A1C, INSULIN & the Damn RANDLE CYCLE with Dr. Ben Bikman

Over the past few decades, thanks to Big Food and Big Pharma advertising and their egregious grip on mainstream media, the news outlets we've been given such a confusing picture of what human nutrition should look like that most of us are like, "I don't know, I give up. I've tried all these diets, I'm just going to eat what I want."

In reality, human nutrition is just as simple as the nutrition of any other animal on planet Earth. I have with me an expert in human metabolism, uh, digestive physiology, and an expert on all things pancreas-related. Today, the Right Honorable Professor Ben Bikman. Welcome, Professor.

Hey, brother. I'm glad to be here. Thanks so much.

Such a pleasure to have you back. And I'll let everybody know this is being filmed live in front of our private community. So for all of our tribe members, you actually have the ability to ask Professor Bikman questions, if, if, if I have your permission to do that, Professor. And so, uh, keep your questions as short as you possibly can. And as they, uh, blend in with the conversation we're having today, I'll bring you on and we'll, we'll answer your question. So think of a good question that, that, that has something to do with insulin, glucagon, the pancreas, beta cells, uh, A1C, fructosamine, caloric phase, insulin response, or that damn Randle cycle. And we will try to answer your questions.

Now, Professor, uh, give, give us just a 30-second CV, uh, so people, for the two people who don't know who you are in the metabolism community, they'll know why they should listen to what you have to say.

Yeah, yeah. I am a practicing professional scientist. Uh, I'm a biomedical scientist. So I have a lab indeed, right down the hallway where I am a professor at BYU. And we are publishing papers all the time, doing real-time research on humans, rodents, and isolated cells. And my PhD is bioenergetics, which means I have a unique appreciation for energy in living organisms and how the, in other words, how does an, how does a cell use energy? Uh, now, there's more to it than calories, uh, which is what brings me, I guess, to my main focus as a scientist, which is to study the, the ability of hormones to dictate how the body uses energy, and then all of the consequences that come from it not doing so very well.

Love it. I want to start talking first with you about insulin. Uh, in the first few years of my medical practice, I definitely knew what insulin was. Uh, 99% of my understanding was exogenous insulin and how to give that to people with diabetes. But increasingly over the past few years, all I care about, all I want to focus on and study about is endogenous insulin, the insulin that's produced by the beta cells in the human pancreas, and how important that is, and how underestimated. And and not even underestimated by the mainstream, uh, primary care practitioner, but just they're completely oblivious to the insulin that's produced by the pancreas.

Indeed. I think if you lined up 100 practicing primary care providers and you asked them what happens to, um, the beta cells in a person with type two diabetes, I think that the, at least 70% of them would say, well, as your type two diabetes gets worse, the, the beta cells burn out and they stop producing insulin. And that's why most people with type two diabetes, when the disease gets bad enough, they have to go on, uh, insulin injections. Walk us through how this is not true the vast majority of the time.

Yeah, yeah. In fact, I would even be more bold and bold enough, indeed, to say that if it is, if it is actually type two diabetes, and that's an important distinction because there is the kind of rare coincidence where someone with type two actually develops true type one. But it's not a consequence of the type two diabetes. That is just a bizarre confluence of events wherein this person has had this later-in-life autoimmune disease, namely type one. So my bold statement is, in type two diabetes, there will never be a situation in which the beta cells are gone. It is true that in some instances, insulin production has been going up for years in this individual. And and then eventually, the body becomes so resistant to its own insulin that the glucose starts to come up. And then in some people, so that's a reflection of the insulin resistance. But in some individuals, the insulin production will start to go down. Not all. Some just have a straight line and the insulin is as high as ever. Sometimes the insulin will come down a little, which further amplifies the glucose. But even when the insulin starts to come down, it is still much higher than it was before they ever started on this descent into metabolic derangement. Uh, it's still multiples higher than it was before. But all of this is just a reflection of how the conventionally trained clinician has been taught to focus on the glucose at the expense of the much more sensitive, much earlier marker, namely the insulin. If we had trained these clinicians to have an insulin-centric view of type two diabetes, in particular, then we wouldn't say, "Let's lower that glucose at all costs, even if we have to push the insulin up even higher," which is a very common course of treatment. And yet, it doesn't work to help improve any outcome. The more you give the type two diabetic more insulin, the more they die.

Absolutely. And do you believe that every clinician should be trained by some society or organization to check fasting insulin levels very, very early in their patients' metabolic career, so to speak? And if so, what do you, what would you consider an insulin level that's too high?

Yeah, in fact, indeed, Ken, that is the drum I beat louder than any other. If I can end my career, um, with having realized one single outcome, namely that insulin becomes a more commonly measured clinical marker, then I will have considered my career a success, frankly. Um, so that is absolutely the drum I beat the loudest. And it's difficult to get a firm cut-off. Now, I'm going to give them anyway, but I want people to know that insulin, like almost every hormone in the body, does have a little bit of rhythm to it, and it has a little play. And and so while I'm going to give some hard cut-offs, please everyone know that it's possible to kind of be outside of this and it be a bit of a false indicator. Now, having said that, if someone has a fasted insulin that is six micro units per mill or less, that's a very, very good sign that their insulin sensitive. If someone has, uh, fasting insulin that goes from seven to about the mid-teens, let's say seven to 17, just to kind of create a nice range there, that's a possible problem. Now, I emphasize possible because it is, it is possible that someone comes in and gets a fasted insulin measurement and it's at 11, but that just happened to be the high point in their natural little rhythm. And in fact, in most of the time, they're down around three or four. So that's why I say that's a bit of a warning range. But then if it's high teens into the 20s, that's generally going outside the natural oscillation of insulin, and then the score starts to get a little compromised. Now, please pardon the shameless plug. In my newest book, "How Not to Get Sick," that's this book right here, I actually give a bunch of clinical tests and have people create a bit of an, an amalgamation of all of these numbers to really come to a firm understanding of their own insulin resistance. But fasting insulin is the first one I talk about because it is the one that I think is the most overlooked for the value that it provides.

