果糖在人类饮食中的作用:健康与否的辩论

@Paul : 我最初认为果糖有害,但深入研究后发现并非如此。我过去在我的书中写道果糖对人类有害,但现在我对此有了更深入的理解。我意识到,当人们只是说糖对人类有害时,他们并没有考虑到糖的来源和类型。我认为果糖在人类饮食中的角色需要更深入的探讨,需要考虑剂量、来源和个体差异。

@Mike Fave : 我也曾认为果糖有害,但现在我改变了看法。我最初来自低碳水化合物背景,当我意识到自己有问题时,我只选择淀粉来源,也就是纯葡萄糖。但当我开始深入研究并进行测试时,我发现并没有出现负面影响。我认为果糖在正常食物来源中并不是问题,但纯果糖可能会引起问题。纯果糖喂养研究中的问题主要是由于果糖在肠道中的吸收限制。我建议从全食物中获取碳水化合物,而不是从精制糖中获取。

我最初认为果糖有害，这在过去撰写的关于肉食饮食的书籍中也有体现。然而，最近与批判性护理注册护士Mike Fave的深入对话，让我对果糖在人类饮食中的作用有了更全面的理解。我们共同探讨了Andrew Huberman和Robert Lustig博士近期播客中的一些观点，并对其中关于胰岛素、果汁和果糖的某些论点提出了质疑。

Mike Fave的经历与我的颇为相似。他最初也持低碳水化合物饮食的观点，并只摄入纯葡萄糖（淀粉来源）。然而，随着研究的深入和自身实验，他发现果糖并非如之前所想的那般有害。关键在于果糖的摄入方式和剂量。 他认为，在正常的全食物来源中，果糖并非问题所在；问题出在那些纯化、精制后的果糖来源，例如高果糖玉米糖浆等。

许多研究使用纯果糖进行动物实验，并得出果糖有害的结论。然而，这些研究存在一个关键的混杂因素：纯果糖的吸收有限制。 未被吸收的果糖残留在肠道中，肠道细菌会将其转化为各种代谢物，包括内毒素，从而引发炎症反应。因此，这些研究结果并不能直接等同于人类食用水果等全食物来源果糖的情况。

我们讨论了蜂蜜和枫糖浆等其他碳水化合物来源。Mike认为，蜂蜜和枫糖浆比白砂糖略好，因为它们含有少量微量营养素和多酚类化合物。但他也强调，关键在于摄入量，需要根据个人的活动水平、总能量摄入量和微量营养素状态进行调整。过量摄入任何类型的糖都不利于健康。

关于果汁，大量研究表明果汁对人体有益，这与一些人认为果汁有害的观点相悖。我们分析了这其中的原因，并指出纤维并非抑制果糖吸收的关键因素。研究表明，在控制碳水化合物摄入量的情况下，食用完整水果和饮用果汁对血糖水平的影响相差无几，甚至完整水果由于纤维的存在，还会引起更高的胰岛素反应。这表明，肠道会通过“回肠刹车”机制来调节营养吸收速度，以适应纤维的存在。

Lustig博士在其播客中提到，果糖会抑制线粒体功能的关键酶，例如AMPK和CPT-1。然而，Mike指出，这种抑制通常发生在糖尿病患者体内，是代谢功能紊乱的结果，而非果糖摄入本身导致的。在正常血糖水平下，这种抑制不会发生。

胰岛素并非“坏家伙”。 Lustig博士认为胰岛素是“坏家伙”，因为它会将葡萄糖储存为脂肪。然而，Mike解释说，这只是在糖尿病患者等代谢功能紊乱的个体中才会发生。在健康个体中，胰岛素的主要作用是降低肝脏的糖异生作用，降低游离脂肪酸水平，并促进葡萄糖在肌肉和肝脏等组织中的利用。糖尿病患者的高胰岛素血症，实际上是由于细胞对胰岛素的抵抗，导致胰岛素无法被有效降解和清除。

我们还讨论了肥胖和糖尿病患者是否可以食用水果或其他升高血糖的食物。Mike认为，是可以的，但需要控制总能量摄入量，并调整碳水化合物和脂肪的比例。长期低碳水化合物饮食可能会导致胰岛素抵抗，因为身体会持续燃烧脂肪，从而抑制葡萄糖的氧化。

总结而言， 果糖本身并非有害物质，关键在于其摄入方式和剂量。从全食物中获取果糖，并控制总能量摄入量，才是健康饮食的关键。 盲目地将果糖妖魔化，忽视个体差异和食物的整体营养成分，只会导致人们对饮食产生不必要的恐惧和误解。 我们需要更全面地看待果糖在人类饮食中的作用，并关注其背后的代谢机制，才能制定更科学、更合理的饮食方案。

Edit:2025.05.05

00:00

How we can use studies that don't replicate what actually happens to humans in nature eating food and make wide-ranging claims about the toxicity of a substance that humans have been eating for hundreds of thousands of years is a little bit baffling to me. But that seems to be what's going on here. On this week's podcast, I had the pleasure of talking to my friend, Mike Fave, about all things sugar and fructose. And we…

00:28

head on tackle a recent podcast between Andrew Huberman and Dr. Robert Lustig from UCSF. Mike is a critical care RN and has a keen interest in the biochemistry of energy metabolism and how we thrive as humans.

00:44

So I wanted to have him on so that we could have a little back and forth and talk about some of the things that were said in this podcast that didn't quite ring true for me and I think are misleading. I believe that Dr. Lustig is a super intelligent human who really wants to do good in the world, and he's brought a lot of really good attention to the problems with processed sugar.

01:05

But I think some of his logic goes off base a little bit when he talks about insulin as, quote, the bad guy, when he talks about fruit juice as being bad for humans, despite a lot of evidence that are interventional trials in humans, that it's not bad for humans. When he talks about fructose basically in all sources being harmful for humans, and it's only the fiber that saves you from the fructose. There are a lot of parts of this podcast with Andrew Huberman that kind of

01:31

made me think that it deserves a little bit of a counterpoint type interpretation. So enjoy this podcast with Mike Fave, where we break down some of the points Robert Lustig was making on this podcast. As I say in the podcast, Dr. Lustig is welcome to come on my podcast for formal discussion. I love these sorts of things. Anytime.

01:48

And I always respect the work that Andrew Huberman is doing as well. This is not meant to be any sort of criticism of either of these people's work, just a counterpoint and a perhaps deeper dive on many of these issues regarding sugar, because I think the nuance here is critically important. And for many of us, including things like fruit, fruit juice, honey, maple syrup in our diets can be very health promoting and help us lead better lives. And I think we should not fear these things. So enjoy this podcast with Mike Favreau.

02:16

Mike Fabe, thanks for coming on the podcast, man. I'm excited for this one. Thanks for having me. I'm excited as well. So before we get started, I just want to give you an opportunity in case people skip the introduction to talk just for a bit about your background in the medicine world. And then we'll jump into this discussion of fruit, fructose, insulin, and it'll be interesting. Yeah, awesome. So

02:40

I have a background working as a RN. I was working in the ICU during COVID. Prior to that, I held multiple different RN positions. Before I even became an RN, I was interested in all this diet, nutrition, alternative health type of stuff. And so I initially went to school pre-med and then switched over to RN so I can finish four years, maybe get my NP. But I dove further and further into the alternative stuff. And then kind of here we are today. So I have one foot in

03:07

the traditional medical model. I have a lot of experience in that. I was working in the hospital for six years. Uh, and then I was doing like a ton of time during COVID. And then I've also been working with clients and going through the research on a consistent basis on the side as well. And so this is like my passion project. And that was kind of a way that I could get enough income to support myself while I was doing this stuff. And then now it's all history at this point. I'm primarily focused on dialing in to the nutrition, uh,

03:35

research and trying to come up and understand what's really going on and structure out plans and systems from there. Love it. I think maybe at the end of the podcast, we'll talk a little bit more about your story and how you got interested in all this stuff. Because it sounds like from what I know about your history, we may have parallel paths. But let's go ahead and get into the science regarding fructose. So this is a

03:56

It's a molecule, it's a carbohydrate. And it's interesting for me because I was carnivore and I wrote a book about the carnivore diet. And when I wrote that book about the carnivore diet, I wrote in that book, fructose is harmful for humans. And here are studies predominantly in animal models to prove it. And I really didn't fully deeply understand the literature on fructose. And what I see happening a lot on social media now is fructose

04:24

People just saying sugar is bad for humans, whether it's someone saying, if you eat sugar, it's going to spike your blood sugar and that's going to cause problems for you. Or in this case, Dr. Robert Lustig from UCSF, I think he's a professor emeritus on Andrew Huberman's podcast going on for three hours, essentially talking about the mechanisms by which fructose is a harmful molecule for humans.

04:47

But what's interesting for me, and I've certainly heard a lot of this from you and Jay, I've had your podcast co-host Jay Feldman on the podcast previously, is that when I heard you guys talking about this, and when I dove into this literature on fructose a little more deeply, I thought, oh, there's more to the story here. And it made sense to me evolutionarily in terms of humans consuming fruit and honey. But let's just set the frame and I'll let you give your perspective. So

05:12

From your perspective, how do you think about fructose in the human diet? Healthy, not healthy. And then we'll use that as a framework to go through a few clips from the recent podcast between Andrew Huberman and Dr. Robert Lustig. Awesome. Yeah. And I want to…

05:30

Also, I kind of align with you there because I came from a low carb background as well. And when I first started adding carbs, when I realized I was having problems, I wouldn't do fructose. I was only doing starch sources, which is just pure glucose. And I started diving in the research and I started testing it out and I started to see I'm not getting these negative effects. And then that's what led to all of this research into what's really going on with fructose.

05:54

Why in the sources, you know, normal source that you would eat fruit tubers,

05:59

um, tubers wouldn't have so much fructose, but like the fruits and fruit juices are not as much of a problem when you, as feeding isolated fructose. So I had like a similar journey as you did, Paul. Um, I know Jay did as well. Jay and I went through that journey together. So we were able to dive through the research together. Now, in terms of the frame, I think it's really important that we set this up appropriately so that we're, people are clear on where we're arguing from. Right? So the first piece is,

06:26

I don't think it's a good idea for anybody to make the majority of their calories in terms of carbohydrates come from things like granulated sugar, honey, maple syrup, or even like pure fructose or gave syrup or something like that, which would be closer to pure fructose. Now, it's not that these things are inherently toxic to the system or anything like that. It's more so that when you feed these heavily purified sources,

06:55

they don't have much nutrition present. They don't really have much micronutrients, vitamins, and minerals. And the other problem, and we'll get into this in just a second talking about fructose, is that they can cause microbiome disruption. And so the microbiome disruption, I think, is one of the biggest issues, particularly around the fructose-only components that are leading to some of the pathology that we're seeing inside the studies. And so I guess we should jump in here is that

07:22

With most of the studies that they are looking at in animal models and humans with fructose, they like to feed really high amounts of fructose by itself in its pure form. And this causes problems in these models because there's a limit to absorption of fructose. And what winds up happening is the leftover fructose gets left in the intestine and then the bacteria present inside the small intestine will start to convert that fructose into

07:49

into different metabolites, including things like endotoxin. And so you have this large confounding variable. And so I think that's a major piece to consider when you're looking at any of this research is dose and route.

