Insulin resistance is when cells stop responding to insulin’s signal to uptake glucose. It’s a hallmark of prediabetes, Type 2 diabetes, and other forms of metabolic dysfunction, and it manifests as several chronic disease, ranging from Alzheimer’s to polycystic ovarian syndrome. Dr. Rob Lustig and Dr. Dominic D’Agostino discuss the importance of monitoring insulin levels, why a high or increasing insulin level is a problem, and how insulin resistance hinders weight management.
- Robert Lustig, MD: https://robertlustig.com
- Metabolical, by Robert Lustig, MD: https://robertlustig.com/metabolical/
- Robert Lustig, MD, on Instagram: https://www.instagram.com/robertlustigmd/
- Robert Lustig, MD, on Twitter: https://twitter.com/RobertLustigMD
- Dominic D’Agostino, PhD: https://www.dominicdagostino.org
- KetoNutrition: https://ketonutrition.org
- Dominic D’Agostino, PhD, on Instagram: https://www.instagram.com/dominic.dagostino.kt/
- Dominic D’Agostino, PhD on Twitter: https://twitter.com/DominicDAgosti2
3:57 — What is insulin?
Dr. Rob Lustig describes insulin’s role in the body.
Insulin is a hormone. It’s a chemical that is made in the pancreas, circulates in the blood, and goes to different parts of the body to do different things. And it does different things in different tissues. The main thing that insulin does is it stores energy. Insulin is the energy storage hormone. Insulin shunts energy in the form of glucose—and sometimes other food stuffs as well, like amino acids and fats—into tissues, especially adipocytes (fat cells) to accumulate energy. Insulin makes fat. More insulin, more fat. And so this phenomenon of insulin resistance has always been a question mark because people say, “Well, if it’s more insulin, more fat, if you’re insulin resistant, how come you get even fatter?” And this of course is the big paradox in insulin resistance, and we’re going to try to answer that for you today.
6:55 — What is insulin resistance?
Insulin levels are high when insulin function is low, meaning when cells are ignoring insulin’s signaling.
The answer is because the receptors for insulin, the proteins that bind insulin on the cells, have been downregulated. They are not working as well because there are fewer of them. And because the signaling that goes on beyond that receptor is dysfunctional. And that is really what insulin resistance is about. Why does that happen? It happens in different tissues, and it happens for different reasons. And in fact, those different tissues are important in terms of why insulin resistance manifests different diseases. So for instance, Type 2 diabetes is a manifestation of insulin resistance at the level of the liver. Polycystic ovarian syndrome is a manifestation of insulin resistance at the ovary. Cardiovascular disease is a manifestation of insulin resistance at the heart. Alzheimer’s disease—we are learning—is a manifestation of insulin resistance in the brain. So this phenomenon insulin resistance is extraordinarily important for all of these chronic diseases, but it’s regio specific. Different tissues manifest insulin resistance at different times, and it is because of that that we end up with these different manifestations.
18:00 — There are three types of insulin resistance
Dr. Rob Lustig explains the three types of insulin resistance he sees: when too much energy is forced into subcutaneous fat cells, when stress elevates cortisol, and when non-alcoholic fatty liver disease occurs. The following is an the explanation of the latter.
Non-alcoholic fatty liver disease is 45% of the American population and 25% of the world’s population—having nothing to do with obesity. And this is true throughout the entire world. One quarter of all the people on the planet, 2 billion adults have fatty liver disease. Now, prior to 1980, if you had fatty liver disease, you were an alcoholic. But these are not alcoholics. We don’t have 2 billion alcoholics. So why do they have liver fat? And why is the liver fat generating the insulin resistance? And the reason is because the liver’s the primary target of insulin action. And so when your liver cells start accumulating fat, they don’t work very well. And so your pancreas has to make extra insulin to make the liver do its job. And so I think that the liver is really ground zero for why we have this phenomenon of insulin resistance, and that’s why you can be thin and insulin resistant, as well as being fat and insulin resistant.
38:00 — Weight management is not about calories in and calories out
The type of calories consumed matters more than the amount, and increasingly people are getting their calories form ultra-processed foods.
You’ve been pelted for the last 50 years with calories, okay? It’s all about calories—calories in, calories out—and therefore it’s about two behaviors. Gluttony, sloth. And so if you’re fat, it’s your fault, you know? And therefore, diet and exercise, you know, ultimately all of these are the mantras of the food industry. And the reason is because if it’s about calories, it’s your problem not theirs. It’s their way of assuaging, their culpability for what they are putting into ultra-processed foods. And you have to understand that there’s an entire literature that basically pushes back against this notion of calories. So let me give you some examples. Number one, there are countries that are diabetic without being obese, and there are countries that are obese without being diabetic. So obesity and diabetes don’t necessarily play the same role. Number two, um, obesity is growing at a the rate of 2.7800000000000002% per year worldwide, but diabetes is growing at the rate of 4.07% per year worldwide. If diabetes was just because of obesity, how come diabetes is going up faster? Number three, if you look at the rate of increase in diabetes in the general population of the United States, it’s going up just as fast in the obese as it is in the normal weight population. If obesity was the reason, that wouldn’t be the case.
45:53 — Adding more insulin to the equation of Type 2 diabetes isn’t necessarily the answer
Dr. Lustig explains his concerns with the American Diabetes Association’s stance on the management of Type 2 diabetes.
The fact of the matter is that Type 2 diabetes is eminently reversible. You have to fix the diet, but they don’t say anything about the diet. What they said was, “Give all the carbs you want, just give enough insulin to cover it,” which is also not true. I mean, yes, you can cover the glucose rise with insulin, but all you’re doing is actually fomenting further chronic metabolic disease. So you’re fixing the glucose, but the glucose isn’t the problem. The insulin’s the problem and the more insulin, the quicker you die. And that’s been shown every 50 ways from Sunday.
51:20 — Insulin is a crucial biomarker to measure for metabolic health
An increasing or high fasting insulin level will generally show up earlier than a high glucose level that’s consistent with Type 2 diabetes. For this reason, Dr. Lustig says we should be measuring fasting insulin levels.
So in fact, you can be metabolically healthy, obese, and have a low insulin, but still be obese because fasting insulin does not correlate with obesity. That’s right. It doesn’t; that’s not why you draw it. You draw it to determine metabolic health. And the thing is that fasting insulin will change way before fasting glucose, way before glucose tolerance, way before hemoglobin a1c. So it is a much earlier arbiter of metabolic dysfunction. And by the way, this is why fasting insulin is part of Levels Health’s Labs 2.0. And the reason it’s there is because I made sure it was. We are accepting that insulin resistance is a problem and insulin is the most important metabolic hormone. Even other investigators and people who teach this subject at medical schools know enough about the data to know that insulin starts to go up before Type 2 diabetes becomes diagnosed.
53:58 — Insulin resistance is a hinderance to weight management
Dr. Lustig explains what causes insulin to go up and the four methods to lower the level.
If you have insulin resistance, you are not going be able to lose weight until that insulin comes down, because that fasting insulin is always there and it’s always pushing on your fat cell. It’s always telling your fat cells, “Store more, store more.” And you can’t reverse that, and you can’t get lipolysis. You can’t get the fat out of that fat cell until that insulin goes down. You’ve got to get insulin down any way you can. Now, in my life, there are four ways to do that: diet, exercise, drugs, surgery. Those are the four ways. Diet is where you start. Fix the diet, fix the diet. How do you get insulin down? Very simple. Don’t let it go up. Well, what makes it go up? Really only two things: refined carbohydrate and sugar. Those are the two things that make insulin go up. Fat does not make insulin go up.
57:07 — The intake of too much leucine can lead to insulin resistance
Dr. Lustig explains that, although the essential amino acid leucine is crucial for muscle building—it can lead to insulin resistance under sedentary conditions.
