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Dr. Michael Snyder on Huberman Lab: Why One Diet Fails All

Snyder found people spike on potatoes but not grapes, or vice versa. He explains why glycemic index misleads; and how a two-week CGM reveals your true pattern.

Andrew HubermanhostMichael Snyderguest
Sep 8, 20252h 45mWatch on YouTube ↗

EVERY SPOKEN WORD

  1. 0:00 – 3:33

    Michael Snyder

    1. AH

      Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Michael Snyder. Dr. Michael Snyder is a professor of genetics at Stanford University School of Medicine. His laboratory focuses on how different people respond differently to different types of food and health interventions. And his overall goal is to figure out how different genes and proteins that different people express impact people's immune system function, reaction to different foods and diets, blood sugar regulation, immune system, and longevity. Today's episode could basically be summarized as, as you suspected, not everybody responds the same way to the same behavioral, drug, supplement, or other treatment designed to improve health span and life span. For instance, the Snyder Laboratory published a paper earlier this year showing that different people spike insulin in response to different types of carbohydrates. Things like the glycemic index, which we may be familiar with, because they are essentially a readout of how much a given food impacts blood sugar, depends on who you are. They identified so-called potato spikers, they literally referred to them as potato spikers in this paper, versus grape spikers, people whose insulin spikes in response to potatoes but not grapes and vice versa. And while this might seem kind of silly or trivial or micro-slicing, the identification of these different sub-types of people in the general population who respond differently to different types of foods is extremely important. Because I think most all of us are getting a little bit tired of all these discussions about carbohydrates are good, carbohydrates are bad, these carbohydrates are good, these carbohydrates are bad, and on and on. Turns out, it depends on which genes and which proteins you make. In other words, individual variability matters. We talk about that individual variability in the context of nutrition, also in the context of fiber. It turns out that fiber is something that people generally believe is good for your health. I certainly believe that. Well, different types of fibers impact people differently. Some people experience systemic inflammation of their brain and body when they eat certain types of fibers. That's bad. Other people experience systematic decreases in inflammation when they eat certain types of fibers. The key is to identify which category you're in, and therefore, which fibers to eat. And as it turns out, different foods have different fiber types. So it's tractable. There are things you can do about it. We also talk about GLP-1 drugs and how those impact longevity. This is something that's very controversial and very timely right now. And we discuss how different psychological interventions ... Yep. The Snyder Lab has even looked at how different psychological interventions impact the genes you make and the proteins you make and their effect on health span and life span. So today's discussion is sure to change your mind about a lot of things related to nutrition and fitness and medicine. However, I promise that thanks to Dr. Michael Snyder, it will not confuse you. In fact, it will clarify many things that perhaps before the episode were confusing to you and many other people. Dr. Snyder's laboratory is recognized for doing extremely rigorous analyses of the genes and proteins that can explain individual variability and what people should do or not do in order to maximize their health and longevity. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. Michael Snyder.

  2. 3:33 – 9:02

    Healthy Glucose Range, Continuous Glucose Monitors (CGM), Hemoglobin A1c

    1. AH

      Dr. Michael Snyder, welcome.

    2. MS

      Great to be here.

    3. AH

      I'd like to start by talking about glucose regulation in food and food choice, exercise, sleep, and how they all interact. But I want to make it very simple to start. How is it that what we eat impacts our glucose response? And maybe you could tell us a little bit about what a healthy glucose response looks like. Because by most people's view, any inflection in blood glucose is a quote unquote spike. But what are the sorts of spikes that matter for health and what are the sorts of spikes in blood glucose, or what are called glucose excursions, that, you know, you go, "Okay, well, that's a normal response to eating some food, and then it goes back down to baseline." Uh, I think this is especially important nowadays with all the interest in metabolic health, in how particular types of foods like processed foods are indeed far worse for us, and on and on. So, um, if you could just give us your view and understanding of glucose excursions. What they mean, when they're good, when they're bad.

    4. MS

      Well, I would say that, um, you know, high, long, prolonged spikes is obviously pretty bad. Um, but certain things, like if you eat a grape, grape's pretty loaded with sugar, but it's a pretty transient spike. It'll go up. Uh, and so that would be a transient one, and actually, when you do strength training, for example, or exercise, you break down glucagon, which is a, you know, it's a polymer of sugar that you break down, gives you energy. That's important for when you're doing exercise and training, and that will give a glucose spike. I get a glucose spike every morning when I weight train. So that would be a normal, healthy one, but it's transient. It goes away pretty quickly.

    5. AH

      What's quickly?

    6. MS

      Within, uh, 30 minutes, maybe most 60 minutes.

    7. AH

      Mm-hmm.

    8. MS

      Um, now, I'm a special case. I'm a type 2 diabetic, so my spikes go higher and longer than most people. Um, so yeah, mine are not good spikes, but we can get into that. So what is a good spike? Well, I, the calibration people mostly uses time and range. It's a simple metric, meaning if you're a healthy person, your glucose is normally, for most people, around 90. Um, and if you're off-... you will go higher than that. For most people, you wanna keep your glucose between 70 and 140 if you're healthy. For diabetics, they say try and keep it between 70 and 180. And that is what people try to do. And, and most healthy people, it's pretty easy. And I think one of the things we've done, you've heard about continuous glucose monitors, these devices. And I'm wearing one, and I, some of your staff, I know, are wearing them as well. And they're over-the-counter now. You put these on your arm and they measure your glucose every five minutes, so you can see exactly what's going on. And so, uh, we put them on so-called normal people, pre-diabetics, and some diabetics. It was already well-known diabetics will spike their glucose through the roof, too high for too long. Uh, and then the people devise, especially Type 1s, control mechanisms for, for releasing insulin and controlling all of that. But for, um, the average person, that wasn't so well-known at the time we were doing this, and it was a bit of a surprise to see that a lot of people... Some were, did have very good glucose control, but some pre-diabetics were what we call moderate spikers. We came up and named glucotypes as, it's a way of quantifying this in a, uh... And then some people were spiking just as bad as diabetics and had no idea-

    9. AH

      Mm-hmm.

    10. MS

      ... uh, and so it was a way of revealing what was going on. So it's recommended that you try to stay in this 70 to 140, but it is a bit arbitrary. But it's not a bad rule of thumb to, to work by for the average person. But again, some people have very, very good glucose control, some are moderate spikers, and some are severe. And it's pretty clear that excessive spiking, especially in diabetics, is associated with cardiovascular disease and other things. There's some, uh, pretty strong papers out there on that. So, uh, you do want to keep it under control. And there's a very strong correlation between this time and range measurement I mentioned, and something called hemoglobin A1C. That's a measure of your steady-state glucose. And so if you have high hemoglobin A1C, that's typically how we classify people for diabetes and pre-diabetes. If you're over, uh, 6'5" or over, you're classified as diabetic. If you're 5'7" to 6'4", you're pre-diabetic. And if you're under that, you're, you're so-called normal. And this time and range will actually correlate very, very well with that. So it is an, it's a surrogate measure for that. But it's actually pretty cool because it's, you can precisely see what's going on in real time, unlike a hemoglobin A1C measurement, which you get periodically. So if you wanna dig into that further, I would say (laughs) that, you know, what's cool about these CGMs is that you wear them, like I'm wearing one now, you can wear them, uh, for about 14 days, depends on the particular device, and you see exactly what foods do what to you. And we're all different. So some people spike to bananas, some to potatoes, some to pasta, some to white bread, some to brown bread. And so, uh, this was shown by Aaron Siegel's lab at the Weizmann, and our lab had found something similar. Uh, and it's very personal. And so we've been spending a lot of time trying to dig into what's behind that.

