Jay Feldman

You've probably heard that you shouldn't eat carbs and fats together due to the Randall cycle, but is that really true? And what does the Randall cycle actually tell us? We'll be answering these questions in today's episode of the energy balance podcast, a podcast where we explore health and nutrition from the bioenergetics view and teach you how to maximize your cellular energy to maximize your health. Today's episode, we'll be talking about how the Randall cycle actually works. We'll discuss whether eating carbs and fats in the same meal actually causes weight gain and insulin resistance.

We'll go over the efficiency of using fats as a fuel versus carbohydrates, as well as how stress impacts fuel usage in the mitochondria and how to determine the optimal amount of carbs and fats in your diet. As always, to check out the show notes where I'll link to the studies, articles, and anything else that we referenced throughout today's episode, you can head over to jfeldmanwellness.com slash podcast. And with that, let's get started. All right. So let's talk about the Randall cycle. It's a.

You know, it's an interesting set of mechanisms that for one reason or another has garnered a ton of attention in the health sphere. You you have a lot of different pathways and some that do gain some popularity, but when it comes to carbon fat utilization, for one reason or another, the Randall cycle is a popular one to discuss. And with that, there's a lot of misconceptions regarding the Randall cycle and misapplications. So because of that, we're going to do an episode here where we'll dig into the mechanisms in some detail. We'll go through some figures explaining it.

and kind of simplified a little bit and explain what it all means. But then we'll also take some time to explain what this actually means for you in terms of your diet and whether you're considering separating carbs and fats, or you're considering trying a low carb approach or a high carb low fat approach due to Randall cycle mechanisms, which are often cited for those kinds of things. we'll be digging into all that. And we'll just start with a kind of broad overview of what

the Randall cycle is, and then we'll dig into each of those mechanisms. Before we do that, Mike, is there anything you want to mention here as far as the Randall cycle in the health world? And then if you want, you can jump into the overview or wherever you want to take it.

Mike Fave

Yeah, think this is our individually, like we've both done many videos on the Randall cycle if you like group them all together and.

And together too, we've talked about it on tons of prior episodes, but you know, not dedicating a whole episode to it.

Yeah, I think this is long overdue because I think I've made episodes about it. Then we talk about it on the podcast. Then we did a big expose on it on the biogenic helpline channel, which it's not there anymore. And now, so now we're like, we're bringing the due diligence and we're putting it straight and energy balance. Every time I go through the Randall cycle, if there's, I learn a new, a new layer to it, or there's a new element that comes back to it and

I do appreciate going through it over and over again because it's I do think it is helpful to understand but I think the biggest piece here is it's helpful to understand in terms of why people are getting dysfunction or what's happening in dysfunctional metabolic states not necessarily what's happening in individual meal. I think that's where what like one of the major things that we'll get into because the Randall cycles waxed in the low carb communities to some extent is a reason why you can't have

carbohydrates and fats together. And then even in the new sugar diet trends or the higher carb trends, it's like why you can only have carbs and you can't have fats. And I think it's important that we actually understand what the Randall cycle is saying in context so we can dispel some of these components so people don't get weird dietary iterations where you only have carbs or you only have fats in general or in certain meals or across the day, because there's benefits of actually having

Mike Fave (03:54.514)

macronutrients in a meal together. And then we can also get into the perspective of where does the Randall cycle actually matter? Where does it make a difference to truly understand the Randall cycle and how that helps us solve problems from a physiologic perspective instead of taking into this area where it doesn't really apply quite as much. So for me, it's an interesting topic, but I'm always thinking about it in the sense of dysfunction, not necessarily in meals.

So think that's the big piece here and I think it's a good frame for us to jump in because it's mostly talked about in the context of how you set up your diet, at least in the influencing types of spheres, social media. But in the research, the conversation is more of what's happening in the individual cell inside the mitochondria and inside these different disease states like type 2 diabetes, obesity, impaired glucose tolerance, stress situations, low carb dieting, etc.

Yeah, yeah, absolutely. And that's a great framework. I think it's, you know, with that in mind, we'll just jump into what the Randall cycle is. And that's actually something that's a little bit malleable. you know, in a very broad sense, the Randall cycle is a set of mechanisms that are at play that govern fuel utilization and competition essentially. And what it's looking at is the different mechanisms that go on when you're utilizing one fuel.

and how those interfere with the utilization of other fuels and basically acts as a metabolic switch. So when a single cell or a single mitochondrion is using one fuel, there are certain mechanisms at play that prevent that same cell from utilizing other fuels or at least mitochondria. mean, there's, we'll get into the nuance there and all the details. But that's really what it's coming down to on a fundamental level. know, this started out, know, Randall is the last name of the researcher who

started describing this in the 1960s and talking about how when a cell was utilizing fatty acids, it interfered with glucose utilization. And on the flip side, when a cell was utilizing glucose, it interfered with fatty acid utilization. And he cited a number of mechanisms and reasons as to why this occurs. We'll be talking about those, but it's really expanded since then, right? There's been a lot of new research since that point in the last 60 years. And so there's been new mechanisms uncovered and extra layers that continue to

Jay Feldman (06:17.442)

kind of developing, you know, add to the complexity of the view and, you know, kind of further it along. So we'll be getting into some of that as well. but yeah, on the basis, what this is telling you is that, and we're going to go through these mechanisms so that you have an idea of what's going on here as the listener. But essentially what we're looking at is how, when a cell is utilizing fat, it prevents or reduces the utilization of glucose and vice versa. When a cell is utilizing glucose, it decreases the utilization of fat.

And it's something that has various adaptive benefits as well that we'll talk about as to why you might want this to occur in certain contexts. So we'll get into that as well. But, you know, I think as a starting place, we'll dig into fat utilization, what goes on there, and then how that interferes with glucose utilization. Is there anything you want to mention, Mike, before we jump into that?

the most important preface here to understand as we're going through this is this is happening at an individual cell. So and I can't emphasize that enough. I mean you have hormonal overlay with insulin, glucagon, adrenaline, cortisol, etc. growth hormone that will shift the body in mass in one direction or another but even with that

The Randall cycle is still largely talking about what happens at one individual cell. And this is really important because it's gonna be the foundation for why what your meal breakdown isn't gonna, like having carbs and fats in the same meal isn't necessarily gonna cause an issue. And the other thing is, overarching context for this as well is that at all times in general, we are using both carbs and fats.

not only for energy purposes, but also for other purposes in the body, different metabolic processes, anabolic processes, etc. And you can see this with something like the respiratory quotient, which is basically a sliding scale of how it's a ratio in terms of the CO2 production and oxygen consumption that basically lets us know, are we using more fats or using more carbs? And it slides based on what the composition of the diet is, because we are always using both

Mike Fave (08:30.446)

because you have different tissues using different substrate at different periods of time, whereas the Randle cycle is just specifically talking about what is going on at the individual cell. And this, again, I think that's a really important anchoring point as we get into this, because this is where I think the major misconception centers around thinking about things in terms of the body using carbs and fats as a whole instead of understanding it on a cell-by-cell basis.

Yeah, yeah, absolutely. And as you mentioned, you know, in the initial part there, normally what's going on at one cell is going on in other cells too. And there's a larger environment that's going to influence tissues and multiple tissues to all be acting in accordance and doing similar things. So we'll talk about that too and where this does come into play. But as you're mentioning, and a very important caveat here that we'll get into is, you know, that we'll talk about in more detail is basically that if you're

Utilizing one fuel and one tissue doesn't mean you can't be utilizing other fuels and other tissues. And as you said as well, it's a sliding scale. Even when it comes down to kind of burning a fuel for energy, even in that case, even if you're eating 0 % fat in your diet, you're still burning some fat as a fuel, produce it from other substrates and then utilize it as a fuel. same thing if you consume 0 % carbs in your diet. And we'll actually talk about that a little bit later as well when we do get into the respiratory quotient and all of that.

