Ep. 110: The True Cause of Insulin Resistance and Diabetes from the Bioenergetic View

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In this episode we discuss:

  • Why insulin resistance and diabetes are not caused by excess carbohydrate consumption and are not actually an insulin signaling problem 
  • The problems with the idea of metabolic flexibility, earning your carbs, and the carb-insulin model of obesity
  • Why carbs are beneficial even for people who have insulin resistance or diabetes 
  • The role of fat burning and stress in driving insulin resistance 
  • Specific diet, movement, and supplement recommendations to reverse insulin resistance and diabetes 

0:00 – Intro

1:14 – metabolic flexibility, earning your carbs, the carb-insulin model of obesity, and dispelling other common insulin resistance myths

7:48 – low-carb, keto, and carnivore diets may improve symptoms but are not the solution for insulin resistance

13:13 – what the mainstream view of insulin resistance gets wrong when it comes to what causes insulin resistance 

15:50 – why you might not want to use a continuous glucose monitor and the unnecessary fear of blood glucose spikes 

17:48 – whether insulin is harmful and whether we want to keep insulin levels as low as possible 

22:15 – whether we can restore optimal insulin sensitivity without low-carb diets   

25:16 –the bioenergetic view of insulin resistance  

27:12 – insulin resistance as an adaptive evolutionary process that is crucial for survival  

31:22 – the difference between physiological and pathological insulin resistance 

34:40 – how inhibited glucose oxidation causes insulin resistance 

40:46 – how fatty acid oxidation causes increased production of ROS, slows cellular respiration, and blocks glucose oxidation (The Randle Cycle) 

51:06 – the harms of ROS production from fatty acid oxidation and other forms of stress 

53:04 – insulin resistance as an energy deficient state

54:19 – insulin resistance is not an insulin signaling problem, it’s an energy production problem

58:30 – the role of stress hormones (like cortisol) in insulin resistance 

1:02:09 – how insulin and carbohydrates decrease stress 

1:05:59 – how to fix insulin resistance and restore insulin sensitivity by fixing our capacity to produce energy 

1:10:38 – specific diet, movement, and supplementation recommendations for insulin resistance and diabetes  

1:17:55 – why you don’t need to tailor your carb intake to your carb tolerance  

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Jay Feldman 0:00
The carbohydrates do not cause insulin resistance, but we'll tell you what does. In today's episode episode 110 of the energy balance podcast, a Podcast where we explore health and nutrition from the bioenergetic view, and teach you how to maximize your cellular energy to maximize your health. In today's episode, we'll be going over an overview of insulin resistance from the bioenergetic view. And we'll be discussing why carbs are not just for young, active metabolically Healthy People. We'll also be talking about why insert resistance isn't actually an insulin signaling problem. We'll be discussing the role of excess fat burning and insulin resistance. We'll be talking about why carbohydrates don't cause insulin resistance and what actually it does. And we'll also discuss how to fix insulin resistance and restore insulin sensitivity. To check out the show notes for today's episode, where we'll make the study's articles. And anything else that we referenced throughout today's episode, you can head over to Jay Feldman wellness.com/podcast. And with that, we're going to jump right in.

So when it comes to insulin resistance, this is a topic that we've discussed quite often before. But we wanted to have an episode where we just provided a clear start to finish overview of the bioenergetic view of insulin resistance and made it very clear so that people understand where we're coming from, and are able to fit this in and potentially, you know, for us to be able to dispel a lot of the misconceptions and myths when it comes to insulin resistance, because there's no shortage of them. And we still hear these from people all the time. And people ask these sorts of questions when we talk about consuming carbohydrates. And we talk about what really causes insulin resistance and why carbs are not the problem here. And so that's what we'll be doing this episode will create that picture kind of go through our view and the bioenergetic view of insulin resistance. And in future episodes, we'll be digging into the evidence for this getting into the studies. But in today's episode, it's just going to be an exploration or explanation of what insulin resistance actually is. And as I mentioned, there's a ton of misconceptions here that I just want to touch on. Because these are incredibly pervasive, not only in the mainstream, but also in the alternative world when it comes to health and nutrition, especially considering that low carb and fasting and different iterations of those things are still the top thing that's been suggested for health, let alone also for insulin resistance. And obviously, we don't see those things as ideal. There's a lot of issues with that. And it's not actually solving the problem when it comes to insulin resistance. And actually, as we'll get to, can make the problem worse. So some of these misconceptions that we hear quite often will be things like that carbohydrates are only for metabolically healthy people, and most people aren't metabolically healthy. So this information are these suggestions, these ideas that we should be eating carbohydrates don't apply to 90 plus percent of the population. We'll be talking about why this is not at all the case. And carbohydrates are important for both metabolically and non metabolically healthy people and actually help the non metabolically healthy people become more metabolically healthy. So we'll get into that. We'll also be talking about this misconception that you can only get away with eating carbs. If you're young and active. Like we have to earn your carbs. That's one that we hear all the time. And when you see some of the main figures talking about the benefits of carbohydrates, people will be commenting and saying, oh, we'll just wait till you get to this age, or it's only because you're just constantly working out, you're constantly active. And you and I both don't fit that side of things. We aren't particularly active, although we aren't sedentary either. But this carbs are not just for athletes, we have basal needs for carbs, we'll be talking about that we'll be talking about, again, why they're so crucial and important, and why you should be eating them even if you're not young and active. So we'll dig into that. We'll also be talking about this metabolic flexibility idea, this idea that everybody's already burning carbs, and you're burning mostly glucose and insulin resistance. This is something that's still pervade by some very prominent figures in the health industry, and is entirely false. We'll be digging into that today and also in the future in those episodes, digging into the evidence, but the issue with metabolic and flexibility is not that you can't burn fat. So we'll be talking about that and why burning fat is actually a problem here and something that's already happening excessively in an insulin resistant state. We'll also be talking about this misconception that if your issue kind of like the earlier one about metabolically healthy people, but if your issue is high blood sugar, high insulin high a one C, you know that you shouldn't be eating carbs to increase those things further, right. The issue is not low blood sugar and stress hormones. My issue is my blood sugar's high, so I shouldn't be doing these things. Right. We'll definitely be talking about that misconception. And why that is not at all case and how carbohydrates are, can be helpful for actually lowering blood sugar, lowering insulin and lowering anyone see, and we see this with clients all the time, and people, you know, other people that we work with in our programs and everything like that. Last couple of misconceptions I want to mention here one is the carb insulin model of obesity. We'll be talking a bit about that. We've also explored that in more detail in prior episodes. So I'll link to those. And why this, this carbon Swan model is essentially totally false. totally incorrect. And it's pretty clear in the literature now, I mean, even on the basis, it was never something that had support for it. But it's another common misconception. The last couple one is that too many carbohydrates are the cause of insulin resistance. That's a central one that's kind of underlying a lot of the earlier ones that I've mentioned. And so we'll be digging into that and why that's not the case, why insulin resistance is not caused by excess carbohydrate consumption. And then lastly, is, on the physiological side, this idea that insulin resistance is an insulin signaling problem, where your cells just stop responding to insulin. That's an extremely common misconception. And it's not only misconception, that's kind of the main theory in the mainstream view. And in most of the alternative views as well. And it's a pretty central one when it comes to the physiology. And when we describe these things today, and then also those future episodes going into the evidence, and make it clear that that's not actually the problem that completely changes. Our approach, or the approach to fixing the problem completely changes if you realize that this actually isn't what's causing the situation, the cell's lack of responding to insulin. So we'll be digging into that one as well. And what actually is causing insulin resistance.