If you’re a body builder, you need muscle, and you can’t build muscle without leucine. In fact, you can’t build muscle without all three branch chain amino acids: leucine, isoleucine, valine. They are 20% of muscle, and they are essential amino acids. You can’t make them; you have to eat them. So if the goal is muscle mass, if the goal is bulking up, if that’s what you’re doing, then you have to consume them. And that’s why they scoop the protein powder into their smoothies and why they have big tubs of this at GNC. I get it. I get it. And that’s okay if you’re building muscle. But what if you’re not building muscle? What if you’re a mere mortal like me and you’re consuming excess branch chain amino acid. Well, what happens to them? Is there any place to store them? Well, muscle. But if you’re not building it, then you can’t store it there, can you? So what happens to the excess? Goes to the liver.
1:02:04 — Fiber feeds the gut microbiome and is crucial for metabolic health
Dr. Lustig describes the gut as the body’s sewer system and explains why the gut microbiome needs fiber for fuel.
So keeping your intestinal barrier functional and optimal is absolutely essential to metabolic health. Now, there are three barriers in the intestine. One is physical. That’s the mucin layer. And the mucin layer is this mucopolysaccharide coating on top of the intestinal epithelial cells. And that basically forms a physical barrier to the sewer that doesn’t let all the stuff in. Now, the bacteria in the intestine—they’ve got to live. They’ve got to eat something. They eat what you eat. But the question is how much did you eat versus how much did they eat? If you are absorbing everything early in the duo and therefore not presenting anything for them to eat in the juju and ilium, then they’re starving. That microbiome, those bacteria, they get unhappy. And what will happen if they get unhappy because you’re starving them, they will eat the mucin layer right off your intestinal epithelial cells. They will use it for energy. They will denude your intestinal epithelial cells, and in doing so, they will then increase opposition of bacteria to the intestinal epithelial cell, which you can see on electron microscopy, and that can ultimately lead to degradation of that epithelial cell layer and what we call leaky gut and also transport of bad stuff across into the portal system, and therefore the liver, and generates systemic inflammation. So fiber is the food for the bacteria. The bacteria will be able to chew it up. We can’t break the bond of fiber, we can’t break that beta-glucan bond, but the bacteria can. So that ultimately means that fiber is the food for your microbiome.
1:13:11 — Is intermittent fasting necessary?
Dr. Lustig explains his take on intermittent fasting and why.
A paper came out two years ago that suggested that time-restricted eating was very important, but it worked only in those patients with liver fat and that made sense to me. I haven’t seen a follow up on that, but that made a lot of sense to me because what that suggested was that the reason time-restricted eating works is because it’s giving your liver a chance to get rid of the fat that accumulated over the previous 16 hours, which I think is the right thing to do. So I’m for intermittent fasting, but I’m for it in the right patient.
Rob Lustig (00:19:07):
One quarter of all the people on the planet, 2 billion adults have fatty liver disease. Now, prior to 1980, if you had fatty liver disease, you were an alcoholic. But these are not alcoholics. We don’t have 2 billion alcoholics. Why do they have liver fat? Why is the liver fat generating the insulin resistance? The reason is because the liver’s the primary target of insulin action. When your liver cells start accumulating fat, they don’t work very well. Your pancreas has to make extra insulin to make the liver to its job. The liver is really ground zero for why we have this phenomenon of insulin resistance.
Ben Grynol (00:19:53):
I’m Ben Grynol, part of the early startup team here at Levels. We’re building tech that helps people to understand their metabolic health. Along the way, we have conversations with thought leaders about research backed information so you can take your health into your own hands. This is a whole new level.
This is a very exciting episode as we tend to experiment with things. In this episode, Dominic D’Agostino and Rob Lustig, two of our friends, advisors, mentors and leaders that we look up to in the space of metabolic health. The two of them sat down and they discussed this idea of insulin resistance. For those of you who aren’t familiar with Rob or Dom, here’s a bit of background. Rob is a New York Times bestselling author, and he’s one of the world’s leading experts on metabolic health. He’s an emeritus professor of pediatrics at the University of California, San Francisco. Dom, he’s a professor at the University of South Florida, Morsani College of Medicine, and he’s also a research scientist at the Institute of Human and Machine Cognition. Both are not only advisors and friends of Levels, but they’re very much an inspiration to our entire team through their work, through their personal lives that they lead, and the lifestyle choices that they make.
Dom and Rob, they sat down and discussed this idea of insulin resistance. What does it sound like when two thought leaders have a conversation that is very familiar to them but maybe not as familiar to people who aren’t as deep in the space? They answered basic questions that many people have. They broke down the conversation to a starting point. What exactly is insulin and what leads to insulin resistance? What can we do about it? What’s the difference between insulin resistance and type 2 diabetes? Does one proceed the other? If insulin’s so important, why is it not part of regular blood panels and testing unless it’s specifically requested? What we know is that insulin resistance isn’t something that can be extrapolated in the way that it manifests across different tissues. Type 2, that is a manifestation of insulin resistance of the liver.
PCOS, it’s a manifestation of insulin resistance of the ovaries. Alzheimer’s manifestation of insulin resistance of the brain. These are all things that we’re learning. The research goes deeper and deeper. As Rob puts it, “You can’t outrun a bad diet. You cannot out exercise poor nutrition. You got to fix the foundation first.” Dom and Rob, they sat down and they discussed all of these inputs to insulin resistance and gave us all a better lens on what exactly it is, how we can think about it, and what to do next. Anyway, no need to wait. Here’s the conversation with Rob and Dom.
Dominic D’Agostino (00:19:53):
Hey, Rob, it’s great to be with you here today, and I’m excited to cover this topic on insulin resistance, what we know, what we don’t know, what we have to learn, and what are actionable things that we can do.
Rob Lustig (00:19:53):
Indeed. So glad to see you as well. We’ve paled around at meetings. We have to now do this on the internet instead, but between the two of us, I think we’ll be able to knock this out of the park.
Dominic D’Agostino (00:19:53):
There’s a lot to discuss in this topic. I mean, it’s central for metabolic health. It’s the etiology of so many of the major chronic diseases, including diabetes, of course, but all the way to even cancer and cardiovascular disease. Let’s talk about maybe what is insulin resistance? How do we define it?
Rob Lustig (00:19:53):
Well, I’ll be honest with you, before we define insulin resistance, I think we do ought to define insulin. Insulin is a hormone. It’s a chemical that is made in the pancreas, circulates in the blood, and goes to different parts of the body to do different things, and it does different things in different tissues. The main thing that insulin does is it stores energy. Insulin is the energy storage hormone, insulin shunts energy in the form of glucose, and sometimes other food stuffs as well, like amino acids and fats into tissues, especially adipocytes, fat cells to accumulate energy. Insulin makes fat. More insulin, more fat. This phenomenon of insulin resistance has always been a question mark because people say, “Well, how come if it’s more insulin, more fat, if you’re insulin resistant, how come you get even fatter?” This of course is the big paradox in insulin resistance, and we’re going to try to answer that for you today.
Dominic D’Agostino (00:19:53):
Good overview, Rob. A question that we get quite often, even from the medical students is, what is the difference between insulin resistance and type 2 diabetes and how do you define it and does one precede the other? Also, I mean, you talk about what insulin is, obviously it’s one of the most important metabolic hormones. I mean, I don’t think anyone would dispute that. Another question that comes about in medical curriculum is why are we not measuring insulin? Separate question, but why is insulin not part of a comprehensive metabolic panel? Two questions there. We’d like your insights from a clinician’s perspective.
Rob Lustig (00:19:53):
The first issue is why is insulin resistance the big issue? The answer to that goes all the way back to 1959 when Rosalyn Yalow and Sol Berson first developed the radio immuno assay. Their very first attempt was to measure insulin. What they found was that when they took the blood of type 2 diabetics, they expected to see no insulin. After all, they have diabetes. But what they saw was that the insulin levels were actually higher. This was like, “Did we get this right? Are we measuring the right thing?” Well, it turned out not only were they measuring the right thing, but they discovered a completely new and important manifestation of chronic disease, the phenomenon of resistance to a hormone. How come insulin levels are high when insulin function is low? The answer is because the receptors for insulin, the proteins that bind insulin on the cells have been down-regulated.