08:01

and in what form is being provided of fructose before you can really get a true understanding of what's going on. So in terms of which carbohydrate sources, at least that I generally advocate with my clients or that we discuss inside the bioenergetic sphere, and Paul, I think your recommendations are pretty much around the same spot that mine are. So if they aren't, please let me know. But we're usually looking at things like

08:27

If somebody's tolerating dairy, you're getting some carbohydrate from your dairy that's in the form of lactose. Then you have whole fruits or frozen fruits or dried fruits. You have 100% fruit juice. And then you have different starch sources that you can tolerate, like white potatoes, sweet potatoes, yams, cassava, et cetera. So that's the perspective here is to get a large portion of your carbohydrate calories from those sources, not from granulated sugar or something like that. And then…

08:52

when you start to look at things from that perspective, you don't really see the problems in the research as when you see pure fructose feeding studies. So I want to set that frame there because this is not an argument for just feeding tons of pure fructose. This is more of

09:08

carbohydrates aren't a problem. Fructose inherently isn't a problem in this context of these whole food sources. And then we'll start to dive into the problems with fructose in these other areas and why we're seeing some of these effects that Dr. Lustig mentions. Game changer in the bathroom. Check out this review on gut and digestion from Heart and Soil Supplements. For years, I was struggling with diarrhea multiple times per day,

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11:01

in Western medicine and nutrition research where people say sugar or they say carbohydrates, and you think, what are they talking about? It's kind of like when someone says fat and you think, well, are they talking about linoleic acid? Are they talking about alpha-linolenic acid? Are they talking about stearic acid or myristic acid or oleic acid? The same with sugars, right? The same with single carbohydrate sources, monosaccharides. Are we talking about galactose? Are we talking about

11:29

Are we talking about glucose? Are we talking about fructose? And are we talking about high fructose corn syrup? Are we talking about disaccharides? Are we talking about processed carbohydrates, which could have other contaminants? So this to me, the devil is really in the details, as you're saying. And this is something that I really did learn from you and Jay, which was that

11:48

When you feed isolated fructose, there's a microbiome problem. You get lipopolysaccharide increasing. We'll talk about this in the podcast. Because it didn't make sense to me previously. I would see lots and lots of studies, and I've spoken about these many times previously on the podcast and in other avenues, that fruit juice, which is something that many in the camp that fructose is harmful will vilify, consistently has positive health effects in humans.

12:16

I did a podcast on fruit juice in the past. I have a document with probably 20 studies, everything from grape juice to cherry juice to watermelon juice to orange juice, almost pomegranate juice, every juice you can think of.

12:28

had beneficial effects in humans, many of them decreasing lipid peroxidation, improving endothelial function at the level of the blood vessels, improving HRV, heart rate variability, improving glucose tolerance. I mean, there's a study where they gave watermelon juice to people during an oral glucose tolerance test, an oral glucose challenge, and it improved HRV and

12:52

And it improved glucose tolerance during the test. It improved insulin sensitivity as they were giving them a ton of glucose. So

12:59

So there's some sort of discordance here that I think needs to be fleshed out for people so they can make decisions. I agree with you. I don't think that we are arguing or suggesting significant amounts of granulated sugar consumption. I do want to ask you a little more about honey because I do consume honey. What is your perspective on honey? I'm getting it locally raw and I've seen some studies suggesting that honey is beneficial. It doesn't have the same micronutrient content that an orange juice would.

13:27

or a watermelon juice, but it certainly has some compounds. Let's say complex compounds, polyphenols, prebiotic starches. And so what do you think about honey?

13:40

I think honey in general and also maple syrup are, there's kind of like a hierarchy that I would say for these sugar sources, right? So I would say honey and maple syrup probably sit a bit higher than granulated sugar. And again, I don't think that they're bad sources to consume. So if somebody is putting a bit of sugar in their coffee or something like that, I don't think that that is causing the obesity epidemic or anything along those lines. I think that honey and maple syrup, um,

14:08

Maple syrup does have some small amount of certain B vitamins and in some manganese, honey doesn't have as much of the micronutrients, but both of them contain polyphenolic compounds and the

14:17

And the polyphenolic compounds have numerous benefits in and of themselves. So I think honey is fine depending on the person's tolerance of it. And especially if somebody is more active, right? So say if you're surfing all day long and you're working out and you're doing all these types of activities, you can handle a much higher carbohydrate load than somebody who's not. And so the other thing that's important to understand here, and we'll see this in the studies,

14:42

is it's also important to look at like what's total energy intake. Because the studies where they see problems with even the isolated fructose content is usually when people are consuming in excess of calories in the form of that purified fructose. So even when you switch the carbohydrate source to purified fructose, but you keep caloric intake the same, you don't necessarily see the same level of problems. So you want to make sure that

15:07

your total energy intake is appropriate. And then from there, do I think honey is a bad source or maple syrup? No, I use that with my clients all the time. It's just the amount that's used. The goal I try to do is to not drown out the rest of carbohydrate sources with those things because it is important to get some of the micronutrients and fibers and other polyphenolic compounds that you can get from whole fruits and fruit juices and whatnot. So it's really… It's

15:34

It's not that those things are bad. If anything, I would, if anything, I'd say eating purified fructose wouldn't be a good idea, but for honey and maple syrup, that's, you know, this is basically a sucrose source. So it's one-to-one glucose and fructose. We can talk about why that's not a problem with absorption and whatnot. So yeah, honey overall, I'd say,

15:52

is a fine source. And then it's more of the amounts that you're incorporating in your diet, given, you know, activity level, total energy intake, your micronutrient status, et cetera. So it's a lot of this comes down to context. Context, I think, is one of the most important things to understand when you're reading the research and when you're

16:10

when you're creating your own diet and trying to understand how these different things are occurring. Because if you just take things out of context and you get stuck in that reductionism, that's where you start to see these weird interpretations come out of things and looking at very reductionistic mechanisms and then relying on those without understanding why are they happening in these specific circumstances. Yeah, it's interesting. For me, I…

16:33

Hope people understand that just because I might talk about eating 200, 300, some days, 350 plus grams of carbohydrates a day doesn't mean that everyone needs to do that. Yep.

16:47

People have mentioned this in the past with regard to my lifestyle, but I surf two to three hours a day every day. It's just something that I love. It brings me incredible joy and it requires a lot of calories, increasing amounts of calories depending on what the waves are doing and how much I'm paddling and how much I'm sort of

17:10

getting tossed around in the waves. But that means that for me, I have found that I feel best, I sleep best, I feel the best in my life overall when I have more carbohydrates. This goes back to the whole carbohydrate issue plus minus with carnivore. But yeah, I feel way better with carbohydrates and I experimented with increasing amounts of carbohydrates. And so for me to get 300 grams of carbohydrates a day

17:32

I include some honey. People know that I also do orange juice. I'll eat mangoes. I'll eat papayas. I will eat passion fruit and I'll do watermelon juice, but it's hard to get that amount of carbohydrates from just those things without some honey. I'll do milk throughout the day, raw goat milk. And one of the things that I think is interesting, and then we'll dive into this thing with the Huberman podcast and look at a couple of clips, is that

17:57

increasingly I'm humbled by how much bio-individuality there is between humans. And this is kind of the popularity of the carnivore diet, perhaps, that there are individuals who

18:09

As I'm learning, I'm one of these that have sensitivities to a lot of different foods. The reason that I went carnivore in the first place was pretty significant eczema that was lowering my quality of life. And when I cut out all plant foods, that got better. Now, long-term, if people know my story, that led to issues with long-term ketosis, electrolyte issues, insufficiencies, sleep issues, lowering testosterone, increasing sex hormone binding globulin, things I've spoken about in the past.

18:34

I'm even releasing a video why I quit the carnivore diet in the near future on YouTube. But for me, including carbohydrates was helpful, but the carbohydrate source matters because as part of the experiments now, I've thought, well, let me see if I can reincorporate white rice. And Mike, even when I do organic white rice and I rinse it and I soak it for two days in apple cider vinegar and reverse osmosis water, and then I pressure cook it, I

19:02

I still don't feel great. I still get kind of a headache. I feel a little brain foggy. And this is just my personal experience. Everyone's going to be a little different. I'm jealous of people who can do white rice because what an interesting source of carbohydrates, right? Amalopectin, I believe. And so that's fantastic. And I've tried the same thing with white potatoes. Well, if I peel the white potato and I take off all the little green parts, I can get rid of most of the solanine, which is one of these…

19:28

kind of plant chemicals and potatoes that are problematic. And if I pressure cook the potatoes, maybe I can reduce the lectins. And then I eat potatoes and I think, man, I just don't feel as good. So for me, I haven't, I've found that this is the way that I feel best. And that's how I get the carbohydrates. As you say, I think everyone should adjust or can consider adjusting their carbohydrate intake based on their activity level and what they're doing. Not everyone is probably going to need 300 grams of carbohydrates plus per day. Um, it,

19:54

If you surf a lot, maybe you do, but if you're doing a lot of workouts, if you're in Malibu hanging out with Laird Hamilton and doing XPT in the pool, or you're doing a bunch of CrossFit or you're training jujitsu, you might, but for a lot of people, you can scale that back and figure out what sources work best for you. So anything to add to that before we jump into the-

20:14

In terms of the starch stuff, it's very interesting because that's the same experience that I've had. When I start to incorporate more starch into my diet, I start to get issues more around like getting sleepy after meals than having insomnia at night. And I see that with different clients as well. Some people can tolerate starches. Some people can't. So in terms of dietary setup, my own carbohydrate intake is like 400 to 450 grams of carbs a day. That's because I'm lifting on a regular basis. And

20:42

And that's almost all sugar. The major starch is whatever I get from bananas or some of the vegetable that I eat. Like I eat peas on some days and whatnot. So and I haven't had issues with weight or anything like that. If anything, I've been relatively lean. But when I start incorporating starches, I don't do as well.

20:58

And so I've spent a little time theorizing perhaps why this is the case. And I think that there's some research looking at things like amylase gene copy. And what they see is that people have an increased number of copies of the gene amylase, which helps to digest starches.

21:13

they start to see that those people can actually tolerate starches better, whereas people who have less that gene copy can't. Now, I don't think that this is the only mechanism and whatnot, but I do think there's a case that some people just don't do as well with starches as other people, just like some people don't do as well with dairy as other people. And there is going to be that inter-individuality. And I also think that a reason a lot of people do well on keto and carnivore and paleo is because they start taking out these problematic foods.

21:40

And then there's this idea that it was the carbs that they took out, but instead it was they took out all these other components that were just grouped in with the carbs. And when you remove those components, you get better and you start to find, oh, well, I feel infinitely better. And I don't deny that. I've never did. For me, when I went paleo, I felt way better as well when I went low carb as well. But it's more so I was having a problem with all the starches and grains and stuff that I was eating on the standard American diet before.

22:05

And when I added carbs back in, I just didn't add in those carb sources, more of the fruits and the juices.

22:10

and things like this. And then I had all the benefits of minimizing those problematic components, but I didn't have some of the detriments and stress of running the low carb stuff. And I think that's it. A lot of people are going through this transition, right? They're in low carb, they go to carnivore, and then they're like, okay, I'm having some issues. So they add carbs back in, but the carb source they add back in are different. And they're like, oh, I'm feeling better. It's like, oh, maybe it wasn't the carbs. I think it's more of these other components. And when

22:37

And I don't want to go too far down that rabbit hole, but I had the same experience as you, Paul. That's really interesting. And I'm struck by a parallel here that most of the work or a lot of the work I do feels like I'm an apologist for meat. I'm trying to help people understand that meat is okay to eat. Don't be afraid of meat. Eat some organs with your meat, but it's okay to eat meat because the mainstream…

23:02

perspective that we get is meat is bad for you. In fact, I'm doing an interview tomorrow with an NPR station in Boston, and they sent me an email saying, we're very skeptical of your work, but it's popular and we're curious. And we've spoken to multiple scientists who disagree with you and don't believe that what you're recommending is ethical based on climate.

23:23

climate crisis, quote unquote, et cetera. And I think, yeah, this is what most people are hearing is red meat is really bad for you. Saturated fat is really bad for you still in 2024. And so I'm saying to people, hey, like this is the other side of the equation. Don't fear red meat. And that's why I feel like this conversation with you, the conversation I had with Jay a little bit and in general,

23:42

I also need to defend, ironically, a little bit of fruit and fruit juice because people end up in this position, whether they're transitioning off of keto or off of carnivore, or they're just looking to feel better. And they're thinking, what am I supposed to eat? I know fruit is bad for me. I know fructose is bad for me. I've heard well-spoken, articulate, intelligent Robert Lustig.