Mike 6:40
The only other one that I think would be important to add is the idea that insulin is some how inherently a negative or problematic hormone, I think a lot of people have this assumption that insulin is a bad guy. And in reality, just because you see the high levels of insulin present in states of insulin resistance, or diabetes, or obesity, or things along these lines, it's not that again, insulin isn't necessarily driving the problem. But the high levels of insulin with elevated blood sugar, our response to this problem, we'll dig into the details of that as well. That's one I see pervade, like, very frequently. And then a lot of people, when they look at their tap their blood tests, a lot of clients that I work with they all the insulin, it's bad, I have my I just have to lower my insulin. And then that's that also, that idea pushes people to stop eating carbs, because that's a trigger for insulin. But then they're like, oh, but my blood sugar is increasing. Why is my blood sugar increasing? And you start to see that the problem isn't necessarily insulin, the insulin resistance pathobiology is what's driving up the insulin and causing the issue in that elevated insulin is just a signal or a symptom of that.

Jay Feldman 7:45
Definitely, yeah, we'll dig into that. And one other thing I want to make clear, we're not saying that if you go on a low carb diet, it won't lower your insulin, or if you have super high, like, if you're very insulin resistant, and you're having super high blood sugar levels, if you stop eating carbohydrates, they will come down, especially postprandial Li, fasting blood sugar will often increase. But we're not saying that that's not the case. If you do fasting, if you go on carnivore keto, or other versions of low carb, it will improve those symptoms. As you're saying, Mike, it's the same as treating cholesterol and heart disease, right, we're treating a symptom, we're not actually fixing the underlying problem. And much like a statin in heart disease, and block blocking cholesterol production, there are major harms, to avoiding carbohydrates. So not only are we not fixing the problem, but we're introducing something that's actually also causing harm and an increasing pathologic pathology long term. In most cases, we talked extensively about low carb and fasting in the past, well, I'll link to some episodes there. Of course, there's nuance where you can have benefits, and try not to get too far down the tangent, tangent, but you can have benefits from low carb from relief of endotoxin production in the gut, for example. And that's huge, that makes a huge difference for our health, that is definitely a benefit. There is also harm, there's also stress that is coming along with the avoidance of carbohydrates. And so the ideal route to go for fixing an issue would not be to go on a low carb diet in this example, it would be to do something else to lower the endotoxin in the intestines. And that way, you can get that same benefit without the stress of low carb. So I felt like, you know, it's important to mention that because I know a lot of people who are probably going to be listening to this episode are coming from that place, or are still doing those things like low carb or fasting. And again, we're not saying it can't improve symptoms, we're not even saying that it can't have an that benefit for a short period of time or even a longer period of time. However, there is also a an inherent cost to it. And you can get a much larger net benefit without the cost if you take another approach to actually fixing the problem. And

Mike 9:42
I think this ties in with the with the relative benefit compared to where people are coming from. Right. So if you're coming from a standard American diet or you're some people are coming from plant based stuff, and then they go on keto, low carb paleo and they have significant benefits. That that's like this not an argument there even I think for you and I, when we switched those diets, we definitively had benefits. The thing is, is that it I don't think all those benefits are purely become are coming from that the lowering of carbohydrate intake and whatnot, the benefits are coming from a variety of other factors that are often just conflated with the idea of lowering carbs, because that's the main thing that's focused on in some of these paradigms, particularly the Keto stuff, and paleo or keto and low carb and paleo and carnivore, there's other things they talk about that are actually beneficial. But I think that the idea that the carbs are inherently the problem that know that that nomer is problematic, the question be more like what's coming along with the carb sources that you're having on a regular basis. So again, it's not to say that these diets don't provide benefit or can't provide benefit or can't, won't even provide or that they don't improve lab values, right. Like I've seen people switch to some of these diets. But there's also they introducing, especially the idea of low carb introduces new problems that a lot of people run into face first, when they go into the low carb, keto, carnivore spheres. And a lot of it is centered around not only carbs, but a lot of it is centered around the idea of, of taking out carbs. And the question is like, maybe if you use specific types of carbs, you'd be able to minimize those symptoms still keep the benefits of some of those diets with adjusting other things as well. So and this is why we're going to discuss the core pathology and the core mechanisms behind insulin resistance. And you'll start to see that it's not actually a carbohydrate and insulin problem as much as it is the fatty acid oxidation problem with stress problem, and things like that, that some of these diets actually push towards, or drive towards, which is the one of the major problems with these diets inherently.

