Full Transcript Introduction to ketogenic research 0:00 When we look at the research to actually see that Parkinson's was arrested dead in its tracks, it was a pretty breathtaking result. 0:07 And now we're seeing, you know, slowing of decline in Alzheimer's patients, and even in diabetic patients a 70% risk reduction in the risk of developing 0:19 Alzheimer in that case, in established diabetic patient, the comparison part of that study to the use of insulin. 0:36 We're hearing a lot about the ketogenic diet lately, that's for sure, and with good reason. 0:41 There is so much to be gained by looking at this science and in fact engaging our bodies in a diet that lowers our intake of simple carbohydrates and actually 0:51 welcomes back the consumption of dietary fat. 0:53 And who better to tell us about the benefits of the ketogenic diet and his research than Dr. 0:59 Dominic Dagostino. 1:00 We've had him on the program before. 1:02 Let me tell you a little bit more about Dr Dagestino Dominik Dagstino is a PhD and he is tenured associate professor at the University of South Florida, 1:11 Morsani College of Medicine in the Department of Molecular Pharmacology and Physiology. 1:17 He teaches medical neuroscience, medical physiology, nutrition and neuropharmacology. 1:23 And he is also a senior visiting research scientist at the Institute for Human and Machine Cognition to assist with their efforts towards optimizing the safety, 1:33 health and resilience of the warfighter and astronaut. 1:37 His primary research focuses on developing and testing nutritional and metabolic-based therapies for a variety of disease states and advancing the use 1:47 of metabolic based therapies into human clinical applications. 1:51 So I'm really looking forward to our time together with Dr. 1:54 D'Acostino. 1:54 I've known him for many, many years. 1:56 He's really a leading voice in how we understand things like the ketogenic diet. 2:02 How we regulate our blood sugar and how can really increase insulin sensitivity, which is a very important goal. 2:09 Let's get right to our interview. 2:12 Dominic, how are you doing? 2:15 I'm doing very well. 2:16 Great to be here. 2:18 It's good to see you again. 2:20 There's a lot of talk about ketogenic diet. 2:23 People are wondering what it's all about, why it is important. 2:26 We're going to unpack that, that's for sure. 2:28 You're the man to do it or the person to it. 2:32 How did you get started? 2:33 What made you so interested in metabolism? 2:37 Yeah. 2:37 Uh, well, I've always been interested in nutrition and I did major in that as an undergrad, uh, along with biology. 2:43 Um, and then I focused on, was mentored by a physiologist and a neuroscientist. 2:50 So I, did my PhD in both of those things and just knew. 2:55 Fundamentally, I did my PhD in a pulmonary critical care division and many of the people even in there were, many these things,
Dr. D'Agostino's background and path into metabolism 3:04 treatments could have been a nutritional intervention for that. 3:08 And I my postdoctoral fellowship mostly focusing on drugs that could mitigate seizures, oxygen toxicity seizures which limit Navy seal diving and hyperbaric 3:21 oxygen therapy. 3:22 So our lab is very, we have a hyperbaric research center at the lab, so I do a lot of work on that front. 3:29 And then, you know, were using drugs that essentially were not working to block the seizures, and then I discovered that, 3:36 the ketogenic diet had been used for, since the 1920s. 3:39 I transitioned into that and really that changed the trajectory of my career, as did your books soon. 3:50 About four years into this, you had published Grain Brain and Brain Maker, Brainwash, and then more recently Drop Acid. 3:57 So your books have really provided me with the fundamental principles and reinforced a lot what I was doing at the medical college. 4:09 Yeah, I was in a tenure track position. 4:10 So it was not really looked favorably transitioning from drug research to nutrition research. 4:17 And, um, but it all worked out. 4:19 Yeah. 4:19 How, how does nutritional research benefit the institution per se? 4:26 Yeah that, well, that's a question. 4:29 yeah. 4:29 so, uh, there's not a whole lot of an age. 4:32 We leave that one hanging in the air. 4:34 Yep. 4:35 So ketogenic diet and you've become kind of the godfather of ketogenetic diet, the go-to guy to really break it down, explain it to people. 4:45 I mean, you know, there's certainly plenty of influencers talking about aspects of ketones and various diets, time restricted eating, 4:54 actual full on fasting. 4:56 But what is it about being more into ketosis and maybe we should first talk about what that means. 5:02 What I want to do is ultimately get to the place that that seems to be a good thing for metabolism Then we'll look at why improving our metabolism is a 5:10 good thing and maybe relate that to the brain. 5:13 Why not? 5:13 But let's just first talk about what it is that you're trying to do. 5:24 Yeah. 5:25 Well, there's even a debate within the epilepsy world as in regards to the levels of ketones and their, you know, how they correlate to seizure control. 5:37 And now I think the data is emerging that if we look at beta hydroxybutyrate and acetyl acetate and also acetone, which these are all things that we measure 5:45 like with mass spec, in the lab in our early studies, we find that the degree of ketosis is, there's good evidence to suggest that that's associated with 5:55 the therapeutic efficacy of this nutritional intervention. 5:59 And the ketogenic diet being a very calculated macronutrient ratio that shifts your physiology from burning Primarily glucose for energy to fatty acids 6:11 and ketone bodies for Energy and then the ketones more or less become the alternative energy substrate. 6:17 In addition to glucose, we're still burning glucose or fuel, but then they become an alternative Energy substrate that not only have metabolic effects, 6:27 of signaling effects and they're being used for, you know, at least two dozen different clinical applications. 6:34 And I know them off the top of my head. 6:35 I can kind of run through them all and why, and you 10 years ago, there might've been three or four like, Lennox-Gastaut syndrome or Dravet and, 6:45 different forms of epilepsy. 6:46 But there's 439 registered clinical trials on clinicaltrials.gov right now for ketogenic diets. 