How Insulin Resistance Drives Fatty Liver, Cognitive Issues, Metabolic Syndrome, And More

Coming up on this episode of the Doctor's Pharmacy.

It drives all the fuel into the fat cells. It prevents them from getting out. It turns these fat cells in your stomach into hormone and cytokine producing machines that dysregulate your biology.

Hey everyone, it's Dr. Mark. Some days it seems like I'm on the go from the time I get up to the time I go to bed. Sometimes it feels like every day. But it's not just me feeling like I'm busy. My patients notice it too because they often ask me how I juggle multiple jobs, frequent travel, spending time with my family while still focusing on my health. To be honest, it's hard. I have to put a lot of planning and systems in place to ensure that I don't really sacrifice my health for my schedule and eating well is no exception. That is what makes Paleo Valley Beef Sticks so great. I keep a stash of them at the house and in the office so that whenever I find myself in a food emergency, I have a healthy and delicious option to keep me on track and get to my goals. They're a great protein snack that's Whole30, Keto, and Paleo approved, plus they're individually wrapped in 100% recyclable plastic, making them portable portable and good for the environment. Paleo Valley beef sticks last a long time too, so you don't have to worry about them going bad in your emergency stash. Most companies promote a long shelf life by using GMO corn-based citric acid encapsulated in hydridated oils to process their products. But Paleo Valley uses natural fermentation without these chemicals or questionable ingredients. Thanks to this process, each beef stick contains naturally occurring probiotics, making them the perfect gut friendly snack. If you're looking for a delicious protein option to add to your list of healthy snacks, check out Paleo Valley Beef Sticks. And right now, Paleo Valley is offering my listeners 15% off your entire first order. Just go to paleovalley.com/hymen to check out their clean Paleo products and take advantage of this deal. That's paleovalley.com/hymen. Now, I'm a big proponent of practicing what you preach. And when I sit down to record a podcast, I truly believe in the information that I'm sharing because I usually try it myself. and that's why I'm so excited to share with you about AG1 from Athletic Greens. I use their incredible supplements every day to keep myself feeling and functioning at my best. Even with a healthful diet, it can be super hard for your body to get all the nutrients you need throughout the day. AG1 helps me fill the gap by providing 75 different vitamins, minerals, and other nutrients you might be missing. But unlike lots of multivitamins on the market, AG1 uses high quality ingredients that your body can actually absorb. I've incorporated AG1 from Athletic Greens into my daily routine because it's something small and I can do it every day to optimize my health. It gives me a natural source of energy and focus and at just three bucks a day, it's cheaper and more effective than drinking espresso. I'm excited for you to experience the same benefits I have with Athletic Greens. Right now, they're going to give you 10 free travel packs with your first purchase. All you have to do is visit athleticgreens.com/Hyman. Again, that's athleticgreens.com/Hyman. Hyman. And now let's get back to this week's episode of the Doctor's Pharmacy.

Hi, this is Lauren Fein, one of the producers of the Doctor's Pharmacy podcast. Each year, millions of people are affected by diseases such as cancer, heart disease, Alzheimer's and type two diabetes, not to mention the prevalence of preventable conditions like hypertension, weight gain, fatty liver, infertility and more. The conventional approach to these issues is to treat the symptoms, without acknowledgement that these diseases and disorders all have something in common. Each of them is caused or made worse by a condition known as insulin resistance. When we eat carbohydrates and sugars, our blood glucose levels rise. The body responds by producing insulin in the pancreas, which is meant to help shuttle that glucose into cells so it can be used as energy. But when your diet is full of empty calories with an abundance of quickly absorbed sugars and carbohydrates, blood sugar and insulin stay high and the body slowly becomes resistant to the effects of insulin. In today's episode, we feature three conversations from the doctor's pharmacy on why insulin resistance drives so many diseases and how the functional medicine approach can reverse it. Dr. Hyman speaks with Dr. Ben Bikman on the science behind insulin resistance, with Drew Proett on how insulin resistance impacts the brain, and with Dr. Ronesh Sinha.

On his multi-pronged approach to treating metabolic syndrome.

Let's jump in.

I believe that in my view, insulin resistance is a coin with two sides. That on one side of the coin, there is this phenomenon of altered insulin signaling, where the hormone insulin itself isn't acting the same way that it used to at various cells in the body. Now that's relevant because literally every single cell in the body has insulin receptors or little doorways for insulin to come and knock on. In some of those cells, insulin isn't working the same way that it used to. Now in some of the cells, insulin's working as well as it ever did. But nevertheless, that's the altered insulin signaling or the insulin resistance per se at the level of the cell. But we're talking about the whole body. So when we flip the coin over, it's this other aspect that you cannot pull apart from the insulin resistance. That is hyperinsulinemia or the chronically elevated insulin.

And you just noted that, that you'd seen that decades ago. So one is how the insulin works on the cell and the problems of insulin actually doing its work because the cells are resistant. to the effects of insulin. And two is super high circulating levels of insulin in the blood and what that does.

Yep.

And it's the convergence of those two things that create the insulin resistance that we're talking about. And, in fact, now that's a perfect segue to talk about some of the disorders. And, you'd mentioned many, just for the sake of illustrative purposes, let's just kind of highlight two. Where if the liver, the liver becomes insulin resistant specifically to what insulin is trying to do to glucose. Insulin doesn't tell the liver to take in glucose, but it tells the liver what to do with glucose. That's thematic of insulin throughout the body. Insulin tells the cells what to do with energy. Otherwise, truly a cell doesn't know. I grow fat cells in my lab all the time. We have little cultured fat cells. We can have those fat cells swimming in a sea of calories. Glucose and fatty acids galore, triglycerides galore, but the fat won't know what to do with it, the fat cells, unless there's insulin. The moment we spike in insulin into the culture, now the cells know what to do. Then they'll start storing the fat, turning the glucose into fat, which fat cells do absolutely, and taking fat in and storing it as a triglyceride stored fat. Now back to the liver, the insulin tells the liver what to do with glucose. Specifically, it tells it to store the glucose. And inhibit the breakdown of the glucose, inhibit the glycogen breakdown. But when the liver becomes insulin resistant, Even though insulin is high, blood glucose levels might even be high in this case, but insulin is trying to tell the liver to store glucose, but it doesn't get the message because it's insulin resistant. Now it's pumping out glucose, it further amplifying the glucose, which is further pushing up the insulin, and the whole thing keeps moving. Now, that's like a vicious cycle. That's exactly right. Yeah. In contrast, the ovaries, the theca cells of the ovaries, those are the parts of the cell of the ovary that produce all the sex hormones, the estrogens and the androgens, testosterone and estradiol, for example. Those cells do not become insulin resistant. So now they're swimming in this sea of insulin, and insulin normally elicits this inhibitory effect on the ovary's ability to convert androgens into estrogens. And you, of course, know this, and your audience, I'm sure, knows it to a degree. But all estrogens were once androgens. They come from testosterone, and there's this enzyme called aromatase that will mediate, that will make this transition. It'll take the testosterone and turn it into estrogens. Well, this high level of insulin in the body that is insulin resistant actually is inhibiting aromatase's ability to convert these sex hormones. So now her ovaries that are desperately trying to convert testosterone to estrogens can't. So her estrogens are too little and she has an abnormal ovulatory cycle. leading to polycystic ovary syndrome and her androgens, her testosterone levels are too high, which is what can give a woman more facial hair or coarse hair, acne, and even male pattern baldness.

