Ben Bikman, PhD | Reversing Insulin Resistance | The Metabolic Link Ep.9

Welcome to the Metabolic Link, a podcast that explores the common thread of metabolism in health and disease. This is where science meets society. Welcome back to another episode of the Metabolic Link podcast. Today we have a great interview with Dr. Ben Bickman. Dr. Bickman earned his PhD in bioenergetics. He then went on to do a postdoctoral fellowship at Duke National University of Singapore in metabolic disorders. He's now a tenured professor at the Brigham Young University and investigates the regulation and dysregulation of insulin signaling, including the relevance to fat oxidation, ketone production, and mitochondrial function. We discussed a range of topics here in this podcast. It includes measuring adipose, insulin resistance, looking at free fatty acids in the blood, which is often not talked about. We talk about basic science research. We talk about practical approaches to managing and preventing insulin resistance. We had a great discussion. I am excited to share this content with you and thank you for following Ben thanks so much for joining us. I was very inspired and educated by your talk at Low Carb USA and in particular you had a number of graphs throughout your presentation that representing data that from your lab probably, but also from the published literature, which is very interesting to me. It's been a topic in our medical education, the importance of fasting insulin and how insulin becomes elevated and that's a precursor to hyperglycemia. And you had a nice start. So I would like for you to, if you wouldn't mind, kind of walk us through what you were representing in the graphs. We don't have the graphs here available. Maybe we can get it in the show notes. We'll have, if you've had that published somewhere online, you know we'll link to it. But I would, first and foremost I would like to you to kind of walk us through the chronologically what happens in regards to insulin resistance and, and what insulin does too. In particular as we age in your graph, and this is something of high interest to me, as we age, that decrease in insulin, how insulin levels sort of tank as we as it passes a certain threshold later.

Yeah, yeah, yeah. This is a nice way to start because it allows me to establish a common, a common definition of insulin resistance. Because that, that was the. Certainly the focus of my talk is that I believe that a lot of people are invoking insulin resistance incorrectly because they just don't properly understand what insulin resistance is. Insulin resistance is a phenomenon with two facets that you cannot pull apart. There is, there's, I've, I'm unaware of any exception to this. So I'm quite bold in how I say it but insulin resistance is both the expected reduced signaling where the hormone insulin isn't quite working the way it used to throughout the entire body. Now that is not a universal effect. It's not that every cell of the body isn't responding to insulin anymore, but it, some cells aren't responding as well. So I'm just kind of couching that in a vague. Insulin isn't working as well as it used to. So that's the insulin resistance part and that's a cell specific phenomenon. But of course these cells are within the entire body, the entire organism. And within the entire body we have another aspect to this, which is hyperinsulinemia. So the elevated insulin, that is what is so important. There is no such thing as insulin resistance without there being an accompanying, and I would say often preceding hyperinsulinemia. And then that touches on that temporal aspect question that if you're following an individual over their life, our metabolic view is very glucose centric and there is precedent for that. I don't criticize that we've had a glucose centric paradigm and I don't even mean to imply that it's wrong. For example, I'm an enormous advocate and I know this is an advocacy you and I share with regards to the clinical utility of cgms. And being able to constantly monitor glucose is a powerful tool because it's the dynamic nature of glucose that helps you get a better insight in, into your metabolic health rather than just a fasting glucose test. But back to glucose, the average. And then touching on the temporality of this, as you alluded to, the average individual who's coming to their physician year in and year out, they will be gaining weight, they will have high blood pressure. Now they're on an anti hypertensive medication, they may have some form of infertility in male or female. And the physician is only ever looking at the glucose levels. And because the glucose levels are staying in a decent range, they assume, well, there's no metabolic problem here. But if we truly want to understand metabolic problems, we have to look at the hormone insulin because the glucose levels are themselves simply a symptom or a manifestation of disordered insulin action.

And so here's not part of a standard comprehensive metabolic panel. So this is. That's right, we were having in medical education and even the students are kind of like very confused by that.

So yeah, oh no, no, I'm, I'm thrilled because with you and I both being professors who, yes, we do research, but we also teach classes. I just last week got done teaching lectures about metabolic syndrome and diabetes to my students. And I had, I was thrilled by how many questions from the students with regards to what was basically their, their befuddlement that we don't measure insulin more often. And so, I mean, the conversation is changing. And that is reflected also in the fact that I'm invited to give talks at grand rounds or CME meetings. So I'm confident that the word is spreading. But it just reflects this skewed paradigm where we have conventionally trained clinicians who just are really taught to look at glucose. But if they were to include an insulin measurement, they would have found that over the years, insulin has been getting higher and higher and higher. And this is reflective of insulin resistance, but it's enough insulin to keep the glucose in check. And then, and then, and so it remains clinically silent. And there is no, there's no thought that there's some metabolic foundation to whatever other chronic disease we're looking at. And that's why, of course, I beat that drum so loudly that we have to include insulin in this paradigm. We have to either broaden the focus or just ditch the fasting glucose entirely and just go to insulin. I'd be fine just broadening it, of course. But it's when there are now an additional handful of events which includes the insulin resistance progresses to tissues like the alpha cells of the pancreas that release glucagon, and it progresses to the liver. The liver becomes insulin resistant. And now we have dysregulated glycogenesis versus glycogenolysis and gluconeogenesis. And then even the muscle, which is of course the main consumer, about 80% of the, of the postprandial glucose clearance. When someone eats a starchy, sugary meal, it goes into the muscle. But then as the muscle becomes insulin resistant, it, its ability to pull in glucose is reduced by about 50%. So it goes down by half. And so you've lost the biggest glucose sink in the body. And so, and when you add so, not only do you combine the insulin resistance of those glucose focused tissues, but you combine that with the potential for some individuals to begin producing less insulin. That is, but, but that is, if I pause that thought for just a second, that is not an absolute. People speak about type 2 diabetes in these subjective, qualitative terms and they will say insulin is insufficient to control glucose. Well, technically that's a correct statement, but it is also misleading because it makes it sound like their insulin levels have gone to zero or nearly zero. And if this is type 2 diabetes, that doesn't happen. It never happens. Even if the insulin levels start to come down a little, and they can, they're still multiples higher than where they used to be before they ever started on this pathway to poor metabolic health. So here's where they used to be. Then it went up to here, and in some people it stays there. It's making 10 times more insulin at any moment, the beta cells. And then in some instances it comes down, but it never bottoms out, not in type 2. That does not happen in type 2 diabetes. But suffice it to say, if we combine all of these variables, the insulin resistance at the glucose managing tissues and tendency to produce less insulin, now we have the glucose starting to change and potentially changing quite rapid. And it's only at that point within this glucose centric paradigm that conventional clinical care will detect the problem. And now the clinical focus will include a conversation about, well, we got to control your, your diabetes, we got to control your blood sugar levels. But even still, Dom, as much as the focus will have now included a metabolic component to it, conventional training wouldn't have shown what is so obvious to many of us, that is that this patient's preceding health problems, the hypertension, maybe the migraine headaches, maybe the infertility, are all to varying degrees impacted, if not directly caused by this insulin resistance that has been lingering in the background for the, for potentially decades, you know, before the glucose ever starts to climb. So the focus on insulin.