6:57 And actually that dropped very slightly from last year, which was like 450 or something, mostly because there's about a hundred or more clinical trials 7:08 on ketone supplementation. 7:10 So many people that are coming to this field kind of see that an innovative path of using various forms of ketones supplementations for some of the same disorders. 7:20 Actually exogenous ketons that ingested and I'm wondering, if there may be less interest in studying a dietary intervention that targets metabolism in 7:34 our current climate, in that now we're seeing such an overwhelming representation in the research and certainly in in clinical application of GLP-1 agonist drugs. 7:46 Yeah. 7:47 I mean, I think that's kind of like a good example, right? 7:52 Our medical college has a nutrition science course, and we're one of the maybe less than 20% of medical schools that have a Nutrition Program. 8:02 And within the various speakers, there's quite a heavy interest, i would say, on GLP-1s. 8:10 But also, Nutrition with GLP-1s, but also the off-ramp to coming off of GLp-ones and how you manage nutrition with that. 8:19 But, you know, GL p-one's have are they're amazing drugs. 8:23 My course director, Dr. 8:24 Barbara Hanson, has worked with Gerald Schulman. 8:28 She spearheaded the original insulin research, and diabetes. 8:33 And she did the originally research in GL P-ONEs all the way back in the 1980s. 8:37 in 1990s. 8:38 I think maybe people don't even know this research was going on back then, but she was involved in that research and they have remarkable effects on metabolism 8:49 primarily through dietary energy restriction, right? 8:52 So the gastroparalysis, and and, they do come with a host of side effects. 8:57 i think in some cases they can be even life-saving for that, you know, obese type 2 diabetic and really add years to their lives,
What ketosis is and why it matters 9:04 Uh, but I think they, they need to be used cautiously. 9:07 And I. 9:08 Yeah. 9:08 Um, it's really sweeping, uh, through like wildfire, you know, an interesting metaphor. 9:15 I would choose that in these times, But nonetheless, in our world, your world and my world related to the brain, I think we're really starting to see some, 9:24 and I'm not arguing in favor of widespread usage of GLP-1 agonists off-label for brain issues, but when we look at the research that the New England Journal 9:33 of Medicine article from April of last year demonstrating in a one-year interventional trial of, 153 Parkinson's patients, 9:42 that placebo group declined on the UPDRS scale by about three and a half points as expected. 9:48 the intervention group getting lixacenetide not only stabilized but had a slight improvement. 9:54 You and I have never seen that. 9:56 I mean, we've seen slowing down of the decline on the ketogenic diet. 10:00 Matthew Phillips' work in New Zealand has demonstrated that, but to actually see that Parkinson's was arrested dead in its tracks, 10:08 that was a pretty as a pretty breathtaking result. 10:12 And now we're seeing, you know, slowing of decline in Alzheimer's patients, and even in diabetic patients a 70% risk reduction in the risk of developing 10:24 Alzheimer in that case, in established diabetic patient, the comparison part of that study to the use of insulin. 10:30 So, I bring these points up because it keeps you and me focused on the pivotal role of metabolism. 10:40 your work in dietary intervention as it relates to metabolism and gets us back. 10:45 to ketogenic diet. 10:47 So let's just, for a moment, unpack the notion of ketogenetic diet, the production of key tones versus pretty much the higher carb approach of the modern day, 10:58 what used to be called the standard American diet than the Western diet now the global diet where we're pretty running on glucose day in and day out. 11:07 How does metabolism look different when people are more ketagenic, i.e. 11:13 cutting way back on the provision of carbohydrates and actually welcoming a diet that brings some fat to the table. 11:22 Yeah, I think it's important to recognize that the ketogenic diet is a pretty restrictive, and some may say severe, some say draconian, 11:31 dietary approach that restricts carbs typically under, in kids it is under 10, but in adults under 20 grams, of carbohydrates per day, 11:42 no added sugar, and no starch, maybe a small amount of fiber you would get from green vegetables. 11:50 So with the balance of the macronutrient energy coming from fats. 11:56 With a classical ketogenic diet, it's about 87% fat, with a modified ketogenetic diet upwards of about 65% of fat. 12:04 And then there's different categories of ketagenetic diets from classical to modified Atkins, MCT, based diet, there's a low glycemic index diet developed 12:14 by Elizabeth Teal from Harvard. 12:17 So, which is not ketogenic, but may have some therapeutic effects like for autism and other disorders. 12:23 But the primary thing is that you're suppressing the hormone insulin and a suppression of the hormones insulin is required for hepatic ketogenesis for 12:33 your body to make ketones. 12:35 And essentially what happens is that with carbohydrate restriction and protein moderation, there's a depletion, a decrease in hepatic glycogen. 12:46 And the liver is more or less like an energy sensor. 12:48 When levels get low enough, that stimulates beta oxidation of fatty acids in the livers. 12:55 Then the accumulation of acetyl-CoA will form acetoacetate and then that makes beta-hydroxybutyrate, which is the more stable ketone molecule in circulation. 13:06 And we have different ratios of acetylacid to beta hydroxy butyrates in the blood, and it's sort of an interesting area. 13:13 of science and research to sort of look at that. 13:15 But the definition, the clinical is that your elevation of blood ketones is about 0.5 millimolar and above, but we can measure ketone in urine and blood 13:27 and also in breath. 13:28 And I've experimented with all these different measurement tools, many of them commercially available. 13:34 And when you achieve and sustain that, we know that ketones are neuroprotective, they're cardioprotective. 13:40 They're anti-catabolic. 13:41 We've published on cancer cocaxia. 13:44 we have models where we inject lipopolysaccharide, LPS, and create massive systemic inflammation that we can mitigate a lot of that with elevating ketone levels. 13:54 they have antioxidant effects, have anti cancer effects. 13:57 So we've, we researched these and we published, you know, multiple, uh, dozens of publications, like on all these different applications. 