So, that's how that works. I've always wondered how does insulin resistance cause high testosterone in women and low testosterone in men? And, I think you just explained it. Yeah.

Well, yeah. So, in fact, the interesting thing in men, to make it one step further in men, oddly, when men's—when a man's fat cells, when his subcutaneous fat cells are expanding, and this does not happen in women, his fat cells start to express higher and higher levels of aromatase, that same enzyme that the woman that has high levels of in her ovaries. And so it's almost like his fat cells begin to act like ovaries, converting testosterone into estrogen.

Dr. Justin so how do you know if you have this problem, right? I mean, you can get your insulin checked after a glucose tolerance test or fasting insulin. That's really important. I encourage everybody to get that checked who has any idea. I mean, it should be just fasting insulin should be just a part of any, any, any diagnostic test.

That's really and you, Mark, you were so ahead of your time. The fact that you were doing dynamic insulin tests and dynamic glucose challenges that, I mean, that really is the value to me. Continuous glucose monitors are valuable mostly because it gives you real-time dynamic assessments where you can challenge your body and see, all right, how long does it take me to get back to normal when I ate that bagel? That's really so illustrative and people, once they see it, they never forget it. But it's more complex than that.

This woman, she would have had a glucose monitor and it would have been normal. You're right, next to having a heart attack. So, I think there's a huge heterogeneity in this. I think you got to watch out for that. I think, so tell us about the sort of ways in which the insulin is actually causing the damage. So because from my perspective, we now know there's a whole downstream set of biological factors. Yes, there's all the diseases we just mentioned. We don't have to talk about those again, but what are the actual mechanisms besides, for example, increasing the testosterone in women, lowering testosterone in men? What else happens? Visceral fat, more storage of fat in the cells. What's going on biologically? Because it's so vast in terms of the mechanisms. I want you to sort of dig.

Into that a little bit. Yeah, yeah.

So, instantly. And the reason I want you to do that is because all the hallmarks of aging, almost all the hallmarks of aging and chronic disease are driven by this mechanism. And if you understand this, it's going to help you understand how to eat.

And live in a way to control your insulin. because, yeah, I agree.

Right?

Yeah. In fact, not to pull this onto a tangent, but so much of the focus on longevity nowadays is focusing on a protein within every cell called mTOR. And, everyone's going on and on about mTOR. And, I think that there's justification to do that now because we see in various experimental laboratory models, if we like insects and rodents, If you inhibit mTOR, the animals live longer. That's very, very clear evidence. Now, we don't have conclusive evidence in humans that that happens, but I am comfortable assuming it's relevant. We just can't do that kind of study in humans. But I do think mTOR is relevant to human longevity. This has had people focusing on protein because amino acids will spike mTOR. But I think that's unfortunate because while amino acids do spike mTOR, it'll turn mTOR on and then it turns it off pretty quickly. Insulin increases mTOR far more than amino acids do, and it keeps it elevated longer, and we're spiking insulin literally. I mean, Mark, most people, as you know, are spending every waking moment in a state of elevated insulin. Insulin has come down overnight because they've been fasting, hopefully, for 12 or so hours. But what do we do around the world, not just in the US, we eat a starchy, sugary breakfast, insulin spikes, and then they're hungry again two hours later. They spike it again and again and again. Yeah, yeah, yeah. In every waking moment, is spent in a state of elevated insulin, which is activating mTOR, which is certainly, I would believe, promoting aging. But that chronically elevated insulin also is part of one of the primary drivers of insulin resistance. It's fundamental of a it's representative of a fundamental biological process where too much of a signal will result in a resistance to that signal. So the body is inundated with insulin.

It's like the boy who cried wolf.

Yeah, that's right. Yeah. Yeah, and it's, that's exactly right. In fact, I use that, I use a joke in my family where my wife raises, my wife's an at home mom, you know, so she's going straight to heaven someday, right? So she's, she's at home with the kids, raising the kids. And when I'm home with the kids, I will notice this interesting dynamic where the kids will be calling out for mom or they'll be fighting or arguing about something or calling out and my wife doesn't hear it. She, she's become deaf to the kids complaints and to their cries for help or whatever it may be. And then when I, when I'm home, because I don't hear it all the time, I'm exquisitely sensitive to it. They're whining or they're bickering, and I'm immediately intervening trying to put the fire out. And mom, she's just kind of deaf to it. Anyway, so when we appreciate again that insulin resistance is these two sides of the coin, we can almost go top to bottom and start to identify how insulin resistance is contributing directly causing or exacerbating virtually every disease. So my lab has recently started focusing more and more on neurological physiophysiologY and Alzheimer's disease. and we published a paper earlier this year where we actually had access to post-mortem hippocampus samples. So the hippocampus is the part of the brain that's involved in memory and learning. That's the part that's presumed to be most compromised in Alzheimer's disease. And we found, this was in humans, that every single gene involved in glucose metabolism was significantly down compared to the in the people who died with Alzheimer's disease. compared to those who had died without. And we compared that with the genes involved in ketone metabolism because those are the two fuels used by the brain, glucose and ketones. And the ketone metabolism genes were fine. And so in the theory in the lab, and others have been looking at this too, like Stephen Cunnane up in Quebec, in Canada, he's a tremendous scientist, but we find that the brain has insulin dependent glucose transporters. And so this is part of what's going on in the body. So in insulin resistance, insulin is high. And you noted this perfectly when you described that case earlier, high insulin but normal glucose. And then the body starts to get so resistant to the insulin that it can't keep the glucose in control anymore. Then 10 or 20 years later, now the glucose levels start to climb. And you express that perfectly. So in the brain, the same phenomenon can start to happen. That even though the brain may be swimming in a sea of glucose, the body might be hyperglycemic, but insulin has to be working sufficiently to come to the hippocampus, the part of the brain, knock on the door, open the doors for glucose to come in and fuel the brain. And that's relevant because the brain has a very high metabolic rate, much higher than muscle does. And because most people are always eating starchy, sugary foods and they're keeping their insulin up, They never have any ketones. Ketones are essentially below the level of detection in most people. But the brain is swimming in a sea of glucose, but because insulin can't work, it can't get enough. The brain's energy needs are right here, but now it can't get enough glucose. So you have this energetic gap and that the body just can't meet. It just can't fill it up because insulin isn't getting enough glucose in. You'd say, well, let's just push the ketones in to fill that gap. the person doesn't have any ketones because insulin stops the production of ketones. So, the brain is swimming in a sea of glucose and starving in the midst of it. So, that's how insulin resistance is relevant at the brain.

