Surprising symptoms related to insulin resistance, and why blood sugar might go up on a low carb diet (Ben Bikman & Casey Means)

If you’re looking to understand the science behind insulin resistance and its link to disease, look no further than this conversation with Levels advisor, Ben Bikman, PhD and Levels Chief Medical Officer, Casey Means, MD. The two professionals dig into the research on the relationship between insulin resistance and disorders of the ear nose and throat, the role of glucagon in raising our glucose on a low carb diet, Dr. Bikman’s own research, and ways to improve insulin resistance.

8:49 – Declining health is not inevitable Dr. Bikman believes that there are many preventative measures that can be taken to help us stay healthy, longer.

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 thus the consequences of poor metabolic health are also to a very large degree changeable.

10:15 – The link between insulin resistance and tinnitus If you have ringing in your ears, it’s quite possible that there is an underlying metabolic issue.

I had a conversation with a physician and he noted to me, this was a local guy that I know. He mentioned to me this high correlation between ear ringing and pre-diabetes 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 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 almost, 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 sending of a signal along neurons within the ear.

13:39 – We look at health through the lens of disease Under almost every disease is another fundamental problem, such as metabolic health.

Part of the reason insulin resistance in these early metabolic disorders aren’t on the radar is because we look at them 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.

22:53 – Insulin resistance and the gallbladder For many years, there was a myth that low-fat diets would help a problematic gallbladder, but that has since been proven false.

We’ve created a perfect storm when it comes to the gallbladder because one, the hyper insulinemia of insulin resistance is making the bile thicker. 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 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 with slowing down the emptying the gallbladder thereby increasing your risk of stones.

28:32 – The appearance of fatty liver disease A relatively new medical diagnosis, fatty liver disease happens when the liver is leaking fat. This is separate from alcohol-driven liver disease.

Conventional medicine, 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, and 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. 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.

31:34 – Ways to clear the liver of fat Preliminary studies have experimented with reducing fat in the liver, such as a low carb diet.

We have some pilot studies, one from Duke I know in particular that confirmed, for example, a low carb diet is a effective at reducing liver fat, but we have other evidence basically for me, 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 regimen 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, improving fat cell insulin sensitivity, and thus removing the key contributors to the fat that’s accumulating in the liver.

35:00 – How fat tissue develops Hypertrophy and hyperplasia are two different avenue by which fat cells grow. Most of us suffer from the hypertrophic side of the equation.

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 cells getting significantly bigger and four or five times bigger than normal or alternatively, the fat tissue, what we can see in 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 relative minority of individuals and this is about 10 to 15% of people who are considered obese, they have this hyperplastic fat growth

36:51 – How fat cells become insulin resistant A fat cell can only grow so large before they no longer function. It becomes insulin resistant in order to protect itself and stop growing further.

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 body are actually having to pick up the burden as the cell is leaking free fatty acids…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 control tribute to fat cell hypertrophy. As much as I’m going to explain that these are 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.

46:21 – The power of a CGM Technology like Levels allows full insight into what food is doing to our metabolism.

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 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 call macronutrient challenges.

48:36 – What is a healthy glucose level? Dr. Bikman is personally skeptical that glucose levels should be below 110. He suspects that a lower number was identified in the last couple of decades in order to further drug sales.

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, and this is just 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, we’re around there, it was really catastrophic to health.” 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. 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.

Dr. Ben Bikman (00:00):

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. Now, 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 thus the consequences of poor metabolic health are also to a very large degree changeable.

Ben Grynol (00:58):

I’m Ben Grynol part of the early startup team here at Levels. We’re building tech that helps people to understand their metabolic health, and this is your front row seat to everything we do. This is A Whole New Level. When thinking about metabolic health, there are all these inputs and factors we know about certain things, glucose being one of the main things that we often talk about, not just as a company, but as a society, but what’s actually important to note is that insulin and insulin resistance, insulin being the hormone, the molecule is such a key contributor, a main factor in maintaining and optimizing metabolic health.