Now, totally agree. And, you know, LabCorp and Quest, the two largest diagnostic labs in the United States, both have, any, any fasting insulin that's less than 25, they consider that normal. Isn't that remarkable? And, and to me, that's severe hyperinsulinemia. If you're F, that's just further evidence that the average American, because those, those blood, those blood, um, cutoffs, those ranges are provided based on kind of national averages, yes. That to me is just further evidence of the problem that the average American is so insulin resistant that we think anything up to the mid-20s is normal. That's not normal. I totally agree.

Let's, let's talk about A1C. Uh, this is a, and again, this, if I ask that same 100 physicians, you've got a 40-year-old patient who's slightly overweight, their blood pressure is a little high, uh, but their fasting blood glucose is normal or just a tiny bit elevated. Should you check an A1C in that patient? I think that at least 40, if not 50% of those primary care providers would say, "No, I don't think it's worth the money." Let's talk about the A1C test, what it checks, what can falsely elevate or falsely decrease it, and is there another test that we should be considering if your A1C seems to be falsely high?

Yeah, in fact, let me start with that last point because there, there are a group of, there have been several biomedical scientists that have bemoaned the shift in clinical practice, um, to focus on A1C, given its, its challenges, which, which I'll elaborate on in a moment. But, but bemoaning it particularly because with the rise of A1C came the death of the oral glucose tolerance test. That used to be a more commonly used clinical intervention. But, you know, it's a little time-consuming, which means it's more financially, it's more costly. Um, there's a little more nuance into its interpretation, but it gives far more detail than the A1C gives for reasons that I'll get into in just a second. But by way of brief background, it's helpful for people just to appreciate that glycation is this chemical process that is, uh, a function of a reducing sugar, irreversibly, non-enzymatically. So it doesn't need an enzyme to do it, it doesn't need something to kind of mediate the two and bring them together. It's just this reducing sugar, glucose, fructose, galactose, even other molecules that you wouldn't think of, um, can fit into this where they will irreversibly bind to a protein or DNA or a lipid and create this glycation end product. Now, importantly, and this, in fact, is somewhat driven from a conversation that Ken and I have had just recently, that term glycation can even be invoked with other reducing sugars. So it's important for people to know that that term is sometimes used as an all-encompassing term, even though, as we'll get into, not all tests will measure all of that. But it's important for people to realize that as much as we focus on HbA1c or hemoglobin A1c, this is, in fact, itself a reflection of of glycation that can be happening everywhere. It's just not easy to measure glycation in the kidney, which is going to be increasing the risk of kidney failure, or it's not easy to measure the degree of glycation in the blood vessels, which is a very telling feature for atherosclerosis or the, the synthesis or the beginning of an atherosclerotic plaque. So as much as we just want to look at HbA1c as some marker of glucose in the blood, we should also appreciate that it can potentially be a sign of glycation that's happening everywhere, even including skin collagen, wrinkling, causing wrinkles and premature aging of the skin. All of these things can be impacted by glycation. So it helps us appreciate HbA1c, which, if we just drill right down to it, is us measuring the degree to which we've had this irreversible glycation binding to the functional part of the red blood cell. And very briefly, within the red blood cell, we have this complicated protein structure called hemoglobin. Hemoglobin's most famous job is to carry oxygen, and at the same time, to carry some other gases, even like carbon dioxide, albeit to lesser degrees. One immediate effect at the red blood cell is that the more it is glycated, the less suitable it is now to carry oxygen. So one immediate consequence of this is the person's reduced ability to move oxygen, potentially creating conditions of hypoxia or compromised oxygen movement through the body. Now, this, of course, becomes a particular problem in a diabetic, in someone who's chronically hypoglycemic. They not only have the, the, the glycation of the blood vessels damaging blood vessels, but to compound that, they also have the blood itself not carrying oxygen as well. So no wonder they develop such poor wounds and, and sort of decay flesh because the blood isn't flowing very well. So it's important for people to appreciate that what glycation is and how the HbA1c is a reflection of a greater whole-body phenomenon. But then, can you mentioned where it can be sort of misdiagnosed or misunderstood? It is so important for people to realize the, the, the problem with HbA1c, namely that while we always focus on HbA1c as a consequence of hypoglycemia, we need to remember that there's another part of this formula. That when we're measuring HbA1c, as much as we say it's a marker of gly, of glucose and glycation, we could also say someone could equally make the argument that no, it's actually, uh, a result of how long-lived the red blood cells are. Because a red blood cell that lives longer, that has gone beyond its 120 average days of life, it just becomes more likely that it will experience some degree of glycation. That's not the red blood cell's fault, it's not even glucose's fault, it's just the longer it has lived, the more likely it is to have undergone some degree of glycation. Thus, you could have someone who has very long-lived red blood cells, has very normal glucose, and yet their A1C is high. It's a false positive. It's a false sign of glucose. And that's more a function of the red blood cell living long. In contrast, you could have someone who has very short-lived red blood cells, perhaps because they're iron deficient or they're vitamin B12 deficient, alcol, yeah, yeah, right, yes. So they, a disease where the red blood cells have a very short life, they turn over much more rapidly. In this case, these red blood cells are never around long enough to even undergo glycation, even if a person's fasting glucose levels are high and they're struggling with hypoglycemia. So in this case, it's a false negative where the A1C looks normal, but in fact, there is a glucose problem. It's just that the fragility of that person's red blood cells masks it. You don't see it. So people, we have to appreciate that while A1C has value, while it can be a sign of glycation occurring elsewhere in the body, it also can't be taken as the gospel truth where it is the end-all marker of metabolic health. Like you started the conversation with, we have become so obsessed with A1C that we refuse to acknowledge its flaws.

