Transcript for:
Ketogenic Diet and Metabolic Health

This diet was standard of care for obesity, type two diabetes, and type 1 diabetes all the way back to the 1700s. What this diet does is it reduces the overall glucose load. So, at the first meal, you start to see this dramatic reduction insulin. Your body starts to shift its primary fuel substrate away from glucose towards fat. The ketogenic diet. Dr. Dr. Andrew Kutnik, a metabolic scientist who has just completed the longest study ever published on a high-fat, low carb diet with some surprising results. One of the common effects of a ketogenic diet is the elevation LDL cholesterol over a 10-year period in a high risk population. The ketogenic diet led to normalization of glycemic control, an over 40% reduction in insulin. But in association with that, no indication of no signs of cardiovascular function and physiology was often superior to individuals without any disease. What do you think are the top five foods that somebody needs to eat to do a well-rounded ketogenic diet? I would primarily think about something like as soon as you start a highfat diet, especially one high in saturated fat, most likely your LDL cholesterol will go up. And when this happens, your doctor will say stop. And why? Cuz they'll say there is no long-term evidence to show that what you're doing is safe until now. My guest today is Dr. Andrew Knick. He's a metabolic scientist, a type 1 diabetic, and has just completed the longest study ever published on a high-fat, low carb diet, and cardiovascular risk. And the results are surprising. Today, we're talking about saturated fat, what happens to LDL cholesterol, APOB, and calcium scores, and what truly matters when it comes to cardiovascular risk. So, Dr. Kutnik, my first question, let's start off with the big picture. Most people know somebody that has type 1 or type 2 diabetes, either fatty liver disease, or a condition of insulin resistance. As a metabolic scientist, what do you think is the biggest factor contributing to all these diseases? That's a very very complex uh question and I think it it often gets watered down but to really try to explain it best to your audience in in in reality of what we understand currently based on the evidence and the science is that there's a very complex disease states obesity type two diabetes and I would argue they're they're along the metabolic spectrum um where you have healthy obese then ultimately pre-diabetes and ultimately something like type two diabetes and it really is an interaction between genetics and environment where the environment interacts with genetics to ultimately express your genes in a particular way. So let's say that you're born with this inherent framework but then you're able to alter that framework or change the way that framework works by altering things like lifestyle um what you're exposed to in the environment uh and other factors. And arguably when you ask you know what's the primary risk factor one would contend altered metabolism. So altered metabolism, dysfunctional metabolism is one of the key underlying root causes of these conditions. So what does that mean? Well, let's first take obesity. A lot of people recognize obesity as this condition of superficial appearance. So this excess buildup of what we as a body mass, but what we really care about is the fat mass. And we've often described this in very simplistic terms. Okay. Excess intake uh reduce energy expenditure. The balance of how much you eat versus how much you burn leads to an abundance of fat if you eat too much. It's been simplified down to that level. But under the hood of someone who's developing obesity, eventually potentially getting to pre-diabetes and ultimately type two diabetes, it's much more complicated than that. So someone who has obesity, they have generally around two to four times the amount of fat. So around two times the amount of total body fat and four times the amount of fat in the abdominal region compared to those who don't have obesity. But what we start to see is these signals in the body of the things that's changing in our metabolism that are causing adverse effects. One your audience is probably very familiar with is insulin. Uh we know that in people with obesity that they can present with up to two times the amount of insulin. I would actually not say up to but they start to present with double the amount of insulin. Not just fasting but also in response to let's say a glucose challenge. So you eat some type of carbohydrates, your glucose elevates. You'll see twice the amount of insulin in people on average uh who have obesity. But this is coupled or often associated with reductions in what we call insulin sensitivity. So things like your whole body's insulin sensitivity or even tissue specific changes in insulin sensitivity like in the liver where that's where you store uh glucose molecules and insulin is what binds to the liver and and keeps it as glycogen. But we see, you know, reductions in 36% of liver insens insulin in insulin sensitivity. Reductions in muscle insulin sensitivity of around 35% using really gold standard techniques of actually doing things like infusing glucose and insulin simultaneously to actually capture how glucose is moving into these tissues and how much insulin is needed to do that. But we also see some early signs in in obesity of disruption to other hormones outside of insulin like leptin which can increase up to sevenfold in obesity. So when we're really thinking about you know obesity we think about the superficial whole body weight changes and fat tissue changes but it's often associated with this change in insulin but insulin sensitivity is reducing often around 33%. But we know that it's much more complicated than that because we actually see in things like obesity of increase in production in liver fat. Uh which your audience will think well why do I care if fats in my liver well your audience may have heard of something called fatty liver disease which is now called metabolically associated steotic liver disease or massel. It's irrelevant. It just means that there's this increase in fat in the liver which can cause widespread metabolic dysfunction and and disease. Well, we see that even in obese individuals that the production in liver fat goes up 65%, oxidative stress goes up 32%. Um, but keep in mind that all this is occurring before we actually see changes in glucose or even liver fat. So, the production the amount of fat from the liver is going up, but the amount and the and the amount of insulin we need on a regular basis to maintain glucose is going up, but the actual glucose level is not changing. This is why we talk about a metabolic spectrum because as you go from healthy to obese, you start to see these changes and obviously the amount of atapost tissue, the amount of insulin required to metabolize nutrients, but we don't actually see the in signal of elevation in glucose or uh disease elevations in fat in the liver. But if you actually look at obese individuals as they progress before they get type 2 diabetes, there's this progressive metabolic dysfunction. So you can take an individual who has the same body weight and same overall fat percentage, you know, and match them for age, match them for sex, match them for muscle mass, and as they progress in metabolic dysfunction, you actually start to see a distribution in where the fat is actually being placed. So you actually see reductions in things like placement in fat in the periphery like in the thigh but a dramatic increase 73% in visceral fat which is the fat in the intraabdominal so the the stomach region which ends up being around 3.3 times that of the general population who don't have obesity. We also know that uh liver fat which we scientifically term intrahypatic triglycerides which is the measurement of the amount of fat in the form of triglycerides in the liver which we do with an MRI scan. Um we see that individuals who got this progressive form of metabolic dysfunction with obesity have 6.4 times the amount of liver fat and virtually all of them begin to get diagnosed with mass D. So the the actual diagnosis of fatty liver or what's now called muscle D requires over 5% of the liver to be saturated with fat. But we know that individuals who start to progress down the metabolic dysfunction uh train uh with obesity can present on average around 15.9% uh liver fat. And ultimately we know things like insulin resistance become even more progressive. So, you know, four to five times more insulin, 70% reductions in insulin sensitivity across virtually all tissues, the liver, uh the muscle. We also know that the incidence of things like pre-diabetes begin to emerge where you actually see now at this stage a more progressive forms of metabolic function and obesity, 20% higher fasting insulin, 15% higher of this measure called hemoglobin A1C. It's a 2 to threemonth average of the amount of glucose that binds to tissues. And we see that that also goes up alongside fasting glucose levels along with other disruptions that we don't see in early forms of obesity like amino acid metabolism, lipid metabolism, further elevations in inflammatory monsters, oxidative stress. These all begin to go up including, you know, a 500% increase in markers of blood clotting and inflammation. So, we know that as you go from healthy to obese, there's there's changes that are being observed under the hood that most people don't realize until they start seeing signals like blood glucose changes as they become more metabolically unhealthy. And at this stage, we know that there's actual clear signs of cardiovascular dysfunction already, increases in things like the stiffness in the vascular wall. The amount of stiffness reduces the compliance of the blood vessels. So you start to see endothelial dysfunction and ultimately changes in the structure of the heart. So an increase in 25% in heart mass. So in summary, when people go from healthy to early obesity to more progressive obesity, essentially they're progressing in the insulin resistance, they're changing the way the fats being distributed in the body. They're getting diagnosed on average with uh fatty liver, what we now call massel. We see widespread metabolic dysfunction in things like amino acids, lipids, inflammation, and ocular stress. That's progressive and ultimately clear signals of changes in cardiovascular dysfunction. And when you get all the way to the tipping point, at the very end, you get something