#265 – How do you know if you are healthy and what your labs tell you? | Dr. Robert Lustig & Mike Haney

Although not one single test can tell you whether you are healthy, some biomarkers and lab results can provide you a picture of your metabolic health, which can then inform you about your overall health. Dr. Robert Lustig and Mike Haney discuss why fasting insulin is one of the best metabolic health biomarkers, how you can use continuous glucose monitoring as a proxy for insulin sensitivity, how fast your metabolic health can change, and why your uric acid level and the cholesterol marker ApoB are also important labs to receive.

3:51 — Multiple factors help determine if you’re getting sicker or healthier

Several biomarkers, not just one, can provide an overall picture of your metabolic health.

You didn’t get sick in a day. You’re not going to get better in a day. And the markers that we look at to determine metabolic health didn’t go south in a day, so they’re not going to get changed in a day either. So this is why this is a mess in terms of people hawking one idea versus another, people hawking one supplement versus another, people hawking one lab test versus another. This is a very murky. And if there was one test that could tell you whether or not you were getting healthy or not, everybody would be doing it. And they’re not, because it’s not that simple. Different people have different problems. Different people need different solutions. And different people respond differently to the different paradigms.

7:52 — Fasting glucose is not a good gauge of your metabolic health

Doctors commonly use a fasting glucose or oral glucose tolerance test to diagnose someone with prediabetes or type 2 diabetes. However, these tests don’t account for insulin levels. Even if someone’s glucose level is in the normal range, they may already be experiencing insulin resistance, placing them on a trajectory toward these conditions.

If you’re waiting for you to develop diabetes, you are so far behind the eight ball. You have missed the train. The train’s pulled out of the station. You are already sick. So the goal is to catch that way before. So you go to your physician, and the physician does your fasting blood glucose, and it comes back 102, and he says, “Well, that’s fine. You’re far away from 125.” No, that’s not fine at all. In fact, let’s say you went and got your fasting blood glucose and it was 91. And you say, “Oh, you’re doing great.” No, you’re not. That’s already a problem. Okay. It’s on the way to glucose intolerance. It’s on the way to diabetes. It’s not there yet, but that’s an early indication. So how you read it—understanding what it means is extraordinarily valuable in and of itself. And it’s the last thing to change. Now, if you take a look at fasting glucose tolerance tests over the last 50 years, the excursion of the glucose is pretty much the same for the last 50 years. But the amount of insulin needed to keep you at a normal excursion has gone up two- to four-fold. And that’s a sign of chronic metabolic disease. That is not measured in the fasting blood glucose. That isn’t even measured in the glucose tolerance test. You’re already sick and you don’ t even know it. So fasting glucose is by far and away the worst metabolic parameter test than you can imagine if you’re waiting for that to change.

10:13 — The concern with a rising insulin level

Insulin is an essential hormone that we cannot live without. But insulin levels are best kept lower.

Everyone thinks insulin is good because it lowers blood glucose. Well, insulin has its own negative side effects. It is a growth factor, so it causes vascular smooth muscle growth, like coronary artery smooth muscle growth. It causes glandular growth—like, for instance, breast growth and prostate growth—so it is a risk factor for both breast cancer and prostate cancer. So things that we associate with aging are made worse by insulin going up. So if you need more insulin to do the same job and keep your blood glucose constant, you’re not in danger because your glucose is rising; you’re in danger because your insulin’s rising.

19:22 — A good goal is to keep glucose levels more stable, but you’re going to have rises

Unless you’re fasting or only eating fat, you will have blood sugar rises. The goal is to avoid extreme spikes and minimize how many spikes you have.

I’m going to start with a controversial saying: We’re all going to die. Okay. You’re going to die sometime. Everyone dies. And no matter how metabolically healthy you are, you’re still going to die. Now, the question is when. Obviously, we all want to put it off for as long as possible. And as George W. Bush famously said, “We all want to die as late as possible.” Right? And that’s why Levels does what it does. And I’m totally for it. I’m totally in support of it. You’re going to have glucose spikes. You can’t not have glucose spikes. You can’t freak out about it either. If you do, now you’ve got something called orthorexia: when you start worrying about actually what you’re eating all the time. Now, we do not want to be contributing to orthorexia. And some people will take this information and use it, shall we say, not for good. And we need to protect against that as much as possible. So I’m here to tell you, you’re going to have spikes. The question: How many spikes?

30:12 — What a glucose excursion can tell you

When your glucose spikes on a CGM, how high its spikes and how long it stays elevated can tell you whether your cells are using glucose efficiently or if you’re storing excess glucose as fat.

I think this is really helpful in understanding this glucose journey and what this glucose journey on a glucose graph is telling me. So if I am healthy, I take in a load of glucose. I see it rise, but I’m seeing it clear quickly, which is a sign that my cells are taking it up as efficiently as they possibly can. It’s not then going to be deposited in my muscle and fat tissue as fat. So if it takes a long time for it to clear, that’s essentially a sign that, in other words—let me see how to phrase this—if it’s being cleared quickly, it means it’s going into the cells. If it’s not being cleared quickly, that means it’s not going into the cells where I wanted it to go and it’s going to go into this other tissue.

31:24 — Why doctors don’t check fasting insulin, even though it’s a better marker than glucose?

Fasting insulin is a better marker for how well your mitochondria are working or whether you have mitochondrial dysfunction, but doctors typically don’t check fasting insulin for several reasons.

If your mitochondria are not working, your fasting insulin’s high. It’s our best proxy for mitochondrial function. And so I think that the fasting insulin is the single best marker for metabolic health that we could order. And I routinely suggest it and order it on my patients. And I’m trying to get the medical profession to, you know, glom onto this idea, but I will tell you there are a super number of obstacles. One is the insurance industry, because they don’t want to pay for it, even though it’s not expensive . . . And of course the food industry. The food industry is not happy about that at all, because it’s one of the ways they get away with putting junk in our food. Because if you’re fasting insulin is going up and the only way to fix it is your food, they don’t want you to know. And then third, the American Diabetes Association. Now, you would think that the American Diabetes Association would be very happy for people to not be insulin resistant. You would think that that would prevent them from getting diabetes. Well, the American Diabetes Association is really not into prevention; they’re into treatment. They’re into pharmacology. They’re into pharmaceuticals. Because their entire budget is basically underwritten by Big Pharma.

46:12 — How often should you get your fasting insulin checked?

Dr. Robert Lustig recommends getting your fasting insulin checked once a year. But you may also wish to get it checked four weeks after making a lifestyle change to see if your level is trending in the right direction. This can help provide continued motivation for healthier habits.

I think that everyone should get their fasting insulin done once a year, along with their standard lab draw, but they need them to be fasting, because if you’re not fasting, you don’t know where you are on the insulin curve, and then it’s useless. But if you’re fasting, then you should get it done once a year. And if you’re changing diet or exercise or, you know, some lifestyle or environmental intervention that you think is going to improve metabolic health, I would strongly suggest getting a second fasting insulin four weeks after the change so that you can monitor it, know that you’re doing the right thing, note that the fasting insulin is coming down so that you will, number one, be positively reinforced and continue on your weight loss or metabolic health journey and be rewarded for your efforts. And it’ll give your physician a new baseline to work off of. So I think that once a year and four weeks after changing your lifestyle.

50:08 — A continuous glucose monitor can show you your glucose excursions

A continuous glucose monitor (CGM) tracks your glucose in real time so you can see how high and how long your glucose stays elevated after eating a specific food. These rises can serve as a proxy for how well your insulin is working.

The longer it stays up, the more of a problem it is. That’s really what I can say. You should be able to clear your glucose within an hour. That’s what I can say. Now, different foods will give you different rises, and different foods will probably have different effects on how fast that glucose gets cleared as well. Those are called Kraft curves. Okay, K-R-A-F-T, for Dr. Kraft who first utilized them. So different foods will provide you with different information. And that’s one of the reasons why CGMs are so great because then you can determine what gives you the lowest glucose excursion, what gives you the best Kraft curve for your personal biochemistry. You can get that out of the CGM. Now, the Kraft curve of course measures insulin. It doesn’t measure glucose. So you’re not getting that, but you’re getting a proxy. Because if you’re clearing your glucose fast, that means your insulin’s in good shape. So you have to understand what we’re measuring: glucose. But really what you want to know about is the insulin.