They are not working as well because there are fewer of them and because the signaling that goes on beyond that receptor is dysfunctional. That is really what insulin resistance is about. Why does that happen? It happens in different tissues and it happens for different reasons. In fact, those different tissues are important in terms of why insulin resistance manifests different diseases. For instance, type 2 diabetes is a manifestation of insulin resistance at the level of the liver. Polycystic ovarian syndrome is a manifestation of insulin resistance at the ovary. Cardiovascular disease is a manifestation of insulin resistance at the heart. Alzheimer’s disease, we are learning is a manifestation of insulin resistance in the brain. This phenomenon of insulin resistance is extraordinarily important for all of these chronic diseases, but it’s regio specific. Different tissues manifest insulin resistance at different times, and it is because of that, that we end up with these different manifestations.
Dominic D’Agostino (00:19:53):
Excellent overview, Rob. I’m glad you mentioned the brain. A question that I got the other day actually was can you have type 2 diabetes without insulin resistance? I could not answer this unambiguously with a particular reference. I printed a couple papers out and I didn’t get a chance to read it. But a question that in our discussion of teaching this is, from your perspective, can you have type 2 diabetes without insulin resistance?
Rob Lustig (00:19:53):
No. But you can have a disease that masquerades this type 2 diabetes without insulin resistance. How do you define type 2 diabetes? Well, anything that’s not type one diabetes. Type one diabetes, we know how to define because there are antibodies in the blood. You can have antibodies against the beta cell. You can have antibodies against ICA2, anti-GAD antibodies. Now there’s a zinc transcription factors, the nT8 antibodies. Point is, all of those demonstrate immunologic destruction of the beta cell. If you have immunologic destruction of the beta cell, you have type one diabetes. If you don’t, then everybody assumes you have type 2 diabetes.
Now, that is actually incorrect because there are many, many different forms of diabetes that are not type one. There’s cystic fibrosis related diabetes, there’s mitochondrial diabetes, okay? There’s a whole host of different diseases, and there are genetic forms of diabetes known as MODYs, M-O-D-Y, mature-onset diabetes of youth. There are 14 of them because there are 14 different genetic defects that will ultimately lead to beta cell dysfunction and lead to hyperglycemia. Those often get bend in with type 2 diabetes. Those patients with MODY account for about 5% of the type 2’s. Those patients don’t have insulin resistance. You have to know which patient you’re looking at. But if you have true type 2 diabetes, you have insulin resistance.
Dominic D’Agostino (00:19:53):
You mentioned a couple different diseases there, like 14 different diseases associated with this. That leads to the question, what’s the ideological cause of insulin resistance? Is that also heterogeneous? I know Gerald Shulman, I’ve read most of his papers in his banting lecture, I think, in 2018, talked a lot about ectopic fat. I know Dr. Shulman is really focused on the muscle, fatty acid oxidation impairment of that in the muscle, but it also occurs in the liver. I guess one of the questions is if we want to get an early precursor of insulin resistance, should we be looking at ectopic fat? Well, we should be measuring insulin, but also ectopic fat in the muscle, in the liver. I know a lot of your emphasis has been on the liver, and I’ve certainly got a much bigger appreciation for the liver as the master regulator even working in mice and rats. I’d love to hear your comments on that. This ectopic fat as a precursor.
Rob Lustig (00:19:53):
Right. Jerry Shulman is of course the ultimate guru, and I wish he were here to say his peace, but Jerry has undergone an awakening of sorts, and I know why. When he started doing all of his analyses of intracellular fat, intramyocellular lipid, et cetera, he was using a magnet for an MRI that was only 1.5 Tesla. It had to be small, and the only magnet he could use was one that fit around the gastrocnemius muscle in the leg. He knew a lot about muscle fat. Throughout the entire early 2000s, he was publishing that this was a muscle fat issue, muscle fat issue. He believed it. Then in the late 2000s and 2010s, we had the advent of the 3 Tesla magnet. Now of course we have a 7 Tesla magnet, and that allowed for a much bigger circumference.
We could actually start measuring liver fat. The first paper that came out was actually on… This was from Sam Klein’s group in 2009, and what they showed was it was actually the degree of liver fat that mattered the most. Jerry Shulman went back to the MRI machine and started to looking at livers and found, “Oh my God, yeah, the liver’s even worse than the muscle. In fact, the liver fat actually predicts the insulin resistance more than the muscle does.” It is true that muscle insulin resistance contributes to type 2 diabetes and to overall general ill health, I don’t argue that, but when you actually do the quantitation, the real problem is in the liver. That’s now been documented 50 ways from Sunday. I think the liver is the big issue. The way I put this together, and I am very happy for your input here, Dom.
The way I put this together is that there are three different insulin resistances. Not one, not two, but three. The first one comes from the general fat, the subcutaneous fat. Now, normally subcutaneous fat is protective against metabolic disease. It’s where your body wants to put excess energy. It’s the place where insulin stores the energy and you can gain a certain amount of subcutaneous fat without any cost to the rest of the body. But then a certain point comes where you start forcing more energy into those adipocytes, the fat vacuoles start to grow, the perilipin border that encircles that vacuole starts to break down, and the fat in those vacuoles starts to actually seep into the cell and kill off the cell. This necrosis that happens… Individual fat necrosis then recruits macrophages to help clean up the grease. Those macrophages then secretes cytokines, TNF-alpha, IL-6, et cetera, which then go via the systemic circulation to the liver and activate a NADPH oxidase and ultimately lead to insulin resistance.
Dominic D’Agostino (00:19:53):
The fat induced hypertrophy and then stretching of the membrane, and then associated rupturing or dysregulation associated with that is the driving, I guess what we’ll talk about later, the inflammation associated with that. But it’s really… As we age, those membranes probably become less viscoelastic and probably that process is augmented by age, too.
Rob Lustig (00:19:54):
Exactly. Subcutaneous fat can lead to insulin resistance, but only at a very high level. That’s one of the reasons why we have metabolically healthy obese people because they’re stuffing energy into subcutaneous fat, but they haven’t gotten to the point where those membranes have ruptured. That’s the first way to get insulin resistance. The second way to get insulin resistance is from stress, having nothing to do with energy and having nothing to do with food. The reason we know this is because patients with endogenous clinical depression who are not eating, I mean, they’re anhedonic, they are suicidal, you have to admit them to the hospitals to keep them from hurting themselves. You stick them in a scanner and they’re not eating, they’re losing weight, they’re losing subcutaneous fat, but they’re gaining visceral fat. You can actually see the visceral fat on the CT scan.
In fact, they have insulin resistance, too. They have it because of cortisol. They have it because of an altered sympathetic nervous system output. They have a different form of insulin resistance, which is not necessarily food driven, not necessarily energy driven, but rather hormonally driven like we see in patients with Cushing syndrome. Then finally, the third group, the patients with liver fat. Now, I just saw that non-alcoholic fatty liver disease is 45% of the American population and 25% of the world’s population having nothing to do with obesity. This is true throughout the entire world. One quarter of all the people on the planet, 2 billion adults have fatty liver disease. Now, prior to 1980, if you had fatty liver disease, you were an alcoholic. But these are not alcoholics. We don’t have 2 billion alcoholics. Why do they have liver fat? Why is the liver fat generating the insulin resistance?
The reason is because the liver’s the primary target of insulin action. When your liver cells start accumulating fat, they don’t work very well. Your pancreas has to make extra insulin to make the liver to its job. I think that the liver is really ground zero for why we have this phenomenon of insulin resistance, and that’s why you can be thin and insulin resistant as well as being fat and insulin resistant.
Dominic D’Agostino (00:20:01):
I have a couple follow up questions on that. If the muscle has impaired fatty acid oxidation, then could that be the site of impaired glucose oxidation and fatty acid oxidation and then that contributes to the buildup of fat in the liver? Or do you think one precedes the other? I know that Gerald Shulman is very… I didn’t have an appreciation for the history of the imaging, how the first measurements were made in the gastrocnemius, and then the 3 Tesla evolved to image the whole body. I’ve always pictured it from the context of impaired fatty acid acid oxidation in the skeletal muscle, which is the glucose sink, and then that creating the bottleneck, which then contributes to the impaired fat oxidation in the liver and de novo fatty acid production in the liver.
