Symptoms & Diseases Tied to INSULIN RESISTANCE & Metabolic Health | Dr. Ben Bikman & Dr. Casey Means

Part of the hope of the book and my message in general, is that when we acknowledge a metabolic underpinning to so many of these chronic disorders, then there is in fact a ray of hope there. Because if there is a metabolic origin, then there can be a metabolic solution.

Hi everyone, this is Dr. Casey Means, co founder and Chief Medical Officer of Levels. I am so thrilled to introduce Dr. Ben Bickman today, who is our guest on a whole new level. Dr. Ben Bickman is at the forefront of research and thought leadership on insulin resistance as a foundational pillar of much of the chronic illnesses we see today in the Western world. He earned a PhD in bioenergetics at East Carolina University and then was a postdoctoral fellow at the Duke National University of Singapore Medical School, where he focused on metabolic disorders and insulin resistance. He's now a professor at Brigham Young University and the director of its Diabetes Research Lab, working to understand insulin as a regulator of human metabolism and and insulin's relevance in chronic disease. He is the author of the incredible book why We Get Sick, the Tour de force on why insulin resistance is relevant to all aspects of our health and what we can do to prevent and reverse it. He produces immense amounts of incredible education and content on social media and via podcasts and is doing incredible service to the world by bringing insulin resistance to the mainstream. Welcome to a whole New level, Dr. Bickman.

Hey Casey, thanks so much for the invitation. I'm delighted to be able to chat with you about all things metabolic.

I can't wait. So I want to jump in with something that's kind of personal to me, which is the relationship between insulin resistance and some ent your nose and throat conditions. In why We Get Sick, you take the reader through just this amazing journey through really all organ systems in the body and how insulin resistance can affect so many different systems. And it really is a testament to how impactful high insulin levels are on all parts of the body. And one that you touch on a little bit in the book is conditions of the ear, nose and throat. And I trained as an ear, nose and throat surgeon. And I can honestly say that I don't think the word insulin resistance was ever uttered in an ENT clinic in my more than five years in that world. So I'd love to just touch a little bit on some of the things you mentioned in the book about this relationship that I do not think many people are aware of. And you specifically highlight hearing loss, ear ringing and vertigo, which are super common conditions in the ENT clinic. So can you just talk us through a Little bit about what we know about, about this relationship.

Yeah, yeah. So there is, we do know some. Although I would say that the evidence, the mechanistic proof connecting insulin resistance to these ear issues in particular, is based somewhat on speculation, with relatively fewer proven connections. But nevertheless, there are some pretty well validated mechanisms. And in short, it's problems of energy use or energy production and blood flow and insulin resistance will impact both of those. In particular, the cells of the ear that would be involved in hearing that you would know more about than me, given your training. They are high metabolic rate cells. They need, they have a high demand for energy and part of that demand is met by glucose. Well, as the body's becoming insulin resistant, then those cells become less capable of utilizing glucose for energy and the cell is forced to rely on other forms of energy. Now, normally this wouldn't be a problem. Most cells, including these of interest, could just shift over to say, fat oxidation and start burning fat for fuel. However, the elevated insulin that comes with insulin resistance tends to preclude fat burning. It wants to try to force a cell to rely more heavily on glucose use rather than fat use. And the, the net effect of this with regards to the bioenergetics of the cell is that it starts producing much higher levels of reactive oxygen species as you're forcing these cells to rely much more heavily on the mitochondria, which of course is the site of fat burning, if you will, or fat use. So we have this much higher rate of production of reactive oxygen species which can activate apoptosis and the death of some of those relevant cells of hearing. And we have the insulin resistance compromising blood flow. This is a phenomenon that happens to varying degrees throughout the entire body, but it's particularly relevant in these cells of very high metabolic rates. They have a high demand for oxygen and the nutrients that the blood is bringing to them. And as the vessels, as the blood vessels in the body, by extension through multiple mechanisms, starts to become insulin resistant, what should have been dilated, well flowing blood vessels become very constricted flow compromised vessels. And as the volume of the blood vessels is narrowing, the, then the pressure starts to go up. We have higher blood pressure that can of course, induce some damage to the fine capillaries in the ear tissue, but also it just means less blood flow. And once again we have a higher tendency for the cells to undergo apoptosis, or basically we start killing off the cells that we need for hearing.

It's so fascinating because it's really this same theme that you see all over the body that I think you talk about, you know, really beautifully in the book, which is the impact on insulin resistance, the impact of insulin resistance on, of course, mitochondrial oxidative stress, but also in endothelial function, how our blood vessels actually work. When you can't get blood to a tissue, it's not going to work properly. And in really small vessel areas like the cochlea, which is, you know, the site of our hearing, our balance, you know, these. These small perturbations in blood flow can have a massive mass, massive impact. And when you're getting ischemic, you know, cell death events from lack of blood flow in these tissues, you can. It makes sense logically that that would lead to something like early hearing loss. And in the book, you talk about how we see that if a person is insulin resistant, inner ear function is significantly compromised. And the greater the degree of insulin resistance, the greater difficulty in hearing at particular tones. And it's just, I think in many ways it's really empowering to know this message because having seen so many patients in the ENT clinic that are dealing with hearing loss, it can be really a huge change in quality of life when you can't communicate properly. And to know that there's actually, and I think the vast majority of people think this is something to do with aging, like this is just part of old age. But to know that there's possibly a modifiable factor to this, not just stay away from loudspeakers at concerts, but actually that what you're putting in your mouth can have an impact on this over time. I think can be really empowering to people, because when you're just told, this is the way it is, you're getting older, you know, there's not much we can do there.

