Dr. Rob Cywes is Dual Board Certified in General Surgery and in Pediatric Surgery. He specializes in Pediatric and Adult obesity, diabetes, insulin resistance, and metabolic brain development, including Autism Spectrum Disorder. Dr. Cywes also focuses on metabolic management, including PCOS, Lipedema, and other endocrine disorders. He aims to help people understand and treat the true cause of their endocrine/metabolic diseases, including obesity and diabetes. He is increasingly working with high-performance athletes as well. Dr. Cywes is a strong proponent of Therapeutic Carbohydrate Restriction and is comfortable anywhere along the continuum of low-carb vegetarian to pure carnivore ways of life.

Dr. Cywes has become one of the foremost clinical authorities in treating and managing obesity and metabolic disease in adolescents. He is active in clinical research. He has written several low-carb book chapters and co-authored Diabetes Unpacked, outlining an effective approach to understanding and treating diabetes into remission. Dr. Cywes' vast experience in pediatric and general surgery serves him well in using bariatric surgery to treat obesity in adults and children.

Dr. Cywes maintains an active clinical practice in Jupiter and Jacksonville, Florida, and conveys the CIMOD message on social media and through his websites – He has many podcasts freely available on YouTube at @carbaddictiondoc. His website is Obesityunderstood.com, and he is active on Facebook, Tiktok, and Instagram.

Follow Dr. Rob Cywes @carbaddictiondoc on all social media platforms and Obesityunderstood.com.

Key point topics and studies mentioned:

1. Dr. Cywes' several ongoing clinical studies look at the best multimodal strategies to reverse insulin resistance, maintain insulin sensitivity and provide healthy longevity
2. The role of fat in atherosclerosis or thickening or hardening of the arteries
3. Mechanisms of inflammation and insulin resistance. Which comes first?
4. Evidence that insulin resistance is causing not only chronic diseases but also autism
5. Breakdown of glucose and lipid metabolism and role of insulin and glucagon in regulation and disease progression
6. Revisit of the Randle cycle, a concept published in 1963 that says an increase in glucose metabolism decreases fatty acid oxidation and vice versa

Transcription

Dr. Latt Mansor:

Hi, this is Dr. Latt Mansor, your host on HVMN Podcast. In this episode I interview Dr. Rob Cywes, a surgeon by training or better known as Carb Addiction Doc on his YouTube channel. His expertise lie in pediatric and general surgery, and he uses multi-modal approach to combat metabolic diseases and obesity at his practices in Florida. In this episode, we explored the relationship of endocrine system or hormonal system with metabolic health, but we also talked a lot about insulin resistance and how insulin resistance became the core of all these metabolic diseases. If you are curious to find out how you can use insulin and glucagon to optimize metabolic health or why GLP-1, when used in conjunction with therapeutic carb restriction, can be a powerful tool against obesity, then this episode is for you. So stay tuned and enjoy this episode. Hi Rob. Thank you very much for coming onto HVMN Podcast. Welcome.

Dr. Rob Cywes:

Oh, Latt, it's great to be here. We met the other day and had just such a wonderful conversation that we're both on our little soapboxes and I enjoyed it so much. So this is going to be a lot of fun and very educational for everybody.

Dr. Latt Mansor:

Yeah, pleasure is mine. We had that conversation about insulin resistance, metabolic diseases, chronic diseases, and it's what you do, it's what I did in my PhD, and I'm still having such a passion around this. So I'm really excited to have this conversation and also for our listeners to learn more about mechanisms of how chronic diseases come about. So let's dive straight into it. Tell us more about who you are, what's your story, your background and everything?

Dr. Rob Cywes:

Well, I'm an anomaly because as you can see, I'm wearing scrubs. I'm actually a surgeon. But I have over the last course of about 20 to 35 years taken a keen interest on some of the background diseases that we treat surgically. So I actually am a pediatric surgeon by training. So we operate on a lot of kids. And the question is why should a child of 13 or 14 develop gallstones or polycystic ovarian syndrome? And as we work that back, the prevailing understanding was it was their consumption of fat that caused all these problems conflicted completely with what was so obvious in front of us. If 80 to 90% of the calories a child is consuming is sugar and starch and less than 10% is fat, how can that pathetically small amount of fat be causing all of these diseases? So I became very interested in sugar. I also was in the laboratory in Toronto where I did some work on glucose metabolism on the liver. So I had a very much more detailed understanding of carbohydrate metabolism. And what we realized is that sugar was the causative agent and the body uses fat to respond to injury rather than to cause injury. And so we changed our perspective tremendously, and over the last 10, 15 years, maybe 20 years now, we've developed a clinical program looking at the root cause of some of these metabolic diseases so that we can treat them, not only at an outcome perspective, but also from a root cause perspective, to get rid of them and keep them at bay. And that's really my story. So we still do surgery, but metabolic health is my primary interest.

Dr. Latt Mansor:

Right. Let's unpack that a little bit. So you mentioned fat is how we respond to injury. What do you mean by that?

Dr. Rob Cywes:

So I'm going to give you a slightly circuitous route. I grew up in a laboratory era where we did basic science. We spent time at the bench, we did experiments on animals or research experiments that were anatomy, physiology, biology, and we determined the mechanism of disease. When I was in the laboratory doing my PhD in Toronto in the 1990s, there was a conscious shift by the university program to switch from basic science to epidemiology. And epidemiology is outcome studies. So we compare two things and we see whether one thing influences the other. And at best epidemiology reveals associations. The problem is that when the lay people attach onto some of those associations, we assign causality to it. And there is a big difference between association and causality. And when that gets confused, we go down bizarre pathways. So I'll give you an example. First of all, just in the obesity space, okay? If you eat a lot of calories, you gain weight and if you reduce your caloric consumption by any form, you lose weight. That's an observation, that is an association. But what it doesn't answer is why the person became obese in the first place. Why did they eat those calories to excess in the first place? And the interesting thing, just as an aside, is nobody eats protein and fat to excess. Protein and fat as macronutrients will never ever make anybody obese to the point of harm. It's exclusively sugar and starch that does that because of the endorphin effect. And we can explore that a little bit more. But now to come to the direct part of your answer, when you do surgery or you do an autopsy on someone that's died of a heart attack or a stroke and you look inside their blood vessels, it's all clogged with fat and the fat is visible. You can touch it as a surgeon. I've had that in my hands. And when you analyze it it's cholesterol and lipid saturated fat. So it becomes very obvious to make the association that aha, their blood vessels are clogged by fat. Where does the fat come from? It must be from their diet. However, when you go back to basic science and you look at the biology, the human body doesn't work that way. If you look at lipid, when a blood vessel gets injured, and this is something I did in the laboratory, we created injury of the blood vessels, actually interestingly using sugar to injure the blood vessel, which is called diabetes. But when you injure the blood vessel, the way the body heals that or plugs that, it forms a little fibrin clot. Think of it like a steel wool plugging the hole. The steel wool activates platelets, which was my PhD, and then the platelets attract other cells, white cells, neutrophils and lymphocytes. The lymphocytes attract macrophages. And as that clock now gets modeled, the activated macrophages attract fat. So for example, if I punch a hole in the wall and that's called sugar or nicotine, now you come along with some spackle and you put it over the wall, that's what fat is doing. So the layering of that lipid, the attraction of LDL to that clot only happens in the presence of a clot, and it's there to stabilize the clot and mold and reform that blood vessel so it can heal. But if you have a repetitive injury, now you get layering and layering and layering of fat. So what's visible at a stroke and a heart attack is the lipid, the reason the lipid got there is because of vascular injury. And the two commonest causes that we can demonstrate in the laboratory of injury to the blood vessels, nicotine and carbohydrates. You can flow fat into a blood vessel all day long at super high levels and nothing happens to the blood vessel. You add hyperglycemia and now you start to get that clotting cascade happening. So that is the difference between epidemiology and basic science. And so blaming fat for what sugar does is something we've done as a society over the last 40 or 50 years with huge erroneous consequences.