Ben Grynol (01:48):

And so Dr. Casey Means, Chief Medical Officer and Co-Founder of Levels and Dr. Ben Bikman, one of our research advisors and author of Why We Get Sick, sat down and talked about everything pertaining to insulin and insulin resistance. Ben is one of the leading thought leaders in the world when it comes to this topic. So no need to wait, here’s Casey with the intro.

Dr. Casey Means (02:10):

Hi everyone, this is Dr. Casey Means, Co-Founder and Chief Medical Officer of Levels. I am so thrilled to introduce Dr. Ben Bikman today who is our guest on a whole new level. Dr. Ben Bikman 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 post-doctoral fellow at the Duke National University of Singapore Medical School where he focused on metabolic disorders and insulin resistance.

Dr. Casey Means (02:47):

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 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 podcast, and is doing incredible service to the world by bringing insulin resistance to the mainstream. Welcome to A Whole New Level Dr. Bikman.

Dr. Ben Bikman (03:20):

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

Dr. Casey Means (03:26):

I can’t wait. So I want to jump in with something that’s 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 impactful high insulin levels are on all parts of the body.

Dr. Casey Means (03:54):

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 super common conditions in the ENT clinic. So can you just talk us through a little bit about what we know about this relationship?

Dr. Ben Bikman (04:27):

Yeah, so 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 inner cells of the ear that would be involved in hearing that you would know more about than me given your training.

Dr. Ben Bikman (05:06):

They are high metabolic rate cells. They have a high demand for energy, and part of that demand is met by glucose. Well, as the body is 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.

Dr. Ben Bikman (05:47):

The net effectiveness with regards to the bio energetics 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 in 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.

Dr. Ben Bikman (06:26):

They have a high demand for oxygen and the nutrients that the blood is bringing to them, and as the blood vessels in the body by extension through multiple mechanisms starts to become and 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, 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.

Dr. Casey Means (07:09):

It’s so fascinating because it’s really the same theme that you see all over the body that I think you talk about really beautifully in the book which is 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 the site of our hearing, our balance, these small perturbations in blood flow can have a massive, massive impact.

Dr. Casey Means (07:43):

And when you’re getting ischemic cell death events from lack of blood flow in these tissues, it makes sense logically 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 their degree of insulin resistance, the greater difficulty in hearing at particular tones.

Dr. Casey Means (08:05):

And 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 I think the vast majority of people think this is something to do with aging. This is just part of old age, but to know that there’s possibly a modifiable factor to this, not just stay away from loud speakers 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.” There’s not much we can do there.

Dr. Ben Bikman (08:44):

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 thus the consequences of poor metabolic health are also to a very large degree changeable.

Dr. Casey Means (09:34):

It’s amazing and 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 on its own in the absence of some other symptoms, it’s often associated with hearing loss, it also can be associated with some disorders like Meniere’s disease, both of which you talk about in the book. And I’m just if you can kind of layout 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.

Dr. Ben Bikman (10:04):

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, this was a local guy that I know. He mentioned to me this high correlation between ear ringing and pre-diabetes and diabetes in his patients. And so I just almost on a whim started to dig into it.

Dr. Ben Bikman (10:31):

And I was dumbfounded by what I found, but I have to of course give a shout 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 almost, 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 sending of a signal along neurons within the ear, within the cochlea.

Dr. Ben Bikman (11:12):

And in particular, insulin is known to affect the sodium potassium ATP channel. That’s a little granular for most of the listeners. But basically, when we are sending a signal along a cell like a neuron, we’re sending that signal by nature of us rapidly shifting ions, positive and negatively charged molecules, almost like we’re sending an electric signal in a way. An insulin will regulate some of the primary channels that are opening to allow these ions to move across sodium and potassium in particular.

Dr. Ben Bikman (11:43):

Insulin is known to alter the rate at which that’s working well in insulin resistance and hyper insulinemia, this is something that becomes actually overactive. And so it can disrupt the conductance of the nerve signal in the cochlea which almost makes it potentially hyper excitable and 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.