called type 2 diabetes, which is the progression, the ultimate progression in this path, which really is the diagnosis of full-fledged insulin resistance. Patients often live with blood sugars around 160 to 180 milligs per deciliter. For those who are in millim moles, that's somewhere around let's say 8.5 to 10 mill moles. Uh 500 to 100% elevations in inflammatory and oxidative stress markers ultimately resulting in 2 to four times the risk of cardiovascular disease and an expected reduction in life expectancy. So how long you'll live by an average anywhere between 6 to 14 years. So we know when we think about the risk factors or the causes of let's say obesity and type two diabetes, it really is a metabolic spectrum that's very complex interactive that progresses over time with a host of different complex changes. So it's not one single factor, but often we can look at key signals, the most prominent ones being insulin and also glucose as measures of where we are in that disease process. Absolutely. Now as you mentioned that with these chronic diseases it could be things like obesity, type 2 diabetes or even fatty liver disease. It is a multiffactorial condition meaning there's a variety of factors that are affecting the metabolic changes. But as you mentioned there are two things that we need to focus on elevated insulin and elevated glucose. However, when most people go see their doctor they're going to say cholesterol. You need to lower your cholesterol especially your LDL cholesterol. So a question for you as a metabolic scientist. What is more important lowering the LDL cholesterol or fixing the insulin and the glucose? This is unpacking a very important question because a lot of people focus on LDL because there's been all these studies in cell culture models in all models and these associative studies at uh general population level that show that progressive elevations in LDL lead to increased risk for athoscerosis or the laying of new plaque within the vascular wall and ultimately that leads to cardiovascular disease. We know that LDL is a required part of putting plaque in the vascular wall. Another reason why many people believe that LDL is causal in cardiovascular disease. And yes, there is plenty of data in the general population that elevations in LDL are incre are associated with elevations in cardiovascular disease. But in diseases like diabetes, uh both type 2 diabetes and we can talk more about this, but also type 1 diabetes, which is a very unique u experimental uh setup where you can really tease apart causes and effects of things like glucose and insulin. We see that LDL is not even close to the top risk factor for cardiovascular disease. We see that glucose and insulin are the not sorry not insulin, but glucose is the primary risk factor for cardiovascular disease. Not even close, far and away the top risk factor in that disease state. In fact, studies in diseases like type 1 diabetes where they've actually given more insulin to get only marginal improvements in glycemic control lead to dramatic reductions in not only the incidence of diseases of the heart and the vascule but also diseases of the eye like retinopathy, diseases of the kidney like nephropathy and also nerve damage. So despite patients taking more insulin, despite patients becoming uh obese, and in fact the study was over a thousand patients over 30 years in a randomized control trial setup, they found that patients went from 0% obesity rates to 30% obesity rates. And despite all of that, the risk for cardiovascular disease through about a 1% absolute unit improvement in HBA1C, a metric of better glucose control resulted in dramatic reductions in cardiovascular disease, which is called macrovascular disease and things like eye damage, kidney damage, and nerve damage. So this brings back the key point that glucose particularly in these settings as you become more progressive in the metabolic dysfunction from healthy obese to ultimately type two diabetes. Glucose is far and away the leading risk factor not just in type one but also multiple studies have shown this in type two diabetes. It is important to understand that LDL cholesterol does not drive cardiovascular risk and by that I mean heart attacks and strokes. It's a very low risk factor and insulin and blood glucose is one of the top risk factors when it comes to cardiovascular risk. I do want to understand more deeply glucose because we hear different things HBA1C fasting glucose and glucose. Can you explain the difference between HBA1C and blood glucose? So blood glucose level is the amount of blood or glucose circulating in the blood. So you have people throw the estimate around 5 L of blood in the average person. Obviously, you know, uh someone who's taller and larger would have more blood flow in their body versus someone who's uh shorter would have less. And ultimately, it's hard to go and and take a singular snapshot of what's happening over multiple months of of lifestyle effects of environmental effects, genetic interaction between those factors and ultimately understand what is the risk. If you just go in and get a blood sample, you know, in a lab and it says, "Hey, your glucose at this single time point is elevated." Well, what does that even mean? You know, a single time point is a single second of a single day of blood work you may get every 6 to 12 months. It's not telling you very much at all about your total control. And when we talk about chronic disease and the impact of chronic disease, what we're really talking about is the accumulation of the impact of these metabolic changes over not just a short term, let's say a few months, but over the lifespan. And so what HBA1C is, it was a measure discovered back in the 1960s and 19 uh '7s from a actually Iranian scientist who looked at his population and found that when he actually looked at hemoglobin molecules, so pooling blood look at hemoglobin, he found that there was levels of glucose being elevated or being attached to these blood molecules, these circulating blood uh cells in what they call the A1 subunit. So you have these blood cells and on the blood cells there's a unit uh a structure of it called A1 A1 C and glucose would actually bind to that subunit and he was able to quantify that and see that patients who had diabetes had much higher levels of this and over time we found that this is actually a representation of around the average glucose control over a two to threemonth period. So when you go to the doctor's office, you get your blood drawn, they're able to look with a single snapshot, what is the average glucose control you've had over the last two to three months. And so it's a better measure of chronic risk. In fact, HBA1C is the leading risk factor for cardiovascular disease and diseases like type 1 diabetes. And and I would argue and contend that multiple studies have shown the same thing in type 2 diabetes. It's it's a more chronic measure. And chronic is what we're really concerned about, not a single snapshot. analogous to cigarette smoking. You don't hear of anyone who went outside and smoked one cigarette getting lung cancer. But someone who's smoked cigarettes multiple times a day increasing their use over multiple years. Those are the people at dramatically increased risk for lung cancer, not someone who did it one time. So HBO1C is a measure of your long-term risk factor. Your risk factors for getting disease. It's not just a single moment like blood glucose. So then to understand cardiovascular disease like heart attacks and strokes because I think people want to understand what do I need to look at to understand my risk factor for that and many doctors are going to consider LDL cholesterol as the main risk factor for cardiovascular risk. Do you think that's true? It is a very context dependent. So when we look at things like uh type 1 and type two diabetes what we're often looking at is the risk factors. what is the risk factor that lead to this endstage disease? And so that's these biomarkers we're talking about like HBA1C that allow us to get an association between okay, if we know we have elevations in glucose levels that are high and more variable over time, we know that this will lead to higher risk for for cardiovascular disease. So it's looking at these intermediary biomarkers that give us a signal for what the risk is for ultimate endstage cardiovascular disease. However, it's also important to appreciate that you can actually see signals of cardiovascular disease changes much earlier on, which we can talk about more a little bit later, but you actually see that the vascular function begins to change, how the blood moves through the body changes, and also how the heart functions begins to change before you actually can detect any plaque within the vascular wall. And that's something that is often not appreciated because most people just look at endstage signals to say, "Hey, do you have dramatically increased cardiovascular disease risk?" But we see that the intermediary biomarkers, things like glucose control, insulin is a risk factor, uh, as these are higher and more uh higher and higher levels, there's a dose dependent response between those in cardiovascular disease. Um, which again associates back to a key question you asked, which is what's the leading risk factor? And we know that there have been studies looking at over a thousand patients over 30 years with diseases like diabetes. And we see that the leading risk factor in this disease again is glycemic control through a measure of HBA1C. This 2 to 3 month average of glucose control. But of all the top modifiable risk factors, the next modifiable risk factor is blood pressure. So how much pressure is against the the vascular wall? your blood vessel walls at any particular time because as more pressure accumulates the vascular wall starts to change uh in ways you don't want. So more stiff vascular walls but also triglycerides resting heart rate all these are risk factors that are much higher in the hierarchy of what leads to cardiovascular disease compared to LDL which is actually the lowest of of let's say the 10 both modifiable and non-fiable risk factors that are often looked at in the context of diabetes. So to your particular question, we look at the intermediary biomarkers because they predict future risk, but we have to focus on the biomarkers that matter most in a hierarchal fashion, right? So if you were to do an intervention that dramatically improved LDL, but worsened