14:06 So there are a lot of popular diets now, a time restricted eating full on ketosis. 14:11 Uh, Dr. 14:12 Walter Longo talks about fasting, mimicking diet. 14:15 And are these all kind of nuances of allowing the body to be trending more, at least directionally towards more ketoses? 14:24 I think that's one of the benefits, you know, with time restricted eating, intermittent fasting, time-restricted feeding, 14:32 whatever you want to call it. 14:33 Essentially what's happening is that you are creating an eating window and a fasting window. 14:38 And during the fasting. 14:41 You are putting your body into typically a mild state of ketosis. 14:46 reducing the level of insulin to levels that would otherwise not happen. 14:51 Maybe if you were even calorically restricting the same amount, at least during that window. 14:57 So the benefits from them are derived largely from the energy deficit. 15:04 I would say like maybe 80%, it's hard to put a number, but then there are probably additional benefits. 15:10 For example, you're letting the gut rest in repair. 15:14 You're enhancing maybe You know enhancing gut permeability or reducing gut Permeability by giving your gut some time to rest So I think there are some 15:25 additional you know benefits by having that fasting window independent of calories and that seems to be the debate Within within people in the field that 15:34 study time-restricted feeding And, you know, and other people looking at energy models will say, well, all those benefits can just be, 15:42 tied to the caloric deficit that you inadvertently eat less food if you're eating within a restricted window. 15:50 And I think that's true too, but I there are some additional benefits as Dr. 15:54 Walter Longo, Dr Sachin Panda, have talked about, I've interviewed them for various podcasts too. 16:02 The work is breathtaking. 16:04 And, you know, when you take a deep breath and step back, it seems true that what we are doing is emulating our hunter gather forbearers who must have 16:14 had times when their hunting and gathering was not as productive and they had to be a bit more resilient. 16:20 I think that you're really presenting here is a hormetic stress that when we're calorie deprived, energy deprived that it is a bit of a stress and what 16:30 we're then taking advantage of and activating are these mechanisms whereby we ultimately become more resilient and stronger metabolically by stressing 16:39 our bodies in this way that by restricting the carbs and allowing our body to utilize our endogenous fat or as is popular today providing exogenous in 16:50 the form of supplementation. 16:52 I think there's also all great points that you make and I also think that there is probably a behavioral component. 16:59 When you do that, that it changes your relationship with food and that maybe it instills in you a level of discipline around food, 17:06 around restriction. 17:08 And the more you it, the easier it gets and the benefits you derive from it. 17:15 a feed-forward sort of thing is that once you start to experience the energy and quite frankly, the dietary control that you have once your insulin is 17:25 suppressed and you started making ketones. 17:27 So the ketone's do, I talked about, we study the neuroinflammation, and we studied anti-cardiac, anti cancer effects and things like that. 17:35 But I think just by virtue of being an energy molecule that your body has access to, It keeps your brain in a state of preserved metabolic energy production, 17:48 even in the face of hypoglycemia, which is associated with a caloric deficit. 17:53 So I think achieving and maintaining a level of ketosis makes Being in a caloric deficit more easier so you don't the hypoglycemic lows do not trigger
GLP-1 drugs and metabolic effects on the brain 18:07 a craving for food and overeating and going off the rails and you know the early work by George Cahill and Oliver Owen at Harvard when they fasted subjects 18:15 for 40 days and injected them with insulin. 18:17 they were asymptomatic for hypoglycemia which is just was in 1967 they published that it was just a very dramatic demonstration that that ketones could 18:28 largely replace glucose as an energy molecule and so that's you know the neuroprotective component to that really interested me but I think more practically 18:37 if you have low levels of ketones, even one millimolar is providing your brain with 10% of its available energy, just one. 18:45 So pretty much, I remember talking to Dr. 18:47 Cahill and Dr Beach about this, and it was like, you know, one one million molar was, like 10 percent of brain energy. 18:53 Two million more is like 20 percent, a brain, energy largely speaking. 18:58 That's very important in the context of many disease processes. 19:02 Well, i think it's interesting from from that research that even at the 40 day point with those subjects, actually they were medical students and I think 19:12 perhaps some pre-med students who got paid for this. 19:15 Even at that point, there were still utilization of about 20% of what was powering the brain was still glucose. 19:22 I mean, we have a notion that while you're shifting over to full on ketones and the reality is there's still residual glucose power in the brand. 19:29 And I thought that was quite interesting. 19:32 Yeah, that's important because that gets confused a lot. 19:36 That's right. 19:38 It's often framed like you switch from glucose to ketones, but there's a transition more. 19:44 But there are very powerful homeostatic mechanisms that maintain our blood glucose. 19:50 And the ketone can fill that energetic gap. 19:55 Even when you fast for a week, which I've done, my glucose still stayed at about 60 millimolar. 20:01 or 60. No one's gonna say that fasting is easy. 20:05 It is a challenge. 20:06 I mean, I, you know, we've all done it. 20:08 We've tried to walk the talking. 20:10 To be fair, it isn't easy, but being on a more ketogenic diet is certainly a lot easier. 20:16 And especially if you cycle, I don't mean bike, if cycle between keto, being in keto and not being keto. 20:27 What would a consumer use to measure his or her depth of ketosis? 20:33 Do you think the breath analysis is adequate? 20:37 Yeah, I have lots of things right around my desk that I'm doing experiments now. 20:43 I don't market any brand, but the Abbott Precision Extra, we've published a lot with that. 20:48 The more recent is the Keto Mojo device that has the glucose-ketone index that we can go into that, that's the millimolar concentration of glucose over ketones. 