Yeah. And any good doctor should know the list of things that can shorten the life of a red blood cell and give you a falsely low A1C. They should also know the list of things that can cause your red blood cells to live longer and thus give you a falsely high A1C. But I, I can just tell you from personal experience, the vast majority of primary health care providers, they might know about alcoholism, but that's, that's literally the extent of their knowledge about what could give a falsely high or low A1C. Uh, so I have noticed a signal. And that's, as a primary care doctor, I look for signal in patients, right? I, I change something, and then when they come back in three or six months, I'm like, okay, has that made a noticeable difference in enough people, routinely enough, predictably enough, that I can say, okay, I need to adjust my practice based on that. Uh, I have seen a signal in the carnivore community, very meat-heavy, meat-centric diets, where I'd say 5%, five out of a hundred carnivores will notice that their A1C's creeping back up. Not never to diabetic levels, but maybe 5.7, 5.8, 5.9. And many of, we, you and I have discussed this before, and I've discussed this with Shawn Baker and many other people in the carnivore community. How likely is that now that they're not eating all the inflammatory, hypoglycemic foods? How likely is it that the red blood cells are just living longer now than 110 days, which seems to be the average? It's leaving 120, 130, 140 days. How likely is that? And how can we ever dig into that and, and maybe provide some proof and some reassurance to the carnivore community?

Oh, yeah. In fact, my whole, um, viewpoint on it that I just elaborated with regards to the failure to appreciate variables that influence the longevity or the lifespan of a red blood cell, actually was born from this very issue where I would hear from carnivores where they would say, "Hey, I don't know what's going on. I reversed my type two diabetes, but yet my A1C is creeping." Um, it's exactly what you just said. And it was me wondering how could the physiology into this that led me to these conclusions, all of which is supported. So, just to kind of revisit that, I had mentioned two variables, namely iron, which is a fundamental component of hemoglobin in order to carry the oxygen. This is why someone who's iron deficient will experience the most common type of anemia on the planet, which is iron deficiency anemia. The number of red blood cells is fine, but the ability of the red blood cells to carry oxygen is not, because in the absence of heme iron consumption, you're not going to have sufficient iron, uh, oxygen binding capacity. And then I'd mentioned vitamin B12. Once again, this becomes relevant the further someone gets from eating animal-sourced foods, because there is no plant version, there's no plant source of vitamin B12. And in this case, it gives rise to another one of the most common types of anemia worldwide, which is pernicious anemia. That's a fascinating physiology to it, or cell biology. And I won't bore everyone with the details that I share when I teach this principle to my students. But basically, in this scenario, the, the bone marrow, which is the origin of the red blood cell, it has enough material to, to prepare the, the precursor cells, the cells that are going to someday become red blood cells. Normally, the process is the cells will grow and then divide, grow and then then divide. In the absence of sufficient B12, because for example, the person isn't consuming animal products, or because they've had gastric bypass and they don't have enough of a stomach left to, to absorb the B12, so they need injections forever. But in that case, the bone marrow is able to grow the progenitor red blood cell, but not actually divide them. So the person has this kind of paradoxical situation where the cells are big, but they're just not nearly enough. And so in this case, once again, the person has, they have the risk of having so few red blood cells that it can give, you know, a sort of mistake can, um, number here with A1C. Then my last point would be the fluidity. Um, the ability of the red blood cell to be as dynamic as it needs to be. The red blood cell is very unique among all cells in the body in that while it doesn't, it has very little by way of internal structure that enables it to slip through incredibly tight spaces, to move in and out of sinuses and capillaries. And to do that, it needs to be very pliable and squishy. Well, the more omega-3 fats you're eating, the more those fats get enriched in the membrane of the cell, allowing it to have a higher fluidity, to give it a little bit of squish and mean making it so that it can fit through spaces without shattering. As opposed to other fats that start to get enriched in that membrane, which can make it a little more rigid. So for these three reasons, in addition to several others, the more a person is changing the diet to be, to quote you, a proper human diet focused on animal-sourced foods, the more those red blood cells are likely to be more robust, a little healthier, longer-lived, and thus increasing the potential of the individual having an artificially inflated A1C. And in people like that, in the 5% of carnivores that I'm seeing, I don't know if you're seeing a different percentage. But if they have an A1C that's a little bit elevated and they're like, "What's going on here?" The test I recommend is a fructosamine test. I used to recommend a glycated albumin, but LabCorp and Quest both stop offering that test. But the fructosamine, even though fructo is in the name, it checks only for glucose glycation. Uh, it looks for the, the glucose lysine bond, I think is what it actually looks for. And invariably, every time a carnivore gets a fructosamine checked, it's within normal limits, verifying, verifying that they are not overly glycating. It's just that their red blood cells almost certainly are living longer because of their healthier diet.

And I, I want to dig into that a little bit. To my knowledge, there is no commercially available test that a doctor can order that checks for fructation or fructose glycation. And this concerns me because there are many doctors out there who are recommending to their patients, "Eat lots of fruits and vegetables." And, you know what? The patient's going to focus on the one that tastes better and the one that they don't hate, which is fruit. And so they wind up living on fruit juice smoothies. But when you check an A1C, you don't, you don't see reflected, you don't, that fructose glycation. And I, and I want to reiterate a point you said earlier, which is super important, because a lot of people, if you're not a doctor or a PhD, you just think, "Oh, well, uh, glucose just glycates hemoglobin, right? In the red blood cell. That's, that's what it does. That's the bad thing that it does." But Professor Bikman was very clear, it glycates every cell in your body. The cells in the nephron of the kidney, the cells in your heart, your cardiomyocytes, literally every cell in your body is also being glycated. We just use the glycation of the hemoglobin molecule, the A1C, as a proxy marker for all this other dangerous glycation that's going on in the human body. Do you know of a test that a doctor can order, because I don't know of one, that checks for fructose glycation, or even when it comes to drinking milk, galactose, yeah, glycation? Because I do not know of a test.

No, no, I don't either. Um, in fact, I love, in fact, this was something that, as you and I have communicated, this, you, you opened my eyes to this. Um, so, so we know that fructose is much more reactive than glucose, which makes this part of the conversation all the more relevant. As much as we focus on glucose, and, and rightly so, fructose is known to elicit these reactive reactions. That's a little redundant. These glycation reactions, again, that being a broad term to refer to any reducing sugar binding irreversibly to these molecules. It's seven times more than glucose. So, to say that again, because it was a bit awkwardly delivered. Fructose can induce glycation seven times more readily than glucose can. And, and thus, I think it is, uh, much more relevant. But no, no. All the more tragic. This fact is made. This is a, this is a non-enzymatic glycation. This is does not require an enzyme. This is not a pathway. This is just a function of basically how much fructose is in your bloodstream. The, the higher the level, the more the glycation is going to be. Is that correct? There's no, there's no clinical test. To answer the question, no.