Yeah, let's stop there because I want to address the different, like, disorders associated with the insulin. But I was just like super engaged by your, the presentation of the chronological, what you just really nicely explained is there human data. My colleague, Dr. Barbara Hansen, who's worked along with like Gerald Schulman and others like, really one of the leaders in understanding like insulin physiology, she's got a lot of data she's collected on non human primates. And the data is not published yet. But it actually looks just like your graph. You know, she's putting it together and she's got a mountain of data. So was there any, was there a particular publication where you showed that data? Because I haven't come across and I should know this, where it shows, you know, the chronological. And I know there's bits and pieces of data, but, but I've never saw it represented or presented in the way that, that you did. Is there a good go, go to publication that kind of has the representative figure like data that, that, that's associated with that figure? Yeah, maybe you had it in the talk, but I didn't.

No, no, I don't think I cited. So that's a figure that I've used as a teaching model, but I adopted and adapted it from a publication from a. You might have met him, and I bet people have heard of him. He's a pediatric endocrinologist and his name was Jake. His name is Jake Kushner. I'll try to find that manuscript so that we can include. So he had put together a figure one time in one of his review articles that he published a few years ago, and it showed that paradigm, and that's why I felt so confident, especially Dom, especially on the. The early part of it, I don't think would be controversial at all, that insulin's climbing before the glucose starts to climb. And then it was this idea that even if the insulin starts to come down in type 2 diabetes, it does not go to zero. And, and that's so important because age.

Though, so, yeah, that was right. So with an aged animal, for example, non human primate, I think the data, it's like almost like you. You got a hold of this idea before it was kind of even published. Is that in non human primates, not published yet. But it goes up. It looks very much like the graph that you displayed, and then it starts to taper off and go down and then it tails down. But that sort of hyperglycemia remains. And it's almost like the, the beta cells got. Got burnout. Although, you know, that that's more of a. Not, not every. Many physiologists may not agree with that, but there's an age dependent decrease in, in insulin, you know, associated with type 2 diabetes. Could lead to like insulin dependent type 2 diabetes. But it's, but it's, you know, that you may have not kind of captured. Maybe it's more like early age and middle age, but, you know, in advanced stage, I think in non human primates, it'll. Insulin starts to tank later on. That's. It could be a consequence of just, you know, what, what you've been talking about, which is another consequence of insulin resistance is just, you know, beta cell burnout.

Yeah. Yeah. So, Dom, I wish I could cite a specific decade. I don't even think Jake Kushner identified a decade. It was a bit of a vague outline, just like I'd had. I. If I had to guess, and I will, I'd say it was about in the 60s, within that decade of people being in their 60s. But interestingly, even then, when beta cell number starts to go down there are human studies to show that with dietary intervention, I would include that, I would add nuance to that by saying interventions that improve insulin sensitivity, although they were not as good as I considered. The intervention they used was just an old fashioned kind of low energy diet which does resolve insulin resistance. I just take issue with the fact that I don't believe such a view is sustainable when it's just lower energy and it's this battle for energy. I think it stimulates hunger and then hunger will win, but that's a little beside the point. But they found in type 2 diabetics, even as beta cell mass starts to go down, which I would say is not a bad thing. After all, beta cell mass expanded significantly during this, these decades of hyperinsulinemia. So when, when we say that and, and you know, you're not unique using this term, that when we say beta cells burn out, in other words, we just have a loss of some of the numbers of the beta cells. I actually do not consider that to be the problem that many do. If anything, it's putting them back closer to where they used to be. And I think there's an opportunity there because in conventional clinical care, you know, insulin's been coming up, they're insulin resistant. Insulin may start to go down and then the glucose levels start to go up because the, the conventional model is only looking at the glucose. That view then justifies pushing the insulin up even higher and giving the type 2 diabetic insulin therapy. And that begins, that's almost that, that increases the descent. They will start to gain weight much more rapidly. Their metabolic rate slows significantly. It's something people don't appreciate. An insulin slows metabolic rate and that of course amplifies weight gain and they become more and more insulin resistant. And dom importantly, the more Insulin A type 2 diabetic needs to keep their glucose in an acceptable range. Even though the glucose is in an acceptable range with all of that insulin, which is so pathogenic, they're three times more likely to die from heart disease. And, and so that just reflects the problem that this is not a glucose problem. These are, this is an insulin problem. And the more we're pushing the insulin up, the more we are pushing them towards poor health. It's, I've used this before, but it's, it's analogous. Giving A type 2 diabetic insulin is like giving an alcoholic another glass of wine, hoping it will cure their alcoholism. You're giving them more of the very substance that's driving the problem. Now I'm Shifting the conversation a little and I'm touching on the origins of insulin resistance. And I won't go any further than that. I won't go further than that. Suffice it to say too much insulin promotes insulin resistance.

Let's talk about defining it too. And then I want to talk about maybe some ways to manage it in regards. Well, I guess maybe take a step back. Are there any, are there any situations where insulin resistance, acutely or chronically, some degree of insulin resistance could be beneficial? So is I guess stated another way, is insulin resistance always pathological or can we have insulin resistance that could be just for acute amount of time or chronically? Can, can that be non pathological and can it potentially even be beneficial in some context? So this is a point of contention and confusion that I always get. I get the question a lot, so I'm deferring to you.

Yeah, yeah. Well, I appreciate it. Yeah. So you and I have heard this debate somewhat, and that's because we're in the low carb kind of ketogenic space in, in a, in a pop culture space, even if not in a scientific realm, although we both are too. But yeah, there's a lot of debate on. I will never forget a few years ago when I first heard people within the Kanakita or, or people who criticize it or even comment on it noting that, well, a ketogenic diet causes physiological insulin resistance. And I was, I thought that was just the oddest thing among many odd things we hear these days. But yes, there are instances in, through human development where we call an insulin resistance physiological rather than pathological. You know, all of the insulin resistance you and I have been discussing up until this point is pathological insulin resistance mostly. But even still within this conversation, some of what I've described applies to physiological insulin resistance. But suffice to say, physiological insulin resistance is a state when the body becomes insulin resistant to serve a purpose. And that purpose is always and invariably to promote growth. Because if you can create an insulin resistant profile or phenotype, all of that insulin and its selective insulin resistance, but remember, it's still insulin sensitive at other, at other tissues, it collectively creates a body that is promoting more anabolism, more growth. And that is, that is utterly essential to the two Ps of physiological insulin resistance, pregnancy and puberty during both of those instances, all accompanied by hyperinsulinemia because there's no such thing as insulin resombination of genetics and dietary influence. Now she's so resistant to her insulin that she can't control her glucose anymore. Now we say she has gestational diabetes. So yeah, a resounding yes, there are instances of physiological insulin resistance, but a low carb or ketogenic state is not one of them.

So in you also discussed in adolescence and during growth that insulin, what is the magnitude, and I meant to look that up. What is the magnitude of elevated insulin in growing kids or I guess in adolescence where hormones are pretty jacked up and you're, you know, you're allocating your more macronutrients to growth and development and it's more of a hormone driven thing where, you know, your body I thought is more sensitive to things like IGF1 and I would think more sensitive to insulin and because that would facilitate. But so do you have through adolescence you showed elevated insulin or you talked about, you know, this just dramatically elevated insulin levels through adolescence. But is that also accompanied by insulin resistance or an increase in insulin sensitivity? Because I associate like an increase in insulin sensitivity to greater muscle growth and development. So maybe kind of disentangle some of that a little bit.