20:58 It's a very important biomarker. 21:00 Uh, I got lots of tools here. 21:03 Lactate meter. 21:03 I've got your, uh, you are sure the, the uric acid presenting that I'm still measure that. 21:09 And then I keep mine handy. 21:13 Actually I correlated my, your shirt to the a, to a blood test. 21:17 Just, and I get the results yesterday and it looks like it's right on target. 21:21 Uh yeah, 4.6 at the lab and then 4 7 on the finger stick. 21:23 So. 21:27 I did. 21:27 Yeah, I got 4.6. I don't know if you could see it from there. 21:30 There you go. 21:31 Great minds think alike. 21:32 Yep. 21:33 And that was sort of after a meal too. 21:34 So yeah, also validated mine with Quest diagnostic labs and it was like plus or minus 0.2 or 0 .3. It was pretty close. 21:44 You mentioned how ketosis is really a good way of restoration for insulin sensitivity by reducing insulin, reducing the challenge of higher levels of insulin 21:56 in the body and good for insulin sensitivity, why should we care? 22:02 Well, you know, broadly speaking, most Americans are insulin resistant. 22:09 And after, especially after 50 in the 60s and 70s, you know, pre-diabetes or diabetes, people have overt diabetes. 22:18 It's a large percentage of the population. 22:20 So the fastest way to bring down your insulin and to restore insulin sensitivity is to restrict carbohydrates and restrict to some extent total calories 22:31 too can help augment that process, but fasting, time restricted feeding combined with a lower carb. 22:40 I like to do time-restricted feeding with the ketogenic diet, but you could do with Mediterranean pattern. 22:47 You know, I liked to use the word low carb Mediterranean style diet. 22:51 you know I'm still confused about what a Mediterranean diet is and how it's defined in the literature, But simply eating a hundred, 22:58 50 to a 100 grams of fibrous carbs per day and following a Mediterranean style diet would probably restore most people's health. 23:10 We tend to target like disease processes and everything from genetic disorders to epilepsy to other things. 23:19 And then a bigger lever for that would be ketogenic therapy in the form of diet or supplementation or maybe even time restricted feeding. 23:28 So, but it's that insulin, it all kind of focuses, just to get back to your question, reducing the level of insulin or restoring insulin sensitivity through 23:38 carbohydrate restriction. 23:38 Well, hi everyone, Dr. 23:39 David Perlmutter here. 23:41 We hope you're enjoying this content. 23:43 And if you would do so, go ahead and hit the like button. 23:46 If you are not already a subscriber to our channel, please consider doing so. 23:49 Uh, we're really grateful to have you as part of our community. 23:53 So let's get right back the presentation. 23:57 I think a question that a lot of people have is on how much protein they should be consuming.
Ketogenic diet, insulin sensitivity, and protein intake 24:03 And you indicated earlier that, you know, if you're consuming a lotta protein, that might help keep you out of ketosis, which is not the goal. 24:12 We're hearing the protein recommendations kinda across the board. 24:15 You know some people are saying as much as 1.5 grams per kilogram ideal body weight, seems like a lots. 24:23 Others 0.8 grams per kilogram, ideal body weight. 24:27 So through the lens of trying to maintain some degree of ketosis, how much protein do you think is best for an individual who's not necessarily trying 24:38 accomplish anything in terms of disease reversal, but just for maintaining good health? 24:43 Yeah, everybody will have different protein requirements based upon, you know, their level of muscle mass or activity level and things like that. 24:50 And I know Dr. 24:51 Walter Longo kind of advocates for a lower protein approach. 24:55 We've had that conversation before, but I kind point to the research by, Donald Lehman and Stu Phillips where Let's do grams per pound, 25:06 upwards of one gram per pounds of protein, I think, especially as we age, we have age-related sarcopenia that we want to mitigate. 25:16 That means loss of muscle mass for our viewers. 25:21 Go ahead. 25:22 This may sound very extreme, but even one to two grams per pound may be helpful for some people. 25:30 If you're in a caloric deficit, then the proportion of protein in your diet, the ratio would be higher, I think, because you want to mitigate some of the 25:42 muscle loss that can accompany weight loss. 25:44 So obviously, we don't talk about exercise enough. 25:49 If exercise was in a pill, it would be blockbuster. 25:52 It would more effective than anything we currently have available. 25:55 Or sleep in the pill. 25:57 Yeah, sleep is super important too. 25:59 Good sleep hygiene and light and yeah, just the balance of those things. 26:05 But if you are, your protein requirements will increase with resistance training, with exercise to help rebuild. 26:12 And so I'm of the opinion that if we do the metric scale about, you know, 1.6 to even two grams per kilogram. 26:23 Of ideal body weight. 26:24 Yes, of ideal, bodyweight. 26:26 Yeah, important to say ideal. 26:28 Well, to be fair, that's kind of on the higher side, correct? 26:31 Yep. 26:31 in comparison to what others are saying. 26:34 Plenty of people are right there with you. 26:36 But then again, does that tend to help steer us away from our ability to engage ketosis? 26:45 It can, yeah. 26:46 So this is like clinically for kids, one of the side effects, I guess most serious would be, well, there's kidney stones. 26:54 And then we figured out if you do potassium citrate, you can like, like there is no higher risk of kidney stone. 27:00 Early studies show a bit of a stunting of growth, like, you know, growth metrics were a little bit reduced and some of the early studies with clinical 27:10 classical ketogenic diets were limited. 27:12 And if you have children need higher protein and we were in ketogenetic diet studies for epilepsy, the protein was restricted to increase ketones more. 27:23 and to control seizures. 27:24 So we know now that a modified higher protein ketogenic diet can have the same anti-seizure effect, especially if that diet is formulated with specific 27:36 types of the early fats were like Crisco and hydrogenated oils. 27:38 These are in like shakes that, that kids would drink. 