your brain especially is very hungry for ketones and your heart. So, if you keep the brain happy, you'll keep your body happier, basically. 

Mark: Right. 

Dominic: You can alter your mood if you are hungry, that hunger, that craving is likely due to hypoglycaemia. If your blood glucose drops, that triggers cravings for food. If your blood glucose drops and you elevate your ketone levels and keep that at a moderate rate, that's going to attenuate the intense cravings you're going to have for sweets and carbohydrates.

So they could be a tool, you know, from the work that I do and, you know, my colleagues, we actually study ketone supplements for military applications as a source of energy for the warfighter and also as a neuroprotective agent to prevent seizures. 

We have known for a century now that the ketogenic diet is a powerful anti-seizure therapy and the elevation of blood ketones is likely causing that anti-seizure or contributing to that neuroprotective effect. 

So, a lot of the work that we do is actually investigating different types of exogenous ketones from ketone esters and various forms of ketone salts. And with the ketone salts, which are being sold on the market now, we find that consuming these salts by themselves is not as efficient as consuming them with, for example, medium chain triglycerides. Because when you take medium change triglycerides, you're stimulating your own ketone production. But if you just take ketone salts, you tend to, by itself, you tend to get a rapid rise in ketones and then it goes back down fairly quickly. 

But if you combine the ketone salts with medium chain triglycerides, that slows gastric absorption, right? Because fat can actually delay gastric absorption and they have a satiety effect. So, they sort of function as like a controlled delivery system of the exogenous ketones into circulation. At the same time, the fats can be metabolised in the liver and then make ketones, you know, just by virtue of a normal process.

So, the work that we have done is demonstrating that even ketone esters, so ketone esters and ketone salts, their efficacy can definitely be enhanced, the induction of ketosis and sustainment of ketosis can be enhanced when you deliver these things with ketogenic fats like medium change triglycerides. 

Mark: Right. 

Dominic: And that's some of the new research we just published last week, actually. And we have been publishing over the last couple of years, but our last paper came out last week.

Mark: So, are these likely to be available soon as a part of a toolbox when a practitioner is talking with their patient? Are they able to say, "Well, here's what I would like," you know, a prescriptive formula? "These are the number of grams of medium chain triglycerides, these are the products?" Or are these yet to come to market? Is there still safety issues? Is there delays that we're going to have to expect?

Dominic: Yeah. They are generally recognised as safe here in the United States. So, they have a GRAS...they have a GRAS approval, G-R-A-S. Which basically means the ones on the market are derived from natural plant-based precursors and they are bioidentical to what the body makes. So, you can ingest them and then measure your blood ketones and it's the ketones that you're measuring, it actually detects what you're consuming. 

So, in that way, I kind of think you have an advantage, right? Because if you're buying a ketone supplement and you can't say that for any other supplement on the market. If you go to the health food store and take something, you can't really measure it in your blood, right? 

Mark: Right. 

Dominic: So, now we have commercially available, relatively inexpensive, you know, kits on the market, meters where we can consume it and actually confirm that, you know, it's elevating the thing that it's supposed to be elevating. 

Mark: Right. 

Dominic: You know, I think we need to have a lot more research on specifically the dosing protocol and the formulations. There are sodium beta-hydroxybutyrate, potassium beta-hydroxybutyrate, magnesium beta-hydroxybutyrate. You know, there's amino acid salts of these ketones. And then there's the ketone esters and probably a dozen different forms of them. So, the research that we need to do, we have to really figure out ways to optimise specific kinds of ketone formulas for specific disorders.

Mark: Which is still a work in progress.

Dominic: It's a work in progress. Yeah. And that's really what many of the talks that I've been giving now is talking about some of the animal work, but also talking about some of the human work that we're starting to do in athletes or in children too, and also in human adult patients.