58:42 — Why uric acid is an important biomarker

Fructose, purines, and alcohol drive higher uric acid levels, which can contribute to high blood pressure and more.

The problem is that uric acid does two things that you wish it didn’t do. One is it is the inhibitor of an enzyme in your arteries called endothelial nitric oxide synthase, or ENOS. And that’s the enzyme that makes nitric oxide, and nitric oxide is your endogenous blood pressure lowerer. It’s the thing that causes your blood vessels to relax. Therefore, it’s the thing that keeps your blood pressure down. And so, if you’re inhibiting it, it means your blood pressure is going to go up. So it is a primary contributor to hypertension.

1:08:37 — Why you should get ApoB checked

Apolipoprotein B (ApoB) is a better biomarker than traditional cholesterol tests because it provides a more accurate picture of harmful cholesterol particles.

What you care about is your LDL, but you care about it in the face of your serum triglyceride. So, high LDL, low triglyceride, not a big deal. High LDL, high triglyceride, very big deal. At Levels, we understood this, and so we are not measuring LDL or triglyceride. We’re measuring something called ApoB, Apolipoprotein B. And the reason is because LDL and triglyceride both have ApoB. Because one’s an evolution of the other. And so that’s a way of figuring it out. So that’s another reason why Labs 2. 0 for Levels includes ApoB as one of the markers. Okay, so that’s basically what we’ve learned. Levels is doing this right now with tests that are normally and routinely available and coverable by insurance.

Rob Lustig (00:00:00):

45% of Americans have fatty liver, 25% of children. Notice I didn’t say obese adults or obese children, all adults, all children. This is something that didn’t even exist before 1980. And here we are now 45 years later, and 45% of the population has a disease that we never heard of before. So we know something’s going on, and this is a clear indicator of metabolic dysfunction, a clear indicator of inability to utilize fat because of defective mitochondria, because of insulin resistance. So these things all go together. So your fasting insulin and your uric acid and your ALT should all line up together because they’re all part and parcel of the same pathophysiologic pathway.

Ben Grynol (00:00:53):

Am I getting healthier? It’s a question that we often ask ourselves. And earlier this year, Mike Haney, our editorial director, found himself asking that same question. He’s been tracking his glucose and paying attention to his metabolic health over time, but he was wondering, am I getting healthier with making some of the lifestyle changes that I have been doing? And so Haney having access to a number of our thought leaders and advisors tapped our good friend Dr. Robert Lustig on the shoulder, and said, “Hey, Rob, would you be interested in having a conversation around biomarkers so that we can understand more about some of these things? Am I getting healthier? What should I be paying attention to?” And so the two of them sat down in Los Angeles and they discuss this idea of the limitations around standard tests, things like fasting glucose and A1C for detecting early metabolic issues.

(00:01:43):

There are a number of limitations when you look at those markers in isolation. When you start to look at things like fasting insulin, you understand why it’s a critical marker for metabolic health and insulin sensitivity. It’s a much better indicator for metabolic health over time because insulin resistance is directly related to mitochondrial function. They also discussed uric acid and why it’s an important marker for cellular health. Uric acid is directly connected to your diet, what you consume, whether it’s increases in things like fructose or increases in purine-rich foods. That being things like game meats as one example.

(00:02:21):

So increases in uric acid can increase blood pressure over time, and we all know that increases in blood pressure are not great for your cardiovascular health. There are also a number of problems with other tests like cholesterol testing when it’s done in its standard way. If you look at cholesterol markers like HDL and LDL in isolation, or if you just look at them in absolute terms, there may be not as great an indicator of metabolic health as other markers like ApoB. There are also other potential future markers that we can start to consider. Things like homocysteine isn’t as widely discussed, but increases in homocysteine have been linked to things like increases in cardiovascular disease, insulin resistance, oxidative stress, and even Alzheimer’s disease. Anyway, Haney and Rob, they had a great conversation. They dug deep. No need to wait. Here is Haney and Rob.

Mike Haney (00:03:12):

The genesis of today, I’ll set this up a little bit before we get into it, the genesis of this conversation is Levels at its core is an app designed to help people get healthier. That’s the mission, cut out everything else. We just want folks to get healthier.

Rob Lustig (00:03:26):

My mission too.

Mike Haney (00:03:27):

But that begs a really key question. How do you know when you’re getting healthier? How do you know the things you’re doing are working?

Rob Lustig (00:03:35):

And it’s really hard to know. You didn’t get sick in a day, you’re not going to get better in a day. And the markers that we look at to determine metabolic health didn’t go south in a day, so they’re not going to get changed in a day either. So this is why this is a mess in terms of people hawking one idea versus another, people hawking one supplement versus another, people hawking one lab test versus another. This is a very murky area. And if there was one test that could tell you whether or not you were getting healthy or not, everybody would be doing it, and they’re not because it’s not that simple. Different people have different problem, different people need different solutions, and different people respond differently to the different paradigms. So this is, shall we say, a mélange of different ideas. And I’m happy to discuss each of them with you for the purpose of the audience, understanding the value of these different things. But if you think you can just go to your doctor and get a test, think again.

Mike Haney (00:04:51):

Well, I think that’s really helpful context, and I think we’ll split this into sort of two parts. One, we’ll talk about broad set of markers, and then we’re going to narrow in a little bit I think on glucose and insulin because that is where a lot of Levels bread and butter is and where a lot of our members are measuring or paying attention to or maybe visualizing their health or at least their metabolic health. So I think that setup is helpful for getting into it, that realizing we’re not going to determine in this conversation, here are the five key markers.

(00:05:21):

Well, I would love that headline as an old magazine editor. We’re not going to come out of this conversation with that. What I think might be helpful is to maybe narrow in on some markers that to my mind, need to have two criteria. One is that they tell us something about our underlying physiology, which is to say there’s some clarity in the signal that relates to something happening in our body, a process that we want to maybe be working functionally. And the second is that they’re movable. There are things we can actually do something about.

Rob Lustig (00:05:51):

Well, and that they’re titratable.

Mike Haney (00:05:53):

Sure.

Rob Lustig (00:05:54):

That is they’re on a scale and they tell you something about severity. It’s not just an on-off type of deal. That there’s a dynamic range of whatever the marker is to tell you, oh, you’re at this level, you’re at that level, you’re at the worst level. That’s very important as well. And it has to then change with either the worsening or with the improvement. Those are hard to come by.

Mike Haney (00:06:21):

So I think most people’s interaction with markers, with biomarkers is if they go to an annual physical, which so many folks don’t, but if you go to an annual physical, you get your labs and essentially in there you’re getting glucose and cholesterol. That’s primarily what’s being measured.

Rob Lustig (00:06:37):

Yeah. And that’s about the worst thing you can get.

Mike Haney (00:06:40):

Yeah. So let’s start there. Tell me what’s wrong with that as a core set of things, maybe what’s right with it, but also what’s wrong with it in terms of a core set that we’re at least checking in on annually?

Rob Lustig (00:06:51):

Okay. Let’s start with glucose. Fasting glucose. Fasting glucose is the single worst thing to measure, but it’s the thing that everyone measures. And the reason everyone measures is because it’ll tell you if you have diabetes or not. And in that way, well, that’s an on-off. If you’re fasting blood glucose is above 125 you have diabetes. If you’re fasting blood glucose is below 125, you don’t have diabetes. And that’s basically what the physician is drawing it for and that’s what they’re referring to and that’s what the guidelines say, and there is so much more information to be gained, and that is just the tip of the iceberg. And most importantly, if you are waiting for you to develop diabetes, you are so far behind the eight-ball, you have missed the train. Okay. Train’s pulled out of the station, okay, you are already sick. So the goal is to catch that way before.

(00:07:55):

So you go to your physician and the physician does your fasting blood glucose and it comes out back 102 and he says, well, that’s fine. You’re far away from 125. No, that’s not fine at all. In fact, let’s say you went and got your fasting blood glucose and it was 91. And you say, “Oh, you’re doing great.” No you’re not. That’s already a problem. It’s on the way to glucose intolerance, it’s on the way to diabetes. It’s not there yet, but that’s an early indication. So how you read it and understanding what it means is extraordinarily valuable in and of itself, and it’s the last thing to change.