27:42 But now we know a lot more, you know, monounsaturated fats, but also medium chain triglyceride or MCT oil can be incorporated into the diet. 27:51 And you can get levels of ketones that are even above a four to one classical ketogenic diet with a 1.5 to 1, which essentially means, 28:00 getting about 20% of the calories from protein and the early diets were like 8%. And that was too low. 28:07 That created side effects and growth. 28:10 Do you think their growth issues might have been just from an overall reduction of protein, or could there have be a more specific targeting that might've 28:18 obviated it by adding in higher levels of branched-chain amino acids? 28:23 Yeah, I think I mean typically like these are formulated with like a casein or whey and they have high amounts of EAAs and branched chain amino acids with 28:34 the leucine content being the primary driver for skeletal muscle protein synthesis so that it was probably sufficient but you still need you know, 28:42 an increase in the total amount of protein. 28:46 And you, know with that level of routine restriction, you're probably not getting to that leucine threshold for, stimulating protein synthesis. 28:54 So I think essentially amino acids can be really important for maybe women or other people that don't like to eat as much protein and that if you were 29:04 doing more of a plant-based approach, EAAs, Essential amino acids and branched chain amino acid could be added to a meal. 29:14 That's for example, more, plant centric or plant based approach. 29:18 And I think that's usually the only time that I would advocate for that because like an egg, you know, even if you're a lacto ovo vegetarian or something, 29:26 or just get a little bit of dairy, You can do okay. 29:29 But if your vegan or vegetarian, I've worked with different registered dietitians to formulate those meal plans. 29:36 that is where we go to essential amino-acids or branch chain. 29:40 In that inflammation seems to be such a central player in the degenerative conditions and certainly let's just go neurodegenerative of conditions. 29:50 What is the mechanism whereby we are reducing inflammation by getting more of a ketogenic program going? 29:59 Yeah, I think it's multiple mechanisms working in synergy, right? 30:04 So a ketogenic diet is by its nature a restrictive diet. 30:08 So it is probably restricting things like grain and maybe certain types of fiber and helping to change the microbiome in a way that probably enhances the 30:24 tight junctions and reduces gut permeability. 30:27 So there's that going on. 30:30 Initially though, what you may see, we see this in rodent models and also in humans, sometimes the stress of the initiation of a ketogenic diet could make 30:41 certain biomarkers jump up like HSCR and then it comes back down at plateaus. 30:47 lower than baseline if you stick into a state of nutritional ketosis. 30:52 But you have many things going on at the level of the gut, at glucose coming down, insulin coming, ketones going up. 31:00 and everything I just sort of mentioned with a properly formulated ketogenic diet that does have fiber in it. 31:07 And I think I'm a proponent of a higher fiber, like 20 to 30 grams of fiber I feel should be important and we could talk about the different types of fibers. 31:17 But yeah, it's a great, great point, though, that people who are eliminated carbs and fibers, by definition, a carb, uh, 31:26 That's risk. 31:27 That something that I think is really part of the induction education that, Hey, yeah. 31:31 It's. 31:32 But you're desperately in need of a fiber. 31:36 Yeah, and some people do thrive on a carnivore diet and I get quite a few people will email me and they're essentially eating no. 31:44 And I think fiber is not, to my knowledge, not essential. 31:48 But, you know, in most of the data, people point to is epidemiological data, but it's really good data. 31:59 And there's a number of studies showing that prebiotic fiber can enhance butyrate and really help to restore gut health, 32:08 fermented foods. 32:10 In some cases, maybe probiotics are helpful. 32:12 But I think certain types of fiber are important for most people. 32:17 I can't let this go. 32:18 I mean, this is really very interesting. 32:20 You know, the messaging has been, well, we need to eat a lot of fibers, vegetables on our plate, various colors for the polyphenols on and on. 32:28 And yet what you just said is, is it's really quite interesting that people who are full on carnivore at times tend to, when you metricize them, 32:37 they're in pretty good shape. 32:40 Obviously their microbiomes are quite different, but when we look at, for example, the Inuit who have very little plant fiber in their diets and yet are 32:49 existing on ocean type protein and certainly fat, And that's, you know, for many months of the year, that the mainstay of their diet and yet seem to be 33:00 pretty resistant, at least to cardiovascular disease. 33:02 Maybe that is the offset by the omega-3s, who knows. 33:05 But, I think this is an area that needs further unpacking, or atleast exploration. 33:13 Yeah, it's not being studied rigorously right now. 33:17 I think Dr. 33:18 Belinda Lenertz might be tracking a number of carnivore followers and she's published something out of Harvard to just more of a retrospective observational 33:32 study looking at the different biomarkers. 33:35 And I've, you know, at least maybe a half dozen people will, have emailed me with longitudinally like sending me their blood work. 33:43 And, I would basically say, the LDL is elevated often in people, but with other, insulin, HSCRP, hemoglobin A1C, triglycerides, 33:58 You know, even B12 status is up, but that APO-B does elevate, you know HDL, APoA1, will go up and that's a good thing, But you see this elevation of APB
