Ben Bikman, PhD | Rethinking Metabolic Health: Insulin, Ketones, & What Comes Next | Metabolic Link

Welcome to The Metabolic Link, a medical and science-focused podcast that explores the common thread of metabolism in health and disease. This is where science meets society. Welcome to a very special episode of The Metabolic Link. I'm your host, Victoria Field, and this is our 100th episode. And over the course of this podcast, you know, we've explored one central idea. Again and again and again that metabolism is not simply about weight or blood sugar, right? It's this common thread connecting nearly every aspect of human health and disease, from cardiovascular and brain health to inflammation, aging, cancer, and longevity. So to mark this milestone, we're bringing back one of the most influential voices in the metabolic health field and one of the most popular guests we've ever had on this podcast, Dr. Ben Bikman. Dr. Bikman is a professor of cell biology and physiology at Brigham Young University, where his lab investigates the molecular mechanisms underlying metabolic disease, with a particular focus on insulin, ketones, mitochondrial function, and nutrient metabolism. He earned his PhD in bioenergetics and completed a postdoctoral fellowship at Duke National University in Singapore, studying metabolic disorders. And he's also the author of Why We Get Sick, How Not to Get Sick, and the forthcoming book The Carb Crisis, as well as the founder of Insulin IQ and the host of The Metabolic Classroom, where he has helped bring the science of insulin resistance and metabolic health to audiences around the world. And for this 100th episode, I am thrilled to be joined by my co-host, Dr. Dominic D'Agostino, for a conversation that goes far beyond the basics. Together, we are looking into how our understanding of insulin resistance has evolved, why elevated insulin may reveal metabolic dysfunction long before glucose does, and what new research is teaching us about ceramides, fatty liver, adipose tissue, and brain energy metabolism. We also explore some of the most exciting and nuanced areas of ketone science, including mitochondrial uncoupling, the very different biological roles of D- and L-beta-hydroxybutyrate, and potential concerns surrounding certain ketone precursors, and emerging research into ketones and cardiovascular function. Dr. Bikman also explains why metabolic health can differ so dramatically between men and women, what changes during menopause, and why he has actually reconsidered some of his earlier concerns about GLP-1 medications while offering a very different framework for how these drugs might be used. This conversation reflects exactly why we created The Metabolic Link, to connect mechanisms with medicine, challenge assumptions, and follow the science wherever it might lead. Here is our 100th episode with Dr. Ben Bikman and my co-host, Dr. Dominic D'Agostino. I hope you enjoy.

Ben, welcome back to The Metabolic Link. It is so wonderful to have you here again.

Oh, I'm glad to be back. Thanks, guys.

Great to see you, Ben.

Great to see you. Um, you know, Dom, really great to have you back here co-hosting with me. I know we usually kind of do these things separately, so it's wonderful to have you here too.

Great to be here.

Yeah, and Ben, we're especially excited about this conversation because it is, you know, our 100th episode. It feels really like fitting to us to really mark that milestone with you because past episodes have resonated so much with our audience. I mean, there have been some of the most watched and shared episodes that we've ever put out there into the world. So clearly your work and the way you so eloquently educate the public is resonating with so many people, and you're really pushing the metabolic health conversation forward. So we're thrilled to have you back. And I will say, today we want to kind of like zoom out, not just revisit insulin resistance, but really where the field is now. You know, over the last decade, what do you think has really changed most about the metabolic health conversation? And maybe what are we not quite getting right?

Yeah, thanks. Well, I'm glad, very, very glad to be back. Thanks for the kind words. Nothing thrills a professor more than to hear that people like the message he's teaching, because my students at my own university sure sometimes don't. They just wanna know if it's gonna be on the test. So what I've noticed the past 10 years, I have, I have a lot of confidence actually with some of the things I've seen. It's been interesting for me to evaluate what, what I have done and, and what I wanna continue to do. When I, in fact, about 10 years ago was right about the time I first got tenure and this, this first step of promotion in the academic pathway. And I had at that moment thought to myself, I have interesting ideas that I think are valuable. And as much as my career demands that I put these ideas into a peer-reviewed paper, I also was extremely aware of the fact that no one will ever read those papers. And no one's life will ever be improved because of what I published in that paper. If the idea only stays in a peer-reviewed manuscript, it almost— the peer-reviewed manuscript is almost where an idea goes to die. As much as we prize that accomplishment in academia, in the real world, it's like Monopoly money. It doesn't mean anything. And so at that time, I thought, I want to try to find ways to share ideas with just people., and that was the beginning of my efforts into, well, I guess social media or lay audiences. And at the time it was, no one's talking about insulin resistance. So as much as our conversation now is gonna move beyond that, I think it's appropriate for me to bring that back just for this brief answer where in the 10 years where I thought I was sort of the lone man in the wilderness talking about insulin resistance, I'm dumbfounded at how big that message has become, including just recently, a few months ago, Dr. Marty Makary, with his, in his role in the FDA, was interviewed and he was asked a similar question being, you know, what's the main pro health problem? And he said insulin resistance. I couldn't believe it. So on that, in that regard, I think the, the overall health awareness of— maybe to say that another way, I think the appreciation of metabolic health as an underlying driver of chronic disease has exploded in a way that I never imagined it would. And then where I think the second part of your question, where I think we still aren't doing great or where there's still room for improvement, as much as we're talking more about metabolic health, I still worry that we're not actually measuring it that the conventional lab tests continue to focus on— not only do they have an, uh, I would say ridiculously heavy focus on lipid, uh, lipid markers, which I consider to be weaker predictors of cardiovascular disease and related problems, but our, our metabolic perspective clinically is still extremely glucose-centric. And I think that one-time measurement of glucose, I was gonna say fasted glucose, but nowadays they don't even do that. They just measure their A1C, which I think has additional concerns or limitations with it. But we still have a very glucose-centric paradigm of metabolic health, even insulin resistance, that, which is discouraging because we have to shift that to have an insulin-centric view to have a— to not only detect these problems at their earliest, but also to treat them better.

