67: Why A1C Isn't Enough - Insights from Dr. Ben Bikman with Dr. Ken Berry

Sam, I want to start talking first with you about insulin. In the first few years of my medical practice, I definitely knew what insulin was. 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 under underestimated and not even underestimated by the mainstream 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 ask them what happens to the beta cells in a person with type 2 diabetes, I think that the at least 70% of them would say, well, as your type 2 diabetes gets worse, the beta cells burn out and they stop producing insulin. And that's why most people with type 2 diabetes, when the disease gets bad enough, they have to go on 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 2 diabetes, and that's an important distinction because there is the kind of rare coincidence where someone with type 2 actually develops true type 1, but it's not a consequence of the type 2 diabetes. That is just a bizarre confluence of events that, wherein this person has had this later in life autoimmune disease, namely type 1. So my bold statement is, in type 2 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, for years in this individual, 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, it is still much higher than it was before they ever started. On this descent into metabolic derangement, 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 help have an insulin centric view of type 2 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 2 diabetic more insulin, the more they die.

Absolutely. And do you believe that every clinician should be trained that 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 with having realized one single outcome, namely that insulin becomes a more commonly measured clinical marker, then I have considered my career a success, frankly. 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 so while I'm going to give some hard cutoffs, 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 6 micro units per mil or less, that's a very, very good sign that they're insulin sensitive. If someone has 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 possible that someone comes in and gets a fasted insulin measurement and it's at 11, but that just happens to be the high point in their natural little rhythm. And in fact in most of the time they're down around 3 or 4. 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 the, this book right here, I actually give a bunch of clinical tests and have people create a bit of 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.

Oh, I totally agree. And you know, LabCorp and Quest, the two largest diagnostic labs in the United States, both have a, 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 fasting insulin.

That's just for evidence that the average American, because those, those blood, those blood cutoffs, those ranges are provided based on kind of national averages. 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 a 1C. This is a. And again this, if I asked that same 100 physicians, you've got a 40 year old patient who's slightly overweight, their blood pressure is a little high, 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 4, 40 if not 50% of those primary care providers would say, 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 are a group of, there have been several biomedical scientists that have bemoaned the shift in clinical practice to focus on a 1C 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. There's a little more nuance into its interpretation, but it gives far more detail than the A1C gives. For reasons that I'll, I'll 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 a function of a reducing sugar irreversibly non, 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 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 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 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 skin collagen, 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 ox. 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 hyperglycemic. They not only have 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 the they develop such poor wounds and sort of decay flesh because the blood isn't flowing very well. So it's important for people to appreciate what glycation is and how the HBA1C is a reflection of a greater whole body phenomenon. But then Ken, you'd mentioned where it can be sort of misdiagnosed or misunderstood. It is so important for people to realize that the problem with HbA1c, namely that while we always focus on HbA1c as a consequence of hyperglycemia, 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 glucose and glycation, we could also say someone could equally make the argument that no, it's actually 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 cells 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 or Algarol. Yeah, yeah, right, yes. So a disease where the red blood cells have a very short life, they turn over much more rapidly. In this case, the 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 hyperglycemia. 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 mask it. You don't see it. So people, we have to appreciate that while a 1C 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 a 1C 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 that 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 a 1C. But I can just tell you from personal experience, the vast majority of primary healthcare providers, they might know about alcoholism, but that's literally the extent of their knowledge about what could give a falsely high or low A1C. So I have noticed a signal, and that's as a primary care doctor, I look for signal in patients, right? 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? I have seen a signal in the carnivore community, very meat, heavy meat centric diets, where I'd say 5%, 5 out of 100 carnivores will notice that their A1C is creeping back up. Not never to die 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 Sean Baker and many other people in the carnivore community. How likely is that? That now that they're not eating all the inflammatory hyperglycemic 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 living 120, 130, 100 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 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 2 diabetes, but yet my A1C is creeping. It's exactly what you just said. And it was me wondering, how could the physiology fit 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 oxygen binding capacity. And then I'd mentioned vitamin B12. Once again, this is becomes relevant the further someone gets from eating animal sourced foods, because there is no plant version, there's no plant source 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 bone marrow, which is the origin of the red blood cell, it has enough material to, to prepare 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 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 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 mistaken number here with a 1C. Then my last point would be the fluidity, 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 cel 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 shatter, 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 heartier, 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 of it, checks only for glucose glycation, looks for 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 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 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, 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, 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 Bickman is very clear. It glycates every cell in your body. The cells in the nephron of the kidney, the cells in your heart, your cardio myocytes. 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 glycation. Because I do not know of a test.

No, no, I don't either. In fact, I love. In fact, this was something that, as you and I have communicated this, you, you opened my eyes to this. 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 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 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 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, unfortunately, 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 them. So the person has this kind of paradoxical situation where the fructose consumption. So yeah, probably the closest we can get is getting a uric acid marker.

I agree with you. I think uric acid is a, a fairly good rough proxy marker for the.

Degree 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 mistaken number here with a 1C. Then my last point would be the fluidity, the ability of fructation.

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 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. 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 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 to have that help them get onto their next part of their lives and career. So what we found was so briefly uric acid. 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 fruit of uric acid, let alone the involvement of fructose, until I read his work. It's 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 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, 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 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 planet like Hong Kong and Argentina, their, their uric acid levels 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 look heartier, longer lived and thus increasing the potential of the individual having an artificially inflated A1C.

And in people like that, in looking.

At how uric acid is a contributor to insulin resistance, however, 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 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 paradox that some people notice on a 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 that much 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 of it, checks only for glucose glycation, looks for the glucose lysine bond, I think is what it actually looks for.

Less inflammation and indeed much greater improvements in insulin sensitivity as evidenced by their resolution of type 2 diabetes. This shouldn't be happening given uric acid's involvement. However, what we are publishing, so this is early data here, 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 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 the red blood cells almost certainly are living longer because of their healthier diet. And I want to dig into that a little bit. To my knowledge, there is no commercially available test.

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 test that a.

Doctor can order that checks for fructation or fructose glycation situation where a person.

Has stubbornly elevated uric acid and yet every metabolic.

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 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.