Yeah, yeah. So again, Dom, I don't believe these are incompatible ideas. Remember, because some tissues still respond sensitively to insulin and in, in that case, like for example, bone, to my knowledge, bone does not become insulin resistant in the adolescent. And indeed all that hyperinsulinemia can promote greater bone growth and the hyperinsulinemia can defend protein synthesis. There was actually a study from the 80s finding that insulin, rather than promoting muscle protein synthesis, it appeared that its main mechanism of action was defending or inhibiting proteolysis. So defending muscle protein. But yeah, yeah, so, so some of the tissues are not responding as well. And this can be manifest in EU glycemic hyperinsulinemic clamps within the adolescent body. So we can measure a reduced overall responsiveness to insulin. But again, it's not a global phenomenon. Some tissues respond perfectly well to the insulin as they did before.

So what's the average insulin level in like a 15 or 16 year old relative to, you know, 25 year old?

Yeah, yeah. So I would say in a healthy individual, you know, because it skews. Of course, if we're talking about a very insulin resistant kind of pre diabetic or type 2 diabetic person, then they're just going too high. If we took a healthy individual who had a healthy fat mass, because that's so important to all of this, their insulin levels as a child would be in a healthy range, kind of maybe around 10, and then in that range you just 10 micro units in the span you just mentioned in the kind of mid teens, like right when growth is peaked and peaking and then about to come down. I would expect insulin levels should normally be in the mid to high teens. And then after that they have grown, they're done making fat cells for the most part and then they've reached adulthood, insulin levels will come down and then should settle back down to under 10 so it can almost double during puberty and then it should come back down.

So even their fasting insulin is. Oh, yeah, elevated. So that's really interesting. I heard you talk somewhere about insulin or adipose IR looking at. So do you in your lab, maybe you could describe some of the experiments that you do in your lab and animal model systems and also maybe the, the human study that you're doing and talk about how you. The methodologies you use to measure insulin resistance in the lab.

Yeah, yeah. So this is maybe. Yeah, the Adipo IR score or index is maybe my favorite one of all of them in part because I believe it reflects insulin resistance at its earliest stages. Because I very much have the view that the first tissue to become insulin resistant is likely going to become. Is going to be the fat tissue. Now the truth is depending on the stimulus, other tissues can become insulin resistant either simultaneously or maybe even before. But I think in the run of the mill average individual, it's going to be the fat cell that becomes insulin resistant. And so, so again, one reason I like that test is that it measures the insulin resistance at the fat cell. And then two, it's such an elegant reflection of nutrient biochemistry and the importance of hormones. It's something I kind of.

Enrico, I heard you talk somewhere about insulin or adipose IR looking at. So do you in your lab, maybe you could describe some of the experiments that you do in your lab and animal model systems and also maybe the, the human study that you're doing and talk about how you, the methodologies you use to measure insulin resistance in the lab.

Yeah, yeah. So this is maybe the. Yeah, the Adipo IR score or index is maybe my favorite one of all of them in part because I believe it reflects insulin resistance at its earliest stages. Because I very much have the, the view that tissue to become insulin resistant is likely going to become. Is going to be the fat tissue. Now the truth is, depending on the stimulus, other tissues can become insulin resistant either simultaneously or maybe even before. But I think in the run of the mill average individual, it's going to be the fat cell that becomes insulin resistant. And so again, one reason I Like that test is that it measures the insulin resistance at the fat cell and then two. It's such an elegant reflection of nutrient biochemistry and the importance of hormones. It's something I kind of rail against as a professor, where I have students who have been taught all of this really cool nutrient biochemistry, and yet they don't realize that hormones totally dictate which nutrient pathways turned on or turned off. And so. So the Adipose IR index is a measurement of both fasting insulin and free fatty acids.

And free fatty acids or non esterfied, also termed like. Okay. Because that's a term we use in our, in our teaching. Yeah. N E F A ye typically. Yeah, yeah, yeah. And that's people like non. Is there a commercial test for non esterified fatty acids and the Adipose IR you're talking about? So.

Yep, yep, there is. Yeah. Now, unfortunately, I don't know of an insurance that would ever pay for it. It's not a cheap test either. But we've been doing it in the human study that we've been doing with levels, so. So Levels Health sponsored a study that we were doing in my lab where we were quantifying and are. We're just finishing it. We've been quantifying the endocrine response to macronutrients in, in the context of people on low carb diets. So these were all, all the patients were adhering to a low carb diet and they had the CGM that they could wear for the month of this study provided by LEVELS with the app to kind of for us to monitor them and then very acutely determine any glycemic response to the macronutrients. But we would pull blood every 30 minutes for two hours. And then we're measuring about 15 separate hormones. GLP1, glucagon, insulin, cortisol, epinephrine, a bunch. And generally. And free fatty acids as well. So that we can do this Adipose IR score, the adipo IR score. But in a healthy individual, typically, and this reflects the metabolic flexibility, you know that at any moment we're primarily relying on glucose or primarily relying on fats. Insulin largely dictates which of those fuels is being used. And if a person is insulin sensitive, when insulin goes up, insulin would promote more glucose burning and it would reduce overall fat mobilization and lipolysis. So if insulin is up in a healthy person, free fatty acids should be down because insulin inhibits lipolysis or non esterified fatty acids. They should be down because insulin's inhibiting lipolysis of the fat. Cells. So all of those fats stay bound up as triglycerides within the lipid droplet of the adipocyte. In a healthy person, when they're fasting or generally avoiding starches and sugars, then insulin comes down. And now this would reflect, it would result in an increase in free fatty acids because lipolysis is no longer inhibited and the body is relying more on fats for fuel be in the absence or in this relatively reduced insulin state. So this dynamic should be at play. If insulin's up, free fatty acids down. If insulin's down, free fatty acids up, unless the fat cells are insulin resistant. And then that anti lipolytic effect of insulin doesn't work anymore. Now you have this, this unnatural state where both insulin is high and free fatty acids. And that's what that index measures. And it is relevant. There was a fascinating study in young women with polycystic ovary syndrome who did not meet any obvious clinical metric of insulin resistance. But then the scientists, in other words, they were generally normal body weight. They didn't have, you know, dramatically elevated fasting insulin, or their HOMA score was normal. But when they measured the insulin and the free fatty acids and computed them together, they were significantly higher. That overall formula was significantly higher than in their equally body weight control group. You know, so same body type, same body mass, and yet no PCOS in those women. Their adipose IR score was significantly lower. And I think that's further evidence that this is a problem that starts in the fat cells. Even if it hasn't manifested throughout the rest of the body, once the fat cells become insulin resistant, it's the first domino to fall, and then it's just a matter of time before it starts tipping over into other tissues.

So I've never heard people talk about this test, and it seems like it's extremely relevant and important to understanding insulin resistance. Any temporal relationship, inverse or proportional of triglycerides to insulin. And how in a fasted state, for example, how does that shift triglycerides relative to this test?