And, maybe we'll just pick one more like blood vessels.

That's why they call now dementia type three diabetes. That's right. That's exactly right. Yep. I actually, I like that term in that it evokes this metabolic origin. But I like the idea of insulin resistance of the brain, just to be once again, just to be really precise because that is the specific disorder.

And to put a visual on it, literally as your belly expands, your brain shrinks. So, big belly, small brain. Small belly, big brain, better working brain, which affects depression, Alzheimer's, many, many biological.

Disorders of the brain. Migraines, yep, migraine headaches. In fact, one of the things that was so interesting for me, Mark, there are published manuscripts from the 1930s from physicians. So these are MDs noting in their clinic and publishing these case reports where they would take patients with migraine headaches. There was two, one in the early 30s and one in the late 30s, I think, or maybe early 40s. But they noted that they would take these patients with frequent migraines and put them onto low carbohydrate diets and fasting regimens to increase their ketones. and the migraines went away. Yeah. Resolved. And this is very common. Now, it's not Universal. There are different types of migraines, of course, but it's surprising to me how common it is where you can detect it. Even in migraine, just like it is in Alzheimer's disease, there's this phenomenon referred to as brain glucose hypometabolism. Essentially, the brain cannot metabolize glucose sufficient to meet its energetic needs.

And so you just start making some ketones and you fill in that Gap. It's really extraordinary. We're going to talk more about how ketogenic diets and other dietary approaches can actually influence things like autism and Alzheimer's and even other neurologic disorders that we're seeing and how that works. But I want to sort of get into this study that you did with my friend David Ludwig, who's from Harvard, where you looked at the metabolic rate from fat samples from belly fat and found that the low-carb diets had a much higher increase in the metabolic rate in the fat tissue compared to the people eating high carb diets. In other words, if you eat a high fat diet, your metabolism is faster. If you eat a high carb diet, your metabolism is slower. How did that work? What happened? What was the study?

Yeah, yeah, yeah. So, Mark, just, I have a slow.

Metabolism, you know, like, well, okay, maybe they're right, you know, maybe they're right. And how is it working?

Yeah, I just have to mention this because it's such a fascinating history. When David and I started collaborating on this, it was in response to some other studies that we'd been doing in my lab looking at the differential effects of insulin and ketones on fat metabolic rate, fat cell metabolic rate. That whole study was born from studies in the early 1900s. Just as a brief history because I know your audience is going to find this fascinating. At least I hope my students sure.

Do, so I'm sure they will.

Sure, sure. Bring it on. Two early scientists, Elliot Joslin, who is considered the godfather of endocrinology, and Francis Benedict. Francis Benedict really considered the godfather of metabolic rate.

The Harris-Benedict equation. Yes, I remember that from medical school.

And the Joslin Diabetes Center at Harvard. Yes, absolutely. That's right. Yes, that's how well known both of these characters are. And they were legends. And they noted working together in the early 1900s that people with type 1 diabetes, they didn't call it type 1, it was just diabetes, People with diabetes had a metabolic rate that was about 20% higher than it was supposed to be. Metabolic rate is connected to body weight essentially. A bigger body has a higher metabolic rate. A smaller body has a lower metabolic rate. What they found in these people, metabolic rate was much higher than it was supposed to be. Then decades later, this is well into the 20th century now, late 20th century, then other scientists found the same phenomenon. These were studies done at the University of Minnesota. that meant that people with untreated type 1 diabetes, because this was before when Joselyn and Benedict were doing this, there was no insulin yet, not discovered, not used. Then decades later, scientists confirmed those original findings that metabolic rate was significantly higher in type 1 diabetes, higher than it was supposed to be. And when they gave the people insulin to control the diabetes, their metabolic rate went immediately down to normal. It dropped that excess 20% went right to where you predicted it should be. Insulin—so that study, as my students and I were noting this and fascinated by it, we thought, well, let's start looking at what happens in the fat cell in these conditions. Sure enough, we found in fat cell cultures and in animals, when we artificially increased the insulin, we could take the brown fat cells. All people have brown fat and white fat. and white fat is the, the prototypical storage fat, what we pinch and jiggle. And it has a very, very low metabolic rate and very, very low.

I don't jiggle. I'm sorry. I don't jiggle. Yeah, I don't jiggle. Yeah. I won't go for jiggling. Yeah.

I got a little bit to pinch, but that's it.

Yeah.

But so, so those are the people that metabolic.

If you jiggle, you're in trouble. That's the, that's what he's saying, guys. If you jiggle, that's the problem. that's, that's, you know, I call it the, I call it the mirror test for diagnosing. If you have this problem, you stand in the mirror with your shirt off.

You jump up in town, and if you jiggle, you have this problem.

Yeah. Yeah. Well said. Yeah. That's what we call the jiggle test.

We call it the jiggle test. So we have that white fat with a very low metabolic rate. Then all people, to some degree, have what's called brown fat, and that's typically up around this kind of a chest area, and that has a very high metabolic rate. as high as muscle does. So, like 10 times higher than the white fat does. Well, we found that when we already fish, when we artificially push the insulin up, the brown fat metabolic rate was depressed. It went much dropped to a level that was quite close to the white fat metabolic rate. In contrast, when we increased ketones, then we took the white fat in a high fat diet. Yeah, like on a ketogenic diet or in the lab cultures, it was just actually treating the fat cells with ketones. It's injecting that metabolic Mm-. That's exactly right. That metabolic rate went up about 10 times almost to the level about of the brown fat. Then in humans, this is where the study comes in with David. Now these are unpublished data. So everyone know please, these have not been formally peer reviewed and published.