Mark: Which brings me to a broader question of... I mean, in evolutionary terms, generally, humans have... There are equatorial, dark-skinned, carbohydrates available all-year round in the diet. Almost carbohydrates fall on you everywhere you move. And then as you move to the poles, seasonal variability and loss of carbohydrates would be a selection pressure on human evolutionary terms. 

It would seem sensible to think that people or races that have had to deal with carbohydrate shortage would have to have an alternate fuel supply or they wouldn't have made it. But for equatorial humans, is there a need to even have a ketogenic pathway when the carbohydrate fuel is so abundant that there would have been almost no circumstances you could imagine where you would need it? 

Are there racial differences that you've found in your research or is it available to everybody and it's just quiet when the carbs are high?

Dominic: Yeah. You bring up a good point in the racial... You know, does the geographical location of your ancestors predict sort of your metabolic efficiency or genetics for predisposition for the diet? And that's a good question. 

I think when it comes to ketosis, I could say, you know, limited food availability is something that happened independent of your geographical location, you know, in equatorial regions. So, going periodically, if you are in equatorial region and you're not catching fish or there's, you know you're just foraging for food and not...you will most likely go into periods of fasting ketosis before you get your next meal. 

So it's not...you could say it's unnatural. Our normal state is to eat three to five carbohydrate-rich meals a day. And that largely silences the metabolic state of fasting. And that state also kicks on various gene pathways that we're also silencing, you know, which can really be beneficial.

But, you know, in northern climates, the Eskimos really lived on, I would say a 60% to 70% fat diet, maybe 20% to 25% protein. The carbohydrates, you know, that the Eskimos or the Inuits consumed are really just from the glycogen in the liver and the muscle. So, they had very, very little plant matter, maybe some seaweed seasonal in the summertimes, maybe a little bit of berries here and there. But mostly it was blubber and meat, some meat. The blubber was really, you know, the thing that they liked most. The meat they would give to the dog often, but the blubber and the skin, were really, you know, the parts that were most sought after, and fatty fish too. 

So, they lived and thrived, you know, in that. Even in the harsh, very dangerous climate, their rates of diabetes, cancer, heart disease were relatively low. But if you put these individuals as, you know, it's happened now that many of them have adopted a western diet because the fishing practices, they hunt the narwhals and the seals, and now they've become protected, so they can only take a limited amount of those animals and need special permits to do so. 

We're actually working with the navy to study, you know, some of these species, the narwhal in particular, and looked at metabolic control of these diving mammals. But it's quite clear that these populations of people, once they... They are kind of adapted to these...evolutionarily adapted to these low carb diets. And when you put them on a standard American diet, that almost instantly, within the amount of 24 hours, makes them type 2 diabetic. 

Mark: Yeah. 

Dominic: And I would say, from equatorial region, you might have the opposite phenomenon going on. Those people in those regions may be more adapted to carbohydrate-based diets or just less likely to have carbohydrate intolerance because of their availability of maybe fruits, and some tubers, and root vegetables, and things like that.

Mark: So, in Australia, we do have an aboriginal population for whom the arrival of the west, and alcohol, and carbohydrates, proved very toxic and diabetogenic. 

Dominic: That’s right. 

Mark: And diabetes became a standard for a people that had a very different, probably higher protein, lower available carbohydrate in desert-like settings. It seems, that's the reason for the question, would you, at face value, say there's a phenotype that you can say or a known geographic ancestry where there are variations in how this whole transfer from glucose use to ketone use would be expected to be different. 

So, what I'm thinking is in equatorial regions, if carbs are high, the usefulness of genes that allow you to efficiently create ketones and utilise them could be lost just as our ability to produce vitamin C was lost because of availability of those. Could it be that enzymes are lost or that genes are silenced? And that when we tried to put certain groups on ketogenic diets, it's pushing against their kind of evolutionary ancestry and we get bad outcomes in that group? 

Or is it simply SNPs are all around the place, they're randomly distributed and people with certain SNPs by just bad luck, have an inability or abilities to utilise ketones better than others? Do you see a kind of geographic or is this just genetic randomness that makes one susceptible or non-susceptible to adverse outcomes of ketogenic diets?