Yeah, absolutely. Well, I have to say, you've been driving a massive conversation through all of your channels around education with metabolic health and insulin resistance. So I'm not really surprised the conversation has kind of exploded. Dom, too. I mean, I'd love to bring you in here early. Dom, you and Ben have really both helped shape the way people are thinking about metabolism, insulin, ketones, all of those things. So Dom, I'm gonna toss it over here to you and ask, what do you feel, I guess, is most important about having Ben back for this extra special 100th episode conversation considering where we're at?

Yeah, well, a lot of topics that, Ben, you just kind of touched on really. And I think even teaching medical students and just general physiology, I'd like to clarify to our listeners maybe a topic of debate, which you touched on, is whether insulin resistance is best understood as a glucose problem, an insulin problem, a lipid problem, or an energy storage problem, or some combination of that, and how you would frame that today.

Yeah, yeah, yeah, that's a, that's a, that's a great question. On the, on the, let me just sort of start on the last one. So the energy storage problem, a lot of— I've been interested in a lot of people invoking that the ectopic lipid deposition kind of idea where as a tissue accumulates fat, that then drives the insulin resistance. I, I, that's actually, I think, a pretty easy one to toss aside or to, to, to say is not a driver because of some, a phenomenon known as the athlete's paradox. Dr., I think Brett Goodpasture at the University of Pittsburgh, probably 30 years ago or so, I think was the first to document this phenomenon where they would pull muscle biopsies from overweight type 2 diabetics and, and they found that the muscle was very loaded with stored triglycerides. So very fatty muscle. And that, that kind of, I think it was one of the first lines of evidence that gave birth to this idea that lipid accumulation or fat accumulation in tissues driving the dysfunction and insulin resistance included. And yet then they found that if you pull a muscle biopsy from an endurance-trained athlete, these exquisitely insulin-sensitive individuals, they have just as much fat in their muscle as, as this other group did. And so I don't think, I don't think energy per se is a driver of insulin resistance. Now having said that, Dom, you mentioned lipid. I think that gets us closer where a lot of my, in fact, my entire fellowship days was spent studying this type of lipid called ceramides, which is in the class of sphingolipid, which is a distinct family. Like the triglycerides that are the main storage form of fat is in the glycerolipid kind of line of, of this genealogy of lipids. And then the, the sphingolipids are a separate one, and ceramides is kind of the backbone of all of them. Where anytime we could induce ceramide accumulation in a cell, it became insulin resistant, where the ceramides are directly preventing or messing up some of the, the activation events in that insulin signaling cascade, just to kinda keep it at a level for the audience. I know with you guys, we could get deeper, but, well, I think that's sufficient. So that's a separate matter where ceramides will accumulate in a tissue in response to a handful of, of noxious stimuli. Now they're built on a backbone of, of, of palmitate, the, the main saturated fat. And so that has definitely given the anti-saturated fat crowd some, some ammo in their arsenal to attack dietary fat, specifically saturated fat. And yet it's not that clear cut. You have to have the stimulus that, if you will, tells the cell to turn palmitate into ceramides. And that can be— that stimuli like inflammation. We published one of our biggest papers at the time was finding that lipopolysaccharide or an LPS or any kind of inflammatory signal, TNF-alpha did the same. Anytime you increase the inflammatory signaling in the cell, it would start to increase its biosynthesis of ceramides, and then the ceramides drive the insulin resistance. Cortisol acts through the same pathway, that, that main stress hormone. It increases ceramides, which drives insulin resistance, and then too much insulin itself will drive ceramide biosynthesis as well. So there's, there is something to be said for lipids driving insulin resistance, but it's important for people to know that Dr. Jeff Volek found that the circulating levels of saturated fat in a person's blood were more respond— were more a response of how much carbs the person was eating rather than how much saturated fat they were eating. So it's very, very important that people keep those, these two ideas distinct. Yes, we can say that palmitate, the main saturated fat, is a substrate or a building block for ceramides,, but that does not mean eating more saturated fat is, is driving that. In, in fact, again, he found the opposite, that he could step down carbs and step up fat, even more saturated fat, and the actual amount of saturated fat circulating was down. Now I know you guys are very familiar with that study.

Mm-hmm.

And, and Dom, so that addresses two of the points you'd mentioned. I'm now struggling to remember kind of one of the other causes you'd, you'd said.

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No, I think you hit on it. The, the insulin, you know, the energy storage problem, and it is, you know, a surplus amount of calories, is the surplus calories, right? Is that— that is like, you know, the, the thing that I think gets debated, or, you know, what is, uh, unambiguously, you know, not sort of quantified or, uh, discussed, you know. And then there's, you know, the ectopic fat in the, in the muscle that you mentioned. And I think maybe Gerald Shulman talks about that a lot, and, and Dr. Lustig talks about the liver fat being— the ectopic fat in the liver being the driver, and there's a debate there. But, uh, but yeah, I think ectopic fat— but I mean, you take it another step further, it's like the, the, the fat but also the ceramides, uh, you know, that, that's kind of like the missing link that nobody's really talking about. Yeah.

And even when it comes to that fat storage, Dom, you know, you're, you're bringing in a broader topic. Victoria, I'm sorry to hijack this, promise I'll be done in just a sec.

You can always hijack the conversation, Ben.