(00:08:43):

Now, if you take a look at glucose tolerance tests, fasting glucose, glucose tolerance tests over the last 50 years, the excursion of the glucose is pretty much the same for the last 50 years, but the amount of insulin needed to keep you at a normal excursion has gone up two to four fold, and that’s a sign of chronic metabolic disease. That is not measured in the fasting blood glucose, that isn’t even measured in the glucose tolerance test. You are already sick and you don’t even know it. So a fasting glucose is by far and away the worst metabolic parameter test than you can imagine. If you’re waiting for that to change, you’re waiting for [inaudible 00:09:34].

Mike Haney (00:09:33):

A couple of things that I want to follow up on, but one, tell me why the OGTT, the oral glucose tolerance test, doesn’t do a good job of capturing that insulin response. Isn’t that what it’s sort of meant to do is to say, here’s how your body responds to a glucose load?

Rob Lustig (00:09:47):

Well, and that’s true how your body responds to a glucose load by having to put out more insulin to handle it. Insulin in and of itself is part of the problem. Everyone thinks insulin is good because it lowers blood glucose. Well, insulin has its own negative side effects. It is a growth factor, so it causes vascular smooth muscle growth like coronary artery smooth muscle growth. It causes glandular growth like for instance, breast growth and prostate growth. So it is a risk factor for both breast cancer and prostate cancer. So things that we associate with aging are made worse by insulin going up. So if you need more insulin to do the same job and keep your blood glucose constant, you’re not in danger because your glucose is rising, you’re in danger because your insulin is rising. And that’s not measured in the glucose tolerance test. We infer it, but you don’t know it.

Mike Haney (00:10:57):

Right. So two people could essentially have the same OGTT score, but one is pumping out twice the amount of insulin, one is much further along in an insulin resistant state than the other one, and that’s not going to be revealed in that test.

Rob Lustig (00:11:11):

Exactly right. So the glucose tolerance test is good, and certainly what we do at Levels can glean a lot of information from that glucose excursion that will tell you, but it’s not necessarily the amplitude, it’s not necessarily the fasting level, and it’s not even necessarily the peak. It’s actually more how it gets disposed of. The decline downward. That’s why the curve is valuable. That’s why we do this. That’s why Levels exist is because the change from the peak down to baseline has lots of information in it. But in fact, what you really want to know is how much insulin did it take to do that and how quickly did the insulin clear to bring you back to baseline? And you’re not getting any of that from a standard fasting glucose or an OGTT.

Mike Haney (00:12:05):

Is there anything, this is jumping ahead a little bit to where I want to go with some of the dynamics of a glucose curve, but I think it’s relevant here. What can I infer about my insulin sensitivity from simply looking at the shape of a glucose spike or a glucose curve?

Rob Lustig (00:12:21):

Right. So the higher the glucose goes, the less insulin reserve you have and the slower the glucose return to normal, the less well insulin’s working. So the more insulin resistance. So there are two phenomena that you can capture, but neither of them are direct measures. So the height of the glucose response basically tells you, hey, what’s going on with my beta cell? I should be able to keep up with this. There must be defective reserve or delayed response. Either way, that’s a problem of the beta cell. Then how quickly things go back to normal. If they go back to normal quickly, that means that insulin’s chugging out and it’s working and it’s clearing and everything’s fine. That means you have good beta cell function with good insulin sensitivity. But if you’ve got a plateau and it takes a while for it to come down, then that’s a marker for insulin resistance. And you couldn’t see that from a fasting specimen and you may not even see it from a two-hour specimen, which is all that your physician is concerned about.

Mike Haney (00:13:33):

I’m glad you used the phrase there, keep up, because one of the things I found that I didn’t really understand in trying to explain even these basic dynamics is a question of timing. So a glucose spike, if I watch my glucose go up very sharply and come back down, that’s at its most core reflection of something that I have done, right? I’ve eaten a high carb load, there’s a bunch of glucose now in my blood that CGM is going to measure that as a peak and then it’s going to come back down. So how much of that spike is the result of what I’ve eaten is directly related to just the amount of carbs I have poured into my body and how much is related to my insulin response, which is another way of saying how fast can I expect my insulin to actually work and bring it down? Is there a world in which I am so insulin sensitive that even if I eat a ho-ho, I’m not going to see a big spike, or?

Rob Lustig (00:14:24):

You’ll always see a spike.

Mike Haney (00:14:25):

Okay.

Rob Lustig (00:14:26):

You’ll always see a spike. The reason is when you consume the glucose, it will go first to the liver. It’ll be absorbed from the intestine, it’ll go via the portal vein to the liver. The liver will take 20% of that glucose and throw it straight into the liver for conversion to glycogen. That means 80% will make it past the liver and generate a glucose response. You will get a glycemic excursion. Now, the beta cell will then see that because it’s got to go circulate in the blood, the beta cell will see the rise in the glucose and we’ll start pumping out insulin saying, “Hey, I’ve got to clear this. This is not the baseline. Let’s get the glucose back down.” So you’ll see a glucose spike no matter what. The only way to not have a glucose spike is to not consume glucose.

(00:15:23):

So if you’re consuming straight fat, you won’t see much of a glucose spike if at all. If you are fasting, you won’t see a glucose spike. But otherwise, if you’re consuming food, you’re going to see a glucose spike. The question is how high and how long? Those are the two questions. How high tells you what was in that, but it also tells you whether or not your beta cell’s keeping up. And how long basically tells you if you’re insulin resistant. So the how high gives you information about the beta cell, how long tells you more about the body.

Mike Haney (00:16:02):

And in terms of that, just to keep on this path of understanding the glucose curve, how much can I expect that to change as I get more insulin sensitive? And if I start eating lower carb, getting my insulin in a proper place, should I expect that if I’m eating the same diet, I’m going to see lower peaks and I’m going to see faster returns?

Rob Lustig (00:16:25):

Right. We did that study in children and we saw that if we changed the diet, we could see changes in the glucose area under the curve, the peak glucose response and the insulin sensitivity in 10 days in children. And my colleagues at San Francisco General did it in adults, and they saw those same changes in two weeks. So it doesn’t take long, but will you see it after one meal? Unlikely. Will you see it after one day? Probably not. But 10 days, most people can tough it out for 10 days to be able to see something that will help, shall we say, solidify their belief in making metabolic health changes for the better.

Mike Haney (00:17:16):

And then if it can change that quickly to get healthier, how durable is that change then? Can I revert it back to being less insulin sensitive by giving up on my low-carb diet?

Rob Lustig (00:17:25):

Absolutely, within two weeks. But bottom line, it’s relatively responsive to changes in diet and also by the way, changes in exercise. So if you exercise, you’ll start seeing improvements in insulin sensitivity too. If you stop exercising within two weeks, you’ll be back to baseline. So I would say there’s a two-week transition from metabolically unhealthy to metabolically healthy, at least as far as glucose dynamics go.

Mike Haney (00:17:59):

And we’ll come back to insulin for a minute because I think we’re going to want to talk a lot about that as a marker. But again, just on the glucose curve side, how do you think about glucose spikes? A lot of what we’ve talked about over the years, and I do all the content at Levels, is the simplified version is glucose spike, bad, glucose spike, unhealthy, don’t do that.

Rob Lustig (00:18:21):

That’s true.

Mike Haney (00:18:21):

Because it can have short-term effects. You might feel really bad, you’ll probably have a post reactive crash. Also, long-term it can do damage, can cause you to be insulin resistant. Can also have some effects on its own like glycation or inflammation that just extra glucose can be having. But in that nuance of what counts as a spike, how many can I have? How tall can they be? These are the questions we get. I was just looking at some member questions this week. These are the questions we get all the time from people. And my worry is that in putting out this message, I have freaked a lot of people out about everything they’re eating. And what I hear from so many of them is an anxiety that if I’m not going keto, I’m screwed. So I’m curious how you think about the detriment of a glucose spike.

Rob Lustig (00:19:08):

All right. So I’m going to start with a controversial saying, we’re all going to die. Okay? You’re going to die sometime, everyone dies. And no matter how metabolically healthy you are, you’re still going to die. Now the question is when? Obviously we all want to put it off for as long as possible. And as George W. Bush famously said, “We all want to die young as late as possible.” For sure. And that’s why Levels does what it does. Again, I’m totally for it. I’m totally in support of it. You’re going to have glucose spikes. You can’t not have glucose spikes. You can’t freak out about it either. If you do, now you’ve got something called orthorexia, you start worrying about actually what you’re eating all the time. Now, we do not want to be contributing to orthorexia, and some people will take this information and use it, shall we say, not for good.