Dr. Latt Mansor:

This is super interesting because you explain it so well, what's the difference between association and causality and the fact that now we have more data than ever to know that the clogged arteries by those fats, by those cholesterols and lipoproteins is not the cause of the heart attack or the cause of stroke, but instead it is be because of the injury that is trying to mask and to fix it and as a result that happens, the clogging happens.

Dr. Rob Cywes:

Correct, correct.

Dr. Latt Mansor:

This is a very new concept, I would assume to many, many, many people.

Dr. Rob Cywes:

Well, it is a new concept, but that's because we've been misled.

Dr. Latt Mansor:

Yes.

Dr. Rob Cywes:

We've become lipo phobic as a society. So another way to look at this, if you look at an egg, Latt, a simple egg, an egg has a lot of fat and cholesterol in it. It's very high in cholesterol. It's got no sugar in it, less than one gram of sugar. And if you don't eat the egg, it typically when it's fertilized becomes a chicken. So if cholesterol and fat was really bad for animals, then that chicken should die of a heart attack or a stroke at about three months of age. So logic would dictate that God and nature made a terrible mistake when they put cholesterol and fat in that egg and God and nature is playing games with chickens, but chickens are pretty darn healthy. So perhaps it is us human beings that have maligned cholesterol and fat as an important substrate. The problem is not God and nature. The problem is we human beings have a misguided theory, and in fact, eggs are very healthy and therefore in us fat and cholesterol is there for a very positive purpose. And I'm not talking about visceral fat, I'm talking about fat in our blood vessels cholesterol, very important for the human brain. And in fact, what's interesting is the human brain is made up about 65 to 70% fat. The human brain is protected from fat getting into it. Long chains of fat can't cross that blood brain membrane very easily. So you've got two substrates that feed the brain. You've got glucose, but when you turn sugar into fat, it forms a very poor source of structural fat. It forms a storage fat that can be used as fuel, but not so effectively these saturated fatty acids, the oleic and the palmitic acid, not so good in cell membranes. However, and there's a guy by the name of Steve Koven that told me about this. He's a big Alzheimer's researcher up in Toronto. About 98% of the fat that gets produced in the brain is made from ketones. And so you can either use sugar or ketones, and if you use ketones to manufacture not the energy fat but the structural fat for the brain, you have very healthy brain membranes. And remember, the brain also has a very, very high concentration of cholesterol in the lipid membranes. Cholesterol is necessary to anchor protein for membrane fluidity. So when we blame fat and we blame cholesterol, we are actually going against nature. So this whole statin theory, the whole fat is bad for us, we need to eat whole grains and sugar is problematic because when the brain is seeing a ton of sugar, it switches off the production of ketones. And if you don't have ketones for your brain, the substrate, it's like the three little pigs. When you build your house of sticks and straw, it doesn't work so well. But if you build your house of bricks and mortar, which are ketones and fat, it does so much better. And this whole surge in Alzheimer's in a lot of the neurodegenerative diseases, Parkinson's disease, are because of poor substrate supply to the brain, including in young children. Autism spectrum disorder that has gone from one in 15,000 in 1970 to one in 42 in 2019. So the substrate that we provide to the brain is crucial in terms of health, and that's true for all cells. But the brain in particular, because other cells can also use other fats, the brain really can't use those very well. And that's where you guys come in. That provision of ketones and the ability to get someone to produce their own ketones is crucial in terms of brain and body health. And we've got to understand this from how the body works, not from these epidemiologic studies.

Dr. Latt Mansor:

Now that's an interesting point as well when you pointed out autism being caused by the excess of carbohydrate. Now, let's dive in there a little bit and unpack that. Is that statistic that you reveal, is that association or is that confirm a causality because of excess carbs?

Dr. Rob Cywes:

No, that's an association. So it really is just a pure statistic. It's not even an association. The incidence of autism's gone from one in 15,000 to one in 42 of eight year olds from 1970 to 2019. So if you look at that trajectory, now, here's where the association comes in, literally billions of dollars have been spent on looking for new genetic mutations in lipid formation and lipid deposition in the brain. So what autism is, the white matter of the brain, which is the insulation of neurons is damaged. So when you think about electricity, electricity flows down a wire and you've got insulation that allows the electricity go down. The insulation is broken, the message goes all over the place. And that is what happens in the brain of these developing kids from fetus through the first five years of life. There isn't adequate tissue in the brain to form that insulating layer. So that is again, a fact. The question is why isn't it there? And the prevailing theory right now is that some new genetic mutation. The problem is billions of dollars have been spent trying to find those genetic mutations without any strong evidence. So there might be a small fraction of people that do have that genetic mutation. But if you look at what else's changed, the substrate that we give to our children has changed dramatically. For a long time in formula, we didn't give them DHA, which is a three omega fatty acid which we know is essential for brain. Now they're adding it to the food. If you look at breast milk, it's got a very high concentration of saturated milk. But for years, we demonized that and give our kids skimmed milk. So we've deprived them of the obvious substrate that is necessary for that brain. And also not only that, we've given them way more sugar by percentage than fat. All kids are born into ketosis. All babies are born into ketosis and the brown fat that they have generates those ketones. And it's specifically there because their high rate of growth need structural ketones. So when you switch them over to sugar and their insulin goes up, even while they're fasting, now you're preventing keto production. And there's a pathway in the liver, the HMG-CoA reductase syntase pathway that switches on cholesterol or switches on keto production. We can go into that. However, now you're precluding them from having ketones available to create that brain structure as they're growing. And so then that brain structure is deformed and it's permanent after about five years of age. And that is the prevailing biochemical theory or the substrate theory of autism spectrum disorder.

Dr. Latt Mansor:

Wow, that is very interesting. And by the way, Rob, your analogy of the egg being cholesterol and full of fat and giving life to little chicks, that is perfect. I'm going to steal that. I'm going to start using that all over. And I think many people forget as well that our bodies, even when we don't consume carbohydrate, even when you're on keto diet, on very low carb intake or even fasting, if you check your blood glucose, we still have a baseline blood glucose. Our bodies are able to produce our own glucose from the storage system that we have. But if we have excess carbohydrate when we spike up insulin, that's what's going to stop ketones production. So know that we are not demonizing glucose because we know glucose is essential to life. But what we are trying to educate people here is to really balance out the macronutrients that we are taking in and to really take a deeper look as to what is actually causing all these chronic diseases. Is it really fat? Is it really sugar? Is it the imbalance? Or is it something that we have to do in order to shape that education from a very young age, education and also lifestyle from a very young age in order to prevent that? So I know you are running a couple of clinical trials. Could you tell us more about what trials are you running? What are you looking at and what are the indications? We are very interested to know.

Dr. Rob Cywes:

So I think, again, I tend to give a slightly broader picture. So one of the key ways in which the human body works optimally, to go back to what you were just saying, and again, this is open for argument, open for debate, but as a species, we came out of the primate vegetarian side of things and migrated primarily toward eating more and more animal products, primarily to support our brain because there isn't adequate fat and some protein, but adequate fat in a vegetarian diet. So we needed that. And what we did is the safest place to get adequate fat, adequate, reliable source of that is along shorelines. So we became a shoreline evolutionary species. And as such, if you look at the shorelines, there's typically an ebb and a flow twice a day. It is a cyclical tidal pathway. And during low tide, we can go and forage in the water, we can get marine animals. So a large part of the fat that we require are marine fats, the DHAs, those are the only two essential fats. And the way our hormonal system works, it works in homeostasis. So it works in a feedback pattern. When something goes up, something else brings it down. And if you look at the optimal human body, it functions almost in a tidal way where you've got an anabolic phase where you're consuming stuff, let's say at low tide, and that is governed by insulin, which is a big growth hormone, human growth hormone, and T3, thyroid hormone. And that should go up when we eat. And then between meals, we should go catabolic. So in insulin we are making protein, we're making cholesterol, we're storing fat, we're storing tissue, we are distributing and growing. Then for long periods of time between meals, we should go into a catabolic phase governed by glucagon and somatomedin and cortisol. Cortisol is an anabolic hormone where we're breaking down those stores, the fat and the sugar from the liver, and we're using up our stores also to replenish, but also to accomplish and do things. So that tidal flow is very important. In the modern era when we consume carbohydrates, for the first time ever in our life as a species, ubiquitously available and highly concentrated by manufactured foods. Now we need insulin for longer periods of time to deal with those multiple meals. Instead of eating once or twice a day, we're now snacking throughout the day. And what we do is we flat line the anabolic phase and the only way the body can protect itself is to become resistant to the effects of insulin, so now we've got this perpetually raised insulin. The glucagon system becomes disconnected, and you've got high glucagon and high insulin, which is a completely broken system. So that's what we're dealing with metabolically in most human beings. And what the consequence of that, depending on how much insulin you can produce, is either you gain a massive amount of weight so you're obesogenic or you can't produce a lot of insulin, the sugar builds up in your bloodstream and you become diabesogenic. So those are two genetic consequences, different, but the consequence of chronic excessive carbohydrate consumption. So now you've got all these broken diseases, and those are the people that walk into my office. And how do we restore the cyclical nature of that? And by the way, pretty much all of the diseases that we doctors treat as endpoint endpoint diseases, whether it's obesity or gout or cancer or diabetes, name the metabolic disease, the eye of the needle there or the collective pathway is through insulin resistance. So a large part of our treatment modalities, the drugs and things we use are treated for the end stage disease. So you go on metformin or whatever it is for diabetes, but that doesn't fix the problem, it just modifies it. If you treat the insulin resistance, if you can restore insulin resistance to that cyclical insulin sensitivity, you get rid of the cause of those diseases. And there are three modalities that we can use to treat insulin resistance. The first most difficult one is therapeutic carbohydrate restriction because we are relying on the person themselves to restrict their carbohydrates, eat more fat, and get into ketosis. And both for societal reasons as well as the enjoyment of the carbohydrates, it's very difficult to change that relationship. The second mechanism of treatment is with medications. And the two medications that we use that are very efficacious is the incretins or GLP-1 agonists. And everybody's heard of ozempic now, rybelsus, trulicity, mounjaro, those drugs directly treat the relationship between insulin and glucagon because they block glucagon, they trigger insulin, and they also have an appetite suppressing phase in the head. The other drug, and I want to call it a drug because for my purpose that's what it is, is a little thing you may not have heard of, which is called exogenous ketones. Okay? So exogenous keto suppress appetite and shift the body toward ketosis. However, when it's done in isolation, it doesn't work nearly as well as when it's done together with a therapeutic carbohydrate restriction diet. So ketones are being generated from within your body. Exogenous ketones can augment that. And then the third component, which most people are going to, "Oh, don't do this," is bariatric surgery. Obesity surgery is the most powerful way to restore insulin resistance, but it's also the most outlandish way. So those are the three mechanisms that we use. And if you start with therapeutic carbohydrate resistance and then as needed, add the others ancillary, that's called multi-modal therapy. The problem we find is that the GLP-1 agonists are so effective for a while at losing weight to treating diabetes that most doctors are just prescribing them as monotherapy. You can't get ozempic, it's on back order right now because everybody's on it and it works amazingly well. And it is by injection, but it works super well. Suppresses appetite, you lose a lot of weight. However, you have to stay on the medication and even then it wears out. So as monotherapy, it treats the insulin resistance. But if you look at trials like the step trials, there's four of them. Step one, two, three, four for various periods of time, people were on the drug, they lost a lot of weight. As soon as they came off, boom, things just exploded. They gained all their weight back, they gained their diabetes back. All those metabolic diseases came back because you were suppressing a problem, you weren't treating the root cause, which was why they ate the carbohydrates. So what we've done in our trials is we are looking not just at the therapeutic effect, that's been studied many times. What we're looking at is something called multi-modal therapy so that you make behavioral changes to your relationship with carbohydrates so that by the time you come off the therapies, you've changed your relationship, you've changed why you're eating the carbohydrates and how much you're eating. So that there is sustainability. And the multi-modal therapy that we are looking at is we are looking at therapeutic carbohydrate restriction, not from a dietary perspective, but from a substance abuse perspective using addiction methodology. So the trials that we are looking at is looking at these comparisons. That's the first one. The second one is we add in GLP-1 agonist, as an ancillary part, as part of the multi-modal/ we are then also looking at a biofeedback device, a CGM, a continuous glucose monitor, that gives you biofeedback. Dexcom is the one that we are using so that when you eat an apple, you see your blood sugar go screaming up and staying up. When you eat a steak, your blood sugar lays level. And you learn because if I'm worried about my blood sugar going up and I eat the apple and it goes up, guess what? I'm not going to eat the apple. So it's a tool that we use to teach. That's the third one. And then the fourth one is the addition of exogenous ketones for the appetite suppression effect and to get people into ketosis. That's the multi-modal therapy, what we do in the office, and we are now studying that in a prospective control trial. The trial that we're using there is going to kick off in January, and it's going to be variations of that with crossover. The other place that we use some of these modalities is in established diseases that are not going to get better. So for example, right now we've got a trial going on with our type one diabetics. Where type one diabetes, oh, don't use the GLP-1s. No, what the GLP-1s do is they block glucagon and they make the management of type one diabetes where they always need insulin so much better because you're getting into ketosis, your dependency on sugar is less. And we're also using some, with great success anecdotally, but now in the trial we've enrolled as of today 40 type ones in that trial. But also using Ketone Esters, the Ketone-IQ is actually the product we're using to augment what these people are doing. And it's unheard of. In fact, these medications are specifically not recommended for type ones, and yet we are having a profoundly positive effect without dropping them low and able to use far less insulin. So multi-modal therapy is the right way to go, but these trials have to prove to people that it's necessary not for the effect, but for the sustainability.

Dr. Latt Mansor:

That's great explanation, Rob. And it's a very exciting trial as well. And I think we ought to look at chronic disease from a multi-modal point of view because it is a lifestyle disease. I always tell people it's a lifestyle disease and it needs to be sorted out with lifestyle intervention. Because just having a monotherapy will not cut it because if it did, we wouldn't have been facing the increase of prevalence over these years. And before you finish explaining it, I was going to ask you two questions, but you actually explained it quite well. One was, what's the role of exogenous ketones in this? Which you explained it. And then the second question I wanted to ask is is there any focus on the mental aspect, the emotional aspect of things? Which is exactly what the first part that you explain which is the addiction point of view when you're looking at addiction to carbs, when you're looking at relationship to food. Because I think from a lot of guests that I've interviewed around transformation, around weight loss, they now realize that part is stronger than the physical part itself because that dictates how you feel and therefore how motivated you are in order to go through the physical change and actually make the lifestyle changes yourselves. So this is really great stuff that you're doing. I would say almost groundbreaking to really correct what people think about carbohydrates, about lipids, about over demonizing one macronutrient over the other. And then just think the other is great. So let's talk a bit on insulin resistance because I did my PhD in type two diabetic heart, in looking at metabolism of the diabetic heart in hypoxia as a subset of ischemia, which is the lack of blood flow. And when you have a lack of blood flow, you have hypoxia, which is the lack of oxygen, and the cells react really quickly because oxygen is such an important component in respiration and ATP generation. At least during my PhD, a few years back now in 2015, I remember writing the paragraph, what causes insulin resistance? Is it a consistent elevation of blood glucose? Is it inflammation? Is it dyslipidemia? Which means the abnormal or dysfunctional lipid deposition in the body. What do you think is the cause? We talked about addressing the root cause of all these diseases, which is insulin resistance, but what causes insulin resistance in the first place?