Yeah, well, it, it starts to touch on just the very nature of fat storage itself and in the liver. Dom, you mentioned the liver. What a perfect example. And this is maybe on my mind because I've just been working on a talk I'm giving at a liver meeting in Philadelphia later this year to talk about the origins of fatty liver disease. And, and most of the fat that is stored in the liver is actually fat that's coming from our fat tissue, where the fat tissue— there was a tracer study published that found that 60, 59% of the fat in the liver is coming from adipose tissue. But why doesn't the liver just burn it and turn it into ketones? It's because it's happening in the midst of elevated insulin. And so when anyone wants to really appreciate the nuances of where the body is storing fat and why it's storing as much as it is, you really can't— yes, energy is a part of it. Like, the calorie has to act as the fuel for that fat storage, but there must be the signal because in another, if you have the liver getting a lot of fatty acids from the fat, if insulin is low, well, it's just, it's burning them and, and converting a lot of it into ketones. That's exactly what's happening during fasting or a low-carb diet. And then on the other hand, if you have insulin resistance and fat cells that have undergone too much hypertrophy, which are now insulin resistant and no longer responding to insulin's inhibitory signal. So you have this, metabolic perfect storm where you have both elevated insulin and elevated free fatty acids coming from the fat. Well, now the liver is getting all that fat and has nothing to do but store it because insulin won't let it do anything else.

Well, Ben, I, I wanna bring up the fact that, you know, you and Dom had a great episode together already on the podcast. Of course, that conversation was fantastic, really dug into the weeds around insulin resistance, but I'd love to like bring us back to kind of an overview of what recent work from your lab or sort of the broader field has most changed or sharpened your thinking about insulin resistance, ketones, and/or metabolic disease?

Yeah, well, with, with you guys here, it'd be, it'd be a shame not to bring up some of the ketone work. And, and Victoria, I appreciate you mentioning even DOMS at the very beginning of our conversation. Dom's, his view and his evolution. I would say another part of, to answer that first question again, what surprised me is just how much ketones have exploded as well, where they've become what was once, you know, like literally considered a metabolic garbage or something to avoid at all costs is now much more warmly being embraced and rightly so. So, where what we've done, some of the coolest work, in fact, I still maintain the coolest paper my lab has ever published was a paper where we looked at the effects of beta-hydroxybutyrate on mitochondrial uncoupling in fat tissue. Now, the reason it's so cool is that with my students, we went through like all 3 levels of biomedical models. We started with adipocytes growing in a Petri dish., and we found that when they were, um, fed some beta-hydroxybutyrate, their mitochondrial respiration skyrocketed, but it did not happen with a concomitant increase in ATP production. And so in other words, we found that this— for the lay audience, we found that the mitochondria were just sort of spinning their wheels. It's like you have the engine in your car, you're in park, but you're pressing the gas. So you're burning a lot of fuel, but you're not really getting anything out of it except just some heat. Well, that's a wonderful way to just waste fuel. And if you have a lot of fat tissue, you wanna waste fuel. So we found that in the fat cells. Then we went to animals where we were giving the mice BHB in their water, you know, sweetened a little bit and sweet matched in the other, in the control group. And once again, when we took their subcutaneous and visceral fat depots, there was a significant increase in their mitochondrial respiration, more uncoupling. And then we went one step further where we actually pulled adipose belly fat biopsies from humans that were in ketosis and weren't. And just as a brief aside, that had never been measured. I hope I don't get in trouble with BYU for mentioning this. We'd never done that before. So we optimized this technique and I was the first one. So my own students were numbing my belly with lidocaine and then going in with a Bergstrom needle, like with another professor, kind of the help who had done muscle biopsies before. And it was me laying on a table and them digging into my belly to get out belly fat. So we, we kind of perfected the technique on me as guinea pig. But we found that in the humans, the response was actually the highest that we had seen in any of the other models. It was higher than what we found in the rodents, higher than what we found in the adipocytes in culture, that when humans were in ketosis with their blood BHB being, of course, substantially elevated, their mitochondrial respiration increased by— it was about 130% increase. So, you know, 2, 2.5 times increase. And again, very little change in ATP. So a huge shift in mitochondrial uncoupling. And now that study's a few years old now, but it's still in my mind is one of the coolest things we've ever done in my lab, going all the way from bottom to the top. And then more recently, actually somewhat— not somewhat, very inspired by a the paper that Dom and his team published looking at 1,3-butanediol and this BHB precursor finding some liver harm. And then I collaborated with Dom to do a follow-up. A lot of what my lab focuses on is mitochondrial bioenergetics. And we found that this, this alcohol precursor of BHB, the 1,3-butanediol, it was really compromising the ability of complex II in the electron transport system to work that we found at first in these rodents. We found that their overall mitochondrial respiration was significantly blunted. And then as we teased out which specific complex appeared to be mediating that reduction, it really focused on— we really found that it was complex II that was compromised. Whereas with BHB, well, and at the same time we found that the liver, we had the animals staged with a kind of a timing protocol and we found that there was this like dose response, not dose response, a temporal response where the 1,3-butandiol was substantially reducing the amount of ATP in the liver. And, and then it would slowly start to come back up after that oral dose.. But with the BHB, of course, it was the exact opposite. We found mitochondrial respiration was very tight, it was good, and then the ATP production was boosted, which makes sense. If this is a substrate that's energetic, it should be giving the tissue ATP in the, in the liver in particular. But the 1,3-butanediol did not. Now that does have real relevance because there are, of course, opportunities for people to purchase what they think is a ketone product, and yes, it can make BHB, but there is a cost that I think people should be aware of.