24:04

say that fruit is bad for me and say that fructose does all the things that we're going to talk about in this podcast that are horrible for me. And I've heard other people online say insulin is the enemy and I shouldn't spike my blood sugar. And it's like people end up boxed into this corner and they don't know what to eat. Now, I will raise my hand and say that in some ways I am guilty of contributing to that because I'm

24:27

putting out in the ether, the idea that some vegetables might not be great for all people. So I'm also recommending that people may limit their diet if they have autoimmune conditions, but maybe I'm also at the same time trying to help people expand their idea of what other foods might be able to be included in their diet when they understand that the entirety or more of a broad perspective on fruit fructose and maybe why they don't need to fear it. Maybe why having your blood sugar go up isn't the worst thing in the world. Yeah. Yeah.

24:56

I think the difference too is that

25:00

This is where that idea of context comes in, right? So when you're starting to look at the foods now, you look at, say, take red meat. You look at the full profile of red meat. You look at all the benefits of the nutrients, the minimal polyunsaturated fat content, the high quality protein. And you say, okay, there's tons of benefits to red meat. Is there some minor detriment for some people with heme iron or whatnot in the colon? Sure. Could that be easily minimized by eating that with fruit or something like that? Sure.

25:28

So it's like, how can I find… Because each food has some pros and some cons. How can I find all the pros of these different foods and create a diet that maximizes the pros and minimizes the cons through these different combination effects and whatnot? The thing is, that's just harder to do than it is to say all carbs are bad or all animal foods are bad. So you have to shift out of this dichotomy and you get into a little bit of this gray area where you start to say, okay, maybe this food has some pros and some cons, but

25:57

But are the pros drastically outweighing the cons? And then also the next piece is taking things into your own hands and using your own experience to sort of guide you in which direction you're going to go with. If I structure my diet X, Y, and Z way, I feel better, I function better, I stay lean, I sleep at night, my focus is good. If that's the case,

26:17

then I would say you're probably doing something right. And so there's, you want to listen to, you know, read some of the research, get some of the theories, see what's going on, but then take some of those things, test them out in real life and then see what the outcomes are for you and go from that perspective. Because for me, that was a huge shift. Instead of like all these gurus or researchers, whatnot, telling me how I was supposed to eat is like, what are the principles that I can distill down, test those principles out,

26:45

And then construct the diet from there. And so that was, you go through all the diets, you start to pull out because in paleo, carnivore, keto, bioenergetic, there's tons of valuable principles that come out of each of those paradigms. Are all of the components in there 100% correct? No, but there's a large portion that if you start pulling from each, like with paleo, carnivore, keto, nutrient density, bioavailability, high quality foods, like those are great tenants. Those shouldn't be thrown out.

27:12

just because you added carbs in the diet. So it's pulling from each area, creating a system of these principles and then seeing how it works in real life and starting to

27:19

incorporate a little bit of that nuance and context so that you can start to build a diet tailored for what specifically works to you and not rely on some external party that doesn't really know what works for you. And it's kind of parsing things out for the research and they are your filter. So it's, you want to listen to the perspectives, but also, you know, put it through your own filter and start to come to that, that perspective as well. And I think that's a huge shift when you break out of the, like running through dietary spheres per se. Absolutely. Yeah.

27:49

All respect to Dr. Robert Lustig. Would love to have him on the podcast, have extended the invitation previously. He's not been interested in doing it. Maybe he will after this podcast. And this is not meant to be any sort of personal affront, just a discussion of ideas. Yep.

28:05

So this clip, this clip is about fructose and addiction and how it stimulates the addictive centers in the brain, right? So we're going to listen to Dr. Lustig tell us about fructose and its addictive qualities. Yeah, this is fructose as addictive. Items in the American grocery store have added sugar on purpose for the food industry's purpose is not for yours because fructose is addictive.

28:33

activates the nucleus accumbens, the reward center of the brain in the same way that cocaine, heroin, nicotine, alcohol do and drive dopamine receptors down just like nicotine, you know, alcohol, you know, cocaine, heroin do. That molecule, fructose, is number one

28:54

completely vestigial to all vertebrate life. There is no biochemical reaction in any vertebrate that requires dietary fructose. So there's quite a few things to discuss here. First thing I would say is just because something activates this nucleus accumbens portion of the brain,

29:18

doesn't inherently mean that it's an evil or negative thing. Now, certain things that aren't that great, like morphine and cocaine,

29:29

will activate this area and stimulate a reward process. But that doesn't necessarily characterize why they're so negative in other areas. As an example, if you had a substance that had a benefit to you and it stimulated the reward process and there wasn't a negative, then it wouldn't necessarily be a problem. So this is where it's a kind of a false dichotomy to say just because this activates this addictive area of the brain means it's a negative thing. So I want to preface with that.

29:58

to start. And the reason why I want to do that is because both glucose and fats stimulate this area of the brain as well. And this is where the idea of context becomes important because like, why are these things, why are these fuel sources for the body stimulating signals of reward or desire to continue to eat these, they call it like hedonistic in the research, hedonistic desires for food or whatnot.

30:27

And the reason why is basically the system needs energy to function at its core, right? Without any without energy, no process in the body will function appropriately. You need ATP at its base. And the major ATP sources are going to be glucose, fructose or fatty acids. And ideally, fructose will be converted into glucose at the liver. So you're basically having a seeking or a drive towards finding these fuel sources.

30:54

So that's the first thing. And there's some quotes here. I don't know if you want to read them, but essentially what the quotes discuss is glucose stimulates nucleus accumbens, dopaminergic pathways as well, triggering the hedonic feeding and binging. Fats stimulate dopaminergic pathways in the nucleus accumbens and also triggers hyperfagia and binging. Now,

31:16

The other piece that I want to talk about here is the models with which they set this up are in rodents. And they use a model called the intermittent access model. And what they do is they cycle the rats between 12 hours of feeding deprivation or food deprivation and 12 hours of ad libitum eating. Now, this is a huge problem for an animal like a rat because the rats have…

31:44

There's a quote here talking about their physiology, but they need to eat on a pretty consistent basis. They

31:51

If they don't eat on a regular basis, they drastically increase gluconeogenesis, which is the endogenous or their own body's production of glucose. And they will burn through their food sources quite quickly. So one of the quotes they discuss is to meet the energy demands. Laboratory mice must eat and drink frequently with the average interval between food and drinking bouts being 34 and 42 minutes respectively.

32:15

a total of 36 food and 32 water bouts in 24 hours. So the rats need to eat relatively consistently, relatively frequently. And in this model, the way it's set up is in order to induce binging behavior by itself.

32:32

So because you don't allow the rats access to food for 12 hours, and then what they do is they make them miss their first meal when they get their food at this point. And then you also give them these food sources. They will inherently binge because they are hungry. So you're setting up a model to create a binging behavior. And then the other thing is you're using an animal model

32:55

that requires consistent feeding on a regular basis because of their metabolic rate and their unique metabolic circumstances. And then you're also seeing that these different food substrates, glucose and fats are also causing this elevation in dopaminergic singling in the nucleus accumbens. So it's to say that fructose, to imply that fructose is bad just because it induces dopaminergic singling in the nucleus accumbens

33:23

is a little bit tenuous with these other pictures presented next to it. I found a study also that I hope the audience will appreciate, which is that it shows that it actually, that steak can do the same thing. That steak activates the nucleus accumbens. So right and neural connectivity of the right and left nucleus accumbens after eating high and low quality steak. So I thought this was awesome. It's just an abstract

33:53

But they found that, no surprise, high quality steak activated the nucleus accumbens more than low quality steak. So I think it's interesting that Dr. Lustig says fructose is vestigial, which is a word that means it has kind of an evolutionary holdover. People say the appendix is vestigial, but we know the appendix probably is a repository for

34:17

cultures of bacteria. So the appendix may not actually be vestigial, but vestigial essentially means it's an evolutionary holdover that has no value anymore for an organism. So he's just saying fructose is in our diets now as an evolutionary sort of fossil. Our primate ancestors ate fructose from fruit, and now it has no role for humans. Well, I think that the idea that fructose activates an area of the brain linked with reward and

34:45

seeking of certain behaviors suggests that fructose is not really vestigial for humans. I mean, it's like you said, this is an energy source. It's in a food that our ancestors undoubtedly consumed. It's in a food that all hunter gatherer tribes ever studied

35:04

on the planet consume. It's in a series of foods, whether it's fruit or honey, preferentially consume. And so that to me is not super vestigial. And I just think it's interesting that he would say it activates the nucleus accumbens and say, oh, it's cocaine, it's dopamine. When…

35:20

Basically, most foods that you want do that. And I believe sex does that. So yeah, these are the behaviors that make us go round as humans. They activate this reward-seeking thing in humans. I was a little bit surprised.

35:35

Andrew didn't ask more questions there. So maybe we'll go to the next clip here, which is about fruit because Andrew Huberman comes back and says, well, I eat fruit. Is fruit okay? And Robert Lustig says fruit is okay because the fiber prevents the absorption of fructose. So he's sort of saying there's a way out here.

36:00

I eat berries galore, especially since the price of berries seems to have come down. It used to be the only get them a certain times a year. I'm what you call a drive-by blueberry eater. So I'll just walk past and just take a fistful. You can't put them in front of me without me eating them. This is even difficult for me when other people I don't know are eating them. So I eat lots of blueberries, strawberries, blackberries if they're in season. I love them. No problem. Loaded with fructose? No.

36:27

Plenty of fiber, low fructose? Low fructose. And berries? Berries are the lowest fructose of all the different fruits. I was so worried about asking you this today. Not a pity. Okay. And fruit is okay because of the fiber.

36:39

So the molecule, the fructose molecule is the same, whether it's in a berry or in a banana, or for that matter, in a Coca-Cola. The fructose molecule is the same molecule. The difference is that in the berry, it comes with a whole lot of fiber. In the banana, it comes with a whole lot less fiber. And in the Coca-Cola, it doesn't come with any fiber. And the fiber is what mitigates the absorption of

37:07

So when you consume the fructose with fiber, so your blueberries, you're feeding your microbiome. That fructose wasn't for you. All right, Mike, fiber makes it all okay. Oh boy. Well, I think the first thing that we should talk about is if Andrew Huberman is a drive-by blueberry eater, so say he's going to smash eight ounces of blueberries in one sitting and

37:34

And I'll give him about 20 grams of carbs and roughly 10 grams of fructose, which would actually be considered a high amount of fructose by Lustig's standards alone. I think the 12 gram amount is something that has been discussed previously.

37:49

But there's a couple of things to talk about. And let's get in specifically to the fiber piece. So fiber doesn't really inhibit absorption of fructose or glucose or many different dietary components. There's a study here that I have looking and comparing fresh orange consumption and a match carbohydrate intake between orange juice.

38:16

And what they essentially show here is the blood glucose levels after consuming the raw oranges versus consuming the orange juice is roughly the same. So the raw oranges, again, match for carbohydrates. The peak glucose value, blood glucose value was 98 milligrams per deciliter.

38:36

And then the fresh orange juice was 104 milligrams per deciliter. So you're not essentially, you're absorbing the carbohydrates from both of them. So it's not going to be a massive difference in terms of what's going on, especially when you start to look at the insulin difference. So the raw oranges actually stimulated a higher insulin value than the fresh orange juice, interestingly. And so

39:00

And so when you see the higher insulin value in the slightly lower carbohydrate intake, I assumed that at least with that perspective, that the absorption of the carbohydrate was actually on par. So that gets rid of the idea that the fiber itself

39:15

is having an effect on the absorption of the carbohydrate because you're seeing the same rise in blood glucose between both groups. It'd be relatively equivalent. So that's the first piece. And that's just to specifically talk about, well, if you had fruit juice versus fruit, is the fiber making a difference? No, at least not in terms of absorption. Now, the next thing that you can talk about

39:37

Soluble dietary fibers do indeed delay nutrient absorption. However, the intestine adjusts for the delayed nutrient absorption and will actually slow, well, the inhibited nutrient absorption and it will slow down the transit through the small intestinal tract or through the small intestine in a process called an ileal break.