Dr. Rob Cywes:

Right. I briefly want to touch on this, but I think we'll talk about mechanism for the most part. If you think about cocaine or some of the opioid drugs. If you go to the Amazon jungle, people are chewing cocoa leaves for medicinal purposes because the load is very, very low, there's not much in there. When you then refine that cocoa and you create crack cocaine or a line of white powder, it's highly concentrated and highly addictive because it's endorphin power to the nth degree. So it really isn't about cocaine, it's about somebody's relationship with it that is the problem. When it comes to sugar, it's exactly the same situation, is that almost all of the sugar that we consume, whether it's in a fruit, whether it's in a pretzel or a piece of bread, has been highly concentrated. And it's the power and the concentration of that sugar and the massive endorphin effect that when you study the brain, it's of the equivalent nature to cocaine. The brain lights up exactly the same. So carbohydrates are not the problem, it's our relationship with them that is. And that's so important to understand, but that's the root cause and we have to deal with that relationship. And a large part of our practice is to use addiction methodology to help people to transform that relationship. However, when you consume excessive carbohydrates, and this is something that we have to understand, there's two different vascular systems in the body. The first one is the portal venous system, and that is the blood supply that runs between the intestine and at the top of that intestine is the liver and all of the blood from the gut, all of the blood from the gut, the spleen, the pancreas runs through the portal vein to the liver. And the liver is the central regulator of everything. So in the portal vein, when we eat and when we're fasting, there's massive fluctuations of sugar, of protein, less so fat but the smaller fats, the medium chain triglycerides and the ketones do go up, the other fat goes directly to the fat cells. So fat does not go through the liver after eating. And that's an important concept to understand. It goes via the lymphatics to the bloodstream. And insulin and glucagon are secreted by the pancreas directly into the portal venous system, and they coincide with the liver's uptake of those substances. And the liver can take up those substances at a very, very high rate. It stores some sugar as glycogen and then it's very effective at turning sugar into fat that gets packaged in VLDL and gets shipped out to the fat cells for storage. However, there's a threshold. And when we are continuously consuming carbohydrates, they spill over into the systemic circulation. So even when you're eating a moderate diet and you're insulin sensitive, your blood sugar vibrates, it doesn't fluctuate, it doesn't spike up and down. It's got very, very small fluctuations and typically stays within about a 10 point range. So when you're insulin sensitive, because the liver is doing all that traffic control and the liver at first allows a little bit of sugar during meals to go to the systemic circulation, and then between meals it's actually releasing sugar into the bloodstream. However, we are in ketosis almost all of the time, and the liver is producing those ketones except maybe right at the time that we feed. Now you talk about the heart, the energy that the heart uses, and most people don't understand this. There's a beautiful paper in looking at the breakdown of energy substrate to the heart. About 85% of the energy that the heart uses is free fatty acids and that's true for everybody and about 2% is lactate. This is your expertise, but the variable part, there's seven to 10% or a little bit more than that is either then going to be ketones or glucose dominantly. And it's that tiny fraction that makes a huge, huge difference because even a small amount of, well, let me ask you this question just so the people can blow their minds a little bit. I'm six foot tall. If you take my body and you melt me down and you extract all the sugar from my bloodstream, you've got around five grams, around a level teaspoon of sugar, in my entire bloodstream that maintains my blood sugar. If I have type two diabetes, which means my blood sugars are running at the 200 range, they're elevated, my A1C is high. If you measure the total amount of sugar in a type two diabetic, it's about 5.5 grams. That half a gram of extra sugar in the bloodstream makes all the difference. And it's really the threshold at which the blood vessels become inflamed, where the endothelial cells become affected by that slightly higher concentration of sugar. And there's two mechanisms by which that works. The first one is activation of the inflammatory cascade in the endothelial cells. The second issue is that the endothelial cells should be flat, they should be like a fried egg, and they don't have a lot of fluid in them so that blood can pass by very easily. And their surface facing the bloodstream is like Teflon. Well, every molecule of sugar has six molecules of water attached to that. And when that high level of sugar enters the endothelial cell, it drags with it a bunch of water. And if the endothelial cell is full of sugar now full of water, it swells up. Well, a flat disc can't hold a lot of water. So it rounds up and it becomes like a ball and a couple of things happen then, it bulges into the lumen. So your blood pressure goes up, that's hypertension or at least one of the cause of hypertension. But the second thing is it forms little gaps. When the endothelial cells ball up, they form little gaps and that exposes the underlying basement membrane of the blood vessels. And that basement membrane is highly coagulable. In other words, it's not anticoagulant, it's procoagluant. So the way the body heals that is to form a little fibrin clot. And as you probably know, that is happening all the time in our body. But if it's happening with greater frequency because of that chronically elevated level of sugar, now those clots instead of being formed and then breaking down, formed and breaking down, lysis and thrombosis, we now have a swing toward more thrombosis and less lysis. And then you activate the platelets, you get the cellular clots forming, and so the sugar triggers inflammation and it's the inflammatory cascade or that intrinsic clotting cascade that is the problem. And that is happening continuously. And under stasis conditions, under lipid conditions, a bigger clot can form that can break off and go downstream. But the other concerning thing, and when you look at the heart, there are two systems that govern the heart. The first one, which everybody looks at is the plumbing or the vascular system, but the other one is the nervous system. And although a transplanted heart has no nerves coming to it from the outside, it still requires nerves so you've got one node in the atria that gets depolarized, it sends a message down to a second node in the ventricles. So the first trigger causes a nerve to go to the atria, they contract, they relax, and a second nervous system goes down to the AV node, SA node to AV node, which causes the ventricles to contract. So you have contraction, relaxation, contraction, relaxation. Well, as we said earlier when we were talking about autism, those nerves get damaged. And you know in diabetics, all of those nerves, the protective layer, the Schwann layer gets thinned out. Those nerves don't work so well. So now we've got arrhythmias or abnormal conduction as well as vascular injury and ischemia. And it's a double hit to that hyperglycemic heart and which one wins? Everyone's focused on the clots, but more people have arrhythmias and have problems with arrhythmias. And then the arrhythmia is called abnormal rhythm. And then you can get clots forming in the appendices of the heart. So it's a complete cyclical process, but the inflammation is driven by that mild elevation of sugar, and you don't have to be diabetic. As far as we know, the hemoglobin A1C at which there is no real vascular inflammation is 5.2, which is very low. Okay? Diabetes is only diagnosed at 6.5. And the bizarre thing is most endocrinologists are happy with an A1C below seven. Well, that is still profound inflammation of the blood vessels. So when you are insulin resistant, your A1C may be 5.7, 5.8, but there's still massive chronic inflammation happening in every organ, in particular the heart. And if you're obesogenic under the influence often of testosterone and males and females generate testosterone. So in PCOS, polycystic ovarian syndrome, females have high testosterone levels. And it's the testosterone that drives visceral fat deposition because it's part of the continuous anabolic state. So all of these things are interrelated. We can break each of them down. But that insulin resistance it's a name that we use for this entire carbohydrate inflammatory process that occurs in every organ. And obviously when the heart goes, it's the most deadly of all these organs.

Dr. Latt Mansor:

Yeah, that's exactly what I've seen in my research as well, because we looked at acute hypoxia when we perused the heart ex vivo and then we reoxygenate it. And what happens is during hypoxia, we saw a dysregulation, dysfunctional substrate metabolism where you supposed to switch from fat. So as Rob says, everyone's heart would prefer to use free fatty acid as the source of energy. However, in hypoxia, the heart will switch over to glycolysis because glycolysis, using glucose, it's oxygen independent ATP generation method.

Dr. Rob Cywes:

A small amount of glucose is not the whole glucose molecule.

Dr. Latt Mansor:

No, no. Up regular glycolysis, but still maintain a significant amount of fatty acid oxidation.

Dr. Rob Cywes:

Yes.