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Yeah, yeah, that's a good point. And yeah, you really— you replicated some of the work that we did, or mechanistically you kind of took it to another level by looking at and explaining, uh, what chronic moderate to higher dose 1,3-butanediol, uh, or 1,3-butanediol-associated esters, which, uh, it does take a large market share of the ketone exogenous ketone space. So I think people need to be aware of that. But 1,3-butanediol is a, is a diol, which means it's a di-alcohol. And it, when it gets metabolized, it robs the liver of NAD+. And what you demonstrated in your lab is that, yeah, it, it de-energizes the liver in a way that decreases ATP. And that's what happens, as you probably know, with alcoholic ketoacidosis. So the alcohol, you know, basically just depletes the liver energetic stores and kind of cripples the liver's capacity for gluconeogenesis. So glucose drops and, and, you know, can trigger alcoholic ketoacidosis. And maybe that explains the 1,3-butanediol lowering effect of glucose too. You're kind of de-energizing the liver, but done prolonged or chronically, that can— what you also showed was an increase in inflammatory markers, which is maybe, uh, if someone is consuming this in a protracted time frame, could be a consequence. But you showed it within a week, I think. Yeah, right, within that paper. Yeah.

Yeah, it was pretty— it was rapid. Yeah, it was fascinating study.

Yeah. Also like to mention that you also looked at the effects of D and L-BHB, and you had a great podcast on your platform about BHB signaling, and you talked about beta-hydroxybutyrate, and L-BHB is sort of ketolysis resistant. So when you consume both, the LBHB stays in circulation 4 or 5 times longer and maybe and functioning at the level of the receptor, epigenetic, inflammasome. So, you know, we think about DBHB can be metabolized quickly for ATP, and I think you showed that, but LBHB too, but LBHB just stays around longer and imparts that signaling effect. So maybe talk a little bit about, you know, that study and maybe the implications there. You do take, I would like to direct people 'cause you take a 1-hour deep dive into BHB signaling on your platform.

That's—

well, I want to learn more, they could go to that too.

Yeah. Well, I'm loath to invoke these ideas in the midst of you, Dom, because you really are the authority here. But yeah, our work, and again, Dom, very heavily inspired by what you've been doing. But yeah, you set that question up really well where people are generally, I think, familiar with the idea that there are two forms of BHB in the body, and D really does seem to be the energy form. That the body's gonna readily, you know, use for, for fuel. And then L capable. In fact, we are— L appears to be maybe more of a signaling molecule, but we're actually working right now on a study. There was a, a group that had done from, from the guys at Ketone Labs. They had given LBHB and in a tracer study found that LBHB was generating CO2. So it is, it was getting burned up for fuel. And then, we are now trying to optimize a technique to measure the degree to which the mitochondria can use L as a fuel and then detect some changes in mitochondrial respiration from that. So, we're further kind of trying to tease that out. With the idea of L being signaling, Dom, you please correct me if I'm wrong. I think the tissue that we've seen has the most L in it is the heart, right? That the heart seems to be either 30%. Yeah. A lot.

Yeah.

That's right.

So, and there was this on that. Yeah.

In fact, that fascinating pig paper. Now, people may think, why invoke the pig if you're talking about cardiovascular system? It's, well, the, the pig cardiovascular system is shockingly similar to human. And they've found that the, with LBHB, even like a very physiological amount of L, it substantially increased cardiac output, um, where, uh, um, but not because the heart was beating harder or faster. So the heart was able to release, to move more blood because the afterload was significantly down. In other words, the pressure that the heart had to beat into, you know, as, as the, the heart is moving its blood into the aorta and through the body, everything was just dilated more.. And that's the work. In fact, we just submitted this for publication, uh, 2 days ago, work looking at L, um, and D, but with a, uh, the results were much more favorable for L, but looking just in an endothelial cell culture, we were using human aortic endothelial cells and we found that L incubation of these endothelial cells, the, which are the cells that line the blood vessel, um, L elicited a huge increase we, uh, in, in nitric oxide production and, and made them in, but it did so in the midst of like an injury model with angiotensin. So we would kind of challenge the endothelial cell and then explore the degree to which LBHB is capable of rescuing that nitric oxide signal to help induce, uh, what in vivo in the body would be a vasodilating signal. So th— th— that, That is something I find very interesting. Victoria, back to kind of how you framed the question about the direction. I think the part of what excites me is this new appreciation for— as much as ketones were considered garbage and now they're not, L was considered garbage even longer and now it's not.

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Yeah, that's super interesting, Ben. Thanks for sharing that. Uh, I have— I mean, you know, that card increasing cardiac output, and you had framed it a decrease in peripheral vascular resistance essentially is what hap— is happening. And we didn't— we have some data we haven't published. Adenosine goes up. There's some speculation about the glycocalyx. But I think you— what you just described, I guess it's under review now, you know, is another mechanism I had not really thought about much, which is nitric oxide, which is, uh, maybe eNOS. It's activating eNOS or iNOS or something. So that is super interesting, and I haven't really considered that as much as other factors. So thanks for sharing that. Super, super interesting.

Yeah, hopefully it gets published soon.

Yeah, we'll definitely be following along for that and certainly post that in the show, uh, show description too, um, once that happens. So, um, Ben, though, I want to kind of shift gears a little bit and talk about something that's obviously fascinating, especially with Dom here too, uh, the brain, right? We often talk about insulin resistance in the context of like type 2 diabetes, obesity, fatty liver, but the brain is obviously highly energy demanding. So Dom, given your, you know, work on the brain metabolism side, therapeutic ketosis side, love your perspective too. I love the fact that you guys are here together to kind of dig into this. Um, but from the ketone side, I guess, what do you think clinicians often maybe miss when they're talking about brain energy metabolism, and kind of discuss the relationship maybe between insulin resistance and brain energy metabolism in, say, neurodegenerative disease.