And the only other thing I want to mention here is obviously if people are listening, watching this, they're probably dealing with various chronic health issues that they're looking at resolving. And so if that is you, if you are dealing with low energy symptoms like chronic cravings and hunger, low energy or fatigue, chronic pain, weight gain, digestive symptoms, brain fog, poor sleep, hormonal imbalances, or any low energy conditions like autoimmune conditions, high blood pressure, insulin resistance, or any other chronic health issues or conditions.

then head over to JfeldmanWalnes.com slash energy, where can sign up for the free energy balance mini course, where I'll walk you through the best diet, exercise, and lifestyle strategies to resolve these low energy symptoms and conditions by maximizing your cellular energy. So again, head over to JfeldmanWalnes.com slash energy to sign up for that free energy balance mini course. Well, let's start by zooming in on that individual cell, as you're saying, and identify what goes on when we're oxidizing fats, which means that we're taking those fats in

Jay Feldman (10:52.536)

convert them into energy and the impacts on glucose utilization especially. I that's what we'll be focusing on along with some other aspects of the utilization of fat as a fuel that are rather unique. So just starting from the beginning and then kind of working through to each part of mitochondrial respiration, we'll start by talking about beta oxidation. Then we'll get into the electron transport chain and the citric acid cycle. And Mike, I'll just start with the first couple of points here and then I'll let you hop in.

But essentially what we have first when we're oxidizing fats is what's called beta oxidation. And so this is basically what allows us to take the really long chain of the fat and chop it up into smaller two carbon chains that become acetyl CoA that can then enter the citric acid cycle. And you can see that in the process here, we have the production of two electron carriers, one being FADH2 and one being NADH. And this is very important because in order to get from

fatty acids to acetyl-CoA, you produce a one-to-one ratio of FADH2 to NADH. You're producing equal amounts of both. When we go from glucose to acetyl-CoA, which is a different pathway called glycolysis, you don't have this. You actually only produce NADH. And so as a result, both FADH2 and NADH get produced in the citric acid cycle. For every run around, you produce three NADH and one FADH2. And so when you kind of add up all of those,

components at the end, you end up with far higher amounts or far higher ratio of NADH to FADH2 for glucose than with fat. Or another way of saying that is that fat has a much higher FADH2 to NADH ratio. These electron carriers are what then go to the electron transport chain, drop off electrons there and create, you know, then that basically energy is used to pump protons and then we use that proton gradient to produce ATP. And when we look at the electron transport chain, there are

some unique differences about where we drop the electrons off that have an impact on other aspects of how we utilize fuel on mitochondrial respiration. So this difference between FADH2 and NADH ends up being very important. And so we can see that depicted here where with glucose, we're producing much more NADH. And so they're depi... you know, they're showing that in this diagram that we're getting that NADH from glucose. You do get some FADH2 as well, but it's a far lower amount relative to NADH. Whereas with beta oxidation,

Jay Feldman (13:15.426)

that FADH2 to NADH ratio is far higher. So we're relying a lot more on that FADH2 and dropping a lot more electrons off at complex 2 and at another set of enzymes that we'll get into in a second. But as a result of this, we end up with some problems at the electron transport chain. Essentially, when we're going from, when these electrons are being taken up by complex 1 and complex 2, they then have to be passed on to ubiquinone, which is also known as coenzyme Q, which then takes them on to complex 3.

when there's this basically huge flood of electrons coming in from multiple sources, the amount of ubiquinone that's filled with electrons increases. Basically, all of the ubiquinone is basically taking up these electrons, but the rest of the electron transport chain can't function fast enough to move those along. And so we kind of see that here and we'll get into some other aspects of this diagram. This is of course slightly more complicated one, but you can see in the center this QH2 and that's the

this case ubiquinol, that ubiquinone that has the electrons there. And so it's pulled those electrons from complex one and complex two, and then also the ETF enzyme complex that we'll talk about in a minute. And so as a result, you get this basically buildup of excess electrons that are in the form of ubiquinol. And as a result of this, you see some problems here at the electron transport chain. We'll have to come up with some analogies, Mike. I'm sure you have some on top of mind, so I'll let you hop in with those in a second.

But basically there's too much energy kind of bound up in the electron transport chain. And so a couple of things can happen. One is you can actually have reverse electron transport where the electrons get transferred back to complex one and then get sent off from complex one or picked up by oxygen and become reactive oxygen species or superoxide, hydrogen peroxide. We'll talk about those. But that's one thing that can happen that's depicted here in this first figure. And in the second figure, they show a number of different sites where we see reactive oxygen species produced.

You can see that they are produced at complex I, the electron transport chain, but also at complex III, and then also at the ETF complex. So ETF is the electron transfer flavoprotein, and then you can see that that works with the ETF QO, that's the ETF oxido reductase, which helps to transfer those electrons onto ubiquinone, but you can also get reactive oxygen species produced there.

Jay Feldman (15:36.462)

So basically have this big buildup of electrons that goes on at the electron transport chain as a result of this difference in FADH2 to NADH ratio from fatty acid metabolism, and that leads to excess reactive oxygen species production. One other thing that it causes here, and then I'll let you hop in Mike, is that because you have this buildup here, this backup at the electron transport chain, you have reduced offloading of electrons from NADH to convert NADH to NAD+.

And so as a result, you have a buildup in the NADH to NAD plus ratio. Another way of saying that is that you have a decreased NAD plus to NADH ratio, and that then has downstream effects. So a couple of the main things we're seeing here are increased reactive oxygen species and a decreased NAD plus to NADH ratio as a result of fat metabolism. And this has various downstream effects that will then interfere with glucose metabolism and have some other effects too.

The way I think about it in general when I'm going through the Randall cycle here and I'm trying to understand what's going on with fat oxidation, inhibiting carb oxidation is in both. you have beta oxidation, is where you basically oxidize fats. start the process of taking the electrons off fats and turning that into a cellular energy in the form of ATP. And then you have glycolysis, which is the glucose side that produces pyruvate to go into the Krebs cycle.

Those are the two different pathways where in both pathways you're basically stealing electricity in the form of electrons off of carbs and off of fats and you're storing them in those batteries. That's where the analogy comes in, the NADH and the FADH2. Those batteries are brought into the electron transport chain which is basically kind of like a wire that transmits

electricity across the different proteins. They basically function to some extent like a wire. have iron-sulfur clusters inside them that are conducting the electrons, bringing them across to oxygen as the final electron acceptor. And as they do that, they're pumping protons or H plus ions across the membrane. And also those batteries are getting drained. So the NADH goes to NAD plus and the FADH2 goes to FADH. So what happens though is if that wire gets backlogged, gets jammed up,

Mike Fave (17:52.658)

and you're basically unable to transfer those electrons. Well, you can't, well, A, the wire starts producing kind of like, I don't know, you get to call it dirty electricity, like a little bit of smoke. And that's where you get the reactive oxygen species, the superoxide, which gets converted into hydrogen peroxide. But on top of that, then you can't bring those batteries, the new batteries that are coming in, can't unload that electricity.

And so you get this buildup of the NADH and you get that buildup of, well, not as much of the FEDH2, but you really get this buildup of the NADH. Now, this is a problem on multiple fronts. So A, if you start jamming up the electron transport chain, then that's gonna create issues at the mitochondrial membrane in terms of allowing things to flow through in general. And so what you wind up seeing is the electron transport chain gets shut down.

You get a high amount of protons on one side of the membrane versus the other side of the membrane and you start to see the flow of those things start to decrease a bit. And you have to have something like uncoupling come in where basically it doesn't couple to produce ATP. So when you're running the fats, you get a shut down electron transport chain. You get a build of the NADH and the FEDH2 and you get a less production of ATP per unit of oxygen consumed.