Yeah, yeah, so that's. You and I have both seen this. Triglycerides are one of the fastest responders to carbohydrate restriction. So triglycerides will just plummet dramatically. I actually consider triglycerides to be perhaps the single best lipid marker of heart disease. As much as we have focused on LDL for now decades, I, I'm very, I consider that to be very unfortunate because LDL is a terrible predictor of heart attack and heart disease risk. And I think triglycerides is a better marker. Now the question is, well, why not look at triglycerides? This is a bit of a cynical take, Dom, and you'll pardon me for expressing it. I think one of the reasons we don't measure triglycerides more often is because we don't have a drug that can specifically target triglycerides like we do with, say, ldl. But, but even then, reflective of insulin's almost dictatorial ability to control fuel metabolism, nutrient metabolism within the whole body, insulin controls not only the measure of free fatty acids through lipolysis, but insulin also controls lipogenesis, the formation of new fat. And when we look at how insulin stimulates lipogenesis in the liver, promoting the synthesis of triglycerides, and then packaging those triglycerides into the triglyceride rich lipoproteins of VLDL and ldl, you know, the main transporters of triglycerides through the plasma. It's no surprise that insulin will dramatically increase triglycerides. And, and that I believe, is maybe the most relevant variable with regards to heart disease risk, or at least the best predictor. And, and again, no surprise, given that insulin provides such a push for triglyceride synthesis. When insulin starts to come down through fasting and lifestyle interventions, triglycerides will come down very rapidly as well. And some of the extent to which this can happen is truly mind boggling. I saw an exchange between David Unwin, that, you know, kind of English gentleman physician that we all know and love. He was one time jokingly bragging about how he had a patient whose triglyceride levels went from something like 800 in the course of just eight or so weeks down to like 60. And just these fantastic reductions, all because when insulin. But mind you, Dom, this is in the midst of the person possibly eating more fat than they've ever been eating.

Yeah.

You know, it's just because it's not. Triglycerides in the body are not a reflection of, of what fat is being consumed, but rather what fat is being produced. It's what's coming from the liver. And insulin will push that. Insulin will dictate that.

I have a colleague that I'm not going to mention by name, but, but you know, him, I think that has, has been low carb for, you know, about a decade and his triglycerides are stuck right about 160, which is, you know, not astronomically high. And it's, it needs to be considered in context, coming from 6 to 800 down the 160. So the relative but very low carb ketogenic and the triglycerides are persistently at about 160. And I believe insulin very low. So you know, and that seems kind of high to me relative to what I mean, I've gotten some trig measurements, 32 was the lowest, but usually I'm about like 50, something like that, 45 or 50. So in the context of some people, and we had, we did a, levels actually sponsored a clinical trial with us where we've collected a lot of biomarkers and looking at glycemic variability and you know, and absolutely, insulin goes down with a low carb diet and triglycerides trend to go down. But you have some people who looked like other biomarkers of metabolic health and even glycemic control are pretty good. But the triglycerides are hanging some of them, you know, but they tend to be outliers. So I'm thinking that maybe there's some fatty acid oxidation, you know, snip or something associated with, with, you know, just, they don't have as much of a robust. And it's not, you couldn't look at it, you couldn't look at them and, and determine that like you know, the relatively lean individuals but with a, with a triglyceride level that's a little.

Well, I, I wonder. Yeah, yeah, I, I can only speculate here. Part of the clearance of triglycerides is a function of lipoprotein lipase. And I wonder whether some people have, I mean we know that individuals have varying levels of lipoprotein lipase expression and we can somewhat manipulate that through exercise and through dietary changes. But I wonder what, maybe there is a genetic predisposition to have relatively, you know, lower density or lower activity lpl. But yeah, I'm not sure. Or even, even liver damage.

It's interesting you bring that up because, you know, the ketogenic low carb diets tend to drop blood pressure too. And people can get off their blood pressure medication and beta blockers. So epinephrine, norepinephrine, you know, adrenaline tends to enhance hormone sensitive lipase. So the sympathetic nervous system. And I could see like as people get off, as their blood pressure improve and then they drop the beta blockers and you tend to see a corresponding drop in those triglycerides. And conversely, when people get on a beta block, a beta blocker, when they get on one, you can see trig spike up in some people. So it's sort of blocking that sympathetic nervous system drive that therefore enhanced fat oxidation. And you know, back in the day, I remember in college, like the drug ephedrine people would use like veteran, it was like stimulant, very potent fat burner that's a beta agonist. So beta blocker being a beta antagonist. So yeah, it makes me think that maybe some, some drugs, you know, could factor into that. One of the questions I had, does, do all cells, you mentioned bone. Do all cells have insulin receptors?

Yeah. Yeah. So I, I really asked myself that question and tried to find an exception. And I will state, I'll state it this way to be cautious and diplomatic. I have not been able to find a single instance of a cell that does not have an insulin receptor. In other words, everything I've seen shows that literally every cell of the body, including red blood cells, who, you know, don't even have a mitochondria, they don't have glut four of the glucose transporters, but even still they have, of course glute 4 expression doesn't have anything to do with it, but they all have insulin receptors.

Yeah. Okay, great. And the relationship between insulin signaling and IGF1 signaling, I taught this like 10 years ago and I kind of forget now, but I remember going through all the different pathways when I was teaching it and maybe just like a little some comments on the crosstalk between insulin signaling and also IGF1 and.

Right.

That hormone sort of parallels physiological levels of insulin.

Yeah, that. So the last part of the question, Dom, I'm embarrassed to say, I don't know, I can't, off the top of my head, think of what IGF1 levels are. It wouldn't surprise me if IGF1 levels are higher than insulin, at least in certain states. But yeah, you're right in noting that they have a tremendous redundancy or rather ability to cross signal. And that's, and that's even reflected in the name where insulin can bind IGF1 receptors. IGF1 combined inactivate insulin receptors. But that is not to say that they're perfectly aligned because overall with IGF1 stimulation from growth hormone, one of the reasons I believe that growth promotes somewhat of an insulin resistant state is that growth hormone and to a lesser degree, IGF1 will. Will is much more glycogenolytic. It wants to mobilize glucose from the liver and so constantly pushing up glucose to, to use that for fuel for growth. Whereas insulin of course doesn't like the blood being flush with nutrients. It wants to be Storing nutrients whether it's using those nutrients for growth or just, you know, energy. So with IGF1, yeah, the levels are going to be different but they do cross react with regards to their receptor. But, but I think that is such an important point. Dom, not to shift the topic, but I know that you've had talks with people who are very IGF1.

I was leaning towards protein. This is kind of like.

Yeah, yeah, exactly.

I was kind of thinking okay, how should I train? This is an important idea and I used to teach it and I should know it more. I taught all the IGF1 signaling and all the insulin signaling to first year med students a while back. Yeah, but yeah, so, and so this idea then because I've interviewed various people on protein and also protein restriction, the benefits of protein restriction as we age. I'm not getting any younger, you know, I, I collect a lot of data. I could see my lean mass kind of falling, falling over time, not what it used to be when I was in my 20s. And you know, I do what I can to maintain strength, but I do have a pretty high protein. Well, I have increased my protein levels after revisiting some of the literature and, and I would like to get your take on protein level optimization. Not necessarily in the context of a low carb diet for any, any diet. And then you know, which I, I get, we get a lot of questions about plant based proteins and verse animal based proteins. People thinking that there are plant based proteins are healthier, there's less toxins in them. But I think some data points to maybe some heavy metals and processed plant based proteins and things like that. So maybe your, your thoughts on plant based and plant based fats and protein and animal based fat and protein for the listener here.