Dr. Latt Mansor:

However, upon reoxygenation, we saw the damage on the nervous system because the diabetic hearts they definitely had a more significant arrhythmia compared to the control hearts. So it's really great to hear you explain the mechanism behind it, because that was what I saw in my hearts. And we know that diabetic hearts, they have a higher percentage of heart failure, even after they survive a heart attack. So that's probably why, because of the double attack of both the metabolic dysfunction as well as the nervous system,

Dr. Rob Cywes:

Right. That's the vascular. And the interesting thing is a lot of the things they talk about clinically is the silent heart attack of diabetics. Well, that's usually not a vascular heart attack, it could be, but it's often an arrhythmia heart attack. And the diabetic is not even aware they're having that heart attack because the nerves, you get neuropathy everywhere, so your feet don't feel anything. And the same thing with a heart, you don't feel that, and yet you're having a heart attack or ischemia, and it's not as classically felt as if you don't have that diabesogenic effect. So it's so cool to see that you've seen this in the lab, I've seen this clinically and when two people that are coming from, basically we don't know each other except for one conversation, and yet there's so much synergy, how can this not be true? And there's no way the plausibility of the lipid heart model just does not make sense. And if you think about, okay, so now I've got all these arteries clogged with blood vessels, I'm going to put you on a statin to lower lipids. Well, the statins don't effectively reduce that risk. But if you look at the GLP-1 agonists, they radically reduce that cardiovascular risk, and it's because they're treating insulin, glucagon and sugar. So how could lipid heart be true if what I call C-mod, the carbohydrate insulin model of obesity and diabetes is being treated with GLP-1s very effectively. So there's logic to it. But also what I love that you do, you bring the science behind it. And that ischemic effect we used that as a technique in the laboratory to maximize the injurious effect. And we saw exactly the same thing in the liver with transplanted livers going through ischemic time and having a worse cause of vascular injury when they are more on the insulin resistant diabetic side.

Dr. Latt Mansor:

Now, interesting you brought up liver here, because I know liver is the most important organ when it comes to ketogenesis, which is the production of ketones when you are low on carbs and when you are on keto diet or fasting. But I also know that ketones are not actually metabolized within the liver itself. So when you are talking about liver injury, does ketones have actually a role to play there, or is that just mainly fatty acids there?

Dr. Rob Cywes:

No, it's mainly the fat accumulation, the triglycerides and the lipid inflammation. But what's interesting about the liver, and this is something I've just written a textbook coming out next year about this, the Ketogenic textbook from Tim Noaks. But I did the liver chapter on that, what's interesting is again, we look into obesity and diabetes. With obesity, you're eating a lot of sugar and starch. The liver has to protect you from the damage of the sugar. So it becomes very efficient under the influence of insulin to turn that sugar into fat in the liver so it forms triglycerides. And you can actually see the lipid buildup in the hepatocytes, which causes a bit of ballooning of the hepatocytes but not a lot of inflammation. So it does injure some of their functions because the rate limiting step is that fat is made very quickly. The sugars turn into fat very quickly, but to transport the fat out to the fat cells takes longer. The molecule is called VLDL, which is actually the precursor to LDL. That's the rate limiting step all under the influence of insulin. However, in the diabetics, because what happens with the obesogenics, their blood sugars are fairly normal because they can clear the sugar out of the bloodstream very quickly. In the diabetics, the rate of clearance isn't that good. So they have higher blood sugars, so they get the vascular inflammation on top of the fatty liver. So an obesogenic person has a fatty liver, but it's not that bad and you can fix a fatty liver in seven days of not eating carbohydrates. But once you have that vascular inflammation from the elevated blood sugar in the liver sinusoids that's where the injury comes in. The macrophages, the cells in the liver get activated, they clog up those sinusoids. Now you're getting exactly the same as what you were talking about ischemic reperfusion injury. And whether it's the heart, it's the ischemia reperfusion that is injurious. So you got the ischemic effects, the cells get damaged, now you open it up and you reperfuse and that's where the injury is happening. And we see that in the diabetic livers, but not so much in the obesogenic livers. So it's fascinating that two organs work exactly the same or the damage occurs in a very, very similar way.

Dr. Latt Mansor:

I've got a question for you around around LDL, but before that, I want to also make it clear to our audience as well who are not familiar with ischemic reperfusion injury. So what I've found when I studied around ischemia and diabetes is that while you have a heart attack, the damage is done because the cells are not getting enough oxygen and blood, and therefore the oxidative damage occurs. The damage is even higher when the blood a vessel is unclogged. So when you get the reperfusion of blood, that's when you get a increased amount of blood flow, increased amount of substrates, and the cells suddenly want to ramp up all the oxidative phosphorylation and ramp up respiration. And because of that, you have a stark increase of oxidative damage and free radicals. So that's when is ischemic reperfusion damage happened. So just to clarify that.

Dr. Rob Cywes:

You are so correct and what's interesting is if you look at stroke and heart attack, at least on the clinical scenario, they talk about time, time, time, time from a heart attack or a stroke to when you get into the hospital to when they put a catheter in and remove the clot or put a stent in, whether it's the brain or the heart, that time is critical for exactly what you just said. Because the longer that tissue, and it's usually about a three to four hour threshold, the longer the tissue is ischemic, even if you unplug the vessel to the brain or to the heart, the damage is done at reperfusion because of the anoxic or the lack of oxygen injury. If you reperfuse early, you can recover almost completely from the heart attack or the stroke. But the longer the heart is ischemic, and you're right, the ischemia is part of the issue, but the bigger issue is the reperfusion injury. And that's where all the inflammatory cascade happens because you've got the inflammation of that tissue. And that's why strokes are really bad after about four hours of stroke. Same thing with heart attacks. And that's why time, time, time. So anybody out there who's having some chest pain, who's having that headache or dropped something, get yourself to the hospital for that reperfusion because we've become very good at reperfusing. But you got to get into the facility.

Dr. Latt Mansor:

Yeah, yeah. Thank you. So the question about low density lipoprotein, high density lipoprotein, I've read in some papers they postulate that triglycerides in your blood it will reflect mainly your dietary intake of fat. However, when it comes to LDL, HDL and all these lipoprotein and cholesterol, it's generally not reflective of your dietary, at least for the past seven days, but more of a lifestyle reflection where your body have that mechanism, have that factory to create cholesterol. So when you eat the fat, like you explain earlier, it goes to the liver, it gets repackaged into cholesterol. Is that what-

Dr. Rob Cywes:

Well, let's simplify this and it won't blow your mind because you know this, but all of the lipid dysfunction, the dyslipidemia is a direct consequence of insulin resistance and for this reason. Sugar in any compartment of the body is toxic at higher rates, gut, interstitial space, bloodstream, and inside of cells. So the human body is very adept at turning sugar into fat to store it. And triglycerides do not cause damage, but they are the best marker that we have of injury because triglycerides, as you said, occur, they get made by the liver, when the liver converts sugar to fat, it produces triglycerides, a little bit of phospholipid, a little bit of cholesterol but triglycerides are the dominant molecule in a fatty liver. And they don't come from the consumption of fat. They come from the conversion of sugar to fat by the liver. Then the liver produces a molecule because the thing of the people need to know about fat is the bloodstream is aqueous, it's water. Fat doesn't like water. So if you're going to transport fat in water, you've got to put it in a little FedEx truck. And the FedEx truck for fat is called lipoprotein. It's made of a lipid outer layer that likes water and some proteins and the proteins are actually the zip code. The proteins tell the lipoprotein where to go. So they're like an address, a zip code. So the liver makes VLDL, very low density lipoprotein, a big molecule and VLDL can either be very large or very small. And if you are a high glucose consumer, you package a lot of lipid in the VLDL, it's this big VLDL molecule. And if you're living on a lot of fat and protein, you have a very smooth VLDL molecule and the number is lower. So my ideal in patients, I look for a VLDL number around 10 with a triglyceride number below 75. VLDL is always associated with high VLDL, high triglycerides. Now here's the cool part. VLDL transports that big fat molecule to the fat cells. It docks with the fat cells or in the fat cell environment, and it dumps the triglycerides in the fat cells. So it's transporting it there. The fat cells also can do something called de novo lipogenesis. They can actually produce inside of the fat cells, they can turn sugar into fat under the influence of insulin, so they can actually make their own fat from sugar. But for the purpose of this, VLDL goes and docks and dumps the fat there. When VLDL undocks, it's a much smaller interior molecule, and it's actually a transfer. So the VLDL has picked up some cholesterol from the fat cell where it's been stored, it picks up some phospholipids, and it is a much smaller molecule called IDL. Very rapidly in the bloodstream, IDL becomes LDL, okay? And LDL can either be big or small. And the difference is this, is that if you eat a lot of fat, the fat goes from the gut in something called a chylomicron gets stored in the fat cells. Now you're producing these small little VLDL molecules that go to the fat cells. And instead of dumping fat in the fat cells, they're picking up fat, they're pricking up phospholipids, DHA, three omega fatty acids, phospholipids and cholesterol to take to the body. So LDL is primarily a transport molecule for fat that is stored in the fat cells between meals to the rest of the body. But if your traffic is liver to fat cells, now the LDL that gets released is a small dense LDL that is devoid of triglycerides, and it's basically on its way back to the liver. But that it occurs in the environment of high sugar. So when your body's using sugar, you're not feeding it fat. When your body's living on fat when you're in ketosis, you have these big fluffy type a pattern LDL molecules that are very healthy. So if you've got a big fat high LDL, and that's why in a lot of our ketogenic patients or patients on a ketogenic diet, they have extremely high LDL molecule and everyone panics, "Oh, you're about to have a heart attack." No, they're not. They're just transporting fat from where it's stored to the body for use as energy as those fatty acids that you talked about. And then to the liver where the liver turns them into ketones. So big fluffy LDL, no matter how high the number, is very healthy. It's the small dense ones that are associated with harm, not because they cause harm, but because they're associated with high sugar state glycosis or where you're burning sugar and they then react to the inflammation. So these are just FedEx trucks. They're just transport vehicles. And what they contain and where the traffic is determines your biologic health. So if the transport is liver to fat cells, that is harmful, not because of the fat, but because it indicates high sugar. And as we've said, that's inflammatory. If the traffic is fat cells to body, that's healthy because now you are living in ketosis and you are living with a non esterified fatty acids and your liver is producing tons of ketones. That happens under glycogen effects. The other thing that happens under glycogen is the liver produces HDL. HDL is produced between meals under the influence of glucagon dominance. And HDL is a little molecule, they call it the good cholesterol, but it goes out and it scavenges cholesterol. It docks with the LDL, takes the cholesterol from the LDL molecule, so the LDL can go onto your cells and feed them fat. It removes some of the cholesterol from your plaques and then comes back to the liver and here's the cool part, dumps the cholesterol in the liver, and how do your liver get rid of the cholesterol? It goes out in the bile. And here's the incredibly cool thing. This is how beautiful the body is. The bile goes out into your liver and when you eat a big ribeye steak, that fat gets put into the little bile micelle, a little soap bubble of bile gets reabsorbed in the lymphatics and goes back to your fat cells. So this is a perpetual cycle. You've got the intrahepatic bile secretion thing. So the liver produces the bile that then becomes chylomicrons, and it's this perpetually cycling thing, and a little bit of the excess is pooped out. That is a healthy human body and dysfunction, disruption to that process is what causes inflammatory disease based on sugar, not fat. The fat is just the marker. It's just the visible. The way I look at it, if you want to understand, if there's a hole in the road that's sugar, if there's a red flag or a flashing red light that's triglycerides, but you come along and you destroy the LDL or the triglycerides, the hole in the road is still there. You fix the hole in the road, the light goes out by itself. That's the way I try to explain it.

Dr. Latt Mansor:

Yeah, that's great explanation. So we talked a lot about how sugar gets converted into fat in both the liver and the fat tissues. And you mentioned de novo lipogenesis. Is that also the same process at which sugar is converted to fat in the liver, or is that something different?

Dr. Rob Cywes:

No, that's exactly it. No, the DNL happens in the liver and in the fat cells. And the other place that it does happen is in the brain. So there are a couple of sites, but those are the sites where we need that fat either for storage and people don't really give homage to it, it's so obvious when we understand this is is that the entire body is made of fat. Every cell has a fat membrane, and those are called phospholipids. So everyone's focused on triglycerides, but the phospholipids are just as important and talking about calories and all that nonsense is so stupid because nobody knows how many calories the body needs. Only the body knows because there's some days where the body will take fat and convert it to phospholipids and cholesterol. There's some days where it'll use it as storage fat or as energy fat. And we don't know what that ratio looks like, but everything is interchangeable. And that's the beauty about it. Even protein. Oh, I'm pumping iron in the gym, I need lots of protein. Well, there's a threshold above which the body will turn that protein into sugar. And if you don't use it into fat. And that is a threshold about how much you eat at one time. So all of those things are interchangeable. And if you don't have adequate protein and you're not eating sugar, the body will go to your own muscles and break them down. So all of these things, I hate this word but I'm going to use it, require some balance. And it's when the body is out of that homeostatic cycling, when that tidal cycle is broken, bad things happen.

Dr. Latt Mansor:

Yeah, and it's interesting you talked about the threshold of protein as well, because to add a kick onto that statement is it's very dependent on your activity on top of having that threshold. Because if you are more active that threshold moves according to your daily activity. And if you are injured in a certain area, maybe the body uses those amino acids for recovery instead of building muscles to adapt to a higher progressive load. And I know a lot of our listeners are biohackers, bodybuilders and all that. And you mentioned earlier that testosterone is a anabolic hormone that direct towards visceral fat deposition. And we also know that testosterone also build muscles. So when does it build muscle? When does it build more visceral fat? How do you control it?

Dr. Rob Cywes:

So let me just back up to the first thing you said because this for me is the most important rule of nutrition that you just touched on. And I've got a phrase, all of energy biology is purpose driven. Everything has a purpose. So when you are in the gym working out or you're doing endurance, there's a purpose to the redirection of amino acids toward proteins. If you're watching Netflix, that purpose is gone. So you have to repurpose the protein. If you injure yourself, if you've got inflammation, that has to be healed. If you're a growing child, there's a purpose to that energy flux. If you are an Eskimo getting ready for the winter, there's a purpose. An Inuit on the land, who needs that fat. If you are some of the Khoisan where I come from in South Africa, they need that energy storage. There's always a purpose to how the body uses nutrients, particularly fat and protein. And you can drive that purpose by what you're doing or by injury repair. And that is such an important concept to understand. And no one hormone regulates that. Everything is highly integrated and your quarterback hormone is insulin. And in fact, we're now starting to discover that the quarterback's quarterback hormone or the coach is GLP-1, which is very interesting and we can explore that a little bit. But insulin is the dominant growth hormone. Human growth hormone is that. And all of the steroid hormones, well you probably know this, but all of the steroid hormones start out as one molecule. They all start out as cholesterol. And cholesterol then goes through a series of enzymatic steps. In all males and females we produce, but mostly females will produce progesterone, estrogen, in cyclical fashion and testosterone. And then a lot of the steroid hormones, the fight or flight, the cortisols are also steroid hormones. They all have cholesterol as a common pathway. And here's what's interesting. Insulin regulates steroid hormone production. Think about that. Insulin regulates cholesterol production and insulin regulates steroid hormone production. So when you've got a high cortisol state or a high testosterone state, that is insulin. And if you are insulin resistant, that pathway gets broken. So for example, in females who are very high insulin producers, that are hyperinsulinemic, that blocks the production of estrogen and progesterone and their testosterone goes up, they have more of an androgenic body type, and they have something called polycystic ovarian syndrome. Polycystic ovarian syndrome is driven by hyperinsulinemia. In males. When we switch that pathway off, we get low T, low testosterone, higher estrogen production in some males, and that is insulin that regulates that hyperinsulinemia. But when you've got lower insulin production, you're more on the diabetic side, you're going to be producing that testosterone but not testosterone is functioning autonomously and it's depositing fat around organs. Does that make sense? Testosterone, however, is a primary growth hormone when it is used together with HGH, together with insulin when you're insulin sensitive, then it's a very powerful thing. And what's interesting in my patient population, we see total testosterone and free testosterone rates go up by a 100 to 150 points when somebody converts from being insulin resistant to being insulin sensitive. Their testosterone goes through the roof. And that is when your musculature improves, the protein metabolism improves. So everything is interrelated and it happens in a cyclical fashion. And when that system is broken, exogenous testosterone only fixes the number. It really doesn't fix the system.

Dr. Latt Mansor:

Right. And what you're saying right now is hyperinsulinemia acts on testosterone differently in male and female. Is that correct?