40:00

And that will increase the absorption of the components inside the intestine. So the intestine, you will absorb the carbohydrates because the intestine is compensating for altered absorption from the soluble dietary fiber. And the soluble dietary fiber is…

40:15

delaying the absorption by adjusting the viscosity, like how thick the food is when it's moving through the intestine. So it makes it a little bit harder to access, but the intestine's like, all right, we know this fiber is making a little bit harder to access. We're going to spend a little bit more time processing the food so that we can get all of the nutrient. So basically in the research, you're not seeing significant delays in absorption of carbohydrates or

40:42

from fiber. And then when you look and compare fruit juice versus whole fruits, you're also not seeing a massive change in what's going on with the blood glucose level, especially like this was whole oranges versus orange juice. And we'll talk more about insulin later in the podcast because there's a section where Dr. Lustig talks about insulin.

41:02

So we'll get to that. He says insulin is the bad guy and a bit of foreshadowing. But as Mike points out, whether it's orange juice or a whole orange matched for predicted calories, insulin response, essentially the same, perhaps even more of an insulin response when you add the fiber. So I don't quite understand his position here either. I think that the body is very keen to

41:26

to get nutrients. And lo and behold, our bodies see, quote, sugars as nutrients. These are what fuel our life. These are the difference between life and death for humans for hundreds of thousands of years. Getting sugar in the form of glucose, fructose, sucrose, whatever, that's what your body is keen to do. It wants those calories to

41:52

to fuel all of the processes in the body, to fuel the production of ATP in the mitochondria eventually, et cetera, et cetera. So it's not interested in wasting those things. It's not interested in dumping calories or not absorbing nutrients of which the carbohydrates are probably some of the most prized. It's going to slow down the digestion to get them out of it. So I think that this position must be taken here because the amount of research showing that fruit

42:21

is not harmful to humans is robust. And so if fructose is harmful for humans and causes fatty liver, obesity, addictions, then fruit must be okay because there's a lot of research there. I don't understand, as we said, how the research showing that fruit juice also has benefits for humans can be ignored, but it's almost like

42:49

There are these collective hypnosis in the health space. And I think that fructose equals bad is one of them. And, um, and, and fiber equals good is another. So if you combine two of these together and say fiber equals good plus fructose equals bad, then you end up with fruit is okay because fruit has fiber. And that's the only way I can manage this in my mind. Um,

43:15

One last thing. So I think it seems like a rationalization to some extent as kind of what you're pointing out where it's like, well, fructose is bad, but fruit's good. So maybe there's some other middle component, but it's just a weak argument when you, especially when you go through the research.

43:30

But the benefit of the fiber on some of the blood glucose regulation, and we'll talk about this when we start talking about insulin, is that when you get a lot of food reaching the lower portion of the small intestine, the ileum, you get the secretion of a hormone called GLP-1. And what this does is it will lower glucagon.

43:51

And the lowering of glucagon is actually extremely beneficial when we start to talk about blood glucose regulation and things along these lines. Now, this isn't a call and all the GLP-1 agonists are all the rage right now. It's not a call supporting those things, but it's just showing that fiber has another mechanism that adjusts the blood sugar regulation, which is maybe why you're seeing the benefits of fiber and fruit.

44:14

And it's not because it's inhibiting absorption or anything along those lines. And it's through lowering glucagon, which actually supports the perspective that we're going to talk about a little bit later on. Okay, great. The next clip, we're not even 30 minutes into the podcast, but we're going to start skipping ahead. We won't get through the whole podcast today, that's for sure, is where Dr. Lustig is talking about fructose inhibiting

44:39

some key enzymes for mitochondrial function. We're going to talk about AMPK and CPT-1. But I did a little research and I thought this was interesting just as a context. And I looked at like the levels of fructose in the human blood and the levels of glucose in the human blood. And it was like

45:00

significantly, there's never any significant amount of fructose in the human blood. It was, what did I find? It was like a thousand fold difference or more between levels of fructose. Fructose was 8.1 plus or minus one micromole per liter. And glucose is the equivalent of 3.9 to 5.6 millimole per liter. The fructose equivalent, which would be 3,900 micromole per liter. So it was like

45:28

there's huge differences in the amounts of fructose versus glucose in the human blood, which is relevant to discussions that we'll get to. Now let's talk about what fructose does. A metabolite of fructose called methyl bioxyl MGO sits in the active site of the gamma subunit of that AMP kinase and actually binds to arginines in that active site, rendering that

45:55

enzyme now dead. It's an irreversible inhibition because of the covalent bonding of that methylglyoxal, that aldehyde to the arginine. And now that enzyme is dead. Okay. So it basically acts like a key that doesn't turn the lock, but prevents the key that you want in that lock from entering the lock. It's like gluing a lock shut.

46:20

Got it. All right. So that's one of the enzymes. That's one. Okay. Second one, ACAD-L, acyl-CoA dehydrogenase long chain. So this is necessary to cleave two carbon fragments of fatty acids to prepare them for metabolism. So it inhibits that one. And then finally, it inhibits carnitine palmitoyltransferase-1.

46:44

Now, CPT1. Now, that's the enzyme that generates carnitine. Carnitine is the shuttle mechanism by which you get the fatty acids from the outer mitochondrial membrane through to the inner mitochondrial membrane so that they can be beta oxidized for energy. So if you don't have that CPT1,

47:05

you're basically carnitine-less and therefore you can't generate beta oxidation. All right, Mike, fructose, mitochondrial poison. Yeah. So let's talk about this. So the setup here from Lustig is that fructose creates something called an advanced glycation end product or a glycating agent called methylglyoxal. Now,

47:34

Fructose can create methylglyoxal and methylglyoxal can then interact with different proteins and affect their functions. That's true. But the context in which this occurs is extremely important.

47:47

And I have a quote here that describes something that you were saying previously. So what the quote says is fructose has not been a major focus of glycation research because of the difficulty in measuring its adducts. And more importantly, because although it's 10 times more reactive than glucose, its plasma or its blood concentration is only 1% of that of glucose. So even though it's 10 times more reactive than glucose, it's 100 times less reactive

48:13

concentrated in the blood than glucose. So the other thing is the formation of this adduct or this addition of methylglyoxal to the AMPK binding site, to the arginine groups, has to happen inside the cell. And so the question is, why are we having this high fructose inside the cell?

48:36

And when you start to look into the research, what you start to uncover is that this is found specifically or theorized to be found specifically because this pathway is theoretical inside patients with diabetes.

48:49

And so this is actually what you are seeing is not a product of fructose consumption per se. You're seeing this as a product of altered metabolism inside the diabetic cell leading to production of fructose inside the cell through something called the polyol pathway. And then that's leading to the dysfunction. So the situation here is you have dysfunction, dysfunctional metabolism. And when we talk about insulin, we'll get to that.

49:16

But you have dysfunctional metabolism and the dysfunctional metabolism is driving this process, not necessarily the consumption of fructose from your oranges or your drive-by blueberries or bananas or watermelon juice or the different fruits and juices that you're having on a regular basis.

49:35

So I actually have a quote here and what they say, fructose is elevated in several tissues of diabetic patients where the polyol pathway is active, reaching the same order of magnitude as glucose. It is plausible that the high reactivity of fructose directly or via its metabolites may contribute to the formation of intracellular ages and devascular complications. The evidence, however, is still unconvincing.

49:59

The polyol pathway is inactivated with normal glycemia. So this is in normal people. Conversely, in hyperglycemia conditions, glucose concentration in insulin-independent tissues, such as neural tissue, glomerulus, which is the kidney, the lens of the eye, and the red blood cells, the erythrocytes, increases.

50:19

Accordingly, the polyol pathway is activated. So basically what happens is in these cells that are having metabolic dysfunction in states of hyperglycemia,

50:30

you get this overflow of glucose into the cell and it upregulates glycolysis and subsequently the polyol pathway. And some of that glucose from the hyperglycemia gets converted to fructose. And then you're seeing the possibility of age formation or advanced glycation end product formation. So the question is, is ingesting fructose causing this specific problem?

50:56

I don't think we have a clear answer that that is the case. More so what we're seeing is in states of metabolic dysfunction, you can have this problem develop as a consequence of that metabolic dysfunction specifically. And do you think this would happen with postprandial, quote, hyperglycemia? Or are we talking about the context of hyperglycemia with inappropriate gluconeogenesis in the setting of metabolic dysfunction? Because this is another thing that gets often repeated in these type of discussions is,

51:27

If you spike your blood sugar after a meal, that's going to cause all sorts of dysfunction. And my concern is that in those statements, there is a conflation of the hyperglycemia that occurs in a metabolically dysfunctional individual and the quote hyperglycemia, which is actually just a normal physiology post-prandial after eating rise in your blood glucose.

51:50

So the first thing I'd say is in normal insulin sensitive people, healthy people, you don't actually get hyperglycemia after a meal, postprandially. What you see is a raise in blood glucose that is normal and that's fine. In people who have impaired glucose tolerance, who are dealing with obesity, who are dealing with diabetes or metabolic syndrome, any of those components, fatty liver disease, they

52:17

They get postprandial hyperglycemia. However, the postprandial hyperglycemia that you are seeing in those states is a function of a lack of shutdown of hyperglucoginemia. So the hormone glucagon increases the production of blood glucose through a process called gluconeogenesis.

52:38

And what happens is in these metabolically impaired states, that doesn't get shut down. So the problem is you still have the liver producing glucose. And then when you take in carbohydrate, you're additive on top of that. And because you have metabolic dysfunction at the peripheral tissues as well,

52:56

so you're not uptaking the glucose as well. You have this jam where you're producing a bunch of carbohydrate and your tissues can't uptake that carbohydrate. And now you're seeing hyperglycemia. So it's not when you eat a meal,

53:10

Does that cause these hyperglycemic problems? No. And normal healthy people, it should not cause a problem at all. I have a graph on my notes here basically showing after a meal of like 100 grams of carbohydrates, the blood glucose in the participants who are healthy went up to 108 or 104.

53:28

which is, that's nothing, especially when most of the ranges for normal, like fasting blood glucose stop at 100. So in normal people, the body can handle the carbohydrate. It's when you have the metabolic dysfunction that you see the hyperglycemia. And then this is where things get foggy in the research.

53:46

Because the question is, is the hyperglycemia driving the problem itself? Or is the metabolic dysfunction that's predisposing the hyperglycemia the primary culprit for the problems alone? And is the hyperglycemia, yeah, maybe it's a problem when blood sugar is too elevated, but that's not the initiating causal factor. It's actually this metabolic dysfunction. So I think the question comes down to the metabolic dysfunction every time.

54:11

And I think this point is difficult to overemphasize because there are a lot of well-intentioned, intelligent people in the health space now telling you that blood sugar spikes are harmful. And what is a blood sugar spike? It's anything that raises your blood sugar above, I don't know, 105, 110 milligrams per deciliter, whatever, arbitrary levels.

54:36

dotted line ceiling you put on your continuous glucose monitor, which inevitably accompanies this type of thinking and says, don't spike your blood sugar. When in fact, having a blood sugar that goes up to 120, even 130, 140, this is normal human physiology and is not problematic for humans. And really there's no evidence that that will cause this polyol pathway to become activated or fructose to be actually created within a cell and increase methylglyoxal.

55:05

One thing I want to highlight here is something that I've spoken about multiple times in the past, but I'll screen share the study just so people have it. There is also evidence that this advanced glycation end product that Robert Lustig talks about, methylglyoxal, is increased…

55:21

on ketogenic diets. Um, I've spoken about this in detail on previous podcasts. I don't want to go into it here, but, um, they, they, the levels rose 1.67 fold, um, with a P value of 0.03. Um, and, uh, even more significantly, um, with, uh, levels of ketosis. So the first one was on a carbohydrate reduced. So 2.12 fold in people who had ketotic

55:47

levels of carbohydrate restriction. So it's very interesting. And I think it brings a lot of context around this discussion saying, don't ever spike your blood sugar because you don't want increased advanced glycation end products is the narrative that I hear. And it gets kind of thrown back at me from intelligent, well-intentioned people in the ketogenic community when number one,

56:10

fructose does not do much glycation because its levels are so much lower than glucose. And number two, it's important to know that if you never spike your blood sugar and you go into ketosis, you will end up making even more of these advanced glycation end products. So that's not the way you want to go either. Yes, 100%. Let's move on to insulin. So I'll find the section here, but essentially,

56:36

Dr. Lustig says insulin is the bad guy. And I didn't really understand this, but we can listen to what he says. He then goes on to say insulin is egregious and I can prove it and talks about something called a Poderko mouse. But he claims that insulin is a bad guy and that blood glucose, rising blood glucose leads to endothelial dysfunction. We kind of foreshadowed this earlier.