Jay Feldman 11:41
Right. Right. And it's a it's a state of inability to oxidize glucose. That's the problem, as we'll dig into. And one thing to clarify or to add on or, you know, just add a little bit of context, what will often happen if someone goes to low carb is they'll see improvements in symptoms, including the bloodwork and they'll see benefits. And that's because as you said, it's not just because we've taken out the carbs, it's because of the gut effects. And also, if we're having trouble oxidizing glucose, it can help to then use a different fuel. But there's the inherent harms and negatives, that will begin to outweigh the benefits as time goes on. And that's why the people who come to us have low testosterone or low sex hormone production, low thyroid hormone production and conversion, I fasting blood glucose as the stress hormones increase, high cortisol, trouble sleeping, all sorts of different issues that tend to crop up over time. If you know somebody's coming from that place, so yeah,

Mike 12:35
high cholesterol, don't forget your high cholesterol that is like textbook from low carb, everybody's like my cholesterol so high, but doesn't cause heart disease. And this sounds like yes, but you still don't want it that high for other reasons, right.

Jay Feldman 12:46
And it's still a sign of some underlying issues. And we've discussed this in the past, both in cholesterol episodes and thyroid episodes. So I'll link back to those. And with that, let's dig in here, as far as the kind of mainstream and alternative view of what is causing insulin resistance. And then we'll explain the problems with that. And the bioenergetic view, that we would say is considerably more accurate when it comes to what's going on in insulin resistance. So when it comes to the mainstream view, and then also the kind of main alternative view, the central idea is that, as we mentioned, the cells no longer effectively respond to insulin, that's what's regarded as the problem. Someone consumes carbohydrates, those carbohydrates are absorbed, blood sugar goes up, and insulin is released, but the cells have over time stopped responding to insulin. And so the blood sugar stays elevated. And that is generally the extent of the problem. And so in an issue, you know, in a problem like that, the solution is to fix whatever caused the problem with insulin signaling. And in the mainstream view, of course, there are a couple of different causes. The first one is always genetic, and, you know, genetic susceptibility to these things, right. I mean, there's, there's nothing else when it comes to health, other than genetics and all of that, because obviously, the food industry, pharmaceutical industry, those things are entirely off the hook. The not even that, but also like the government food recommendations, and diet recommendations, all those things have nothing to do with insulin sensitivity or insulin resistance. It's just genetics. But that aside, the mechanism that's often pointed to in the mainstream, is that there's an overproduction or excess amounts of fat inside the cells. And this impairs the insulin signaling it's and so when the cells have excess fat, and often in the mainstream, this is pointed to as again, often it's a either a genetic issue more than anything, but also genetics plus maybe you're consuming too high of a fat, you know, too high of a fat diet. Of course, the types of fats have no issue nutrients of no issue, you know, have nothing to do with this type of carbohydrates like approach just

Mike 14:52
it's just calories J that's all that it is. You're just eating too much. You're just gluttonous.

Jay Feldman 14:56
Totally. Yeah, absolutely. And yeah, some Times excess fat intake is pointed to but you're right, really more than anything, it's just too much calories and people being gluttonous. And yeah, so that causes excess fat inside the cell and that blocks insulin signaling. When it comes to the alternative view, their view is more in line with what you were saying earlier with the neurotransmitter idea where we've stimulated the cellular response to insulin so much that the cells have gotten tired and numb to the signaling. And so they stopped responding. And so in that case, the cause is that we're consuming too many carbs too frequently during the day. And so we've had too much too many rises in insulin, to many rises in glucose causing too many rises in insulin. And so the cells have become fatigued to insulin signals. And this happens to the extent that eventually, they'll just stop responding entirely. And again, the key here from that view is that if, you know, if we just stopped, these constant increases in blood sugar and the constant increase in insulin, then we would stop the insulin resistance. And there's another aspect here, as we've talked about, that, that a lack of, of being able to burn fat is a problem, too. But I would say the main kind of effect you get out of this is all of the use of CGM, the glucose monitors in this in the biohacking sphere. And this idea that anytime you're spiking your glucose, and then you're causing a spike in insulin, you are driving this insulin resistant state. And so this is leading people to just not only avoid carbohydrates, but avoid any increases of blood sugar with the idea that those are pathologic and causing disease. And as we'll talk about that, as very little, I mean, has nothing to do with what's actually causing the situation here. And the consumption of carbohydrates doesn't either. And instead, if you will, again, we've kind of alluded to it, but insulin resistance is a state of issues with using the carbohydrates we're consuming. And avoiding them like is often suggested on a low carb diet, or fasting, or you're just not eating at all, and relying on fats, or any kind of other versions in between there. Those are just band aids at best, right. And they're harmful mandates to they come with some negatives, but all they're doing is just avoiding the problem, they're not actually fixing the insulin resistance, they're just taking out the carbs so that you aren't experiencing the issue anymore. But as we've talked about, there are some major negative some harms that come alongside that. And I'll just refer to previous episodes where we discussed, you know, the chronic elevation of stress hormones, the issues in terms of thyroid hormone production and conversion. And on from there as far as the issues with these kinds of low carb diets and fasting. But the central point that we want to get to here is that that is in it's an intervention that has nothing to do with what's actually causing the issue and insulin resistance. I