  3. 9:02 – 12:18

    Individual Variability & Food Choice, Glucose Spikes & Sleepiness

    1. MS

    2. AH

      So different people s-... Glucose spiked to different foods. It's hard to predict on the basis of something like a chart of glycemic index, for instance. Um, so if I understand correctly, and I have glanced at those papers, um, you know, I might be able to eat mango with nothing else and my blood glucose doesn't go out of range, or at least not for very long, whereas somebody else might have a s-... A very big and prolonged spike in blood glucose to mango. But maybe there are things they can eat that I can't eat, like, uh, I don't know, sourdough bread or something. By the way, I can eat sourdough bread.

    3. MS

      (laughs)

    4. AH

      But just by way of example.

    5. MS

      100%, yeah.

    6. AH

      Mm-hmm.

    7. MS

      Yeah.

    8. AH

      And so, and so really, the only way to know, as you're pointing out, is, is to measure. I, I wanna talk a lot about measurement today.

    9. MS

      All right.

    10. AH

      Um, for those that are just listening, not watching, uh, uh, Mike is wearing many sensors.

    11. MS

      (laughs)

    12. AH

      How many sensors... You have got four watches on.

    13. MS

      Uh, I have my four watches and my ring, and even my hearing aids are sensors, believe it or not. So (laughs) -

    14. AH

      (laughs) Okay, we're gonna get-

    15. MS

      ... they are for hearing, but, uh-

    16. AH

      (laughs) We're gonna get into all of that.

    17. MS

      All right.

    18. AH

      Um, but maybe we could talk a little bit about some of the subjective experience of blood glucose excursions, both healthy and unhealthy.

    19. MS

      Okay.

    20. AH

      Um, most people are familiar with eating a big meal, like the, you know, the cliche is the, you know, the Thanksgiving meal after which you're, you're tired, where you stuffed yourself with protein and carbohydrates and dessert, et cetera, maybe some alcohol too in some cases. But I think people are also familiar with, you know, eating a certain food. Um, like for me lately, I'll have my bowl of oatmeal with some berries and my protein drink after I train, and I'm noticing with each successive year, I'm getting really sleepy after I eat this. And I've swapped out the, the oatmeal for a different carbohydrate recently, just some white rice, and I feel fine.

    21. MS

      Right.

    22. AH

      And I, I don't think this is my imagination. I mean, in one case, I wanna take a nap afterwards. In the other case, I'm good to keep going, and I generally have a lot of energy, so-

    23. MS

      Right.

    24. AH

      ... is what I just described atypical? What are some subjective-

    25. MS

      Yeah, I think so.

    26. AH

      ... effects of high, high glucose spikes?

    27. MS

      Yeah. Well, certainly, uh, sleepiness is one. I can put myself to sleep with a piece of pizza. Um, I'm diabetic. I'm a unusual diabetic. We can talk about that too. Uh, and yeah, if I eat pizza, my glucose goes through the roof and, um, I will get sleepy. (laughs)

    28. AH

      So, uh, so does that mean that you eat and you feel sleepy, or there's a, uh, a period after you eat... Because this is what I experience, where I feel very energized for a short while, and then it's almost like my vision gets a little blurry-

    29. MS

      Mm-hmm.

    30. AH

      ... and I feel kind of like, um, you know, like I just wanna curl up and take a nap even if I slept great the night before. Is that a blood glucose response?

  4. 12:18 – 15:16

    Sponsors: AGZ by AG1 & Wealthfront

    1. MS

    2. AH

      We've known for a long time that there are things that we can do to improve our sleep, and that includes things that we can take, things like magnesium threonate, theanine, chamomile extract, and glycine, along with lesser known things like saffron and valerian root. These are all clinically supported ingredients that can help you fall asleep, stay asleep, and wake up feeling more refreshed. I'm excited to share that our longtime sponsor, AG1, just created a new product called AGZ, a nightly drink designed to help you get better sleep and have you wake up feeling super refreshed. Over the past few years, I've worked with the team at AG1 to help create this new AGZ formula. It has the best sleep-supporting compounds in exactly the right ratios in one easy-to-drink mix. This removes all the complexity of trying to forage the vast landscape of supplements focused on sleep and figuring out the right dosages and which ones to take for you. AGZ is, to my knowledge, the most comprehensive sleep supplement on the market. I take it 30 to 60 minutes before sleep, it's delicious by the way, and it dramatically increases both the quality and the depth of my sleep. I know that both from my subjective experience of my sleep and because I track my sleep. I'm excited for everyone to try this new AGZ formulation and to enjoy the benefits of better sleep. AGZ is available in chocolate, chocolate mint, and mixed berry flavors. And as I mentioned before, they're all extremely delicious. My favorite of the three has to be, I think, chocolate mint, but I really like them all. If you'd like to try AGZ, go to drinkagz.com/huberman to get a special offer. Again, that's drinkagz.com/huberman. Today's episode is also brought to us by Wealthfront. I've been using Wealthfront for my savings and my investing for nearly a decade, and I absolutely love it. At the start of every year, I set new goals, and one of my goals for 2025 is to focus on saving money. Since I have Wealthfront, I'll keep that savings in my Wealthfront cash account, where I'm able to earn 4% annual percentage yield on my deposits, and you can as well. With Wealthfront, you can earn 4% APY on your cash from partner banks until you're ready to either spend that money or invest it. With Wealthfront, you also get free instant withdrawals to eligible accounts every day, even on weekends and holidays. The 4% APY is not a promotional rate, and there's no limit to what you can deposit and earn. And you can even get protection for up to $8 million through FDIC insurance provided through Wealthfront's partner banks. Wealthfront gives you free instant withdrawals where it takes just minutes to transfer your money to eligible external accounts. It also takes just minutes to transfer your cash from the cash account to any of Wealthfront's automated investment accounts when you're ready to invest. There are already a million people using Wealthfront to save more, earn more, and build long-term wealth. Earn 4% APY on your cash today. If you'd like to try Wealthfront, go to wealthfront.com/huberman to receive a free $50 bonus with a $500 deposit into your first cash account. That's wealthfront.com/huberman to get started now. This has been a paid testimonial of Wealthfront. Wealthfront Brokerage isn't a bank. The APY is subject to change. For more information, see the episode description.

  5. 15:16 – 21:06

    Glucose Spikes, Tools: Post-Meal Brisk Walk; Soleus “Push-Ups”; Exercise Snacks

    1. AH

      Yeah, there was this idea that, um, if something is rather high on the glycemic index, meaning i- it spikes your blood sugar robustly, that by combining that food with another food or, l- let's say some fiber.

    2. MS

      Yep.

    3. AH

      Um, you know, as opposed to fruit juice, you know, eating the whole fruit, which of course includes the fiber, um-

    4. MS

      Right.

    5. AH

      ... at least in a different form, um, or adding some fat. You know, so I've tried doing this, you know, adding a bit more fat to that meal, but i- you know, in some cases, it still happens. It doesn't matter if you try and blunt the blood glucose response with, with fat or with fiber. You just find that you get that kind of, like, buzz and then crash.

    6. MS

      Right.

    7. AH

      And it's not the kind of crash where y- you can't do anything. It's, it's actually more sinister than that. It's, um, it's more of a, like a brain fog that then transitions into the desire to take a late morning nap, which, if you've slept well the night before, you really shouldn't be feeling.

    8. MS

      Well, y- you can mitigate that, of course, by doing a walk and try and burn off a little bit of that glucose. We can get into that.

    9. AH

      Tell us about walks 'cause we, we've talked a little bit about those on this podcast before, but what is the effect of a short walk and does it need to be a, a brisk walk or can it be... Yeah.

    10. MS

      Yeah, I think brisk walks seem to be better. Uh, there's day, there's studies from, uh, from other people on that, that a brisk walk for 15 minutes or 20 minutes after you eat will help suppress those glucose spikes. Uh, and so, um, and, uh, yeah, so there are in fact some of these, um, companies that have set up around personalized management of glucose, uh, uh, I'm involved with one called January AI and there's others out there too, they actually recommend that. If you eat something that spikes your glucose, you should take a, uh, a brisk walk and that will suppress your spike and they connect to actually teach you that. And you can see it personally. And so one thing, uh, we've done is, for example, most people spike to white rice, believe it or not, it's high glycemic index, but glycemic is more personal than people give credit for. Anyway, you will spike your glucose, but if you take a brisk 20-minute walk, you can just see that spike is much, much less.