Rob Lustig (00:21:03):
I believe it can, I’m not saying it can’t, but there’s one piece of scientific evidence that would argue against that, and that is the fat insulin receptor knock-out mouse, the FIRKO mouse. As you know, Ron Kahn’s lab at Joslin Diabetes Center created eight, count them, eight separate tissue specific insulin receptor knock-outs. They’re all insulin resistant in their own ways, but they’re insulin resistant in different tissues. They’re regio specific insulin resistance, and they all have different diseases. For instance, my favorite mouse of all time, Bar None is the podIRKO mouse, the glomerular podocyte insulin receptor knockout mouse. This mouse has had its insulin receptor extracted by transgenic means by Cre-Lox from the kidney. The animal is completely, totally insulin sensitive except for the kidney. This animal has normal blood glucose. This animal has normal ketones. This animal has normal insulin tolerance. This animal is not fat, but this animal has the worst diabetic nephropathy on the planet even though the animal is euglycemic, even though the blood glucoses and the glucose tolerance is completely normal.
Why is that? How can that be? How can you have diabetic nephropathy with normal blood glucose? The answer is because it’s not the glucose, it’s the insulin. The insulin makes the difference. In Jerry Shulman’s hands, yes, there is absolutely defective fatty acid oxidation in the muscle. No argument. I agree with that. The question is, is it cause or effect? I believe in most patients, not in all, but in most patients, it’s effect because of the hyperglycemia that’s ultimately leading to it. The reason I feel that way is because of the FIRKO mouse, which is not fat and is not diabetic.
Dominic D’Agostino (00:23:23):
If it was in the muscle, then exercise being a very powerful activator of AMPK, independent of PI3K would quickly reverse that, but maybe not so much in the liver. I do… It brings back some questions related to athletes who are consuming two, 300 grams of sugar a day and their insulin’s maintaining low, but they’re on a different spectrum. Then actually, we just published a study. High carb athletes are essentially pre-diabetic, even if you adjust for calories, which surprised me, the results really surprised me. We just published this.
Rob Lustig (00:24:09):
Well, this is the story of Sammy Inkinen, and he’s happy for me to use his name. Sammy, one of the original founders of Nokia when he was 19 years old, he sold out, he cashed in, took his money, moved to the United States, went to Stanford Business School, started the real estate website, Trulia, which was bought by Zillow for $3 billion. Sammy’s got more money than God. Now Sammy was an amateur triathlete and he would win. He actually would win triathlons. This guy exercised five hours a day and at age 38, all of a sudden he realized his performance was going down and he didn’t understand why. He saw his doctor and the doctor said, “Hey, you’re pre-diabetic.” He didn’t understand, how can somebody who’s a triathlete who’s exercising five hours a day be pre-diabetic. He went to see Steve Finney, who is one of the low-carb physiologists and physicians at UC Davis.
Steve Finney said, “Well, it’s obvious. It’s the sports drinks. Stop drinking the sports drinks.” Sure enough, Sammy stopped drinking the sports drinks and his performance went up, his type 2 diabetes or pre-diabetes reversed. He said, “Wait a second, this is crazy.” What did he do? He started Virta Health. Virta Health now uses the ketogenic diet to reverse type 2 diabetes because he knows that even exercise can’t fix this metabolic problem. You cannot outrun a bad diet and you’ve got to fix the diet first. Yes, exercise is important, but it’s not enough.
Dominic D’Agostino (00:26:07):
That reminds me, I connected with Sammy early on, maybe about 10 years ago when he was transitioning, and met him on occasions and we had a lot of emails back and forth and stuff, too. He dropped his carbs very low, but would actually add some carbs back in, I think in the form of chocolate or dark chocolate, but a small amount like 50 to 100 grams or something when he was doing this crazy rowing feat. It was really interesting. That was… I was mostly focused on epilepsy and other neurological disorders.
But then Virta came along while after I met with him at a meeting related to that, and I got more and more interested in the use of low-carb, which I thought was an odd application of using low-carb diets in athletes because at the time I was just hyper focused on epilepsy because that was the only legitimate application of a ketogenic diet, at least from randomized controlled trial point of view. But then he opened my eyes about 10 years ago to the application in athletics, as did Jeff Olick and Finney’s book. It was really interesting to see that come along. Now the problem exists as a pediatric endocrinologist. This problem is not… It can happen in adults and athletes, but also in the pediatric population, which I guess, you were practicing in the ’80s. Is that right? Did you see?
Rob Lustig (00:27:48):
Well, I graduated med school in ’80.
Dominic D’Agostino (00:27:51):
Okay. Did fatty liver disease exist in kids in the ’90s?
Rob Lustig (00:27:56):
Dominic D’Agostino (00:27:57):
Did it start to evolve?
Rob Lustig (00:27:58):
I remember my very first case of fatty liver disease and it was in Memphis, Tennessee, and it was 1997 and I was called to see this 13 year old who was pre-diabetic, who was obese of course, who had these enormously high ALT, AST gamma-glutamyl transpeptidases. They wanted to know, “Well, why is he pre-diabetic?” I looked at her, I said, “I don’t know, this is crazy. What’s wrong with this kid?” I figured he had hepatitis or something, he had hep C or something like that. But no, he was negative for all these things. Sure enough, they took him and they did a liver ultrasound and they saw that he basically had 30% liver fat. I said, “What the hell is this?” That was my very first case of non-alcoholic fatty liver disease. He was only 13 years old, so he wasn’t an alcoholic.
Well, that was my index case. Then they started rolling in after that and we started then looking for it. We realized in 2005 that we could use ALT alanine aminotransferase off the chem panel for being able to screen for it. Of course, the other thing that we did was we would do fasting insulins in order to determine the degree of insulin resistance. The combination of fasting insulin and ALT was very potent in terms of being able to determine what was really going on with these insulin resistant and fatty liver kids. The answer was in two words, soft drinks.
Dominic D’Agostino (00:29:43):
In your practice, did you ever come across kids who have inborn errors of metabolism? I just came from a lysosomal storage disease conference where we’re doing research on mice who have very large livers and we’re going to do the histology on them, but one thing that I didn’t know going into this is that the mice that have Pompe disease or glycogen storage disease type 2-
Rob Lustig (00:30:10):
Dominic D’Agostino (00:30:10):
… they have overproduced glycogen and then they can’t-
Rob Lustig (00:30:14):
In the heart.
Dominic D’Agostino (00:30:15):
… break down. Yes. Then this causes problems in the muscle, but I was pretty much focused on the muscle and the brain because it’s like our wheelhouse. But in communicating with parents who have these kids too, the liver is a big problem and their liver is really swollen and it needs to be a focus of attention. But now it’s looked at and I was wondering if you just came across… It also leads to the question, are there genetic predispositions to this?
Rob Lustig (00:30:54):
Well, these diseases that you’re talking about, these glycogen storage diseases are actually pretty rare. They’re not that common. We have GSD 0, glycogen storage disease, type 0, which is glycogen synthase deficiency all the way up to GSD 9. We have 10 of these diseases. The point is that they store glycogen. Now, there’s certain organs that can store glycogen, for instance, the liver. That’s where your body wants to store glycogen and you can store it in the muscle as long as you can fish it out, eventually you can pack enough glycogen in so that it becomes a problem. But there’s a glycogen storage disease, GSD type 1, also known as Von Gierke’s disease, which you’re missing the glucose 6 phosphatase, you’re missing the ability to get glucose out of glycogen. You’re not able to release it. These patients are enormously hypoglycemic.