Yeah, and Dom, allow me, indulge me for just a second. Let me riff on the IGF1 and insulin and how I believe it is relevant to this conversation but overlooked. So a lot of the these individuals who study longevity and generally promote a low protein diet, they, they do so if I may put words in their mouth and I don't, that might not be fair. I believe they do so because it's their view that dietary protein will stimulate MTOR in the body in cells and if MTOR is activated that will inhibit autophagy and then now you're promoting cellular aging. That is certainly the justification for the use of rapamycin, which is a very strong MTOR inhibitor. So that's the idea that it sort of centralizes on that enzyme, the protein in the body in the cell that protein, mtor that if they can, if they can turn down MTOR now, they disinhibit autophagy and then longevity would be promoted. That is of course all based in, in animal studies. There is no. Even they, even these individuals would admit. There's no conclusive human evidence. The best we can come to with humans is kind of correlational which, which, you know, you and I don't have a lot of tolerance for general or.

Just to interject or the idea of, of during a time, restricting feeding window, suppressing an MTOR for a period of time, IGF, IGF 1 signaling an MTOR for a period of time and then having a window of eating where you spike it to regenerate protein. But to avoid the chronic elevation through, you know, multiple feedings of protein during the day or higher levels of protein. Yeah. Has been sort of a point of contention behind people who are protein experts and then other people are advocating certain, certain protein requirements.

Well, my view on it is that if someone is encouraging a restriction of protein because they believed that there's a therapeutic benefit to restricting MTOR activity, if, if again to say that a slightly, another, a different way, if the primary goal is to inhibit MTOR or keep it turned down more often than it's turned on, all the more reason to scrutinize the hormone insulin rather than amino acids. A study done in human in muscle cells found that leucine, you know, the most anabolic mtor stimulating of all the amino acids. It, yes, it did activate mtor, but it did not activate it as much as insulin did. Insulin stimulated MTOR much more dramatically than leucine did. And I think that to me neither of those is inherently bad. But if lowering MTOR is the primary outcome, all the more reason to focus on insulin. Because Dom, we both know it's the average individual who is living every waking moment in a state of elevated insulin. Not constantly elevated, you know, leucine or amino acid. And that's because we wake up in the morning, insulin has come down throughout night the night. We spike it with the starchy sugary breakfast, we do it again with a mid morning snack, again at lunch, again in the afternoon, again at evening, et cetera. Every waking moment is spent in a state of elevated insulin. That is the problem. If, if the worry is that MTOR is too constantly activated, it's not because of dietary protein, because most people don't eat a lot of protein, it's because of the, I would say the starches and sugars elevating the Insulin. And so to ignore insulin if we're focusing on mtor is absolutely laughable. And I think just, well, yeah, I don't know how it's justified. Anyone who believes inhibiting MTOR is good for longevity must somehow reconcile that insulin stimulates MTOR more than dietary protein does. And people are eating a diet that is spiking their insulin much more. And moreover, Dom, if you and I ate a protein load, our amino acids are up and down and generally they're going to be cleared within about an hour. Ish. Right? Or, or so, yeah. Insulin. Depending on what we eat and depending on how insulin sensitive we are, insulin can be elevated for three hours, for even four hours. So multiples longer than amino acids are going to be elevated in response to a protein heavy meal. So anyway, that's my kind of riffing on that, that I think we have to look at insulin before we ever worry about protein. But now with regards to protein quality, yeah. I am unabashedly an advocate of animal proteins simply because of the assurance that you're going to get everything you need. There's no need to worry. Am I getting the right mix of amino acids? The moment you go to plant sourced proteins, you do have to ask, am I getting everything? Now, Stuart Phillips, who is kind of the expert on muscle protein synthesis, he has found that if you just go to the base amino acids from plants and animals and load a human with those, their ability to promote muscle protein synthesis is equal. So there's nothing inherently problematic about the amino acids from a plant. It's just, are you going to get all of the proper mix of amino acids and are you getting it in the kind of cleanest, most absorbable form? And you noted there, it has been confirmed that some plant source protein supplements are very high in metals and they can be elevated, they can have higher levels of oxalates and phytic acids, things molecules that actually inhibit amino acid absorption. So my thoughts on animal protein are that if a person is primarily relying so on plant protein, if a person is primarily relying on plant protein for their dietary protein, then they should make an attempt to consume it the way our ancestors would have, depending on who our ancestors are. But, but like for example, throughout Asia, you know, a culture that has been relying on plant protein in the form of soy for, you know, since time immemorial, I, I or even instances of communities in South America, they would ferment the plant protein. And so I, and, and we know that fermentation enhances absorption in part because it removes some of these Absorption inhibiting molecules like oxalates and phytic acids. So my view on it is if a person's going to be relying on plant protein, then make every attempt to focus on a fermented source of plant protein, whether it is tofu that's fermented, for example, or whether it's a protein supplement from plants that has gone through a process of fermentation, if there is such a thing. In that case, I have very little reservation with it. I still believe animal proteins are ultimately better, but even still, in that case, if it's gone through a fermentation process, I believe it's removed some of these problematic molecules and now you're left with more of what you actually want, which is just the amino acids.

Yeah. For people that are listening to this, that want to be more plant centric in their approach, are there a few plant proteins that you would refer? Because I get this question asked a lot, so it'd be good to direct them to this podcast. Are there, are there, you know, two or three plant based proteins that you would kind of direct people to? I mean, you mentioned the fermented.

Yeah, well, Dom, this is, I, I'll be delicate in answering this. So I'm unaware, I'm unaware of any plant protein supplement that has, that comes from a fermented source. Now I, I say I'm delicate in answering this because I, full disclosure, am a co founder of a meal replacement company and we're, we're actually in the process of bringing to market a fermented source for these very reasons. It's just that there's not been something that's done it quite right. So.

Yeah, anyway, I'm unaware needle be met. Yeah.

So.

Well, going back to animal based proteins, are there any particular sources that you think are ideal that we should include or I guess more importantly, not exclude from our diet? I know there's a lot of discussion.

Around.

Animal saturated fat driving up certain lipid biomarkers like LDL C or APOB and things like that. So maybe, maybe some thoughts on what you feel are animal based proteins that people should be including.

Yeah, well, in fact, it's appropriate that you mentioned fats because my view on animal protein is that I believe it should come with fat. We know that in humans, if you give a human a load of protein, even like among the best, like egg white, and then you measure the amino acid uptake and muscle protein synthesis as a result of that, it will be significant, of course. But if you couple that protein with fat, we absorb the protein better. And we have greater muscle protein synthesis. But part of the reason we absorb it better is through the actions of bile, the bile acids in the stomach, in the intestines. We always look at bile as only being relevant to fatty acid or rather lipid digestion and then subsequent absorption because it will, you know, separate all the fat out.

Yeah.