    11. AH

      And is that simply due to the low level mus- muscle contractions associated with walking are just pulling, th- they're just acting as a glucose scavenger?

    12. MS

      That's what I assumed, yes, uh, that you're burning it off.

    13. AH

      Did you see the study out of, um, I forget the university in Texas, I think it might've been University of Houston, where they looked at, um, people doing what they called soleus pushups. Did you see this study?

    14. MS

      No, I haven't seen it.

    15. AH

      This is wild.

    16. MS

      Tell me about it.

    17. AH

      So they, they basically had someone, uh, subjects, there was more than one subject, of course, sit in a chair and, um, essentially do the equivalent of, of what gym goers would call a seated calf raise. They called it a, uh, calf pushup, but-

    18. MS

      Okay.

    19. AH

      ... uh, that, all that nomenclature is kind of silly. Uh, what, what it really is is keeping your toes on the floor and lifting your heels. It's like being, like, a knee bouncer-

    20. MS

      Oh, okay.

    21. AH

      ... in, in class where we're all told-

    22. MS

      Interesting.

    23. AH

      ... we shouldn't do it. It turns out the soleus, even though it's only 1% of the total body musculature, um, acts as more of a glucose sponge...... than, uh, other muscles in the body, which sort of makes sense given the, the walking-

    24. MS

      Okay.

    25. AH

      ... thing we've been talking about.

    26. MS

      Yeah, yeah. Huh.

    27. AH

      And, um, now, people had to continue doing this, but, um, it was pretty effective, and I'm, I would prefer to see people go out and take a walk after they eat, but not all of us can get up and, and walk after a meal.

    28. MS

      Yeah.

    29. AH

      If you're on a plane, sure you can, you know, you, you don't wanna fill the aisle 'cause people need to go to the bathroom. You know, it gets-

    30. MS

      Right.

  6. 21:06 – 28:34

    Glucose Dysregulation, Diabetes & Sub-Phenotypes, Tool: Larger Morning Meal

    1. MS

    2. AH

      So these glucose excursions, if they're brief, not a problem. But if people are finding that certain foods or food combinations are making them feel sleepy afterwards, I do think that the glucose monitors are, are useful for parsing which foods are, are doing what. I, I'd like to talk a little bit about meal timing-

    3. MS

      Okay.

    4. AH

      ... and food timing.

    5. MS

      Sure.

    6. AH

      Um, for many years, just by virtue of preference, I will hydrate and I made sure to get electrolytes, water, and caffeine in the morning.

    7. MS

      Okay.

    8. AH

      And I try to exercise in the morning. Um, if I don't, I'll do it in the afternoon. But generally in the morning, and my first meal always lands somewhere around 11:00 AM-

    9. MS

      Okay.

    10. AH

      ... or so-

    11. MS

      Yeah.

    12. AH

      ... roughly. Plus or minus an hour. Is there any evidence that introducing a period of fasting at one point in the day versus, say, later in the day, like having breakfast, lunch, and an early dinner, versus lunch, an afternoon snack, and a typical dinner of, you know, between, you know, 6:30 and 8:30 PM, I think is pretty typical, at least for Americans, is better or worse for glucose, um, control?

    13. MS

      Yeah.

    14. AH

      And general health? I know y- your lab's been focused on, um, I guess it's called intermittent fasting, but this time restricted feeding.

    15. MS

      Right.

    16. AH

      We're not talking about weight loss now, I'm just talking about glucose control.

    17. MS

      There's a lot to unpack there. Um, so we have some studies where we put CGMs on people, smartwatches so we can track their activity. Uh, they did food logging, uh, (laughs) and exercise logging as well. Tracked them in incredible detail, and they were also very well phenotyped for their glucose dysregulation. And we should probably talk about that a little bit about muslin to resistance, uh, beta cell defects, things like that. So we were trying to relate what was th- th- what this du- glucose dysregulation, some phenotype with their lifestyle, and not just their lifestyle, what they did, but when they did it. And what we found is that, first of all, some simple things already known is that, uh, if you have your bigger meal first thing in the morning, you generally have lower glucose and, and don't, and not later at night. Some people had their biggest meal, their biggest energy consumption later in the day as dinner, which is awkward socially 'cause that's when most of us (laughs) have our big meal, or many of us do. Those folks w- will have higher glucose, and starchy vegetables is well known. Those folks have higher glucose. But interesting, fruits, people who ate a lot of fruits as their major source of carbs had lower. That's because of the fiber-

    18. AH

      Mm-hmm.

    19. MS

      ... that's in there that helps them. Turns out most people don't get enough sleep, and so those who slept longer actually had lower glucose. Uh, but some of the things we could tease out were when should you exercise? If you look at the party line out there from various studies, well, you should exercise in the afternoon to get your best benefit. But we found that that depends on the form of dysregulation you have. If your muscle is resistant, you actually get better benefit by exercising in the morning for glucose the next day.

    20. AH

      If you're muscle insulin resistant.

    21. MS

      Right.

    22. AH

      Okay.

    23. MS

      So to unpack that a little bit, um, so y- you probably know that, you know, we, you eat something, you get glucose if it's sugary, and your insulin obviously, you know, helps control that, stimulates your cells to take that up.... and if you're insulin resistant, especially muscle insulin res- muscle is a major consumer of glucose, means you're not taking up your glucose right. So you're insulin resistant and you're, don't take up glucose and you wind up with high glucose spikes. But there are other forms of diabetes, so to break this down, or glucose dysregulation, there are people who don't make insulin early in life, that would be called type 1. Uh, you can still become, uh, insulin, uh, deficient and making insulin later in life for type 2. But, um, you can also have what are called beta cell defects. So insulins produced by your pancreas, your beta cells, and I myself am type 2 dia- diabetic, I have a beta cell defect, took me a while to figure that out, meaning I make insulin, find my cells respond, but I don't release it from the pancreas. Uh, and then there's things called hepatic insul- insulin resistance, so your liver is insulin resistant and other forms as well, uh, fat insulin resistance as well. So we've now gotten into dividing up diabetes. So in, you know, basically classically people will, uh, group people into type 1, which is 10% of people, or type 2, which is the other 90% of diabetics. Well, it turns out that's a really broad category. That can easily be subdivided into what we call subphenotypes, these different forms of glucose dysregulation, and we think that's a big deal because it affects the drugs you take. So for example, I am a beta cell defect and I didn't respond. I, I, um, went through exercise, used to be a runner, and I shifted to weight training about, uh, it'll almost be nine years soon, uh, with the idea of building muscle mass, which failed miserably. My glucose was gradually going up, so I shifted to weight training, I gained 10 pounds of muscle mass, I do whole body MRI, uh, 20 of them the last eight or nine years, and I basically did gain 10 pounds of muscle mass, had, had no effect on my, uh, uh, my glucose control. And the reason for that was that I'm not muscle insulin resistant, I'm a beta cell defect. So I can gain as much muscle as I want, it's not gonna help me release, uh, insulin from my pancreas. So knowing your subphenotype is a big deal, but then I respond to certain drug repenilide that actually promotes that release. So knowing your subphenotype determines your drugs, but it also turns out this whole lifestyle thing I mentioned earlier is a big deal in coming back to some of the food stuff. So we found that if you're, um, uh, basically insu- insulin resistant, muscle insulin resistant, you will spike to potatoes and pasta, but not if you're insulin sensitive. And if you have beta cell defect, you'll also spike to potatoes. So you actually, you can subphenotype people according to what their glucose dysregulation is, and that affects how you'll react to foods, and so then the obvious thing to do is modify your eating behavior on those foods so that you can basically live a healthier life is the idea. Um, and so how are you gonna subphenotype? Well, the way we do it now is super expensive. It's, you know, we do these gold standard tests, take several hours, hundreds if not thousands of dollars, depends how you do it. Uh, we, believe it or not, can do it just from a simple glucose curve. So you may or not realize that when you put one of these glucose monitors on you, you, and you drink a shot of glucose, you'll have a curve. And that shape is different for different people, and that depends on their subphenotype.