It's in review.

You hear it first here, folks. Yeah, that's right. Yep. Before it's even hot off the press. Exactly. Yeah, so in the printer. So what David did, They had access to this population of people that they'd taken a fat biopsy from the belly at day zero and then followed it up several weeks later, about anywhere between, I think, 12 to 15 weeks after being on three diets.

Humans not mice, right?

Humans not mice. Humans.

That's exactly right. This was something that was so important because me at a PhD at a primarily undergraduate university, it's difficult to do this. We've done fat biopsies before.

You're like a doctor, but you're a mouse doctor.

Yeah, that's right. I can tell you what's happening in the cells much better than I can listen to someone's heartbeat.

So, tell us, I'm so excited. I'm on the edge of my seat. What happened?

I won't interrupt. So, these three groups, people put on three different diets. They all had the same amount of protein and same amount of calories. So, the caloric level between all three diets was the same. So, protein was clamped and then all it did was differ in the ratio of fat to carb. and we found that the group that had the highest carb diet had no change in their metabolic rate on their fat cells specifically. However, the groups that were the low, the two other groups that had the lower carbohydrate, higher fat, they had significant increases in their fat cell metabolic rate. Now this coincides with low carb, give us the ratios.

Is it like, what's the amount of fat, amount of carbs?

It was like, yeah, David would confirm. So I think, I think the, the moderate group was for, about 40 carb, and then the other group was 20 carb or so. I think it was right around. So the low carb was 20.

It wasn't, like, ridiculously low, like less than five grams of carbs or 50 grams a day. It was. That's right. It was really. It was really actually doable.

Oh, I would absolutely say that it's very doable. That's the kind of.

It wasn't a ketogenic diet. It was actually a. Just a lower starch sugar diet.

Yep. Yep. That's right. Yep. and sure enough, the metabolic rate went up about two or three times in these people from the same person, from their fat tissue, from the same area in their body. So it just goes to show that as much as what that means, folks.

By the way, what that folks means is if you're sitting watching Netflix, you're burning two to three times more calories.

That's what that means. Yeah, right? Yeah, that's right.

Yeah.

If you have any, I would say if you're living a life where your insulin is low and there's some hint of ketones coming up, then you absolutely are experiencing a higher than normal metabolic rate. And this is so important because in my mind it starts to represent this convergence of what has been viewed as these two opposing ideas of human obesity. On one hand we have the pure caloric thermodynamic enthusiasts that obesity is purely a matter of calories in, calories out and anything else be damned. On the other hand, to sort of straw man each of these, we have this idea that no, it's purely a matter of insulin, that it's purely a matter of hormones, and then the energy component is less relevant. In my view, the two actually go hand in hand.

For sure.

That we have to account for energy. Of course we have to, but we have to account for it through the lens of human biology. We are not these perfect little thermodynamic machines. We are complex biological organisms and hormones tell the body what to do with energy. And when insulin is low, we have these advantages. One, we have an actually elevated metabolic rate. This has been shown in David Ludwig's group multiple times through multiple different tests, and even some of his detractors have shown the same thing. Others have found this where when a person has low insulin, elevated ketones, their metabolic rate is higher. So, one, metabolic rate is high, so the caloric output is higher. But two, also, if someone has low insulin, then they're making ketones, as we noted, and when ketones are elevated, the person is literally excreting ketones from their body. They're breathing ketones out, they're urinating ketones out, and every single ketone has the caloric value comparable to a molecule of glucose. We are actually taking energetic molecules and then just dumping them from our bodies. These are calories that didn't have to be burned, didn't have to be stored.

Or burned, eat less, PMs.

You breathe them in your PMs. Yeah, and you breathe them out. Because that's what ketones are. Imagine a long kind of string And a ketone is when we basically cut that string into pieces. That's what's happening when we're burning fat. We're taking a big, long carbon molecule, pulling off two little carbons at a time. If someone is making ketones, it's literally those little pieces of fat that we're splitting apart. That is what a ketone is. And so the person is literally breathing out these byproducts of fat burning or.

Urinating these byproducts of fat burning. That's really incredible. You know, we now are really understanding this. And what What I've seen in other studies that David has done, for example, this was a mouse study. So I don't like animal studies, but sometimes we have to do them in medicine. What they did was fasting. They took these mice who are identical and they gave one group a very high carb, low fat diet and another a low carb, high fat diet. And they gave them identical calories. And then what happened was in the group, like you're saying, would be low carb high fat, they started losing too much weight. So they wanted to keep the weight of the animals the same. So they actually had to increase the calories on the low fat group. And then at the end of the study, they harvested these animals and the low fat group that was having more calories didn't have the problems that the high carb group had, which is all this belly fat, inflammation, poor metabolic function. It was fascinating to me. And, and, you know, the other thing that's so fascinating about this, and I had dinner with David once and he said, Mark, you know, if you look at type one diabetics, what happens to them, right? They lose weight because they can't get the fuel into the cells because they have no insulin because their pancreas is basically demolished by an autoimmune disease. Yep. And they literally come in with the classic symptom we learned in medical school, which is polyphagia, which means you eat and eat and eat and eat. So they're literally could eat 10,000 calories a day or 100,000 calories a day and lose weight.

And they're scrawny. Yep.

And right. And, and, and it's an exact example of this phenomena in an extreme situation where if your insulin is low, it's very hard to gain weight and it's easy to lose weight. And I think a lot of the keys to understanding our metabolism, by the way, there are, there are a lot of factors that drive obesity and we're just focusing on I think the biggest one, but toxins play a role, other hormones play a role, the microbiome plays a role, inflammation from various insults plays a role. So it's not just this, but I would say it's the predominant mechanism for obesity in America.

And, I would add in type 1 diabetes, like you mentioned, this phenomenon is so known by type 1 diabetics that insulin is controlling their fat growth, that you have this disorder nowadays called diabulimia. where you have type 1 diabetics. Dr. These type 1 diabetics are deliberately underdosing insulin in order to stay thin. Dr. Yeah. So they learn early on. And imagine how tempting it is. You have a young teenage, usually a girl, certainly who has— they have more pressure than boys do—but even still a young teenager who's very self-conscious of their growing bodies. And they've learned—imagine the temptation. They've learned they can eat anything they want. They can eat that cake. They can eat those brownies, those cookies, whatever, that soda, and they don't have to go vomit. They don't have to go through the discomfort of throwing up. All they have to do is not poke themselves with a needle. And, they can stay in their blood sugar behind. Is there blood sugar behind? They want to. Oh, it's catastrophic.