So it's not really you all these it's basically the fats are slowing everything down, clogging everything up to some extent. And then the other thing is those batteries. Well, where are those batteries? Where are they needed? They go back to the Krebs cycle and the Krebs cycle again is harvesting those electrons off of the fats and the carbs, but they don't have enough of the empty batteries to fill those batteries. So that and they don't have enough NAD anymore.

So you see isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, and then PDH-perruvate dehydrogenase, which links the Krebs cycle to glycolysis, they can't function appropriately. And then it starts to back up that electron transport chain a bit with citrate and also acetyl-CoA. So then now you're seeing this whole backlog of the system that then backs up and then that starts to shut down the entrance of carbs into the mitochondria at

Mike Fave (20:12.194)

particularly at Pruvate Dehydrogenase because of the lack of NAD +, but also because of the build of a citrate, the build of Acetyl CoA, which activate other proteins like Pruvate Dehydrogenase kinase that inhibits Pruvate Dehydrogenase as well. And so you basically, you can't oxidize the carbohydrates fully now. The electron transport chain is backed up a bit and you're producing more smoke with those fatty acids across the board. So yeah, the fats are inhibiting the utilization of glucose, but they're also

changing they're creating that ROS inside the mitochondria the electron transport chain and they're also leading to shifts in the NAD plus NADH ratio and they're they're jamming the electron transport chain up a bit. They're like basically backlogging the wire that's transferring those electrons so it's not moving appropriately. So it's this is not really an ideal circumstance and when I've seen other people in the low carb community talk about the the Randall cycle

They kind of dismiss a lot of times talking about the mitochondrial component of it. They dismiss talking about the electron transport chain and some of the stuff that goes on directly in the Krebs cycle and the NAD plus and NADH ratios and the NADH to FADH2 ratios. And you can't dismiss that because this is telling us like this is actually not ideal. This is showing us why this is a problem. And it's also giving us hints on why carboxidation

would actually be superior in this circumstance compared to fat oxidation because of the effects that we're seeing from the fat oxidation. So it's for me, I think the understanding what's going on in the mitochondria is absolutely key and seeing that change in ATP produced for per amount of oxygen consumed, seeing that change in that NAD plus NADH ratio, seeing that change in NADH to FADH2 ratio and seeing that ROS production

and that slowdown across the electron transport chain, those are all not great signals in terms of energy production when you're looking at the utilization of fatty acids beyond the fact that it's inhibiting carbohydrate oxidation as well. Even those things by themselves are problems. And I think this is a really big piece and this is where the Randall cycle actually gives us indication. I remember when I was first going through this like, this is why I want to oxidize carbohydrate instead of primarily oxidizing fatty acids.

Mike Fave (22:29.166)

And then when we get into it later, it'll help us understand what's going on in disease states and how is this process involved in some of these metabolically dysfunctional states like type 2 diabetes, like obesity, etc.

Yeah, yeah, absolutely. And to highlight what you're saying here, of course, the reactive oxygen species in and of themselves are a problem that you're getting from fat metabolism. And that's because these basically are going to create oxidative stress. They'll end up causing damage to your protein structure, your lipids. You end up with lipid proxidation, end up with a ton of issues if there's excess oxidative stress. So we don't want to be producing this excess reactive oxygen species at the electron transport chain.

so much so that our bodies will undergo uncoupling or the cells will undergo uncoupling, the mitochondria will undergo uncoupling as you were saying, which basically says this is so inefficient and we're producing so much reactive oxygen species, we're just not even going to produce ATP at all. We're just going to burn this fuel right off. So we have that go on, which also leads to a state of a lack of energy available. But then also, as you were saying, the low NAD plus to NADH ratio

slows down the entire path of energy production. It slows down the entire citric acid cycle because you need to have the NAD plus available for those steps, as well as course pyruvate dehydrogenase. But even if you're just utilizing the fats as a fuel, the whole process, you basically are putting the brakes on because of this low NAD plus to NADH ratio. And just to kind come back to the analogy, because I think it was a good one, you know, talking about the batteries, right? It's like adding onto the analogy a bit, you have like these rechargeable batteries, right? And you're trying to

use the energy from the fats or the carbs to charge up the batteries. And so we have the NAD +, which is the uncharged batteries and the NADH, which is the charged batteries. And if all of the batteries are charged, you don't have any more available to pull the energy off of the fuel that you have. So you can't use the fuel. It's just sitting there. And the reason for this is because you have a backlog at the construction site or the assembly line there where they have all of these extra charged batteries, but they don't have the materials. They can't continue working at the...

Jay Feldman (24:32.908)

batteries are accumulating at too fast of a rate. And so you're not actually able to use them and you get this whole backup through the whole chain, as opposed to things moving very efficiently and everything being kind of properly orchestrated. So that's what we're seeing here in this state of fat metabolism. So as you said, Mike, there's the low NAD plus to NADH ratio, which interferes with the citric acid cycle, leads to a buildup of citrate. then also another factor there is aconitase, which is the enzyme that converts citrate to isocitrate. You can see that.

in this diagram, that gets inhibited by reactive oxygen species. It's one of the most sensitive enzymes in the citric acid cycle to oxidative stress. So you also have inhibition there and these things lead to a buildup of the citrate and a buildup of the acetyl-CoA as well. And so as you were saying, those things inhibit pyruvate dehydrogenase along with the low NAD plus to NADH ratio. It's not shown here, but we have this other diagram here where you can actually see that the pyruvate dehydrogenase enzyme also needs

NAD+. It also needs that uncharged battery. And so you have multiple layers of inhibition at this step, as well as you said, Mike, as the activation of pervade dehydrogenase kinase, which also decreases this enzyme activity. So you have multiple steps here that not only are causing general oxidative stress and slowing the citric acid cycle, but also this is where, as you said, you block the utilization of glucose as a fuel. And this continues out into the cytosol. This is a figure from a paper titled The Randall Cycle Revisited, a new head for an old hat, which

one that we've referenced in the past. And you can see here that this is showing under the case of fatty acid metabolism, you have the buildup of acetyl-CoA and citrate inside the mitochondria, and that those things will interfere with peruvian dehydrogenase. But then you also see that because there's this increase in citrate, it ends up making its way into the cytosol, and the buildup of citrate there will then interfere with some of the other enzymes needed for glycolysis. One of the main ones being phosphofructokinase, which is the rate limiting step for glycolysis.

So this is another major way that you're seeing a slowdown of glucose utilization from fat utilization. And again, this part in particular is not necessarily a problem. It's just one of the mechanisms through which we're seeing, you know, one fuel being utilized and blocking the other. So this isn't necessarily pathologic. We'll talk about cases where it is pathologic, but this is just some of what we see happens when you're utilizing fats as a fuel and how it further interferes with glucose utilization.

Mike Fave (26:56.494)

I just want to add one piece to this. The hexokinase inhibition and the phosphofructose kinase inhibition isn't complete. So the hexokinase is only 20 to 30 % and the phosphofructose kinase is only 40 to 60 % inhibition. But PDH is a complete inhibition. So you can still have glucose come in in these states when you're pushing the fatty acid oxidation into the cell. So don't get this shut out of glucose from the cell.