    24. AH

      Hmm.

    25. MS

      So meaning if your muscle insulin resistant, you'll have a certain shape, and if your beta cell, it's a different shape, and if you're a combination of things, and there are other factors by the way that play in here, like your microbiome, so the guts in your, uh, the microbes in your gut all play in this. And so they basically affect the shape of your curve, and now we're not there yet, but we're good for some of these, like for muscle insulin resistant, we can quite accurately predict whether you're muscle insulin resistant just from the shape of that glucose curve, which you can get now from an over-the-counter purchase at, at a drug store.

  7. 28:34 – 30:49

    Exercise Timing, Muscle Insulin Resistance

    1. MS

    2. AH

      Super interesting. There's a, a, as you mentioned, a, a ton to unpack there.

    3. MS

      (laughs)

    4. AH

      I just wanna make sure I understand-

    5. MS

      Sure.

    6. AH

      ... a couple of the points you made, um, before we go forward. Uh, you said the vast number of, of, uh, papers that have explored ideal exercise timing-

    7. MS

      Right.

    8. AH

      ... point to the afternoon as the best time.

    9. MS

      Right.

    10. AH

      I've seen those papers also, and my takeaway from those, the kind of gestalt of, of, of those papers in my view is that if you're interested in performance, that the afternoon is better because your body's warm, body temperature tends to be appropriate for performance. Whereas although some people wake up ready to go first thing in the morning, most people don't feel as energized first thing in the morning. Some do, but most don't. Um, but if I understand correctly, for many people, in particular people with muscle insulin resistance, doing resistance training would be preferable to doing cardiovascular training for blood glucose regulation, and doing that resistance training early in the day, uh, it sounded like you were going to tell us that it sets a, a kind of a, a trend toward better glucose regulation throughout the day. But I don't want to, uh, lead the witness here. I wanna make sure that, that that's true before we conclude that.

    11. MS

      Well, we haven't taken apart for that particular study the difference between resistance training and, and-

    12. AH

      Okay.

    13. MS

      ... it's more a general activity measurement.

    14. AH

      Mm-hmm.

    15. MS

      So people are more active in the morning if they're muscle insulin resistant will benefit, have better glucose levels the next day.

    16. AH

      Mm-hmm.

    17. MS

      So we haven't yet done resistance, but I'm very interested in this. In fact, we have a separate study around high intensity training running versus long distance running, uh, and-

    18. AH

      Mm-hmm.

    19. MS

      ... can, happy to talk about that, that, but that's still in progress. So I, I wouldn't say we've totally done what you've gotten at, but we would like to dissect the resistance training versus a aerobic or endurance type of training. Uh, I mean, the bottom line is of course exercising any time is better than not exercising at all.

    20. AH

      Sure.

    21. MS

      So I, I think we'd all agree with that. But we do think you get better glucose benefits if you are muscle insulin resistant doing the morning. And I also do believe that, yeah, building your muscle mass will help.... uh, with actually reducing muscle and s- resistance.

    22. AH

      Thank you for that clarification.

  8. 30:49 – 35:41

    Diabetes Subtyping, Weight, Glucose Control; Incretins

    1. AH

      Uh, you mentioned different types of diabetes. So general categories are type 1 diabetes, uh, these people don't make insulin. They need to inject insulin or- or- or deliver insulin through a time release mechanism or something of that sort.

    2. MS

      Right.

    3. AH

      Type 2 diabetes, I understand to be insulin insensitivity, which, um, is bad. You want your cells to be sensitive to insulin so that c- insulin can bring the glucose into those cells, so they can use them.

    4. MS

      Right.

    5. AH

      You're now subdividing this type 2 diabetes, the insulin insensitivity into muscle insulin insensitive, as well as other tissues being insensitive. What percentage of-

    6. MS

      But it's more than that, meaning there's a beta cell defect where you don't release insulin from your pancreas.

    7. AH

      Mm-hmm.

    8. MS

      That's n- has nothing to do with insulin resistance. That's more a mechanistic thing. Now why that- that defect exists isn't so clear. Uh, in my case, it's kind of interesting, uh, although we still don't fully understand it. But, um, then there's also incretin defects. So incretin are these GLPs that everybody's heard about. Ozempic is a mimic of those and Mounjaro and things like that. Uh, and so there are people with defects that way. So we're all different, and we can now subtype that. We can say this person's got mostly an incretin defect. This one's muscle and s- resistant. This is a beta cell defect. Uh, and so... And some people are combinations of those.

    9. AH

      Mm-hmm.

    10. MS

      It's not pure one or the other. So we think actually the subtyping is a big deal because again, it determines your lifestyle choices you might make to better control your glucose and of course drug responses as well. So we think that's-

    11. AH

      Mm-hmm.

    12. MS

      ... important.

    13. AH

      We know that many, many people in the United States and elsewhere sadly, are overweight or just clinically overweight, and I think it's about 30% of people in the United States are clinically obese. When you talk about type 2 diabetes and these different, um, subphenotypes, as you're referring to them-

    14. MS

      Right.

    15. AH

      ... um, what percentage of people in the United States do you think are type 2 diabetic that have some sort of either insulin, um, insensitivity and that's th- the- the reason versus, you know, they're making plenty of insulin but they can't release it? I mean, what- what sorts of numbers are we talking about here? Because I think for listeners, they're probably thinking like, "Okay, like I... Uh, as long as I don't eat too much sugar, I feel fine." Does that mean that they don't have type 2 diabetes? People who, um, perhaps are o- of a healthy weight, does that mean they don't have type 2 diabetes or any of these insulin management problems? It sounds like we don't know the real numbers, but if you were to guesstimate what the percentages are of people out there who have some issue with insulin management at a physiological level.

    16. MS

      Uh, well, if you include beta cell defects as part of insulin management-

    17. AH

      Mm-hmm. Yup.

    18. MS

      ... then the number is probably very high.

    19. AH

      Yes, sir, like-

    20. MS

      But I honestly don't know the answer. I don't think we fully know the answer 'cause people haven't done the subphenotyping-

    21. AH

      Mm-hmm.

    22. MS

      ... like I've described. We don't know how many people have incretin defects. We are getting there with i- insulin resistance and such, but I don't think we're fully there. But I want to correct something that you said. I mean, it's very much the case when you see someone who's thin, you can't assume they're not diabetic. This is very common, especially in South Asians to see thin diabetics. Uh, and I'm a good example. No one would call me overweight, uh, by any definition-

    23. AH

      Mm-hmm.

    24. MS

      ... yet I'm a diabetic and I have a beta cell defect. Uh, and I used to think a lot of people who are thin diabetics probably have beta cell defects, but it's not that simple. It's some do and some don't. Some are- some are insulin resistant. And so, um, and then there are other people, believe it or not, who are very obese (laughs) by any clinical measure and what have you, and they have very good glucose control. So there are a lot of things we don't fully understand, and a lot of it probably does, uh, uh, fits in this idea that this is not a simple process. (laughs) Uh, we have many organ systems involved in glucose control, your liver, your pancreas, your muscles we've mentioned, but even your brain is a major glucose consumer. Uh, and so we have all these different organ systems, then on top of that we have all these different biochemical pathways that are engaged as well. We mentioned the insulin one, but there's incretin, uh, which are these GLP things that promote insulin r- release, but they probably have other effects as well. I don't fully understand. I don't think everyone does all the effects of incretins. They're, these r- the receptors were all over the place. And in fact, some of these drugs you may have heard are actually now being touted as maybe anti-longevity drugs (laughs) because they seem to improve cognition and stuff. Now, whether that's tied to weight and things like that is less clear, but-

    25. AH

      As anti-longevity drugs or as longevity drugs?