They're in ketoacidosis.

Their glucose is 800 milligrams. So, they're dying. Wow. They look great. Yeah, but that's just a testament. That's just the proof of how powerful insulin is in controlling this. where you have type 1 diabetics who deliberately underdose insulin because they know they can eat whatever they want and they'll stay as thin as they want.

Well, what you're talking about also explains the phenomena of why ketogenic diets reverse type 2 diabetes better than any other treatment and why people who do time restricted eating and give themselves 12, 14, 16 hours between dinner and breakfast actually are more effective at losing weight or why people who are in calorie restriction, which also does the same thing, like the fasting-mimicking diets also does the same thing. So we are seeing from the science emerging that the key if you can keep your insulin low is that it helps to release everything. And from my experience as a doctor, the thing that insulin does is just catastrophic. One, it drives all the fuel into the fat cells, whether it's fats or sugars. Two, it locks them in there. it prevents them from getting out. Three, it turns these fat cells in your stomach into catastrophic hormone and cytokine producing machines that dysregulate your biology, increasing inflammation. For example, why is COVID ravaging the obese? Because their fat cells are making IL-6 or interleukin-6, which is a powerful cytokine inflammatory molecule called the cytokine storm. that is what's driving all these problems. And in addition, it changes your hormones, as you mentioned, with estrogen, testosterone. It also changes your brain chemistry and makes you hungrier. And it creates a catastrophic effect on your cholesterol, on your blood pressure. It drives oxidative stress, inflammation, increases your blood clotting, it increases uric acid levels. It causes a whole series of downstream effects. It causes fatty liver. It starts to affect your kidneys and increase protein in your urine. So you've got these massive effects that are explaining all the underlying biology of aging. And so the take-home message from what you're saying in your research and David's research is that if you keep your insulin low by various mechanisms, right? Diet, exercise, stress reduction. I mean, if you're stressed, your blood sugar is gonna shoot up. Meditate to lose weight. That's my new slogan, right? So this is really The biggest pandemic to actually face humanity ever. We're talking about COVID being a problem, but I mean, gosh, three quarters of the deaths globally, which is, you know, I think it's like 60, 70 million a year, I mean, are actually are caused by some level of this poor metabolic health. And it's driving, of course, not just weight issues and diabetes, but cancer and dementia and depression and infertility and all these other phenomena. So, your research is so important to help us kind of tease apart these mechanisms. And the question I would have for you is, for people listening, how do we start to think about changing? Because not everybody wants to go on a ketogenic diet, nor is it advisable, or is it good? Even though, by the way, you mentioned Jocelyn, the way they treated type 1 diabetics was a 75% fat diet, 20% protein, and 5% carbohydrates. And by the way, it was kept alive, but it also, by the way, was the way that we discovered America was through borrowing the Native Americans' superfood packet, which was called pemmican, which was made up of basically rendered fat from bison, a few berries and the protein. And literally a man needed a pound a day and a woman needed a half a pound a day. And so if you had 30 pounds of stuff in your backpack, you could basically eat for a month and survive.

Yeah, yeah.

There's no question that you and I, of course, are aligned when it comes to having a favorable view of fat. And Mark, with, I like what you were saying a moment ago, where, and you're being careful in your language, which of course, as a scientist, I appreciate precision. You and I, we're not claiming that insulin resistance is the cause of every disorder, but there's little doubt that it is a key contributor. It is causing many chronic disorders and it's contributing to virtually every other one. So my view, one of the things I hope people take away from this discussion is I can imagine someone who's opening their medicine cabinet, not that either of us is giving any Medical advice here, but they're looking at their medications and they see their medication for their diabetes, or one or two or three medications for their diabetes. They may have a medication for their migraines, a medication for their fertility disorder and their blood pressure, little knowing that all of those do have a common connection with insulin resistance. When it comes to controlling insulin resistance, you are absolutely right. There are multiple inputs into this. I consider, there are various ones, and I've looked at them and consider various levels of them. To me, there are three primary causes of insulin resistance. By primary, I mean that literally I can cause insulin resistance in isolated cells in laboratory rodent and in humans with all three of these. That is elevated insulin itself, elevated stress hormones, and elevated inflammatory proteins or cytokines. All three of those things are considered primary in my definition because you can just make insulin resistance happen at the cell, in the rodents, and in humans, all three biomedical models. But as you were kind of alluding to, if we were to tell someone, all right, but there are others, like you said, like noxious toxins that can accumulate in fat cells and alter fat cell growth. Absolutely, that is relevant. So I'm not suggesting that there aren't others. There are. But I put these ones as the holy trinity or the unholy trinity of insulin resistance. We would tell someone, Control your stress. They would say, well, great, Doc, how am I going to do that? It's a little difficult. Stress is one of those difficult things to truly wrap your head around. You'd mentioned meditation and quiet. I wholly agree with that. Even still, it's a little difficult to fully manage stress. Same with inflammation. We would say lower your inflammation and say, well, how do I do that? We'd have to find out what are the stimuli that are inducing that increase in that immune level. But if we say control your insulin, easy, easy. That is a lever we can grab with both hands and immediately start to pull down just through time-restricted eating and intermittent fasting and by just managing macronutrients and altering that ratio, focusing more on the foods that have the lower effect on insulin like fat and protein and controlling the starchiest of the carbohydrates or the most sugary. Now, neither you nor I are declaring war on carbohydrates. And, I'd hate for someone to leave this talk, leave this discussion thinking we are. We're not, you know, neither of us is advocating a carnivore diet. But we are certainly, my view is, don't get your carbohydrates from bags and boxes with barcodes.