your HBA1C, that's not a good trade-off. But if you can improve something that improves your glycemic control, but it may alter LDL, glycemic control is the primary risk factor. So that may be an ideal trade-off. Ideally, you want to improve both, but you have to focus on hierarchy. You have to focus on what we know matters to long-term risk and ultimately what is the end stage of that which is cardiovascular disease. Let's talk about the biomarkers that you say matters which is HP1C, fasting glucose or glucose and insulin. What is the number one dietary intervention that someone can do to fix those biomarkers? Yeah. So, one thing that we've been very interested in is these diets that reduce glucose load in the body. Because when you think about diabetes, both type 1, type 2 and uh diabetes in pregnancy called gestational diabetes, the diagnosis for this isn't elevated insulin. It isn't elevated LDL or amino acid changes in metabolism. It's not any of these factors. It's actually the elevation in glucose. So, when you think about what intervention could we consider that could dramatically improve outcomes, it's very logical to consider an intervention or a diet that reduces the amount of glucose in the diet. And obviously, how would you do that? Well, the most potent macronutrient, so macronutrients are protein, fat, carbohydrates. Carbohydrates far and away are the most potent factor increasing glucose levels in the blood and they do so in a dose dependent manner. Protein does increase glucose but it only does so at at 2.3 times less per gram. So let's say you consume 50 g of glucose from potatoes and 50 g of glucose from chicken breast or sorry from uh 50 g of protein from chicken breast. the amount of insulin with carboh or the amount of glucose from carbohydrates and associated insulin levels are going to be 2.5 times higher. But what about fat? Fat has virtually no meaningful effect on insulin level. And so there is this diet that many people have heard of called the ketogenic diet. And this diet is a diet that is much it's much lower in the amount of carbohydrates in the diet. It prioritizes uh protein and fat and reduces the amount of carbohydrates. Now, it's not zero carbohydrates unless you go to the far end of the spectrum like let's say carnivore diets or there's something called the lion diet. But with a ketogenic diet, it still has some forms of carbohydrates typically less than 30 uh grams per day. But in the form of like spinach, broccoli, cauliflower, very fibrous forms of carbohydrates, which most people would think, okay, I know spinach, I know cauliflower, I know broccoli. Those are those are healthy carbohydrates. And so it's it has those type of carbohydrates to maintain fiber and phytonutrients, but it has uh well formulated levels of protein to maintain muscle mass. And then the rest of the calories are made up from healthy forms of fat uh that come along with a diet. So it's this diet dramatically reducing the amount of carbohydrates in the diet. Now, it's important for people to appreciate that this diet, which we now term therapeutic carbohydrate reduction because of its powerful therapeutic effects, has been around for well over 200 years. In fact, this diet was standard of care for obesity, type 2 diabetes, and type 1 diabetes all the way back to the 1700s. In fact, uh many people may be familiar with this world famous diabetes center called the Joselyn Diabetes Center associated with Harvard Medical School. Well, uh Joselyn himself as well as another physician called Dr. Allen were actually doing these these forms of diets in patients with type 1 diabetes to extend the life of patients before they discovered insulin. So, it's been around for hundreds of years. It's been around for over a hundred years for neurological disorders like epilepsy. But what this diet does is it reduces the amount of carbohydrates in the diet which immediately within less than a day reduces the overall glucose load. So at the first meal you reduce the amount of carbohydrates. The body is experiencing less glucose in the blood and then immediately what happens is you start to see this dramatic reduction insulin again at the very first meal. Well, keep in mind when we talk about diabetes, we're talking about these elevations in glucose and these elevations in insulin. But when you reduce carbohydrates in the diet, you at the very first meal see reductions in glucose and reductions of insulin. When you see the reduction in insulin, you have this massive physiologic cascade. So insulin, I would contend, is the most powerful hormone in metabolism. It really is dictating not only multiple hormones but many of the enzyatic and physiologic processes of various tissues like fat, liver and muscle. So when it reduces insulin's reduced when insulin's reduced the amount of uh the amount of fatty acid oxidation, so the amount the body starts to break down fat increases. So insulin stops the body from breaking down fat tissue to be utilized for energy. But when insulin is lower on the diet again at the first meal, you start to see subtle shifts in the body's ability to what they do a process called lipolysis. So lipo meaning fat and lasis meaning breakdown. So the breakdown of fat tissue that you have on the body and that really starts this cascade of events where you start increasing the amount of fat being broken down from the fat tissue. You start to actually metabolize that fat for energy. you start to produce ketone bodies and then ultimately your body starts to shift its primary fuel substrate away from glucose towards fat. And we know that in the context of things like type 2 diabetes, besides it being standard of care for virtually 200 years, we actually know that the American Diabetes Association in 2019 in their consensus report in nutrition regarded this as the most evidence-based dietary strategy for management of type two diabet at least nutritional management of type two diabetes. And so we've known that for a long time, but type 1 diabetes is a unique case where when we think about a disease state and we're trying to understand processes in the bodies and how things work. Let's say if we're trying to tease apart the impact of glucose and insulin and their ultimate association with risk. In experimental scientific lab settings, we often use anom models or these cells in these petri dishes where we'll directly block a process of the body. So, we'll directly change uh how glucose is absorbed. We'll delete a receptor or delete a hormone. Well, type 1 diabetes is an example of a deletion in the ability to produce insulin. So type 1 diabetes is a unique model of what we call insulin knockout model and really allows us to tease apart the direct impacts of how insulin and glucose interact with the body. But in type 1 diabetes, we also know that the ketogenic diet based on an abundance of emergent evidence can be a very effective, potent, not only safe but uh uh powerful strategy and potentially regulating glucose and also lowering the primary medication of this disease, which is insulin, which both are associated with uh risk of things like cardiovascular disease in these settings. So, we know that the ketogenic diet, not only has it been around for over 200 years as standard of care for managing diseases like diabetes and obesity, but it's it's a very physiologically sound approach due to the reduction in carbohydrates leading to reduced glucose load, leading to reduced insulin, the two primary risks and biomarkers associated with the diseases of type 1, type two diabetes and gestational diabetes. And we know that they have been shown to be effective at managing these primary risks that we know we talked about earlier ultimately lead to future disease. And that's the focus and that's the interest is finding strategies that have powerful effects at regulating those processes. As Dr. Cutnick mentions, there are two main factors that drive metabolic disease. Insulin and glucose. And a really easy way to fix this is to follow a ketogenic diet. Now, you can do this by simply dropping the carbs to under 50 grams a day. And some people need to even try zero carb or a carnivore diet. And that is the ultimate low insulin state. And I have seen so many people who have followed a zero carb or a carnival diet and get incredible results. People have lost hundreds of pounds and even reverse metabolic conditions, things like heart failure and diabetes, conditions that your doctor would say it is something that you have to live with. And I myself have followed a high-fat carnivore diet for the past few years with incredible results. And what I found kept myself and my community on track was support through medical doctors. And that's why I created a private online community called Go Carnival. It is a safe place completely off social media where you can ask all of your questions to our medical doctors, including the ones that you see on this health podcast. One of the best things about the community is our monthly challenges. We do challenges like a highfat challenge, a dairyf free challenge, and this is what helps our members get the best Carnival results. So, if you'd like to try Carnival with medical support, just head to go carnival.com and get 10% off your first month. For someone considering a ketogenic diet, maybe they have insulin resistance or diabetes, do you think they have to count calories to lose weight? So there's been some evidence that even despite controlling calories that some individuals who shift to uh lower carbohydrate intake can see reductions in body fat. That's actually from David Lovewig's group uh where they showed this. However, the amount of weight loss independent of calories is is very marginal. We see the most powerful effect of these diets when we talk about weight loss when it leads to reduced intake of calories in total calories. ultimately causing the body to uh start breaking down its own tissue to make up that caloric deficit. Uh but it's also important to distinguish that from its ability to regulate risk. So independent of weight loss, we know that the ketogenic diet can improve glycemic control not just in type 2 diabetes but also in type 1 diabetes, which is again this very unique uh example where typically patients aren't weren't historically overweight. They're a normal body weight. They have elevated levels of glucose analogous or similar to type two diabetes. Elevated insulin in the periphery just like type two diabetes. Uh same increase in cardiovascular