Mike 17:49
think another thing that that's central to the alternative view, the I guess, the mainstream alternative view, right, because there's like the alternative to the alternative at this point. But what the alternative view is the the idea that insulin is actually the problem as well, right? Because there's this tendency to see, oh, we have elevated insulin levels and diabetes, we have elevant, elevated insulin levels in obesity, and therefore, like the insulin is driving this process, you have the insulin is this pathologic hormone, it's going to induce all this fat storage and you want your insulin levels lower than a certain point, because of the problems that insulin brings, instead of seeing that the elevated insulin itself is a response to this dysfunction that's going on at the cell. And when you're seeing the elevated insulin levels on your labs, it's not because the insulin it per se itself is the problem. It's that there's a problem elsewhere in particularly at the cellular metabolic environment, where the cell is not responding effectively to the insulin and you're needing more insulin to drive the carbohydrate into the cell. But it's that's not necessarily fixing that underlying problem. So I think there's the focus of insulin as a problem is, is counterproductive, as well as the focus as just a blood sugar as the problem. And I think in both of these circumstances, again, we're looking at these these symptoms, and we're saying this is it, we found it, it's the insulin, it's the carbohydrate, instead of saying, Why is this insulin and carbohydrate elevated? What is actually going on in the cell? What's going on in the bloodstream? What's going on, when you eat the food, what's going on at the liver and the pancreas and trying to like see the whole process play out and see like, where all these pieces where you're finding this dysfunction, instead of just saying, oh, there it is. We see the elevated insulin levels, you see the elevated blood glucose levels, it must be those. So we need to stop having carbohydrates that will lower insulin and lower blood glucose levels. And as you alluded to, Jay, I mean, people do that and their values do improve, but then they still can't eat carbohydrates. So it's like, is there really a cure at that point? Are we just seeing a change in lab values and even within the mainstream view? What you're seeing is the drugs that they give people to manage diabetes, for example, some of the drugs, the what's the sodium, like glucose transporters at the kidney just cause you to pee out your your glucose and so your blood glucose levels are better your hemoglobin a one C levels are going to be better, your insulin levels are going to be better. So on your lab profiles, like wow, look, these drugs work so well, these markers are improving, it's like yeah, if you PL all of your blood glucose, of course, those values are gonna go down because you just again, you don't have the blood glucose. But the problem is those don't actually solve the dysfunction going on at the cell. So the you don't see any, like they're not curing anyone's diabetes, they're just improving lab values. That's it. And it gets, I think that's another important piece. And it ties in with seeing the elevated blood glucose and elevated insulin is that these lab markers are giving you a snapshot and indication of a problem, they are symptoms of this problem. They can give you an idea of how things are moving, but they need to be interpreted based on what the mechanism of the thing that you are doing is, if you don't understand the mechanism, and you don't actually fully understand the problem, then you can make assumptions that things are moving in the right direction, even though they're really not moving in the right direction. That's the same thing. You see what reading thyroid does the same thing you see with looking at stress hormones, or looking at cholesterol values and whatnot, and then saying, oh, you know, let's just give statins look, the cholesterol levels improved. All they must be great. And then it's like, well, we're not really seeing the outcomes that we want. Things aren't getting as good as we want them to get. And it's like yes, because you're still not solving the problem. And it's the same idea with the insulin resistance and diabetes stuff. But it's just it's interesting, because the alternative health sphere will say, Oh, it's cholesterol is not the problem. But then they'll like you have a similar situation over here with insulin and carbohydrates. They all it's the insulin and the carbohydrate. So it's like they want to like have this one perspective, where they're recognizing that this value, this symptomatic value for cholesterol is not the issue. But then the same similar perspective where you see the elevated insulin, elevated glucose, blood glucose, I was like, Oh, those are the problems. And it's like a bit of it's not consistent. When you start looking at them together. I think that's it's important to, to understand. And again, figure out where's that root cause which we'll dig into? Absolutely,

Jay Feldman 22:11
yeah. And there's two points I wanted to expand on. One is like, like in the cholesterol issue, if you just block cholesterol production, or you just block cholesterol absorption in the intestines, neither of those are going to fix any problem, especially considering cholesterol is just a symptom anyway. And you have that exact same thing here when it comes to the carbohydrate situation, either not consuming them, or if you're taking things that block carbohydrate absorption, that's also not not only not fixing the problem, but actually going to make these things worse. And the caveat I do want to mention when it comes to the low carb diets and fasting, while they are generally harmful and stressful, and don't solve the underlying problem, they of course can have some benefits. So we're not saying people don't lose weight on these diets. We're not saying that people don't have relief from we've got symptoms and autoimmune conditions and things like that on these diets. But what we're saying is you can accomplish those same things by actually fixing the underlying issue without the harms and stress that come alongside those interventions. And we've discussed this at nauseam before. It's all linked back to prior episodes. But I just wanted to throw that in there. We're not saying that you can't have some version of success here, both due to benefits on the gut side benefits in terms of avoiding carbohydrates when you don't oxidize them effectively. But it's not actually solving the problem. And there are inherent negatives and harms that come with them. So just wanted to throw that caveat in here before we discuss the bioenergetic view of insulin resistance. Are you okay with that, Mike? Or was there anything you want to mention? Before?

Mike 23:38
No that that that's basically I mean, it just a conflation, right? Like people change their whole diet from standard American to paleo or keto. And then it's like, Oh, it must have been the carbs. And it's like, no, it's there's these 20 Other factors that you change in your diet don't have anything to do with it, it was entirely the carbohydrate. Well, and what

Jay Feldman 23:55
most people even think of carbohydrate is, you know, pizza doughnuts, which a are higher in fat, typically than they are in carbohydrates, and B have a ton of ingredients in them that are extremely problematic, that are not just carbs, right? We're talking canola oil and, and you know, processed wheat flour and things like that, that are problems for tons of people. So yeah, totally missing the issue. And again, another thing I want to mention as a result, I mean, it's I would say it's extremely harmful these sorts of, of ideas that carbs and insulin are the problem. It's not just oh, we're, we're slapping, like we're slapping on a band aid with low carb, but we're actually creating some massive issues, not just the avoidance of carbs, but also the raging people's views of these things. I mean, people think that like an apple, you eat an apple or two and you're gonna be on a high carb diet and don't realize that if you're eating actual high quality, good, good sources of carbohydrates, it's not easy to like eat a high carb diet unnecessarily. You know, people think, you know, they had some berries and they had, you know, a serving of white rice and they're on a high carb diet, not realizing it is still a low carb diet. So That is just, you know, a an example of the arrangement we've had in in terms of our mental framework around these things as a result of these erroneous ideas.

Mike 25:10
Yeah, yeah, I don't have too much more. To add to that, I think let's jump into the bioenergetic view. Yeah.