Emulsify it. Yep. Just to enable all the enzymes to get at the lipid better. But we also, bile acids also accelerate and facilitate proteolytic enzymes in the intestines as well as. This is why when I hear someone who says, well, I can't take whey and you know, whey protein is like maybe the single best protein source for humans, but they'll say, I can't have a whey based shake. It upsets my stomach. And the number of times I have seen this happen is so much, you know, the anecdotes just keep stacking where I will say, well, what if you mix a little bit of fat in there? Either a little bit of, you know, warmed butter or a little bit of cream, then how? And they will try this. And sure enough, their digestion problem is resolved. It's because in nature, I don't think there's an exception to this. I'm unaware of one. In nature, there is no such thing as a protein that does not come with fat. I don't believe that exists. We, in our, in our hubris thinking we know more than, than the gods, you know, to invoke kind of ancient Greece here, we, we've pulled them apart. And that's partly born from our fear of fat. Which touches on a part of your question that I haven't really addressed yet. But it's. We have a fear of fat. And that has led us to take the protein from the fat, dump the fat and only focus on the protein. That is not how nature intended it. We are supposed, those are together for a reason. And that's one of the reasons why one of my dietary pillars is don't fear fat. Fat will come with these best sources of protein. Fat comes with that beef, it comes with those eggs, it comes with that, that, that whey, you know, in that dairy. That's how we should eat it. We will absorb it better. And the muscle protein synthesis response to fat and protein is significantly greater than to that protein alone. Now and then with regards to the fats, there is, this is such a contentious area. Of course, my view on dietary fat is if it comes from an animal or if it comes from a fruit like coconut, avocado, Olive oil, you know, not from the seed, but if it comes from the flesh of a fruit and from an animal. Those are our ancestral fats. Humans have been eating them since time immemorial. That's how we should continue to eat them. And if someone notes that they adopted a diet that was higher in animal fats, but, you know, lower in refined starches and sugars and that their LDL went up a little, I would say, well, what about your triglyceride to HDL ratio? Because that's actually a better predictor of heart disease. If your triglyceride to HDL ratio has gone down, in other words, lower triglycerides, higher hdl, then I actually jokingly tell the person congratulations, because they're probably going to live longer. One of the inconvenient truths of longevity research is that a lot of it shows that the people with the highest LDL levels live the longest. And we know that as LDL gets lower and lower, risk of severe infection skyrockets, risk of blood based cancers goes up. Risk of even Alzheimer's disease goes up. I think that was the Shanghai Longitudinal Study that found that. So if someone has high LDL but a low triglyceride to HDL ratio, I am inclined to give them a high five.

Yeah, okay, thanks. Thanks for sharing that. I know that, yeah, it's definitely a point of contention in the lipid community, often citing the Mendelian randomization trials and, and then apob, which correlates and then lp. But that's sort of, and I think we do not, at this point in time, there's not enough data to, on people who are following low carb diets, it's kind of like a new thing. And, but I could say from the context of the world of epilepsy, where people are put on a ketogenic diet for decades, there does not appear to be an atherogenic risk. And I think, I mean you're talking about people that are 80, 90% fat. So I think that's an important, important aspect. So with protein sources, you'd recommend whey. And what about beef? I mean, you think beef versus chicken versus other, other plant, other animal based protein sources. So there's sort of some pushback on, on red meat, you know, being a, a risk factor for things like colon cancer or other things. But I get with the heme iron associated with, with red meat and I have, I eat a lot of red meat, but I backed off a little bit and kind of transition more occasionally chicken, but I have turkey. I usually don't eat that much chicken, but we have turkey. Turkey's been around for like hundreds of years, people eating it, whereas chicken, not, not so much. And not that I do it for that reason. I just like turkey.

Yeah, no, no. In fact, that I think you've touched on something that I have almost laughed at sometimes, which is our obsession with chicken because a hundred years ago we didn't eat chicken. You know, chicken was a fantastic. Christopher. Christopher Ramsden at the NIH has, has done his best to kind of quantify what is the consumption, what are the eating patterns with regards to meat and the fats that come from those meats. And chicken was this minuscule part of the meat that we used to eat and now it has become the single most commonly consumed meat, all because it's so low fat. We used to keep our chickens around for their eggs and then it was this kind of fear of fat that drove us to eat more chicken meat. But you're right, turkeys, we never kept turkeys around for the eggs. We ate them.

So forever. Yeah, we got wild turkeys running around and I gravitate. I just like the taste of turkey better too.

Yeah. Well, I bet it's because it's a little fattier, but that's certainly how I feel.

The dark meat. Yeah, but you don't hear a lot about people eating turkey. It's like when I, you know, during Thanksgiving I just buy a bunch of huge turkeys and putting in the freezer, you know. Yeah, we cook the whole bird, you know, with the, with the bones and everything. Whereas just chicken is just like, I mean, you know, there's a big push to switch from beef to chicken. And I mean we go to chicken like fairs and things like that and it's like the, the, the amount of hybridization and odd forms of. I mean it's just like a whole breeding experiment in progress, you know, to, to build bigger breasted birds and, and birds that could barely walk. And I mean we see it, you know, in our farming community here. But, but yeah, I'm not chicken, but I think people recognize beef.

Yeah. Well, that my view is any meat is going to be good and generally you're going to get all the amino acids you want. But I actually, I put chicken at the bottom that I would put Any meat I believe is a superior source of ultimate and like more, more complete nutrition is, is going to be better than chicken. So. Which, which is frustrating because of course chicken's so easy to like as a dad, my kids want chicken more than anything. And I'm always trying to like insert some kind of beef, especially for my girls. I want them to get that iron. But even still, I would stack any meat as being better than chicken. But I'm also fine with chicken. I would just say maybe make sure that it's not too lean because again, fat helps the digestion of the protein.

Yeah, yeah, that's, you know, I don't, I teach the whole GI section and really have to revisit it the, the bile acids to facilitate. Yeah. Protein digestion, things like that. I mean I usually talk about fat being packaged in the chylomicrons and actually how some MCT fats can go directly to the hepatic portal vein and actually.

Yep.

To the liver. I know we're kind of coming up on time, but I do have a, just a few questions. I mean it could be, you know, we talked a lot about insulin resistance and we touched upon, you know, ways to reverse it. But what are your thoughts on just, you know, people that are on a carbohydrate based diet, sort of the idea how they should go about carbohydrate management and, and then time restricted feeding. Your thoughts on that? Like I tend to eat, I do the opposite of what you're supposed to do. I kind of, some days I undereat during the day and overeat, grossly overeat at night. And if I don't do that I lose weight. So I know, you know, eating less at night or shifting more is supposed to be better by all metrics and if you eat at night you're more likely to gain weight. But I actually for me that's a positive things because if I don't eat at night, my weight slips and I start to lose actually muscle. So some thoughts on that and then just general like not carbohydrate management but just weight loss isn't. I mean we teach, what we teach is basically insulin resistance is purely a function of, you know, body weight and it's all calories in, calories out. So I know it's like a lot of questions but you know, you know, top, you know, just kind of 30,000 foot view on carb management, on just, you know, body weight and then time restricted feeding.