Oh, I totally agree with that. And that, of course, is relevant to so many aspects, even beyond hearing. One of the things I really rail against is this idea that there is a hopelessness to a decline in health. Some things will decline, but we don't have to just go quietly into all of this. And hearing, I think, is one of them, that too often, as you noted, people just shrug their shoulders and get ready for their hearing aid. But part of the hope of the book, and my message in general, is that when we acknowledge a metabolic underpinning to so many of these chronic disorders, then there is in fact, a ray of hope there. Because if there is a metabolic origin, then there can be a metabolic solution, because we can intimately, exquisitely and rapidly start to change metabolic health. And. And thus the Consequences of poor metabolic health are also, to a very large degree, changeable.

It's. It's amazing. And. And, you know, another symptom that I think we see all the time in the ENT clinic that can sometimes be totally debilitating for people is ear ringing, otherwise known as tinnitus. And tinnitus can happen, you know, on its own in the absence of some other symptoms. It's often associated with hearing loss. It also can be associated with. With some disorders like Meniere's disease, both of which you talk about in the book. And I'm just curious if you can kind of lay out what are some of the information that we know, at least in terms of how these are associated, how insulin resistance is associated to these conditions.

Yeah, this was another one of those areas when I was preparing the book. In fact, it's kind of funny, Casey. This was actually the last part of the book that I put together, because I hadn't known about it until I started. I had a conversation with a physician, and he noted to me that he finds this. He noted. This was a local guy that I know. He mentioned to me this high correlation between earringing and in prediabetes and diabetes in his patients. And so I just almost on a whim, started to dig into it, and I was dumbfounded by what I found. But I have to, of course, give a shout out to the people who are publishing these papers, in particular physicians who are noting this. But the correlation between insulin resistance and tinnitus is remarkably high where it's. It's almost. I mean, it's very uncommon for someone to have tinnitus and not have some underlying metabolic problem, namely insulin resistance. This is an area where there's, again, not too much confirmed, but part of the connection between the two is thought to be a result of insulin changing the membrane potential, the nerve conductance, or the conductance, the. The sending of a signal along neurons within the ear, within the cochle, cochlea, and in particular, insulin is known to affect the sodium potassium ATP channel, or in that. That's a little granular for. For most of the listeners. But basically, when we're sending a signal along a cell like a neuron, we're sending that signal, by nature of us, rapidly shifting ions, you know, positive and negatively charged molecules, almost like we're sending an electric signal in a way. And insulin will regulate some of the primary channels that are opening to allow these ions to move across sodium and potassium. In particular, insulin is known to alter the rate at which that's working well in insulin resistance and hyperinsulinemia. This is something that becomes actually overactive. And so it can disrupt the conductance of the nerve signal in the cochlea, which may almost makes it potentially hyperexcitable in what should be a quiet nerve conveying no sound at the moment becomes a bit of a hyperactive nerve giving you a lot of static or that ringing.

Yeah, that's just fascinating. I mean, those mechanisms and I think that was explained very well. You know, it's like these are ultimately hearing and the way we perceive sound. And then of course, earring, a lot of these are nerve conduction. You know, this is all based on nerve conduction. And these are based on then channels and opening and closing and, and sending different electrical signals. And to put that together with insulin, which is, I think a link that most people are not making, is a big step forward. I remember in the book, I recall that you mentioned that 92% of people with tinnitus, which is earring, have hyperinsulinemia.

Yeah.

And then of Meniere's disease patients, which is can be a debilitating ear disorder that involves ear ringing. 76% of patients with Meniere's were also insulin resistant. And something that was fascinating is that in the studies that were linked in the book about ear ringing and hearing loss and Meaner's disease, many of these studies were not looking at a diabetic population. They were looking at a pre diabetic or non diabetic population that had high insulin levels, which I think is incredible. This is, I mean this, this could be applying to people who their doctor has never told them they had a metabolic problem. But of course we know that hyperinsulinemia can happen years, if not decades before we actually see the changes in glucose on our standard lab tests. So this is not just relevant to people who are out there who have a diagnosis of diabetes, but for people who may be on that earlier part of the spectrum.

Yeah, absolutely. And I echo that sentiment only to emphasize what you just did, which is that part of the reason insulin resistance and these early metabolic disorders aren't on the radar is because we look at them through the, through the wrong lens. We're not looking at them correctly. And so they often go undiagnosed entirely or misdiagnosed. The person will say, well, you have Meniere's disease or tinnitus. And that would certainly be true. But not acknowledging that there is in fact a more fundamental problem, there's a fundamental issue that has gone wrong that is in fact manifesting. As this auditory problem.

Yeah. So moving away from the ear, one last condition you mentioned in the book that was so relevant to, to my training because we see it literally all the time is reflux esophagitis and gastroencephal gastroesophageal reflux disease, otherwise known as GERD for those who aren't familiar with those terms. Basically heartburn. That's often the symptom and you know, one of the reasons I actually moved away from ENT towards a more root cause approach to health, ultimately functional medicine and then starting levels actually related to GERD because we were basically so often prescribing super high dose proton pump inhibitors like omeprazole to basically just totally shut down the acid production in the stomach as a, as a, you know, quote unquote treatment for this condition, when really, you know, of course that's not doing anything to address what's maybe leading to the symptoms in the first place, which we know is very related to diet and lifestyle and weight and other factors that are modifiable. But that, that really strong bias towards just shut down the acid, give them a heavy duty, maximal, do heavy duty, maximal dose twice a day. A lot of these pills have never been studied for long term use. We know that reducing the acid in the stomach has a huge impact on digestion, absorption of minerals and vitamins. It has long term outcomes. But you know, we, we still kind of give these people these large prescriptions and they're on their way.

So.

So this was really interesting to read that there may actually be a relationship between insulin resistance and GERD and flex esophagitis. What, what did you come across when you were preparing for the book and writing this section?