Dr. So, when I was in medical school, we were trained that your brain is the number one utilizer of energy in the body, the number one utilizer of glucose. It's, you know, it's like, I don't know, 2% of your weight, but 25% of your glucose consumption. And so you need, you know, the whole idea is you need sugar for your brain. Turns out it's not true. It turns out that your brain runs much better on fat, particularly ketones. Your brain is about 60% fat and that the, the, there's brain phenomena which they're calling type 3 diabetes, which is really what they're now calling Alzheimer's because inside the brain, you get insulin resistance. Think of it as diabetes of the brain. And when you get that, you get increased inflammation, you get increased oxidative stress, you get the production of what we call ages or we call advanced glycation end products, think of it like the crispy thing on a creme brulee or the crust on a bread or a crispy chicken skin. Those are proteins and sugars combining to form this crust. That's what happens in your brain. And you end up having this really terrible inflammatory brain degrading process called insulin resistance within the brain. And so you wanna design a way of eating that it keeps your insulin levels as low as possible. If there's one single thing that we know about aging and all age-related diseases, the single common denominator across almost all of them, and there are exceptions, but pretty much for the common stuff, it's insulin resistance, meaning your body makes too much insulin in response to the carbohydrate load that you're eating. And it gets worse and worse over time. So it's a vicious cycle where you eat more carbs, you get more insulin resistance, you can eat more insulin, you eat more carbs because you're hungry and crave them, and you end up actually getting very high levels of insulin. That is just a disaster because when that happens, you're getting not only belly fat storage, you're getting increased hunger, increased cravings for carbohydrates, you're slowing your metabolism, you're causing your brain to get demented, you're causing heart disease, you're causing cancer, you're causing kidney failure, you're causing high blood pressure. you're causing all the things that we think of as disease of aging and we treat them in silos. We treat them all as separate problems, but they're not. They're all connected by this underlying mechanism. So, insulin resistance, I've written many, many books about it, but essentially if you're gonna design a brain healthy diet, it would be extremely plant rich. So you'd get all the colorful plant compounds that you see from colors of reds, blues, yellows, greens, orange, purple, all in fruits and vegetables. So eat as many deep colored varieties of vegetables as fresh as possible, as local as possible, as nutrients dense as possible. Second is you need a lot of fat. And fat is really important for the brain. So you need olive oil, avocados, nuts and seeds, and something called MCT oil, which is really a super fat. And the brain loves this fat. It's great for mental clarity, it's great for focus, it's the preferred fuel for your mitochondria. which is the energy production organelles inside your cells. So that's really key. And you also want a diet that's high in omega-3 fats. So you want sardines, mackerel, herring, small fatty fish, not the big fish, because that has mercury and that's gonna cause a problem. And you could even take fish oil. You also want a diet that's very rich in choline and B vitamins. So choline comes from eggs, comes from sardines, and also the B vitamins B6, B12. folate, which are critical in this particular pathway called methylation. And I just tell you a quick story of a patient who was about maybe 75-ish and she was diagnosed with early dementia by her doctor and told to get her affairs in order. She was a very wealthy woman. She was on the boards of all these companies, but she couldn't function anymore. And she had to pull back from everything. And she came to see me, and she had a relatively simple problem to solve, which is what she had. Homo cysteine that was really high and a methylmalonic acid that's high. And those are blood tests that measure your a more accurate functional measurement of B12 or Folate and Folate. And so I gave her B12 shots of methyl B12. I gave her a high dose of methyl folate and B6 and the whole cocktail of methylation support, which is this critical cycle in your brain and in the rest of your body. And she was completely cured. And about maybe five, six, seven years later, she was like 84 or something. I got a call from her. I thought, you know, you know, because the thing is, with functional medicine, you're like, you get people better, you teach them how to take care of themselves, and you may never hear from them again. Right. So which is actually the good thing. You don't want an annuity of patients coming back for their refills on their blood pressure or cholesterol or, or their dementia medication. And I was like, oh, maybe she went downhill. Is she all right? So I was worried about her. So I got on the phone with her. I'm like, hey, how's it going? You know, she's like, well, I'm planning a trip to Bhutan trekking and I just want to know what I should take with me from a medical point of view. I'm like, oh God, okay. So, you know, sometimes it's as simple as that. Sometimes it's more complicated. You know, sometimes people have tick infections or mold or they have mercury or they have other issues. But hers was relatively straightforward. So we look at all those things in food. How do we upgrade those nutrients through colorful cruciferous vegetables that are full of folate? vitamins, how do we maybe eat liver? Liver is probably one of the greatest brain foods. I know people go, Ugh, liver, but, you know, I thought liver was like a gourmet food because when I was in a little kid, we lived in Queens and my mom, my sister and I, in a one bedroom apartment, and we were very poor. I mean, she worked as a teacher in Harlem. And for dinner, we'd have fried onions and chicken livers over rice. And I was like, this is a gourmet meal. It was so good. but if you, if you actually, it's actually surprising, you know, we all think plant foods are the most nutrient dense foods, the most vitamins, the most minerals. If you look at liver and then you look at the best vegetables on the planet and you compare them side to side, basically the liver looks amazing and the vegetables look like, you know, chump change. And it's, it's pretty impressive to see. It's like if you look at a bar graph, all the nutrients on the liver like this and all the rest are like down here. So, you know, there's a lot of ways to get these nutrients through food, obviously, for supplements can be helpful, but the diet is so key. So lots of good fats, lots of phytochemicals, very low starch and sugar. And, and obviously, microbiome healthy diet. The microbiome is super important. So I've written a lot about this, but how do you create a healthy microbiome? It's really a critical factor through tending your inner garden. We're coming out with a new product called gut food, which is sort of a One-Stop multivitamin for your gut. to help the bugs grow good and have good bugs in there. But there's a lot of ways to tend your inner garden through eating pre and probiotics, through eating lots of fiber, fibrous foods that actually help fertilize the good bugs. So that's also really important. So you got to kind of look at the whole spectrum of your diet and how do you optimize for immunity? How do you optimize for insulin? How do you optimize for your microbiome? How do you optimize for your mitochondria? How do you optimize for methylation? So as a doctor, I'm thinking, I got this whole like pharmaceutical cabinet full of powerful drugs that is basically what it ends up on the end of your fork. And that's the stuff that actually really works and it works better than most drugs. And there's many studies on this. There's the men diet, which is showing really amazing results in terms of dementia. And it wasn't even that great a diet, honestly. It was like kind of a Mediterranean diet, a little bit healthier than most people eat, but they showed significant improvement in cognitive function. So When you push the envelope and I just did a podcast with my friend Kara Fitzgerald, it was amazing. They did a functional medicine, food is medicine intervention, very nuanced selection of different foods that specifically contain nutrients that regulate aging and your biology. And they were able to do this really in a very prescribed way using food as pharmacology and actually reverse biological age by over three years. within an eight week period, which is staggering. I mean, nobody's ever to show that even in these other drug studies, intervention studies, it was mind boggling. And basically they didn't have supplements. All she did was basically use foods and identified the most important nutrients around regulating biological aging. And she gave those nutrients in the form of food, and it worked so much and it was so much more powerful than any other intervention. So, that's the kind of thing we think about when we look at food and diet. One of the things, including that study, which I'd love to have you talk about a little bit, was targeted spices, things like spices and herbs, like rosemary, other things.

How important are spices.