You basically just get a circumstance where the glucose goes in, it runs through glycolysis, and it can't go into the mitochondria because PDH is shut down. And so that's why you see in people who have diabetes, and we've talked about other papers, lactate production gets increased pretty heavily. Because you can take that pyruvate and convert it to lactate. And then also this goes with the intracellular ages stuff, where the pentose phosphate pathway and the hexosamine biosynthetic pathway and the glycolytic pathway as well, glycolysis,

When you have metabolic dysfunction, the substrates or the glucose moving through glycolysis and not being able to move into the mitochondria because PDH is shut down leads to this backlog through those pathways and then that's where you see age formation. So it's not under normal circumstances where everything is kind of like flowing in nice and well. Glucose comes in, credits converted to pyruvate, pyruvate goes to the Krebs cycle. You get this nice beautiful NADH to FADH2 ratio.

flow through the electron transport chain and you get your ATP, right? When things are flowing through great, everything is going well. It's only when you start to get the significant metabolic dysfunction that you then start to see things start backlogging in all the cells. The glycogen contents get increased, the pentose phosphate pathway bumps up, the polyol pathway, the other one is what I wanted to mention that one before, that gets backed up and then that's where you start seeing the problems. Because people like to say, glucose causes X, Y and Z and it's like,

metabolic dysfunction causes X, Y, and Z and glucose doesn't necessarily cause that. It's just in the state of metabolic dysfunction when you're forced to burn fatty acids, it shunts glucose into all these other pathways because again, PDH that we talked about gets completely shut down but phosphofructose kinase and hexokinase don't get completely shut down. So these are, I think, important things to put in context here when we're thinking about some of these states because they, this

Mike Fave (29:21.42)

This also all directly ties in and helps you understand the full picture of like, well, when are you, why are we seeing ages, advanced glycation end products in diabetics when it's like, cause they're not using the glucose well, they're not using the carbohydrate well because things aren't working well, PDH shut down. They're not going to be able to bring that carbohydrate and oxidize it appropriately into the mitochondria. So it's like, it's just going everywhere else. It's basically like if a river floods because it's damned.

Well, all the other areas just get saturated and it's the same thing that happens in the cells and in these pathways. And the problem is not that there's too much water. The problem is that the water flow has been stopped. It's the same thing with the carbohydrate. The problem isn't necessarily that there's too much carbohydrate. The problem is that the flow of carbohydrate to energy has been blocked for a variety of different reasons. And in the metabolically impaired states, and this is the central hypothesis that we work off of, the problem is

is issues in the mitochondria directly and the Randall cycle helps us to see this where it's like if you're stuck running stress hormones and burning fats, you can't bring that glucose into the Krebs cycle and the batteries that you filled into the electron transport chain to effectively oxidize them. So this is where the Randall cycle shines with this perspective. Not, well, can't have, you know, I can't have some olive oil on my vegetables with my big potato and a little bit of butter. It's like, that's not where...

That's not where this necessarily is so applicable.

Right. Right. And as you're saying, what is applicable is what you actually see in a case like insulin resistance, which we'll talk about in more detail, but it's actually this, you actually see chronic upregulated fat oxidation. And at the same time you see increased glycolysis heading, you know, glucose heading to lactate. You're not actually oxidizing it properly in the mitochondria. And yeah, as you said, there's tons of problems in that state or a number of those come from the inability to actually utilize the substrate and you get built up of all the intermediates and you can have a number of issues from that, including

Jay Feldman (31:19.924)

age production, as well as the case or the fact that you see elevated oxidative stress in this condition, both from the fatty acid oxidation and the general metabolic dysfunction and then, you know, and the reduced antioxidant production and all of the rest. And as a result of that, you also see increased lipid peroxidation, which is also a precursor to ages. So a number of issues there. And as you're pointing out, this idea of it being as simple as having a certain amount of glucose as a fuel equals dysfunction. It's the same as people say with insulin resistance.

you know, where hyperglycemia and hyperinsulinemia happen in the case of insulin resistance. So you never want to have any glucose or insulin. And obviously that is a huge conflation. And we've, we did a few episodes talking about insulin resistance that I'll link back to so we don't get too bogged down going through that again. But coming back here to one of the other things that's important to mention here, because it is different in the state of fat metabolism versus glucose metabolism. And that's looking at this buildup of citrate in the cytosol.

where we'll see with glucose metabolism, the citrate is more likely to head down to acetyl-CoA and malonyl-CoA. You see that drawn here, but that's not actually happening as much. And the reason why this is not going to be the case in the case of fatty acid metabolism, there's a few different factors. One is that there's actually a lack of CoA, is needed along with the citrate to become acetyl-CoA because of the basically the CoA is being used by the fats.

you know, to be added to the fatty acid. So it can then be brought into the mitochondria. You can actually see that on the right side of the diagram. We have the long chain fatty acyl CoA. That's where all the CoA is going. So you have a depletion of CoA in the case of fatty acid metabolism. And then also the enzymes that convert citrate to acetyl CoA and then acetyl CoA to malonyl CoA. There's a number of things that regulate them, but one of them is the hormones, glucagon and insulin. And so in this scenario, you're going to have elevated glucagon, which inhibits

those steps that decreases the activity of the ATP citrate lyase and the acetyl-CoA carboxylase, which are the two enzymes that are involved there. Those are both slowed down by glucagon and they're actually supported by insulin. So those are a couple of the mechanisms as to why the citrate won't be converted down that pathway. Another one as well is the presence of AMP kinase, which is generally increased from the oxidative stress and ROS themselves and tends to go alongside fatty acid metabolism.

Jay Feldman (33:39.8)

And that will also decrease the acetyl-CoA carboxylase, the conversion from acetyl-CoA to malonyl-CoA. So for those reasons, see, especially in this case, the excessive citrate buildup interfering with glucose metabolism. And with that, Mike, is there anything else you want to mention as far as the fat metabolism side goes?

Just on the diagram that you were showing before, where you see basically the citric acidyl CoA and malonyl CoA, there's another enzyme I think is important to talk about. And one thing I want to mention to kind of preface what you're saying, the malonyl CoA is important. And we'll see this in the glucose inhibition of fatty acid oxidation, because the malonyl CoA blocks that transport that brings fats into the mitochondria from the cytosol. So when carbs are flowing back to malonyl CoA,

it inhibits fat oxidation. Whereas in the fat oxidation inhibition of carbohydrate, because the citrate buildup in the cytosol that we see there, the cytosol is that orange area on the graph, that's what's inhibiting the carb utilization or glycolysis inside the cytosol. So the toggling between those two substrates is what actually determines the utils, but the malonyl-CoA is actually extremely important for the inhibition of utilization of fatty acids.

But the citrate is important for inhibiting glycolysis. There's another enzyme that plays into this as well that is not pictured here. Neither is the ATP citrate lyase or the acetyl-CoA carboxylase that you mentioned, but it's malonyl-CoA decarboxylase. And basically the general idea of the enzymes is to either allow for a lot of malonyl-CoA to be produced or be present. Not just produced, but like not be degraded or be produced at the same time or for the malonyl-CoA to be dropped.

so that there's very little malonyl-CoA, so a lot of degradation and a decreased production. And this is where that hormonal overlay becomes really important. As you mentioned, Jay, the insulin increases the flow of citrate to malonyl-CoA and glucagon while decreasing its breakdown. And glucagon decreases the flow to malonyl-CoA while increasing its breakdown. And that's the switch in the cytosol, which is

Mike Fave (35:52.788)

on top of what we're seeing in the mitochondrial layer. So there's multiple pieces here. The other thing I want to mention with this is there's some influencers who have talked about the Randall cycle and have talked about, like looked at these graphs and said, well, you you get to this question, it's like, well, why doesn't citrate, you know, when carbs build up citrate or stuff like this, why don't they inhibit themselves? Like you get to that question, like, if they have too much carbs, they will inhibit themselves. And it's like, well,

This is why you need to understand the specifics here because the flowing of citrate to malonyl-quay when you have carbohydrates will stop that. Well, you're going to just stop the fatty acid oxidation. You're not going to build up citrate to inhibit itself. Whereas with the fats, you're not going to be able to build up malonyl-quay. So it's not going to inhibit itself. And you're just going to get a build up of citrate, which is going to inhibit the carbohydrate utilization. So these are like, there's really important nuances in this picture here, I think, to understand. in the, the

hormones directly play into this because they're controlling the enzymatic function that allows some of these things to build up like malonyl CoA versus citrate inside the cytosol of the cell. So I want to highlight that here because there's other people who have talked about the Randall cycle that people cite all the time in our comment section and they made videos where they clearly don't understand that and it's important to understand that you have these switch and these mechanisms because if you don't get that then you get a very weird interpretation.

of what happens with the Randall cycle and the utilization of these different fuel sources.