Um, yeah, I could— I can start just with the insulin side because of course everyone needs to remember I'm, I'm the insulin guy, and Dom's, I think, the ketone guy, if either of us has a label. But But they are related, of course, where in the human body or in any animal, insulin sort of has a chokehold over ketogenesis. So with regards to insulin resistance in the brain, there is an interesting overlap with these two concepts because there's a particular tragedy that happens in the insulin-resistant body where not only are some of the cells of the brain, indeed some of the cells involved in cognition and memory, insulin responsive, well insulin dependent with their glucose uptake. But the, the very milieu metabolically that's driving the insulin resistance is also depriving them of, of, of the ketones. So to say all that another way and maybe less confusing, the brain can become insulin resistant, which means these cells are deficient in their ability to pull in glucose. And Victoria, as you noted, the brain has a high energy demand. It needs to be fueled. It stands to reason that if it cannot get its fuel, then its function will start to sputter, just like an engine that's running on empty in, in the car analogy again. So the brain becomes insulin resistant, which is depriving it of its glucose. And so the brain would maybe say, if we assign some personality to it, okay, all right, I can't use the glucose very well, so I'm just gonna use ketones. Ah, but the very, as I said, metabolic milieu that's driving the insulin resistance is also preventing the liver from making those ketones. And that of course is elevated insulin. There is no such thing of, as insulin resistance without elevated insulin, whether the elevated insulin is driving it, whether it's so cause or whether it's a consequence of the insulin resistance. In the body, if there's insulin resistance, insulin is elevated. That's back to earlier in our conversation where I said we need to be measuring insulin. Cuz again, whether it's cause or consequence, it'll be a sign that the body is an insulin-resistant state. And so the, the brain is insulin-resistant, can't get enough glucose. It wants to then rely on ketones, which it can use very readily if the ketones are available., but that high insulin is preventing the liver from making the ketones. It's inhibiting ketogenesis so thoroughly. So when I teach this idea, I, I joke with my students that it's, it's kind of a metabolic version of the, of an old poem, written by Samuel Taylor Coleridge called The Rime of the Ancient Mariner. Very briefly, this is the tragedy of a sailor who has, has been shipwrecked and he's afloat on the sea and he's surrounded by all this water, and yet he's dying of dehydration because he can't drink it. And that's like the brain, where you can imagine the body may be hyperglycemic, the body is swimming in a sea of glucose, but the brain can't get it. And, and so the life raft, or the, the fresh water in this case, would be the ketone, but the, the, the insulin is preventing the body from providing that fuel for the brain.

I love that. I love that kind of analogy.

Well, I know that poem because I had to memorize it in 6th grade when I was sent to the principal's office. True story.

That worked well, right? Now it's a great example to be used in education. I love that. Thank you for that kind of breakdown. Dom, I'd love to hear your thoughts. Obviously, you know, I know that the two of you, a lot of this work kind of overlaps, but brain-specific, if you speak, um, just what Don— or, uh, what Ben here has been saying.

Yeah, a couple themes kind of come to mind. And, you know, we talk about, uh, ketones are typically produced in the con— you know, in the context of suppressed insulin or suppressed insulin signaling. That stimulates— you know, insulin needs to be suppressed to open the floodgates of fat oxidation, fatty acid oxidation, especially in the liver. Beta oxidation of the fat is kind of driven by glycogen depletion And so a lot of, a lot of people ask the question then, are ketones sort of only clinically useful when someone is in a strict state of nutritional ketosis? And this gets a lot of discussion and a lot of play that people don't realize that there's the ketogenic diet and exogenous ketone supplementation. And I think there is a lot of overlap there, but also there are two distinct thing. So, but a lot of, uh, there's some antagonism towards, you know, the use of exogenous ketones because it— and asking if it can occur in the context of, uh, a carbohydrate-based diet. So we want to, you know, get some— I have some thoughts, and I know you have some thoughts.

Oh, I think so. In fact, yeah, in fact, I think it's— as much as I think we are all advocates of a low-carb diet and even ketogenic, I also, I think we also can acknowledge that there are just, most people don't wanna do that. Or even if they want to, they, they, they just can't because of their habits, dare I say addictions, or their culture, their food culture or whatever. In, in these instances, in fact, I would even say even in someone who, like, I generally adhere to a low carb diet and yet I still find a benefit to exogenous ketones. Because there's just gonna be a variability in my own lifestyle, in, in my own diet that, where, where, like, for example, I will eat carbs for dinner with my family, but I also want to go to bed in a state of ketosis for improved sleep. And so that's, and, and at the same time, I, when I'm gonna work out, I know I'm gonna have a little more energy demand than normal. So I think that there is absolutely a place for exogenous ketones. In fact, not only in a low-carb diet, but most especially in a high-carb diet. In fact, those I suggest are the people who would benefit the most because that's a person who should want the benefits of the ketones, whether it's brain energetics, whether it's the anti-inflammatory principles, whether it's maybe the improvements in blood pressure, you know, to be determined. But I think everyone benefits from ketones, and that then means, uh, that there's all the more reason to supplement with exogenous ketones if you are on a higher-carb diet.

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Yeah, and I think even in the context of a low-carb diet that you many, even maybe me included, uh, unless I'm incorporating like MCTs into the diet too, uh, that maybe the healthiest version of a, of a very low-carb diet or low-carb diet is not necessarily ketogenic. And outside of the context of its clinical scenario for epilepsy and other things where nutritional ketosis can be very beneficial, like the default diet is a low-carb diet that is probably not ketogenic because, uh, or sustainably ketogenic for the large majority. And I love very low-carb diets, and it's even hard for me to keep that ketone level elevated. So just, you know, dosing a few times a day can elevate ketones into that therapeutic, you know, what would indicate therapeutic ketosis as by a clinician. Um, and so you're getting the benefits of, of ketones, you know, and you're also getting the benefit of maybe what is an optimal low-carb diet, a little bit mixed with some vegetables, a couple pieces of fruit here and there. And yeah, that's, that's a question that comes up so much that, you know, and even in the last couple conversations I had is that, you know, are you getting any benefit at all by taking ketones outside of the context of the— and I think it's— I'm glad that you mentioned a higher-carb diet. Someone on a high-carb diet may benefit from ketones because that's— I mean, that's what they do.