    26. MS

      As longevity drugs. Sorry.

    27. AH

      Got it. Good.

    28. MS

      Thank you for that correction. Yeah.

  9. 35:41 – 38:40

    GLP-1 Agonists, Diabetes, Tool: Muscle Maintenance & Resistance Training

    1. MS

    2. AH

      Yeah. Uh, actually just for fun-

    3. MS

      Yeah.

    4. AH

      ... let's explore for a moment some of the things that we've heard these GLP-1 drugs, uh, are effective for.

    5. MS

      Yeah.

    6. AH

      Uh, certainly for, um, diabetics to better... Type 2 diabetics to better control their, uh, blood glucose.

    7. MS

      Yeah. If I can intersect there.

    8. AH

      Yeah.

    9. MS

      I am a type 2 diabetic, and they were great for me. I... My hemoglobin A1C got to 8.4, which, you know, it's not the highest, but it's pretty high. And I went on the GLPs, and it went down to 5.7.

    10. AH

      Just like that?

    11. MS

      Pretty fast, yeah.

    12. AH

      Independent of weight loss?

    13. MS

      No, it c- well, initially yes. It's a little complicated. I went on a- a lower dose thing called, um, Farxiga, and that one dropped me down to about the 6.4, 6.5 level, and I didn't lose too much weight. I did lose some. Uh, and then I went on Mounjaro because I had some nausea effects. That is a common side effect. They were modest, but they were there, and I w- and so I shifted to Mounjaro, which is a more potent version, and that dropped me down to 5.7, and I did lose weight. I went from 144 to what I am now, 128, which I didn't like to be honest. And it- it... But I can tell you my... I t- mentioned I do whole body MRIs. I've done 20.... uh, a sale, uh, over the last almost nine years. And I could just see my fat evaporate once I went on these. I get, I'm the coldest guy in the room now. Uh-

    14. AH

      But you maintain muscle mass because you do resistance training?

    15. MS

      S- mostly, yeah.

    16. AH

      How many days per week are you doing it?

    17. MS

      I do it every day. So, but I have light days 'cause, you know, you can't strain yourself hard every day or that's a problem. So I have light days with more reps, and then heavier days for more of the strength stuff. And then I have a specialty day where I do, like, snatches and things to build my core, this sort of thing. Uh, and so, uh, combination of, of those things. And so I do it every day, and the goal is to keep my muscle mass up. And I mostly did it 'cause I do get measured a lot, although it plummeted when I got in a bike accident and hurt my shoulder. Uh, and then certain exercises I couldn't do, and so those things, as you might imagine, diminished. So I did lose some muscle as a consequence of that. I have mostly built my strength back up, not entirely back to where it was, so I, it's still there, but yeah. It, it's not 100%. And then there's a question of how much strength versus muscle mass (laughs) is important. I don't have, maybe you know the answer to that. I don't know. Uh, but anyway, I, I do try to keep it up. It's down a bit, uh, in terms of muscle mass, and, and a touch in strength as well. I do, my, uh, yeah, and my hemoglobin A1C isn't too bad, but I don't like losing that much. I'll be honest with you. I, I thought I looked a little gaunt. So (laughs) actually am now backing off on the Mounjaro. I don't do it every week like you're supposed to. I'm on the lowest dose, so I'm a great responder there. And by the way, uh, when you're getting these drug response, it turns out I'm metformin non-responder. I did try that early on.

    18. AH

      Oh, this is interesting.

  10. 38:40 – 41:01

    Metformin, Berberine, Headaches

    1. AH

      So just to remind people, metformin and then the poor man's version of it is berberine, which is sold as a supplement, they basically do the same thing. They lower blood glucose. In fact, I will tell, uh, anyone that decides to take metformin or berberine that if you don't consume enough starchy carbohydrates with it, it can give you a brutal headache because you become hypoglycemic.

    2. MS

      Oh, I didn't know that. Yeah.

    3. AH

      Oh, it's, uh, it's really rough. Years ago, I used to, uh, take a little bit of berberine. Um, I used to do these, uh, cheat days.

    4. MS

      Okay.

    5. AH

      It was many years ago. I would eat really clean all week, and then I would, like a Saturday, I would just go for it, like, uh, anything you wanted. Um, and I felt lousy. You'd have these energy, you know, peaks and valleys, and then you just felt like by the end of the day, you're just like, "I'm done with food for the next 10 years." And of course, you fast the next day, you feel fine, you go right back to it. But it wasn't healthy. But taking berberine, it was remarkable, because it would allow me and other people, uh, that recommended it to me, that you could just eat, like, an entire box of donuts and feel fine because it would blunt your blood glucose response. However, if you don't have enough glucose in your system, you kinda, you become hypoglycemic and, and you, you get k- y- you get these brutal headaches. Um, so anyway, that's a little-

    6. MS

      And this is becoming a big deal now, right? Hypoglycemia is now being recognized as a big concern actually, so, and people are picking up a lot of this with the CGMs, so-

    7. AH

      Interesting. And this is because people are taking Mounjaro and taking other things that are dropping their blood glucose?

    8. MS

      Yeah, and just it's probably been out there more than people realized in the first place-

    9. AH

      Mm-hmm.

    10. MS

      ... that, and now with the CGMs, people realize, well, if you, uh, we talked about these glucose spikes. Well, it's very common if you get a really giant spike, you make a lot of insulin.

    11. AH

      Mm-hmm.

    12. MS

      So the consequence is then you come down on the other side, and you actually get too low glucose from those spikes.

    13. AH

      Yeah.

    14. MS

      So, so people are recognizing that, and that can, people are now concerned about that. Certainly leads to fatigue.

    15. AH

      Mm-hmm. Yeah, uh, glucose troughs are definitely bad.

    16. MS

      Right.

    17. AH

      I, I don't do any sort of cheat day anymore. I, I actually, just a few years ago, I just quit eating bad food.

    18. MS

      Yeah.

    19. AH

      I don't eat non, uh, I don't eat, you know-

    20. MS

      Well, that, that's gotta be best, right?

    21. AH

      Or, or I aim for, you know, 90% of my food intake to come from, you know, whole unprocessed foods.

    22. MS

      Yeah, great. Ultra-processed food, yeah.

    23. AH

      And then occasionally a slice of pizza or a bowl of ice cream or something. No big deal, right? Um, especially if you're exercising regularly. But,

  11. 41:01 – 47:41

    GLP-1 Agonists, Cognition, Longevity, Tool: Habits Support Medication; Cycling

    1. AH

      so to go back to, um, these, uh, these drugs, these, these GLP-1 agonists, which is basically what they are, right?

    2. MS

      Right.

    3. AH

      And, uh, we had a guest on here, a Zachary Knight, who's at UCSF, Howard.

    4. MS

      Yeah.

    5. AH

      He was an investigator who, um, kinda shocked me by telling me that these drugs all increase levels of GLP-1 in the blood and brain by about a thousand-fold.

    6. MS

      Wow.

    7. AH

      That any less doesn't really have an effect on appetite, doesn't have an effect on the various things they're designed to, uh, to do. Um, so these are massive supraphysiological increases in GLP-1 that people are achieving with these drugs. I know nowadays some people are starting to get them from compounding pharmacies and microdosing them-

    8. MS

      Right.

    9. AH

      ... to great effect actually.

    10. MS

      Okay.

    11. AH

      The big pharma companies don't like this because it's sold at a fraction of the price, and you can get away with very low dosages.

    12. MS

      This is what I wanna do, by the way. I wanna, I wanna-

    13. AH

      Yeah, and no nausea.

    14. MS

      Right.