(00:20:12):

And we need to protect against that as much as possible. So I’m here to tell you, you’re going to have spikes. The question, how many spikes? Well, preferably three spikes a day called breakfast, lunch, and dinner, or maybe two spikes a day, lunch and dinner. Do you need breakfast? I mean, that’s the concept of intermittent fasting and maybe that’s one of the reasons why intermittent fasting works is because you only have two spikes. We don’t know that yet. I’m just throwing it out there as a possible. We do know that intermittent fasting helps if you’re insulin resistant. Now, the reason I think intermittent fasting works is because it gives your liver a chance to metabolize the fat that built up over the previous 16 hours.

(00:20:58):

Well, that will help your spike because you’ll be able to process the glucose because you’re less insulin resistant. These things are all related to each other. It’s not like these things work separately. They’re not in silos. So what the glucose spike is doing, what the insulin spikes doing, what the fat is doing in both the liver and the muscle, all of these things relate to each other. Now, if you’re going to have a spike, you want to have a spike that doesn’t go to say 180 or above because that’s when the kidney starts spilling glucose. So that causes damage to the kidney.

Mike Haney (00:21:38):

Unpacked spilling glucose out of the kidneys for a minute.

Rob Lustig (00:21:40):

So your kidney resorbs glucose, so the glucose filters through it as blood filters through it, and your kidney has a method for pulling the glucose back into the bloodstream instead of it going out in the urine. And that system works until what’s known as the TM, which is basically the maximum amount that you can resorb and that occurs at a blood glucose of 180 milligrams per DL. So at 180 you start spilling glucose into your urine, and when you spill glucose, you take water with it and that dehydrates you. And that’s one of the cardinal signs of diabetes is polyuria and polydipsia, too much peeing, too much drinking and dehydration. So you obviously don’t want that. And in addition, the higher the blood glucose goes, and it’s been, glucose has been equated with grains of sand. You can imagine if you had grains of sand running through your arteries, it might do some damage like the finish on your car when you’re out on Pacific Coast Highway just from the sand and the salt water hitting your car.

(00:23:00):

Well, if you’re running around with high blood glucose, a lot of the time you’re going to have some endothelial dysfunction, and that may be actually one of the contributions to high blood pressure. So high blood pressure can occur due to sugar, dietary sugar because of the increase in uric acid, which reduces Nitric oxide, which raises blood pressure or it could be because of the endothelial cell dysfunction. You can see that in the release of hormone called Endothelin-1 that you can measure. Again, it’s a research test for the most part. We don’t do that routinely, but either one of those is a sign of arterial damage, and, ultimately, that would shorten your lifespan. It’s been shown that if you can get your blood pressure down by two millimeters of mercury, you have a 10% reduction in risk for stroke. So even a little change in blood pressure has big changes in terms of vascular health.

(00:24:06):

So all of these things are related to each other. Obviously you don’t want your blood glucose to go super high, but more importantly, you don’t want it to hang around. You want it to clear, and that is a sign that your insulin is working. That’s a sign of insulin sensitivity. That’s a sign that your muscles are working, your liver is working, your whole body is working. I would say that insulin sensitivity is the pathogenic factor most associated with all of the chronic diseases that we have today. If there’s one thing to fix, it’s your insulin resistance. And so then the question is, okay, how do you measure that? And we’ll get to that in just a minute.

Mike Haney (00:24:50):

Yeah. I just want to go one step further on this story we’re talking about, and I think this is a useful framing of what’s happening to the glucose in the body and how it relates to the sort of height of the spike. So when we talk about, let’s say two people are spiking to 160. One is insulin sensitive and the other is less so, and so it’s taking longer to clear it, but when we talk about clearing, where does it go? Even if I’m healthy, is there a difference in where that glucose goes between the insulin sensitive person and the non-insulin sensitive person once they’re back to baseline, has a different thing occurred in each one of them?

Rob Lustig (00:25:28):

Absolutely. So where does it get cleared to? Where does glucose get cleared to? Well, every cell in the body uses glucose for energy, but not every cell in the body is responsive to insulin. Okay? Now, every cell has glucose transporters, but those glucose transporters are not necessarily insulin dependent transporters. Which glucose transporters are the insulin dependent ones? GLUT4. So there’s GLUT1, GLUT2, all the way up to GLUT11. Okay? 11 different glucose transporters depending on which tissue you’re talking about. Fructose by the way, is handled by GLUT5 and also GLUT7. So the different glucose transporters do different things in different tissues. Like for instance, the brain uses GLUT1, no other tissue uses GLUT1, but GLUT4 is the only one that’s insulin sensitive. So where’s GLUT4? Because if your insulin level’s high, that means that the GLUT4 specific tissues are going to be influenced the greatest.

(00:26:37):

And the answer there is your muscle and your fat. And so you’re going to drive energy into muscle and fat. If you drive energy into muscle that your muscle is not using, you’re going to get fat deposition in your muscle called intramyocellular lipid. That’s a cardinal feature of insulin resistance. If you drive the glucose into fat cells, well, the fat cell is going to turn that into actual adipose tissue, it’s going to turn it into triglyceride in the adipose tissue. It’s got all the enzymes to take glucose, turn it into fat, and so you’re going to lay down more fat and now you’ve got obesity. And of course, if it’s visceral fat, you’ll have insulin resistance yet worse. It’ll basically be a vicious cycle.

(00:27:24):

So the higher the insulin, the more your fat and muscle are going to gain fat because of the GLUT4 transporter, it’s not going to make much difference in terms of the GLUT1, the GLUT2, the GLUT3, the GLUT5, and all the way up to 11. It’s really going to be that GLUT4, but that’s what causes the illness. So getting the insulin down is job one, and the only way to do that is to become insulin sensitive. And the only way to do that is lifestyle.

Mike Haney (00:28:01):

Let me just make sure I understand this. So if I take in the same amount of glucose, but I am insulin sensitive, what is happening such that I’m not getting those fat deposits either in my muscular tissue or in the adipose tissue that are all the risk, if I’m insulin sensitive? The glucose has to go somewhere, right? If I’ve taken in that amount of glucose load.

Rob Lustig (00:28:25):

If you’re insulin sensitive, it will go into all of your other tissues equally and will be burned by the mitochondria to carbon dioxide and ATP and will fuel all of those metabolic processes, and you will therefore be metabolically healthy. As soon as your insulin goes up, what that’s a sign of is the fact that you’re not burning that glucose to carbon dioxide and ATP. Well, okay, if you’re not burning it, you’re getting a backup and you need insulin then to clear it. What is that saying about your cells? What that’s saying is that the mitochondria, the little subcellular organelles, and inside each cell, the little energy burning factories inside each cell, what it’s saying, those aren’t working very well.

(00:29:15):

For whatever reason, those mitochondria are fallen behind because if they weren’t fallen behind, your insulin wouldn’t be high and you’d be clearing the glucose well. So insulin resistance and mitochondrial dysfunction are part and parcel of the same phenomenon. So what that’s telling us is if you’re insulin resistant, you’ve got something wrong with your mitochondria and you need to step up your mitochondria. Well, what’s wrong with your mitochondria? And that’s where the whole question of our environment starts coming in.

Mike Haney (00:29:54):

Right. Okay. So let’s go back to this question of timing for a moment because I think this is really helpful in understanding this glucose journey. And then what I’m seeing about this glucose journey on a glucose graph is telling me, so if I am healthy, I take in a load of glucose, I see it rise, but I’m seeing it clear quickly, which is a sign that my cells are taking it up as efficiently as they possibly can, it’s not then going to be deposited in my muscle and fat tissue as fat. So if it takes a long time for it to clear, that’s essentially a sign that, in other words, let me see how to phrase this. If it’s being cleared quickly, it means it’s going into the cells. If it’s not being cleared quickly, that means it’s not going into the cells where I want it go and it’s going to go into this other tissue. Is that right?

Rob Lustig (00:30:45):

Exactly right.

Mike Haney (00:30:46):

Okay.

Rob Lustig (00:30:47):

Exactly right. The longer it stays in your bloodstream, the worse off you are. And you can’t learn that from a fasting glucose. You actually can’t even learn that from a fasting insulin. Although fasting insulins are much better arbiter of that. Because the fasting insulin basically tells you how well your mitochondria working. If your mitochondria working, your fasting insulin is low. If your mitochondria not working, your fasting insulin is high. It’s our best proxy for mitochondrial function. And so I think that the fasting insulin is the single best marker for metabolic health that we could order. And I routinely suggest it and order it on my patients, and I’m trying to get the medical profession to glom onto this idea. But I will tell you, there are super number of obstacles. One is the insurance industry, they don’t want to pay for it, even though it’s not expensive, runs between $12 and $120, medium, $48.