57:04

I thought it was interesting then in response that I could just mention that, well, I don't understand how fruit juice can improve endothelial function at the same time, because there's lots of studies, perhaps 10 to 15 that we could just rattle off right now, showing that orange juice, watermelon juice, cherry juice, many, many fruit juices are shown to improve endothelial function. So I'm not sure how insulin is the bad guy, but let's find the, let's find the clip here.

57:31

That glucose rise led to endothelial dysfunction. Transient, but nonetheless, endothelial dysfunction. Could you just remind people what endothelial cells are? Inside of your arteries. Okay. And it will change blood pressure. We've got plenty of data to demonstrate how it changes blood pressure. And over time, that will cause coronary artery disease. That will cause kidney disease, et cetera. But it's the insulin response that is really the bad guy.

58:00

Now, people think insulin is good because it lowers blood glucose. After all, diabetics take insulin to lower their blood glucose. Okay, let's take a diabetic, a patient with diabetes. Blood sugar is 300. That's bad. We give them a shot of insulin in the arm. Blood sugar goes down to 100. Blood sugar went from 300 to 100. Where did the 200 points of blood glucose go?

58:31

I'm assuming that the insulin sequestered it. To where? I'm assuming to the liver. To the fat. Interesting. For storage. That's insulin's job. Insulin takes whatever you're not burning and puts it into fat for storage. Insulin is not the diabetes hormone. Insulin is the energy storage hormone. How quickly does it do that? Pretty quick. Because if I'm having a very busy day, I'm

58:58

So we can pause there and then we'll come back to the Poderico mice. But insulin is the fat storage hormone, Mike. Insulin is the bad guy, he says. Oh, man. That one is a little difficult to watch because…

59:16

it there's, you're describing two different circumstances. If you take a diabetic and you give them insulin and that when they have high blood sugar, will it push the insulin into fat storage? Yes. But why will it push, push or what the glucose and the fat storage, but why will it push it in the fat storage? Because in an individual who is diabetic and who has blood glucose levels at, you know, to that degree, uh,

59:43

Number one, their liver and their muscles and also their fat tissue are already likely insulin resistant. That's why they are diabetic. So they already have metabolic dysfunction at those cells. And then the other thing and something to note here is that insulin doesn't just lower blood glucose levels, particularly in diabetics.

01:00:04

by increasing GLUT4 receptors on cells and then creating an uptake in glucose. What actually happens is insulin, and this is a good thing for insulin, insulin lowers gluconeogenesis at the liver. It lowers glucagon. So it stops the production of glucose from the liver. And it also lowers the release of free fatty acids. And so

01:00:26

The problem with free fatty acids is if you are burning a large amount of free fatty acids in the peripheral tissues, in the liver, in the muscles, in the fat tissue, et cetera, you will have insulin resistance via the Randall effect. So the burning of fatty acids will directly impair the utilization of carbohydrates. And so that will, the other thing is,

01:00:48

It's not that glucose can't get into the cell in these tissues. Glucose can get into the cells in diabetics.

01:00:56

It just can't be used. It's not being used. And so I have some studies that we can talk about here that basically show that in people with diabetes, when you give them insulin or you create hyperglycemia, you'll increase the uptake of glucose. But what you won't do is you won't increase the utilization of glucose through the Krebs cycle and the electron transport chain and the conversion ATP through that mechanism. So there's a paper here. And what they describe is…

01:01:25

They say insulin resistance of skeletal muscle in glucose-tolerant obese individuals is associated with reduced activity of oxidative enzymes and a disproportionate increase in the activity of glycolytic enzymes. So what they say is activity for glycolytic enzymes, so these are the enzymes in glycolysis that don't go to cell respiration in terms of the Krebs cycle and the electron transfer chain, was highest in non-insulin-dependent diabetics

01:01:54

And then after that, it was the obese people and then the lean people. So highest in the diabetics, medium activity in obesity and lowest in the lean people. And then what they say is the maximum velocity for the oxidative enzymes, which are the enzymes in the mitochondria like cytochrome C oxidase, were lowest in subjects with type 2 diabetes. And then so what they're basically showing here, they say in summary, an imbalance between glycolytic and oxidative enzyme capacities

01:02:21

is present in non-insulin dependent diabetic subjects, and it's even more severe than in obese or lean glucose tolerant subjects. The altered ratio between glycolytic and oxidative enzyme activities found in skeletal muscles of individuals with diabetes suggests that a dysregulation between mitochondrial oxidative capacity and a capacity for glycolysis is an important component

01:02:44

of the expression of insulin resistance. So what they're showing in this paper here, and they do a study, they do a clamp study as well, where they give diabetics and different people hyperglycemia, hyperinsulinemia and see what happens. But in this study, what they're specifically talking about is that the mitochondrial function inside people with obesity and diabetes is actually impaired in terms of their ability to use glucose.

01:03:10

And what winds up happening is their ability to run glycolysis is still is actually compensating for that problem.

01:03:17

And there's a couple other things I want to get to, but I don't want to monologue here too long. So there's a lot of that. That is the problem is more so this metabolic dysfunction happening at the cell, specifically in the mitochondria of people with impaired glucose tolerance, obesity and diabetes. And it's not so much a problem of just like insulin or not insulin or whatnot. And the insulin in and of itself is having an effect not just by increasing glucose uptake,

01:03:43

or shuttling things into fat, but it's also lowering glucose output by the liver and also lowering free fatty acids, which are high in these different states because of the metabolic dysfunction. It's just a mischaracterization in my mind. And I love that you pointed out that the reason insulin is shunting the blood glucose into the fat is because the other tissues are insulin resistant. This doesn't happen. So I think that the

01:04:09

The misleading part of this statement is the idea that, okay, Mike, I eat a glass of orange juice. I drink a glass of orange juice. My blood sugar goes to 120. Maybe it's a big glass of orange juice. My blood sugar goes to 120.

01:04:24

insulin comes along and where does that blood glucose go? It goes down to 85 or 70 and that went into fat. No, it went into my liver, it went into my muscles. Like the fate of that to adipose tissue when you're normally consuming it is completely different. And this does not implicate insulin as a harmful thing. I think it's also important to point out that insulin signaling, I think that insulin has gotten such a bad rap

01:04:53

it's kind of like LDL. It's an essential hormone for human health. It's tied with glutathione. So insulin upregulates two enzymes that are essential for optimal levels of glutathione. Glutathione is this master antioxidant in the human body. So when we give diabetics insulin, their glutathione levels also go up. So their ability to handle, quote, high-level oxidative stress, which is

01:05:16

this is a much deeper conversation, goes up. They're able to handle oxidative stress. They do redox balance better when you give them insulin. Insulin also connects with GnRH, which is growth, like a tonic thing, growth hormone releasing hormone. So it affects your sex hormones, not surprisingly. And insulin lowers levels of endogenous cannabinoids, AEA and 2-AG in the cell. And we know that when people have high levels

01:05:44

of 2-AG and AEA, these endogenous cannabinoids lead to overeating. And this is part of the problem in humans, potentially in terms of impaired satiety. So to suggest that insulin is the bad guy, it's like this massive mischaracterization of a critical hormone with kind of a misused anecdote of insulin putting things in fat. But I just wanted to get that in there and I'll let you keep going on where you want to take this.

01:06:10

Yeah. So there's, there's a couple other things. I don't, I don't want to read some of these because they get a little bit long, but basically what you show, another thing to that insulin does to a couple other beneficial things is that insulin actually lowers glucagon levels and glucagon levels are highly associated with type two diabetes.

01:06:30

So what they talk about here is patients with type 2 diabetes suffer from fasting and postprandial hyperglucoginemia, which stimulates hepatic glucose production and thus contributes to hyperglycemia characterizing these patients. It has become apparent that suppression of glucagon secretion or antagonization of the glucagon receptor constitutes potentially effective treatment strategies for patients with type 2 diabetes.

01:06:56

So lowering glucagon is key in managing diabetic complications because the diet, the glucagon is what's creating that elevated fasting blood glucose and the higher postprandial blood glucose levels. And then what they talk about here, the other thing is that insulin lowers free fatty acids. And so the burning of fatty acids I mentioned before is what's contributing or partially contributing to the inability to effectively use glucose in the peripheral tissues.

01:07:25

So what the researchers say here is they say, even under conditions of extreme ketoacidosis, there is no significant membrane barrier to glucose uptake. The block occurs lower down in the metabolic pathway where the excess of ketones competitively blocks the metabolites of glucose entering the Krebs cycle. Under these conditions, glucose is freely transported into the cell, but the pathway of metabolism is effectively blocked at the entry point to the Krebs cycle. So that's the mitochondrial respiration.

01:07:53

by the excess of metabolites arising from fat and protein breakdown. As a result of this competitive block at the entry point to the Krebs cycle, intracellular glucose metabolites increased damming back through the glycolytic pathway. And that also is where you see that damming into the polyol pathway with the production of intracellular glucose and then possibly age for the advanced glycation end products.

01:08:15

leading to accumulation of free intracellular glucose and inhibiting initial glucose phosphorylation. As a result, much of the free intracellular glucose transported into the cell is transported back out of the cell and into extracellular fluid. Thus, under conditions of ketoacidosis, glucose metabolism, but not glucose uptake, is impaired as a direct consequence of the metabolism of fat or the glucose fatty acid cycle. And then they cite Randall. So what you're seeing there is the

01:08:40

the fatty acids and the impaired glucose utilization in the mitochondria is leading to the backlog. And that's actually the problem. That's why you're not having the hyperglycemia for these other reasons. It's the hyperglycemia and the problems with the metabolism. And then insulin can't have its effect. That's where you're seeing insulin resistance. That's why the cells are not responding to insulin.

01:09:02

And then what they also talk about and what you can get to is that, let's see if I can find this study here. But basically what they mentioned in this specific study is insulin actually will lower the free fatty acids. It'll lower the glucagon. And I don't have it here. And then the reason for the elevated insulin concentrations inside diabetics

01:09:29

So this is another thing. They think, oh, high insulin levels are bad. They have all these negative effects. And this goes with the high blood glucose and everything because he talks about hyperglycemia and hyperglycemia. The reason that you're getting hyperinsulinemia is because when insulin docks on the receptor of the cell, the cell internalizes insulin and degrades it.

01:09:51

But when the cells are resistant to insulin, what winds up happening is you just get a lot of insulin floating around. So when they did, they did a study on normal people and they made them hyperglycemic to quite high levels for 72 hours. And then they wanted to see what happened with their insulin secretion.

01:10:07

and like their insulin levels and blood glucose regulation. What they basically say is the increased plasma insulin response following 72 hours of hyperglycemia resulted from a small insignificant increase in insulin secretion and a large significant reduction in metabolic clearance rate of insulin. Since insulin degradation involves binding of insulin to its receptor, followed by internalization and subsequent degradation, it is possible that the hyperinsulinemia-induced insulin resistance

01:10:36

interferes with the internalization degradation process or inhibits the insulin degrading enzyme. So the high blood glucose in the diabetic state is a function of impaired metabolism and upregulated gluconeogenesis.

01:10:49

and an upregulated fatty acid oxidation. And the high insulin levels are because the insulin can't interact with the cell to have its effect to be internalized and degraded. So it just floats around a lot much longer. So again, this is very different from eating carbohydrate, pushing it into the cells with insulin, and then having everything come back down to baseline.

01:11:10

These are two different contexts. So to describe insulin in this type of way with the diabetic context and whatnot, it's not a fair characterization of what happens under normal circumstances. And it doesn't necessarily mean that the normal circumstances with glucose and insulin is what's causing this dysfunction. You're looking at what's happening in this function and trying to work your way back, and it doesn't necessarily work that way, especially if you don't see the full picture of what's going on at the cell.