    15. AH

      And oftentimes they're combined with, um, some other things that, uh, off the top of my head I can't remember, but, uh, oh, right, some of these more, um, experimental peptides, like SS-31, which are designed to improve mitochondria. And people are getting really spectacular effects from the microdosing of compounded, um, uh, compound pharmacy, uh, GLP-1 agonists. But even those are probably boosting GLP-1 several hundredfold. So none of this is, like, natural, uh-

    16. MS

      Right.

    17. AH

      ... for, for the body. And yet, um, there are other positive effects. Like, I've heard of, uh, reduced craving of alcohol.

    18. MS

      Mm-hmm.

    19. AH

      Um, what are some others that you've heard of?

    20. MS

      Cognition is a big one, and it's certainly something people worry about a lot as they get older. It's almost becoming the number one thing people worry about as they get older, getting dementia and, uh, related conditions. So, and there's, you know, we'd like to see more studies out there, but there's some evidence that it may improve cognition. Now, how much of that is intertwined with weight loss and things like that, I don't think has been totally deconvoluted. So I think we need to sort all that out. But, um, yeah, but people are now... You know, uh, you may know that people used to talk about metformin, this diabetes drug, as potentially the longevity drug-

    21. AH

      Mm-hmm.

    22. MS

      ... that this may be the way to live a lot longer, healthier. Um, and the side effects are not high as far as we know, if, if at all for most people. Uh, and now a lot of people are very interested (laughs) in these GLPs as possible longevity drugs. And there are trials underway to look at this sorta stuff, so we'll, we'll see, you know, what ways they impr- improve people.

    23. AH

      I, I will say, as long as we're on this topic, um...You are a perfect example of a very diligent patient. Meaning, you're taking these GLP-1 drugs. You're, as you mentioned, aiming for l- taking lower dosages, maybe even, quote unquote, "microdosing."

    24. MS

      Yeah, I'd like to. Yeah.

    25. AH

      Um, but you're also resistance training daily, alternating heavy and light days. You do your exercise snacks. Uh, you, you, you know, you're getting brisk walks after you eat. I mean, I think it's important to point out that, um, you're doing all the things that help maintain muscle mass, cognition, et cetera, uh, while taking these GLP-1s. Many people won't.

    26. MS

      Yeah.

    27. AH

      Or just, uh, unless they're highly motivated to. Um, they just, they want a drug that's gonna melt the fat away, and they are unwilling or uninterested to do the, the exercise piece. Wh- what, if any, data from your genomics, uh, data and, and these large-scale studies that you're doing point to the fact that the combination of augmenting GLP-1 with these drugs and exercise is, is beneficial? Is it all just about maintaining muscle mass?

    28. MS

      Uh, good question. I don't know, but it's pretty clear that people who do do strength training, again, b- larger studies would be nice, but it's pretty clear they can reduce their muscle mass loss. That, that's clear. And, and it's definitely been the case for me. I mentioned my bike accident. I went from pretty m- good about maintaining muscle mass, then I did lose some when I lost some of that. Um, so I can tell you personally (laughs) it had an effect.

    29. AH

      Don't cycle. I tell my friends, we... I know so many people who have been on a bicycle. You're traveling next to these 3,000-pound, uh, vehicles moving much faster than you. People are texting. I, I say this out of love, uh, for the audience and for, and for you, even though we, we just met. Uh, we're colleagues at Stanford, um, all these years. And, and I have to say, uh, everyone I know who cycles regularly gets hit by a car eventually.

    30. MS

      I-

  12. 47:41 – 49:10

    Subcutaneous vs Visceral Fat, Organ Stress

    1. AH

      I have a question about, um, subcutaneous versus visceral fat.

    2. MS

      Yeah.

    3. AH

      You know, we hear that fat around the viscera, around our organs, is the one to really worry about. Um, and any time I hear something like that, I think, "Okay, that sounds like a reason to not lose fat elsewhere." But, you know, what, what do we know about the, the health risks of intraviseral fat versus subcutaneous fat?

    4. MS

      Yeah, I'm not an expert here, but it does seem pretty clear that obviously fat around your (laughs) organs isn't good, fatty liver being a good example. And by the way, when I went on GLPs, my, I had a little bit of fatty liver, just disappeared. So, I think a lotta people are thinking this way, that your pancreas is, and beta cells in particular, are very subject to stress. And fat does put stress on your organs, no question. And so, it may be one of the reasons, you know, your pancreas and your beta cell, in particular, is very sensitive to fat, is because it does cause stress. We know fat's very associated with inflammation. So, obesity a good example. Uh, the more obese you are, the higher BMI. Again, not perfect correlation, but higher inflammation. And so all that does tie together. And, and your immune system is tied in this in ways I would say we don't fully understand. But, uh, in general, the party line is that visceral fat is worse, and I think it's because it's putting stress on your organ systems, uh, yeah, say, versus subcutaneous.

  13. 49:10 – 51:58

    Sponsors: David & Eight Sleep

    1. AH

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  14. 51:58 – 57:16

    Meal Timing & Sleep, Tools: Post-Dinner Walk, Routines, Bedtime Consistency

    1. AH

      I'd like to talk a little bit about meal timing and sleep. I do my best to eat my last bite of food at least a couple of hours before I go to sleep. Doesn't always happen. What do we know about how evening and nighttime meals impact sleep, and next-day glucose levels and regulation?

    2. MS

      Well, the party line is that you should not eat three hours before sleeping, uh, and I believe that, and that's true from the studies we've run, that people who do have a gap, and actually people who walk after dinner have lower glucose the next day. And if you go into the evening (laughs) with a high glucose spike, in general, that correlates with poorer sleep. So, um, I, I think it's more complicated than that. I think the, again, the party line will be, "Well, your glucose is kinda high at night and gradually goes down during the day and spike in the morning." You got a cortisol spike, as you probably know, when you wake up, and that's normal and that's healthy, helps energize you for the day, and, and cortisol and glucose are related. Uh, but when you actually look at people's glucose patterns, it's much more complicated than that, and I think a lot of that has to do with what their sub-phenotype is, is what, uh, we don't fully understand as we're trying to s- sort this out. And what you did the day and especially the evening before, eating that big piece of pizza then go falling right asleep probably is not a great thing for you. You will go to bed with a high glucose spike for man- many people. Again, unless you have perfect glucose control. So, uh, you know, I, I think getting your glucose under control, it is a bit of a problem for me. We tend to eat late in my household just because both my wife and I work kinda late. (laughs) Uh, and so we tend to eat a little bit later, but I definitely do better if I can try and eat earlier, and, and I definitely don't snack before bedtime, that sort of thing. And these days, I try not to make my biggest meal my dinner, uh, which again, can lead you into sleep with that. And we always take a walk. We have dogs, and walk our dog after dinner. It's become a routine. You mentioned earlier about behavior, and I think the key for good behavior is to get into these routines, uh, where you can just get into that, and I think it really makes a difference. So, um, yeah, always, and as I'm sure you know, going to bed, people, we'd found that in some of our studies as well, going to bed the exact same time, those folks have lower glucose than those who have highly variable sleep timing. Now, that's not so great for me because I travel a fair amount. (laughs)

    3. AH

      Yeah, likewise.

    4. MS

      But I, but I try when I'm not traveling to keep constant hours. At least that part I'm, I'm okay at, but you know.

    5. AH

      I think we forget sometimes the number of interesting things that happen in sleep, and one of the most interesting papers, to me anyway, in the last few years was a paper that I saw where they essentially had people breathe into a tube while they were sleeping-

    6. MS

      Okay.

    7. AH

      ... and evaluated the different types of metabolism that were occurring during sleep. And i- it turns out that as we go from light sleep to deep sleep and then more rapid eye movement sleep as the night progresses, the brain and body transition through essentially every form of metabolism, glucose metabolism, ketogenic metabolism, a mixture of the two, and it seems like sleep is this, um...We don't know if it's a, like a test run or if it's a reboot or... We don't know what to call it, right? But it's just very clear that during sleep, there's a lot of metabolism happening. So when you tell me that getting to bed at roughly the same time or the same time every night improves blood glucose regulation, my first thought is, "Oh, well, that makes sense because if you go to bed at the same time, then you're eating at roughly the same time, you're exercising at roughly the same time." But it could also be the case that in sleep, we're getting a, a, a tuning up of the, of the metabolic processes for the brain and, and body. Is there any evidence that, that supports that?