Dr. Rob Cywes:

Exactly right. It really is the sex hormones. And in females high insulin shuts off the female hormones, turns on the male hormones. High insulin shuts off testosterone production in males and turns on the female. So for example, if you look at some men who are obese, they have all their fat on the outside of their body and those are estrogen dominant males. On the other hand, if you've got that guy who's got the big belly, very little subcutaneous fat, but it's all visceral. It's around his heart, he's testosterone dominant, but he's insulin resistant. And it really depends on that play. So you've got some females who are estrogen dominant, they also have a lot of fat on the outside. But then there's a third category of females, and it's actually the healthiest obese female you can get. And that is a disease, or not a disease, but a genetic condition called lipedema. And if you look at a female, for example, where I come from in Africa, it's a very common genetic expression in the local Khoisan Bushman people where they have these very skinny upper bodies and then from about the top of their pelvis, their butts are huge, their thighs are very big. They store all of their fat in the lower half of their body. And that is actually biologically the healthiest state to be in. We call that lipedema. L-I-P-E-D-E-M-A. And that is a progesterone dominance state. So you've got progesterone dominance, you've got estrogen dominance where you're fat everywhere and then you've got testosterone dominance where you've got that central visceral fat. And it's not that the visceral fat causes the damage, it's the testosterone dominance, the hormonal dominance that causes the fat. So that, again, we talked about epidemiology, the association with visceral fat is there, it's not causal. But it's how the visceral fat gets there through that estrogen dominance that is the most harmful in terms of cardiovascular disease.

Dr. Latt Mansor:

And what causes the estrogen to dysfunction in the first place. And that's why I always tell people metabolism is very complicated. It is not a linear pathway, even though in school we often learn it as a linear pathway. We go from glucose to pyruvate to acetyl CoA down to oxidated phosphorylation, but ultimately everything is interlinked. I know in our call we talked about Randle Cycle where fatty acid and glucose, they are interrelated in the sense that if you up-regulate fatty acid oxidation, you downregulate glucose metabolism and vice versa. So that's how fat and glucose play a role in the mitochondria, that they balance each other out. And that's just substrate metabolism. On top of that, Rob just explained the whole endocrine system, hormonal system where that would then up-regulate the uptake of the substrates, up-regulate the rate of the substrate being metabolized, as well as turning on and off certain cascades to make sure that we are functioning in our most optimal state. And without that, if something in that cog goes wrong, it cascades down. And when it cascades down, we see the symptoms. Most of the time it's obesity, diabetes, hypertension, clogged arteries and all that. And when we treat the symptoms, while we may get temporary results, ultimately they will still develop those complications again because the root cause is not fixed.

Dr. Rob Cywes:

Exactly right. And I think one of the beauties about the human body is that when you push one direction, eventually something's going to break. But what breaks can be genetically influenced. In other words, whether it's your insulin, whether it's your high insulin, low insulin, whether it's glucon, something breaks. Whether it's testosterone, progesterone, estrogen, that is genetically predetermined, but the push to break is communal. And that's what's also difficult to understand. And when you talk about the Randle Cycle, this is something that's so important. I've got a video coming out on this in a little bit. When Philip Randle wrote his paper in 1963, he was looking at that substrate. And again, it's a feedback system. When one goes up, the other goes down, he demonstrated they regulate each other, and that is not correct. And this is interesting about the Randle Cycle. The Randle Cycle is correct, what goes up goes down, but the controlling force is not the concentration. Philip Randle wrote his paper in 1963, and I have a copy of the original paper right here behind me. So actually let me get that for you. So here is Saturday, 13th of April, there's Philip Randle's original paper.

Dr. Latt Mansor:

I remember citing that paper in my thesis.

Dr. Rob Cywes:

Right. And the interesting thing, it's a beautiful, beautiful paper. But the interesting thing about this is when I read this paper, everything about it seemed to be a glucagon phenomenon. So why doesn't he mention that? Well, the paper was published in '63. Glucagon was only isolated in a pancreatic extract in 1959, and it was only really isolated for use in the lab in 1976. So what's interesting in Randle's paper, just see if I can find the quote, somewhere in this quote, he has a line, oh, so here. There are several differences between the insulin sensitivity induced in muscle by fatty acid in these experiments in the insulin antagonism observed with albumin preparations. Albumin preparations by valance Owen and Lilley. Now those are the guys that emulsified pancreas. They didn't know what they had in there. They just had this mush of stuff in the pancreas. They are therefore unlikely to be the same. In particular effects of fatty acids are much smaller than I've seen in the absence of insulin in vitro. In other words, he tried, he did experiments with this emulsion, but he had no idea of what glucagon was. And so therefore, the Randle Cycle was described in the absence of knowledge of glucagon. And once you understand the glucagon dynamics, then you can understand, okay, this governs the Randle Cycle. The Randle Cycle is true, but what controls it? What regulates it? And it is glucagon. And he didn't know that because he didn't have access to the substance. Here's something very interesting in the modern era, and we're only just discovering this, and this is another one of those association causal things. As a medical student, I was always told that rising systemic blood sugar triggers insulin release. Okay? Because as your blood sugar goes up, your insulin goes up. But that is an association. It is not causal. And the reason I can say that categorically is for two reasons. Number one, when we put an IV into someone in their systemic circulation and infuse sugar, they don't get an insulin rise. Maybe a little one but nothing like they need to clear the sugar. So infusing insulin to someone's bloodstream does not cause a rise in insulin. The second thing that we see is in our carnivore population which is becoming very popular, and I love the carnivore diet, I'm about 95% carnivore myself. But when you eat that meat, those amino acids take a very long time to be digested. And then for the liver to turn amino acids into sugar, that takes three or four hours. So in these carnivores, you see a slight rise in blood sugar three or four hours later. And it doesn't come down effectively. Why? Because insulin isn't being released. And the reason for that is because GLP-1 is required to release insulin. But five, 10 years ago, we knew nothing about GLP-1. We knew it existed, but we had no idea what it did. So when I was in the lab in 1990, I knew what GLP-1 was, it looked like glucagon but what the devil does it do? Now we're starting to find out, wow, this is what this hormone does, and you need sugar in the gut to trigger GLP-1 to trigger insulin.

Dr. Latt Mansor:

So what you're saying is that what I learned in school about glucose stimulated insulin secretion, GSIS, is not entirely true.

Dr. Rob Cywes:

False. Correct. So if you think about a pennyfarthing, that old bicycle, the back wheel is the sugar bump for insulin. The big front wheel is GLP-1.

Dr. Latt Mansor:

Yeah, go ahead.

Dr. Rob Cywes:

No. You go ahead, you go ahead.

Dr. Latt Mansor:

I was going to say, that's why I'm so fascinated with science, because science is ever changing and we are always learning new things. And the key here is to put away our egos and say that yes, what we learned was wrong or was inaccurate, and here is the new data with the new concepts and new ideas and new knowledge that we know about the system because there's so much more about human body we don't know.

Dr. Rob Cywes:

Well, what's interesting Latt, it's not that we were wrong. We didn't have adequate knowledge. And sometimes we want perfect answers when we have imperfect information. And like in a mathematical formula, if you're missing one number, you can come to wrong answers. And the beauty about what we do is for our entire lives and beyond us, our children, our grandchildren, wherever we go, they are going to have more and more information, more and more knowledge available to them. Now we have the whole human genome. So we can do so much more than when I was in the lab and probably even when you were but it's an ongoing thing and that's what I love about it. We just have to be humble enough to look at associations and not assign causality. And that is so important because we could have taken the Randle Cycle at face value until I said, "Let me go look at the history of glucagon because this sounds like glucagon." But if you don't make that connection, you're never going to figure this out.

Dr. Latt Mansor:

I was going to ask you that.

Dr. Rob Cywes:

It just resonated with me. But then when I looked at the year then I realized, okay, we've got to go back and look at where glucagon, and you look at the history of glucagon, it parallels this but they didn't have it available, just like I didn't have GLP-1 available when I was doing my experiments in the lab.