Dominic: Yeah. I think the populations are so heterogeneous at this time...

Mark: Yeah. I agree.

Dominic: ... It's hard to make sort of any definitive kind of comment on that. I know a couple of people that are, you know, studying this, but you really need large sample sizes to... But what we do know, you know, is that a couple of projects with different people in different places that the American Indians, you know, the native Americans, I should say. They have a much, much higher rate of type 2 diabetes, and obesity, and they are relatively carbohydrate intolerant. And that likely has to do... There's people studying the genetics of this. 

And we don't really know enough to comment specifically on what SNPs they may have, but what we do know is that they are relatively carbohydrate intolerant and that's... To make matters a little worse is that their diets that they've adopted now are very high in refined carbohydrates. 

Mark: Yeah. 

Dominic: So, you have sort of two strikes against them in that way. So, there's a number of programs that some of the universities that I'm working with in El Paso and other areas down there are trying to adopt the culture and trying to formulate low carbohydrate diets that actually use some of the cultural foods that they've at least been consuming. So, yeah, there's absolutely no doubt that certain populations of people are distinctly genetically metabolically different.

Mark: And, again, that's the work in progress of determining the differences.

Dominic: Yeah. 

Mark: Seeing where the enzymes and the SNPs occur and then adapting to the individual or adapting to the population. So, that would be an example where you would expect a population difference.

Dominic: Yes. 

Mark: Whereas as doctors, we see the individuals and we want to know the individual's susceptibility, variability, and likely therapeutic outcome.

Dominic: Yeah, it's a little bit... But food is so, you know, it's such an individual thing. There's so many lifestyle factors in it that you could have, you know, 10 people eating the same diet, but some of them are eating 20% or 30% calories more. But that's hard to capture from a data collection standpoint. Because, sometimes, well, oftentimes, it's been shown that maybe people who are over-consuming calories fail to report that.

Mark: Ahh, there's a very good reason for that, that I can tell you. That's called guilt.

Dominic: Yeah. Yeah. I think, well, that's part of it too. So, when you're ramping up to do these studies and you're trying to figure out what, you know, generally, you want to get...capture two weeks of everything that the person has eaten and if they have lost, or gained weight, or maintained their weight. And then you can make some predictions as a very, very minimal baseline. 

And that sounds very easy, right? You just get a food diary and write down every morsel of food that you've eaten over two weeks and then you also...you assess the body weight over that period of time. And if your weight has not changed and you consumed 2,800 calories each day, you can predict, you know, the basal metabolic rate. 

But that's really hard to do, believe it or not. And not many studies do that. It seems so simple to be able to do that. But these are just some basic things that need to be done throughout these populations and from an individual standpoint, to be able to capture, you know, usable data and make some predictions here. 

Mark: Yeah. 

Dominic: But it's harder than you think. It sounds simple but nutrition research is very hard. It's so easy. I do most of my research right now in various rodent models. And that's much easier, but it's still pretty hard.

Mark: It is difficult to ethically manipulate dietary and population, you know, availability of food. 

Dominic: That’s right. 

Mark: And as you said earlier, getting ethical approval to do many of the things that you'd like to do or that you can do to rats is probably never going to happen. 

Dominic: Yep. 

Mark: And, of course, as every doctor and every practitioner knows, people bend the truth, especially when reporting what they've done, the chocolates that they had to get themselves out of a feeling of depression is never reported when they are meant to have been on the ketogenic diet. 

So, we work in practical areas. There's a few areas that I'd like to get just a kind of pragmatic view on. The major reason that people turn up is either type 2 diabetes or weight loss. And the mythology, at least, of the ketogenic diet is, "Here's the easy way for me not to feel like I need to eat anything, for the weight to melt off and all I have to do is just go pure ketogenic." Is that true? 