Yeah, yeah. So lest people think that the problem would stop at just say heartburn, there are even more catastrophic consequences to chronic gerd, like it converting or leading into something called Barrett esophagus, which then can, is one step away from esophageal cancer. Basically once you get to that point, your risk of developing cancer at the lower part of the esophagus right above the stomach is like 30 times higher than normal. So if someone's experiencing chronic heartburn, that's more than just feeling a little uncomfortable. You could really be flirting with disaster ultimately. So insulin does numerous things and in the case of the person who's insulin resistant, I think there's probably two relevant variables here just off the top of my head. One would be that insulin does in fact alter the production of hydrochloric acid. It might be making the stomach a little more acidic, which could aggravate not only the stomach, but potentially splashing the CHYME up. And that leads me to my second point. Normally the stomach is separated from the esophagus in large part due to the presence of the diaphragm, the diaphragm, which is that kind of primary breathing muscle, expanding the volume of space for the lungs for us to breathe. What can happen is that a portion of the stomach can bulge up past the diaphragm, up into a space that should have been just relegated to the esophagus. So we sort of lose the functional sphincter or the functional narrowing of the esophagus when it goes from esophagus into stomach. When you've had a portion of the stomach bulge up, something called the hiatal hernia, as it's bulging up past the diaphragm. Now you have all the chyme, or all the very acidic contents of the stomach splashing up into the esophagus much more easily than it does before or than it did before. And how this would be connected is that a person who has more fat mass, it doesn't even have to be in the visceral space, but even in the subcutaneous space around it. But the more fat mass you have in that abdominal space, let alone in the abdominal cavity or the visceral fat, the more pressure you have. And so you are pressing the intestines, pressing the stomach and anything else around there, the kidneys, the liver, et cetera. And there's only few places for this to kind of bulge into or herniate. If something's herniated, it means it's one thing moving into the area of another thing. And so pushing the stomach up through the esophagus might be a consequence of really increasing the intra abdominal pressure. And now you're just forcing the intestines to go somewhere. And I guess it could be a prolapse, you know, down, or it could just be a herniation up through the diaphragm. This is something that is known to happen in women with pregnancy entirely a consequence of a higher intra abdominal pressure because of the growing fetus. The same thing can happen with obesity. The person basically has a big fat baby in their, in their space, in that space. And that big lump of that higher volume of fat is increasing the pressure and then pushing the stomach up, so it's bulged up or herniated up above the diaphragm. Now it's just so much easier when the stomach is busy digesting and splashing all that chyme around, all that kind of acidic food mix, it's just splashing up into the esophagus. And the esophagus doesn't have the protective mucus layer that the stomach has. And so it starts getting very aggravated and inflamed because of the chyme or the higher acid load.

And.

And then you start to get the wounds and the inflammation of the esophagus and then potentially other problems later.

Really interesting. Yeah. And I think, you know, for those listening who may not be familiar with this concept of the visceral adiposity, you know, this is the. Dr. Beckman goes into it in deep detail in the book. But really the fat that's around the organs in the abdominal cavity, that's going to be more impactful in this process that you're talking about because it's intra abdominal pushing up on the stomach. This is different than the subcutaneous fat that's like on our, you know, in our, in our arms and legs and things like that. So, so really the fat that is associated more with insulin resistance is the one that's going to have this impact on pushing up the stomach. And you mentioned a study in the book that I thought was fascinating because, because you might say, okay, well, so the fat is pushing up on the stomach. That's kind of a mechanical thing. But there was an interesting part of the study that showed that the insulin resistance, independent, even independent of visceral adiposity, could increase the risk of GERD by 15%. Meaning that regardless of the pushing up on the stomach via the fat, the insulin resistance alone had a factor. So that might get to what you're talking about with the hydrochloric acid production and whatnot. So not just a mechanical, but also some, some physiologic element as well. So super interesting. I mean, this is one that gerd, while it's more of a GI issue, it comes into the ENT clinic because people end up coming in with chronic cough, hoarse voice or laryngitis or other things like that. And so these things can be super troubling. And I think it's helpful to know there is that, that metabolic component, so moving down in the body. I've got one more question for you because I also, before I did my ENT training, I did a general surgery intern year and one of the most common surgeries that is done.

You're a Jane of all trades, Casey.

Well, we all do. We all do a general surgery intern Year, So it wasn't just me, but that's just sort of get the basics of how to do, you know, the surgery stuff. And. And. But the most common. One of the most common procedures that's done as a cholecystectomy, which is a gallbladder removal. And you get into this a lot in. In the book and in other work that I've seen, you talk about this. But I think it's fascinating because no one is talking about insulin resistance in relation to gallbladder stones. And. And so what is that relationship there?