Yeah, yeah, absolutely. Great points there. And just to clarify for anyone who's interested, the meloneal CoA decarboxylase is what converts meloneal CoA back toward acetyl CoA. So that's something that's active in the case of fatty acid oxidation and not in the case of glucose oxidation.

Mike Fave (37:41.646)

Yep, 100%.

Great. Well, let's dig into the other side here of what goes on during glucose metabolism that reduces fatty acid metabolism. Do you want to start us off on this one,

Sure. So I think the first thing that I typically would start out with in terms of the glucose oxidation is under most normal states, under all states that you don't have carbohydrate, you're fasting, you're eating a low carb diet, you're under significant stress, fatty acid oxidation is going to predominate. And I think that needs to be said here because what winds up happening and this is the value of insulin and this is the importance of insulin.

When you eat carbohydrate, insulin's job is to come in and say like, hey guys, have, you know, it's a party's, you know, we brought the beers, we got the good stuff going, we have carbohydrate. And insulin's job is to start switching these processes around so that you start to use that carbohydrate. Because the thought process that I look at when I'm looking at some of the components with the Randall cycle is like, well, fatty acid oxidation is prevailing, right? So if you're in a state where you're...

you're burning fats, which you're going to be, if you're not eating, you're probably going to be burning fats within a couple hours or so. It's going to up regulate the fatty acid oxidation as glycogen starts to drop and blood sugar starts to drop, etc. So, the thing is like, well, the fat oxidation is inhibiting the carb oxidation. So, you can't even get the carbs in. But what happens is the insulin comes to the cell when you take in that carbohydrate and it adjusts that those enzymes, the acetyl-CoA carboxylase.

Mike Fave (39:19.822)

and it adjusts the ATP citrate lyase and malonyl CoA decarboxylase, those enzymes we were just talking about, so that you actually allow the citrate that is in the cytosol to build up and flow towards malonyl CoA and you stop breaking down malonyl CoA. So that you start getting this inhibition of fatty acid oxidation, because that's going to be important, right?

Just to clarify, you're not saying build up of citrate, you're saying the citrate starts to flow and you actually get a decrease in the citrate as it converts toward melanil-CoA.

Yeah, the citrate is able to flow towards malonyl-CoA, which will inhibit that blockage at phosphofructose kinase and hexyl kinase. And then the malonyl-CoA will stop the fatty acid oxidation because it will block what we see there, carnitine pymotoyl transferase 1. And the insulin does this by upregulating acetyl-CoA carboxylase, as we see there, which takes the acetyl-CoA, converts it to malonyl-CoA and increasing ATP citrate, lyoase, which we see there, which takes the citrate, it to acetyl-CoA.

And also there's the other enzyme malonyl-CoA decarboxylase, is in pictured, which basically breaks down malonyl-CoA. So you stop having malonyl-CoA break down. You have more, you have the citrate that's in the cytosol flow towards that malonyl-CoA. The malonyl-CoA inhibits carnitine palmitoyl transferase 1. And then now you also have more of the CoA available in the cytosol to, for ATP citrate lyase to work as we, as we, as you alluded to earlier before today. So you have that plus you have the increased recruitment.

You see there Glut4. Insulin increases Glut4 uptake at the cell membrane. So the insulin dependent tissues like the fat tissue, the muscle and the liver can take up that glucose effectively. So insulin is coordinating this when we eat. This is where the hormones become really important. So we can actually bring in that carbohydrate and we can upregulate that malonyl CoA to shut down the carnitine palmitoyl transferase 1. Then this is also important. You have to stop the fatty acid oxidation as we talked about because

Mike Fave (41:17.258)

If you are still burning fats and you're still producing a higher amount of FADH2 and ratio to NADH compared to what you do with carbohydrate oxidation, you still get inhibition of these different enzymes because you don't have enough NAD+. You don't have enough of the empty batteries for things to work effectively. So the insulin's main job is actually to just stop fatty acid oxidation and allow carbohydrate oxidation to come in and work effectively. So I think you have to understand insulin in this circumstance.

to see how things are moving effectively. And again, like we don't have the graphic up here, but once the carbs start coming in, the fat stops being oxidized. We shift that ratio. We get the higher NAD plus levels, the better ratio NAD plus NADH. You have a decreased buildup of acetyl-CoA because things start to flow through the citric acid cycle, the Krebs cycle a little bit better. And then PDH starts getting activated as well, which allows for pyruvate to come into the

into the Krebs cycle and the which privates the end products like colicis and then move into the electron transport chain and create the NADH that moves the electron transport chain to get converted into ATP. So this full like you have the insulin signaling shuts down the fatty acid oxidation allows changes the ratios of these different components we just showed you with the mitochondrial layer and it allows the carbohydrate to come in and be used effectively. And then you

When you're not burning the fats, can, as long as you keep having the carbs flowing, you keep having malonyl CoA present, keeps shutting down CPT-1, and then the citrate that goes to the cytosol still flows towards malonyl CoA. It doesn't build up and inhibit the carbohydrate oxidation, which again, was a mechanism that was discussed by other people in the low carcery, talking about how the carbs will maybe inhibit themselves or the fats will maybe inhibit themselves, but they shouldn't under normal circumstances. The fats will just be rerouted.

towards triglycerides, towards basically fat storage once they're not being oxidized in the mitochondria and the carbs are being utilized, which we see there on the graphic as well.

Jay Feldman (43:19.906)

You know, either one, like on the glucose side, would route it toward glycogen, on the fat side, you'd route it toward triglycerides in that individual cell, of course, if it has those fats available. But another factor that happens with insulin is decreasing the availability of free fatty acids. In general, we have these, you know, it's especially phrased as like the glucagon to insulin ratio or insulin to glucagon ratio where

On the fat metabolism side, again, as you said, starvation, fasting, low carb, yeah, low carb, high fat diets, you tend to have a high glucagon to insulin ratio. And on flip side, when you have a lot of carbohydrates available, you have a higher insulin to glucagon ratio. You have more insulin, less glucagon. And that also shifts the substrate availability. So there's less fatty acids available to be oxidized. So on one hand, you have the mechanisms you were talking about, Mike, that shift the state inside the mitochondria and inside the cells toward.

reduced uptake of fat and reduced utilization of fat. And then we also have less fatty acids available because we're turning down the glucagon especially, which causes the release of free fatty acids and has its own effects also on shifting back toward into cytosol shifting back from malonyl-CoA to citrate. So it's the shift in hormones alongside the change in fuel availability that allows us to recalibrate the fuel utilization to what's coming in essentially. And so that's kind of the overview of the

the individual mechanisms with fat utilization, how it interferes with glucose metabolism and vice versa. And that brings us to the kind of application side of the Randall cycle, where it comes into play and where it doesn't come into play. And there's one thing that's worth noting, which again, I think, you know, I've definitely heard mentioned by a number of other people, especially in the low carb space, talking about the Randall cycle, which is this idea of not wanting to activate the Randall cycle. And this, we'll talk about this, you know, when it comes to eating carbs and fats together.

This idea that if you eat both of these together, you activate the Randall cycle. And I just wanted to at least take a moment to explain that there's no activation or inactivation here. It's not like an organ system that turns on or off or a pathway that turns on or off. These are sliding scale mechanisms that are always at play, right? When you're, whether you're oxidizing fat, glucose, or even like amino acids, ketones, there's a number of mechanisms at play that are going on at the electron transport chain that are going on at the citric acid cycle that are going on at the cytosol.