01:11:36

Yeah, that's a little technical, but I think most people can understand that. You've got the Krebs cycle, you've got glycolysis, which is sort of a shunted pathway where the glucose doesn't go into the Krebs cycle because it's being inhibited by intermediates that are involved in fat metabolism, which kind of compete for those things. And we're looking at a disordered metabolism when we have diabetes and normal metabolism when we don't have diabetes. And so I think that the question that I always get, Mike, and I'd love for you to weigh in on this is,

01:12:05

I have people who follow me who are obese, right? I have people who are not metabolically healthy. So is it okay for someone who's obese, maybe pre-diabetic, maybe even diabetic to consume fruit or glucose? I mean, specifically here, he's not differentiating fructose, glucose, whatever. He's just saying blood sugar rise, insulin is pushing it into fat. So what about someone with diabetes who does have maybe some baseline insulin resistance?

01:12:34

that person, can that person consume, you know, anything that raises their blood sugar?

01:12:40

So yes. And I have clients who I've worked with who came to me who were obese, like from actual technical considerations to like can be defined as obese and who did have impaired glucose tolerance. And they were able to have a higher carbohydrate intake than they had previously. And they were able to lose weight and improve their blood glucose levels and whatnot. And essentially there's, there's research studies showing that putting normal individuals and putting, um,

01:13:08

diabetic individuals on a higher carbohydrate diet actually improves peripheral insulin sensitivity because it lowers fatty acid oxidation. So driving fatty acid oxidation, if you are in a lower carbohydrate diet, keto, carnivore, low carb, paleo, what have you, will make you more insulin resistant in the long run because you continue to burn fats inside the cell

01:13:30

And then when you're burning fats inside the cell, you cannot oxidize carbohydrate effectively. So while your blood glucose levels will tend to be lower for a period of time because you don't have carbohydrate coming in, what happens over time is you become more insulin resistant at the cellular level.

01:13:47

And then you start to increase gluconeogenesis and glucagon levels. And then that's where you start to see people in keto and carnivore and low-carb paleo start to say, hey, I'm not eating any carbohydrates, but my fasting blood glucose levels are starting to peak up. And it's because you're becoming more insulin resistant. You're driving further gluconeogenesis from glucagon to maintain your blood sugar levels. Because

01:14:06

And Lustig says this in his podcast, glucose is so required, so essential to the body that your body will make it in times that you don't have it. He specifically describes this and says this, I think in the beginning,

01:14:20

And so that is 100% true. That is what happens. And that's why people on low carbohydrate diets tend to see those problems. So yes, you can have carbohydrate. The one thing I will say is if you are in any of these states, you want to make sure that your total energy intake is appropriate for what you're doing. You do not, because, and the reason I say this, I have a lot of people that I've worked with that come from a low carb background and they just add carbohydrate intake on

01:14:44

on top of their fat intake and they don't adjust their fat intake downward. And that is a recipe to gain weight and, and worsen lipid panels and things like this, because now you're in a surplus and now you have two substrates going in that are competing to a large extent. And that can cause problems directly with,

01:15:02

at the liver and in the lipid profile, et cetera. So you need to make sure your total energy intake is adjusted appropriately. And then you're going to want, then you can shift to a higher carbohydrate intake as you lower the fatty acid intake down. I have many clients that I've worked with with this and I have clients that I work with to this day

01:15:17

that haven't seen improved insulin sensitivity, blood glucose handling, metabolic parameters on a higher carbohydrate diet. Again, this doesn't necessarily mean you have to have zero fat, but it doesn't mean that, it does mean that you can have carbohydrates and see these outcomes.

01:15:32

Thank you. That's one of the most common comments, questions that I get. And I've tried to address it, but it's always good to repeat it. And I've spoken about the rice diet. You know, Walter Kempner, who's kind of a colorful, interesting character, who put people who literally look like the blueberry girl from Willy Wonka's Chocolate Factory, they were so obese on a diet of mostly white rice and processed white sugar diet.

01:15:56

and saw them improve insulin sensitivity even after they liberalized their diet and lose massive amounts of weight. Because I think that connected with all of this, so we're really kind of in the meat of this now, is this idea that

01:16:10

insulin, spiking insulin leads to insulin resistance. I'd love to get your take on this too. This idea of insulin induced insulin resistance. It's kind of like, oh, of course it makes so much sense. You eat orange juice that spikes your blood sugar. Mike, if you eat enough orange juice and you spike your blood sugar enough, your body's going to have to pump out so much insulin that you're going to become insulin resistant. This is all part of this, this, this perspective. This is the whole paradigm of

01:16:36

Insulin resistance is predominantly driven by hyperinsulinemia, which is driven by too many carbohydrates. And it makes me a little bit conflicted to even say that, but I'm curious about your perspective there. Yeah, so I think the primary thing to understand is at the cell that oxidizing carbs versus oxidizing fats will determine what's going on with insulin sensitivity to start.

01:17:06

And so this is important to understand because with insulin sensitivity, basically what happens is you can have more carbohydrate and require less insulin to actually have the carbohydrate be utilized to push into those tissues, dispose of, et cetera. So when you eat more carbohydrate, perhaps initially you will start to increase the amount of insulin that you need to manage that carbohydrate.

01:17:27

But as your cells start to oxidize primarily carbohydrate, what happens is they start to become more insulin sensitive because they're not being blocked by the fatty acids. And so then you need less insulin for higher carbohydrate intakes to actually drive things in an appropriate direction. So it's not that you just eat carbohydrate and then you have insulin or the insulin comes and then it pushes things in and your cells get tired of responding to the insulin over time through

01:17:56

through receptor downregulation. It's not the same thing that happens inside the nervous system with downregulation of different receptors in response to drugs or things like this. It's not the same process. It's an entirely different process where the lack of response to insulin is a function of what's going on metabolically in the cell. And so this is where, this is why you need to understand that burning carbohydrates increases your ability to burn carbohydrates.

01:18:21

And then if you are, excuse me, if you are oxidizing carbohydrates, then you don't, your cells will uptake the carbohydrates much more easily in response to insulin if you're oxidizing fatty acids.

01:18:31

So inside disease states, fatty liver disease, when you see issues with heart disease, heart failure, et cetera, those states are characterized by increased amount of lipids and lipid oxidation at the expense of glucose oxidation and the inability to effectively switch back over. And then that lipid oxidation, that burning of fats in the cells actually creating a bunch of reactive oxygen species and damage to the cell.

01:18:54

and downstream consequences in the long term. So you want to, in general, you want to prioritize carboxidation and prioritizing carboxidation over time makes you more insulin sensitive peripherally, and then you will need less insulin in the long term to actually use that same amount of carbohydrate. So that is actually what happens instead of the cells kind of getting fatigued and responding to insulin.

01:19:15

That's not what you're seeing in the research. You're seeing the fatty acid oxidation and mitochondrial dysfunction is driving the poor response to insulin. So in some ways, somebody diabetic, limiting carbohydrates and pushing their body toward exclusive or predominantly fat oxidation is kind of the opposite of what you'd want to do. So I have a couple of clients that I've worked with who…

01:19:45

type two diabetic and they went low carb and initially their blood glucose values and hemoglobin A1C and whatnot started to improve. And then over time, despite eating less and less carbs, their values actually got significantly worse and they started to get higher fasting blood glucose levels and then

01:20:03

And then the hemoglobin A1C started to reverse trend and go in the opposite direction. And then when they had carbohydrates, their tolerance to them was even worse. It was kind of abysmal. And what happened was is they drove the fatty acid oxidation. They kept increasing gluconeogenesis because you need blood glucose. So your liver, if you don't have the blood glucose,

01:20:23

is going to make it. And so they kept driving that pathway. And then what eventually happened is you have this gluconeogenesis and worse peripheral insulin sensitivity. The cells are not responding to insulin and the carbohydrates just going higher and higher and higher. And then you're seeing this higher levels of carbohydrate long-term in the bloodstream. And then that's what drives the process. And when they start to add in carbs, things start to reverse in the opposite direction as the carbs stimulate an insulin response, lower the

01:20:50

gluconeogenesis, lower the fatty acid oxidation, and you start to see an increased oxidation of carbs peripherally and an insulin sensitivity improves. But that transition period has to be adjusted delicately because you're in this weird metabolic limbo zone where your body is still, you have problems oxidizing carbohydrates as a fuel source, and you're trying to increase your ability to do so while you slowly lower the fat intake. So it does take

01:21:16

a little bit of careful adjustment to make that transition. But once you do that, I've seen them insulin usage drastically decreased. I have one guy I'm working with who was keto. He was doing, you know, he was on ridiculous levels of insulin, you know, hundreds of units of insulin a day. And we changed up his diet, lowered his fat intake. He's doing 150, 200 grams of fat a day. He

01:21:38

We brought him up to about 240, 250 grams of carbs, brought his fat down to maybe 70, 60 grams of fat. And then we cut his insulin usage down in half.

01:21:49

just from making the dietary changes. So those things alone can make a huge difference. And then, you know, it seems initially like it's a little bit paradoxical, but when you start diving into the mechanisms and you start understanding, okay, what's going on in the metabolism in the cell and then why is like, how does that affect what's going on with insulin? Then you start to see the picture much more clearly. And then you can get like a full view on what's going on. And then you start to change the treatment protocols and whatnot from there.

01:22:15

I think it's very important for the listeners to understand that blood glucose is a symptom in diabetes. It's not a problem. It's a symptom. And so you have to really address the underlying insulin resistance. And we've talked about a few mechanisms of insulin resistance, but we haven't really… I want to get your take on that more specifically. But I think that one of the mental hurdles people run into is

01:22:42

Why would I do something that could increase my blood sugar when I have diabetes? And that's the problem because that's the way Western medicine thinks about it. We need to get your blood sugar down. Giving insulin and diabetes makes very little sense. It corrects nothing of the problem. It's just the absolute band-aid. The blood sugar is a symptom. And so in diabetes, mainstream Western medicine is just treating the symptom. It's not addressing the root cause in any way, shape, or form. But diabetes,

01:23:07

So improving overall dietary quality and shifting the macronutrient ratios, that can begin to improve the actual issues at a biochemical level, which is complex. I think that I just want to give people a little tool here. So as I've increased my carbohydrates, I did kind of like what you were talking about. I felt the need to have less fat. But I do think that, as you suggested, people need some fat.

01:23:34

So maybe we just give people a little bit of an idea. Like if you're going to increase your carbohydrates, where do you think the macros should be? I think that macros are incredibly powerful. I talk a lot about micronutrients and the value of certain vitamins and minerals and unique foods. But thinking about the amount of protein, the amount of carbohydrates, the amount of fat in your diet, that's very powerful. And I think for most people, protein is kind of a no-brainer, 0.8 grams per pound, whatever, just get it from high quality sources. But how do you think people can navigate the carbs,

01:24:02

And the fat, because that's been the most interesting lever for me thinking, okay, what do I need with my activity level? Where does, where should my fat be? And where should my carbohydrates be? Because as you said, if you just push both up, that doesn't work for a lot of people in terms of metabolism. Yeah. So I, as you said,

01:24:20

I start with protein when I'm looking at macros and then I do the 0.82 grams per pound and I keep that stable. And that's because protein is more of a structural component and less so something that you want to use as an energy source. So your fats and your carbs are what's left for your caloric intake. And those wind up being more your energy sources. Now,

01:24:41

In terms of carbohydrates, the target I usually shoot for and people who aren't struggling with blood glucose issues or coming from really low carbohydrate backgrounds is about two times the amount of protein. So say your protein intake's 100 grams, then I would say carbs to start would probably be 200 grams per day. Now, if somebody is…

01:25:02

like has to work their way up and they're having a really hard, hard time. And they had the blood glucose dysregulation or diabetes or obesity or something like that. Then what I do is I try to get them to 150 grams of carbs per day to start. And the reason why is because the central nervous system has a requirement for about 120 to 150 grams of carbohydrate in the form of glucose to

01:25:23

per day just by itself. So that's just for the central nervous system. That's not for activity level and the other tissues utilizing carbohydrate. So what we're trying to do is provide enough carbohydrates. You don't have to keep pushing gluconeogenesis on a regular basis to make the carbohydrate from protein and glycerol and other storage components from your body. So we want to get that from the diet instead. So that's why that's the bare minimum I usually try to shoot for. And then I go to two times protein and then I'll adjust upward from there.