Yeah, yeah, so I'll start with that last one first. So with time restricted feeding, you're right to note that in the human studies, people who have an earlier eating window appear to be more metabolically, it's more metabolically beneficial. So eating, you know, for example, breakfast and lunch appears to be better than Lunch and dinner. Now, as much as like you, I admit that and I acknowledge that research and there's a lot of nuance to that that I found fascinating. It's also just very difficult. I have a family and I don't want to be sitting around dinner with my family like last night. We're all eating and if I'm just sitting there looking at my wife and kids while they're eating because I'm fasting through dinner, no, forget about it. You know, I'm, I'm a family man and eating dinner is a very important social moment. So I'm not going to do that. But what I have found is Dom, when I would try to do time restricted feeding similar to you, probably because I didn't manage it well, but I would get hungry and I would eat a lot in that later evening dinner and then for the next several hours, and it would have a dramatic impact on my sleep. I have found that the single most important variable that will determine whether I sleep well or not is how full I am when I go to bed. More than anything else, more than light exposure, more than any kind of activity. If I go to bed on a really full stomach, I will be hot, my heart, my HRV will be low, I will not sleep well and I wake up and I'm miserable the next day. And so if what I've tried to do to help offset that, I still fast through breakfast. I just have never really, since I've been an adult, at least I'm not really hungry in the morning. It's just easy for me to kind of sip on some tea or something else through the morning. But I try to get a full lunch. I like to try to stack it at my lunch and then a more modest dinner. And I have found that that helps so much. It helps control cravings and it allows me to kind of go to bed on a relatively emptier stomach or more digested. So I eat a big lunch. So it's nothing through breakfast, big lunch, a more modest dinner, and then I just can. And then I just am done at dinner and it's much easier for me to be done at dinner and not snack into the evening when I've had a bigger lunch. So that, that's my view, my personal application with time restricted feeding and then with regards to weight loss, insofar as I have the parrot of the view that insulin resistance starts in the fat cells, I believe that should be a primary point of addressing insulin resistance back to the fat cells. And basically it's when the fat cell becomes too hypertrophic. You know, someone can be gaining fat mass through two different mechanisms. It can either be that the number of fat cells is relatively static, but the size of the fat cell is getting ever larger hypertrophy. Or in some people, largely due to genetic tendency to go one way or the other. But this is a minority of people. There are individuals who, even throughout adulthood, have the genetic potential to continue to make new fat cells. And that's getting fat through a process called hyperplasia. And in that case, the fat cells stay very modestly, but they're, of course, just much more abundant. Well, that person paradoxically has an almost limitless potential to store fat. They, these are the people who go, who get fat through hyperplasia, who can become fantastically obese. 500 pounds, 600 pounds, and, and they don't become insulin resistant. And their insulin levels stay quite modest. However, on the other side, where the majority of people fall, their number of fat cells is set. So if the fat cells are storing more and more energy in them due to an abundance of energy and elevated insulin, that's important, though those two signals are both essential to storing, to promoting fat storage. You need abundant energy and elevated insulin. In the absence of one or the other, they cannot get fat. You can eat all the energy in the world, and if insulin is down, you cannot store it as fat. You'll be wasting it as ketones. Your metabolic rate will be higher if it gets too high, then you'll even be peeing out glucose. You cannot store energy as fat if insulin is low. But of course, if insulin's high, it must have energy to store. And so there has to be sufficient calories. So there, those two become the strategy for shrinking a fat cell. So it is the hypertrophic fat cell that becomes insulin resistant in order to prevent further growth. That's why free fatty acids start to go up, up. It's the hypertrophic fat cell that becomes pro inflammatory in order to correct hypoxia and stimulate new capillary growth to those hypertrophic fat cells. So some of those inflammatory cytokines will promote new vascular growth. Some are just promoting inflammation and stimulating insulin resistance. So the strategy has to be to take that big hypertrophic fat cell and shrink it. And you can shrink it through two different ways. Low energy and low insulin. Or, or low insulin. They're not the same, although one, you know, they tend to bleed into each other. But someone can look at their weight loss journey and think, I gotta shrink my fat cells. And they have two steps they can take. They can say I can either start with lowering my energy or I can start with lowering my insulin. I believe one's better than the other. If someone takes their first weight loss journey or fat cell shrinking step and it's with a low energy approach, usually they're going to start fighting hunger. If energy is coming down and they're still insulin resistant, then as they just start cutting back energy, then the availability of energy in the blood will start to drop a little bit because insulin's still high enough in them and it's going to be hard to shrink the fat cell. They're going to get hungrier and hungrier and usually hunger wins. So rather than take a low energy approach for the first step, my recommendation is to shrink fat cells, Take the low insulin step. And the low insulin step is kind of what we've been alluding to, which is, you know, control your carbohydrates. You know, don't, don't get starches and sugars that come from bags and boxes with barcodes. Focus on whole fruits and vegetables. You eat them, don't drink them, prioritize protein, don't fear fat, those. But if you're hungry, eat. There is no, there is no hunger that has to come into this. And so it becomes much more sustainable. And as insulin is down, free lipolysis is activated and the person's mobilizing fat more, they're burning fat more, they're converting it to ketones which they use for energy. And they are just dumping from the body in the form of in the breath and in the urine. The ketones are energetic molecules that are just wasted. They don't have to be burned or stored in that case. So it just makes it easier.

That brings up a good point. So you know how many calories are wasted in the context? I know that. I think I looked into this one time and I think it was, I forget the amount of ketones that were collected in a 24 hour urine. Collected collection in a fasted subject. It was not insignificant like it was, I think in some suggest it was. Well it wasn't like huge, but it was maybe like in larger subjects up to 200 calories or 250.

Yeah, but even Dom is relevant. There was a fascinating study in young women with polycystic ovary syndrome who did not meet any obvious clinical metric of insulin resistance. But then the scientists, in other words they were even, that's just urine. And then you think about the ketones that aren't being captured in the Breath right. Like that is another so altogether Dom, when you. This is why I say a ketogenic state is is a metabolic advantage or generally normal body weight they didn't have, you know, dramatically that this is just conveniently ignored because you are both wasting energy in the form of ketone excretion through breath and urine which can be to the tune of a few hundred calories potentially. And overall metabolic rate is elevated. David Ludwig, even Kevin hall have found that David Ludwig in particular found that a metabolic rate can be up by almost 300 calories a day. So when we combine these not only the higher metabolic rate and the wasting of energetic molecules in the form of ketone excretion, the elevated fasting insulin or their HOMA score was normal. But we have several hundred calories now of a wiggle room where if when they measured the insulin and the free fatty acids and computed them together they were significantly higher, that overall formula was significantly higher. If we're eating these calories, this is how someone could still be losing weight and not higher than in their I equally have to go hungry because they can eat as much as they want. If insulin's down, the body's just in a. Is so inclined to be in a state of fat burning. Suffice it to say the fat cells.

Yeah, I challenge that they could eat as much as they one but I would because I do think calories matter. But what I think. What were you.

So do I your main. I do too.

Okay. I think your main point is when you eat that way you tend to auto regulate just kind of into the model that David Ludwig has developed. When you eat low carb or to the extreme of ketogenic, that body weight.

Control group, you know, so same body type, same body mass and yet no PCOS in those women, their adipose IR score was significantly lower. And I think that's further evidence that this is a problem that starts in the fat cells.