If people just adopt a ketogenic diet, given all the variability of SNPs, what kind of intensity do we need to reach a kind of two millimolar value and what kind of weight loss occurs? Part of it's fluid, part of it is fat. Can you fill me in on what we can expect and what's reasonable goals for a patient who sees this that way?

Dominic: Yeah. Well, I think it's important to emphasise, and this does not get emphasised enough, is that with a ketogenic diet, as with all diets, the weight loss that you have and sustainment of that weight loss will likely be due.... And this is an area that...it's very controversial on social media. So, there's people who feel that the ketogenic diet gives you a metabolic advantage. In that it's so easy to lose weight and you can eat all this fat and it's clear evidence that the ketogenic diet is giving you a metabolic advantage, you're burning more fat. 

You are definitely burning more fat on a ketogenic diet because you're eating more fat. But the regulatory control that happens is that it does bring down your glucose and your insulin levels independent of the calories you're eating. But the weight loss that you have… a little bit, you know, you have some water weight loss in the beginning. But then your kidneys and your body water adapt over two or three weeks and then your body water stabilises, generally speaking.

But the sustainment of that weight loss, I think, is what's most important. And I feel that if you follow a ketogenic lifestyle… And I believe the early work for diet, you know, actually it meant, like life, like lifestyle. So, a ketogenic lifestyle, you know, you go to the food store and you avoid the middle of the grocery store and you just really stick to whole foods, low carbohydrates. It doesn't even need to be ketogenic per se, just low carbohydrates. That has an appetite-suppressing effect, a satiating effect. And if you do not have sugary foods, hyper-palatable, you know, processed foods in your house, you're less likely to eat them. 

So, there's a lot of things going on and a lot of it's sort of associated with the behaviour, human behaviours. But I think from a metabolic standpoint, you are really shifting your body to burn more fat and in doing so, you're changing the neuropharmacology of your brain, you're changing your hormone levels to have less fluctuations in glucose, less fluctuations in insulin, things that generally, can be a trigger for cravings. 

These things, if not abolished are significantly attenuated, and you are more likely to have control over your eating behaviour if you adopt this strategy. And I think that's what's really important for sustained weight loss. So, that's the big benefit.

Mark: You're right as well because carbohydrate eaters have habits. And habits can be very hard to break, even highly-motivated individuals, the comfort foods tend to still be the things that they return to under stress. They can be managing a ketogenic diet, very well, stressors hit and they return to their chocolates and return to the sugars and the refined carbohydrates and seem to rapidly break out of it. It's almost like you need to sustain the ketogenic pathways to not exit it in a dumping way with the high carbohydrate load for comfort or stress management. 

But are there good-tasting keto bars that people could mistake for comfort foods, I suppose?

Dominic: Yeah. So, there are, you know, there's new companies emerging on the market now. And as a researcher, I'm excited to see that. That there are ketogenic chocolate chip cookies, low carb, you know, options that are entering the market, various baking flours. Instead of a wheat flour, you have sort of a nut-based or coconut flour, coconut oil, sort of flour-based products. 

And some of these I have on ketonutrition.org because companies will send them me and we test them and maybe about a third of the companies have legitimate ketone products and I tend to put them, you know, on the site.

Mark: Right. 

Dominic: So people can see what products are really qualified for that. And there's also a market, I think, for prepackaged whole food meals. I really like to stick to whole food meals whenever possible. But when I'm traveling, you know, sometimes I do rely on various products that are sent to me like keto cookies, and keto brownies, and bars, and things like that that are emerging on the market.

And I think, you know, it's nice to have that comfort food too sometimes that tastes really good. And I think, you know, these can be really valuable tools for the practitioner and for the patient when they're trying to, you know, manage things like type two diabetes, obesity. And I communicate with a lot of families that are dealing with epilepsy or various seizure disorders… 

Mark: Yes. 