01:25:52

In terms of fats, the level that I generally shoot for with clients is between 20 to 30% of caloric intake. And if somebody is more…

01:26:04

insulin resistant, the goal would be to get a lower fat intake closer to that 20%. Now going too low in fat can make people feel quite bad. So less than 20%, you can start to see a rapid utilization of your, of your food. So you'll eat the food. You'll be, you'll burn through it pretty fast. You'll get hungry like an hour later, and then you're going to eat again. You're snacking all day long and you can start to see issues with brain fog and libido and some of the steroid hormone components because fat has other functions in the body.

01:26:33

besides just being an energy substrate. So you want to have adequate amount of fat. You also can develop digestive issues because the fat stimulates the release of bile acids and some of the hormones like cholecystokinin in the intestine, which help optimize digestion. So it's quite important to actually have enough fat. So I shoot 20 to 30% of calories.

01:26:52

Now, in terms of the caloric perspective, I usually have people calculate their calories based on an estimation of their lean body mass because lean body mass is the most metabolically active tissue. And then we see where they're at with an activity multiplier. You know, it's an average of what their activity is across the day. And essentially with that,

01:27:12

you're able to say, okay, if I have somebody who's obese or somebody who's diabetic and they have a lot of extra body weight and their system is having a hard time metabolically, I don't want to drive a surplus with them. Because if I drive a surplus with them, I'm dumping fuel into a system that's having a hard time using the fuel. And the way you can think about this is if you think the cell has a furnace and you have a pipeline of fuel going to that cell,

01:27:39

If the furnace is all types of messed up and you keep dumping fuel into the furnace, you don't have the controlled flow of fuel. The fuel doesn't get burned properly. You get a lot of smoke production and that smoke production and the buildup in the furnace starts to actually damage the furnace. So that's kind of what's happening in these pathologic states. And

01:27:59

And so we want to kind of make sure we have enough supply for what the body needs, but not so much that we're worsening this dysfunction. So you want to make sure we're also managing energy intake

01:28:11

And that's through calories. It's not that calories are the be all to end all or anything like that. It's just to get a rough estimation of somebody's energy intake on a regular basis. And I do have a guide available on my website to back to calculate all these things and which foods to use and whatnot. So people can check that out. But essentially, that is the flow that I work through to initially understand

01:28:30

how am I going to set up somebody's diet and how am I going to lower their fat intake and then bring their carb intake? We need to have targets and solidified values so we can actually say we're at point A and we need to go to point B and not be just kind of ambiguous about it because the ambiguity, I think, causes problems for people in the long term. Yeah. I think maybe we'll do one more clip here and kind of end on a little more fructose talk, but thank you for all that. I think that's like a good guide for people. And I've seen that in my own life. Like if I

01:29:00

If I get too low on the fat, I don't feel great. I can push the carbs and then I can tell like, oh, I need more fat. And whether that's, usually I just add butter and I put butter on a burger or extra butter on a steak. And some of the meats I'm eating now these days are pretty lean. I've been making burgers out of heart. And so it can be very lean and it doesn't get enough fat.

01:29:20

enough fat. If I'm eating steaks in the States and they're ribeyes, they're full of fat and it's not an issue. But sometimes, especially depending on the cows that I'm eating, if they're Brahman cows down here where it's warmer, they're much leaner and I don't get as much fat. So I have to just add a good butter to that to get a little more. So let me find this next clip. Let's talk a little bit about the fates of fructose. I think this is really important. We're back to fructose. And again, the characterization here

01:29:49

is that fructose goes into fat, basically. Fructose is harmful for humans. And then when you eat fructose, it becomes fat. The intestine will metabolize that fructose through what is known as intestinal de novo lipogenesis. About 10% of that fructose will be turned into fat right in the intestine. And that's because fructose, it just wants to be fat? Yeah, fructose wants to be fat. Fructose is the lipogenic substrate.

01:30:20

Here, we're not talking about body fat. We're talking about fat molecules that can potentially be used as energy. That's right. Triglyceride molecules. Okay. So 10% of that fructose will be turned into triglyceride right in the intestine and be released into the bloodstream. And it is the reason for a postprandial triglyceride response. Postprandial is, and I'm including myself in this group, is nerd speak for after eating lunch. It

01:30:43

Typically it's lunch. So that's actually one of the drivers of cardiovascular pathology, that intestinal de novo lipogenesis, turning that fructose into triglyceride right in the intestine. Now, there's a limit to how fast and how much the intestine can do that. The rest of the fructose will be absorbed into the portal vein, but not before some of that fructose will make it further down and it will nitrate

01:31:14

tight junction proteins. Okay. Porto vein of the kidney. Porto vein goes to the liver. Porto vein goes from the visceral, from the intestine to the liver. No kidney. It doesn't feed the kidney. Okay. No kidney. Intestine to liver. Okay. Okay. But fructose nitrates, tight junction proteins. Now let me explain that to your audience. So here we go, Mike. We've got, uh,

01:31:43

We've got fructose wants to be fat. Fructose causes postprandial increase in triglycerides leading to cardiovascular disease. And then fructose nitrates, tight junction proteins leading to leaky gut. So that sounds pretty bad to me. What do you think about this?

01:32:02

Yeah. So as far as the intestine undergoing lipogenesis and then turning 10% of ingested fructose directly to fat. So there's a couple of things here. One,

01:32:16

The research isn't settled on what exactly is going on there yet. So is it releasing fat and lipoproteins triglycerides that it's, you know, from uptake? Is it is it coming from the fructose being directly converted? Is there an alteration in metabolism of lipids in general? Because when you ingest carbohydrates and particularly fructose,

01:32:36

it starts to lower fatty acid oxidation and push for carbohydrate oxidation. So there's a lot of unanswered questions specifically on what's going on there. It is true that after ingesting fructose, particularly high dosages and particularly like free isolated fructose sources, you can see a bump in triglycerides. But the

01:32:57

but it's just not, it's, it's, I think a bit unclear if that's directly from de novo lipogenesis, specifically from the intestine. Now, when you start to look at what goes on in the liver, what they show is that de novo lipogenesis of fructose reaching the liver, there's a study here looking at the isotopic tracers of fructose where they basically label fructose. They can see what happens, what it converts into the carbons and fructose. And what they show is

01:33:23

is that de novo lipogenesis of fructose at the liver accounts for less than 1% of lipid creation. So we're not really seeing a high amount of de novo lipogenesis at the liver from fructose. And then as far as the de novo lipogenesis in the intestine, the picture is not 100% clear there yet. Now, with that said, just because a source gets converted into fat

01:33:49

doesn't mean anything. Because as an example, if you were to eat butter, or if you were to eat olive oil or coconut or whatever fat source you're going to have, you would just be also getting the fat. So you would be taking the fat anyway. So it's not inherently bad that you have this conversion to fat from carbohydrate sources. And some carbohydrate sources, especially in overfeeding, will increase the production of fats. So that is normal. But with fructose,

01:34:17

In terms of de novo lipogenesis, I don't think that that's a major component. What I will say is I think it's more likely that fructose alters metabolism in general, and then you can see a bump up of triglycerides and different components because of an alteration in the metabolism. And the isotopic tracer studies, particularly looking at what goes on with fructose at the

01:34:42

About 28% is converted to lactate. About 30% to 62% is converted to carbon dioxide and ATP. There's some conversion to glycogen and glycerol. And then there's a question mark in less than 1% of conversion of fructose into lipids. And then only a very small amount of fructose actually leaves the liver. And we talked about that before where you don't really see high amounts of fructose in the blood.

01:35:08

So I think that this is like something that gets played over and over again inside the anti-sugar crowds. But I don't think that, number one, that it's necessarily always a problem. And then number two, that it like that mechanism is very clear as fructose just increases novel lipogenesis hands down. And I do want to talk about a mechanism. I know I'm going to stop here. There's a mechanism on why we're seeing the increased lipids from fructose.

01:35:33

Yeah, and this is important to point out. The questions here are, are these studies with isolated fructose feeding? Even if 10% of the fructose you were ingesting turned into fat in your intestine, that's going to be a small fraction of the fat that I ingest every day.

01:35:49

And the fat that I ingest every day is immediately, is directly into fat in my intestine, taken up by the body and increasing postprandial triglycerides. So we talked just a moment ago about getting enough fat in your diet. I probably get 30, 35% of my calories from fat.

01:36:05

which for me means that if I'm eating 3,000, 3,500 calories a day, I'm eating a significant amount of fat. And so let's think maybe I'm doing, I don't know, a thousand calories of fat per day, maybe more. That's a hundred calories. That's a hundred grams of fat per day.

01:36:22

And 10% of the fructose, maybe I ate 50 grams of fructose. That's five grams of fat that we're talking about here. So it's 5% increase it. Like that's, that's a teaspoon of butter that I'm adding. So for him to say, uh, that's increasing cardiovascular disease. It does. I don't, I don't understand the connection here at all. Maybe he's saying that in people with diabetes or they can trace, uh,

01:36:46

disordered postprandial hypertriglyceridemia to cardiovascular disease. But to say that fructose goes to 10% DNL in the intestine, which leads to fat production in the grander context of how much fat someone is eating and that that's contributing to cardiovascular disease, that's very misleading to me. And what you said after that is so important for people to understand.

01:37:06

There are isotopic tracer studies with fructose showing the fates of fructose. I think Andrew didn't do us any favors here by saying, what, so fructose just wants to become fat? And then Lustig says, yes, fructose is the major fat-making molecule. And you think,

01:37:26

I don't understand. That doesn't make any sense. Number one, it's very low in the blood. It's a small fraction of what you're ingesting in the fructose. And the amount of fat you're eating is 10 to 20 times that amount. Relatively speaking, fructose is not going to fat. That doesn't make any sense at all. And when you look at these isotopic tracer studies, as you said, less than 1% of the fructose actually becomes fat at the level of the liver. It's converted to glucose, lactate. It's oxidized directly. Most of the fructose just gets burned.

01:37:54

So where's the problem here? I don't get it. I think the thing that they're seeing with… So there's a couple of things that I've thought about in terms of why you're seeing this effect with fructose. So the first perspective is that

01:38:10

When you ingest fructose, you will lower fatty acid oxidation. And so then you'll get the fatty acid, more fatty acids floating around to some extent because the fructose is going to force carboxidation. And that could possibly be seen as an actual benefit in somebody who's having problems with carboxidation. They're not really oxidizing carbs. So fructose can kind of force that. Depends on the context that you look at it. Now, so there's that. But the next piece is…

01:38:37

When you start to look at some of the fructose feeding studies, what you start to see is, and I mentioned this earlier, fructose in its pure form is often not absorbed very well. So what winds up happening is the fructose gets left inside the intestine and then bacteria are able to capitalize on that fructose inside the intestine and then they start to create bacterial products. And one of the major ones is called endotoxin or lipopolysaturide.

01:39:05

Now, endotoxin is a potent inflammatory stimulus that induces the inflammatory mediators tumor necrosis factor alpha and interleukin-6. And what these mediators do is they increase lipogenesis at the liver to increase the production of triglycerides and LDL and whatnot. And this could be considered a defense mechanism because the lipids in the blood can start to bind up

01:39:31

the endotoxin and different bacterial components, pull them back to the liver without triggering the inflammatory or immune cells in the liver to create a further inflammatory response. So what you're seeing is

01:39:44

is you're basically seeing if I feed a bunch of animals or humans, free fructose in high amounts, I get malabsorption, then I get inflammatory bacterial metabolites or compounds produced, and now the liver has to deal with that. And so there's an interesting study, and what they did was they took two different types of mice,

01:40:05

One mouse was a normal, regular mouse, wild type mouse. The other one was a mouse that didn't have a receptor. They knocked it out genetically called toll-like receptor four. And toll-like receptor four basically senses endotoxin. That's one of the major components that it senses. And so what they show is that

01:40:24

In the mice that didn't have toll-like receptor 4, they had decreased lipid peroxidation. They had decreased ALT, which is a marker of liver damage. They had decreased fat and hepatic triglyceride accumulation inside the liver. And then they had decreased inflammatory mediators. So what you're essentially seeing is if you don't have the inflammatory stimulus

01:40:48

in these mice that are fed high amounts of fructose, they had them on 30% fructose solution.