Like, I think they'd benefit the most.

Yeah, yeah, I think that's a good point.

Yeah, but it can be a powerful tool even for those of us obviously on a ketogenic diet. I have my MCT, a little bit of exogenous ketones here before interviews and things like that. It's amazing what it does for the brain as you go into stuff like this. So, um, thank you guys for that and sharing your thoughts around that. I want to kind of shift gears a little bit, um, in talking about sort of insulin resistance. People often kind of talk about it in the same way that it sort of presents in the same way for everybody, right? But, sex hormones, as you know, fat distribution, pregnancy, menopause, things I've— well, pregnancy specifically and postpartum, I've recently gone through. And, it's wild to kind of, when you're so in tune with your body, to kind of see what happens there in that regard. But, life stage really can affect all of this. So, how should clinicians, I think, think, or patients think about sex differences in insulin resistance and metabolic health? This is obviously a topic of conversation that I think is starting to get more airtime, especially at the menopause side of things. But, to hear from your perspective, Ben. Yeah. You know what that looks like? Yeah.

Yeah.

Well, that's an— that's a nice opportunity to bring back in what Dom had mentioned earlier about energy overload, where one of the quirks of human physiology is that women are uniformly fatter than their male counterparts and yet more insulin sensitive at any given body fat and even at substantially higher body fat levels. And so that once again kind of challenges the idea that it's just all about energy being stored. And so a lot of that touches that a lot of the differences between the sexes actually comes back to, well, one difference is how the bodies store fat and the, and estradiol or the, the pro, the, the typical female sex hormones, the estrogens, they will determine that a woman will store her fat in a, in a healthier way, which is not only location, but also the, the propensity to make new fat cells. And, and that's the, so, so the human body can store fat through two different mechanisms. One is hypertrophy, which I alluded to earlier, where you could, so imagine two, two bodies and they both gained 10 pounds of fat. One person gained that fat through hypertrophy. So the number of fat cells stayed the same, but the size of each fat cell got bigger. On the other hand, this person who also gained 10 pounds of fat gained that primarily through hyperplasia, where the fat cells had the ability to, to multiply. And now there are more fat cells, but each fat cell is very modest in its dimensions, its size. So it's more but smaller fat cells, offset in another individual with fewer but larger fat cells. Hypertrophy is an unhealthy way to get fat. Because as the fat cell gets larger and larger, there are two, kind of self-survival, but ultimately pathogenic changes that happen. So as the cell's getting larger and larger, the first thing is what I already had mentioned, which is that it becomes insulin resistant. If you look at it from the perspective of the fat cell, it's probably happening because the fat cell, can, can only, a cell can only get so large and keep its cell membrane intact.. And I am unaware of any cell in the body that is capable of the degree of expansion that a fat cell can undergo, where it can, it, it can go tens of times larger volumetrically as it expands. And so as the fat cell gets larger and larger, it starts to become, uh, resistant to insulin's growth signal, essentially telling insulin, insulin, you want me to keep growing, but I can't, I'm already too big. And so it starts leaking out the fats as much as insulin continues to try to force more in. So that's one pathological change. And then the other one is that as the fat cell gets larger and larger, it starts to get pushed too far from capillaries where cells need to be within just a few micrometers of a capillary for normal substrate and oxygen and gas exchange. But the hypertrophy of the fat cells is pushing them too far. And a response to that, as the fat cell is suffocating, if you will, or becoming hypoxic to use the the, the technical term, it starts to release, uh, a catalog of pro-inflammatory cytokines, these, these pro-inflammatory proteins, because some of those proteins are capable of diffusing through the interstitium, getting to the capillary, and inducing the growth of new little capillaries to go out to that suffocating fat cell. So you now have these two things. The fat cell becomes insulin resistant to prevent further growth, it becomes pro-inflammatory to try to correct its hypoxia. But now the rest of the body is left to pick up, to, to suffer the damage, the consequences of this. There's more fatty acids in the midst of elevated insulin driving ectopic fat storage. Then there's more pro-inflammatory cytokines driving inflammation, which among the, its many outcomes, uh, it will also drive insulin resistance as inflammation is one of the primary causes. So all of this to bring it back to the difference between the sexes. I sometimes joke with my students that a premenopausal woman is a metabolic superhero, that she's, she's generally, if, if not immune, she's very protected against the effects of body fat, even, even a lot of body fat. Now, that's not to say women can't develop consequences from body fat if it goes too far, but she's gonna have a lot more wiggle room than her male counterparts will have. And, and that is almost entirely driven by estrogens. Now, that brings us, of course, to the logical evolution in her life cycle, in her lifetime, of moving into menopause, where now she, she's lost that. So, so her, her ovaries, with the, with, as the eggs are no longer there, the, they, they stop, the ovaries stop being the main site of hormone production., and then she ends up having this kind of interesting dynamic between her adrenal glands, the adrenal cortex, and then her fat tissue, which— so it's these two tissues working together to try to create a manageable level of estrogens, but never being as high as they were before. Now she is subject to the consequences of that excess body fat. Maybe not quite still to the degree of her male counterpart, but it's, it's now much higher than it was before. Because she's not going to continue to store her fat through hyperplasia, because that's heavily driven by estrogens. And she's also not going to continue to store her fat as much in her subcutaneous fat space, that the fat that we can pinch and jiggle. She's going to have relatively more going into her visceral adipose tissue, like her man— male counterpart has had his most of his life, where men will selectively have more body fat in the visceral space. But even visceral fat is commonly misunderstood as just being uniformly evil. Even there, it's probably and mostly because it only will grow through hypertrophy. And this is logical where that visceral space, that space tucked within our abdomen, that's a really busy space, you know, around the kidneys, the intestines, the liver, everything. There's a lot there. And they each need their space. And so imagine the consequences if that fat tissue depot was capable of undergoing hyperplasia. And so visceral fat only expands through hypertrophy because, pardon me for saying it this way, it knows it cannot grow in an unlimited degree, otherwise it's physically crushing all of those other tissues. It'd be so incompatible with survival. So it, it limits its growth by only allowing hypertrophic growth, which means if visceral adipose is higher, it's much more leaking its fatty acids and it's much more pro-inflammatory. So in all of those things, ladies are generally more protected from until the estrogens start to go away. But one other comment with regards to the menopausal woman and then the brain. I'm sure you guys are familiar with this paper.