disease risk and even further reduction in life expectancy just like type two diabetes. And when we look at this, we we know that we can look at the biomarkers or changes. So a lot of people who go on a ketogenic diet with type 1 diabetes, their intent is not to lose weight. In fact, they often don't lose weight, but they see dramatic improvements in glycemic control. And the same is also true of many examples where calories are controlled in type two diabetes. But again, in the context of a disease like type 2 diabetes where the change in glucose is really the end signal of this cascade of metabolic dysfunction. When we start to see improvements in glucose related to diet, it is an illustration of an improvement of multiple underlying metabolic factors. And we know that the ketogenic diet through its reduction in carbohydrates, glucose load, and insulin are able to improve outcomes even independent of weight loss in both of these conditions. Let's talk about the long-term effects of a ketogenic diet. And you've just completed the longest study ever published on a highfat keto diet. Can you discuss the methods and the results? Yeah, this this is a a very passionoriented project. The reason is because I myself have type 1 diabetes. I myself have lived with this disease for over 17 years. And I really embarked on my scientific career. Yes, I was interested in science. Like it is a really it's a really cool way to like you make money actually like exploring cool ideas and concepts that interest you. Like it's a really cool path. But I really got into it selfishly because I myself had obesity as a kid. I also an adolescent. So my my risk my long-term risk was dramatically higher for all the obesity related complications. But I also got diagnosed in adolescence with type 1 diabetes. And throughout my life and career studying science selfishly I wanted to understand how do we improve this condition? 99% of patients with type 1 diabetes will never achieve normal metabolic health, normal metabolic function. Uh only less than 1% of patients will ever get a normal glucose value, an average 2 to three month glucose value ever again after they're diagnosed. And when we think about these diets, they have these powerful therapeutic effects on regulating glucose and insulin. again two of the most powerful risk factors in the context of not just type two diabetes but also type 1 diabetes and type 1 diabetes as I mentioned before is this very unique condition where you don't have the elevation in fat tissue on average you don't have increased ataposity like type 2 diabetes you don't have elevated lipids amino acid changes you really just have elevated invariable glucose just like type two diabetes and elevated insulin so you're looking at these two signals in isolation And you can look at how interventions change that. But what was also really particularly interesting to me is that there was really no long-term evidence on the net benefit or risk of a ketogenic diet on cardiovascular disease. Because one of the common effects of a ketogenic diet, particularly if someone's eating more animal-based fat, saturated fat, is the elevation LDL cholesterol. And so what we were very interested in is looking at the longitudinal pre-toost effect of type 1 diabetes when they there was a switch from the you know whole foods American diabet American diabetes association diet shifted to a ketogenic diet with data throughout a 10-year period predos where the calories were controlled the entire time exercise volume was controlled body weight and composition was controlled medication was controlled and looked at the long-term effect isolating out these key confounding variables of the net effect of the ketogenic diet which can improve glycemic control and insulin but people were concerned about the elevation in LDL and in our particular study it was over 10-year ketogenic diet with all these factors controlled but there was a doubling of LDL cholesterol so going from around 60 milligs per deciliter to over 120 milligs per deciliter in association with elevations and things like apo um and known risk factors or known lipids associated with the athoscerotic process in the general population. But what's so unique about diabetes is that there is this clear signal of risk related to glycemic control and insulin. So, if you can do this diet that can potentially improve glycemic control and reduce insulin, what would the net effect be on over cardiovascular function over a 10-year period, I mean, the longest trial that I was familiar with that looked at any type of serious cardabolic, so the interaction between cardiovascular health and metabolism effects was really around one maybe two years where they actually looked at the prevalue and the post value. But this was a case where we were looking over 10 years in a patient population at tfold higher risk for cardiovascular disease doing a diet that could dramatically improve glycemic control and insulin but elevates LDL while controlling all these confounding variables. So this very unique study giving us uh potential incredible insights into this long-term effect because there's really nothing uh over this period of time. And in fact, the longest even case report of someone doing uh a ketogenic diet or something analogous to a ketogenic diet, so lowering carbohydrates, had been self-reported 10 years, but it didn't have pre and post data. It was just a a post data report. And so, we really didn't know what was happening. But in this example, we found that in type 1 diabetes, consuming a ketogenic diet over a 10-year period, the average glycemic control maintained over that 10 years was 5.5%. That's illustrating that in this population, the ability to maintain the top 1% glycemic control in normalizing glucose control over that period, something that most people believe is impossible. and and doing so without additional medications essentially the the utilization of the shift in macronutrients in the diet the reduction in carbohydrates but it also led to a 40% reduction in insulin which we know again is associated with insulin resistance even in type 1 diabetes as well now one other concerns that people were worried about beyond cardiovascular disease which we'll talk about here in a minute because there was a doubling in LDL uh cholesterol was concern around kidney health liver health, thyroid health and bone mineral density. There have been, for example, in the context of bone mineral density, multiple studies uh that hypothesize that, you know, within the first one or two weeks of changing to a ketogenic diet that you see these adverse effects on um uh molecules associated with bone mineral density health, but there was never any long-term data. Uh same thing with thyroid health. There was this speculation that reducing carbohydrates would lead to thyroid dysfunction or the the alteration in things like uh kidney or liver health. It's always been at the forefront of most clinicians mind uh in association with the ketogenic diet. But what we saw over a 10-year period in a high risk population where we see early signs of cardiovascular disease dysfunction uh alterations and reductions in bone mineral density etc. There was no signal of any dysfunction in kidney, liver, thyroid or bone mineral density and no adverse events of actually administering this diet over a 10-year period. Again, something that is often cited as a concern for doing this particularly in patients with type 1 diabetes. So again, this looked extremely promising. One, we were showing that over a 10-year period controlling all these various in this very high-risisk population that this diet had profound therapeutic potential, but also was safe. But when we we looked a step further, the main concern that most people cited was cardiovascular disease risk. And so in association with a a close colleague of mine, Joe Watso, we looked at the advanced cardiovascular physiology uh uh in type diabetes related to a ketogenic diet. And this was so important because a lot of times people are looking at calcium score, which we can talk about and is a very important measure of cardiovascular disease risk. But well before someone's going to see an elevation in their amount of calcium in the body, which is an associate basically a long-term measure of the amount of plaque in the body, we see early signals of cardiovascular and heart changes that ultimately lead to future risk. So in cardiovascular disease, there's a step-wise change in how the body is able to respond to pressure changes. um and stress within the the cardiovascular system. And one of those early changes is we see within the first three to four years in children with type 1 diabetes because of these high and variable glucose levels that the vascular wall begins to stiffen. The amount of smooth muscle in the vascular wall starts to shift towards collagen and so the vascular wall becomes very very stiff. We also see that the endothelium, the inner layer of the vascular wall becomes dysfunctional. It is no longer able to respond to what they call shear stress. So when the blood pressure becomes high that that pressure starts to uh rub against the vascular wall, shearing against it. So it's a a form of of stress. And normally when that happens, you're young, healthy, uh without disease. Your body will vaso dilate. Okay, higher pressure. We need the vascular wall to be bigger. But in those with advanced uh cardiovascular disease or early on in diseases even in childhood with type 1 diabetes, we start to see that the vascular wall can no longer vaso dilate the same way. It is now stiffer. It's analogous for your audience if they turn on a hose and then they pinch the hose. Okay. Uh the water goes out much faster. Imagine if your vascular wall is much the same way where you you make the hose stiffer and you don't allow it to expand. The blood's going to move much quicker. It's going to cause much more uh stress against the inside of the hose or in our case inside the vascular wall. And these are the known early changes that eventually lead to inflammation processes, damage within the vascular wall that ultimately LDL and plaque goes in to fix. And so the plaque that's being laid is actually there to um to almost uh heal a wound. So if you have a you fall down and you scrape your elbow, your body puts this protective layer over it of a scab. Well, inside the vascular wall, the same thing is happening where you have these high pressures, very stiff vascular