Jay Feldman 25:15
So the essence of the bioenergetic view here, as we said, the blood elevated blood glucose, elevated insulin, these are just symptoms, the cell not responding to insulin, this is just a symptom. And it's not even really what's happening. It's just something that is kind of seen as an effect. And these things also are not what are causing the disease and damage the elevated blood sugar of elevated insulin, these are not causing the problem, these are symptoms of the problem, again, just like cholesterol and heart disease. Instead, what's going on is that insulin resistance is a state where the cells are not effectively able to oxidize carbohydrates, oxidized glucose, that means burning them in the mitochondria to produce ATP efficiently. That is not happening effectively. So what we're having is issues with the utilization of the carbs that we're taking in. Our cells are then forced to rely on fatty acids as a fuel and also convert that glucose to lactate, which a has problems of its own and B doesn't produce anywhere near the amount of energy that it would if it was fully oxidized, through the Krebs cycle, and then the electron transport chain, and we'll talk about that. So that's what's going on in the cell. And as a result, the intermediates all the glucose, intermediates that are used to or that are the different steps of energy production, those will build up. And that leads to a buildup of glucose in the cell, which prevents the cell from taking up more glucose. So there's a couple things going on, we'll dig into the mechanisms. But essentially, the cell is utilizing fatty acids, that is going to block the uptake of glucose in the cell. And there's a buildup of glucose and its intermediates in the cell. And that will also block the uptake of glucose. And both of those will then cause a increases in blood sugar, and be impairments in the response to insulin that's causing insulin resistance. But it's again, it's not actually an insulin problem, or a signaling problem or a receptor problem. So we'll explain or expand on each of those. There's one other thing I want to mention before we kind of dig into the to the details here. And that's an insulin resistance. In the larger view, like the larger bioenergetic view, the larger evolutionary view, the electrophysiological view, is a means of, I mean, just like anything is a means of our body's responding to their environment. And it helps. Insulin resistance specifically helps our body partition nutrients and substrate meaning carbohydrates and fat to different tissues. And so essentially, if certain tissues are utilizing fat, and are doing that adequately, they don't need more glucose. So those tissues become insulin resistant to prevent the uptake of glucose. And that saves that glucose for other tissues that might need it like the nervous system, for example, or the kidneys, or the red blood cells, or whatever it is. And so insulin resistance in itself is not necessarily pathological. It is an adaptive mechanism, which doesn't mean it's ideal, but it's an adaptive mechanism to an environment or to an internal, you know, an external or internal internal environment as a way of partitioning fuel into different tissues. And you know, this, this in the extreme state of, let's say, fasting, this is even more important, because we don't want our muscles using up all of our glucose, which is something that we have very little of, we don't store very well, right, there's only several 100 grams of glycogen, I mean, we store it decently well, but if we're fasting and not getting any more in, we have a very limited glucose supply relative to fat supply. And certain tissues preferentially use that glucose, specifically, our nervous system is the largest one. And so it's really important that our muscles don't use up all that glucose that our brain needs. And so that is why that sort of insulin resistance is going to happen in the state like that. And it's an adaptive effect. It's something we want to be aware of it doesn't mean it's beneficial or ideal. But it's, I think, a really helpful framework for understanding the role of insulin resistance in these states. And we did discuss this in a little bit more detail in Episode 83, we went through an extensive paper talking about fuel nutrient partitioning and how insulin resistance plays a role there. So yeah, just an important framework to keep in mind before we dig into some of the more detailed mechanisms.

Mike 29:25
Yeah, so I think it's important in terms of understanding this and how how I understood and how it helped me was understanding kind of like the different compartments, right? So you have the cell, then you have the bloodstream, and then you have the what's coming into the digestive tract in terms of carbohydrate and whatnot, right? And so the dysfunction that we're talking about lies inside the cell. And then that's when the ability of the cell to utilize that carbohydrate, and then everything else is getting backed up from there. So the way I think the way the Visualize this is kind of like the If you had a say or say to sell as a car, and you're filling up the car with gas, what happens is the tank is already full, and the car's engine is broken, so it can't use the gas. So no matter how much gas you keep trying to put in the tank, it's coming back out, it's the gas is leaking out, it's leaking out in all the different ways that it can go. That's the same thing with the cell and glucose. With this metabolic dysfunction, it's like no matter how much insulin you hit the cell with, there's just no more room in the cell. Because that that glucose is not being used, it's basically just building up and backing up. And then it being used only minorly, or not to the same capacity that it could be when you're using it through something like glycolysis, which we'll get into the specifics. So to that first piece that you were talking about with the dysfunction and whatnot, I think the central piece is a problem inside the cell. And then all the dysfunction that we see after that is a symptom of this specific problem. And so it's really important understand the problem lies inside the mitochondria. The problem lies with the ability of the mitochondria to oxidize that glucose fully and produce the What's it 32 to 30, or 3638, ATP, something like that, versus the two ATP you get from glycolysis. So again, the main piece of keep in mind is dysfunction in the mitochondria at the cell. Everything else extends back from that. And we're going to walk through all those processes. And what I want to mention here, and what I want to bring up to relate it to that piece you're talking about with the this idea of an adaptive insulin resistance understates of starvation or low carb diets or stress or something along those lines, is that the difference between this this, this state, this low carb state, or this fasted state, where you can eventually become insulin sensitive, again, where you can have carbohydrates and have things work is that in the low carb fasted states, the you're up regulating fatty acid oxidation, which basically inhibits your glucose oxidation. And it does that on purpose. As you're saying, Jay, it's an adaptive response. The cell is, the body is doing this on purpose to save this carbohydrate to spare it for the tissues that vitally need it. And then these other tissues, like the muscles and whatnot are more oxidizing the fatty acids. So it's an adaptive response. It's useful in those states, it's not ideal, because again, there's problems with oxidizing fatty acids long term. But essentially, what you see going on in that state is the insulin resistance caused by these states is by burning the fatty acids. Whereas in the diabetic state, and the impaired glucose tolerance state, fatty acid oxidation is central to that. But there's also some other dysfunction inside the mitochondria that is leading the mitochondria to be unable to oxidize the glucose. And so the the cell is basically just having to rely on fatty acids. So you have two states, they both have insulin resistance, one of them is easily reversible by just adding carbohydrate back into the diet and eating again, because there's not this severe dysfunction inside the mitochondria. And in the dysfunction was created here by the fatty acid oxidation. And then the other state is diabetic state, this obese state, you have a dysfunction inside the mitochondria that's requiring fatty acid oxidation, because glucose oxidation can't work effectively. Now, the last piece that I want to mention here is that running low carb long term running fasting and starvation type things long term because of the damage that occurs with oxidizing fatty acids. I think at least from my perspective, I think it's likely that you can transition from this in to start to getting into problems with your mitochondrial function, whatnot, because you're producing a lot of RLS, reactive oxygen species when you oxidize fatty acids. And again, we're going to go through the direct mechanisms. Now, Jay, has some good graphics to go through with us. So I'll leave it there.