Dr. Casey Means (12:09):

Yeah, that’s just fascinating those mechanism, and I think that was explained very well. It’s like these are ultimately hearing and the way we perceive sound. And then of course, ear ringing, a lot of these are nerve conduction. This is all based on nerve conduction and these are based on then channels and opening and closing and sending different electrical signals. And to put that together with insulin which is I think a link that most people 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 ear ringing have hyper insulinemia.

Dr. Ben Bikman (12:43):

Yeah.

Dr. Casey Means (12:43):

And then of Meniere’s disease patients, which is, can be a debilitating ear disorder that involves ear ringing, 76% of patients with manures 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 Meniere’s disease, many of these studies were not looking at a diabetic population. They were looking at a pre-diabetic or nondiabetic population that had high insulin levels which I think is incredible.

Dr. Casey Means (13:11):

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.

Dr. Ben Bikman (13:34):

Absolutely. I echo that sentiment only to emphasize what you just did which is that part of the reason insulin resistance in these early metabolic disorders aren’t on the radar is because we look at them 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.

Dr. Casey Means (14:10):

So moving away from the ear, one last condition you mentioned in the book that was so relevant to my training because we see it literally all the time is reflex esophagitis and gastroesophageal reflex disease, otherwise known as GERD. For those who aren’t familiar with those terms, basically heartburn, that’s often the symptom and 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 “treatment” for this condition.

Dr. Casey Means (14:55):

When really, 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 really strong bias towards just shut down the acid, give them a 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.

Dr. Casey Means (15:27):

It has long-term outcomes, but we still give these people these large prescriptions and they’re on their way. So this was really interesting to read that there may actually be a relationship between insulin resistance and GERD and reflex esophagitis. What did you come across when you were preparing for the book and writing this section?

Dr. Ben Bikman (15:46):

Yeah, so less 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.

Dr. Ben Bikman (16:10):

So if someone’s experienced in 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 chime up and that leads me to my second point.

Dr. Ben Bikman (16:42):

Normally the stomach is separated from the esophagus in large part due to the presence of the diaphragm, the diaphragm which is the 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 lose the functional sphincter, the functional narrowing of the esophagus when it goes from esophagus into stomach. When you had a portion of the stomach, bulge up, something called a hiatal hernia, as it’s bulging up past the diaphragm, now you have all the chime 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.

Dr. Ben Bikman (17:31):

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, kidneys, the liver, et cetera. And there’s only few places for this to bulge into or herniate.

Dr. Ben Bikman (18:00):

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 intraabdominal pressure. And now you’re just forcing the intestines to go somewhere and I guess it could be a prolapse 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.

Dr. Ben Bikman (18:31):

The same thing can happen with obesity. The person basically has a big fat baby in their space, in that space, and 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 chime around all that 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 chime or the higher acid load, and then you start to get the wounds and the inflammation of the esophagus and then potentially other problems later.

Dr. Casey Means (19:15):

Really interesting. Yeah, and I think for those listening who may not be familiar with this concept of the visceral adiposity, this is the … Dr. Bikman 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 interabdominal pushing up on the stomach. This is different than the subcutaneous fat that’s on our arms and legs and things like that.

Dr. Casey Means (19:40):

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 you might say, “Okay, well, so the fat is pushing up on the stomach, that’s a mechanical thing.” But there was an interesting part of the study that showed that the insulin resistance 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.

Dr. Casey Means (20:11):

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 physiologic element as well. So super interesting. This is one that GERD, well, it’s more of a GI issue, it comes into the ENT clinic because people end up coming in with chronic cough, horse 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 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 for-

Dr. Ben Bikman (20:47):

You’re a Jane of all trades Casey.

Dr. Casey Means (20:49):

Well we all do, we all do a general surgery intern year. So it wasn’t just me, but that’s just to get the basics of how to do the surgery stuff, but one of the most common procedures that’s done is a cholecystectomy which is a gallbladder removal and you get into this a lot in the book and another 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 so what is that relationship there?

Dr. Ben Bikman (21:15):

Yeah, it is fascinating and cholecystectomy 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.