Inflammation, fiber, and carnivore diet questions 34:11 or LDL cholesterol and should we be concerned about that? 34:14 I think that is an area of ongoing debate and research. 34:17 Well, I think it's a question of how, you know, as well, the personalized medicine approach, how much can that individual tolerate? 34:22 I know for me, i cannot tolerate any further elevation of LDL. 34:26 So I guess that's where the personalised medicine comes into play and certainly genomics aswell would factor into that. 34:34 Yeah, there's a, you know, I was at a conference and I said I thought genomics was, genetic testing was important for cardiovascular health. 34:44 And that was quite debated with me on that. 34:47 But personally, did a GB health watch. 34:51 I don't advocate for any specific testing. 34:54 company or anything, but it did. 34:57 And someone said, I think you are a hyper responder of cholesterol, you know, just based upon what I've seen in your dietary patterns. 35:04 This is someone that looks at thousands of patients. 35:07 So I have a mutation for the MPC1L1 transporter. 35:12 That's the transporters in the gut. 35:15 Zetia, also a generic name, azetamide, blocks that and I could take a baby dose of that, and it literally cut my APO-B like in half and trended to increase 35:26 my HDL. 35:27 And my triglycerides went down a little bit too. 35:30 I didn't change anything. 35:31 So that was, I'm not in favor for my situation for taking a statin, but azetamide monotherapy five to 10 milligrams per day had a remarkable effect on me. 35:46 Other people have told me that and I said, well, you should go get tested to maybe see if you, but I think, there's a lot of different drugs. 35:55 We have very good drugs for lipid lowering. 35:58 And I they should be considered for people that have a history, or maybe if they have APO, APoA is elevated like APa. 36:12 And really on the basis of their cardiac workup as well. 36:15 I mean, what is the calcification score? 36:17 That's the big one. 36:18 What is their CT angio looking like? 36:21 And, you know, these are very valuable. 36:23 But, I would also think it's important to rein them in metabolically as it relates to insulin and glucose as Yeah. 36:31 I think, you know, we have to look at it more, uh, get the whole picture. 36:36 And I. 36:37 You know having a calcium scan and a CT angiogram or something like that is really important, especially if you have a family history of obviously had 36:46 a heart attack or. 36:46 Yeah, um, but, yeah, I, think we need to be cautious at this point in time, when it comes to carnivore diets and that, cause I get a lot of questions. 36:58 Completely agree. 37:00 I would add to the data set that looking at epigenetic expression or tags, very important. 37:08 I just did a test called True Diagnostic and it's very helpful in terms of indicating where you are epigenerically in term of risk moving forward. 37:17 The good news is to some degree you can change your epi genetic expression based upon lifestyle intervention. 37:25 based upon pharmaceutical intervention as well. 37:27 Let me get back to the notion of ketogenic diet and its role in insulin sensitivity and it's role and glucose metabolism. 37:37 Can we just momentarily touch on Glute 1 and Glut 4 transporters and how that's influenced, what they do and that influence in the presence of a ketogenetic diet? 37:49 Yeah, let's start with Glut1. 37:52 And we actually have the glucose transporter type 1 deficiency mouse model. 38:01 You know, but maybe your listeners don't know that the standard of care for a deficiency in Glute1 is the ketogenic diet. 38:07 So that is like this, literally the, standard to care, for that rare inborn error of metabolism. 38:13 So the glut one is, you know, it's in the blood brain barrier and it helps to transport glucose, into the brain and its on a wide variety of different tissues, 38:25 even in cancer tissues. 38:26 We're developing drugs to potentially target that. 38:30 So, Glut 1 is not insulin activated, whereas the Glute 4 transporter can be translocated. 38:40 It probably has its most profound role on skeletal muscle and activity, resistance training, cardiovascular, stretching the muscle, 38:50 and an increase in You know insulin and different things can translocate that receptor to the muscle and make it can enhance glucose disposal and that 39:01 can be done sort of independent of insulin to that you there's like a insulin independent trans location of the glut for. 39:10 that's sort of an activity dependent thing. 39:11 So if you're like a type one diabetic and you eat a carby meal and then go exercise, some can even like inject way less insulin or no insulin at all because 39:22 that response is so powerful. 39:25 You had also mentioned that There's some signaling activity associated with the production of ketone bodies, specifically beta-hydroxybutyrate. 39:36 I think it kind of gets to our brief discussion on epigenetics. 39:41 What are some of the important signaling aspects of this ketones, beta hydroxy butyrates that we increase as we're in more of a ketogenic diet? 39:51 Yeah, that's really like the hub, the main focus of the lab. 39:55 And it started over 10 years ago. 39:57 We looked at just looking at the brain, and the neuropharmacology of brain changes with the ketogenic diet and with exogenous ketones. 40:04 So it increases the GABA to glutamate ratio by activating GAD65 and 67 are proteins that are glutamic acid decarboxylized. 40:16 convert glutamate to GABA. 40:18 So there's, you know, the brain neuropharmacology. 40:21 We published a paper in 2015 and I helped formulate the diet in Nature Medicine that showed the beta hydroxybutyrate can function as an NLRP3 inflammasome suppression. 40:36 Actually, and then if we look more into it, the activation of the complex that's an inflammasome and the assembly and activation, 40:46 both processes are regulated in part by beta-hydroxybutyrate. 40:53 reduce and suppress that and downstream that would reduce IL-1 beta. 40:59 It's independent of the enantiomer. 41:02 Your body makes primarily D beta-hydroxybutyrate, but also makes L beta hydroxy butyrates as a mirror image and enantimer. 41:11 And what's interesting about L, and now there's, you know, a bunch of people patented it. 41:15 I think the Buck Institute and other, there was a number of different patents on the L but that simply sold as racemic. 41:20 You have a 50-50 mixture. 41:22 The L seems to retain that signaling property. 41:24 And if you consume a racamic mixture, the D gets burned up quickly as energy and then that L stays elevated in the blood about four times longer and retains 41:36 that signalling effect. 41:37 So there's a GPR109A receptor, the NLRP3 inflammasome and different sirtuins that too are sort of activated and that's epigenetic. 41:48 And then my student just graduated about a month ago with her PhD dissertation. 41:54 Her focus was metabolic control of epigenetic regulation. 41:57 So, there is something called beta hydroxybutyrolation where beta-hydroxy butyrate can interact directly with the histones.