Jay Feldman 33:38
Yeah, yeah. All all great points there. And again, just to clarify that distinction, what you're saying is that in one case, the fatty acid oxidation is the result of impairments in glucose oxidation, and then the other state, it is the driver of the lack of glucose oxidation. But that will become clear as we as we go through some of these mechanisms here, starting with these issues with energy production and what's actually going on. And one thing I want to mention before we dig into those issues is that if you are dealing with insulin resistance or other related issues, and as a result, you're dealing with weight gain, you know, low energy, brain fog, sleep issues, hormonal imbalances, or various other issues like that. I do have an energy balanced mini course, that you can go ahead and sign up for that walk through the basics from diet and lifestyle from that perspective, the basic things that you can change in order to improve your capacity for cellular energy production, which as we're getting to is really what underlies this state. So to sign up for that mini course, you can head over to Jay Feldman wellness.com/energy. And so, to start out here with these issues with energy production, the first thing that we have is issues with glucose utilization with the oxidation of glucose, the conversion from glucose, all the way through glycolysis, the Krebs cycle, and then through the electron transport chain to effectively produce energy. And instead as we'll get to that gets blocked. There's a buildup of intermediates, that glucose and state gets converted to lactate, and the cell is forced to rely on fatty acid oxidation. While because of these blockages, there's also a depletion in ATP, there's a lack of ATP production. So we have this here in this graphic, where essentially what we can see in more detail that we need, we're not going to go through each of the individual steps here. But the important point that we want to get to is on the left, we have this conversion from glucose to pyruvate, that's glycolysis, that pyruvate gets converted to acetyl. Co A and enters the Krebs cycle that's going on in the right there inside the mitochondria. And then different products of the Krebs cycle will then go over to the electron transport chain, which you can see at the top right there, which is where the ATP gets largely produced, there's a little bit that gets produced elsewhere. But that's the main site of ATP production. And so what typically is happening is that there are a number of different things, and we talked through these all the time on the podcast, there's a number of different things that can lead to issues during any of these steps, within glycolysis, within the Krebs cycle within the electron transport chain, most of them will actually go on at the electron transport chain and block, essentially electron transport and drop off at the electron transport chain. And that will then cause issues all the way backward. So that will often start things off. And then we will have issues within the Krebs cycle. And then we will have issues of blockages within glycolysis. And essentially, this is just due to, as you were saying, I think a really good analogy of the car and the engine, what we're, this is a an engine problem. This is the engine of the cell, where we're producing energy, the problem is not the gasoline that we're putting into glucose or carbohydrates. But the problem is that we're not effectively converting that glucose in all the way through into energy. So we have all this gasoline that's not being used properly, we have a car that's an ongoing, and yet we're blaming blaming the gasoline instead of the engine. And so this is that engine. And what is going to happen, we'll get to in a second, what happens when this is blocked. But the first thing I wanted to note is that as these intermediates all build up, you end up with a build, like a slowdown of the gasoline entering the engine, essentially. And so the gas tank gets full, right, that's like the cell is full of glucose, and can't accept more glucose. So that is an aspect kind of the first aspect of what's going on here blockage with the usage of glucose, and then a buildup of all those intermediates and a buildup of glucose itself.

Mike 37:29
Yeah, I think the other thing that you start to see too, is then the glucose starts to actually you have this blockage, and that backs up into the bloodstream. So you have if you look over at the right hand side versus Krebs cycle, and then you have that little magnifying glass of the electron transport chain, you get problems in the electron transport chain that leads to issues in the Krebs cycle that leads to issues in glycolysis. And then that leads to a backup of glucose in the cell and in the cell saying to insulin, Hey, man, I can't take any more gas, you already overfilled the tank, chill out, like just just back off a little bit. And then essentially, the the other thing is the reason why one of the major reasons why the cell can't take up that carbohydrate, or that glucose is because it's it's running fatty acids instead. So you're you have this other fuel that's going in, that's blocking the use of the carbohydrate, and then the carbohydrates getting backed all the way up. And then the body saying are the cells saying to the insulin, insulin go away, like, we're good, we don't need any more glucose right now, we can't even take any more glucose right now. And then you see a lot of you know, the lot of the pathways within glycolysis want to all get backed up. And then you get a whole bunch of dysfunction across those pathways. And what winds up happening, and I think you have the graphic right below j is that the instead of going instead of that glucose, turning to pyruvate, and then go into acetyl, CO a, it just gets shunted towards lactate. And so you just get this, this basically the body's like, well, whatever glucose we have, we have to, we have to kind of get rid of it, we need to make sure we have enough of these some of these important products like NAD plus and whatnot. So we're gonna just move it to lactate, we're not really going to get all the energy out of glucose that we want, we're gonna continue to burn these fatty acids inside the mitochondria. And then we're like, we're just gonna keep shunting things through there. And you see this in diabetics. And you see this and people with impaired glucose tolerance. And obese individuals, they're lactate values are higher, and then their fatty acid oxidation, their burning of fats is higher. And then they have all this glucose in the bloodstream and in the increase insulin levels in the bloodstream better because the cells are not responding. So that's this actually is a mechanism to explain why we're seeing the elevations in the glucose and the insulin and incorporates this a really important compartment that's not discussed in these other models as much as what's going on inside the cell inside the mitochondria as the central point and not what's going on inside the bloodstream and the association values in the bloodstream.

Jay Feldman 39:53
Exactly. And as you said, what's commonly seen because the glucose isn't going all the way through and oxidative phosphorylation isn't good. mingled with glucose, it gets converted to lactate. This is a backup mechanism that helps to regenerate NAD plus, which is important for kind of trying to salvage the issue. But the other thing is it allows that lactate to suddenly leave the cell. So you can keep converting some glucose lactate and produce a little bit of ATP. This is what happens when we use our muscles at a really high pace. And anaerobic state, you know, if you're sprinting or something will rely on this pathway, because it's very fast, even though it's very inefficient. And you can only do it for a very short period of time. So even this pathway will get backed up as well. But it's one of the things that you do see happening when you're not fully oxidizing the glucose, and as you said, you'll see higher levels of lactate. In the States. You also see elevations of lactate dehydrogenase, which is the enzyme that converts the pyruvate to lactate. So those things are both seen here. And then the other thing that happens, of course, the cell needs ATP. And so if it's not able to effectively oxidize glucose, and it's again converting some of it to lactate as a defensive mechanism or a mechanism to try to get some amount of ATP. The other thing it does is it starts to rely on fatty acid oxidation, because these two things are essentially opposed when it comes to cellular respiration. So when there's this issue with glucose oxidation, and we're relying on glycolysis, for some amount of energy in terms of producing lactate, it's not going to get us very far. And so then the other thing the cell will do is start to use fatty acids as a fuel. This will allow the cells to produce some amount of energy. But it comes at a major cost due to increase production of reactive oxygen species. And as a result of that, and some things that happen in the electron transport chain, it's does two things. One is it slows down respiration, it slows on the production of energy, but it also further blocks the utilization of glucose and then the uptake of glucose. So we're going to go through that very briefly here. And just explain how fatty acid oxidation then goes and actually blocks the usage of glucose further, and also blocks the uptake of glucose. And this is a key feature of what's going on in the cell and insulin resistance. Yeah,