Dr. Ben Bikman (21:47):

So bile itself is what the gallbladder’s holding onto are all products of what the liver’s producing. So the liver and the little gallbladder 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.

Dr. Ben Bikman (22:10):

In hyper insulinemia which exists in insulin resistance, it’s accelerating the production of cholesterol from the liver. This is naturally happening when insulin is elevated. That means it is increasing the cholesterol in the bile, literally making the bile more thick or sludge-like as they say. 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 conglomeration or this condensing of molecules and the higher the cholesterol is getting, the more east stones start to form.

Dr. Ben Bikman (22:51):

Now at the same time, we’ve created a perfect storm when it comes to the gallbladder because one, the hyper insulinemia of insulin resistance is making the bile thicker. 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 to regularly empty the gallbladder.

Dr. Ben Bikman (23:28):

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 with slowing down the emptying 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 stasis.

Dr. Ben Bikman (23:57):

It’s just sitting there with all the stuff in it, never emptying itself, so we’ve ended up with this perfect storm. We’re eating low fat foods, low fat diets which means the gallbladder isn’t emptying very frequently. The 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 increased seeing the cholesterol production from the liver, enriching the bile, making it even thicker, promoting the formation of stones.

Dr. Ben Bikman (24:32):

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 had had their gallbladder removed, two things had 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.

Dr. Ben Bikman (24:59):

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, 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 back into the blood only to be again, put back into the intestines without the liver having to make it this time.

Dr. Ben Bikman (25:33):

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 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 reabsorbed, it’s just happening a lot more.

Dr. Ben Bikman (26:00):

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 cell have a much higher metabolic rate.

Dr. Ben Bikman (26:29):

So there’s this delicious paradox and irony 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 an interesting phenomenon here is it’s a balance between gut bile purposes and blood bile effect 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.

Dr. Casey Means (26:56):

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?

Dr. Ben Bikman (27:05):

That’s a wonderful question. I don’t know that anyone has ever quantified that. I’ve never seen it, but 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.

Dr. Casey Means (27:23):

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

Dr. Ben Bikman (27:29):

Yup, that’s exactly right. Yeah.

Dr. Casey Means (27:30):

Fascinating, oh, that’s really interesting. Okay, so last surgical adjacent question is about the liver. So we’re staying in the same area. An unfortunate surgery that is done quite not infrequently, unfortunately in the US is liver transplants. And it used to be that hepatitis was a key cause of liver transplants. And now, the vast majority of liver transplants are caused by alcoholic liver disease and increasingly fatty liver disease.

Dr. Casey Means (28:00):

And there was an interesting paper in JAMA, one of our top medical 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.

Dr. Ben Bikman (28:31):

Yeah. Well, you and I both know that conventional medicine, 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 and 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.

Dr. Ben Bikman (29:07):

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.

Dr. Ben Bikman (29:34):

And so 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 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.

Dr. Ben Bikman (30:09):

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 hyper insulinemia of insulin resistance where the elevated insulin is promoting lipogenesis within the liver itself now.

Dr. Ben Bikman (30:38):

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. Every paper that studies every scientist, every group that studies fructose and fatty liver disease notes that fructose is a massive contributor.

Dr. Ben Bikman (31:04):

In fact, Luke [Tappy 00:31:05] 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 a effective at reducing liver fat, but we have other evidence basically for me, 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.

Dr. Ben Bikman (31:57):

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 regimen 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, improving fat cell insulin sensitivity, and thus removing the key contributors to the fat that’s accumulating in the liver.

Dr. Casey Means (32:31):

Yeah, I think 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 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.

Dr. Casey Means (32:53):

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 fat cell hypertrophy story. And I’d want to dig in a little bit since we are on the … You did bring up this fat cell hypertrophy concept in the book and in your other work, you’ve talked about this which is that there’s sort of two different destinies of 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 course can then go to the liver and contribute to fatty liver disease, or you can have fat cells that replicate.