Ketones as signaling molecules and epigenetic effects 42:05 uh to activate different genes and we started looking at this in the context of something called kabuki syndrome we had the kabuky syndrome mouse model 42:15 uh but you know i'm convinced that these metabolites especially ones that are robustly elevated with a ketogenic diet have epigenetic effects. 42:25 And it's probably not just beta hydroxybutyrate. 42:28 We know that there's something called lactylation too. 42:31 So lactate can also, lactates very interesting and was my original interest before ketones actually. 42:38 These metabolites that are changed profoundly by our diet, by fasting, but ketone supplementation have very remarkable epi genetic effects in a positive way. 42:50 Respectfully, let me just step some of this down for our viewers. 42:54 One of the byproducts of getting into ketosis from a ketogenic diet is the production of something called beta hydroxybutyrate, 43:01 which can be used as a fuel. 43:03 But the question was, it also acts as signaling molecule. 43:07 Why is that important? 43:08 What does it do? 43:09 And what you describe, one thing that you described that I think is really very important is It binds to certain cells in the immune system, 43:19 receptors on certain cell that activates something called the NLRP3 inflammasome. 43:24 Why is that important? 43:25 Because that then causes genetic changes within the cell, these immune cells, in brain, for example, the microglial cell. 43:32 that subsequently then will, when it's activated, will increase the production of damaging inflammatory chemicals called cytokines, 43:41 but also influence the mitochondrial function within that cell, the energy metabolism part of what goes on within the cell and can help propel that otherwise 43:53 helpful immune cell the microglial cell to becoming a harmful phenotype, M1 phenotypes such that its metabolism is affected and its production of inflammatory 44:06 cytokines is effected. 44:07 And the worry there is that those inflammatory cytochines can then feed back and through the same pathway influence neighboring microglial cells and convert 44:17 them from being friend to foe, to becoming the evil twin as it were. 44:21 So basically what we're saying then is that aside from the fuel aspect of ketone providing great fuel to produce energy, 44:30 that they are producing at least beta hydroxybutyrate, most gets most of the attention, is acting as a signal molecule in terms of gene expression through 44:40 modifying epigenetics, through what are called histone deacetylase activity, but also through influencing, through this inflammation pathway we just described, 44:52 NLRP3 inflammasome, a reduction of activation, influence the level of inflammation in the brain. 44:58 And that's key. 45:00 When we recognize the role of information in Alzheimer's and Parkinson's, multiple sclerosis, autism, that this is really what we're looking for. 45:08 This is pretty much the home run. 45:11 Let me shift our conversation for a moment it to something that you and I have been exploring, and that is the use of allulose. 45:19 And it's a new player for us. 45:22 We've only been looking at it for a few years. 45:26 So there's lot of excitement about alluose, tell us what this is and what you have found in your research on alluleose? 45:34 Yeah, alulose is really fascinating. 45:37 So it's a rare sugar. 45:40 It's found in nature, things like fig and it even in wheat, I think, you know, in various fruits. 45:46 Yes. 45:47 so it is a rarer sugar that is an epimer of fructose. 45:53 So very similar molecular structure like on paper. 45:56 It also uses the Glut5 transporter to get into cells. 46:02 And it's very low calorie. 46:06 I think it is like 0.2 to maybe 0,4 calories per gram. 46:11 So, very essentially like no calories. 46:14 Its absorbed in the gut, its excreted primarily I thing in urine. 46:21 non glycemic, non insulinogenic, you know, compared to other has very minimal insulin response, very minimum, if at all, 46:31 glycemic response. 46:32 Actually a lowering effect. 46:33 Some studies coming out in animal models and maybe there's, I think there is about, there at least a half dozen randomized controlled trials for allulose. 46:43 And we are, full disclosure I guess, multiple medical students were working on a systematic review of natural sugar alternatives with erythritol, 46:55 alluolose, monk fruit, stevia. 46:57 Allulose seems to shine for many different reasons. 47:00 It seems have functional effects, perhaps anti-inflammatory effects on the gut. 47:06 Generally recognized as safe by the FDA. 47:10 Again, it is found in nature. 47:11 If you take large amounts of it, which I did the very first time I tried allulase in 2014, I dumped a bunch into my coffee. 47:19 It's about 70% as sweet as sugar. 47:22 And if you put 30 grams in your coffee, on an empty stomach, you'll likely have some intestinal bloating and things depending. 47:30 So I think it's good to start out with maybe five grams. 47:34 I can now tolerate 30 to 40 grams per day if the Iolus is taken with food, but it also has some GLP-1 releasing effects, 47:41 which is very interesting. 47:45 sweeteners out there so it can when I consume allulose I wear a continuous glucose monitor my glucose goes down even if it's the alluose is in a chocolate 47:55 bar like an arc sugar bar and I've measured insulin it has essentially no insulin response and i have not measured my own glp1 but there's research out