Mike 42:01
so essentially, what you see here is you have a picture of the electron transport chain. Now I'm not going to go into all the exact specifics of how this works. If you want to know how this works, I do have a video discussing it on my channel, microwave, it's a microwave on YouTube, or my face science. And it's essentially what you're seeing with fatty acid oxidation. So you see on the bottom there, it says beta oxidation. And on the left there you see glucose. Now with the beta oxidation, you get an increased amount of that value that is pointing to called FA D h2 in ratio to NADH. Whereas with glucose, you get more NADH and ratio to that FA D h2, then those things change what goes on at the electron transport chain here. And with that, what winds up happening is you get a buildup of that NADH when you're burning fats. And that leads to problems when you go into the Krebs cycle, which is the picture right below, specifically at that the enzyme up top pyruvate dehydrogenase or PDH. And so what happens is if you don't so NADH and NAD are kind of the same compound, they just one has electron more electrons than the other. And what happens when you burn fats, you get too much NADH, and you don't have enough NAD. And then that shuts down that enzyme there that you see converting pyruvate into acetyl, CO a, it shuts down pyruvate dehydrogenase. Now the problem with that is that prove at hydrogenase and pyruvate are what are the main products that's created from glycolysis. So if you have heard of Adi drogyny, shut down, because you're burning a bunch of fatty acids, you can't feed pyruvate, which is created from the splitting of glucose and glycolysis, into the Krebs cycle. And if you can't feed glucose into the Krebs cycle, there's only so many places else it can go including glycolysis. And so what you're left with, which is what fatty acids can produce is just the Acetyl Co A, so the fatty acids will produce that Acetyl Co A and the fatty acids will continue to run the Krebs cycle, and the glucose will continue to be blocked. And again, it's kind of this weird feed forward loop that continues to happen because as you burn more fatty acids, you block PDH even more so and then you can't bring that glucose into the Krebs cycle. And it's so it's in this is actually something that's really important for anybody interested in all the hormetic stuff, as you're looking at, oh, it's really you know, what's this NAD to NADH ratio. And why is that so important? And it's because it's involved in the reactive oxygen species production. And all this. All of the defensive pathways in the cell and fatty acid oxidation, which is something that's discussed as a as a healing strategy inside the hormetic spheres of the alternative use actually worsens the NADH to NAD ratio inside the mitochondria because it leads to this overproduction of FADH and NADH as as we just talked about in the electron transport chain, and drives an inability to oxidize glucose effectively by blocking that enzyme PDH which converts the pyruvate to acetyl. Co A. So essentially, then this goes with the metabolic flexibility piece. If you want to be metabolically flexible, you don't want to be oxidizing primarily fatty acids, because the fatty acids will inhibit The prove a de pyruvate dehydrogenase function, which will inhibit the ability for you to oxidize carbohydrate. And this whole process that we're describing is called the Randle cycle or the Randall effect. And so this is I mean, this is this is essentially, you know, this is, this is showing that the metabolic flexibility idea in terms of oxidizing permanently fatty acids is incorrect. This is showing that inside states where you're insulin resistant, or you're not able to oxidize carbohydrate, a key portion of that is oxidizing fatty acids. And the mechanisms are laid out here of how fatty acids are actually blocking that process very directly.

Jay Feldman 45:34
Right, and as you're saying, if you want to fix not only if you want to be metabolically flexible, but if you want to fix an insulin resistant state, avoiding the oxidation of carbs and focusing entirely on oxidation of fat, or trying to upregulate fat burning is going to do the opposite, it actually blocks your ability to utilize carbs. This is very well known if you look at any low carb or keto circles, where if they then go and take a glucose tolerance test, it will be terrible, you're very insulin resistant in that state. Again, as we had the caveat earlier, this is not the same as a state where insulin resistance is being caused by other means. It's instead of state where you're where this is being caused by just fatty acid oxidation over glucose oxidation, where you're avoiding carbs, but it is still insulin resistance. And the important point here in terms of this context, is that in this state of insulin resistance, whether it's caused by other means or it's caused by avoiding carbs, and we'll talk about what the other means are later, but essentially, it's things that block function at the electron transport chain or the Krebs cycle, essentially things that block up the engine and things that block mitochondrial respiration, that will force the cell to rely on glycolysis to lactate production, and fatty acid oxidation, both of which will block the uptake of glucose. Now that you were talking through the Randle cycle effects here are the Randle cycle or the Randall effect, as well as the NAD to NADH ratio being largely involved. We've discussed this in previous episodes, so I'll link back to those. But just to expand on one other point. So you mentioned how the increase in NADH to NAD plus ratio will block pyruvate dehydrogenase. And there's a couple other things that go on in the Krebs cycle here, which is one is that ISO citrate dehydrogenase, which relies on NAD plus also gets blocked, and that will end up leading to a buildup of citrate. And then the other thing is that you'll as a result of that also have a buildup of Acetyl Co A, the buildup of Acetyl Co A will block pyruvate dehydrogenase. And the buildup of citrate will then block glycolysis. And so we see that here, where you see excess Acetyl Co and excess excess citrate as a result of beta oxidation, the excess Acetyl Co A being another factor are blocked pyruvate dehydrogenase, and then that citrate in the cytosol will then block phosphofructokinase, which is the limiting rate limiting step of glycolysis. And will also block the uptake of glucose. And as you know the buildup of intermediates here will also further block the uptake of glucose. There are some other mechanisms that go on. But these are just some of the ones we want to highlight where essentially, when you're burnt when the cell is burning fat, this is how it blocks the uptake of glucose and causes insulin resistance. So it's really important to highlight that. And as we come down here, we can also see other steps. So we mentioned the phosphofructokinase step. But there's also a step farther down, which is glyceraldehyde three phosphate dehydrogenase where a low NAD plus NADH ratio will be inhibiting that step as well. So that's another area where we're seeing this. And it's just another important one to highlight. So, again, the mechanisms here are all just a way of saying is that there are ways of saying that when the engine is burning fat, that's going to block the utilization and uptake of glucose. So that is a huge component that we see in the state of insulin resistance.