Dominic: And these foods that are entering the market have been tremendously helpful for the parents that have kids, you know, with seizure disorders because often, the kids feel ostracised because they have to stick to a particular diet. And if they go to a party, or...and they're in school, they're not eating what the other kids are eating and that can cause some problems sometimes. But if they have, you know, access to these...ketogenic chocolate even, that's available now. So, that becomes very helpful for adherence to this diet that is really medicine, right? 

Mark: Yes. 

Dominic: So, using food as medicine.

Mark: I mean, it literally is that. I am amazed always that the neurologists don't take this up more. They regard the ketogenic diet as a kind of hypothetical diet that if the drugs fail, why not give it a try? 

Whereas it would seem reasonable to try a ketogenic diet as a first-line treatment and if it fails, move on to the medications. And people with epilepsy are extraordinarily well motivated to not have epileptic attacks. And so, that's a group that I've found that will adopt a diet very easily and stay with it under almost all circumstances as they see it working.

Dominic: Yeah, that's a really good point. You know, I feel...I have always felt that it was grossly underutilised as a way to control epilepsy. Especially in the paediatric population. Because some of the antiepileptic drugs and some of the compounds used to treat paediatric epilepsy can cause developmental problems in the children, developmental delays, and maybe even permanent sort of, you know, high doses of these antiepileptic drugs can have long-term consequences. 

Whereas the ketogenic diet, that's not the case. You know, the outcomes are much, much better if you can abstain from high dose of some of these antiepileptic drugs that we know cause side effects, long lasting side effects.

Mark: And many of those drugs even interfere with fatty acid metabolism, you know, beta-oxidation of fats. So, the drugs, in effect have... The effect's almost the opposite of what we want, but they're toxic in a particular way to stop epilepsy. But they're not good-for-you type drugs. They're not health foods in any sense of the word. They cause a damage that we would ideally like to not have. And the ketogenic diet does not seem to have those long-term consequences, or does it? 

Is a long-term ketogenic diet known to have any downsides? Should we be paying attention, as clinicians, to potential ‘gotchas’ with the ketogenic diet?

Dominic: Yeah, that's a good point. Just to touch on the first part of that statement, you know, that the doctor's role should be to do no harm. You know, "First Do No Harm." It's actually... That's the title of the movie that Meryl Streep starred in about the ketogenic diet called "First Do No Harm." 

And that was the story of Charlie Abrams and his father, Jim Abrams was quite angry that the ketogenic diet was not offered to his son as a legitimate treatment. And I think there's various reasons for that. That doctors are not nutritionists, so they kind of shy away from... It's much easier to prescribe a drug. It's thought to be challenging to get patients to adhere to the diet. And I think, you know, especially 20, 30 years ago or longer, high-fat diets were stigmatised as being dangerous.

Mark: Yes. 

Dominic: You know, because such high consumption of saturated fat, but that kind of leads to the other question is, what are the long-term, you know, consequences of following this diet? If you follow patients that have adhered to this diet for a long time, for decades, even, so, patients maybe that have glucose transporter type 1 deficiency syndrome. And I work very closely with the foundation and communicate and talk with the families and the adults that manage their GLUT 1D which can cause seizures with a ketogenic diet. And their biomarkers of general health are fantastic. Their bloodwork looks fantastic. And I think they're in a much, much better situation having gotten off the diet or gotten off the drugs, rather, and just adhered to the diet for controlling their seizures. 

So, some of the concerns that doctors have had in the past, and they still do in kids, some of the kids on a dairy-based classical ketogenic diet showed elevated triglycerides and elevated LDL. You know, now... And that was the Hopkins study about 15 years ago. 

And now, we know a well-formulated ketogenic diet can be more monounsaturated fats and they are...this is less of a concern now. 

Mark: Right. 

Dominic: And we generally actually see a decrease in triglycerides. So, a lot of it has to do with our understanding of nutrition and not using hydrogenated fats, which were actually a pretty big component of the KetoCal, which was a medical food that was used in some of these studies. It was based upon hydrogenated fats. And now, they've been pretty much completely removed from the market.