That’s how they present. That’s why they call us as an endocrinologist because these kids show up with hypoglycemia, then they’re in the neonatal or in the early postnatal period and they will stuff glycogen into their livers nonstop. They will be hypoglycemic like all get out. They will be ketotic because they can’t use their glycogens, they have to end up using fat, and so they will be ketotic. But the question is do they get liver failure? The answer is no, they don’t get liver failure. Glucose, for lack of a better word, glycogen for lack of a better word, is non-toxic. Now, it’s not good to have too much obviously, but hey, that’s what your liver wants to do with excess energy is make glycogen. That’s why marathoners carb load before a race. I don’t see glucose and glycogen as being the big problem.
Now a lot of people think glucotoxicity is the big issue in insulin resistance, bringing it back to insulin resistance. There’s some data that supports that. But I think that the reason that glucotoxicity is the problem is because what’s happening in the liver is the glucose is getting turned into fat by this phenomenon called de novo lipogenesis, DNL, where you take glucose and turn it into fat or you take fructose more likely and turn it into fat. It is the lipotoxicity that actually interferes with liver functioning not the glucose. It is because of these patients with Von Gierke’s disease that I think so. The glycogen storage diseases I think play a very minor role in this story. I don’t think it’s as big a problem. I think the bigger problem is the turning of glucose into fat.
Dominic D’Agostino (00:33:59):
I was wondering if it was analogous because we do see in Pompe disease, GSD 2 is that when the glycogen… There’s hyper source of glycogen and the decrease in autophagy that tends to impair muscle function and it becomes painful. Then that leads to an analogous to that that is occurring in the liver. But probably we did not think to look in the liver and we haven’t really so far, but we just see that the livers are quite large as we’re starting to do necropsy on these animals. But the histology I guess will determine… The mouse model’s new, so we don’t really have a lot of… But I was thinking that it could be somewhat analogous to that. You talked about the fat really being the de novo lipogenesis and the accumulation of fat as being the toxin. Would the lipotoxicity be from the swelling and just could it be just a mechanical swollen liver that’s just breaking membranes and releasing inflammatory factors?
Rob Lustig (00:35:04):
I don’t think we know the answer to that yet, Dom. Exactly, what is the fat doing in the liver that’s generating the problem? We know that for instance, there are pathways that alter insulin receptors IRS-1, the insulin receptor substrate one, that Syrian phosphorylate, that IRS-1 instead of tyrosine phosphorylating IRS-1. There are enzymes that are turning on that are doing that. This is the Hotamışlıgil Harvard School of Public Health story about JNK1, c-Jun N-terminal kinase one, which is Syrian phosphorylating IRS-1 instead of tyrosine phosphorylating it. I don’t think we really know the pathway to a defective insulin receptor completely yet. I think we still have to work on that.
Dominic D’Agostino (00:36:02):
I don’t want to get too far down in the weeds mechanistically, but I do… I understand that Gerald Shulman and other people are looking at ways to augment fatty acid oxidation perhaps with an uncoupling agent, UCP3, I believe, which would be specific to the liver, more in the liver. That would then address the de novo lipogenesis and augment liver fatty acid oxidation in a way that could… Do you think that’s a good direction to go into? Obviously we could talk about food and we’re going to talk about food, but to just address impaired fat oxidation in the liver, is that a potential strategy?
Rob Lustig (00:36:43):
I think fixing the liver is paramount. I think that that’s where the action is. Now the question is food or drugs, and we need both. I mean, ultimately we need both. I do think that going that route as Jerry is, is right, and I think the reason is because there’s another group that’s also going that route, and that’s Ron Evans at Salk Institute and they’ve got a compound that activates PPAR-a, peroxisome proliferator-activated receptor alpha, which is liver specific. This compound called GW1513. It doesn’t work the same way, but it ultimately does the same thing. That is increases fatty acid oxidation in the liver and by doing so, improves metabolic health. Every which way you turn, the answer comes back to the liver, fix the liver. That’s one of the reasons why I’ve been so strongly advocating for, number one, protecting the liver as a primary preventative and also treatment for chronic metabolic disease. Of course, that is our entree to food.
Dominic D’Agostino (00:37:58):
We’re taught, I mean, just from conventional medical education on nutrition and metabolism, that there’s really not a specific macronutrient, it’s just an excess amount of calories.
Rob Lustig (00:38:13):
I don’t know about that.
Dominic D’Agostino (00:38:14):
Yes. I want you to just quickly overview because it would be another three part series of how, for example, 200 grams of calories from sugar or fructose has a different effect on the liver than, for example, protein or fat. Just explain how redox control in the liver and just some basic hepatic physiology of handling these things.
Rob Lustig (00:38:48):
Well, for the audience, “Look, you’ve been pelted for the last 50 years with calories. It’s all about calories. Calories in, calories out. Therefore, it’s about two behaviors, gluttony and sloth. If you’re fat, it’s your fault. Therefore, diet and exercise.” Ultimately, all of these are the mantras of the food industry. The reason is because if it’s about calories, it’s your problem not theirs. It’s their way of assuaging their culpability for what they are putting into ultra processed foods. You have to understand that there’s an entire literature that basically pushes back against this notion of calories. Let me give you some examples. Number one, there are countries that are diabetic without being obese, and there are countries that are obese without being diabetic. Obesity and diabetes don’t necessarily play the same role. Number two, obesity is growing at the rate of 2.78% per year worldwide, but diabetes is growing at the rate of 4.07% per year worldwide.
If diabetes is just because of obesity, how come diabetes is going up faster? Number three, if you look at the rate of increase in diabetes in the general population of the United States, it’s going up just as fast in the obese as it is in the normal weight population. If obesity was the reason, that wouldn’t be the case. Number four, there are two diseases that we as pediatric endocrinologists take care of that I want to alert you to. One of them is called Laron dwarfism. Now, Laron dwarfism is a defect in growth hormone signaling. There is a founder effect group of Laron dwarfs in Ecuador, and they’re known as the little women of Loja. They were written up in the New England Journal of Medicine. The reason is because number one, they’re very short, but they’re also very obese. The reason is because they can’t lift fat out of their fat cells because the of the fact that their growth hormone doesn’t work.
Okay. These little women of Loja should be very sick, shouldn’t they? Turns out, they get zero diabetes and they get zero cancer, whereas their wild-type relatives all get diabetes and cancer. They’re fat and they’re healthy, whereas their relatives who don’t have the growth hormone signaling defect are all thin and sick. Just being obese doesn’t make you sick. All right? There is a disease on the other side called lipodystrophy. These people can’t put fat into fat cells because they don’t have it. They don’t have the fat cells to do it, so they end up having to take excess energy and put it into fat in their muscles and in their liver.
They have the worst diabetes of all, even though they don’t even have any fat stores. In each of these cases, it’s not about how fat you are, it’s not about the calories, it’s not about the obesity. The notion that calories are the cause of type 2 diabetes just has to be stricken. That is not what’s going on. Yes, no question, fat in the wrong places, definitely the problem. Yes, your food contributes to that, but it’s not because of calories per se, because not every calorie’s the same.
Dominic D’Agostino (00:42:58):
If we’re talking about the general population and you lower the BMI, I don’t like BMI, but, and you’re not doing a DEXA scan, if you lower the BMI, we just put this into a simple bucket. You treat insulin resistance just by losing weight, you lower your BMI and then you maybe switch to drugs after that to help lose weight.
Rob Lustig (00:43:25):
Well, the question is where are you losing the weight from?
Dominic D’Agostino (00:43:28):
Rob Lustig (00:43:30):
Are you losing the weight from your subcutaneous fat or are you losing the weight from your visceral or liver fat?
Dominic D’Agostino (00:43:36):
Well, it’s not going to be one or the other, right? There’s going to be a proportion of each. I think if… The faster we manage insulin… This is how I… The faster we can suppress the hormone insulin to augment fatty acid oxidation, which would occur at the level of the muscle, but also at the level of the liver. On a ketogenic diet, the barometer for enhanced fatty acid oxidation is the production of ketones because that’s where ketones come from. You have the ketogenesis is actually driven very site specifically in the liver by accelerated fatty acid oxidation, and that involves carbohydrate restriction. It could occur with calorie restriction, it would be quickly reversed with consumption of sugar. We see that in kids with epilepsy who even get a little sugar from a vitamin, it can kick them out of ketosis and trigger a seizure.