Fortunately, there's no way to do it. So basically, people who are living on fruit juice smoothies are eating hundreds of grams of carbohydrates in fruit or fruit juice per day. There's currently all healthcare providers are blind to the fructose glycation. You cannot detect it.

Yeah, that's right. In fact, I would say, Ken, at the risk, just to give some answer, if perhaps the closest a person could come to understanding their fructation, or the degree of fructose-induced glycation, it would probably be uric acid, just as a surrogate marker. Because uric acid just runs so tightly with fructose metabolism, which itself, of course, is a product of fructose consumption. So, yeah, probably the closest we can get is getting a uric acid marker. And I think we had a question, uh, from some one of our tribe members. I'm trying to find it here, about uric acid. But I, I agree with you. I think uric acid is a, a fairly good rough proxy marker for the degree of, of fructation. Uh, what else do people need to know about uric acid levels and how they, how they give us insight into our own metabolism?

Yeah, yeah. In fact, what a timely question, because what if, if what I was doing literally one hour ago was working on a manuscript that we are preparing to publish. This is something I've alluded to over the past year or so, it's finally come to fruition, and we're going to submit it for publication. The joys of being a publishing scientist is the frustration of trying to then get your work published. But I do it for the students, because these are all student-led projects, and I want them to have that experience and then have that help them get onto their next part of their lives and career. So what we found was, so, so briefly, uric acid, um, and, and my friend and even collaborator on this project, Dr. Rick Johnson, has really been the champion. I was unaware, I'll confess, of the effects of, of fructose, let alone the involvement of fructose, until I read his work and became familiar with him. And it's been one of the great joys of my life professionally to get to know him better and now consider him a friend. He's a wonderful gentleman scientist, great guy. He was really the one who highlighted that every time your cell is metabolizing a molecule of fructose, it's giving birth to a molecule of uric acid. Which makes it far more relevant to uric acid production than any amount of meat or fish consumption, which is an idea that just continues to really fail. You see in the highest meat-consuming populations on the planet, like Hong Kong and Argentina, their, their uric acid levels are, are nothing. They're absolutely bottomed out. And so let's, we just have to kind of drop this idea that it's meat and fish that's contributing to uric acid. No, it's fructose. Look at those societies that are eating a lot of fructose or a lot of sugar or drinking a lot of fruit juice, then you'll see the uric acid. Then uric acid itself can have myriad consequences, including what Rick has outlined, namely stimulating hunger. What I have focused on, and back to the paper we're publishing, is looking at how uric acid is a contributor to insulin resistance. However, I consider it a secondary cause, because it happens through its increase in inflammation. Uric acid is known to be an activator of inflammation. Now, what we're studying is to try to reconcile the, the paradox that some people notice on ketogenic diet, which is twofold. On one hand, they may notice that in some people, the uric acid levels stay high or even go up a little. Second, their inflammatory markers have absolutely dropped. So they much less inflammation, and indeed, much greater improvements in insulin sensitivity, as evidenced by their resolution of type two diabetes. This shouldn't be happening, given uric acid's involvement. However, what we are publishing, so this is early data here, um, so unpublished results at the moment, is that ketones are, are sufficient to wipe out the inflammation caused by uric acid. So ketones are known to be anti-inflammatory molecules. So this is another instance whereby ketones have gone beyond their simple caloric value. Ketones have a caloric value roughly comparable to glucose, which is good news for all the cells that want to use the ketones as energy. But at the same time, ketones act as a signaling molecule, and in this case, controlling, literally inhibiting inflammation. So whereas uric acid levels are trying to stimulate this kind of metabolic inflammation, ketones are inhibiting it. And that might help us reconcile how we could have a situation where a person has stubbornly elevated uric acid, and yet every metabolic and indeed inflammatory marker has improved. It's because there's a lot else going on, including the contribution of the ketones to directly antagonize the pro-inflammatory effects of the uric acid.

Yep. I love that. I think that's vitally important. And I've had Dr. Johnson on once or twice on the channel, and, and he's a brilliant, brilliant scientist, and I have great respect for his work. Um, let's talk about something that I think is more important. Most doctors have never heard of this, but I think it's more important than a lot of people give it credit for, and that's the caloric phase insulin response. And I'm going to try to describe this. Feel free to correct me if I get it wrong. Basically, the human body has evolved in a set of circumstances over a long damn time where if we taste a sweet taste in our mouth, that is a signal to our body that sugar is about to come down the, the digestive system, and the body preemptively gets ready for that by increasing insulin levels. Now, I think that even smelling a wonderful cake baking in the oven probably raises, can raise your insulin, at least in some people. I think probably seeing a Sonic commercial for their hot fudge cake, I, I'm almost certain that that raises my fasting insulin level, my insulin level, if I watch that commercial and I think about that too hard. What is the research on caloric phase insulin response with regards to, and not only, um, sugar, but also non-nutritive sweeteners? Allulose, erythritol, stevia, monk fruit. Do you think there's an insulin response to using these sweeteners? Is it a big enough response for people to care about? Does the normal distribution curve in human physiology apply? In other words, some people need to worry about it, other people, maybe not?