Even if it hasn't produces or regulates various counter regulatory mechanisms that play a huge role in appetite suppression, appetite moderation. One could argue that a very low carb diet is hypo palatable and maybe also hypersatiating too. So you know, I know if you put a lot of, you know, sugary stuff in front of me, especially at nighttime, I'm going to overeat it to the point that I'm full and even I remember, you know, even being, you know, satiated but still hungry, you know, in that context of when I was.

Eating that way and manifested throughout the rest of the body once the fat cells become insulin resistant. It's the first domino to fall.

And then I think that's a big point. But then I guess when, you know, you did talk about you when your insulin is low, you can't gain weight, you can't put on fat. And I was gonna stop you there, but then I thought about type 1 diabetes. So, I mean, that's a pathological condition where you have people eating massive amounts of they're very hypercaloric, but they're still losing weight. Presumably they're losing adipose tissue, but maybe they're also insulin's kind of anabolic, maybe more catabolic, but probably losing some muscle too. But you have a scenario nonetheless of what you just brought up where insulin is low and yet you're getting surplus amount of calories and still losing weight now. So they're very hypercaloric, but they're still losing weight. Presumably they're losing adipose tissue, but maybe they're also insulin's kind of anabolic, maybe more catabolic, but probably losing some muscle too. But you have a scenario nonetheless of what you just brought up. So, and I think you know a less much where insulin is low and yet you're getting surplus amount of calories and still losing weight.

It's just a matter of time before it starts tipping over into other tissues.

Very interesting. So I've never heard people talk about this test and it seems like it's extremely relevant and important to understanding insulin resistance. Any temporal relationship, inverse or proportional of triglycerides to. To insulin. So, and how in a fasted state, for example, how does that shift triglycerides relative to the less extreme version of that, you know, I'm talking about the type 1 diabetic is that you're mimicking some of that naturally mimicking some of that in a ketogenic diet or a very low carb diet state. So, and I think you know, a less, much less state where you're leveraging that low, less extreme version of that. You know, I'm talking about the type 1 diabetic is that you're mimicking some of that naturally mimicking some of that in a ketogenic diet or a very low carb diet, low insulin facilitating fat oxidation, but also that's. And in state where you're leveraging that low some degree of metabolic enhancement, but you're coupling that with. With appetite regulations, low insulin facilitating fat oxidation, but also that's. And, you know, some degree of metabolic enhancement, but you're coupling that. So I think that's the real benefit. And I think it's multifactorial with, with appetite regulation. This test.

Yeah. Yeah. So that's. You and I have both seen this. Triglycerides are one of the.

So I think that's the real benefit.

And I think it's multifactorial fastest responders to carbohydrate restriction. So triglycerides will just plummet dramatically. I actually consider triglycerides to be perhaps the single best lipid marker of heart disease as much as we have focused. Yeah, well, that's why I say if someone is controlling carbs and prioritizing protein and not being afraid of fat, they can, when I say they can eat as much as they want, I mean there's no need to be counting calories. There's no need to be hungry if someone's hungry. Yeah, well, that's why I say if someone is controlling carbs and prioritizing protein and not being afraid of fat, they can, when I say they can eat as much as they want, I mean there's no need to be counting calories, there's no need to be hungry. If someone's hungry, so much better in, in a generally a carbohydrate restricted state that there's just. They're disinclined to eat in excess.

I think that's true in like 90% of where their, their reason for eating. So there. It's almost like they need like a.

Nutritional psychist on LDL for now decades. I, I'm very, I consider that to be very unfortunate because LDL is a terrible predictor of heart attack and heart disease risk. And I think triglycerides is a better marker. Now the question is, well, why not look at triglycerides?

This is a bit of a psychiatrist, right? You know, they eat for different reasons. So they're eating even when they're not hungry to fulfill a certain need. But I think the important aspect, you know, the important component is that when you do eliminate those starchy foods, sugary foods, then you restore your metabolism and your eating behaviors to where it should be. And then you kind of auto regulate your own caloric consumption. But then you have subjects, you know that I and I fielded a lot of emails where people are like, I've been on a ketogenic diet. It didn't work for me, I didn't lose any weight. And you kind of ask them if you probe a little bit more of.

A cynical take Dom and you'll pardon me for expressing it. I think one of the reasons we don't measure triglycerides more often is because we don't have a drug that can specifically target triglycerides like we do with say, ldl. But, but even then reflective of insulin's almost dictatorial ability to control and ask.

Them what they're eating. You know, they're eating like nut butters and you know, macadamia and, and sort of these. So if they gravitated more towards like a carnivore diet or just, you know, eliminated, you know, nut butters and nuts and maybe some dairy too, then you'd probably start to get better. And. But many people are of the opinion that if you just eat ketogenic or low carb, then you're automatically going to lose weight and maintain your weight, which is the case for the majority of people. But there's definitely people who can. It's very easy to get amount an increased, you know, surplus calories on a ketogenic diet.

Well said.

Yeah, thank you so much for taking time out of your busy day from the lab. The research, important research you're doing in the lab to share your insight and.

Fuel metabolism, nutrient metabolism within the whole body. Insulin controls not only the measure of free fatty acids through lipolysis, but insulin.

Also knowledge on a topic that is central and probably the most important topic.

In metabolic health also controls lipogenesis, the formation of new fat. And when we look at how insulin stimulates lipogenesis in the liver, promoting the.

Synthesis of trig, which is insulin resistance and insulin signaling. And yeah, yeah, we look forward to hopefully having you as a speaker again at Metabolic Health Summit and maybe doing a part two on this podcast too, because I only touched on about a quarter of my questions I had for.

You, but yeah, well, I'd love it, Dom. I have such a, such a respect for everything you've contributed to the field of metabolism and ketone metabolism in particular. And I loved every minute of it. This was great. Thanks so much.

Thanks, Ben. Thanks for coming on. Thanks for tuning in to this episode of the Metabolic Link. If you're interested in this podcast and it was relevant content for you, please share, subscribe, like and leave a comment.

We appreciate you listening glycerides and then packaging those triglycerides into the triglyceride rich lipoproteins of VLDL and ldl, you know, the main transporters of triglycerides through the plasma. It's no surprise that insulin will dramatically increase triglycerides and and that I believe is maybe the most relevant variable with regards to heart disease risk or at least the best predictor. And, and again, no surprise given that insulin provides such a push for triglyceride synthesis. When insulin starts to come down through fasting and lifestyle interventions, triglycerides will come down very rapidly as well. And, and some of the extent to which this can happen is truly mind boggling. I saw an exchange between David Unwin, that, you know, kind of English gentleman physician that we all know and love. He was one time jokingly bragging about how he had a patient whose triglyceri levels went from something like 800 in the course of just eight or so weeks down to like 60. Just these fantastic reductions. All because when insulin. But mind you, Dom, this is in the midst of the person possibly eating more fat than they've ever been eating.

Yeah.

You know, it's just because it's not. Triglycerides in the body are not a reflection of, of what fat is being consumed, but rather what fat is being produced. It's what's coming from the liver and insulin will push that. Insulin will dictate that.

I have a colleague that I'm not going to mention by name, but you know him, I think that has been low carb for, you know, about a decade. And his triglycerides are stuck right about 160, which is, you know, not astronomically high. And it's, it needs to be considered in context, coming from 6 to 800 down the 160. So the relative but very low carb ketogenic and the triglycerides are persistently at about 160. And I believe insulin.