Yeah, yes, it is fascinating, and it's cholecystectomies. And just general gallbladder issues are becoming so much more common and have been increasingly common for years. So there's several things to mention here. And briefly, the insulin resistance, and then why else? It might be a growing problem. Insulin alters the rate at which the liver is producing cholesterol, and cholesterol that might seem only relevant to blood vessels and atherosclerosis, although it might not be that relevant there anyway. But we know the bile is enriched with cholesterol. So bile itself is. What the gallbladder is holding onto is. Are all products of what the liver is producing. So the liver and the little gallbladder kind of tucked beneath the liver in a way, it's receiving everything that it's supposed to hold from the liver. It's getting water from the blood. So there's water there, and then there is cholesterol. There's the bile salts and a handful of other little things. But cholesterol is a primary component of it. In hyperinsulinemia, which exists in insulin resistance, it's accelerating the production of cholesterol from the liver. This is naturally happening when insulin is elevated, but that means it is increasing the cholesterol in the bile, making literally making the bile more thick or sludge, like as they say. And the higher the concentration of the components are getting in the bile, the more likely it is for these molecules to precipitate or to come out of the solution, if you will, where what had been a nice dissolved kind of solution starts to have this conglomeration or this condensing of molecules. And the higher the cholesterol is getting, the more these stones start to form. Now, at the same time, we have. We've kind of created a perfect storm when it comes to the gallbladder, because one, the hyperinsulinemia of insulin resistance is making the bile thicker. But that wouldn't be as much a problem if we could just Empty the gallbladder. Well, tragically, we've given people the perfectly wrong advice for decades now. By telling them to eat low fat, low calorie diets, we are basically ensuring that the gallbladder stays full as long as possible, just giving more time for the cholesterol and the bile salts and other molecules to start forming stones. Because the best way to prevent stones is, is to regularly empty the gallbladder. Even the nih, the slow moving ship of the nih, has acknowledged this years ago, decades ago, that noting that low fat, low calorie diets were among the worst things you can do to with, with slowing down the emptying of the gallbladder, thereby increasing your risk of stones. In other words, we only empty the gallbladder when we eat fat. And because so many people have been so afraid of fat for so long, the gallbladder has a very low motility or high st basis. It's just sitting there with all the stuff in it, never emptying itself. So we've ended up with this sort of perfect storm. We're eating low fat foods, low fat diets, which means the gallbladder isn't emptying very frequently. These same low fat foods are almost always going to be very high carbohydrate. And I don't mean fruits and vegetables, of course nowadays it's going to be high processed, refined carbohydrate, in other words, high insulin spiking foods. And as insulin is going up, it's increasing the cholesterol production from the liver, enriching the bile, making it even thicker, promoting the formation of stones. Now one interesting thing about all of this is what happens once the gallbladder is removed. And there is a study that was published in Rodents, and there is no reason to think this doesn't apply to humans. This is one of those phenomena that appears to be very tight across the species. But they found that when the rodents have, had, had, had their gallbladder removed, there are two things that happened. And the first one, both of them appear to happen in humans too. There's a higher rate of what's called enterohepatic recycling of bile. So if someone has lost their gallbladder, they would say, well, then I can never eat fat again. Well, that's not true. What happens is that the liver becomes both. The liver is able to produce bile more quickly on demand, and we allow the liver a break in a way by recycling bile and then putting it back in. So basically we release bile into the intestines to help digest fat. That's its main purpose. And then we, having digested or emulsified the fat, we reabsorb that bile back into the blood, only to be again put back into the intestines without the liver having to make it this time. So we just have this rapid recycling of bile. One, that happens, we can more rapidly recycle bile to make up for the loss of the gallbladder. But two, it's interesting that when we recycle bile salts, now we have a chemical in the blood that was originally intended to just be dumped into the intestines. Now, I say originally intended, but the body is designed to have bile reabsorb. It's just happening a lot more. One of the totally overlooked aspects of bile salts is that they actually stimulate mitochondrial uncoupling in fat cells. And so these animal models show that when you have removed the gallbladder and induced this higher rate of bile recycling, metabolic rate goes up significantly in these animals. So there's this totally unrelated aspect of bile salts that when it's in the blood, is inducing the burning of fat by making our fat cells have a much higher metabolic rate. So there's this kind of delicious paradox and irony that, that when we eat more fat, we produce more bile, and when more bile is getting into the blood, it induces the burning of more fat. So there's a kind of an interesting phenomenon here, is it's a balance between gut bile purposes and blood bile effects on both sides. So lest someone think having removed their gallbladder is entirely bad, maybe the upside is you probably have a higher metabolic rate because of it.

And just to drill into that a little bit more, is that also saying that someone on a high fat, low carb diet would have higher bile salts in their blood?

Yeah. So that's a wonderful question. I don't know that anyone has ever quantified that. I've never seen it, but it's. I think you and I could both speculate that's very likely the case, because when you're making more bile or releasing more bile in response to eating fat, you will reabsorb more bile. That's just a natural part of the process. So that's probably true.

And that may actually be a mitochondrial uncoupling trigger which helps increase our metabolic rate.

Yep, that's exactly right.

Fascinating. Oh, that's really interesting. Okay, so last sort of surgical adjacent question is, is about the liver. So we're staying in the same area. An unfortunate surgery that is done quite, you know, not infrequently, unfortunately, in the US is liver transplants. And it used to be that hepatitis was a, was a key cause of, of liver transplants. And now the vast majority of liver transplants are caused by alcohol, alcoholic liver disease and increasingly fatty liver disease. And there was an interesting paper in jama, you know, one of our top medical journals from last year that said that now more than 30% of liver transplants are caused by the downstream effects of fatty liver disease. And that there are lack of effective therapies for non alcoholic fatty liver disease that contribute to the increasing disease severity among patients with these diseases leading to cirrhosis and end stage liver disease requiring liver transplantation. Would love to hear your thoughts on this statement that there are a lack of effective therapies for Nash and fatty liver disease.