Yeah, well, I, I hate to take the diplomatic route for fear that someone accuses me of just being a bit of a wuss, but I'm, I'm going to, my default answer is the latter, what you just said, which is I feel very strongly that there is not a uniform response. And I'm comfortable stating that not only because of people's experiences, the anecdotal reports, which is a scientist, I have to take very, very lightly or loosely, but also these scientific evidence showing that you can alter, at least in animal studies, you can alter an animal's insulin response to a sweetener by altering its microbiome. And so it is likely so. I do have some justification in saying it probably depends on the individual. Now, Ken, you mentioned a couple interesting points. So this, the caloric phase is this state or this idea that you can elicit insulin secretion in the absence of actually consuming something before it even ever hits your bloodstream. Um, the original research touched on this by looking at the degree to which the moment you're tasting it, which is what you'd alluded to. But then you also touched on, indeed, this is supported by evidence, smelling certain foods will elicit this gastric and then phase and insulin secretion. I've not seen the evidence on seeing food, but it's entirely possible. It makes sense to me. If smelling it, if tasting it, then why not seeing it? This other sense that is inextricably linked to, to the eating centers of our brain. It makes sense to me that it would also play into it. And I wouldn't be surprised at all that within seconds, I could probably find multiple studies to support it. So all of that would fall under the umbrella of the cephalic phase. Now, I, I know this is going to be a sensitive topic. My general takeaway is, don't, some people respond poorly to sugar substitutes? Everyone, I would say, responds poorly to sugar. As much as I'm amused when people want to, um, really start vilifying sweeteners, and then I say, "Well, why aren't you vilifying sugar?" Uh, you know, it's, you know, they'll say, "This study in in rats gave aspartame, they cause cancer." Yeah, but if you gave them that much sugar, they would have not only had cancer, but also diabetes and kidney failure and blindness and everything else. So maybe in the grand scheme of things, it's not so bad. But we need to appreciate the limitations of those animal studies, of course, which, which are significant. My general takeaway is most of the sugar substitutes are going to be better than sugar itself. That's, that's right. That's right. Yeah. And then, and then when we start to map them all out or put them on a spectrum, it's enormously variable. Where on one hand, you have the sugar alcohols, which tend to have a pretty robust or at least a significant increase in insulin, and not all of them, though. Erythritol appears to not. But then others like xylitol kind of does. Maltitol, mannitol does have an insulin effect. Aspartame has little to no effect, although it might amplify an insulin effect if it's consumed with starches and sugars. So that's an important consideration. Some of these will have no insulin secretion on their own, but will amplify insulin secretion if it's being consumed at the same time the blood is getting loaded with actual glucose. And then on the other hand, we just published a paper, and we're doing a human trial now on allulose, a rare sugar. So it doesn't quite fit into the sweetener categories, which in our evidence with the animals, we already published no insulin response whatsoever. And in the humans, the, we've had about five humans come through, early data also suggests no insulin response. Now, interesting, having said all of this, having said all of this, I do think a person should pay attention to how they behave after they've consumed this sugar substitute. That's probably a decent surrogate for whether you are experiencing a cephalic phase or any phase of insulin secretion. Because if you consume this and then it triggers hunger, that is causing this, um, kind of starchy sugary craving behavior, you probably did have an insulin bump, which is now affecting, causing a hypoglycemic bump. And when the body gets hypoglycemic, it wants to correct that hypoglycemia and will drive you to want to consume starches and sugars to try to correct what it perceives to be a little bit of a bump. So as unscientific of an answer as that is, if a person, if, if there's someone listening and they drink a Diet Coke and it absolutely just satisfies them and doesn't lead to any other eating or drinking behavior to try to fill that glucose gap, then I would say that's a person who's likely not experiencing a cephalic phase insulin secretion and can enjoy that as a, as a, a treat. However, if someone does this, and maybe you need a CGM to really know what's going on, um, sometimes you can't rely on your own behavior because as my old dad taught me so well so many years ago, humans are great self-deceivers. It's hard to be honest. Our, yes, yes. So we, if you can see on your CGM or you notice that you start to crave stuff, then I would say that is something you need to start weaning yourself off of.

Totally agree. Here's the question. She Jerry re asked it. She's one of our tribe members. It was my uric acid question. Maybe we can talk about allulose. So this is relevant to what we're talking about here, and how it can affect uric acid. It seems to lower Jerry's uric acid level when she uses allulose. Yeah. So what do you think about that?

Yeah, in fact, I am really looking forward to more studies coming out about this, including some from my own lab. But the human study we have going on now, this is anecdotal, but I will state it a bit emphatically because the evidence is just so convincing. I have seen people cut their uric acid levels in half. Um, so to go from problematic to very good levels within just weeks by doing, like they're, they're ketogenic, they're kind of carnivore consumers or very low carb, and they just start taking 10 to 20 grams of allulose per day, and their uric acid just gets corrected like that. The, the, the phys, the biochemistry of it is probably because uric acid is fructose's twin. It has literally one single carbon is flipped at the third, at the third carbon. It has one little unit that is flipped down. So it's what's called an epimer in chemistry terms. But because of its similarity, it's a direct competition for fructose. And the consequences of this mean that fructose metabolism plummets, and thus uric acid synthesis plummets as well. So that is something I, um, see really getting evidence to support in the near future. But the anecdotal evidence is incredibly compelling. Now, full disclosure, I am an advisor for a company called RX Sugar. But if I will say it shamelessly, if someone's interested in some allulose products, just check out RX Sugar. The only reason I'm affiliated with them at all is because their allulose products are just so well done.

Yeah. And everybody keep in mind, Professor Bikman's a lot like me. Uh, it is really irrelevant how, how many zeros are on the check that a company offers me or Professor Bikman, if their product is crap, he and I both are going to say it's crap, and we're not going to take that check, no matter how many zeros are involved, because we have higher priorities than a large bank account. So I, I don't fault you at all for recommending something that, that with your scientific mind, you see benefit. So would you, would it be fair to say that allulose is, is maybe your favored sweetener, non-nutritive sweetener of choice? And what, what would be the three non-nutritive? Because the reason I ask is, it seems like every damn week, Professor, there's a new article out, you know, "Allulose causes butt crack cancer," or "Erythritol causes your head to explode." Like every week, as, as sugar becomes more and more unpopular, yeah, it seems like that one of the non-nutritive sweeteners gets attacked. What's your, what's your currently your favored based on the research? And then maybe what are your top three that seem to have escaped, um, really meaningful research showing that they might harm human beings?