wall. It's not able to vaso dilate as well. And you have these these damaging molecules at high levels like glucose that are starting to do the same thing. They're almost uh almost scabbing up the inside of your vascular wall. And so LDL goes in and lays as a part of the process of laying plaque goes in and helps facilitate healing that internal vascular wound. But in doing so starts to progressively olude or reduce the blood flow within the vascular wall which ultimately over time leads to blocking the vascular wall in a heart attack or a stroke if it happens in the brain. And so what we found in this high-risisk population with 10-fold higher risk for cardiovascular disease with early signs of aththeroscerotic progression even in childhood within uh 3 to four years we found that the ketogenic diet despite doubling in LDL cholesterol led to not only normalization of glycemic control and over 40% reduction in insulin but in association with that no indications of stiffening of vascular wall. No indications of any signs of internal endothelial dysfunction. No signs of what they call left ventricular dysfunction or adverse effects in how the heart functions. Even though we would expect all of these to occur within the first 3 years of the vascular changes, within the first 10 years of heart changes. And this patient had had type 1 diabetes for 17 years and on the ketogenic diet for 10. And not only were the cardiovascular physiology showing no indications of risk, but when you actually compare it to age and sex individuals with type 1 diabetes, they had better cardiovascular physiology on average. But what's super fascinating here is that when we compared it to population level norms and individuals who had no disease whatsoever, we found that the cardiovascular function and physiology was often superior to individuals without any disease in a population at high risk for cardiovascular disease and having that disease for almost two decades. This this was a rather remarkable finding because at present there was mostly concerns and risk related to this topic and the disease. But what we talked about earlier here is that if we focus on the most important risk factors and correct those, it appears that that was the most important factor in regulating this process. Otherwise, if LDL was the primary risk and it led to early laying of of plaque over things like glucose, we certainly would have expected to see adverse effects in the vascular wall and we did not. We actually saw better cardiovascular function and health than individuals not only with type 1 diabetes but also without type 1 diabetes. And this really laid the the the groundwork for an eye-opening insight into what is one the priorities in regulating risk, but doing so in a population who's at dramatically higher cardiovascular disease because of the elevation at much higher levels of glucose and insulin which the average person also has to think about because if they develop overweight, obesity, pre-diabetes, and type two diabetes as we spoke about before, we start to see elevations in insulin. Then we start to see elevations in glucose and it progresses as metabolic fun uh dysfunction progresses. So I believe this study provides incredible insights at least preliminarily into the long-term implications of this diet and ultimately what is the net benefit and it appeared to be remarkably effective uh as a profound therapeutic strategy for regulating disease. We're not talking about a medication. We're not talking about a technology. In fact, in type 1 diabetes, there is no medication or a technological strategy despite hundreds of years of advancement that actually improves glycemic control to the same degree. In fact, over the last decade, patients with type 1 diabetes, despite dramatic increases in technological and pharmaceutical advancements and increased use of those tools, glycemic control has actually been shown to get worse. So, what we're talking about here isn't a technology. It isn't a medication. It is a therapeutic strategy that is in the grocery store. It's in your pantry and has amazing and remarkable effects on your body, but also and potentially regulating risk for chronic and even irreversible metabolic disease. I do want to ask about the LDL cholesterol pertaining to saturated fat. When somebody increases their saturated fat, we do see an elevation in LDL cholesterol. Why does that happen? Yeah. So, there's a lot of associated data between the elevations in specific types of food within the diet. So if you actually look at fat intake, um it isn't so much the fat itself that is causing elevations in LDL. Although although there is some data that suggests that if you actually dissect apart the type of fat, it appears that things like saturated fat are in part contributing directly to the elevation in LDL, but not just LDL, but also things like Apo B, which people are often more concerned about because it's a more direct measure of the atheroscerotic component of LDL. Um, so it's more about it appears the type of fat that's consumed in the type in the diet than inherently fat itself. Um, but it is diet related. So why does that actually happen? And is that a concern for somebody that is worried about heart disease and heart attacks? if they're eating more saturated fat from a highfat ketogenic diet, so more meat, more butter, more tallow, more lard, should they be worried when they see higher LDL and higher APOB, but their HBOC is coming down? This is a very interesting and complex question because this gets back to what we're talking about before. Let's say in the context of my disease in type 1 diabetes, this this unique kind of circumstance um where you have high invariable glucose levels and high insulin. Well, if you're able to do a ketogenic diet, you you have to think about the hierarchy and risk. So, the risk factors that ultimately lead to long-term negative outcomes. And so if you're able to do a diet or any pharmaceutical intervention, any technological intervention or any combination therein, you have to immediately focus on what's the primary risk that I need to focus on. It's like driving a car. I need to focus on the engine and the chassis before, you know, getting a better sound system or fancy rims, you know, or the type of leather in the seats versus cloth seats, you know, you don't focus on those things if the car doesn't function at all. So you you think about priorities here and risk. And of course in the context of of diabetes, we know that glycemic control is the primary risk. We know that blood pressure is a second again modifiable risk. We can't change age. We can't change how long we've had the disease, but we can change things like glycemic control. We can change things like blood pressure. We can change uh you know triglycerides, resting heart rate. uh and those are the things that are in a dose dependent manner ranked one through four in modifiable risk factors in in this disease. LDL is actually the lowest of those when associated with other uh risks. So it doesn't mean that LDL doesn't matter. In fact, LDL does have an association with risk in diabetes and in the general population. The risk is just infinitely lower comparatively. For example, there was a study this the big study called the dcc and edict trial on type 1 diabetes the one that I referred to earlier that had over a thousand patients over 30 years in a randomized control trial setting looking at the various risk factors and that what they found is at the 30-year mark what actually associated with the incidence of cardiovascular uh disease or events and they found that LDL was significantly associated with cardiovascular disease but the the associ ation had a hazard ratio of 1.07. So what does that mean to your audience? Well, 1.07 is relative to one. Meaning that the risk, the increased risk associated with every 10 milligs per deciliter elevation LDL was only 0.7% higher. So as you increased your LDL 10 milligs per deciliter, you increase your cardiovascular disease risk 07%. But things like HBA1C, triglycerides, blood pressure had infinitely higher risk. So as you elevated or as you changed glycemic control, as you change blood pressure, as you change triglycerides or resting heart rate, those had much multiffold higher impacts on the incidence of cardiovascular disease in this population. And one of the most refined studies ever done because it was not only a randomized control trial, but it was in over a thousand patients over a 30-year period. I mean, you almost never see a study like this. Uh, and you may never uh really again, it it's it it cost hundreds of millions of dollars and probably won't ever be repeated, but it was done and it did show that those are the factors we have to worry about. So, it doesn't mean you shouldn't worry about LDL. So, let me give my personal example. I myself have type 1 diabetes. All the data says that I'm increased risk for all 10 leading causes of death. I'm expected to have 10fold higher risk for cardiovascular disease. I'm expected to get at least one-term complication related to high invariable glucose levels, whether it be damage to the eyes, the kidney, vascular dysfunction, heart dysfunction, one of these various risk factors. I'm not I'm not not might get them. I'm expected to get at least one of them. Every patient is expected to get at least one of them. And in that particular case, I'm thinking, what can I do to dramatically reduce my risk? I have a wife and two kids. I want to live a happy and healthy life. I want to feel good today, but also I want to feel good forever and live as long as possible. And I have to look at the data. I have to look at the evidence. What actually associates with risk and when I look at those the data on that is very clear that if I I need to focus on my glycemic control first. Once I have that fixed, I need to focus on my blood pressure. Then I need to focus on my triglycerides. Then I need to focus on my resting heart rate. Things like exercise can improve that. and those other metrics. Then after I got all that corrected, I can worry about the .07% elevation risk in in LDL cholesterol uh for every 10 milligs per deciliter increase. So these marginal increases, these marginal risks, yeah, I would love to have all them corrected, but the the reality is that almost no therapeutic strategy doesn't have a risk-to-benefit ratio where it may improve some things and not improve all things. And so I want to improve the things that matter most. And