Yeah, well, you and I both know that conventional medicine doesn't have much to be, I think to be accurate and diplomatic. I'll say it this way, doesn't have much training in the appreciation of dietary interventions in any disorder, let alone fatty liver disease. So it is interesting to note the evolution or the history of non alcoholic fatty liver disease. A couple generations ago it wasn't a thing even, it was just alcoholic fatty liver disease. And now we have this little addition to the prefix non alcoholic fatty liver disease. This again is a newer problem with regards to the history of liver problems or the history of fatty liver. There are. So basically the primary problem, the liver is too fat. There have been some very well done studies to look at the source of that fat. However, as well done as these studies are, they weren't able to be totally all encompassing. And I'll mention that briefly, most of the liver fat is coming from adipocytes or fat cells that are leaking that fat. The vast majority, 80% ish of the fat in the liver is leaking into the liver from fat cells. And so this is when, when fat cells become insulin resistant, one of the ways they attempt to survive. And we haven't even brought up fat cells. So I don't want to, I don't want to make it overly complicated, but as a fat cell is undergoing hypertrophy, it essentially starts to reach a point of maximum dimension. The physical dimensions are becoming problematic. And while insulin is continuing to force feed fat into the fat cell, normally insulin would prevent the leaking or the breakdown of that fat. But now the fat cell, knowing it's reaching maximum dimensions, in order to not get too big and explode or have to undergo apoptosis, it starts leaking the fat. So insulin induced inhibition of lipolysis fails and that Part of the fat cell becomes insulin resistant. So we have a hypertrophic insulin resistant fat cell now leaking free fatty acids that is the primary source of the fat that is accumulating in the liver from the leaking fat cells. At the same time there's a more minor contribution which is the hyperinsulinemia of insulin resistance, where the elevated insulin is promoting lipogenesis within the liver itself. Now so those are well done studies that have quantified by using radio labeled or tracing fat movement in the body and accumulating in the liver. Unfortunately, those same studies did not attempt to find the contribution of fructose, which we absolutely know is a contributor. The every paper who that studies, every scientist, every group that studies fructose and fatty liver disease notes that fructose is a massive contributor. In fact, Luke Tappy, I think is one of the scientists in Switzerland who studied this the most. And his quote is something like fructose is the most lipogenic molecule in the liver in the body. So I think that needs to be considered. So fatty liver disease is remarkably common and it's only going to get more common. Now to the author's point that there's no real solution to this to a degree, I am empathetic to that statement because there aren't a lot of studies, clinical studies that have done this. But we have some pilot studies, one from Duke I know in particular that confirmed, for example, a low carb diet is effective at reducing liver fat. But we have other evidence basically for me, that clearing the liver is the same of fat, is the same way of clearing your fat cells of fat, that there are two ways to go about it. Controlling insulin and controlling energy. Now those aren't necessarily the same thing, but there is some redundancy to them. And so even if you put anyone on a fasting regiment that is of course going to lower their caloric load, there's no question the liver is going to start lowering its fat and do so very dramatically at the same time. If you're lowering insulin through say a low carb diet and or fasting coupled, then you will once again be lowering the insulin and improving fat cell insulin sensitivity and thus removing the key contributors to the fat that's accumulating in the liver.

Yeah, I think the, the, those studies sound really elegant. What you're talking about with the radioactive labeling and really understanding where the fat is coming from, that it's the fat spilling from these hypertrophic fat cells that's actually going to the liver and causing that fatty liver disease. And then of course, the fructose component. And I think I'd have to imagine we're certainly seeing a huge rise in fatty liver disease in children, which is devastating. It should really never exist in children. And have to assume a lot of the story there is fructose, given the amount of fruit juice and packaged foods that kids are eating, of course, coupled with rising childhood obesity, which could be related to the sort of fat cell hypertrophy story. And I want to dig in a little bit since we are on the. You did bring up the. This fat cell hydro hypertrophy concept in the book and in your other work. You've. You've talked about this, which is that there's sort of two different destinies a fat cell, fat cells can have, which is one, they can grow really, really large and reach their maximal dimension and then start leaking fat out of them, which they're not supposed to do, which of the course can then go to the liver and contribute to fatty liver disease. Or they can. You can have fat cells that replicate and you've got tons of little tiny fat cells, which is fat cell hyperplasia. So hypertrevers hyperplasia. And that these are kind of two different signs of two different metabolic states in the body. Can you talk about that a little bit? And what lifestyle or dietary aspects sort of promote driving us towards this not so good hypertrophy versus sort of possibly better hyperplasia. And the reason I'm asking about that is to kind of maybe start to paint us a bigger picture here about what are some of the dietary and lifestyle things that, aside from fructose, that can kind of protect us from this.