Yeah, so I do think it is discouraging, though, Ken, just to add on to what you just said. It seems like anytime there can be an article that vilifies an alternative to sugar, boy, it makes the headlines. Just like anytime there's even a whiff of evidence that red meat is bad from all these horrible correlational studies, boy, it makes every headline. And, and I, I hope people are increasingly skeptical of what mainstream media outlets are trying to tell us with regards to perhaps all kinds of things, but certainly diet. Um, so, yeah, it's, it's discouraging. Um, anytime, uh, this evidence comes out, and there's always substantial flaws with the way the data are interpreted. Um, so my favorite is allulose. That is the one I use the most readily, and the one that we use for baking. That's the one that the kids indulge in. Um, that's what I want to stock the pantry with by way of indulgences. And thankfully, allulose is growing in its use across a variety of products, so it's just getting easier and easier to want to default to it. Other sweeteners that I like are, um, Stevia. I like Stevia, monk fruit extract. Um, and to be honest, I, this is probably going to ruffle some feathers. Yes, even aspartame. I think the, uh, aspartame is fairly benign. Pretty darn benign. It just gets converted into amino acids, for goodness sakes. Um, unless someone has a known genetic defect in the ability to metabolize asp, which is tested for at birth, then I don't believe there's any reason to be worried about it. Now, on the other end, the ones that I'm the most, um, wary of are probably some of those sugar alcohols that I mentioned, um, early on. Um, the evidence on sucralose is a little, um, a little murky. That one is sort of to be determined the degree to which it is capable of, you know, causing some problems across the blood-brain barrier or, etc. But until that is really settled on that, you know, the jury's out there. But in the meantime, I'd really point a finger and try to avoid some of those sugar alcohols.

And let me be very clear. Um, I don't disagree with Professor Bikman. But when I, when I look at human biology through an evolutionary lens, it becomes very apparent that never in the history of humanity was it ever considered normal, or was it ever even possible, to have a, a sweet, sweetened cup of coffee every single day of your life, right? Never was it, never was it possible to have a dessert after every meal. That is a very, very modern innovation. I would say, innovation, is that a word? The opposite of innovation, yeah. Uh, I, I, I fear that there are ramifications and repercussions from people being trained by basically mainstream media to think, "Oh, I need sweetener in every cup of coffee. I need sweet, something sweet with every meal." Well, regardless of what it's sweetened with. And so I would, I would just caution everybody. Biology is important. It matters. It's literally what the rules that you're built by. Don't discount that for 99.999% of human existence, you would have something sweet in your mouth for a few weeks each year, and that was it. Um, do you, do you agree with that?

I do. I do. I, I, I absolutely think that we need to be mindful of behaviors where we are, um, leading ourselves into constantly into, I guess, a form of disordered eating where we feel like we have to, it's a reward, always at every moment, especially as a parent, where everything has to end with something sweet. That's not, I just don't think that's the case. Now, Ken, if you'll allow me, someone in my community asked about the study that showed erythritol and blood clotting. That was a study, of course, that made headlines about six to eight months ago. The great, the great flaw with that study, while it was human, they found that people with higher erythritol levels in their blood had higher risk of blood clots. One of the great problems with that study was the absolute failure to acknowledge that erythritol is actually a molecule that can be endogenously made. So our own bodies can actually make erythritol from glucose. And so one of the great confounding variables in that study, and boy, did it make headlines, is the fact that people with hyperglycemia or even type two diabetes, which is the greatest risk of heart disease, that's the greatest contributor to heart disease, type two diabetes, that that's a huge confounding variable that these people who are hyperglycemic probably have a lot of other things going on, including insulin resistance. And while erythritol was positively correlated, we have to remember that in that study, the great flaw was that it could not prove causality. It's just another instance of correlational evidence being mistaken as causality. And again, in this case, to really put a fine point on it, chronically elevated glucose will start to get converted into erythritol. Um, that's not the only molecule, by the way, even sorbitol. There are a handful of molecules that are created by elevated levels of glucose, thus creating, as I've stated already, a pretty huge confounding variable in that study.

Yeah. Uh, my next question might be a little sensitive. It might upset some folks. And so I want you guys to all know that we're, we have these conversations to try to help expand your paradigm of thinking about the world. We're not trying to convert anybody to anything. Um, I was raised a very devout conservative Church of Christ family. That's, that's how it was raised. The, the very word evolution was anathema. Like it would, it would get you banned from the dinner table when I was growing up, okay, to even discuss that. It was not, Overton's window had no runway for that word when I was growing up. But the more, the more deeply I've delved into medicine, nutrition science, I've come to believe the statement that really, you can't really understand anything in human physiology, human nutrition, unless you look at it through an evolutionary biology lens. Do you agree with that statement? And if so, how do you reconcile? Because you, you're like me, we're, we're both devout in our belief of a Divine Creator. We, I don't think either of us have any doubt whatsoever about that being the truth of the matter. How, how someone, how can we hold these fervent, deep religious beliefs, but yet say the common sense truth that you have to, you have to look at evolutionary biology if you're going to understand any of this physiology?

Yeah, yeah. You know, let me just say, what a, what a fun question. This isn't something I normally get to talk about, but as much as people, it's very important. Don't you agree? Oh, I, I hope so. I hope it's important. I hope this is something people think about. I, I, in fact, if you'll allow me for saying, I think one of the problems, certainly within the United States and maybe the Western world in general, is our forsaking of religion and the community and the.

Morals that come with that, regardless of your religious tradition. Uh, so I, I do think it's important, and I'm, thus, I'm happy to talk about it. It is something I've thought a lot about because I am a scientist. I am a very religious, devout, um, member of my church and, and Christian, but I'm also a professor at a religious university. And, and so this actually is something at BYU, um, has decades ago was a really big issue where, where it was really debated. Is this a principle we're teaching or not? Now, it's, it's very readily taught. Um, now, having said that, my own thoughts, if, if everyone allow me just to really be personal here, and you've opened up the ability for us to do that, I think, to me, evolution is a principle that I believe is real.