    8. MS

      Yeah. Again, I don't know from the metabolism standpoint. I, I like to say the things we do the most, we understand the least. Nutrition, right? How does it exactly does that work on all your different organs? Sleep. You know, uh, I do like the idea that sleep, you may know your (laughs) ... You, you would know this better than me, but your spinal fluid and such, it, you know, expands and contracts. The idea of emptying out the garbage, so to speak, while you sleep.

    9. AH

      Mm-hmm. Yeah, it literally rinses out your, your system.

    10. MS

      Yeah, and I, I like that concept. I think, uh... And, and, you know, to what extent that is beneficial, I'm sure it is, I don't know, and all the other facts. But even people argue what's better for you, REM versus deep sleep. Even some of that is debated by experts in the field. Again, I'm not a sleep expert. Um, I have a tendency to move into fields I know nothing about. So because I'm so naive, I hope to learn something, uh, especially these areas that aren't so well-understood. So it's an area we're gonna be studying a lot more around the glucose control. But there's no question. If you look at some people, they're spiking really bizarrely, and, and I have mixed days myself. I'm trying to sort that out. Some where I do hit the party line. Higher glucose, gradually go down by the morning, but then I have nights where, um, quite irregular, and I wanna correlate that with what's going on. And it's not just me. It's true of a lot of people, and I don't think that's sorted out in my mind.

  15. 57:16 – 1:02:52

    Microbiome, Immune System & Gut; Diet & Individual Variability

    1. MS

      And I think metabolism in general... Uh, at some point, we can talk about the microsampling stuff, but we found that... Uh, we had 32 people drink this Ensure shake while they were fasted, and they all reacted very differently to it. This is during the day now, not, not sleep. And, um, for some people, it was proinflammatory, for others, antiinflammatory.

    2. AH

      So interesting.

    3. MS

      I assume a lot of this got set early in life because your whole microbiome... So backing up a little bit, uh, just (laughs) so people realize that, you know, you have a lot of microbes. You have, in fact, more microbes in you than are human cells, and they are critical for digesting your food and all this, and, and they're, they heavily interact with your immune system. 70% of your immune cells are in your gut. So you have this whole interplay between your immune system and your gut, and obviously, then the foods you eat, which, uh, it goes through your small intestine first, and the small molecules like glucose get absorbed, but then all the fibers, the big molecules go into your, your, your culinary, your large intestine, where they basically, you know, are interacting with these immune cells, so I think a lo-... And a lot of that gets probably set early in life. In fact, people have shown your microbiome gets set in your first three years of life. So I think that interplay all gets established an- and then you are reacting to some of that, your food, later in life. That's at least the postulate. Not that you can't modify it. In fact, you know, switching from carnivore to veggie diets and/or Mediterranean-type diets, which are sort of healthier, f- like fish heavy, uh, um, veggie diets, I think are helpful for people. Um, but I do think some of this gets set early, and I think getting that set right, I, I think we probably need to, as a society (laughs) , get that all set a lot earlier probably now, too. And, uh, and it's estimated, some work from Justin Sonnenburg, that, um, uh, you know, native populations, these Aboriginal, they have three times the number of microbes that, say, people in the US. They... So we just don't have the same community that is probably handling diverse foods and, and probably making essential ingredients for our health that we're now missing. So we probably need to restore that in some fashion. Otherwise, this obesity and diabetes trend is just gonna continue.

    4. AH

      Mm-hmm. I totally agree. I think the gut microbiome is, without question, one of the more fascinating aspects of our biology, and, um, in no small part because of the way that it interacts with the brain by the vagus nerve. You know, e- everyone's obsessed these days with the vagus nerve as a calming pathway, but it's, uh, got a bunch of different avenues within it, and, um, and it is the major route by which your gut communicates with your brain.

    5. MS

      Right.

    6. AH

      And, um, I, I do wanna, um, just say one thing in fairness to, uh, m- an observation. Um, I completely agree with you that many people who've been eating certainly standard American diet... It's sad to think that anyone still does that anymore because it's such a terrible diet. I think everyone agrees on that, a lot of processed foods. But, um, you mentioned, uh, switching, uh, carnivore for, uh, more Mediterranean or plant-based. I have seen that, uh, work for many people. I will just also mention I- in fairness that there... And this relates to the gut microbiome. There do seem to be some people who, despite their best effort to eat fiber, fruits, vegetables, fish, so-called Mediterranean diet, that for whatever reason, um, they have persistent autoimmune issues, and I have observed over and over again that if they switch to an elimination diet that's largely just meat...... believe it or not, and nothing else, they seem to resolve those autoimmune issues. Now, I personally don't follow that diet. I don't think it's the mo- the healthiest diet out there. It's very hard to f- uh, to stick to. But in my mind, it seems like the data are pointing to the idea that there are diverse microbiomes out there, set up early in life, and probably genetics play a role also. You're a professor of genetics-

    7. MS

      (laughs)

    8. AH

      ... so hopefully that's not too, uh, uh, uh, too heretical an idea.

    9. MS

      By the way, some of this has been broken down of, of say, y- how much is your microbiome for general glucose levels-

    10. AH

      Yeah.

    11. MS

      ... versus genetics. And I think for the general, uh, um, microbiome, it's about 20 some, 20 to 30%. Depends on the cohort that was studied. There's some work from, from the Weissman. Uh, and then for genetics, it may be about 20% as well. So-

    12. AH

      So 20%-

    13. MS

      ... or maybe even a little less.

    14. AH

      ... of your microbiome is determined by your genetics?

    15. MS

      Uh, no, the other way around. Sorry, of your glucose levels-

    16. AH

      Hm.

    17. MS

      ... 20%, 20 to 30% is determined by your microbiome-

    18. AH

      Mm-hmm.

    19. MS

      ... and about 20% by your genetics for glucose.

    20. AH

      And the rest by lifestyle?

    21. MS

      Yeah.

    22. AH

      Okay.

    23. MS

      And by the way-

    24. AH

      That's a very u-

    25. MS

      Yeah.

    26. AH

      ... that's a useful set of metrics.

    27. MS

      Yeah.

    28. AH

      Yeah. I mean, I, I just have to believe, based on the observation of people who are really careful, really care about their health, they're not doing standard American diet, and they've tried vegan, they've tried vegetarian, they've tried omnivore without many processed foods, and then they try ketogenic diet and they feel better, and then they go full just meat, and their issues disappear.

    29. MS

      Yeah.

    30. AH

      And you, you kinda have to acknowledge that.

  16. 1:02:52 – 1:09:50

    Fiber Types, Cholesterol & Glucose, Polyphenols

    1. AH

      I'd like to talk for a moment about fiber-

    2. MS

      Sure.

    3. AH

      ... because I think there's general agreement in the medical community that fiber is important. Um, reduces risk of cancer, improves digestion, adds bulk to food, reduces inflammation. I mean, just on and on and on. But then again, our colleague, Justin Sonnenburg, um, and Christopher Gardner-

    4. MS

      Yeah.

    5. AH

      ... both of whom have been on this podcast before, did this really nice study of comparing increasing fiber in the diet versus increasing intake of low-sugar fermented foods. And it's very clear that the increase in low-sugar fermented foods supported proliferation of the healthy gut microbiota, reduced the inflammatone. Whereas increasing fiber allowed some people to reduce inflammation, other people's levels of inflammation went up. And so this brings us to this question of when we talk about fiber as a general category, maybe that's too broad.

    6. MS

      It is.