Yeah, yeah. So I am very interested in fat cells because I believe that the fat cells are the cells that become insulin resistant first. As you have an individual who through the course of his or her life is moving towards insulin resistance and diabetes, type 2 diabetes. There are several tissues that are going to become insulin resistant in that journey. Certainly by the time they become type 2 diabetic, multiple tissues have become insulin resistant. But it makes sense that there would be an origin. Now, this is. I would want everyone listening to know that this is a matter of discussion and debate among scientists in the field. I very much espouse the idea that it is a fat cell first issue, that the fat cells are the first to become insulin resistant and then having done so, start to kind of spill that insulin resistance throughout the rest of the body. But then to go back to the hypertrophy versus hyperplasia aspect, because we need to to understand how the fat cells become insulin resistant, we can have our fat tissue growing. What we can pinch and jiggle through two different processes. One, as you noted, is hypertrophy, where each individual fat cell is getting significantly bigger, and I mean four or five times bigger than normal. Or alternatively, the fat tissue, what we can see and pinch and jiggle, and why the scale is going up every year over year, the fat tissue can be growing through hyperplasia, which is a situation where the fat cell size is actually quite modest. Still, they're not particularly bigger than normal. We just have a lot more of them, so we're multiplying. That's what hyperplasia is. So we have hypertrophic fat and we have hyperplastic fat. Now, interestingly, on the hypertrophic side, that's where things start to go wrong. And that's where the vast majority of us fall. The vast majority of people will go through the path of hypertrophic fat gain. And only a relative minority of individuals, and this is about 10 to 15% of people who are considered obese, they have this hyperplastic fat growth. So it's much less common now with the hypertrophic side. In fact, maybe one tangent quickly, before I mention that, is most of us go that hypertrophic route because by the time we've finished puberty, late teens and girls, and maybe early 20s in most boys, then we have set our fat cell number. So we're growing our fat cell number throughout infancy, childhood, and pubescence or adolescence. And then by the time we're wrapping up adolescence, we have flatlined and we have plateaued. And the number of fat cells we made at the end of adolescence is the number of fat cells that we essentially keep perfectly until we get to around 70 years old. And now we start losing fat cells. But lest that seem like a good thing, as you start to lose your fat cell number, you force a greater burden on the remaining fat cells to store the fat. Thus bringing us back to the story of hypertrophy. Now, when a fat cell is getting big, I already mentioned the first problem, which is that it starts to reach a point of maximum dimension that becomes damaging to a cell. A cell can only get so big. Every cell has its natural limits. The fat cell is reaching its natural limit, and thus it becomes insulin resistant in order to prevent further growth. So it becomes insulin resistant to save itself, little knowing that the cells downstream, which eventually would be all the cells of the body, are actually having to pick up the burden as the cell is leaking free fatty acids at the same time, even though fat cells have a very low metabolic rate, they nevertheless have a metabolic rate, which means they need blood, they need oxygen, and they need nutrients. But what starts to happen is as the fat cells themselves are getting bigger and bigger, they're pushing each other further and further away from capillaries or from blood flow. And thus the hypertrophic fat cell becomes hypoxic or low in oxygen. And the fat cell has many, many tricks up its sleeve, many, many tools it can use. One of them is it can start to secrete pro inflammatory proteins or prototypical inflammatory proteins that rather than inducing inflammation in cells, actually increases the formation of new capillaries. So one of the molecules that the fat cell can release is vascular endothelial growth factor or vegf. Now it's doing so again. It's secreting among. So it starts to, as it becomes hypoxic, it starts to secrete numerous pro inflammatory proteins, vegf, and the synthesis of new blood is only one of them. But you can't really get that one without all the others, essentially. And so the hypertrophic fat cells are trying to correct the poor blood flow by secreting this whole panel of pro inflammatory proteins in the hopes that it will improve blood flow. Because it's better to improve blood flow than to die through necrosis. That's a messy death. So once again, the fat cell is attempting to ensure its own survival by increasing blood flow and thus trying to correct the hypoxia. But in the process, it's now leaking this whole stable of pro inflammatory proteins throughout the body. So we have the hypertrophic fat cell leaking both free fatty acids contributing to the so called lipotoxicity throughout the body. All these tissues are starting to have to store more fat than they want to and at the same time releasing pro inflammatory proteins. And the combination of those two things partially starts to amplify the problem within itself. One, those are not only promoting insulin resistance throughout the rest of the body, because those will stimulate the production of a type of lipid called ceramides in all the other cells of the body. Which is why I'm an advocate of the fat first view. It's because you have all the perfect ingredients to promote the formation of ceramides in any other tissue like the muscle or the liver. And now you're just a step away from type 2 diabetes. But to bring it back to the fat cell, and to your point that there are some kind of actionable items here, we would think, well, how could we help prevent our fat cells from getting too big. Well, there are multiple ways to do this because we know there are multiple molecules that will contribute to fat cell hypertrophy. Now, as much as I'm going to explain that these are kind of actionable items, people should know that there's also just a very strong genetic component to this. We know across ethnicities, people will have certain polymorphisms or altered gene expression in the genes that dictate whether they go down hyperplasia or whether they go down hypertrophy. So there's only so much we can move the needle, but we may as well move it however we can. So, first of all, inflammation and elevated insulin will promote the accumulation of a type of ceramide called ceramide 1 phosphate. Ceramide 1 phosphate is a molecule that will promote hypertrophy of the fat cell, precluding the hyperplasia. So kind of closing that avenue off. And again, that was inflammation and elevated insulin. Kind of some of the typical characters that are causing insulin resistance in general. And the relevance of insulin cannot be overstated, because we know at the site of insulin injection in diabetics, the reason we tell a diabetic to rotate their injection sites is to prevent the insulin induced hypertrophy. And the study from Japan has done this, where they sample, they pulled fat biopsies of areas where the insulin has been injected chronically and just a few inches away in that same fat pad, but where the insulin wasn't injected and the fat cells were about three to four times bigger at the site of the insulin injection. So the person will start to develop these big humps of fat wherever they've been chronically injecting their insulin. Thus they need to rotate their injection sites. Now, independent of insulin and inflammation, those signals promoting ceramide 1 phosphate, we actually have a product of seed oils. And this is where I become an advocate of controlling seed oil consumption. I know there are a lot of voices in this space now, and I only would want mine to be one of the quiet voices, because this isn't a drum I beat too heavily. I have my own drums that I beat very readily. But insofar as linoleic acid, the primary fat from the primary fatty acid found in these refined seed oils, does, in fact, alter fat cells. I'm interested in them. But basically, when we consume high levels of linoleic acid, we force that linoleic acid down this pathway of peroxidation. We always talk about oxidation, which is normal burning of fat, which linoleic acid can do. Linoleic acid can get burned for energy or via oxidation very readily. But alternatively we eat so much more of it than our body knows what to do with that. We can't go down that pathway all the way. Some of it gets pushed down this peroxidation pathway. Once it's gone down that pathway, it can turn into numerous harmful molecules. One of them is a molecule relevant to the fat cell which is 4 hydroxy nonenol, which is or 4HNE. Once again, just like ceramide 1 phosphate, 4H and E will push the fat cell down the path of hypertrophy. So forcing hypertrophy, which of course means forcing the fat cell to become insulin resistant and pro inflammatory.

Wow, that was an incredible, incredible walkthrough, Ben. Thank you. And you know, I think one thing I just want to hit home is just that for people that the majority of our processed foods and processed foods is about 80% of the grocery store are going to have these seed oils in them and refined sugar. It's kind of the perfect storm of what you're talking about and why I think towards the end of the book we really get into talking about eating whole foods and real foods. If it's in a package you really want to look for, does this include these refined seed and vegetable oils that are going to be high in the linoleic acid? And just kind of thinking through everything you just said there and what is driving the fat cell hypertrophy, this more dangerous path compared to hyperplasia? Um, some of the takeaways I'm hearing is we want a diet and lifestyle that reduces our hyperinsulinemia, so keeps insulin low, avoiding fructose and avoiding seed oils. Those would be three things that can be likely helpful in, in this sort of journey towards, towards not pushing the. Pushing towards the hypertrophy and just overall metabolic dysfunction route.