If I'm—

it was a few years ago, and if I recall it correctly, most of it was mechanistic in preclinical animal models. And then I think they had some human correlational evidence to find that in the, in the menopausal brain, the— as, as she has just— there's more insulin resistance in her body. There was such a demand for ketones that the brain was metabolizing its own white matter. Dom, do you remember this paper? Do you guys, Victoria, do you remember this one?

Yeah.

It was metabolizing its own white matter. So, so the menopausal brain was eating itself, its own substance in order to convert those fats into ketones. And so back to the earlier part of the conversation, I think a menopausal woman who has a, not a higher risk of Alzheimer's disease, like that's one of the few chronic diseases that influence— that women are gonna suffer from uniformly more than men. It's, it's Alzheimer's and, and other brain-related brain disorders. Her brain is so desperate for ketones that it's eating itself in order to make those ketones. So of all the people I think who should be taking exogenous ketone supplements, it ought to be a more mature gal.

My goodness.

Yeah. Well, thank you for that breakdown and that little tip there. So we don't have to, yeah, go through our brain eating itself. Ketones could be a good tool. That's—

yeah, do you guys remember that paper though? I, I hope I didn't brutalize the explanation of it. I think I got it right.

We'll find it and link it for sure. Go ahead.

Yeah, I think that was the implication too. And I think, uh, another paper maybe similar just showed glucose hypometabolism as a prominent feature, you know, in premenopause and menopause. And that's like a, uh, pretty, you know, almost a hallmark. Yeah, brain energy characteristic is glucose hypometabolism, that, uh, hormonal shift. So, yeah, I mean, I guess estrogen supplementation may help that, but yeah. Right.

Yeah, there's a lot of tools in the toolbox that thankfully are now being talked about a little bit more. And ketones too, as you mentioned, could be one of those. So, that's great to know. Thank you for that, Ben. Dom, I know we have some— we have limited time with you, Ben, and we could spend hours asking you questions. But, we have some great, maybe some rapid-fire unique questions over here that Dom and I have talked about that we'd love to kind of dig into here as we go about the episode.

Yeah, we have a bunch, and I think, I think we'd be remiss if we didn't talk about GLP-1s. And just— and you've covered that really well on your platform, Ben, would direct people there on— but there's a kind of a new kid on the block, uh, Kygra-Sema, uh, Kygra-Linatide, and Retruditide. Uh, and, you know, both suggest that the next decade may sort of belong to a multi-hormone pharmacology. So, uh, so what piece of like human physiology have we misunderstood about, you know, the GLP-1s and sort of the— this combined dual agonist or triple agonist? Uh, and just like to get your thoughts on that. And it's, you know, an emerging topic over the last— but it's super relevant to the field, metabolic health.

It is, yeah, it's very relevant. And I, I want to just confess here as much as I can. I, I think I was wrong. Now, I don't mean for this confession to be an admission of a free-for-all with these drugs, and I'll share kind of my nuanced thoughts on that. But my, my largest concern with these drugs was the apparent loss of fat-free mass, you know, including muscle and bone. And yet it appears with further analysis that a lot of what is called what was the free fat, uh, or the fat-free mass loss was actually the liver that a lot of these DEXA scans they use will— it cannot distinguish between a liver that is filled with fat or just liver. And so if you have a big fatty liver that actually is in your lean mass pool as it's measured on a DEXA. And so apparently a lot of the loss of, of the fat-free mass or the lean mass wasn't so lean at all. It was the liver getting smaller because it was— had much less fat. So my own view on the drugs, um, has evolved where at first it was just direct opposition. I thought this was just gonna be a mess. I, I, I think I was wrong that I, I think there's absolutely a place for these drugs. And, and Dom, you mentioned, I can barely keep my finger on the pulse of these new drugs as they're coming out. There's so— seems like there's so many. I, I do think it's, an improvement though. I think that when it was semaglutide alone, I think that was failing to acknowledge that you would not have just GLP-1 activation in the absence of these other signals like GIP or even glucagon with, with the retatrutide and, and amylin. Now, I think, I think amylin is the addition of one of the other ones you mentioned, Dom. But yeah, these are all they're all complementary hormones. And so, I think it's to be applauded that they're put together. I think they're better together. I hate to use this word. I think there's a bit of synergy with them together. So, the sum is greater than just what the parts. Now, having said all of that, what still worries me is almost a philosophical view, which is a person who is taking these and just thinking this is a weight loss drug, I think that they're doomed to fail, which is that, uh, they're not gonna learn to actually change their habits. So I am an enormous advocate of the idea that these are not weight loss drugs, they're carbohydrate addiction recovery drugs.

Mm-hmm.