Jay Feldman (45:40.258)

that affects and decrease the utilization of other fuels. So even if you're not eating anything, you're mostly going to be oxidizing fat at that point. And these mechanisms will be at play then. If you're only eating glucose, know, or only eating carbohydrates, you're going to be oxidizing far more. These mechanisms will be at play then. And at any scale in between any amount of fat, carb, protein coming in, if you're only consuming protein, these mechanisms will also be at play. There's no activation or inactivation.

inherent mechanisms to the oxidation of fuel that are always occurring in a sliding scale. So just wanted to mention that really briefly in case you ever hear somebody talking about it being activated as if it's an on or off cycle or path, and it's really not a cycle. It's kind of a misnomer of it being a cycle. And one other thing to mention here when it comes to glucose metabolism, and you alluded to this, right? You said that there's an increase in NADH to FADH2 ratio. And so when we do go to the electron transport chain here, there is a difference because since there's much less drop off of electrons from

complex two and the ETF complex, the ubiquinone, the coenzyme Q there isn't overloaded with electrons. So you don't have this overflow and this backup at the electron transport chain. You don't have this excess reactive oxygen species production. And so instead things flow relatively freely here. You, not only don't see that ROS and the uncoupling and all of the other things that come with it, but you also don't have that issue that you can, you actually see the conversion here. You don't have a problem with NADH dropping electrons off at complex one.

converting to NAD+. So you actually maintain a good NAD +, to NADH ratio, whereas when anything interferes with electron transport chain function, if anything causes a backup here, that causes an increase in that NADH to NAD +, ratio because you can't drop off electrons there. So this is pretty central here to glucose metabolism and it's really important to note that a low NAD +, to NADH ratio is present in basically all chronic health conditions and aging and degeneration. So it's generally not something that you want.

And when it comes to glucose metabolism, it's an important way to maintain a healthy NAD plus to NADH ratio. Obviously, if there are other problems here at the electron transport chain, you can still have a low NAD plus to NADH ratio because of that, even if you're oxidizing glucose. But yeah, just worth highlighting those couple of things.

Mike Fave (47:53.944)

Yeah, a couple of things that go in with that that I think are really important as well is with the glucose oxidation, because you're not jamming up coenzyme Q, that less ROS would be less likely to shut down a connotase. So you have better flow through the Krebs cycle from that perspective. Then on top of that, and this is kind of, this is something theoretical that I've been thinking about with fat oxidation, you have increased ROS present, right? And you need more oxygen. You need more oxygen at the cell to

per unit of ATP because of the uncoupling effect and because of what's happening in the electron transport chain. And so now you have an increased exposure to oxygen for the same amount of ATP with a higher amount of ROS and the oxygen is going to be one of the major sources to some extent of driving some of the ROS inside the cell. And this is on top of the fact that carboxidation actually produces, it's not pictured in some of the graphs we showed, but the carboxidation produces more CO2.

and the higher CO2 allows for better oxygen uptake as well at the cellular level via the Bohr and the Haldane effects. So with carbs in general, you have a better NAD plus to NADH ratio, which is basically a marker of aging. You see all the biohacker bros and the hermetic guys like taking all the NAD supplements and it's like, or you could just eat carbs guys. So you have this where you have a better NAD plus to NADH ratio. You have lower ROS production.

You don't need the same amount of oxygen to produce a higher amount of ATP. you like with fats, you're gonna need more oxygen to get the same amount of ATP. And on top of that, you have better oxygenation of tissues and uptake of oxygen because you have a higher CO2 production. So these are all multiple mechanisms. And this is when you start to look at this stuff. This is why you start to think, well, it sounds like carb oxidation, like effective carb oxidation is a much better way to go.

than the fat oxidation. The fat oxidation almost seems like a backup pathway when you don't have adequate carbohydrates present. And it's like we even have an entire hormone that's job is to make sure that when we have carbs present that we switch towards carb oxidation. So it's when you start to think about this, these types of things on top of the fact that the carbohydrates are important for the pentose phosphate pathway.

Mike Fave (50:13.996)

which is involved in producing NADPH to produce glutathione, which further improves antioxidant defenses. So there's multiple mechanisms here where effectively oxidizing carbohydrate is better across the board, not to mention the thyroid benefits and all these components, than pushing fatty acid oxidation, especially when you start getting into these mechanisms. And the Randall cycle shows us some of this directly. And then when you look just comparing beta oxidation,

glucose oxidation through glycolysis you start to see this stuff. I remember when we were going through this we first found Dr. Pete's work and we were calling from low carb like nah like what is this guy what is this guy saying and we start going through the pathways and like wow this is actually this is like he's right like this is this is he's right like you can see it play in his day based on the mechanisms and obviously you eat some carbs like okay I feel better too so he's probably right.

Yeah, yeah, of course, of course. And just to touch on a couple other pieces that fit in this picture, the extra CO2 that's produced, it's a lot more. It's 50 % more CO2 from carbohydrate metabolism, assuming it's happening at the same rate. But because you don't have the brakes on the system, it's actually happening at a faster rate. And that extra CO2 also leads to protection against reactive oxygen species, reactive nitrogen species, and reduces their production too, and kind of allows them to be converted to less harmful

free radicals. So it's very protective. this difference between fat utilization and glucose utilization is the reason why the brain can't utilize fats as a fuel. It's a really sensitive organ to oxidative stress, has very high energy demands. And so this is why you don't see the brain oxidizing fatty acids and instead it has to use glucose or ketones. We won't be digging into ketones here just because it's...

older story.

Jay Feldman (52:04.824)

For reference, it's kind of in between fatty acid metabolism and glucose metabolism, a little bit closer to glucose you could say. And so that's why the brain can still use it, but it can't use the fatty acids. So yes, some really important mechanisms here to detail.

Yep, and this is where I think the Randall cycle shines. It helps to elucidate these components. And then it also helps us to understand, and which I think will drive us into this now, why metabolic dysfunction, why the Randall cycle becomes very important in metabolic dysfunction. At this point, like what you're talking about before where we discussing, you can flip, you know,

You don't want to be activating the Randall cycle or stuff like this. It's like it's happening all the time no matter like whenever you eat as long as you have any change in substrate if you have carbs or or not like you are you are it's you're turning that process on right when you have the insulin signaling when you have the carbohydrate present you're shifting out of that metabolism and then when you don't have the carbohydrate you run out of glycogen stores or you just haven't had a meal for a period of time you will start to shift back to fat metabolism. So that is

That's going on no matter what and on top of that, that is true metabolic flexibility. So when people say I need to be on keto or I need to burn fats so that I can have metabolic flexibility. When you start looking at this mechanisms like you're going to burn fats period. The question is can you burn carbs? Can you oxidize carbs? The problems that people have in these different states is an inability to effectively oxidize carbohydrate all the way through glycolysis.

Krebs cycle electron transport chain. That's the fundamental problem. It's not necessarily with fats. Over time there's problems with both substrate because the mitochondria are dysfunctional and everything is all messed up. You get incomplete fat oxidation. A bunch of things go on but fundamentally the baseline state and I think this is really important to talk about is fat oxidation as a rule when carbs are not present. And it's whenever you eat carbs you shift towards carb oxidation.

Mike Fave (54:11.618)

And that's where you see the true metabolic flexibility. You don't get stuck in a state where you're just burning carbs and you can't burn fats. You get, you get stuck in a state where you have problems, oxidizing carbs or eventually have problems with oxidizing all substrate in general because of total, like general mitochondrial dysfunction. And I think that goes hand in hand kind of what you're saying. I don't want to activate the Randall cycle. It's like, it's always going on as anytime you have a meal, even if you have a high carb meal, as zero fats, you still are switching.

from burning fatty acids, because you had to upregulate fatty acids from the last meal when you didn't eat. Yeah, I hope that pulls us into this nutrient partitioning piece that you want to talk about here, Jay.