Yeah, yeah. In fact, I think Casey, I think you summed it up really well, which was eat whole food even if a person. And it pains me, well, actually not at all to say this as much as I am an advocate of a low carb diet. But I also acknowledge that even if someone is on a high carb and a lower fat diet, if it is primarily coming from whole food, then there's no question that is going to be a better strategy than the standard American diet. So there are numerous ways to go about solving this problem. But I think you summed it up well. If by avoiding processed foods, one you're avoiding, you're eating less fructose dramatically because you're just not drinking it and then Two, you're lowering your insulin by avoiding these other processed carbohydrates and you are avoiding refined seed oils. If someone is doing that, they're doing it well.

Definitely. Well, I'd like to do a major shift of gears here and actually start talking about your research. You are working on several fascinating research projects and one that we're collaborating on with levels. And so I'd love to talk about this a bit. Um, the, the title of this, this project is understanding the paradoxical rise in blood glucose in the context of a low carbohydrate diet and the use of real time glycemic status to alter behavior. And it, this project gets into a lot of interesting physiology around glucagon and insulin. And I think, honestly, I think for most people glucagon gets heard about a lot less than insulin, but is really, really important. So I'd love for you to maybe describe this research project and, and also talk to people a little bit about why studying glucagon in the context of this project can really shed some light of some actionable things that people can learn about their own metabolic health.

Yeah, yeah. In fact, maybe the best way to go about it is kind of answering that two part question in reverse. So glucagon is a hormone that is going to increase glucose, whereas you know, and that's kind of the opposite the Yang to the yin of insulin, which is wanting to lower blood glucose at any moment. Interestingly, and part of the justification for this project, we know that in people with type 2 diabetes when they eat certain foods like protein, for example, and I'm an enormous advocate of eating protein, but they have a much higher than normal glucagon response and we know that in type one diabetics that's even more amplified. So the, that was part of the rationale for this project and the other part of it was because there are a certain number of people that adopt a low carbohydrate diet that notice that their blood glucose levels one might not drop like they expected and or alternatively they might actually go up and so they will have fasting glucose levels that are in the high 90s or low hundreds and just sort of always hovering around there rather than being in the 70s or the 80s like you'd expect. This project is actually a little personal because I find that I'm one of those guys and I wouldn't have known that if it weren't for levels, which is a tangent and I don't mean to beat it, to go off on that path. But part of the power of a continuous glucose monitor is that it democratizes this sort of information that someone can see where they are and they can't unsee what happens when they eat certain foods or engage in certain lifestyle habits with regards to sleep or caffeine consumption. So the general project is to track people that are on low carbohydrate diets. By using the cgm, we can have exquisite information with regards to their glycemic control. And then we will do what I'm what I call macronutrient challenges. And this is what we have been doing. We've had 10 subjects come through currently, but basically they have, over certain days they have a protein solution, a glucose solution and a fat solution. And then we're just going to quantify numerous hormones because in order to understand what the body is doing with energy, including blood glucose levels, you have to understand what hormones are doing. Because hormones tell the cells of the body what to do with energy, full stop. That's why I'm such an advocate of scrutinizing insulin and other hormones in the context of metabolic problems. A cell be told what to do with the energy that it has available. So we're going to be doing a full survey of about 2020 hormones and, and, and, and cytokines actually in inflammatory markers, just to try to get an idea of what might be coming into play to help explain this paradoxical increase in glucose, when you'd expect, based on the amount of glucose they're eating, that their glucose level should be going down?

Really interesting. And, and, and what does this sort of tell us about glucon in terms of its function and maybe just for people who aren't familiar with the hormone in general, sort of like what the normal role of it in metabolism is, and is it problematic if on a low carb diet where your insulin is low and glucagon might be a little bit higher, to have that glucose be in a slightly higher range?

Yeah, that's a great question. So as I noted, glucagon does create an upward pressure on glucose. Its primary job is to make sure blood glucose is high. Now, if it had its way, it would make sure glucose is much higher than we'd want it. Now, to that kind of second part of your question, where should it be? I'm actually one of those kinds of guys that really pushes back at that. Glucose should only be below 110 all the time, in part because I know the history of glucose levels once upon a time. This is just a couple decades ago. Normal Glucose levels were considered anything below 150. And I'm just cynical enough to think, why have we lowered that? Now, on the generous side, we would say, well, because we found that if it was higher than that or around there, it was really catastrophic to health. That might be true. That might be true. Alternatively, it's also a wonderful way to diagnose people with a disease and put them on drugs much, much earlier. So by lowering the threshold, a lot more people are getting over that bar, you know, where glucose, when glucose levels were considered normal up to 150, not a lot of people were getting over it. Thus, few people were being diagnosed with the problem. And there was much less drugs to be sold by lowering that, that bar, that threshold. Now a lot of people are just stepping right over it because it's so low. So I am admittedly a little bit of a cynical guy as I'm getting older. And moreover, as much as SO one, I can't help but see what's in it for them by lowering the glucose threshold and calling it a problem at a much lower level than we used to. But also I'm too aware of the fact that in diabetes or pre diabetes, insulin resistance, it's insulin that's really causing the primary problems. It's not the glucose. Now, I'm not saying glucose is benign. I'm not saying that at all. There's no question it can contribute to problems, in fact, even catastrophically when it comes to like poly dumping glucose into the urine and lowering blood volume and the person going unconscious. But that's very uncommon. And that's glucose levels that are up into the 2000s when that normally starts to happen. But. So I'm just, I'm a little bit not indifferent, but I just cannot muster the enthusiasm for being worried about glucose like I can being worried about insulin. And that touches on almost how we started this conversation, which is the average person is sitting at a state of normal glucose, yet hyperinsulinemia because of the insulin resistance. And this is the person who's starting to experience cognitive decline, which is an area of research in my lab, where it's an insulin problem, the insulin resistance of the hippocampus. They're starting to experience hypertension. They're starting to experience auditory issues and infertility, fatty liver disease. These are not problems of glucose, these are problems of insulin. So if I see someone who's on a low carbohydrate diet and their insulin is at 3 micro units per mil and their glucose level is at 100, I am inclined to give them a high five because to me that's a perfectly healthy range for the person to be in.