This seems like the low hanging fruit, if you will. But then there are other drugs like GLP-1 inhibitors and Metformin that people will tinker with before even suggesting a dietary intervention, which should really be targeting at lowering insulin. Then postprandial insulin too, the spikes in insulin. It leads us back to an early question. I don’t know if we addressed it. It’s a question we often talk about in nutrition metabolism class is like, why are we not measuring insulin? I actually spent my whole life… It was only when I started studying metabolism that it was like, “Okay, when I go to Quest, I’ll put the insulin on and start looking at that.” I think that’s a problem because if we see hyperinsulinemia, you have a type 2 diabetic that gets diagnosed because their glucose is above 126, could we have caught that half a decade earlier if we were just doing once a year or a couple times a year insulin measurement? Some comments on that as an endocrinologist.
Rob Lustig (00:45:43):
I couldn’t agree more, Dom. That’s the holy grail right there. I totally agree. Here’s the problem. We have this thing, it’s called the American Diabetes Association. I’m not a fan, to say the least. I’m not a fan, and the reason I’m not a fan are twofold. The first is that they state categorically that diabetes, it is a chronic degenerative, unremitting, chronic metabolic disease with no treatment and no cure. That’s what they say, go to their website. That is what they say. None of those things are true. Virta Health has proven it among others. I mean, you’ve proven it too. I’ve proven it. The fact of the matter is that type 2 diabetes is eminently reversible. You have to fix the diet, but they don’t say anything about the diet. What they said was, “Give all the carbs you want, just give enough insulin to cover it,” which is also not true.
I mean, yes, you can cover the glucose rise with insulin, but all you’re doing is actually fomenting further chronic metabolic disease. You’re fixing the glucose, but the glucose isn’t the problem. The insulin’s the problem and the more insulin, the quicker you die. That’s been shown every 50 ways from Sunday also by a zillion different studies, the United Kingdom Prospective Diabetes Study, the Accord Study, the Muraglitazar Study, the Advanced Study, et cetera. The bottom line is we don’t need more insulin. We need insulin to work better. The American Diabetes Association is basically saying, “Give more insulin,” which is why I am not a fan.
Dominic D’Agostino (00:47:56):
Rob, what you’re saying is the American Diabetes Association does not think that insulin is important enough to measure. I think the tide is changing on that because some of the data… Even my colleague Barbara Hansen, who we teach the med students, she has a lot of non-human primate data that clearly shows hyperinsulinemia precedes that. You’re saying… I never heard anyone put it in those terms, but essentially what they’re saying is that the American… Insulin is not important. I mean, it’s a pretty simple hormone to measure. I heard that there’s maybe not a standardized test for it, and I know it’s tricky to measure, and I’ve used a variety of different approaches, but I don’t know if that factors in, too.
Rob Lustig (00:48:46):
No, no, that’s exactly right. The American Diabetes Association, very specifically, again, on their website says, “Do not measure fasting insulins.” Now, why do they say this? I think it’s the most important thing to measure. It’s the first thing I measure, but they say don’t measure it. Why is that? They say it for two reasons. The first reason is, as you just said, insulin assays across the country are not standardized. That is true. Now, one of the reasons it’s not standardized is because certain assays, radio amino assays will pick up other structures that will be confused with insulin. The main one being proinsulin. Now proinsulin, as you know, is the precursor insulin. Proinsulin is a single polypeptide that then has to be cleaved by prohormone convertase 1 in two sites in order to liberate a piece of the peptide called C-peptide. Then you have the mature insulin. When your pancreas is under duress, when it’s trying to lower the blood glucose and it can’t because insulin resistance is so severe, it’s got to get every molecule that it’s making out into the periphery as fast as it can.
That prohormone convertase 1 doesn’t have enough time to cleave off the C-peptide and generate the mature insulin. It will release this immature non-cleaved form called proinsulin. Proinsulin has about 5% of the activity of the mature insulin molecule. The problem is that proinsulin will get picked up in the insulin assay. When you measure insulin, especially within a radio amino assay, you’re not just measuring insulin, you’re measuring proinsulin, too. Sometimes you’ll even measure IGF-1. Depending on the assay, your assay may not be specific for insulin. That is true. Who cares?
Dominic D’Agostino (00:51:06):
Who cares? I mean, it’s relative changes over time, longitudinally.
Rob Lustig (00:51:13):
Exactly. The point is, in any given patient, if the insulin’s going up, it’s a problem. If it’s going down, it’s good. That’s all you need to know within any given patient, not how the patient fares against any other patient, but within the same patient who cares, as long as the insulin assay’s being done in the same place each time, who cares? That’s problem number one with the ADA’s stance.
Problem number two, with the ADA’s stance, they say fasting insulin does not correlate with obesity. That’s correct. I agree. Does not. It correlates with metabolic health and for all the reasons that we just talked about just a few minutes ago because subcutaneous fat is protective. Well, subcutaneous fat is the majority of the BMI. In fact, you can be metabolically healthy obese and have a low insulin, but still be obese because fasting insulin does not correlate with obesity. That’s right. It doesn’t, that’s not why you draw it. You draw it to determine metabolic health. The thing is that fasting insulin will change way before fasting glucose, way before glucose tolerance, way before hemoglobin a1c. It is a much earlier arbiter of metabolic dysfunction. By the way, this is why fasting insulin is part of Levels health’s labs 2.0. The reason it’s there is because I made sure it was. My decision.
Dominic D’Agostino (00:52:53):
It’s unfathomable to even think. I mean, we are accepting that insulin resistance is a problem and insulin is the most important metabolic hormone. That even other investigators and people who teach the subject that medical schools know enough about the data to know that insulin starts to go up before type 2 diabetes becomes diagnosed. It just seems unfathomable that this is not part of a standard that someone needs to step up and put this… I mean, there’s some historical baggage there with the assays and everything, but geez. It’s like, what do we do moving forward? Something’s got to change to acknowledge this. Then I guess most importantly, I mean, we should probably discuss what are evidence-based… Because in school, we have to teach about evidence-based therapeutic interventions to treat and also to reverse. What should be taught from an evidence-based perspective?
Rob Lustig (00:53:58):
In my view, having done this for 40 some odd years, what I say is that we need to get the insulin down any way we can.
Dominic D’Agostino (00:54:10):
What range? Let’s talk about what the ideal ranges should be and what to do once it starts creeping up.
Rob Lustig (00:54:20):
Ideally, the fasting insulin should be less than 10 microunits per milliliter. Ideally, the lower the better. Okay. Marathon runners who eat well will have fasting insulins of two or three. I would say anything less than 10 is fine. Once you get above 15, you’ve got insulin resistance, and that’s the breakpoint. If you have insulin resistance, you are not going to be able to lose weight until that insulin comes down because that fasting insulin is always there and it’s always pushing on your fat cell. It’s always telling your fat cell store more, store more, and you can’t reverse that and you can’t get lipolysis. You can’t get the fat out of that fat cell until that insulin goes down. You got to get insulin down any way you can. Now, in my life, there are four ways to do that. Diet, exercise, drugs, surgery, those are the four ways.
Okay? Diet is where you start, fix the diet, fix the diet. How do you get insulin down? Very simple. Don’t let it go up. Well, what makes it go up? Really only two things. Refined carbohydrate and sugar, those are the two things that make insulin go up. Fat does not make insulin go up. Amino acids do make insulin go up, but you need amino acids. I mean, 15% protein, you can go up to 20. But the amino acid that really makes insulin go up is leucine branched-chain amino acids. Branched-chain amino acids are what’s in corn, corn fed beef, chicken, and fish. That’s one of the reasons why we also say skip the ultra processed foods, because that’s basically what corn fed beef, chicken and fish is.
Dominic D’Agostino (00:56:33):
Those foods are high in leucine, and leucine is used as a branched amino acid supplement for many people who lift weights. But I think maybe you have to view this in context. You’re saying if I do blood work and I measure high levels of leucine, and I don’t work out that that’s driving insulin resistance, is that what you’re saying? Because the fitness community that I’m familiar with, they’re all about throw as much leucine in as possible in your meals because it’s stimulating muscle protein synthesis. But you’re saying that may not be a good idea or in the context of a sedentary person?