Now, first and foremost, let me just say, we're getting into a realm where there are no firm answers, which is uncomfortable for a cell biologist because I like to be able to do X and see that it leads to Y and Z. I can directly intervene in the human or the rodent or the cell, and so I know that I know exactly that what I just did caused this outcome. Um, with evolution versus creation, we truly cannot know. Um, and there's no way to definitively prove this. Now, what I think is very provable is the concept of adaptation, um, which lends itself to an evolutionary view. And so whether God used evolution to create all life or not, you know, I could see that it would, I could say so. These ideas are not irreconcilable. Absolutely not in my mind. They're not. That, that God could have created humans through a process of evolution, no problem. I'm good with that. If, if that is the way, and I have no problem with it.

However, Ken, and this is where I'm going to get in trouble. If you look across every animal kingdom, every, every sort of line, and I'm not an evolutionary biologist, I'm a cell biologist, they're not the same. If you look across all of these lines, you know, look in the kind of canine family, you look at the pinnacle of that canine family, and you're going to see all of the kind of near descend or or precursors that that connect it to being the pinnacle animal. Look in the, I don't know, other, other families, whatever they are, you can see a very tidy line that goes from the most basic version of what they are to the most complicated version. It, to me, is a point of interest that if you look in the primate line, where we get lumped in, we're at the top. And there is so many gaps between us and the next closest relative, if you will, and I use that term loosely, the chimpanzee, that even as a, a very rational scientist, now, I don't mean to use the word rational in a weaponized form. I'm also a very rational religious person. Yep. Every scientist, as much as he or she may hate to admit it, everything we do as a scientist is based on faith. I have faith that this experiment is going to work. You know, so the idea that it's irreconcilable faith and science is, is kind of laughable to me. But as a religious scientist, and a religious and rational religious scientist, I can't help but look at that enormous gap between humans and our next closest relative and say, well, where are all the links here? Because we see them in every other line, and yet they're not here. And so I kind of wonder, is that evidence that we really were created in a moment?

And, and just to add to that, because I have, I have been digging deeply into primate evolution, human evolution, I'm right in the middle right now of reading this, our, our closest cousin, chimpanzee. In every other, uh, uh, clade of, of mammal that you brought up, carnivore, uh, or canines, they, the, we know exactly the lineage. Yes, it's there's, it's not up for debate. The, all dogs come from the gray wolf. There is no argument. There is no doubt. And when you look for what's the human lineage or the human family tree, as descended, uh, six and a half million years ago from our, our last common ancestor with the chimpanzees, the gorillas, the bonobos, it looks like this. It's also laid out like, oh, we know this. This is what it was, right? Australopithecus, and, and then Homo habilis, and all the others. But when you, when you get a paleoanthropologist and you hold their feet to the fire and say, and say, who was for sure, no ifs, ands, or buts, what is the human lineage from our last common ancestor with chimpanzees? They'll hum and haw. But when you really say, no, no, I want to know what is the lineage, they will admit, well, we don't, we're not currently sure. We don't know. And you're right, there are all these seeming branches that come off, and, and then there was probably also cross-breeding, uh, but while we were still able to do that. It's not known. The, the lineage from our last common ancestor with the chimpanzees, it is not known. Our family tree, there are hypotheses, but it is, it is not nearly as clear as it is if you say, okay, well, what about whales? I hear that they're very closely related to hippos, and they're like, oh, yeah, here's the exact lineage how they separated, went back to the ocean. But that we do not have that degree of certainty with the human, human ancestors. And I think that that may speak to the point that you were making.

Yeah. In fact, maybe Ken, if I were to sum up my sentiment on it, I'm open-minded to any of these ideas, but I wish other people were too. I wish that when we talked about evolution, people should appropriately use the word theory, and even use the word believe. Um, these are terms scientists don't like, and yet you cannot speak about human evolution to authoritatively because there are so many, it's all unknown. And so I think that scientists nowadays, it is so, it is so, um, unforgivable to be humble or meek. How tragic, you know, that the scientists should be among the most humble people because we should at any moment be prepared to reject our entire career and everything we've ever published if the data refutes it. What a humbling thing. And so as much as we scientists are supposed to be seekers of truth, which is what we are in our purest sense, we should talk about this thing as using words that are uncomfortable to us, like, I believe in the theory of evolution, because we cannot, we cannot state it as fact. There's nothing to prove that it's absolute fact. Now, I'm not saying it's wrong. I'm not. But it does mean we should be careful in our language and, and say, emphasize that it's a theory. Why? First and foremost, no one can debate that. But the moment you're talking theory, you have to start using softer language. You can't say, you could say, I know it's a theory, but you cannot say, I know humans evolved. No one can state that. That is an erroneous statement currently.

I totally agree. Now, let's talk about a subject that, uh, is not quite as contentious as evolution, uh, and, and where humans came from, but it's quite contentious in the keto and carnivore community, and that is the damn Randall cycle. Uh, you, you published a short video recently which I thought was very clear and very helpful for people, uh, because the Randall cycle is being talked about more and more, even though it's quite obscure, and there's not a lot of, of, of research really laying this out and, and showing long-term, like, yes, this is more than just a hypothesis, this is something that really, really matters. Give us your take on the Randall cycle. How important is it really for somebody following a proper human diet, low carb, keto, ketovore, carnivore, and is this something that we should think about and, and explore more? Is more research needed? What should we think about the Randall cycle?

Yeah, yeah. So, Philip Randall, he'd just be turning in his grave, I bet. He's just laughing at everyone who's invoking this idea that I think he was pretty casual to put together. So, to answer one of your questions directly, to what degree do we need to be worried about it? Uh, laughably irrelevant. Um, this is an academic idea, and, and as happens too often, academic ideas need to be challenged as to their relevance in the real world. In other words, to what degree should this idea leave the Ivory Tower and be turned into, um, practical applications in the real world? This is one of those where it's an interesting, it's an interesting, um, feature of biochemistry, no doubt. But it is also so intuitive that if a cell, like imagine, is this, is this analogy going to work? Imagine a hybrid engine that has two fuel sources. I, our family car is a Toyota hybrid van. We love it. Incredible, incredible car. I wish it had a little more clearance because we're in Utah, we go skiing all the time, but incredible car. I love the hybrid aspect of the engine where if we need an immediate rapid burst of power, the engine is going to rely on battery, it's going to go electric. But when we're just cruising down the freeway at 80 miles an hour, hey, that gas-powered engine is far better. So that is reflective of a cell with the mitochondria, everything but the red blood cell. Um, it has the ability to choose fuel. Mind you, far more than just two fuel sources. And so it's no surprise then that if the cell has an abundance of one of those fuel sources, but not another, well, then it's going to just burn more of that other one that it has more of available to it. It's so intuitive that it, it is, I hate to say it, a little laughable that people get so worked up about this Randall cycle, the glucose fatty acid cycle.