Yeah, I think that's a great. It's a good perspective because we often can be quite glucose centric and I think looking at the, looking into the historical precedent of why that might be the case that is in relationship to medications and whatnot is really interesting. Two questions I have about that just to sort of get your thoughts on. So one is just the general concept of glycation. Like we know that when glucose is high, glucose sticks to things and that can cause dysfunction in certain parts of the body. Would your take be that the difference between 80mg stress liter and 110mg just liter, that's not really clinically relevant when it comes to glycation. And that's more something we need to worry about when glucose is much, much higher. And so how does that type of process factor into this?

Yeah, that's in fact, I'm thrilled you brought it up. I wouldn't have. But yes, that is there are a couple known distinct biochemical problems when glucose is chronically elevated. Glycation is one of them. And of course the hemoglobin A1c or hemoglobin glycation is a, is a test in order to kind of capitalize on that. What's interesting and very relevant to levels, this is part of my enthusiasm for levels as a company and as a with, with its mission is that the hemoglobin A1C test came in into vogue and basically single handedly killed the oral glucose tolerance test. Because it was thought that the A1C is going to give us a better kind of better overall information than one, than a fasting glucose, which may or may not be true, but two than an oral glucose tolerance test, which I believe is not at all true. But that really is part of the evolution or the death of the oral glucose tolerance test was partly born from our obsession with hemoglobin A1C. But to answer your question explicitly and then I'll kind of come back to that point, there's no question that glucose is a problem. I however don't know that it's ever been quantified. Measuring the degree of glycation from say 85 to 110. Is it, is it really moving the needle that much? I don't know that it is. I've not seen that quantified. I've never seen that really put together well. So I'll be a little agnostic until we can see something, and I'll continue to kind of poo poo it. But the dynamic test is not the same as the fasting test. And this is why I think this is why I'm enthusiastic about levels, as I noted, because if someone can't get their clinician to do an oral glucose tolerance test, and that would not be easy to do because it takes a lot of time at the clinic and time is money, where you're having to sit around and go in for multiple tests, you can do it on your own. That is what is so powerful, is that while I am somewhat indifferent or don't have too much respect for just chronically measuring fasting glucose because insulin could have changed years before the glucose is changing, that is not the same as that's dynamic. That static measurement of glucose at a fasted state coming into the clinic once a year is not the same as the dynamic glucose changes that can happen when we're eating foods and someone can see I've eaten this carbohydrate heavy food or whatever it may be, and oh my gosh, my glucose levels spiked up to high hundreds and it stayed elevated for four hours. In fact, it's funny, that was something that happened with me when I ate two bowls of shredded or little the frosted Mini Wheats.

Oh, gosh, I bet that pains you to do that experiment.

Well, that's the thing. It's actually a consequence of my college days. I'm sure I blame it on being a college student, but I still to this day have, for lack of a better word, a total addiction to cold cereal. To cereal. And one of the reasons that the little Bickman babies in my home don't eat cereal is because daddy can't handle having cereal in the house. If there's cereal in the house every evening, it's like calling my name from the pantry. And so we just don't have cereal. Breakfast is always a homemade meal, whatever it may be. I make it every morning for the kids. But I ate two bowls of frosted Mini Wheats one time and my glucose stayed elevated. I ate it in the evening, so I didn't sleep very well. But it basically lit this hyperglycemic relatively state for almost 12 hours. And I think it was of course exacerbated by my poor sleep because I went to bed full, full of these glucose, insulin spiking foods. And that amplified my sympathetic nervous system and increased my body temperature and heart rate, all of which is known to happen. So I think there are multiple variables coming into play. Here. But the dynamic, back to my point, the dynamic view of glucose, I think has tremendous diagnostic value because if someone is insulin resistant, another word or another outcome, I won't say word because it's not totally synonymous, but an outcome of this is typically going to be a glucose intolerance. If you're insulin resistant, you're going to generally be glucose intolerant. Now, you can be glucose intolerant and not insulin resistant for other reasons. But nevertheless, if you are insulin resistant, you will have some degree of glucose intolerance. So you've eaten that carbohydrate heavy snack and it's going to take you a long time to clear it and it might be really messy on the way. You've come down and you're right back up and now you're high again, it's dropped and come back up. All that kind of noise is a warning sign. And you don't get that noise when you just measure one single moment in time. Or in other words, the fasting static blood glucose test that everyone is, goes in and does and that we're all content with because too few of us know that there's another option, namely getting a continuous glucose monitor and tracking it for yourself.

Right, Yeah. I mean, this is where the research, I think, over the next five to 10 years is going to be so interesting, like really drilling down on some of these different metabolic phenotypes. What is the person with low insulin, high glucagon, high normal fasting glucose, but low glycemic variability? Is that a perfectly okay state? You know, like, it's just we don't totally know the answer to these things and, but I think context matters so, so, so much. And so the person with a fasting glucose of 95 high normal, whose insulin is 2 versus insulin is 30, very different picture. And I'm really excited that some of this research that you are doing is going to start to elucidate some of this. So.

Well, kudos to levels in all sincerity. And I mean this. It is very hard to get support for these kinds of studies that don't have, you know, some massive clinic supporting it. You know, we are just a research institution. We're not working with the clinic or a hospital to do this. It is very hard to get the funds to do this. So strictly speaking, from a scientific view, I'm very glad to have been able to partner on this study. And then selfishly, it's a topic that I'm fascinated in and I can't wait to share what we're learning. Morning.