Dr. Casey Means (33:38):

And you’ve got tons of little tiny fat cells which is fat cell hyperplasia. So hypertrophy or hyperplasia, now these are signs of two different metabolic states in the body. Can you talk about that a little bit and what lifestyle or dietary aspects promote driving us towards not so good hypertrophy versus possibly better hyperplasia? And the reason I’m asking about that is to 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 protect us from this?

Dr. Ben Bikman (34:11):

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’s through the course of his or her life is moving towards insulin resistance and diabetes, Type II diabetes, there are several tissues that are going to become insulin resistant in that journey certainly by the time they become type two diabetic, multiple tissues have become insulin resistant, but it makes sense that there would be an origin.

Dr. Ben Bikman (34:37):

Now 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 understand how the fat cells become insulin resistant.

Dr. Ben Bikman (35:00):

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 cells getting significantly bigger and four or five times bigger than normal or alternatively, the fat tissue, what we can see in 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.

Dr. Ben Bikman (35:33):

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 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.

Dr. Ben Bikman (36:02):

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 finished puberty, late teens in girls, and maybe early twenties in most boys, then we have that 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 flat-lined 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 less 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.

Dr. Ben Bikman (36:51):

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 body are actually having to pick up the burden as the cell is leaking free fatty acids.

Dr. Ben Bikman (37:23):

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 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.

Dr. Ben Bikman (37:53):

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 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.

Dr. Ben Bikman (38:26):

And so the hypertrophic fat cells are trying to correct the poor blood flow by secreting this whole panel of proinflammatory 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.

Dr. Ben Bikman (38:56):

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.

Dr. Ben Bikman (39:32):

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 II 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 control tribute to fat cell hypertrophy. As much as I’m going to explain that these are actionable items, people should know that there’s also just a very strong genetic component to this.

Dr. Ben Bikman (40:06):

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 closing that avenue off.

Dr. Ben Bikman (40:39):

And again, that was inflammation and elevated insulin, 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 sampled, 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.

Dr. Ben Bikman (41:16):

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.

Dr. Ben Bikman (41:44):

I have my own drums that I beat very readily, but insofar as linoleic acid, 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.

Dr. Ben Bikman (42:23):

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-Hydroxynonenal which is for 4-HNE. Once again, just like ceramide-1-phopsphate, 4-HNE 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 proinflammatory.

Dr. Casey Means (42:49):

Wow, that was an incredible walkthrough Ben, thank you. One thing I just want to hit at home is just that the majority of our processed food and processed foods is about 80% of the grocery store are going to have these seed oils in them and refined sugar. It’s 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 it does this include these refined seed and vegetable oils that are going to be high in linoleic acid?

Dr. Casey Means (43:18):

And just thinking through everything you just said there and what is driving the fat cell hypertrophy, this more dangerous path compared to hyperplasia. 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 this journey towards not pushing towards the hypertrophy and just overall metabolic dysfunction.

Dr. Ben Bikman (43:48):

Yeah, yeah. In fact, I think Casey, I think you summed it up really well which was eat whole food. Even if a person, 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, 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.

Dr. Ben Bikman (44:15):

If by avoiding processed foods, one, 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.

Dr. Casey Means (44:31):

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. The title of this project is understanding the paradoxical rise in blood glucose in the content of a low carbohydrate diet and the use of real time glycemic status to alter behavior, and this project gets into a lot of interesting physiology around glucagon and insulin.

Dr. Casey Means (45:01):

And 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 to research project 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.

Dr. Ben Bikman (45:21):

Yeah, in fact, maybe the best way to go about it is answering that two part question in reverse. So glucagon is a hormone that is going to increase glucose, whereas and that’s 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 II 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.

Dr. Ben Bikman (45:52):

And we know that in Type I diabetics, that’s even more amplified. So 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 90’s or low hundreds and just sort of always hovering around there rather than being in the 70’s or the 80’s like you’d expect.

Dr. Ben Bikman (46:21):

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 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 call macronutrient challenges.

Dr. Ben Bikman (47:02):

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. 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.