That these are drugs that appear to change the, the reward systems in the brain. And I'm not a brain guy, But, but this is why you see people who are using these drugs to help people with alcohol addiction. And there was a paper just published looking at cocaine addiction recession.

Yeah.

Wow.

With the use of these drugs. So I think that to me reveals the best use case even in, in diabe— in obesity and diabetes. It's that hopefully they've been told you need to control your carbs. I maintain that is the single best step for someone to lose weight. Don't worry about counting your calories. Yes, energy matters, of course, but you're going to find that the body is going to lose weight more readily. You'd have that metabolic advantage as your insulin comes down and your ketones go up, including the uncoupling that I talked about earlier. You'll just have a higher metabolic rate. But they need to— so some people can be given that information and make those changes. Some people can be given that information and come back to you a week later, say, I just can't do it. I cannot stop eating these carbs. Uh, there is such a thing as an addiction to these things and that to these foods. That's where I think these drugs are best used. I think they should be given this as a prescription and told, this is gonna help you learn how to control your carbohydrate cravings and follow a low-carb diet.

Mm-hmm.

And it doesn't have to be ketogenic low, but just lower carb, cut out these processed refined carbs and sugars. And that's the key. And then that gives them an off-ramp as well, because then maybe in a year or so, the clinician can say, hey, let's see how well these habits are sticking, and let's kind of dose you down a little bit on these GLP-1 drugs and see if, if you're able to— if maybe your brain's kind of been, you know, rewired, if you will, and that you are now able to look at these former temptations that was once an undeniable temptation, but now you can, you can deny yourself that, that indulgence and, and follow the, that smart carb diet more effectively. So anyway, as much as there are new forms of these drugs coming out, I still really maintain that the best use is to help people learn how to eat differently and specifically control their carbs. In so doing, they're able to get off the drug someday because I do not think a person should be on them indefinitely. Not that I'm claiming some long-term long-term negative consequence, it's just not prudent for anyone. I don't think anyone should ever have to be on a drug forever.

Yeah, well said. I think, you know, GLPs as a tool for behavioral change, which you kind of summed up there. And, and also, I really appreciate you kind of, uh, maybe, or back course correcting or backtracking, maybe admitting you were wrong— sign of a good scientist— that, you know, as the data came out, uh, that these drugs are powerful, have many benefits. But I totally agree, they should be used as a tool for behavioral change and viewed that way.

So yeah, that's great points. Thank you guys.

And, um, well, Victoria, we got through one question.

I know.

Well, we have so many more for you and I'm, I'm thrilled that you're gonna be coming on our medical education platform in August. Um, for that purpose, we have so many questions and this gives our audience an, an opportunity to ask you them live. So check out the link below because we're gonna have, um, Dr. Ben Bikman on our platform where you can ask him your questions and the thousands of others that Dom and I have too. Be sure to check that out. It will be in August. Real quick before we go, after 100 episodes of The Metabolic Link, you know, we constantly come back to that theme, that same idea of metabolism is this common thread in health and disease. It ties it all together, right? So, for you, what do you think, I guess, the next 100 episodes in field need to explore so we can direct the course of our entire podcast?

Go ahead. Yeah, yeah, yeah. Well, I, I'm hoping that there is a lot more to be said as we start to further understand and characterize the differences between D-BHB and L-BHB. In fact, if I'm excited about any aspect of, uh, of future ketone research, it's L, uh, specifically. And then, and then hopefully we're about to— we just had this week a paper published looking at the use of low-dose GLP-1 drugs when combined with coaching on low-carb ketogenic diets. And the results were just phenomenal. People were able to stay at very low doses and have substantially greater fat loss than when it was just the drug, um, alone. Now, that was not a randomized trial. We're publishing it as a case series. But I think, so part of what we've touched on, further elucidating or characterizing these, ketones. And then second, seeing how ketones complement a lot, uh, the use of these GLP-1 drugs, whether it's for, you know, helping preserve muscle mass, if that is a concern, ketones can help with that. Whether it's just helping them find a better way to use the drug at lower doses and then have an off-ramp.

Yeah, that's a great thought. Yeah.

Great insight.

Thank you so much again, Ben, for joining us and for everything you're contributing to this field. You're making such a massive difference, impact, and we so appreciate all the work that you do. And we'll continue to, uh, follow it along and are thrilled again to have you on our platform again.

My pleasure. Thank you.

And Dom, thank you as always. And thank you all for being here for this 100th episode. Um, together we can make a difference. So thanks, guys. We'll see you soon.

Thank you so much for watching this episode of The Metabolic Link, our 100th episode. And thank you for helping us make that happen. It wouldn't be possible without you, the listener, the watcher on YouTube. We so appreciate you. Thank you for helping us share the science on metabolic health and therapy. And I am thrilled to share that we're actually going to continue the conversation with Dr. Ben Bikman. He's coming on our medical education platform for a live Q&A session where you can ask your own questions to him. I know I have a bunch more, but head on over to membership.metabolicinitiative.com /bikman. That's membership.metabolicinitiative.com/bikman. I'll include it in the show notes there. The link will be below if you want to register. It's on August 19th at 9:00 AM PT, 12:00 PM ET. You won't want to miss it. Members can also access exclusive private episodes of the podcast that have never been released publicly, along with the addition of tons of medical education for the lay public, healthcare professionals, all dedicated to metabolic health and therapy. Head on over, register so you can ask him your question. This conversation really, I think, captured what the podcast is all about though. Challenging assumptions, following emerging science, and exploring the metabolic connections that shape human health.

Thank you to Ben.

Thank you to my co-host Dom, and thank you all for helping us reach this amazing milestone of our 100th episode. Together, I truly believe we're making a difference. We'll see you next time on The Metabolic Link.