But at the same time, to maybe just put one last comment here about it, it's that we still, even still, we cannot assume that the cell will behave rationally with regards to what it has access to, because it's hormones like insulin that dictate what the cell does with energy. Even Dr. Randall knew this, that if a cell has equal access to fats and glucose, it's the presence or absence of insulin that will dictate which fuel is getting used. So even to the hormone, back to the hormones, that hormones, especially insulin, tell a cell what to do with the energy that it has. And then the most, the most obvious application of this, and when I elaborated on it in my, my metabolic classroom episode, is looking at a type one diabetic. A type, if you measure the f, the, the nutrients in a person with untreated type one diabetes, they have levels of glucose that are through the roof. They have levels of fats that are through the roof. Their free fatty acids are astronomically high. So we have a perfect situation where both of those are elevated, and guess which one they're using? They're only using the fat because if insulin is low, the cell is fat-burning, even though it has abundant, 10 times more glucose than it should have around it, it has access to, and it's still not using the glucose. That is a direct refutation of the idea that it's just a matter of balancing out which one the cell has access to. In contrast, the moment you give that type one diabetic a proper dose of insulin, immediately the use, the reliance on fat is turned off. The reliance on glucose is immediately maxed out. Thus, it is the hormone insulin, especially, that dictates which part of that Randall cycle, or which fuel, to really put a fine point on it, the cell is relying on. So the Randall cycle is an interesting academic thought experiment, and it has a very intuitive aspect to it as well. But the more we try to then separate that out from hormones like insulin, we're not only spitting on the work of Dr. Randall himself, um, but we're also just ignoring fundamental biochemistry and cell biology that seems very well explained and, and fairly self-evident.

Uh, thank you for that. Uh, as we wrap up, Professor Bigman, you and I are both on the board of directors of a new diabetes society called the American Diabetes Society. And if any of the viewers want to check that out, there's a link in the show notes. Uh, we, when I first talked to you about this, you were as excited about this as I was. Why do we need a new diabetes organization to help people with type one, type two, MODY, LADA, and all other variants of diabetes? Why is this so needed, and what do you see the role of the American Diabetes Society being going forward in the future?

Yeah, yeah. Thanks for bringing attention to this. Of, of course, one reason I'm excited about it is because the trends globally for diabetes prevalence continues to go up. So this is obviously a problem that needs our ongoing and continued attention. Now, I have long, or I should say, had long been a member of, of the American Diabetes Association, um, and I had stopped my membership a number of years ago because I became so disenchanted with their total, I would say, capture by entities that I don't believe have the best approach to diabetes resolution. Um, that the ongoing efforts almost to ignore the substantial and, in fact, almost total role of diet in several of these, particularly type two, which is by far the most common, it really put, was such a, a conflict for me that I could no longer become a paying member of that society. What? Yep. So what I'm imagining here with the American Diabetes Society, which Ken, to your credit, you were the leading push on this, this really can become a new version. Um, as diabetes trends continue to be troubling, this is a direct, a new alternative where people can support. Just like the American Diabetes Association gets support overwhelmingly from drug companies, we have the ability to start fresh and to, and to stay clean where there's no obvious, there's no conflict. But even getting to the point where, just like the American Diabetes Association has an annual meeting where they invite scientists from all over the world to come and present their data, the ADS, the ADS can get there too. Just like the ADA funds diabetes-related research projects, the ADS can get there as well. So this is something that really does have a tremendous potential, and it's off to a great start to start changing the conversation at a almost a national level, um, with regards to how we are looking at diabetes problems and then ultimately how we're treating them.

Yeah, I totally agree. And if anybody wants to check out the ADS, they'll link to the websites in the show notes. Uh, the ADS now has a Twitter or X account, an Instagram account, a TikTok account, and a Facebook page. And so I would encourage everybody to go and follow those. In the coming months, me, Professor Bigman, Eric Westman, Tony Hampton, Dr. Kevin, Dr. Marela Glant, and our list of, a growing list of registered dietitians are going to be putting out position papers. We're going to be putting out, uh, treatment guidelines for physicians and other, uh, healthcare providers, and lots of recipes that will rather than, uh, satisfy your sweet tooth, will actually help you get your type two diabetes into remission and keep it there. And if you have type one, allow you to have a normal A1C and normal, and also use 80% less injectable insulin. And so I'm super excited about that, and I'm so glad to have you on board. Uh, thanks for doing this interview today. This has been absolutely one of my favorite interviews I've ever done. Uh, you're one of my favorite people, so I guess that makes sense. Thanks for the work you're doing. Now, I see a book back there on the bookshelf. Before we go, I want you to tell everybody about this new book I've heard about.

Yeah, yeah. Ken, I feel the same way. What a pleasure. You're just such a great guy. I'm very, very glad to be connected with you and grateful for the association we have professionally and personally. Yes. So, of course, I always talk about insulin resistance, and that was the justification for why we get sick. It was, this was just a conversation I thought was not being had enough. And then the follow-up book, How Not to Get Sick, is just more of the actual application. As much as I put myself in the realm of teacher, and, and I've always loved the idea of, I just teach principles and then let people apply them how they will. Some people want a little more application of some of these ideas, and that's where How Not to Get Sick comes into play. And they're both available anywhere books are sold.

I love it. Thank you so much, Professor. Now, back to the lab. You've got work to do. Uh, I appreciate it so much. Everybody, I've got links in the show notes for Professor Bigman. If you want to learn more, have a great day, Professor.