if something is uh at risk and associating with improving the things that matter most, that's okay for me as a patient living this disease because I want to have the the largest net benefit for whatever I'm doing with my lifestyle uh over the long term. And so yes, LDL does matter. Yes, it is associated with risk, not only in diabetes, both forms, but also the general population. But the risk particularly in these high-risisk cardiovascular disease settings is so much higher for things outside of LDL and that means that we should focus on those first and foremost and then also focus on LDL once those are fixed but never compromising the most important risk factors for something that is much less important. So it's always a a net benefit and ideally you fix them all uh but sometimes interventions don't allow for that. So you have to consider the net benefit of anything you do in regulating your long-term health. So if somebody is just thinking about this, maybe they don't have a chronic disease. So we spoke about diabetes, type 1 and two, um elevated insulin, fatty liver disease. What if they're just kind of healthy? So a question for you, who should never or not do a ketogenic diet? It's an interesting question that's not often asked because there's so many therapeutic effects of a ketogenic diet across many different settings that people often only focus on the excitement around the fact that wow, you can change what you buy in the grocery store and what you consume from the grocery store. And it can have these massive impacts in these diseases where pharmaceuticals and technology that cost, you know, hundreds of millions of dollars uh aren't able to do. But there are some contraindications meaning in uh examples of when someone shouldn't do this and and those are usually specific to what we call inbornne errors of fat metabolism. So when fat metabolism you aren't able to actually metabolize fat that that would be a clear indication that doing a diet very high in fat would be contraindicated or not recommended. We used to think that things like eating disorders should were contraindicated, but that's in question now because there's emergent evidence that shows that people with eating disorders have actually been able to appear to correct in part some of their eating disorders by changing their diet. And that's a very interesting uh paradigm because often one of the high risks for someone developing an eating disorder is restrictive eating. And when someone, you know, does a ketogenic diet, they're reducing the amount of carbohydrates. Some people assume that to be restrictive. I will also state that restrictive or reductions are all relative, right? So, if you went to the grocery store and the only thing that was in there was fat and protein and there's a little bit of carbohydrates, most people would probably be consuming a a higher fat and higher protein diet and less carbohydrates. It's really society driven what we're predominantly eating. It isn't because we have to, it's because what's available and in higher portions. So, what's normal is very relative to the individual and circumstance. But those used to be so inborn errors of metabolism, those are contraindicated for sure. If you can't metabolize fat, that would be problematic. But also, um, what we used to think like eating disorders would be contraindicated and in some circumstances, it may be ill- advised. Uh, there's actually emergent evidence, at least in in smaller case report and pilot studies, that that might it might actually benefit some people with those conditions. So, those are the ones where we're more concerned about risk, but we also have to talk about where it may apply, right? Where are some of the the net benefits of this diet? I mean the the therapeutic potential of this diet has been shown again it was standard of care for type 1 and type two diabetes for 200 years has been shown by RO back in 1796 I believe um to correct obesity uh and again use as standard of care correct obesity and type two diabetes for over two centuries. Um we know that it has been used for neurological disorders uh since the Mayo Clinic uh Wilder report um back in 1921. And there's all this emerging evidence that this shift in metabolism associated with reduction in carbohydrates in the diet which leads to reduction in glucose load, reduction in insulin, this physiologic cascade of events including the elevations of ketone bodies can ultimately uh have powerful therapeutic effects not just on let's say obesity and type two diabetes and type 1 diabetes but emergent evidence that it could have a powerful effect in in fatty liver we now call massel d um through the elev ation in the enzyatic process of just ketogenesis which seems to have an implicative effect in the disease process. Uh we also know that things like neurological disorders, Alzheimer's, Parkinson's that there's emergent evidence that either ketogenic diets or just the administration of metabolites associated with the diet like exogenous ketones potentially have therapeutic potential um in attenuating some of the symptoms of these diseases. What's really really fascinating is this emergence in evidence revolving mental health or um what this field of of metabolic psychiatry where this these these cluster of conditions you know when we think about that we're talking bipolar schizophrenia anxiety depression uh amongst others we often thought okay right now there there are very I mean virtually no really long-term studies that any medication is effective in these conditions. Yes, people use medications uh over the lifespan and have been for a long time, but we really don't have studies to show that you know beyond one or two years that these medications are are that are commonly used for standard of care for treating these conditions like SSRIs and others really have therapeutic efficacy or safety beyond these these windows of time. And these these conditions are rising at rapid rates in our society. We know that um the rates of of psychiatric or psychoactive substance use is dramatically higher even in children. Um rates of uh unfortunately suicide and and otherwise the incidence of psychiatric diagnoses are much higher um dramatically higher in fact in the last couple of decades than previously seen. But there's this emerging evidence that the the reduction in carbohydrates associated with the the the state of physiologic ketosis and the elevation of ketone bodies associated with that appears to have the potential for profound impacts in regulating a this this set of conditions in psychiatry that we would have I mean arguably never thought that something like nutrition would have an impact on. But what we're appreciating and what we talked about in the very beginning is that not just in obesity and diabetes conditions, but also in virtually all conditions, metabolism has a clear either causal or associated effect with health and in disease. And we know that changing mitochondrial u functionality uh the processes of of metabolizing nutrients to um uh metabolite changes within the blood to hormonal changes associated with that. These are all effects of metabolism and almost all I don't know of a condition that doesn't have changes in those conditions that either have direct causal impacts on regulating the disease process from occurring in the first place or potentially being reversed. but also in regulating symptoms related to the disease. And so underlying the hood of virtually all these issues is metabolism and the dysfunction of metabolism being associated with many of these issues. But the correction of metabolism by uh altering or reversing a lot of the adverse metabolic effects uh often accumulated over time to lead to disease or happen within the disease can often be altered through nutritional change. in the ketogenic diet or therapeutic carbohydrate reduction as we now call it is one of the most powerful ways to change physiology in association with diet and it's it's quite remarkable and how much data we see in that. So it's there are conditions inbborne aeros metabolism conditions we once thought like eating disorders that would be contraindicated but there's this emergence of evidence uh really showing incredible promise across the board and and hopefully we'll learn more and more as we go about where and when it would apply and how to optimally apply these strategies in the context of each person. We're really honestly in early stages of understanding uh that end of things which is is how and when and how to optimize application of of these strategies when they're applicable. Absolutely. I do see people in the comments saying that when I did a highfat diet, it didn't work because of XY Z reasons. For example, triglycerides, LDL, I gained weight. So, understanding who it's for and who it's not for, and you gave some people that it might not be for is important to understand. I I want to move on to um understanding physiological insulin resistance versus pathological insulin resistance. First, talking about physiological insulin resistance. If somebody's doing a long-term ketogenic diet and their blood glucose is slightly elevated, a doctor's going to say, "You have become insulin resistant because you're not feeding your body with sugars and carbohydrates." Is that a real thing and something that that person should be concerned about? Yes and no. So when we think about insulin resistance, we're talking about in the where we associate it with risk. We're talking about in the context of diabetes and we see it often in early signs and obesity as body weight and atapost tissue accumulates. We're worried about that because of its known association with cardiovascular disease. It um the elevation and uh circulating levels of insulin can lead to downregulation of the insulin receptor. um changes in insulin signaling uh this this where the insulin molecule binds to the receptor and then ultimately causes a cascade of molecular changes within the cell to ultimately cause glucose uptake and normalization of glucose within circulation. We see that many of those molecules are altered in the their their signaling cascade IRS1 hexokinus and others. Um we also see the reduction in insulin clearance um in in the context of insulin resistance. In fact, one of the best examples of understanding the impact of insulin and its impact is actually in type 1 diabetes where again we talked about patients who are norm off to normal body weight, normal lipids, normal amino acids