To be including in our repertoire when it comes to our brain health? It's huge. I mean, you're Indian, Drew, and India is just like the king of spices over there. It's a country of spices. And I think it's a very powerful way to upgrade your diet with extremely powerful phytochemicals that are found in things like curcumin and cumin. I mean, like for example, nigella seed, black cumin seed is very effective against viruses and it's being used in poor countries, for example, for treating COVID. So, we really have to look at the world of spices as an adjunct to our pharmaceutical cabinet of food. So, I have, if you look at my, I have like a giant drawer at home, it's like literally It's like this big and it's like really deep and I've got like rows and rows of spices. And I, I'm a very big spice guy cuz they're so powerful in regulating inflammation, detoxification, they're made the polyphenols in them can be great for your microbiome. So it's really important to think about using some of these things like rosemary and curcumin, like peppers, chili pepper, peppers are amazing. So there's all kinds of things you.

Can use, but I encourage people to really focus in on spices. I've been a lifelong devotee of healthy practices. And even back then when I started my practice in Silicon Valley, I was following the standard dietary guidelines. I was exercising four or five days a week.

But what I was doing was- oh.

Wait, wait, that was the problem. You were following the standard dietary guidelines. That's exactly right. You nailed it right there, right? And my standard dietary breakfast was pretty starchy with a lot of fruits and oatmeal. I'd have a Whole Wheat Bread Sandwich for lunch. So it was a lot of those healthy carbs that were so-called healthy carbs that were really overwhelming my system. And then also my exercise was really a lot of HIIT training, a lot of high intensity interval training, and not really that steady, more long grade sort of cardio. And as a result of that, I started seeing my patients developing insulin resistance. I was giving them advice, but then I was getting insulin resistant too. So I'm like, okay, so this is not gonna work out. How can I be a health leader if I'm developing the same conditions as my patients? And then that really caused me to dig deep into the literature. I have the benefit also of being mentored by Jerry Reaven who actually coined the term insulin, you know, metabolic syndrome. Oh, really? Yeah. So, yeah, so I used to drop by his office in Stanford and he really helped highlight this triglyceride HDL, this issue. And he was really such a pioneer. He literally told me that sometimes he doesn't get invited to conferences because his metabolic syndrome criteria doesn't include LDL, right? He kind of nailed the triglyceride HDL insulin resistant axis. And so, I took that learning and then really dug deep and then made changes in my body, which I basically translated to my patients. But that was eye-opening. That was over a decade ago. So, when I saw that, I'm like, okay, standard diet, trey guidelines, the websites and resources I'm giving my patients are actually making them worse. They're making me worse as well.

And that really kind of led me to really create the resources they need to really address this problem. That's amazing. You know, I had a lot of Indian patients in my practice and I and I see exactly what you see. And I often wanted to create a cookbook that's like a high fat, low carbohydrate vegetarian Indian cookbook.

Oh, Mark, I would love it if you did that. People ask me to write a cookbook. I have no interest in that. So if you did that, I would love to promote that. Please put that in your long to do list.

A friend of mine was an Indian woman. She was gonna get her mother to do it, but she never did. But it's, it's, It's challenging. So, what do you tell your patients? Because, if they're already kind of set up with a deficit because of genetics, then it's a little bit frustrating. How do you help them? So, we do two things simultaneously.

So, the first thing, I have a bit of a clever mnemonic that I use with my patients called CARBS. So, they can basically just identify the framework for the sources of their carbohydrates. So, the C in CARBS stands for chapatis, which are flat Indian bread. Okay, the A is alu, which are starchy potatoes, because most of the vegetables they're consuming are a lot of starchy potatoes and samosas. The R is rice, the B is beans and lentils, and the S is sugar and sweets.

So when they have that framework, I love that.

It works perfectly.

I love that.

Rice, beans, and sugar sweets, right? So if you have that framework, and I'm not telling them they're going to eliminate all of those, But let's have just small portions of that with each of the meals. Maybe one meal is gonna have a little bit of rice. Maybe we'll have some lentils with that, but then where are our protein sources coming from? Like how do you really composed a meal so they're not like 100 to 150 grams per carb per meal, which is what I see in my vegetarians, but how do we mix proteins and healthy fats into it? And this is the hopeful part is a lot of the fats and oils and foods that we thought should be banned in the Indian diet, they're actually now becoming healthy, right? A lot of the paleo primal movements, They're using a lot of our traditional healthy fats.

So once you- I mean like coconut or ghee.

Yeah, exactly. Coconut oil, ghee for people who tolerate it. So one trick I teach them, for example, is when you have starches that are not mixed with other ingredients, that's when the problem happens. If you love rice, eat it more like biryani or fried rice style where you mix vegetables into it, nuts and seeds, healthy oils and fats, and you're gonna see that's gonna dampen the glycemic impact. A lot of people are making chapatis or flatbreads, but they're adding eggs to it like egg paratha or they might mix almond flour into the batter.

So, I teach them how to make higher protein flatbreads.

Yeah, like chickpea flour, chickpea flour, almond flour. And, you get full off having one or maybe two max and your glycemic stability is much better. So, dilute out the effects of that starch by mixing the vegetable proteins and fats. And, the Indian diet has plenty of those. So, when they feel miserable about that, I really add that diversity and they feel fuller, their energy is better. And oh, by the way, their net carb intake has gone down by 30-40%. And then simultaneously we do have to upgrade their physical activity levels and really work on the things you talked about. We got to make up for the loss of lean, you know, body mass muscle. We got to gently elevate that VO2 max. But I start with food first because immediately they start to feel better. And as you know, the numbers are magic, right? Within a month we see triglycerides drop and if they see that metric, we're very metrically motivated as population, you see those numbers go down, you're like, okay, what do I do next to get the numbers even better than that? So, that's one framework that I use.

Yeah.

That's powerful. You said something that's very provocative and I think I want to dive deep into it with you right now, which is the fact that in the criteria for metabolic syndrome, LDL doesn't matter, which seems to be the only thing that matters to traditional doctors and cardiologists. the thing that matters is the ratio of triglycerides to HDL, which is they call it the good cholesterol, but it's just one of, you know, LDL isn't bad. It's just it's just has a different role. And the striking thing to me is that there's so much nuance to understanding lipid profiles rather than just the LDL or total or even the HDL triglycerides and work of Dr. Ron Krauss has really underscored the importance of the lipid particle number and the size. So it's not just the weight of your cholesterol, which is what we measure, but the actual number of total particles in the size.

And.

You.