    7. AH

      Could you tell us about the two major types of fiber, which foods, uh, tend to deliver one or the other type of fiber, and if indeed there are differences in which fiber are best for different people?

    8. MS

      Right. So, uh, as you're alluding to, fiber is very heterogeneous, very different. And we even break it down further than that. You're probably thinking of, you know, soluble versus insoluble, uh, or resistant starch versus starch, but I look at fiber as, like, just a giant community of different substrates, if you will. So we have long chain, short chains, hydrophobic, hydrophilic, positive, negative. It's like saying all animals are the same, humans are the same as cockroaches, the same as cats and dogs.

    9. AH

      You just can't let, you just can't lump that broadly.

    10. MS

      You can't, and their-

    11. AH

      Yeah.

    12. MS

      ... effects are very, very broad.

    13. AH

      Yeah.

    14. MS

      And so we've started tearing this apart. I was a chemistry undergrad by training, (laughs) so I guess that's where I'm coming at this. So we just started, and being somewhat practical too, we started putting people on, we took two common fibers, arabinoxylan and inulin, which are these two, uh, just commonly used. Uh, arabixylans and psyllium husks, and it's associated with Metamucil, and inulins and those chicory pea fiber things. And-

    15. AH

      Well, could you, before we dive into this-

    16. MS

      Oh.

    17. AH

      ... what are some foods that one type of fibers is more abundant in versus the other type of fiber?

    18. MS

      Well, Metamucil is a good example for the, the, um, uh, arabixylan would be in that. And arabixylan's kind of interesting. Uh, as the name sounds to chemists, it has arabinose and, (laughs) uh, and it does have some glucose, but it has polyphenols in it too. And I don't know if, you probably have covered this on your sh- show.

    19. AH

      No, not yet, but they're super important.

    20. MS

      They are. They're, they're, and they're being, especially in the last, I'd say, you know, six, 10 years, being more and more appreciated for all their positive effects as antioxidants-

    21. AH

      Mm-hmm.

    22. MS

      ... antiinflammatory.

    23. AH

      Mm-hmm.

    24. MS

      So, uh, anyway, they're part of arabixylan. This inulin is a glucose polymer, but there are short chain and long chain that has similar properties as well too. Uh, that's in various, uh, um, certain fruits and certain, uh, other things. And when we went into this, if you read the literature, you would say, "Well," there'll be some says, said, um, "Well, inulin lowers your glucose." Another say, "No, it has no effect." And some saying it lowers your cholesterol, and others it doesn't. Same with arabixylan. It was all over the map, although there might have been more of a consensus about this arabixylan lowering cholesterol. So we just did it. We took 18 people. I know it doesn't sound like very many, but they did a, what's called a crossover study, where they went on increasing doses, where they took either 10 for the first, 10 grams a day for the first week as a supplement, 20 the next week, 30 the next week, and then did a washout, and then switched to the other one. So they're, uh, they're randomized. They might do arabixylan the first period, and then inulin the second, then a mixed fiber, which the party line would say is, is supposed to be the best for you. So we put, and then we do what we're known for, these deep measurements, these deep ohmic, where it measures many molecules of people's blood, and as well as clinical measures. And so what we discovered is that as a general rule, uh-... arabinoxylan did reduce cholesterol, and actually quite substantially. It went down about 25%.

    25. AH

      So this is in Metamucil, but what other, um, what sorts of foods contain high amounts of th- of this compound?

    26. MS

      Most do, actually. (laughs)

    27. AH

      Oh, okay.

    28. MS

      It's very-

    29. AH

      So broccoli?

    30. MS

      Yeah. Broccoli, yeah.

  17. 1:09:50 – 1:18:48

    Food As Medicine; Fiber, Microbiome & Individual Variability; Probiotics

    1. MS

    2. AH

      Which is remarkable. Uh, I mean, if we really just take a step back, it's like forever, you know, bipolar, depression was one of the most difficult things to treat. And it turns out the ketogenic diet can be very effective in some people. In some cases, curing people. Not every person. But that's a remarkable breakthrough.

    3. MS

      I agree.

    4. AH

      Uh, you know, and as you said earlier, I think it's, uh, such a key, uh, thing for people to keep in mind. We understand the least about the things we do the most.

    5. MS

      Yeah.

    6. AH

      So you can imagine for many years, people are eating. Like every- everyone eats sooner or later. And, um, some of these people are dealing with serious mental health issues, and the foods they were eating very well were exacerbating their symptoms.

    7. MS

      Yeah.

    8. AH

      It's just wild to think about. But then when we, uh, we talk about it, and I've heard you say, you know, "Food is medicine," I think most people don't think of food as medicine. I think most people think as food as something, uh, they need, that they crave, that they enjoy, uh, and that eventually becomes problematic for them. You know, I don't think people really understand the extent to which what they put in their mouth can support them, that it really can be health promoting.

    9. MS

      Yeah.

    10. AH

      Right? I think it's because we are so calorie oriented. Like, oh, you know, it's all a battle between what you take in-

    11. MS

      Yeah.

    12. AH

      ... versus what you burn.

    13. MS

      Yeah.

    14. AH

      But you really view food as medicine.

    15. MS

      Oh, yeah. Because I think we are, uh, I mean, the way I look at it, we're homeostatic systems. We're very... And complex ones at that, right? We have all these organs, all these biochemical pathways. And you know, the one we also understand (laughs) least is people's behavior.

    16. AH

      Mm-hmm.

    17. MS

      That came up earlier, and I'm sure (laughs) it'll come up again. Uh, and you have to tune all this stuff to keep it right. And in general, most people do pretty well. But I think we could, uh, all improve that, I'm sure. And, and that is the goal, to keep this... You know, your car, right, you want, if you want it to run forever, you wanna keep all the systems working right and in balance. You don't let things get off too far. And I think there's a tendency, and I think this is a problem with medicine today, we wait till things are broken and then try and fix it. And so obviously, what you wanna do is have people as well-tuned cars for their entire life, and then, you know, pass away then. That's how it should work. Uh, and so I think that's what we wanna do, keep people tuned. And so we probably don't get off to a good start (laughs) early in life, uh, when we start people with all these not-so-good diets, like all this excessive processed food and sugar and losing our microbiome diversity. I think we really want to keep our car off and running right from the get-go. It's, you know, it's a little bit late for some of us, 'cause we're probably a little bit hardwired, although I think we can tune that. I try to do that as best I can, I guess.

    18. AH

      Seem to be doing a good job. (laughs)

    19. MS

      Yeah. (laughs) Well, anyway, we'll do it the best we can, so.

    20. AH

      When I, um, travel, I will occasionally take a probiotic-

    21. MS

      Okay.

    22. AH

      ... in addition to all the other things I'm doing to support my gut microbiome. I do take a supplement to support gut microbiome. I also try and eat lots of fruits and vegetables. I will say I'm very intrigued by the- these fiber data.

    23. MS

      Okay.

    24. AH

      The different types of fiber data.

    25. MS

      Yeah.

    26. AH

      I'm intrigued because I notice that some vegetable foods just don't agree with me, even if I'm careful to chew them properly and do all that. Um, and I find that over time, I've just oriented towards eating the same...... you know, six to eight vegetables. But, uh, I'm tempted to do the following experiment. Tell me if this is a good experiment, Snyder, uh, if I'd be, uh, get a shot at a sabbatical in your lab. Keep eating the same thing I'm eating, exercise the same, do, do things th- the way I'm, I'm doing them now. But try a supplement, like you said, Metamucil, which is one particular type of fiber.

    27. MS

      Right.

    28. AH

      And do the before and after, um, LDL cholesterol, apoB, blood glucose regulation with a continuous glucose monitor. Then stop, do a washout, swap that out for increasing, like, inulin fiber through some other source. So, so in other words, add, add in a, a pure fiber source-

    29. MS

      Right.

    30. AH

      ... uh, on top of an existing diet, and see how that impacts, um, blood metrics and subjective well-being.

Episode duration: 2:45:04

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