(00:31:55):

So it’s not that expensive. So then they can learn, patients and their doctors can learn so much from it if they knew how to interpret it. And of course, the food industry. The food industry is not happy about that at all because it’s one of the ways they get away with putting junk in our food. Because if your fasting insulin were going up and the only way to fix it is your food, they don’t want you to know. And then third, the American Diabetes Association. Now, you would think that the American Diabetes Association would be very happy for people to not be insulin resistant. You would think that that would prevent them from getting diabetes. Well, the American Aiabetes Association is really not into prevention, they’re into treatment, they’re into pharmacology, they’re into pharmaceuticals because their entire budget is basically underwritten by big pharma.

(00:32:53):

The fact of the matter is the American Diabetes Association says do not draw a fasting insulin. And that’s one of the reasons by the way that the insurance industry doesn’t cover it because the ADA says that. All right, so why do they say that? Two reasons. And they’re both specious, they’re both wrong. First reason. They say the different assays for fasting insulin are not standardized across platforms. So if you get it done at your local lab, if you get it done at the hospital, if you get it done through a send out, you’re going to get all different results from different assays, not standardized. And there’s some truth to that. I don’t even argue that, that is true. One of the reasons that this occurs, because there ought to be something that you should be able to measure easily, one of the reasons this occurs is because some of the cheap assays use antibodies, use basically what’s either a radioimmunoassay or an ELISA enzyme-linked immunosorbent assay.

(00:33:52):

And so it’s looking at epitopes, it’s looking at specific areas of the molecule to determine whether or not the molecule is there or not. And that determines the level, and that’s worked for us for a long time. But you can have cross reactives, you can have other peptides or proteins that you’re measuring in the same sample that cross-react with the antibody and will give you a fictitiously elevated level. The most common of this is pro-insulin. Now, what’s pro-insulin? You’ve heard of insulin, what’s pro-insulin? Pro-insulin is the peptide that has to be cleaved to make insulin. So it is a pro-hormone, it is not a hormone. You should not be releasing pro-insulin. You should be releasing the mature insulin after the C-peptide is cleaved out of it. Now, there’s an enzyme in your beta cells that cleaves that C-peptide out of it. It’s called pro-hormone convertase 1. Well, when your beta cells are stressed, when they’re working overtime because you’re insulin resistant and you then have a big glucose load, you need to bring that glucose down and that’s insulin’s job.

(00:35:10):

And that beta cell is going to work as hard as it can to put out as much as it can, and it doesn’t have time to cleave the piece of C-peptide out. And so it’s going to release the pro-insulin too. Now, pro-insulin has only 5% of the activity of insulin, but basically, what it’s a sign of is beta cell exhaustion, but it gets measured in the insulin assay because pro-insulin and insulin look a lot alike. So you’re measuring something that’s not insulin in the insulin assay, and so can throw off the assay.

(00:35:48):

Well, the American Diabetes Association is saying, well, then don’t draw it because it’s not necessarily measuring what you want to measure. And that at a, shall we say, at a common sense level makes sense. But who cares? Who cares? If it’s high it’s a problem, irrespective of whether you’re measuring insulin or pro-insulin or anything else for that matter, if it’s high, it’s a problem. And as long as you’re using the same assay on the same patient over time, you can still use those to understand dynamic changes. So I think that’s a specious reason that the ADA says [inaudible 00:36:30].

Mike Haney (00:36:31):

What’s the degree by which that pro-insulin can throw off that reading? Are we talking small, or?

Rob Lustig (00:36:36):

Quite a bit. So we know that there is a phenomenon called hyperproinsulinemia was first espoused by Dr. John S. Yudkin, not the John Yudkin of sugar fame, but his cousin John S. Yudkin, famous British endocrinologist. Wonderful guy. And he was the one who demonstrated this phenomenon called hyperproinsulinemia. And it is without question, if you’re putting out pro-insulin, it means you are sick. That’s a bad thing to be doing. So no, it’s a very real thing. So that’s the first reason. Then the second reason that the American Diabetes Association says don’t draw it. They say fasting insulin levels do not correlate with obesity. That’s exactly right. They do not.

(00:37:24):

They correlate with metabolic health because they correlate with mitochondrial dysfunction. And you can be obese and have normal mitochondria, and you can thin, it can be thin and have crappy mitochondria. And the fasting insulin will tell you that. Of course, it’s not correlated with obesity. That’s exactly why you should draw it because it’s telling you something. Otherwise, you could just get on the scale and you find out the same thing. No, no, no. So the reason they say not to draw it is exactly the reason to draw it, but they don’t get it. So I’m working on them, but boy, oh, boy, I tell you, it’s like pulling teeth.

Mike Haney (00:37:59):

Just to dig into, let’s dig into insulin as a marker a little bit because we do offer it in the blood test that we offer. We include fasting insulin.

Rob Lustig (00:38:07):

Right. We do labs 2.0 and fasting insulin is at the front and center of that.

Mike Haney (00:38:11):

So what’s the best faith argument for maybe not ignoring it entirely, but what’s the context with which I should look at that insulin marker? How should I understand that insulin number in the context of the other things that I’m measuring? And let’s say for these purposes, the other things that you would like us to measure, not just the things I’m getting at my standard physical.

Rob Lustig (00:38:34):

So fasting insulin is in a dynamic range. So the lower it is, the better off you are. As long as you don’t have type one diabetes, then it’ll be zero, and that would be really bad. You need some insulin. Otherwise, you end up in diabetic ketoacidosis, which will kill you pretty quick if you don’t do something about it. And the only treatment for that is insulin. So you always need a little insulin, and that’s one of the reasons why we age is because you always need a little insulin. There’s no way to do without it.

(00:39:05):

But the lower it is, the more functional it is, the better off you are and the longer you will live. So it’s one of the best longevity markers there is. And the great thing about it is it will change in two weeks. Now, it’ll also change back again in two weeks if you stop applying whatever lifestyle modification that you used to get it down. So to me, fasting insulin is where the action is. And it’s cheap, and it’s available, and you can do it tomorrow. There are even now fasting insulin assays you can do at home. So you don’t even have to go to your doctor, but they cost money. And then the question is, is it reliable? And those are questions that are yet to be answered for each of the different assays that are out there.

Mike Haney (00:40:03):

So the type of question we get all the time when we start talking about markers is when results don’t line up with the story that we are telling, right? With this sort of basic picture of how things work. And I won’t go through all of them because that could be an hour’s long podcast of what if this and then that?

Rob Lustig (00:40:20):

Yeah, yeah, we’re not doing that.

Mike Haney (00:40:21):

But just to stick to glucose and insulin for a minute. If my insulin is low, and I’ll be personal here, my insulin is low, it’s under two.

Rob Lustig (00:40:28):

Good for you.

Mike Haney (00:40:29):

I’m a child of the 80s, which means I grew up eating sugar cereal every morning for breakfast for 30 years, which means daily, and I know this now because I have a CGM on. I would spike my glucose to 200 and it would come back down. And yet in my late 40s, my insulin is under 2.

Rob Lustig (00:40:44):

I’m delighted.

Mike Haney (00:40:46):

Explain how that is to me?

Rob Lustig (00:40:47):

It’s very simple. It means that you are insulin sensitive now and it means you have good beta cell reserve and it means you’re fine now. It doesn’t mean you were fine when you were 12. The fact is we have this pandemic of childhood obesity and childhood type two diabetes, and clearly they’re not okay. The fact that you escaped that period of Froot Loops, and Cap’n Crunch, and Cracklin Oprah and lived to tell the tale and have a fasting insulin now of two hats off to you. I wish I were so lucky, but that’s great and it portends good things for the future if you can maintain that.

Mike Haney (00:41:37):

So how should I think then about my A1C, my fasting glucose, my average glucose or sort of glucose stability if I’m wearing a CGM, if those are not, as I remember my last A1C was like borderline pre-diabetes, right? So I look at my insulin and I go, “I’m great.” Walk away, put the paper down. All good. Nothing to worry about here. I look at that A1C and I go, if this weren’t a member, they would be emailing us going, that looks high, what should I do about it?