Dr. Ben Bikman (47:35):

A cell needs to be told what to do with the energy that it has available. So we’re going to be doing a full survey of about 20 hormones and cytokines actually, 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 would expect based on the amount of glucose they’re eating, that their glucose levels should be going down.

Dr. Casey Means (47:58):

Really interesting, and what does this tell us about glucagon in terms of its function and maybe just for people who aren’t familiar with the hormone in general, 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 yeah be in a slightly higher range?

Dr. Ben Bikman (48:21):

Yeah, that’s a great question. So as I noted, glucagon does create an upward pressure on glucose. It’s 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 wanted. Now to that 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, and this is just couple decades ago, normal glucose levels were considered anything below 150.

Dr. Ben Bikman (48:54):

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, we’re around there, it was really catastrophic to health.” 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. When glucose levels were considered normal up to 150, not a lot of people were getting over it.

Dr. Ben Bikman (49:24):

Thus, few people were being diagnosed with the problem and there was much less drugs to be sold. By lowering 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.

Dr. Ben Bikman (49:49):

But also I’m too aware of the fact that in diabetes or, 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 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 200s when that normally starts to happen.

Dr. Ben Bikman (50:19):

I’m a little bit not indifferent, but I just cannot muster the enthusiasm for being worried about glucose. 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 hyper insulinemia 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.

Dr. Ben Bikman (50:57):

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 three micro units per mill and and their glucose level is at a hundred, I am inclined to give them a high five because to me, that’s a perfectly healthy range for the person to be in.

Dr. Casey Means (51:16):

Yeah, I think it’s a good perspective because we often can be quite glucose-centric, and I think looking into the historical precedent of why that might be the case i.e. In relationship to medications and whatnot is really interesting. Two questions I have about that, just to get your thoughts on. So one is just the general concept of glycation. 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 80 milligrams, stress liter and 110 milligram stress 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?

Dr. Ben Bikman (51:59):

Yeah, in fact, I’m thrilled you bro 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 test in order to capitalize on that. What’s interesting and very relevant to Levels, this is part of my enthusiasm for levels as a company and with its mission is that the hemoglobin A1C test came into vogue and basically single-handedly killed the oral glucose tolerance test because it was thought that the A1C is going to give us better overall information than one, than a fasting glucose which may or may not be true. But two, then an oral glucose tolerance test which I believe is not at all true.

Dr. Ben Bikman (52:44):

But that really is part of the evolution or the death of the oral glucose tolerance test was part the born from the obsession with hemoglobin A1C. But to answer your question explicitly, and then I’ll 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 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.

Dr. Ben Bikman (53:14):

So I’ll be a little agnostic until we can see something and I’ll continue to poo-poo it, but the dynamic test is not the same as the fasting test. 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 in 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 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.

Dr. Ben Bikman (54:04):

And someone 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 the frosted mini wheats.

Dr. Casey Means (54:23):

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

Dr. Ben Bikman (54:25):

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 cereal. And one of the reasons that the little Bikman 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.

Dr. Ben Bikman (54:49):

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 stayed for almost 12 hours. And I think it was of course exacerbated by my poor sleep because I went to bed 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.

Dr. Ben Bikman (55:20):

So I think there were multiple variables coming into play here, but back to my point, the dynamic view of glucose I think had tremendous diagnostic value because if someone is insulin resistant, another word or another outcome, I won’t say word cause 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 non-insulin resistant for other reasons. But nevertheless, if you are insulin resistant, you will have some degree of glucose intolerance.

Dr. Ben Bikman (55:53):

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 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.

Dr. Casey Means (56:28):

Yeah, this is where the research I think over the next five to 10 years is going to be so interesting, really drilling down in 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? It’s just we don’t totally know the answer to these things but I think context matters so, so much. And so the person with a fasting glucose of 95 high normal whose insulin is two 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.

Dr. Ben Bikman (57:06):

Kudos to Levels in all sincerity, I mean this. It is very hard to get support for these kinds of studies that don’t have some massive clinic supporting it. 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.