01:40:55

If they don't have the ability to respond to endotoxin, they don't actually get the same pathology of the mice that can. So you're basically seeing if the endotoxin here is likely the major contributor in the fructose feeding studies for the dysfunction than the fructose itself because when you don't have the inflammatory pathway working in mice that are fed 30% fructose, you don't actually see the same levels, dysfunction, and triglyceride accumulation, etc.,

01:41:22

So those types of studies are very interesting because you get to see, well, is it really just the fructose and the metabolism of fructose? Or is it these bacterial products that are induced by the malabsorption of fructose? And that's a point that's very difficult to overstate. And it's also important to add that fructose without glucose doesn't occur in nature. Humans are never going to be exposed to that. You're always going to get fructose.

01:41:45

with glucose. So the closest thing would be agave syrup, which has a lot more fructose than glucose. And so maybe don't eat agave syrup, but that still has glucose in it. And like you said earlier, honey,

01:41:58

We're not advocating for table sugar, but table sugar, these are essentially 50-50 glucose and fructose. And so how we can use studies that don't replicate what actually happens to humans in nature eating food and make wide-ranging claims about the toxicity of a substance that humans have been eating for hundreds of thousands of years is a little bit baffling to me. But that seems to be what's going on here, that with all…

01:42:27

due respect and with all good intention, I believe that people talking about fructose and sugar negatively have, it just doesn't seem that they're telling the whole story of what happens when you eat foods with fructose as opposed to feeding isolated fructose in a lab to a human or an animal or increasing concentrations in the human body to levels that you would never see. I don't understand it.

01:42:53

Yeah. And then there's the thing is, is like when you add when you use your if your fructose sources are whole fruits or juices.

01:43:02

what you wind up seeing is that the polyphenolic compounds actually minimize microbial dysbiosis inside the intestine and adjust some of the lipogenic pathways and different components and, and the, um, and they'll feel the old dysfunction and whatnot. All the polyphenol compounds from the fruits and juices across the board pretty much have a universally beneficial effect on these different components and minimize the lipid peroxidation, et cetera. So

01:43:28

The difference between looking at purified sugars and then looking at what's happening with a fruit juice or a whole piece of whole fruit is they're non-comparable. It's massively different because you have many other components going in that will modify some of these possibly negative effects, which again is even tenuous in the beginning because what you're seeing is if you were to give them sucrose or if you knock out the inflammatory pathways, you don't see the same types of problems.

01:43:56

The other thing that I want to point out here is Dr. Lustig usually or in the past had talked about fructose being the same as alcohol because and he talks about the effects of alcohol, you know, causes fatty liver. And you also see this activation of this JNK pathway, this inflammatory pathway, and

01:44:16

And the thing is, is alcohol… There's different studies in rats with alcohol where when they don't have a microbiome, when these are germ-free mice and they give them alcohol, they actually don't see the same level of dysfunction that you would if they had…

01:44:30

the bacteria present, the microbiome present, because alcohol's main negative effects are through causing a leaky gut and increasing the influx of endotoxin to the liver. And so I think that the parallels you're seeing there are more, again, a function of the endotoxin. I'm not calling for people to start taking shots every night. That's not what I'm saying. But

01:44:52

What I am saying is that the parallels that are drawn, oh, fructose is like alcohol or this or that is more so a function of endotoxin. And then their metabolism is actually very different from each other. So I think that's, that's kind of where you're seeing those comparison points and it's,

01:45:07

giving us further evidence to say, look, it's probably this endotoxin piece and this microbial dysbiosis problem going on that's affecting and causing the leaky gut and causing this liver damage and whatnot, because all the blood supply coming from the gut goes directly to the liver. So the liver is going to get pounded by this stuff and kind of protect the body from some of the other problems. And that's kind of what we're seeing here is a lot of evidence pointing to it, not inherently fructose being a problem. Um,

01:45:32

especially not fructose from whole fruits or fruit juice. And it's more so how these studies are set up and the way that these protocols are being run. And when I look for evidence in humans that fructose in fruit or fruit juice causes leaky gut, I come up empty. When I look for evidence in humans that fructose in fruit or honey nitrates

01:45:59

any of the components of the intestinal wall come up empty. But I do find a study where they gave free fructose to piglets, to pigs, little pigs, and lo and behold, they had leaky gut, potentially through the same mechanisms that we just discussed, overgrowth of the wrong type of bacteria, leading to increased polysaccharide and leading to a gastrointestinal response. So I

01:46:24

Yeah, it's a little suspect. So I think we can wrap it up there, Mike. The podcast goes on for another two and a half hours with a lot of the same notions. Eat things that spike your insulin, you'll get fat. Fructose is a metabolic toxin. Fructose inhibits the mitochondria, et cetera. And I think we did a really good job, at least as a start, of telling people why those notions should at least be questioned.

01:46:53

And the research should be looked at a little more carefully. Again, I hope that Dr. Robert Lustig will come on this podcast. I continue to extend that invitation to him. And we can have these discussions directly because he's quite vocal about these things. And he's clearly considered to be an expert on the matter. And I hope that the collective consciousness can be enriched with further knowledge and discussion. So

01:47:19

Uh, thanks for coming on, man. Where can people find more of your stuff or connect with you if they want to work with you directly? Yeah, I appreciate the invitation. Paul is a pleasure. Uh, people can find me at my website, mikefave.com. They can also find me on YouTube channels, Mike Fave Science and Mike Fave Simplified. There'll be new videos coming this year. And then I'm also, I mentioned in the course in this podcast earlier that I have a, uh,

01:47:46

I have a guide to basically discuss all the, you know, how to set up your diet, what food source to use, calories, macros, et cetera. So they can find that on my website, MikeBabe.com. Yeah, they can meet me, see me over there. Awesome. Anything you want to say as we wrap up? I'll kind of let you have the last word if you want to tie a bow in this and your perspective on all this that we've gone through. I think it's important to…

01:48:09

Really understand why something is happening, like what the mechanism is that's occurring before you characterize something as good or bad or try to create a dichotomy and understand the full context so that you can you can really flush out why and what is happening and how do we go about adjusting this.

01:48:29

Because if you get too heavy in these reductionisms and this reduction, the reductive mechanisms, then sometimes you can get these weird outcomes. And I think when you're going through the different dietary spheres, you start to find it's like a minefield because this person says that and that person says this. And so when you try to understand what's going on, test things out for yourself, see how things adjust and move from there and, you know, kind of

01:48:53

try to take multiple perspectives from a step back so that you're not jumping back and forth. Because a lot of people that I work with have jumped from different diet to diet, to diet, to diet, to diet. And then a lot of times just getting the foundations, right? You need adequate carbs, you need adequate fat, you need adequate protein, you want to eat across the day, you want to keep stress low. Things like this is what makes the big difference. And you and I can riff on all these in-depth mechanisms on fructose and the microbiome and AMPK and whatnot.

01:49:21

But those aren't the things that are really getting the outcomes for people. It's getting eating appropriately on a regular basis, having nutrient density, high quality foods, keeping stress low, et cetera. That's what's making the difference from people. So I don't want people to get too attached into the weeds, into the specific mechanisms and whatnot, but really try to figure out what's this dietary setup and lifestyle that's going to make me feel better, function better, improve my health outcomes, et cetera.

01:49:47

Awesome. I meant to ask you this earlier in the podcast. Maybe you can give me your minute-long explanation of what you think causes insulin resistance, because I think it all boils down to that for a lot of people. And in the podcast, I tried to set up a different position that it's not glucose, it's not blood sugar, it's not insulin from eating carbohydrates. But I'm curious what you think actually is at the root of insulin resistance for humans.

01:50:16

Yeah. So I think that's actually a great question. I think that there's like a multifold problem going on that kind of spins out of control. And so

01:50:28

What I think is going on is you get some type of metabolic dysfunction at the mitochondrial level, and that could be stress hormones over the long term can cause that. Gut dysbiosis and endotoxemia and things like this can cause that. I think long-term consumption of polyunsaturated fats and incorporation into mitochondrial structure

01:50:48

can start to cause problems as well. Seed oil. Nutrient deficiencies. Yeah. Heavy amounts of reactive oxygen species production from nutrient deficiencies or exposure to different components can start to cause that. And then what winds up happening is you start to see these problems with oxidation, the body of fuel oxidation, carboxidation, the body immediately reverts to fatty acid oxidation. Then you start seeing this insulin resistance start to peak up.

01:51:14

and the cells are not responding to insulin, and gluconeogenesis increases, now blood glucose levels are increasing. And then what happens, and I didn't mention before, but when you have hyperglycemia, like chronically, like over an extended period of time, not just after a meal, but over an extended period of time, that creates stress.

01:51:33

at the pancreatic beta cells because the beta cells are what produces insulin. And they're trying to constantly produce insulin to make up for this. And they essentially become fatigued because they usually make insulin, store it. And then when you have a meal, they release the insulin from storage and then blood sugar comes back down and they have more time to make it. When you're in this diabetic state,

01:51:53

and you have this chronically elevated blood glucose levels, you have a constant stimulus to try to make the insulin that starts to create stress in the pancreatic beta cells. There's multiple different components that are driving this, but I think the absolute central piece is the metabolic dysfunction at the cell, and correcting that is the key to solving diabetes instead of just managing it, or to solving what's going on with obesity, or what's going on with blood glucose dysregulation,

01:52:21

instead of just managing it. So that is the primary area that I focus on when I work with people. And then I would ideally want to see people shift towards thinking about, instead of focusing everything on the bloodstream, it's what's going on inside the cell. At the level of the mitochondria predominantly. Yes, exactly. So lower cortisol, sleep enough, get some exercise, avoid significant amounts of polyunsaturated fats.

01:52:50

Yep. That, that I agree with you a hundred percent. I feel like that's the formula for any carbohydrates. Yeah. Correct. Nutrient deficiencies, make sure microbiome's working well. And then if you are having excessive amount of body fat, the body fat itself can be an inflammatory stimulus and dump fatty acids consistently. So you want to make sure that you're, you're losing weight, but you don't want, not necessarily weight. You want to lose body fat

01:53:15

But you don't want to do it in an excessively stressful way like starving yourself. And then also you don't want to you want to do it in a slow and controlled type of manner. And that doesn't necessarily mean you have to be on a low carb diet. You can do that with carbohydrates. I have worked with hundreds of people to lose weight with carbohydrates in their diet.

01:53:32

So there's multiple components, but it's all about fixing what's going on metabolically at the cell, particularly in the mitochondria. And there's multiple lifestyle things that you do to actually affect that response. It doesn't have to be as super scientific. I'm going to go in the cell and fix all these things. It's like, how are you living and adjusting your lifestyle

01:53:52

to get these outcomes. And that's something that people talk about in the low-carb sphere as well. They just tend to focus on the carbs being the problem. But I think a lot of the other lifestyle components that they discuss, like sunlight and stress and getting nutrient density and adequate protein and minimizing processed foods, those are all still great things. It's just you don't have to lower carbs in that process. And there is actually problems to keeping carbs too low over the long term because of what happens with stress hormones. Robert Leonard

01:54:20

Exactly. And I've talked about that in the past. And you guys have talked about that, that the fact that acutely when you limit carbohydrates, you get cortisol, epinephrine, and then chronically glucagon elevated. And there are stress hormones that come with limiting carbohydrates. So thanks for the discussion, man. It went longer than I thought, but it was just, there was just too much to discuss. And I hope people, I think people get a lot of value out of that. I appreciate you. Thanks for coming on. Yeah. Thank you for having me.

Edit:2025.05.05

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