Rob Lustig (00:42:04):

Right. Well, understand that the A1C is not the fasting insulin, okay? They’re not necessarily the same. There are various, I won’t say disorders, but conditions that can lead to a slightly elevated hemoglobin A1C and it doesn’t necessarily portend anything bad. Example, there’s a disorder. It’s really a condition because needs no treatment and has no downstream side effects. This condition is called MODY2, M-O-D-Y2, mature onset diabetes of youth II. Now, MODY is a set of diseases that are all genetic defects in the beta cell. There are 14 of them, 14 different MODYs, and some of them are really bad. Some of them will ultimately cause significant diabetes, very intractable to treatment and will ultimately, lead to early aging and death. No argument. MODY2 is a defect in the sensing of the beta cell. The level of glucose in the blood has to get a little higher before the beta cell will start kicking out insulin.

(00:43:25):

It just basically means that the gain has been reset. The threshold for releasing insulin has been reset. So these people run higher blood glucoses routinely, but they still get an insulin spike when their blood glucose goes up, they still clear glucose just as quickly. They just run a higher blood glucose. So their hemoglobin A1C is higher, has absolutely no implications for aging or for disease. It’s just a factitious. It’s not spurious. It makes sense. But it’s a factitious biomarker that’s out of range and means nothing. So it only means something if the physiology is consistent. So if you have a high fasting insulin and a high glucose and a high A1C, that means something because they’re all going in the same direction. So you can point to the path of physiology and say, yeah, that’s what’s going on. We need to do something about that. But if you see one lab test that’s out of whack and it doesn’t make sense with all the others that are in the same pathway, probably best to ignore it or possibly it’s even lab error, maybe it needs to be redrawn.

Mike Haney (00:44:48):

Yeah, let’s stay on that for a minute.

Rob Lustig (00:44:49):

Remember, 5% of all lab tests are errors.

Mike Haney (00:44:55):

That’s exactly what I was just going to ask is how reliable labs tend to be in general, and does it vary among markers? Are there some we can trust more than others?

Rob Lustig (00:45:02):

It depends on the marker. Yeah. So some are much tighter than others. Like glucose is a pretty tight one, although CGM glucose has a much wider variation than lab glucose, so we need to keep that in mind. But some of the other assays, there are things that can interfere with it. Hey, somebody spits in the tube. There’s all sorts of stuff that goes on in laboratories, and I know because I used to work in a laboratory and you do the best you can, but stuff happens.

Mike Haney (00:45:37):

So given how rapidly insulin can change, for instance, in response to our lifestyle and what we’re doing, how often should we be testing it? How frequently should I look at my insulin to understand, let’s just focus on metabolic health for now, and we’ll get back to the sort of broader health markers, but how should I keep a pulse on my metabolic health? What are the things I can be looking at?

Rob Lustig (00:45:59):

Personally, I think that everyone should get their fasting insulin done once a year along with their standard lab draw, but they need them to be fasting. Because if you’re not fasting, you don’t know where you are on the insulin curve, and then it’s useless. But if you’re fasting, then you should get it done once a year. And if you’re changing diet or exercise or some lifestyle or environmental intervention that you think is going to improve metabolic health, I would strongly suggest getting a second fasting insulin four weeks after the change so that you can monitor it, know that you’re doing the right thing, that the fasting insulin is coming down so that you’ll number one, be positively reinforced and continue to, on your weight loss or metabolic health journey and be rewarded for your efforts. And it’ll give your physician a new baseline to work off of. So I think that once a year and four weeks after change, changing your lifestyle.

Mike Haney (00:47:04):

And how should I read it then? In conjunction with, let’s say I’m wearing a CGM or occasionally I’m wearing a CGM, how should I think about it in conjunction with the kinds of curves that I’m seeing relative to what I’m eating and what I’m doing?

Rob Lustig (00:47:17):

Well, if you’re insulin resistant, then the thing you want to look at is not necessarily the peak glucose, but you want to see how quickly it returns to baseline. If it returns to baseline in 30 to 45 minutes, you’re doing great. If it takes an hour, not as great. If it takes 90 minutes, clearly not as great. And so you should look at your fasting insulin in that context. If you’re fasting, insulin is say above 10, and you’re clearing your glucose slowly, that is an hour or greater, you still have some work to do. If you are clearing your glucose rapidly and your fasting insulin is low, you’re in great shape. Keep doing it. So you should look at the trends. You should look at the pathophysiology. You should understand that each of the markers doesn’t exist in isolation. They’re not siloed. They work together.

Mike Haney (00:48:21):

So if I have relatively low fasting insulin and I’m seeing generally a trend of pretty quick return to baseline, am I somebody who can then take in more carbs without worrying too much about what that actual glucose I’m taking in is going to be? What kind of long-term damage that might be causing my body? Can I be more tolerant of spiking 50 points as opposed to trying to stay under 30 or whatever the sort of guidance is?

Rob Lustig (00:48:47):

Yeah, absolutely. Because you’re clearing it. And the clearing is much more important than the spiking. That we’re very sure of. Yeah, the spiking tells you about reserve, but the clearing it tells you about sensitivity, and the sensitivity is the thing that is associated with disease.

Mike Haney (00:49:05):

So if I’m in good metabolic health, how do you think about how flat my glucose curve should be? You mentioned earlier that we can expect to see spikes or maybe rises is the word we want to use instead, three times a day when I eat. But we also know, and we see this in a lot of our members, they’re trying to eat to keep that glucose line as flat as possible. How flat do you want to see that line?

Rob Lustig (00:49:28):

It’s going to undulate. If it doesn’t undulate, that means either you’re not consuming glucose or you’re fasting, one or the other, it’s going to change. We don’t know. We don’t have the data to tell you, oh, the amount of change predicts when you’re going to die. We don’t have that. I don’t think we’ll ever have that. What I can say is the longer it stays up, the more problem it is. That’s really what I can say. You should be able to clear your glucose within an hour. That’s what I can say. Now, different foods will give you different rises and different foods will probably have different effects on how fast that glucose gets cleared as well. Those are called Kraft Curves, K-R-A-F-T for Dr. Kraft who first utilized them.

(00:50:26):

So different will provide you with different information, and that’s one of the reasons why CGMs are so great, because then you can determine, well, what gives you the lowest glucose excursion? What gives you the best Kraft Curve for your personal body habitus and your personal biochemistry? You can get that out of the CGM. Now, the Kraft Curve, of course, measures insulin. It doesn’t measure glucose. So you’re not getting that, but you’re getting a proxy because if you’re clearing your glucose fast, that means your insulin’s in good shape. So we have to understand, we’re measuring glucose, but really what you want to know about is the insulin.

Mike Haney (00:51:13):

So if I’m having those rapid returns to baseline, how much do you care about glycemic variability over the course of the day? If my line is still moving quite a bit, but it’s coming back down, or if I’m spiking every time I eat?

Rob Lustig (00:51:26):

Not that much. As long as it’s coming down. If it goes up, it goes up. If it’s coming down, that means your body’s okay.

Mike Haney (00:51:35):

So let’s go back then a little bit out of the, actually, there’s one more thing I want to follow up on the glucose and insulin side. This is maybe a bit of a tangent, but I want to go back to diabetes. We talk about diabetes is diagnosed via glucose, via a fasting glucose test or an AIC, but as I understand it, what diabetes is describing is a state of insulin resistance.

Rob Lustig (00:51:58):

Well, not necessarily. Type one diabetes is not a state of insulin resistance. It’s a state of defective insulin reserve. So if you can’t make insulin, doesn’t matter how sensitive you are. So it’s a combination of the two. It’s like two levers that are working in concert with each other, and the more defective one lever is the harder the other one has to work in order to keep it stable. So that’s why you need both pieces of information. You need the spike to tell you about the reserve. You need the rate of clearance to tell you about the sensitivity. There’s information in both of those, and they’re related to each other.

Mike Haney (00:52:40):

So why do we diagnose diabetes with glucose and not insulin?

Rob Lustig (00:52:44):

Well, because some people will have high insulin for a certain glucose, and some people will have low insulin for a certain glucose. Where are you going to draw the line? It’s not going to tell you. And in addition, because the glucose is doing damage, it’s obviously the thing to measure. And in addition, because your kidney is now excreting the glucose, it’s an easy to measure in the urine. So that’s a better marker for diabetes, but it’s not necessarily a biomarker with dynamic range for metabolic health. Insulin’s much better for that. And because insulin changes early and glucose changes late, like I said, if you’re waiting for the glucose to change, horse is out of the barn.