Yeah, yeah, definitely dovetails in there and dovetails in with what you were saying in terms of the fact that we're not eating if we're under stress, if we're starving due to the elevation of the stress hormones, which are also fat metabolism hormones, we shift into utilizing fat for fuel. And one of the places, I mean, there's a number of contexts where this comes into place, comes into play. And we'll talk about those, you know, in terms of insulin resistance and chronic health issues, but

In this case, what we're talking about is a biological mechanism that allows us to spare glucose, right? So if we're starving, we don't want our whole bodies running on glucose. We only have, you know, probably four or 500 grams of glucose stored in the form of glycogen. Could be much higher, but we'll just call that as, an average. So you don't have that much glucose to go off of. It's expensive to convert it from other substrates and we need to spare it for the tissues that really need it, especially in the nervous system. And so.

This is a way that when we're in that state and we see an upregulation of fatty acid availability and production with the stress hormones, we're able to decrease glucose utilization and save it for the tissues that really need it. And of course, you when you look at the brain, that's not even taking up the fatty acids that allows it to continue utilizing the glucose, even though the fatty acids are, available. You know, it's not burning the fat and getting stuck in that state.

Mike Fave (56:11.52)

And on top of that, something to keep in mind is the body produces ketones under more extreme circumstances of carbohydrate restriction to further spare glucose. Because it's basically a circumstance where you have to, like we estimated about 150 grams of requirement just on average, just for glucose for the brain. Over time, if you have to produce that through gluconeogenesis, depending on how long that's going on, like you're going to have that absolute requirement, you will

basically start to shred your lean tissue because it's going to come in part from your amino acids. So you start producing ketones, which again, they burn more like glucose, more like carbohydrates than they do like fats. And then a portion of the brain is able to run on those ketones instead of running on the glucose. But you still have some glucose requirement and it's even further sparing mechanism across the board. And you could when you look at the picture to when you start to see.

At least when I start to look at this and I try to put it into context, you start to see that, well fats are kind of slowing down the flow across the entire electron transport chain and slowing down the metabolism in general. And it's usually seen in states where you don't have carbohydrates and you're kind of running on these adaptive mechanisms. It also kind of makes sense, right? You have a circumstance where everything is slowing down because you have a substrate that you, like you don't have this, you're basically signaling a state where you don't have adequate

fuel sources or you're in a state where you don't have adequate carbohydrate coming in. And so the body is starting to down regulate and adjust things to account for what's going on inside the environment. So thyroid hormone starts to drop, which is a signal of metabolic rate. And you start bringing these adaptive hormones on board the glucagon, the adrenaline, the cortisol, the growth hormones will start to force fatty acid oxidation. And then eventually you start to get the ketones come in to further spare that glucose.

So you're not in a circumstance where you're shredding your lean tissue to provide that glucose. So it's like these are all the backup systems that we're seeing with fatty acid oxidation that are helping us deal with not having enough carbohydrate and all the systems are centered around well, hey, we need to like, we don't have enough carbohydrates. We need to like spare as much of the carbohydrate that we are producing. And now we have for the tissues that absolutely need like the central nervous system. And we're going to do all these backup things afterwards and slow everything down.

Mike Fave (58:32.878)

and run from there and that's basically what I think we're seeing. Yeah, you see some benefits with like ketones in certain circumstances and things like this, but it's because of some of the dysfunction that you see in some in different disease states. They're helping with inability to oxidize glucose effectively in some of different circumstances and changing some of the metabolism in these circumstances. But I'd still say the optimal state that we're shooting for based on some of the mechanisms we're talking about.

is the oxidation of carbohydrate, particularly of glucose.

Yeah. And that's a great segue because these contexts, these circumstances where ketone utilization is beneficial are states of chronic stress and mitochondrial issues, basically metabolic syndrome. So situations like insulin resistance, heart failure, fatty liver disease. And so these are states where an aspect of the random cycle also comes into play where essentially you have impaired mitochondrial respiration and impaired glucose metabolism.

This leads to chronic stress, which, we discussed this in detail on the insulin resistance episode, so I'll link to those. But this then leads to a chronic elevation in fatty acids, which, and between the fatty acids and the stress hormones, they drive the utilization of fat as a fuel. So you have an increased lipid oxidation in these states, which a lot of people have this conception that's the opposite, right? They think that in type two diabetes, you're utilizing more glucose. Think in fatty liver disease, you're utilizing more glucose, same in heart failure and things like that. But the reality.

you actually see increased lipid metabolism in these states. And because you have this chronic stress and chronically upregulated lipid metabolism, you have this, the state where you're basically chronically blocked from utilizing glucose effectively. Like there was already inhibition there and then it just gets worse with the elevated stress hormones and the elevated fatty acid metabolism. And this is partially due to those Randall cycle mechanisms. And in this scenario, the fat metabolism didn't necessarily cause the problem.

Jay Feldman (01:00:32.664)

But now it's contributing to the pathology because it's causing excessively high lipid metabolism, which has those issues we talked about earlier, like increased oxidative stress, not being able to produce ATP as efficiently. And then on top of that, now, if you have glucose coming in, you're not able to effectively use it. And what you actually find in this case is that if you turn down the stress hormones to lower the free fatty acids, to decrease fat metabolism, you see improvement in the condition. Or if you just directly block the fat metabolism itself,

then you also see improvement and you see resolution of the issue and you see that you can oxidize the glucose again and that you see, you know, improvement of the pathology. And an alternative to that, if you weren't going to do those things, would be to provide ketones where they can help when you do have this interference with glucose metabolism and you can provide the ketones there to provide some benefit, but it's not actually fixing the underlying problem that we have in the first place. So just another scenario where you do see these randall cycle mechanisms play out.

Yeah, I think even when in these, in the disease states that you're talking about, when you block the free fatty acid oxidation and the release in general, you see improvements across the board in insulin sensitivity because of what's going on with the fatty acids and how they actually impair glucose utilization. And I think that the big thing here is that in these disease states, and this is very important, the Randall cycle in the disease states, you are stuck.

in fatty acid oxidation. So the Randall cycle becomes important there because if you're oxidizing fats in general or in large across the body, you won't be able to oxidize carbohydrate effectively. And so the Randall cycle is detailing some of the mitochondrial mechanisms in these disease states that help us understand why people would not be oxidizing carbohydrate effectively on top of, know, there's other mitochondrial mechanisms at play besides just the Randall effect.

So they have studies with this, right? Where you lower free fatty acids or you provide free fatty acids directly into the bloodstream. And you see when you lower it, improvements in insulin sensitivity. And when you increase it, insulin sensitivity worsens. And there's even drugs that you can use that block fatty acid oxidation like Mildrenate in the heart and actually improves heart failure outcomes by inhibiting excessive fatty acid oxidation.

Mike Fave (01:02:52.846)

and which allows for a shift more towards some of the carbohydrate or the glucose utilization. So you're seeing there's multiple circumstances here or other cases where you can increase or improve the dehydrogenate function. You can see improvements in multiple markers of insulin resistance. And they see this with using something like Benfotiamine and type 2 diabetes. You see improvements. So you're seeing circumstances where trying to modulate these pathways can give us signals and let us know

what's going on between the carb and the fat oxidation. And again, the Randall cycle is showing us in this disease state, not in this state where you're just having a normal meal. The normal meal, you're supposed to be able to switch between fuel sources. You're supposed to be able to partition and distribute the fuel sources effectively. When things start to break down, you start to have problems. You get stuck in fatty acid oxidation at large on average.

And then that's where you see the problems with glucose oxidation in the Randall cycle showing us this or showing us some of the mechanisms by how this works. And then it's basically that's helpful because then it's like, okay, well, we can go and try to adjust these different components to get things back under control. Get PTH active again, inhibit excessive fatty acid oxidation, bring down free fatty acid release, minimize oxidative stress. You can kind of reverse engineer some of the problems when you actually see that dysfunction. And this is where I think it really shines, not where we see in some of the different

Crazy dietary spheres.