Can'T really look at cardiovascular disease without looking at all of the picture here. And what's unfortunate is that a lot of medicine gets practiced without ever diagnosing metabolic syndrome. 90% of the time, it's not diagnosed. And yet it probably affects, I would say, 88% of the population. Think about it. You've got a condition that affects 9 out of 10 Americans and doctors miss it almost every time. And they don't know how to treat it because there ain't no drug for it. I mean, metformin is something they give, but it doesn't really work that well. and, and, and so they go, oh, it's like the patient I had who was, was blood sugar was creeping up, and I was like 115. I'm like, hey, did you see your doctor? Get your, you know, stuff checked out? And she's like, well, yeah. I said, what do you say? Well, we're gonna watch it. I said, watch for what? Watch till I get diabetes, and then I'll give me a treatment. Oh, my God. So, so I want to sort of dive into this is sort of framework of how do we think differently about lipids? What is your approach to lipids and what should we be thinking? And, does everybody need a statin? Yep.

Great. A lot of topics here, but yeah, let's tackle this one together. So, let's move from cars to boats because I think boats are the best analogy for explaining lipids. So, when you think about the lipoproteins, the LDL particularly, they're literally boats that are floating through your blood vessel and they carry cholesterol and energy to your cells, which is a great thing to do, right? They've been demonized so much, but they're so essential for a body to function properly. clearly. When you look at LDL, so when I say that LDL is not part of the metabolic syndrome criteria, I'm not saying that LDL doesn't matter. LDL has to crash into the vascular wall, the blood vessel wall, and cause inflammation to cause heart disease. But on your regular blood test, we're measuring the wrong part of LDL. So if you think of these lipoprotein boats, you nailed it. You said the particle numbers and the size are more factors. But when you look at a standard lipid panel, it's not measuring those factors. It's just looking at how much cholesterol cargo was that boat carrying? And here's the part that misleads people because I don't know how many people I've seen that had an early heart attack and they were told by their doctor that their LDL looks fine. The problem is the more insulin resistant you are, the higher your triglycerides go. And when triglycerides are high in most people, they push your LDL down. Because what happens is these small particles, they carry less cargo. So that's going to make your LDL-C on the standard cholesterol panel low. so when I had triglycerides above 300, my LDL was like in the 70s or 80s. And my doctor at that time told me, thank God your LDL is fine. But what he didn't recognize is that my LDL-C was low, but it's because I have these small particles. So anybody that's got a triglyceride, even if you don't have access, luckily these tests are accessible and they're affordable now. But even without doing that, once your triglycerides climb above 130, 140, 150, 80-90% sure that your LDL particle numbers are high. And in fact, what I started teaching doctors in my group is if you make the right lifestyle changes and you reverse insulin resistance, the LDL is actually going to go up on a standard lipid profile. Because now what's happening is the LDL is going to go up because you're generating larger boats and they can carry more cholesterol. But that's a good thing because you want less boats carrying more cholesterol than these tiny boats carrying small amounts.

So just to clarify what for people, the total number that you get on the cholesterol panel goes up, but the particle number goes down.

So.

The actual problem gets better. It's not that your cholesterol is getting worse, it's actually getting better, but it's just how we look at it. I mean, I'm much more worried about someone with a cholesterol of 150, an LDL of 70, an HDL of 30 and triglycerides of 300 than I am of someone who's got a cholesterol of 300. and HDL of 100 and LDL of 150. I got much more worried about that person who's got a cholesterol of 150.

That's something in traditional medicine just kind of misses. It doesn't. And you know the other element of the total cholesterol, why it goes up if you're doing the right thing in a lot of patients is because the HDL goes up, right? So all of a sudden LDL is going up, HDL is going up. So that's why ratios are key and we hinted on this, but I tell people just forget absolutes and just look at triglyceride to HDL ratio. That's a key number for insulin resistance. Now, having said that, obviously if your total cholesterol is above 300, yeah, your LDL level, regardless of size, it's probably too high. But, you know, for most people, if you stick to ratios, that's a far more powerful number to look at.

Yeah, I think that's important. And the triglyceride to HDL ratio should be ideally less than one or about one. If it's, if it's more like two or three or four, right? If your triglyceride, let's say 300 and your HDL is 30, that's a ratio of 10.

Yeah, exactly.

So I think those are the challenges and we don't know often what to do with these people. How do we fix those other profiles? And so what do you do in terms of statins for these patients?

So good point. So again, if they've got the insulin resistant profile, we got to focus on lifestyle first because even if you put them on a statin and they're high risk, I mean, the incremental benefit is still small relative making lifestyle changes. I mean, I've got loads of patients who are in statins that have their first MI, right? So, because you know, one of the problems with statins, we can talk about a lot of issues with statins, but when patients go on and they see their numbers magically transform, often they think it's a free pass to go back to whatever they were doing. I've seen that it does have a negative impact on lifestyle. So, so I sometimes put the statin a little bit in the background and we definitely focus on lifestyle first. But having said that, The other test I often have to do in these patients because they're so high risk is I do a coronary calcium scan. So, that's a CT scan to look at the blood vessels to see if there's early signs of plaque. And in those patients that are already developing pretty large plaque sizes, I do get concerned. These are patients where statins probably do make sense. You know, I might prescribe it in those cases, but I want a lot more data before I put patients on statins. What's your inflammation status? What's your CRP? What are the advanced lipid profile shown before we jump into sort of putting everybody on a statin.

Yeah, it's important what you just said because in the Jupiter trial, one of the largest trials on statins, they found that the LDL, if LDL was high and the CRP was high, which is inflammation, statins helped. If the LDL was high and the CRP was normal, they didn't help. So, it's really about much more nuanced than we typically think about. And one of the challenges of statins is that it infects insulin resistance and it impairs mitochondrial function and may affect your risk of diabetes. And there seems to be in some studies up to 80% increased risk of diabetes. How do you reconcile that in this population so at risk for diabetes?

Yeah, good point. I mean, basically you've got to weigh both arms here. And you're right, because you're insulin resistant, we don't want to put them on a drug that's going to make the insulin resistant worse. But at the same time, if they've already got elevated CRPs, they've got early signs of plaque, then you've got to weigh those two. I have had some patients that we did an initial trial of statins. We got their lifestyle in shape by four, six, nine months, and we often took them off the statins. That's the other, I think, misconception is a lot of doctors and patients feel like once you're on a statin, it's a lifelong sentence, right? But sometimes you can mitigate risk temporarily, make some changes, and then maybe we can get you off the statins. Just think about that. It's a kind of a novel concept in traditional medicine. Can we take people off their drugs? But it's something that we should be addressing every time we see our patients.

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