um and normal blood pressure at least initially within immediately upon diagnosis when they start um injecting exogenous insulin they see insulin resistance. And what this is telling us is that even in children in normal body weight uh just the administration of exogenous forms of insulin immediately cause insulin resistance. Uh and this actually occurs also uh within 48 72 hours in individuals who don't even have diabetes if you just infuse high levels of insulin into the peripheral vasculature. So just the presence of higher levels of insulin has pathological consequences. But there's all there's this interesting conversation, right, about this physiologic insulin resistance where, oh, if you go on a low carb diet, you're going to reduce the amount of glucose um that you're metabolizing and then you're going to increase fatty acid metabolism and that you're going to become more, let's say, resistant to your ability to ultimately metabolize glucose. And a lot of that is largely focused on this this this process called the Randall cycle. You know, a lot of people focus on this like molecular pathway called the Randall cycle where just simply put, you know, in layman's terms, it's like how your body decides to what's fuel to utilize, you know, sugar or or fat. You know, depending on what's available and what's needed. So, if you have more fat, you're fueling the body with um you would burn more fat. If you give more glucose, you burn more glucose. And as you increase the amount of fat and lower glucose, uh you would preferentially shift towards my fatty acid metabolism. Um and it's kind of like you know two fuel sources you know like uh electricity glucose and gasoline for fat and uh whatever one you choose to use um you preference in that way and and but I I also want to one problem with the random cycle is very reductionist right it assumes that this is a a a one or the other type of circumstance and I will tell you that oversimplification that reductionist mindset in science almost never applies. In fact, we know it doesn't apply because we have studied numerous individuals over, you know, multi-week and often sometimes uh multimonth ketogenic diets where we've actually assessed whole body substrate oxidation. So, the amount of carbs being metabolized, amount of fat being metabolized, not only at rest, but actually during stress, like exercise. And what we find is that individuals who completely adapt to a ketogenic diet over four to six weeks, we see ketones elevate, we see insulin lower, we see glucose reflective of the diet change. Uh we and they have multiple other adaptation changes that occur like ketone elevation that eventually normalizes. Once they normalize in this state, we still see they're oxidizing glucose. We even though they're oxidizing infinitely more fat. So, it's not that people can't oxidize glucose, they're just using more fat and less glucose proportionately. And yes, if you fuel with more glucose or more fat, um you may preference it. And that is true. In fact, that's also why uh oral glucose tolerance tests are not valid on a ketogenic diet because uh it's and that's been known for almost a hundred years. It it if as a part of the methodology of the test, it specifically has stated for 100 years. If you do this assessment, you should not do so if you're in a carbohydrate restricted state because of the known shift in fuel preference. But I the oversimplification using kind of pathways like the renal cycle, which is a real pathway, it is applicable, often leads people to think that, oh no, I'm going to get insulin resistance associated with a change in in diet because I'm going to shift more towards fat and then I can't really tolerate carbohydrates anymore. And while in part that may be true for some individuals, we know in our studies over multiple studies, not one study but multiple studies that you never stop utilizing essentially all fuel fuels. You just preference some more than others and you always will use some um verse others depending on the context whether it be diet induced, whether it be exercise induced and beyond. Is physiologic insulin resistance um real? There's partial shifts in the amount the body responds to glucose with dietary change. If you lower glucose uh and increase fat, you'll be able to burn more fat preferential over glucose. But is that pathological? Absolutely not. Um we know that the pathological component of insulin and related to insulin resistance is tied to the peripheral elevation over time that is marketkedly higher. I mean uh two to fourfold up to sixfold higher in these conditions. This is not the same thing as physiologic insulin resistance and arguably physiologic insulin resistance is more of a kind of interesting term and topic that I I don't really feel is as applicable as people think it is in these circumstances. certainly isn't pathological in any particular way. So I often don't don't put much into that but uh it is an interesting physiologic effect for some individuals to on on the spectrum um if that makes sense. It makes sense. I just thought I'll ask that because a lot of doctors will say you need to eat carbohydrates so that your body knows how to burn glucose but as you mentioned due to the randle cycle or your body just knows how to the idea about a a healthy metabolic state is that the body can shift towards burning ketones or burning glucose as an independent variable for fuel. But it does both even if you're on a highfat ketogenic diet consuming low carbohydrates. And so that the path the pathological form of insulin resistance is when you have a disease, insulin resistance, or if you have diabetes or anything causing that. Physiological is when you deprive your body of carbohydrates and then it's saying you're going to get insulin resistance because of that. It's not actually real. I want to talk about how somebody can create a very well-rounded ketogenic diet. How much fat did people eat in that long-term study? So around 70% which is actually very common you know historically speaking when someone when we thought about the therapeutic effect of a ketogenic diet it was often citing historical studies in epilepsy um because people thought that was some of the original work on a ketogenic diet when in reality obesity and uh type 1 and type two diabetes was the original work um historically speaking in the ketogenic diet but that was a extremely high level fat over 90% of total calories by fat, which when someone says I'm doing a ketogenic diet, virtually no one is doing that. Um, they may think, oh, and they call it a 4:1 ketogenic diet or or 90% by fat ketogenic diet. Almost no one is actually doing that. Uh, it's very actually hard to achieve. It's it's it's a lot of fats, a lot of oils, and very little protein and and virtually an absence in carbohydrates. So, um, you don't see that. But in the studies that uh we have conducted we often see more like a 2 to1 ketogenic diet which is around 70% of the total calories by fat around 25% 20 to 25% from protein around five to slightly less than 10% of calories from carbohydrates. Uh which is the actual definition of what we term a very low carbohydrate diet. Uh your audience should probably um become familiar if they're not that there is distinction between just low carbohydrate and very low carbohydrate. And an even further distinction between that and the ketogenic diet where low carbohydrate is actually around 51% of 50 to 51% to up to 100 or um so so 51 gram of glucose up to 130 gram of glucose or around 10 to 25% of all the calories from the diet coming from carbohydrates. But very low carbohydrate is what most people think of when they think of the therapeutic diets that they've heard of like a ketogenic diet because those are typically less than 10% of total calories coming from carbohydrates in the diet and typically less than 50 gram of total carbohydrate intake. But again, it's dependent on the situation. So if you're a child doing this for epilepsy, you probably aren't consuming 50 grams. Uh you're probably consuming, you know, maybe closer to 10 to 30 grams of net carbohydrates or less. Uh, so it it really depends on the circumstance, but we usually go based on percentages because percentages account for age and body size differences. But that's the typical breakdown when we think about uh keto uh these different diets. But keep in mind when we talk about a ketogenic diet, it's also often ascribed to this 70 to 75% of total fat, 20 25% from protein, around five maybe up to slightly less than 10% of total calories from carbohydrates. But it's actually in the term ketogenic, meaning the production of ketones that is the metabolic biomarker of whether someone is in ketosis or not. And so I often like to think of these in categories which we've have have published on it defined as high carbohydrates which is greater than 45% of total calories by carbohydrates moderate carbohydrate which is around 26 to 45% of uh calories by carbohydrate which is actually what most people are eating nowadays. This is similar to a western diet where you kind of high carbs and high fat. Then you have low carbohydrate which is 10 to 25% of total calories by carbohydrates. And then less than 10% of total calories by carbohydrate is the very low carbohydrate diet which most people think of when they think about therapeutic effects of low carbohydrate intake. When you have the elevation the ketone bodies on top of that that's when we start thinking about therapeutic ketosis or what we call a ketogenic diet. So there's there's clear distinctions between the various types of diets based on the amount of carbohydrates, but also the amount of let's say metabolic increase. So things like ketone bodies as well. So if someone is thinking about those macros, might sound a bit confusing. What do you think are the top five foods that somebody needs to eat to do a well-rounded ketogenic diet? Oo, good question. Um, and that's actually really hard for me to answer because I usually don't think of it that way. I usually think about because it's so, you know, context dependent. It's so person by person, individualized. Uh maybe they have cultural uh factors, individual factors, or they respond better to some foods versus others, or maybe they don't have access to certain foods. But typically, when people think about a ketogenic diet, and let's say you let me let me rephrase it and constrain myself a little more and say, "What would I consume if I was only given five foods to