Allulose, CGM effects, and exercise response 48:06 their nature communications showed that me someone my size taking an equivalent of 30 grams of alluvose they had like a a three to 500% increase in GLP-1 48:18 secretion in a rodent model. 48:20 And that has not been fully replicated, I think, in human studies, but there's research around that. 48:26 Very exciting. 48:27 I mean, you know, there's every month that goes by, There's another popular sweetener, it seems. 48:33 And I think lately we've seen some concern, at least from a cardiovascular risk perspective with respect to erythritol, a sugar alcohol. 48:42 Um, I that, by and large, the more we can do to help people not cater to their sweet tooth, I think it's a good thing. 48:50 But I too, as you know, am using Iulis. 48:53 We've talked about this quite extensively. 48:55 And I'm very happy to say that. 48:58 I am taking in about 10 grams a day in the morning. 49:02 It's clear that it is having an effect on my continuous glucose monitor. 49:05 There's no question about it. 49:07 Especially what I've noted is that You know, there's generally, I find when I run that I get a little bump in my blood sugar as I'm starting my run. 49:15 Well, within the first 10 minutes or so. 49:17 And I found that that bump seems to be a bit blunted when consume Allulose ahead of time. 49:23 Any thoughts? 49:24 I have the same same response. 49:26 I've even like posted about this on social media. 49:30 You know, if you engage in really intense exercise and I think there's a threshold for heart rate stimulating, you know their sympathetic nervous system 49:39 activation and same can be said for exogenous ketones too. 49:43 It seems to for reasons I don't fully understand, I think it's decreasing hepatic gluconeogenesis and maybe decreasing hepatoglycogenolysis in a way, 49:55 and probably perhaps enhancing glucose disposal in peripheral tissues, which is kind of maybe more exciting. 50:03 So nonetheless, this has been reported by, I mean, you just reported it, and I think it's also in the literature that when, 50:11 yeah, probably the most profound thing in literature is that, when you consume allulose with carbohydrates, with glucose, 50:19 it significantly attenuates the glucose-induced elevation when it is coupled with alluose. 50:26 And allulose may be delaying gastric absorption, but even the area under the curve is reduced. 50:34 And that's remarkable. 50:35 I don't know of any other sweetener that has that functional property. 50:39 Well, again, it's a great argument in favor of using a CGM. 50:43 Yeah. 50:44 Yeah, you wouldn't know it. 50:45 You never know without that. 50:46 So yeah, I think for the diabetic population, type 2 diabetes, Type 1 diabetes. 50:52 I know, allulose could be, especially if you have a sweet tooth, could like a really important component. 50:58 You can bake with it, you can cook with, it you, can incorporate it into various things. 51:04 And it can make, I'm working with the Moffitt Cancer Center because ketogenic diets can augment the adaptive immune system to perhaps make checkpoint inhibitors 51:13 work better. 51:13 So we're working like the big kind of pushback is the unpalatability of and the lack of not having sweet foods, but you know with things like alulose, 51:24 their dietitians and their metabolic kitchen that they just built, they can formulate foods and a whole array of different food products that could incorporate 51:34 aluose and be, you palatable to that person who's uninitiated to low carb or ketogenic. 51:39 And that's really important. 51:42 Need we say more of Walter Longo? 51:43 I mean, he's made it very clear as an adjunct to standard care, chemotherapy, radiation therapy, surgery, that challenging the body with a ketogenetic 51:55 diet goes a long way to enhancing outcome and great work.
MCT oil and closing thoughts on metabolic health 52:00 Let me ask you as we close, what is the efficacy, the role, and the utility of MCT oil in hopes of pushing people to a better metabolic state? 52:13 You know, I love MCT oil and I think it's like the poor man's ketone ester, right? 52:19 Some of the ketones esters on the market, they're kind of derived from a 1,3-butanediol, which has some questionable things. 52:25 I'm more inclined to use ketona electrolyte salts. 52:29 But one thing that we observe is that when you take any exogenous ketone and couple it with MCT oil, the therapeutic effect of that is greatly augmented. 52:40 And MCO alone by itself can elevate ketones levels in the blood independent of diet, meaning that you could be eating a standard diet consume MCC oil and 52:52 you have about 20% I think more if you're fat adapted and you are making lots of ketones, a significant percentage of that oil is converted to beta hydroxybutyrate 53:05 and gets into circulation. 53:06 Also, MCT oil can cross the blood-brain barrier. 53:09 So they can actually, unlike long-chain fatty acids, when you consume MCTs, those fatty acid can directly get across the brain barrier and into cells and neurons. 53:19 In addition, they help your body to stimulate fat oxidation in the liver because they go directly to the livers via hepatic portal circulation. 53:30 It's almost like the live is getting a big hit of fat, which could be uncomfortable for some people. 53:36 So I think it's important to titrate it in slowly over time, but I they are inexpensive. 53:42 They're remarkably therapeutic. 53:43 And I thing they're a cornerstone fat for a ketogenic diet. 53:49 Dominic D'Agostino, we've covered the waterfront today. 53:51 Thanks for spending time and sharing your wisdom. 53:54 It's always great to see you. 53:56 Great seeing you, David. 53:57 Yeah. 53:57 Thank you for having me on and I appreciate it. 54:00 You bet. 54:01 We'll talk soon. 54:02 Bye for now. 54:04 Well, I'm sure you all learned a lot today. 54:05 I know I did. 54:06 Dr. 54:07 D'Agostino is a wealth of information. 54:10 Again, the value of cutting back on simple carbohydrates, getting ourselves into a state of ketosis from time to time. 54:17 We talked about fasting, intermittent fasting. 54:20 All the potential inroads to better health, regaining insulin sensitivity, and really overall improving our metabolism, which is essential goal for us. 54:30 as it relates to our brains and even overall health. 54:34 Thank you for joining us. 54:34 I'm Dr. 54:35 David Perlmutter. 54:36 We'll be back soon on The Empowering Neurologist. 54:39 Bye for now.
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