Mike Haney (00:53:32):

Right. One more question on diabetes. How arbitrary is 125?

Rob Lustig (00:53:37):

It’s pretty arbitrary. It depends on where you are in the curve. If you’re at the baseline, then 125 is diabetes. If you are in the middle of metabolizing your meal and that’s your peak, you’re doing great. So a blood glucose out of context tells you nothing. That’s why you need it to be fasting. But it’s the last thing to change because your body’s doing everything it can to maintain a normal blood glucose. It’s the absolute last thing to change. The hemoglobin A1C is the second to last thing to change. It will start to rise before the fasting glucose will. So if you’ve got an hemoglobin A1C of 5.4, you’ve got a little bit of defective glucose clearance. If it goes to 5.5, you’ve got a little bit more defective glucose clearance and up and up and up until you hit six, when now you’ve got pre-diabetes. And when it hits 6.5, that’s full-fledged diabetes.

(00:54:45):

So you can actually see the problem before the fasting glucose changes in the hemoglobin A1C, but even that is late in the game, the fasting insulin will change before that. And how do I know that? Because you can go into any metabolic syndrome clinic in this country and see patients who have normal glucose tolerance but are obese and insulin resistant. So they are not hyperglycemic. They do not have an abnormal glucose tolerance test, but they’re insulin resistant. Their fasting insulin is high to keep them at that glucose level, and they are already spilling protein in their urine. They already have metabolic kidney disease because the insulin caused the metabolic kidney disease, not the glucose. So there are things you can look at to tell you as an early diagnostic, and I’m actually giving a talk at Stanford in two weeks on early diagnostics and fasting insulin is job one.

Mike Haney (00:55:59):

And do you watch insulin on the way down? If you’re treating a diabetic patient and you’re trying to get that fasting glucose down, are you also testing their insulin as you’re treating them and expecting that to also be coming down? How do they move on the reverse side?

Rob Lustig (00:56:15):

If you are improving their metabolic health then their fasting insulin should be coming down. Now, if you are giving metformin, you’ll be improving insulin sensitivity. So the fasting insulin should come down. If you are giving thiazolidine diones to improve their diabetes, their fasting insulin might actually not change. So it depends on how you’re doing it. If you’re doing it with diet, it definitely should be coming down. And if it’s coming down, then that’s a good thing.

Mike Haney (00:56:45):

Okay. So let’s leave the world of glucose and insulin for a moment so we have time for some other markers.

Rob Lustig (00:56:48):

All right.

Mike Haney (00:56:49):

You mentioned earlier uric acid. That’s also included in our current Levels labs panel. Does uric acid fit this criteria that we were talking about in terms of a marker that reveals something about underlying physiology is titratable and can actually be moved?

Rob Lustig (00:57:04):

Yes. And it’s also got a dynamic range, and the higher it is, the more problem it is. So yes, then that’s another reason why we include uric acid in our biomarker panel for just that reason. The question of course, is what does uric acid mean? People don’t even know what it means. It is a breakdown product of energy generation. It is a breakdown product of ATP. So when ATP, the energy’s in the phosphate bonds, when ATP cleaves a phosphate off to generate energy, it becomes ADP, adenosine diphosphate. So the energy gets released, it gets used power molecular motors within the cells so that the cells can do their job. Then the ADP goes to AMP, adenosine monophosphate, which then goes to IMP inositol monophosphate, which then finally goes to uric acid. And uric acid is then excreted in the urine. So it is a measure of how fast your body is generating energy.

Mike Haney (00:58:24):

So marker of cellular health?

Rob Lustig (00:58:26):

Marker of cellular health. Now, the problem is that uric acid does two things that you wish it didn’t do. One is it is the inhibitor of an enzyme in your arteries called endothelial nitric oxide synthase or eNOS. And it’s the enzyme that makes nitric oxide and nitric oxide is your endogenous blood pressure lower. It’s the thing that causes your blood vessels to relax. Therefore, it’s the thing that keeps your blood pressure down. And so if you’re inhibiting it, means your blood pressure’s going to go up. So it is a primary contributor to hypertension. Well-known, been known since 1967 that uric acid is a driver of hypertension. The second thing it does, and this was work from Rick Johnson from University of Colorado, he showed that uric acid inhibits an enzyme that’s necessary for mitochondria to do their job called CPT1, carnitine palmitoyltransferase 1. Now, what is that?

(00:59:37):

That’s an enzyme that regenerates this compound in your cells called carnitine. And carnitine is a shuttle mechanism for bringing fatty acids into the mitochondria so that they can be burned. If you don’t have enough carnitine, you can’t cleave fatty acids into two carbon fragments and use them for burning, in which case you end up with fatty liver. And so if you inhibit CPT1, you can’t transport the fat. Good reason for fat buildup, which causes insulin resistance and clearly mitochondrial dysfunction because it’s interfering with ATP generation because it’s interfering with mitochondrial function. So keeping your uric acid down is super important. Now, what makes uric acid go up? Well, obviously kidney disease, because you have to excrete it. But what else? Because kidney disease you can’t do much about, at least not, I mean, you could improve your metabolic health, that’ll help. But it’s not like you can fix that from one day to the next.

(01:00:45):

What makes uric acid? Well, two things make uric acid. The first is purines, because purines are adenosine and guanosine. They are nucleosides that are in meat. So Benjamin Franklin knew that his meat habit was the cause of his gout, and he wrote an ode to his gout back in 1785. So it’s been known for a long time that uric acid is a driver of gout, and that meat is a primary driver of uric acid. But the other thing that causes uric acid is not so well known and it’s sugar. And why does sugar increase uric acid? And that’s a complicated one, but let me explain it. Remember, sugar is two molecules, glucose and fructose. The glucose will get metabolized in every cell in the body, fructose only in the liver. The fructose enters the liver, and the first thing that happens is that the fructose gets phosphorylated.

(01:01:52):

A phosphate is added to the fructose, so it can then go on its biochemical journey to either energy utilization or more likely fat storage. When it’s phosphorylated, a phosphate has to be given to it. Well, where does the phosphate come from? It comes from ATP. So ATP has to go to ADP in order to metabolize fructose, which starts the uric acid. That’s the pathway to uric acid. So sugar consumption increases uric acid too. So both meat and sugar consumption both increase uric acid. If you want to get your uric acid down, you have to cut your meat, you have to cut your sugar consumption. It’s just that simple.

(01:02:38):

But because of the effects on blood pressure and because of the effects on this carnitine transport that, ultimately, leads to mitochondrial dysfunction and fat deposition, uric acid is a bad player in metabolic health, and the goal is to keep it down. All right, so how down should it be? If you look at the lab slip, it’ll tell you that the cutoff for high uric acid is at seven. That’s wrong. That’s wrong. Okay? The cutoff should be at 5.5. Now, why do I say 5.5 and the lab slip says seven? Clearly they know something.

Mike Haney (01:03:20):

I’m guessing gout is the answer.

Rob Lustig (01:03:22):

Well, no, no, no. It has to do with the normal distribution. It has to do with the Gaussian curve.

Mike Haney (01:03:29):

Okay?

Rob Lustig (01:03:30):

So today, if you take 100,000 “healthy” and we know that they’re not healthy because 93% of Americans manifest some form of metabolic dysfunction, but they may not know it and they say they’re healthy, but they go into this assay, you’re going to generate a bell-shaped curve, and then you get the mean. And then what we say is two standard deviations from the mean, that’s what we consider abnormal. That’s just a statistical fudge is two standard deviations from the mean. So if you do that for 100,000 “normal” healthy adults who are not healthy, that number’s going to be seven.

(01:04:17):

But if you did that 50 years ago, the number would’ve been 5.5. And the reason is because we were healthy then and we’re not healthy now. The entire bell shaped curve has shifted to the right. And of course, there’s no way to know that just doing that today, you have to actually look at what happened before to show that. And we have, so this is true for insulin. This is true for uric acid. It’s true across the board for hosts of things. It’s true for ALT, which is a liver function test because everyone has fatty liver now.