eat for the rest of my life for a ketogenic diet?" Um I would primarily think about something like, honestly, not a very fancy answer, but eggs. Eggs is a very macronutrient, micronutrient dense fuel source that has both protein and fat at at good ratios. Um, you could consider beef or something like salmon. Um, one would, you know, people like the idea of fish better because of the association with health benefits of fish. So, you can say things like salmon. Um, I I don't exclude vegetables. Some people do if they're doing something like carnivore diet and you know power to them if it's it's producing benefits for them. But I do like to have fiber in the form of let's say broccoli or spinach. I would actually contend that if I could choose one of those, I'd probably go with broccoli. It has a a higher fiber to total carbohydrate net ratio and it has a lot of it's very micronutrientdense. Some people probably are mad I didn't say kale because it's supposed to be a superfood, but whatever. I chose broccoli. Um, be beyond that, I would probably go with uh some form of nut. Um, I am a big fan of macadamia nuts. In fact, I don't actually have them that much because I was definitely and h, you know, I'm I was formerly obese. And so, if someone throws a bag of nuts in front of my face, I'm not going to sit here and pretend like I don't have uh uh subconscious levels of desire to eat not only the whole bag, but maybe three of those bags. So, but I probably would do macadamia nuts if I could choose. um they have a high fat to uh high fat content and they're also plant-based. So, I like the idea of diversity. I'm not all or nothing. I'm not all animal-based fats, not all plant-based fats. I think a balance is a good strategy. And so, I'd probably choose macadamia nuts. Um and then I'd probably choose some type of intermediary between those, something like olives or olive and the because you can make oil out of it. Um which is also kind of it's a plant. It also has oils and and fats. Um, and it comes from a healthy source, but it also comes from plant source. So, I'm diversifying between animals, fish, uh, fiber sources, um, that are low in the the net carbohydrate impact and also things like nuts and or olives. If I had to be constrained and choose, um, of course, I want all the options and extreme flexibility. But if I didn't and I didn't have those options, that's what I go for. That is such a detailed response. Okay, last question for you. If somebody's just on the fence about a ketogenic diet, thinking, I don't know if I can do it because my family is not doing it. It's too hard. It might be expensive. All the fat and all this kind of stuff, what is your best advice for them? The biggest constraint that we often hear about uh is, you know, and I think about this a lot in the context of type 1 diabetes because the type 1 diabetes is peak age of diagnosis is 10 to 14 years of age. So, it happens in childhood. Uh is I want to be able to eat like my friends eat. I want to be able to go to my friend's party and have the food they're having. You know, I don't want to give up my favorite foods forever. And I guess the way to think about this is what are the foods that you think you should be eating? You know, when you visualize health, most people are visualizing a salad. Most people are visualizing, you know, like blueberries or blackberries, um, salmon, uh, foods like this. And then, you know, having all of them within reasonable amounts and in moderation. You might think of squash, too. you might think of, but we don't think necessarily of like rice as a health food or bread as a health food. Um, you often think about what's healthy. A lot of the things in a well- formulated ketogenic diet pop up in your mind. And so it's it's something that you can formulate and be health focused. Uh, but when you think, okay, well, I don't want to give up I don't want to give up my pizza. I don't want to give up my donuts and da da da. Well, keep in mind that if you ideally probably shouldn't have any of those foods, you know, at least not a lot of it and not often, but if you really did want to have it, um, you can make low carb versions of this. And arguably, that's a better alternative. And why do I say that? Well, a lot of times, if you were to go to the store and buy a cake for someone's birthday, it is absolutely loaded to the brim with rapidly digesting sugar and carbohydrates and fat simultaneously, both at the same time. This is when you have the worst metabolic effect is when you have high fat and high glucose simultaneously together. But what you could do is you could have made that cake that is let's say with almond flour or coconut flour instead of whole wheat flour. Um, and now you can actually exchange things like sugar for things like stevia, monk fruit, alulose, one of these other um, safe and healthy alternatives that don't have calories in them or virtually no calories in them. And so actually doing this diet, I think, is a really powerful way to learn how to actually replace what is arguably very unhealthy forms of food that are abundant in Western society. and it actually make them healthier because no, you don't I'm not telling anyone you have to do the ketogenic diet. You don't have to. Don't do it if you don't want to. Don't do it if it doesn't benefit you. If you don't feel great, you're not as long as you've done it the right way and you've had good guidance and and and how to do this because there's a ton of bad advice out there on how to do this. But if you're doing it the right way, uh you've had good clear guidance, you know, do whatever you want. But that said, um you should do it appropriately and you should uh arguably focus on how to make this diet sustainable. And so I I have done this diet for o, you know, over a decade and I live with a disease where it helps manage my primary risk factors. And so I want to make it sustainable. So if I have my birthday, you know, my wife's amazing and she's incredibly supportive cuz she sees how profound of an impact it has on my disease control. She's not waking up every night checking my blood sugar, worried about whether I'm going to go low all the time. Like it's it's dramatically improved our family's life, my life on a regular basis. And so if we want to make something fun for a birthday, she'll pull up, you know, a website. Actually, you can use chatbt nowadays. It's really, really effective. But there's a website called All I Dream About Is Food by Caroline Ketchum, which has an amazing list of very, very uh dectable foods. Um, wouldn't say they're low on the calorie end, though, but they sure do taste good. So, if you ever wanted to to make something that's fun or you're going to a birthday party, you want to make pizza, um you want to make donuts or cake, you can make all of those foods and make them low carb. But in doing so, you are actually learning not only yourself but your whole family if you do it together. um how to often swap out ingredients of foods, make it on your own and arguably make it way healthier because you're often replacing things that we know ubiquitously are not ideal in the diet like high sugar uh with things that are safer alternatives that allow you to have that sweetness if you so choose. But you don't have a huge caloric load. you don't have that huge glycemic spike that huge insulin response and the associated metabolic consequences of that over and not only at that meal but if you consume it over time uh over time so um I think it's it's important for people to understand those things because nowadays if you don't understand them you're really vulnerable to what is a extremely dysfunctional food environment particularly in the western world where you go to the grocery store you can find a food that says oh healthy um whole food uh you know a ketogenic diet and reality is that that's not actually true at all. I've consumed foods that have the same calories, the same macronutrient distribution, both say keto friendly on the front and one spiked my my insulin over 300% increased my blood sugar over 100 milligrams per deciliter. Whereas the other one had no effect on glucose, no effect on insulin. And so as if you're if you're focusing on a diet like this and you make it whole foods, you'll learn how to eat the right way with the right ingredients. You're often learning how to eat better in general and you can apply that strategy whether you stay with the diet or not that not just for the person who may do this primarily. Let's say you have a son with type 1 diabetes or a daughter with epilepsy and you're doing it for them, but you yourself will learn along the way and I I I would be surprised if it won't have an effect on them as well because in today's society over 40% of kids some type have some type of chronic condition. Over 70% of all uh adults have obese or overweight. Over 50% of the adult population is pre-diabetic. Um some would contend that the levels of insulin resistance are even higher than than that. Uh there have been studies that have looked at the incidence of optimal metabolic health. Let's say you don't have elevated glucose or waistline or you know body composition uh normal glucose levels. They show that less than 10% of the American population actually fits optimal metabolic health. So at this point when we think about optimal dietary strategies almost the entirety of western society is dealing with this. And so as a result understanding diet, understanding powerful therapeutic dietary strategies that can correct metabolic dysfunction like therapeutic carbohydrate reduction and ketogenic diets is an extremely important learning tool. I would contend to uh understanding how to live a well life. But I won't negate, you know, things like exercise, sleep, and other factors are also really important. Absolutely. Couldn't have said it better. Andrew, if people want want to find you more more, where can they find you? Andrew.com. It's a website. I've provided a ton of free resources where people can go and and and learn as much as possible. I also have a Substack letter where I uh post articles on, I think, key topics. Uh you know, you can find me on Instagram, uh X or Twitter, whatever you want to call it, Tik Tok, um and beyond. So, if anyone's interested in following me on one of those various platforms, they can find it all at my website. It's andrew.com. Perfect. All the links are going to be in the description. Thank you so much for your time. Thank you so much for being here.