Rob Lustig (00:57:13):
Well, I was going to say in the contexts of a sedentary person. If you’re a bodybuilder, you need muscle and you can’t build muscle without leucine. In fact, you can’t build muscle without all three branched-chain amino acids, leucine, isoleucine, and valine. They are 20% of muscle and they are essential amino acids. You can’t make them, you have to eat them. If the goal is muscle mass, if the goal is bulking up, if that’s what you’re doing, then you have to consume them. That’s why they scoop the protein powder into their smoothies and why they have big tubs of this at GNC. I get it, I get it. That’s okay if you’re building muscle, but what if you’re not building muscle? What if you’re mere mortal like me and you’re consuming excess branched-chain amino acids? Well, what happens to them?
Is there any place to store them? Well, muscle. But if you’re not building it, then you can’t store it there, can you? What happens to the excess? Goes to the liver. Liver takes the amino group off. Now you have a branched-chain organic acid like oxoacetate, which then enters the tricarboxylic acid cycle, overwhelms the TCA cycle, Vmax, the maximum velocity, can’t turn fast enough, throws off the excess as citrate. The citrate leaves the mitochondria through a process called the citrate shuttle. Now the citrates in the cytoplasm. Then those three enzymes, ATP-citrate lyase, Acetyl-CoA carboxylase 1, fatty acid synthase, these three enzymes, which we call de novo lipogenesis, new fat making, take that citrate to Asetyl-CoA to malonyl-CoA, and then finally to fatty Acyl-CoA, which then gets packaged. Now you’ve got triglyceride, and that triglyceride either makes it out of the liver, in which case your serum triglyceride goes up, which is a potential midas for cardiovascular disease or obesity, or it doesn’t make it out and it precipitates in the liver. Now you got a lipid droplet and now you got fatty liver disease, and now you got more insulin resistance.
Dominic D’Agostino (00:59:35):
Rob, are you s saying that this is specific to leucine? Leucine and lycine are purely ketogenic amino acids. I think valine and isoleucine are maybe mixed gluconeogenic ketogenic amino acids. The scenario that you described… Because I’m telling you leucine is such a hot topic in the fitness community, the scenario that you described in the liver with leucine, is that specific to leucine?
Rob Lustig (01:00:02):
Yeah, that’s specific to leucine, but isoleucine and valine do it, too.
Dominic D’Agostino (01:00:06):
But leucine you’re saying… Okay, leucine is disproportionately high in certain food products, especially if they’re over consumed and you have excess calories, then you have a scenario with a surplus amount of leucine and that surplus amount of leucine, same thing could happen. It’s driving surplus calories in the form of sugar and stuff too are detrimental. But it’s that surplus amount of leucine that is really an issue because I haven’t really heard this that much. I remember reading about in your book.
Rob Lustig (01:00:38):
This is work from Christopher Newgard at Duke.
Dominic D’Agostino (01:00:41):
Okay. Leucine then… It’s almost like a biomarker if you have excess amounts of leucine and you’re not working out, that that’s really driving and fueling. Okay.
Rob Lustig (01:00:51):
Dominic D’Agostino (01:00:52):
Rob Lustig (01:00:52):
… we don’t tend to draw serum leucine levels, but you could.
Dominic D’Agostino (01:00:57):
I just got mine measured. It was mid to upper range of normal. Interest… But I do eat a lot of eggs and meat and things like that. In regards to… You went through nicely four different scenarios with diet being the low hanging fruit of that. But also in your book you talk about the role of fiber too and gut health and from the fiber perhaps delaying gastric emptying, the phytonutrients in fiber, the mucin layer of the gut. You touch on a lot of different topics and I encourage people listening to this to if you want to real deep dive and references and everything, check out Metabolical. A little bit about fiber, because fiber is a contentious topic. I don’t know why it is, but it’s a contentious topic in their nutrition community, especially from the context of a carnivore diet where they say fiber is not important. Fiber is not essential. You have people eating zero fiber and claiming that it’s curing their autoimmune diseases and things like that. What’s your take on fiber and why is it important? If it’s important.
Rob Lustig (01:02:19):
Your intestine is outside your body, okay? I mean, it’s inside, but functionally, the lumen is outside your body and presents a barrier, okay? It’s a sewer in there, and the goal is to extract the nutrients from what you eat without letting the bacteria or the cytokines, the lipopolysaccharides get across into the bloodstream. Because if they get across into the bloodstream, then they go via the portal vein straight to the liver and induce inflammation. Keeping your intestinal barrier functional and optimal is absolutely essential to metabolic health. Now there are three barriers in the intestine. One is physical, that’s the mucin layer. The mucin layer is this mucopolysaccharide coating on top of the intestinal epithelial cells. That basically forms a physical barrier to the sewer. That doesn’t let all the stuff in. Now, the bacteria in the intestine, they got to live, they got to eat something, they eat what you eat, but the question is how much did you eat versus how much did they eat?
If you are absorbing everything early in the duodenum and therefore not presenting anything for them to eat in the jejunum and ilium, then they’re starving, that microbiome, those bacteria. They get unhappy. What will happen is if they get unhappy because you’re starving them, they will eat the mucin layer right off your intestinal epithelial cells. They will use it for energy. They will denude your intestinal epithelial cells, and in doing so, they will then increase opposition of bacteria to the intestinal epithelial cell, which you can see on electromicroscopy. That can ultimately lead to degradation of that epithelial cell layer and what we call leaky gut and also transport of bad stuff across into the portal system, and therefore the liver and generates systemic inflammation. Fiber is the food for the bacteria. The bacteria will be able to chew it up.
We can’t break the bond of fiber, we can’t break that beta-glucan bond, but the bacteria can. That ultimate means that fiber is the food for your microbiome. We know that increasing the fiber content of food increases microbial diversity. It lets the good bacteria battle off the bad bacteria, which is good from an inflammation and chronic metabolic disease and autoimmune disease standpoint. That’s one reason. Then there’s the second barrier, which is the biochemical barrier. There are proteins in the intestinal epithelial cells called tight junctions, and what they do is they bind cells to each other and don’t let stuff get through the pores. These tight junctions present a complete barrier against the stuff in the sewer, so it doesn’t make it into the bloodstream. Those tight junctions have to work. Now, the most famous of the tight junction proteins are zonulins, which are the ones that go defective in celiac disease.
Well, that’s if they’re immunologically targeted, but you can nitrate tight junction proteins and they will become dysfunctional and allow stuff to seep through also. What nitrates tight junction proteins? Well, how about fructose? Fructose nitrates tight junction proteins. You increase your gut permeability with sugar. That’s another problem. Then finally, the third part of the barrier is the immunologic barrier. As you probably know, there are more immune cells in your gut than there are immune cells in the rest of your body. All these Peyer’s patches, et cetera. I mean, basically there’s an entire immune system running around your intestine trying to keep things out. All right?
Those immune cells for the most part are Th17 cells. Those Th17 cells are presenting an immunologic barrier and preventing stuff from getting across as well. But they get depleted on a high sugar, high fat diet, and that allows for the entry of stuff that you don’t want to get in either. Bottom line, inflammation is in the gut, and the goal is to control the inflammation. There are different things that will control that inflammation. Obviously getting rid of fructose, which of course carnivores do. Controlling this Th17 cells, which carnivores do. But fiber is an important one, too. Yes, it’s true. Carnivores don’t do that.
Dominic D’Agostino (01:07:54):
Fantastic overview. I need to incorporate some of that in my lectures. But the things that we teach that fiber fuels the production. I think you touched on it of the short chain fatty acids like butyrate, and then butyrate then is one of the primary fuels for the colonocytes. That by increasing the availability of butyrate then, which also not only functions as a fuel, that it has important signaling properties. We’re looking at beta hydroxybutyrate, the ambutyrate functions as the histone acetylase inhibitor has epigenetic function on top of that and actually really helps to preserve that brush border membrane, the barrier function just by its own anti-inflammatory effects and functioning as a fuel, too.