Now, there is a concern, sometimes, of elevated LDL and small dense LDL. 

Mark: Right. 

Dominic: So, that has been a concern and we still don't really understand, you know, in some patients that do, interestingly in athletes, very high-performing athletes that follow a ketogenic diet. And Jeff Volek at the... Ohio State University is studying this and has even published on this. I still have to read the paper, but essentially, they demonstrated that elite athletes that follow a ketogenic diet often present with a very high LDL and also very high, small dense LDL. Which is classically shown, you know, to be very atherogenic. 

Mark: Yes. 

Dominic: But every other thing is in the right direction. Their blood pressure is lower, their inflammation rates is lower. I think, you know... And I think, you know, many people who study this, the elevated LDL and even the small dense LDL is a sign for a higher demand for lipid and phospholipid transport, right? 

Mark: Right. 

Dominic: So, the LDL, these, lipoproteins, their function is to transport not only cholesterol, right? They're transporting fats and they're also transporting phospholipids. And you have much greater turnover and a much greater demand for the transport of fats and phospholipids in the blood.

So, my belief is that, you know, when doctors will see an elevated LDL and prescribe a statin drug, if everything else is going in the right direction, especially things like, you know, HDL is elevated and that's your good, you know, considered good cholesterol. Your blood pressure goes down, your inflammatory markers go down. A large one-year study that was just published showed ApoB remained unchanged and triglycerides generally remain unchanged in subjects that followed a ketogenic diet. They were overweight and had type 2 diabetes, for one year. 

So, one year of a ketogenic diet generally showed improved cardiovascular risk factors with a slight elevation in LDL cholesterol. But it was primarily due to the larger molecule.

Mark: Right. 

Dominic: The large LDL sub-fraction, if you will. That was primarily contributing to the elevated LDL.

Mark: Yeah. it reminds me of that line of "First Do No Harm," the modern variation on it is, "Or if you do harm, make sure the harm is minimal compared to all the benefits." And that sounds... 

Dominic: Yeah, good point. 

Mark: What's going on with the ketogenic if there is a negative in one direction and it's completely outweighed by the other cardiovascular and other metabolic risk factors. It's a shot that you would take. And then you watch the population carefully, which it seems that you are doing now, so... 

There is so much more to talk about, but I'm not going to deal with that today. It's been delightful to have your input, Dominic. You startled me at the BioCeutical Symposium last year travelling, I think, from Florida nonstop and eloquent talks. It was a kind of good ad for the ketogenic approach to brain and energy metabolism. Because I don't think any other human would have been able to deliver what you did at the other end of that kind of a journey.

So, thank you very much for today and thank you for your time and, hopefully, one day, we will talk about other things. I believe there's lots of other potentials for the ketogenic interference with cardiovascular disease, cancer, or Alzheimer's. 

There's a whole lot of other areas where, I think, this is just the opening of the door right now. And as clinicians, those of us who are involved in nutrition and metabolism, we're watching with anticipation and the work you're doing, I want to congratulate you on. It is the kind of work that is so hard to do and so necessary for clinical decision-making. 

So, thank you very much, Dominic D'Agostino.

Dominic: Thank you very much for having me on. I appreciate it.

Mark: It's been a pleasure. This is FX Omics and I'm Dr Mark Donohoe.


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Dr Dominic D'Agostino

Dr. Dominic D'Agostino is a tenured Associate Professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine. He is also a Research Scientist at the Institute for Human and Machine Cognition (IHMC). His laboratory develops and tests nutritional strategies and metabolic-based supplements for neurological disorders, seizures, cancer and metabolic wellness. He was a research investigator and crew member on NASAs Extreme Environment Mission Operation (NEEMO 22) and has a personal interest in environmental medicine and methods to enhance safety and physiological resilience in extreme environments. His research is supported by the Office of Naval Research (ONR), Department of Defense (DoD), private organizations and foundations.