Dr. Latt Mansor:

That's right. So just to satisfy my curiosity, so you said the Randle Cycle is governed by glucagon. Where is GLP-1? What role does GLP-1 play in this and how does it work mechanistically? Just for my own knowledge.

Dr. Rob Cywes:

Okay, so we know very little about it. In fact, a classmate of mine has been working at Oxford, as we told your Alma mater, did his PhD there in '93 on GLP-1. And he's now working for a big pharmaceutical company working with GLP-1. However, we know some of the effects, and I think the primary effects is GLP-1 is released in two parts of the intestine. The upper intestine, the lowest stomach, the upper duodenum, where it has an early effect and then a secondary effect in the lower part of the intestine. And GLP-1 is typically triggered by bile acid released into the intestine that triggers GLP-1, and that is a fat mediated substance. So it is fat that releases GLP-1, but GLP-1 acts on insulin, which is an interesting thing. I'm still trying to sort through, don't quite get that. But GLP-1 number one, slows down the contraction of the stomach. So you release food much slower, you feel full earlier, you eat less. That's the satiety part in the stomach and then it also has an effect in the brain where it affects satiety. Hormonally. GLP-1 triggers insulin release, it stimulates the beta cells to release insulin. But it also, because the beta cells and the alpha cells are right next to each other, and I don't know if it's a location issue or how it works, but it blocks or reduces glucagon release. So it triggers insulin release, blocks glucagon release, which is exactly what you want when you're eating. You don't want your liver and your fat cells releasing substrate into an already flooded system, which is what happens in insulin resistance where you've got food coming in and being released from the liver. So it blocks the liver from gluconeogenesis and from ketogenesis, and it rises up insulin because that whole cholesterol pathway, HMG-CoA, the syntase takes it down the ketone pathway, the reductase takes it down the cholesterol pathway, exactly the same pathway. One governed by insulin, one governed by glucagon. And you actually want one to be switched off and one to be switched on. That's what GLP-1 does. So I would think of it football terms, it's the coach that's telling the quarterback insulin how to play, and without that insulin doesn't function properly. And then you've got this high glucagon level. So even in our type one diabetics where it's not affecting insulin, it is affecting release of substrate at mealtimes additionally into the bloodstream. But it has also cardioprotective effects. It has muscular skeletal protective effects. So it is going to be over the next two decades, one of the most fundamental discoveries as we learn more about it. And we haven't even talked about the regulation of hunger and lipids by release of GLP-1 in the distal intestine. Remember if we are correct that we are mostly a carnivorous species, fat esterification, fatty oxidation, which is what causes a carnivore to have those poops where you're losing fat in that bile in the lower intestine, that also regulates the absorption of that fatty acid in the lower ileum, small bowel. So GLP-1 is a very, very important hormone together with GIP, peptide YY, ghrelin and somatomedin, the other incretins in the gut, they all interplay and they all have a role to play to switch on and switch off. And we are just starting to discover the roles of all of these hormones in the human body. As I said, I'm still perplexed by, okay, fatty acids trigger this thing, the release of bile acids trigger, which very plausible because historically we ate a lot of fat. How does that factor into the glucose side of things? So all of those things are still to be explained.

Dr. Latt Mansor:

I'm glad you mentioned that because I was about to ask you that. I'm like, so fat triggers that, but then it has effect on glucose. So how does that work? Well, we just have to have-

Dr. Rob Cywes:

Well, let me blow you away with one other thing.

Dr. Latt Mansor:

Yeah.

Dr. Rob Cywes:

And this is again, in my little book chapter that's coming out soon. But the incretins GLP-1 and all the hormones are released into the portal venous system, but the portal venous system is traffic out of the pancreas. So GLP-1, if it's going to have an effect on the pancreas directly, has to go up the portal vein through the liver, through the lungs, through the heart, through the systems back to the pancreas. So the pancreas is as far removed from the site of release of GLP-1. And I still haven't been able to figure out, is GLP-1 the direct hormone or is it happening through another messenger? We don't know that. But if you think about the system and also why blood sugar doesn't trigger insulin, because what you want is insulin to be released by portal venous sugar, not by systemic sugar. But the only blood that the pancreas sees is from the systemic system. It releases everything into the poral venous system. And once you understand the anatomy, it's like, whoa, blow my mind on that one.

Dr. Latt Mansor:

Yeah, I wonder if you can use isolated beta cells to just simply test direct effect of GLP-1.

Dr. Rob Cywes:

And that is happening. I'm not as familiar with that research, but absolutely that's being done.

Dr. Latt Mansor:

I'm glad my scientific brain is still working in tact.

Dr. Rob Cywes:

And you know what? This is what we love to do. So we'll go back and look at these and one thread leads to another, leads to another. And that's why what you and I do is passion, it isn't work. It's the love of what we do because it's that mental exploration of, well, let's tug on this thread and see where it leads.

Dr. Latt Mansor:

Yeah, absolutely. Well, I want to be respectful of your time because I know we are slightly over time here. Before we go, I would like to ask you, what does health and modern nutrition mean to you?

Dr. Rob Cywes:

Health for me is about biological and mental happiness. When your body is happy and functioning in that psychical fashion and your brain is empowered and healthy, that is optimal health. And both of those, if you think of carbohydrate addiction, both of those are governed by the same relationships. We are fortunate as human beings to be in an era of abundance for the first time for most of us, but we have to be so cautious about how we handle abundance. And that for us is something that human beings have never done. We've always dealt with scarcity. Now we need to put our ingenuity into regulating abundance, and that's the challenge.

Dr. Latt Mansor:

Very well said. And lastly, of course, to our listeners, Rob, can you please tell our listeners where can they find you? Where can they get your new book coming out? And all of the details, please go ahead.

Dr. Rob Cywes:

Yeah, so I'm a clinically practicing doctor here in Florida. My contact information on all of our social media, we're on everything. We've got a pretty decent YouTube channel. It's Carb Addiction Doc. Now, it's not my book. I'm a contributing author. They are 62 authors. Tim Noakes is the editor, and it's called Ketogenesis. It's going to be published by Elsevier, and it'll be released in March of next year. And it is going to be the first scientific textbook that covers all of the ramifications of everything we've talked about, the hormonal imbalances we've talked about.

Dr. Latt Mansor:

Can't wait for that textbook to be the standard textbook in biochemistry and universities and metabolism and PhDs and all that. So thank you.

Dr. Rob Cywes:

And I just want to say one other thing. I want you to thank you very, very much for this little thing over here because these have, and I'm not plugging you, I'm not paid to do this, but this has become a huge asset to what we do in our practice. So thank you very much for bringing something that doesn't taste impossible. My wife actually had a bottle of your earlier stuff, and I literally said, "This stuff tastes impossible." But this is so much more palatable and thank you for this because it's helping our patients.

Dr. Latt Mansor:

No, thank you so much. I'm so glad that what we do at HVMN and our product is helping people who actually need it. And that's my goal personally because of my passion in chronic disease, driven by my family prevalence as well, is to be able to get as many people out there who needs it, who can benefit from it. And as I always tell people, it's not for everyone. I'm not just selling a product. If you find it useful on Ketone-IQ there's a discount code down in the description as well. Feel free to give it a try, and if it works, it works for you. And I'll be very happy that I'm able to bring some form of positive influence into your lives. So thank you Rob so much. It has been a pleasure. I would love to have you as our episode two guest once you start your clinical trials, and we can talk more around the details and the data around it as well.

Dr. Rob Cywes:

Yeah, we'd love to do that because sustainability is the key. When you asked about health, anybody can be healthy for a day, but you want to be healthy for a lifetime, and that's what this study is all about. So thanks very much for what you do and thanks for having me. I appreciate it very much.

Dr. Latt Mansor:

Thank you. If you have enjoyed this episode, please like, share and subscribe, and we welcome any comments or feedback in either the comments section or you can fill up the Google form provided in description. You can find us at HVMN or at Latt Mansor for myself on all social media platforms. Both HVMN Podcast and myself are powered by Ketone-IQ, the most efficient way to elevate your blood ketone levels for optimal cognitive and physical performance, as well as metabolic health. Thanks again for listening. Until next time.

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