Mike Haney (01:04:59):

So maybe let’s wrap this up by coming back to where we started, which is what is our set of markers? What kinds of things we want to look at? We’ve talked about insulin a lot. That being a really key one. We’ve talked about uric acid, which I think is still pretty much on the fringes of what people are measuring. We’ve talked about some way of looking at glucose in relation to your insulin, whether it’s with the CGM or whether it’s with testing. What else do you want to see? What other markers fit these criteria we’ve talked about? And give us some indication of our health.

Rob Lustig (01:05:30):

Right. So you had mentioned cholesterol at the very beginning. Let’s turn to cholesterol for a minute. Everyone thinks cholesterol is important. It’s not. Now, there are different kinds of cholesterol, and some of them are important, but the total cholesterol doesn’t tell you that. So the amount of cholesterol on the side of the package, they took it off because they know, the FDA knows that’s not valuable. That’s number one. Number two, your total cholesterol on your lab slip is not valuable. It shouldn’t even be listed because all it does is confuse people and it’s spurious. So what does matter? Well, there’s this thing called LDL. Does that matter? And the answer is no. It doesn’t matter either. And here’s why. Because there’s not one LDL, there’s two. And the LDL on the lab slip measures both at the same time, and they’re not the same.

(01:06:26):

Now, if we had a way of separating, and we do, the two different LDLs, you can actually learn something. So that’s called a VAP analysis or lipoprotein electrophoresis, where you basically can distinguish the LDL that causes heart disease called small dense LDL from the LDL that doesn’t cause heart disease, which is called large buoyant LDL. Then you can learn something, but insurance isn’t paying for that. That’s a $500 test to figure that out. So people don’t know. Now, if you can afford it, great, but that’s not helping the masses. So we still have a problem there. Triglyceride turns out to be a more egregious lipid than LDL ever was. The hazard risk ratio for LDL in heart disease is 1.3. Meaning if you have a high LDL, you have a 30% increased risk of having a heart attack. Whereas the hazard risk ratio for triglyceride and heart disease is 1.8.

(01:07:30):

So if you have a high triglyceride, you have an 80% increased risk for having a heart attack. 50% increased over the LDL, but we don’t even talk about it. We don’t pay it any heed. And there are two reasons why. First reason is because a lot of people get their blood drawn not fasting. And you need to be fasting for a triglyceride to mean something because as soon as you eat, your triglycerides go up. Just like your glucose and your insulin have to be fasting in order to mean something.

(01:08:02):

And number two, the triglyceride doesn’t just stay triglyceride. The triglyceride circulates in the bloodstream, goes to your fat cell, offloads the lipid into your fat tissue, and then it becomes the small dense LDL. So your triglyceride and your small dense LDL are related to each other. So what you care about is your LDL, but you care about it in the face of your serum triglyceride. So high LDL, low triglyceride, not a big deal. High LDL, high triglyceride, very big deal. Now, at Levels, we understood this. And so we are not measuring LDL or triglyceride. We are measuring something called ApoB, Apolipoprotein B. And the reason is because LDL and triglyceride both have ApoB. Because one’s an evolution of the other. And so that’s a way of figuring it out. So that’s another reason why Labs 2.0 for Levels includes ApoB as one of the markers.

(01:09:07):

Okay. So that’s basically what Levels is doing right now. With tests that are normally and routinely available and coverable by insurance. Is that all? Are there other tests? Are there things that we could get that would give us information as well? And the answer is, yeah, there are. Let me give you an example. There’s a test called homocysteine. Now we are not getting it. Now, it turns out homocysteine is a metabolic metabolite of protein. It’s part of the TCA cycle, but it’s also in the protein cycle, and it is responsive to B vitamins and omega-3 fatty acids. When you’re B vitamin deficient and when you’re omega-3 fatty acid deficient, your homocysteine goes up.

(01:10:02):

And it turns out homocysteine levels predict cardiovascular disease and heart attack as well. And now we’ve also learned that homocysteine levels also predict Alzheimer’s disease. Now, we’ve known for years about a disease called homocystinuria. This is a disorder of the enzyme that clears homocysteine in the body. If you have this disease, you’re tall and you’re actually kind of gangly and you’re mentally retarded and you get very early heart disease. It’s a disease I used to take care of as a pediatric endocrinologist. Well, people have now done a lot of work on whether or not that homocysteine was the cause of the mental retardation and the cause of the heart disease. And we now understand that that is a primary risk factor. It’s part of the pathogenesis, and it may even be part of the pathogenesis of Alzheimer’s routinely. So could we get total homocysteine in our patients and learn something about their metabolic status? And would that be fixable? And the answer is yes.

(01:11:16):

It’s also on a dynamic range, and it’s also modulable. It means something, but it’s not covered by insurance today. Should that change? I think so. So that’s an example. What other tests could you do that would be valuable? One of the cardinal features of aging is methylation. So your DNA gets methylated, and the longer you live, the more methylated your DNA gets. Well, it turns out the degree of methylation predicts the degree of aging. You can measure methylation status by measuring something we now have a test for called epigenetic age. Can you measure epigenetic age? Yeah, but insurance is not paying for it. It’s relatively still expensive. Our colleague, David Sinclair offers a methylation test known as the DunedinPACE method. And you can determine that.

(01:12:20):

And we know from other studies, like for instance, my colleague Bruce Blumberg at UC Irvine has shown that the methylation status of an enzyme called insulin degrading enzyme predicts insulin resistance because you can’t clear the insulin because of its methylation status. And that is a primary hallmark of obesity and aging. So the problem with the DunedinPACE is you have to chop up all the DNA. So you don’t know which enzyme it’s with, or which gene it’s with. So it lacks a certain, shall we say, specificity, but it gives you a sense of how you’re doing from an aging standpoint. And my colleagues at UC Berkeley and UCSF, Barbara Laraia and Elissa Epel just showed a cross-sectional study showing that the degree of ultra-processed food that you eat predicts your epigenetic age compared to your biological age.

(01:13:21):

Now, does that mean you could fix your food and fix your epigenetic age? We don’t know that yet. No one’s done that. But is that something to look at for the future? And could that ultimately be a good marker for us to be able to draw? Very possibly. That’s an exciting place to go. And then the last thing is inflammation. So the degree of inflammation that’s going on in the body, how do you determine that? Because the more inflammation, the sicker you are without question. And where’s the inflammation coming from? It’s almost always coming from the gut, gut inflammation. So are there tests for gut inflammation? And the answer is not good ones, unfortunately.

(01:14:04):

But we can look at systemic inflammation. We can look at high-sensitivity C-reactive protein. So that’s a test that’s immediately available. It doesn’t cost too much. The problem is it doesn’t have quite the dynamic range that the others do. It’s not quite as good a biomarker, but it still tells you whether there’s inflammation going on or not. And so if you know that your HSCRP is low, that’s a good sign. It means that you’re doing something right and if it’s high, it means clearly things are not right and you need to start thinking about what it is you’re eating in order to get that HSCRP down. It doesn’t tell you what’s wrong, just tells you something’s wrong.

(01:14:47):

So that’s another potential test that can be added to the armamentarium and it’s not too expensive and it’s available now. So this is an evolution. We’re working on it. We’re getting there. We need the science in order to be able to justify the cost and the expense and certainly the insurance coverage. Because they’re not going to pay for anything unless it works. So we’re still working on those things. But for me today, the things to know are your fasting insulin and your uric acid and your ApoB, and then we can talk about the rest.

Mike Haney (01:15:30):

Well, maybe last question on this then, which I think this leads into is we do now have companies like Function Health from our friend, Dr. Hyman, and other companies like his that are offering these very broad arrays of tests. I think they do over 100 annual markers. What do you think about the utility of tests like that? Are there things that would be on your wish list, either because they’re precursors or because a good indication that somebody’s going to get as part of that large set that you’re just not going to get at your doctor setting cost aside because that is the barrier to getting those larger arrays. But if one has the means, what do you think about people getting that amount of data?

Rob Lustig (01:16:09):

I think it’s probably premature. And the reason is because we don’t know what to do with it. We don’t know how to analyze it. We don’t know what goes with what pathway, because you’re trying to influence a pathway. You’re not trying to influence a specific biomarker. The biomarker is a marker for the pathway. When we have some more data and we know that those things are actually manipulable and that the manipulation actually results in clinical benefit, then I’ll be ready to support those. I think it’s a little too early for those. I think that’s a little premature. It’s nice to think about. It’s definitely a hot research topic and I’m for that. But in terms of clinical utility, I think don’t put the cart before the horse.