But it’s interesting that people, for example, with Crohn’s disease and other diseases can be on a diet completely void of fiber, and they seem to do well on just eating meat and I would’ve not predicted that and I don’t… It’s more anecdotal reports and things. But I mean, there’s I think, some research now on carnivore diet and looking at… But it could be just from eliminating things that were toxic or irritating to the gut and triggering a breakdown of zonulin and the tight junctions. It’s not what you’re eating, it’s what you are not eating, could be the therapeutic effects.
Rob Lustig (01:09:29):
That’s likely true. I will also tell you that carbohydrate often makes the wrong bacteria grow. This is work that may be related to Crohn’s disease. It’s definitely related to autoimmune disease. This is work from Alan Ebringer immunologist from the University of Oxford. What he showed years and years ago was that patients with ankylosing spondylitis, a classic autoimmune disease, had antibodies against an intestinal bacteria called Klebsiella. It turned out that the Klebsiella was making the enzyme that we use alpha-1, 6-glucosidase. Now starch, as sure the audience knows, okay, are alpha-14 and alpha-16 linkages. If they’re alpha-14 linkages, they’re amylose which are long linear strings of starch, and if they have alpha-14 and alpha-16, then they look more like a tree because of all the branching. That’s why glycemic index is important because it chops up the glucoses off the starch quicker because there are more branches, so you can absorb it faster.
Well, turns out that alpha-16 isn’t not ours, it’s the Klebsiella’s. When you feed starch to a patient with autoimmune disease, they get worse because you’re actually generating more Klebsiella and more Klebsiella means more antibody production against it, which then as an anti-idiotypic antibody affects the bone and causes the ankylosing spondylitis. This is also true for rheumatoid arthritis, different bacteria, Proteus instead. The bottom line is what we put in our intestine has enormous ramifications for how well our immune function works based on what we’re doing to our bacteria. This is not a little issue. This is a big issue, and we’ve ignored it in general medicine up to this point. Even another reason why we have to watch the refined carbohydrate in sugar.
Dominic D’Agostino (01:11:58):
What you’re talking about too would also be termed small intestinal bacterial overgrowth from excess carbohydrates. That’s one issue, but I know I teach the fructose is transported in the gut by the GLUT5. That’s an energy dependent mechanism. I know that there’s some evidence that if you bolus a lot of fructose and sugar, that it’s not purely diffusion. It’s a facilitated energy dependent fusion. It could in some ways de-energize the gut in a way. If you consume a lot of fructose, that could cause bloating and intestinal… Basically, you’re really stressing out the intestinal energetic systems by trying to overproduce it.
Rob Lustig (01:12:45):
That’s right. You’re depleting the intestine of ATP and those zonulins are ATP dependent. They’re going to become dysfunctional in the presence of excess sugar. Another reason why sports drinks really don’t make sense.
Dominic D’Agostino (01:13:02):
I think that’s really not discussed, that these things, especially fructose, is an energy dependent transport process. If you overwhelm it, especially in the context of exercising where you have blood flow diverted from the… Then it can contribute to a lot of performance related GI disruption and things like that. Since we’re on the topic of gut health, and I get this question a lot, it does make sense from the perspective of eating within a restricted window to give your gut rest time so it can rejuvenate, make the stem cells and just sleep. Then also ties in with sleep, too. Sleep being super important, and also this time-restricted feeding as a way to restore gut health and also to lower insulin as fast and as low as possible. Restricting the feeding window.
Rob Lustig (01:14:01):
A paper came out two years ago that suggested that time-restricted eating was very important, but it worked only in those patients with liver fat, and that made sense to me. I haven’t seen a follow-up on that, but that made a lot of sense to me because what that suggested was that the reason time-restricted eating works is because they’re giving your liver a chance to get rid of the fat that accumulated over the previous 16 hours, which I think is the right thing to do. I’m for intermittent fasting, but I’m for for the right patient. I’m not necessarily for it for everybody.
Dominic D’Agostino (01:14:37):
Makes sense. Rob, another topic that I really wanted to cover because I get a lot of questions about this, and there’s of course a lot of discussion because people want something easy to enhance insulin resistance and facilitate glucose disposal is the use of supplements that could potentially enhance. We know about berberine and alpha-lipoic acid and other things that are on the market, and there’s not a whole lot of evidence behind many of these things, at least for insulin resistance, but in some cases they may work. But I’d like to get your opinion and experience with these things and patients, what you’ve seen.
Rob Lustig (01:15:17):
I mean, there are a whole bunch of supplements out on the market, and they’re advertising on TV. GOLO and what have you. Show me the data is the way I look at it. They all work in the dish, but I have not seen any of them work in people yet. Now, maybe there’ll be a combination that’ll work, but individual components, there are just no strong pieces of data yet that demonstrate in a randomized controlled trial that any of these have any specific and durable effects on fixing insulin resistance. I mean, we have chromium, we have alpha-lipoic acid, berberine, as you said, turmeric and a whole host of other compounds. But the reason that they can put them on the shelf is because they’re supplements. They’re “nutraceuticals”. They don’t have to demonstrate efficacy. Well, I’m a scientist, I’m a clinician, and you do have to demonstrate efficacy, and I don’t see it.
Dominic D’Agostino (01:16:25):
Good point. I know there’s a debate with berberine and comparing it to… It’s like the herbal form of Metformin and maybe some small studies out there that compare the two. I’ve used these things, and I think maybe in the context of someone with used with postprandial glucose excursions, it may maybe knock down the peak of that, but what’s it doing long term and are there side effects to it? Also, I don’t think anyone’s just measured insulin, which we’re talking about. I think we just have a lot to learn before these things can be suggested for patients to use.
Rob Lustig (01:17:05):
Dominic D’Agostino (01:17:06):
The hot topic now, and we’re talking about it in class, is the implications of these GLP-1 inhibitors.
Rob Lustig (01:17:15):
They’re GLP-1 analogues, not inhibitors, but the bottom line.
Dominic D’Agostino (01:17:19):
Oh, yeah. Analogues.
Rob Lustig (01:17:20):
I don’t think we know the answer to that. What we do know is that they cause insulin release. That’s why they work for diabetes. But more importantly, they work at the level of the brainstem to actually tell your brain that you’re full. They’re part of the satiety signal. They always have been. We’ve known that for a long time, but basically we’re telling the brain we’re full all the time, which is one of the reasons for the weight loss is because of the reduction in food intake. Whether or not it’s a direct effect on insulin resistance or an indirect effect because you’re actually getting rid of the things in the diet that are causing the insulin resistance, I think is still unknown.
Dominic D’Agostino (01:18:01):
I mean, it’s a little bit counterintuitive because the GLP analogues do cause a release of insulin and an augmented release of insulin. Are they working centrally and in some way enhancing insulin sensitivity, where prolonged administration… It’s hard to look at this independent of weight loss because that’s just a side effect of these drugs, mostly through nausea and things that are unpleasant, more or less.
Rob Lustig (01:18:31):
Dominic D’Agostino (01:18:32):
To be determined. I guess.
Rob Lustig (01:18:35):
At this point, I don’t think we have the answers for that yet.
Dominic D’Agostino (01:18:38):
Thanks for the discussion, Rob. I’ve learned a tremendous amount, and you just further shown that you are encyclopedia of information on this topic from the clinical perspective, from the actionable things that people can do. I just commend you for what you’re doing and the information that you’re putting out, your books, your podcasts and everything, and I just think you’re helping so many people through the outreach that you’re doing, and I really appreciate that.
Rob Lustig (01:19:02):
Well, thank you. Dom, you are, shall we say, at the cutting edge of this entire metabolic health movement that is now at the precipice. We are at the tipping point, but I hope that this has been helpful and useful to the general public in terms of understanding why this insulin resistance phenomenon exists, why it’s so important, why we as metabolic physiologists focus on trying to understand it and also ameliorate it. This is where the action is.