Right, although speaking of some of those extremes with the diets, this is a scenario where if you're stuck with excess fatty acid metabolism, this is a case where decreasing the fat considerably in the diet, going on a lower fat high carb diet can be really beneficial, can help to basically force the decrease in fat metabolism and allow for you to properly metabolize glucose again. So this is one of those cases, and we talked about this in that insulin resistance series, where going on a lower fat

Jay Feldman (01:04:46.946)

high carb diet can be really beneficial, really dropping that fat lower than we would normally recommend in this case of insulin resistance or metabolic syndrome, which are all kind of constellations of the same underlying pathology where we see this elevated fat metabolism and blockage in terms of glucose metabolism. So that is one aspect to consider when we're talking about finding the optimal amount of carbs and fats to consume. This is a scenario where dropping the fats lower can really help by basically preventing the utilization of fat, preventing the availability of the fat.

So that is one thing worth mentioning there, but as you were saying, you know, and coming back to that, that kind of broad overview we're talking about the Randall cycle mechanisms are going on inside the cells, right? So you can have some cells that are utilizing carbs and some that are utilizing fats at the same time, or you can have different tissues utilizing carbs and fats at the same time. And this is pretty well known. know that different tissues like to use different types of fuels. The nervous system really likes glucose, assuming there's glucose available, you know,

the heart and muscle tend to like fat. And even though they, you know, they heavily rely on fat, they'll increase that even further in insulin resistance and these negative disease states. So doesn't mean that it's, well, we want to see increased fat neutralization in those tissues, but in general, they do fine oxidizing a good amount of fat. And so you can have different organ systems, different tissues, utilizing fats and carbs at the same time. So this idea that if you eat both carbs and fats together, you're going to confuse your body and

All of the, you know, if you're eating fat, all of the extra carbs is automatically getting stored as body fat. Or if you're eating carbs, all of the extra fat that gets automatically stored as body fat is just not at all the case and is not what is not what's dictated or determined or suggested by the Randall cycle at all. And so you don't have to choose between just eating carbs or eating fats. Our bodies are really intelligent and they're able to scale based on what you're eating and utilize the same proportion of fuels. And there's a number of studies that demonstrate this.

where what they basically find is that they look at the food quotient in the food, which is a way of determining the amount of carbs versus fats in there and compare that to the respiratory quotient of the person eating that food. And they find that it's about the same, that if you're eating higher fat and lower carb, then you're burning more fats and less carbs and vice versa and everything in between that whole scale. The situation where it actually doesn't apply as much is in the extremes. That's when your body's actually burning

Jay Feldman (01:07:09.452)

different proportions from what you're taking in, because if you're taking in very, very little fat, your body still needs to utilize fat. So you actually find that's a case where you're utilizing more fat that comes in. You know, on average, the RQ is higher, or in this case would be lower than the food quotient. Whereas on the flip side, if you're eating a very high fat, low carb diet, this is a case where you're actually utilizing more carbs than come in. So the RQ is actually higher than the food quotient. So yeah, just, just going to demonstrate this idea that.

We need to avoid having multiple fuels available at the same time. It's also especially notable considering that you're never avoiding either fuel. Even if you're not eating any carbs, you still have blood sugar. It's provided by gluconeogenesis. If you're only eating carbs, not eating any fat, you still have fatty acids available, just less so. So the idea that having both fuels together automatically leads to metabolic issues is not at all the case and not supported by the literature or the mechanisms that a lot of people are citing for it.

And I think the other thing that's important to talk about too is that I think there's a general tendency to think about this as stagnant in the sense that like the tissue that like maybe just your muscle tissue uses fat and then your central nervous system is going to use carbohydrate, but it has a fluctuating time course. So at different points in time, you will shift substrates relatively quickly based on the context and based on, you know, what's going on, the larger context diet.

All this type of stuff. if we start running right now at full speed, our muscle tissue is going to shift towards carbohydrate oxidation. If when we come back to sit at rest, we're going to go back to fatty acid oxidation. So you're having and this is you have multiple systems overlaying this process where the hormones come in to help you shift which which substrate you're using under these different circumstances. And it's supposed to happen. That's where that's your true metabolic flexibility. So you can also have different individual cells.

Even within a tissue like your liver, you can have different cells processing fatty acids and others processing carbohydrate. And you can within that same organ, you can have different organ systems using different fuel sources. And then even within those cells that may be using fats now, could be shifting to carbohydrates at another time point. And the other thing is even with that, you don't only have we're oxidizing this or oxidizing that. You can your body can say, okay, we have fat, we're going to store some of this in the fat tissue. You see it in a Randall cycle. The cells start uses.

Mike Fave (01:09:38.326)

starting to use carbohydrate, the fats get moved to triglycerides. They get stored as fat, right? You put it away in a storage. Because they all, then that's going to make you fat. It's like, yeah, but then when you don't eat and you don't have the carbohydrate, then you're going to liberate those triglycerides anyway. So, I think it's important to understand you have different tissues, even within different tissues, different cells using different substrate. They can change it at different points in time. And then on top of that, it doesn't only have to be used in an oxidative sense where you're just turning it all to fuel. They can be stored.

They can be incorporated into cellular membranes. There's a lot that goes on that when you start putting these layers of context like, oh wow, like it's really not as simple as just this switch that happens across the whole body based on what's going on in a particular meal. And again, like how many cells are there in the human body? Trillions of cells. So it's like there's a lot going on in these different circumstances. And that's why the dietary stuff, like yes, you...

But at large, shifting all the one side or the other side can make a difference in the respiratory quotient and what's utilized, but you're still always using both substrates pretty much simultaneously all the time just in different cells and tissues and at different time points.

Yes, very, very much. just wanted to highlight that, you know, even different cells, different types of tissues within a, within a single organ can be utilizing different fuels at the same time. You know, in the kidney, have highly glycolytic cells. We have cells that are largely using fats. You know, this happens in different organs. And so again, just adds to a bit of complexity here, but also adds to, I think the, a little bit of nuance and helps to, hopefully if people recognize that it's not a matter of

of needing to demonize either macronutrient, right? We talked about a sliding scale of both and, you know, I wanted to spend some time talking about how to determine that proper amount of carbs and fats, depending on your needs. We touch on it a little bit with insulin resistance, but we're running out of time here. So I'll just recommend that you guys refer back to episodes 101 of the podcast, where we talk through those things in more detail and help to talk through different factors that you might want to consider for determining the optimal amount of carb and fat intake.

Jay Feldman (01:11:47.544)

The only other thing I wanted to come back to real briefly, you were talking about, you know, carb utilization and during that time, then the fatty acids being stored as in triglycerides. And then just want to highlight as well, we're talking about again, an individual cell here, not the whole body. So this doesn't mean that you eat carbs and your whole body just starts storing, you know, all fat as fat. Again, you can be eating carbs and a huge portion of your body, of your tissues, of your metabolism can still be coming from utilizing fats as a fuel. It's just that that individual cell is going to stop taking up fats.

and will push them towards storage, at least in the cells that are more prone to that. But again, as soon as they finish oxidizing the glucose available to them, they'll start to use that fat. This is a constant malleable changing and dynamic system that's utilizing the fuel that's available. So yeah, I think that effectively wraps it up. Mike, do you want to share where everyone can find more of your work?

Jay Feldman (01:12:51.598)

Awesome. Thanks for sharing that. always, if you guys enjoyed today's episode, please leave a like or comment. If you're watching on YouTube, if you're listening elsewhere, please leave a review and five star rating. All of those things really do a lot to help support the podcast and are very much appreciated. As always, take a look at the show notes, relink to the studies, articles, and anything else that we referenced throughout today's episode. You can head over to jfeldmanwellness.com slash podcast. And if after listening through the podcast, you're not really sure where to get started, not sure how to.

Optimize your macro intake or not sure what to do in terms of the diet, or if you're just looking for extra guidance in terms of resolving various health issues that you might be working on, then head over to jfeldmanwellness.com slash call, where you can sign up for a free call with a member of the J Feldman wellness team who can provide you with insights and next steps to take on your health journey. So again, head over to jfeldmanwellness.com slash call to sign up for a free call. And with that, I'll see you on the next one.