Mike 48:44
And a couple of things I want to add, Jay, if you can go back up really quick to the electron transport picture, electron transport chain picture. So what you see there is if there's a little white box that says RLS and has the arrow going up, and that's the RLS is increased when you're burning fatty acids. And I think that over the long term, if you're chronically oxidizing fatty acids inside the mitochondria and out the electron transport chain, and you're building up a large amount of reactive oxygen species, those reactive oxygen species can actually damage the structures of the mitochondria. So the way you can think about it is when you're burning carbohydrate or you're burning fat inside the mitochondria, and you have the fat basically creates more smoke than the then the carbohydrates do. And then that smoke can damage the or the smoke can ignite the structures of the mitochondria. And that's what I think long term prioritizing fatty acid oxidation, whether that's low carb or whether that's intermittent fasting, whether that's keto, any of those things, you can actually lead to long term issues with mitochondrial function because of this production of reactive oxygen species. And this is especially in the case of somebody who came from a diet beforehand that was laden with large amounts of polyunsaturated fatty acids. Because the structure of your mitochondria are it can be come increased with those polyunsaturated fatty acids, which we've talked about this many times in many episodes before with the membrane, pacemaker theory and whatnot. But essentially, you can think of if your mitochondria is built out of steel, which would be the mono unsaturated and saturated fatty acids, it's less likely to melt in the face of this increased smoke or these fires that the fatty acids are creating. But if you start to make your mitochondria out of wood, which would be the polyunsaturated fatty acids, when you expose that wood to high heat into the fires and whatnot, then you start to get damage to that wooden structure. And then that that basically degrades mitochondrial function. And so I think long term running on fatty acid oxidation, actually leads to that. Now initially, you may find that the cell tries to create a defensive response, which you see. But the problem is, is how long can this defensive response be maintained? Right, because it, there's a chronic effect of this, and the selesa chronically be able to respond to it. And so this is again, like, I think that could be problematic. And that could even be inducing the dysfunction. And this is a, you know, this ties into a key piece that stress, which directly up regulates fatty acid oxidation. So you don't even have to do low carb, you don't even have to be fasting or starving yourself or anything like that. You can just be under significant stress, releasing a lot of cortisol and adrenaline and glucagon. And we'll talk about these when we get into the studies and in a later episode. But essentially, those stress hormones will directly increase fatty acid oxidation and directly increase reactive oxygen species production inside the mitochondria. And over time J and I actually talked about this in a paper that will actually damage the cell itself from the RLS. And in the mitochondria, it will be damaged, and it can't actually oxidize the substrate effectively. So this is another reason I think, to not oxidize the fatty acids, not just because it blocks glucose oxidation, but long term, I think that it actually causes damage to the mitochondrial structures and whatnot.

Jay Feldman 52:00
Right, and that increase in RLS, which is often referred to as oxidative stress will also impair the activity of different enzymes in the Krebs cycle, we've discussed this as well as something that is one of the main causes of not only issues with energy production, but also weight gain. And when you have increased reactive oxygen species, increased reactive nitrogen species, essentially increased oxidative stress as a result, often of increased reductive stress, you actually also impair function at the Krebs cycle, regardless of NAD NADH ratios, the enzymes and they're very sensitive, toxic stress. So that's another thing to mention. To others I want to touch on one is as you're getting at, there are other causes of RLS production and oxidative stress that are not just the utilization of fatty acids is a feel. And so we'll touch on those. I mean, it could be radiation, it can be stress damage, it can be heavy metals, it could be other toxic inputs, like endotoxin, it can be polyunsaturated fats. So a number of other things that we'll be touching on that create the state. And another thing I wanted to touch on here, it's actually two things. So one is just coming back to the Krebs cycle. figure here, when we're running fatty acid oxidation, because of the lower NAD to NADH ratio, it also just slows down the entire activity of the Krebs cycle. So when you're in this insulin resistant state, you're not just fine burning glucose, lactate, and burning fatty acids, but you're actually operating in an energy deficient state. And when we're operating in an energy deficient state, and this is kind of a sneak peak of the next point, we have to upregulate stress hormones in order to maintain our ATP production. So we survive. So normally, you don't see this until more intense versions of insulin resistance, where you actually see lower levels of ATP, and with aging. But this is happening early on as well. But then you just have, as you said, the defense of the reactions to restore that a detented H ratio and restore ATP production. But not only can we just not run those forever, but they come at a direct cost. Because I mean, essentially what it what they require is signaling that we're in a sub optimal state, which requires us to redirect resources from other tissues from other areas to support our basic functions. And then we end up with degeneration. So we'll dig into that here in a moment. But I just wanted to go over a couple of depictions of the difference between what we're told happens in insulin resistance versus what is actually going on. And so the simple version here of what we're told happens is that the insulin receptors on the cells lose their sensitivity. So the glucose that's in the blood here, can't get into the cell, the cells are just left with a lack of glucose, actually, they can't get enough glucose and your that that is what causes this insulin resistance state. But as we're saying, as the result of problems with glucose oxidation, the conversion of glucose lactate and especially the reliance on fatty acid oxidation that results from those things. That's not actually what goes on and instead what goes on There's a cell that has actually high levels of glucose. And those high levels of glucose go to block the uptake of further glucose and block the quote, you know, activity or response to insulin. And also, if we could throw other things in this graphic, we would see an engine in there running on a lot of fat, also blocking the uptake of glucose. And so that is the key difference we're wanting to get here, get at here, which is, again, a very important takeaway, because it completely changes the recommendations as far as what we want to do to resolve this issue. Yeah, yeah.

Mike 55:33
And I think the important piece to important thing to understand is, all of the hormones and neurotransmitters are signals from some cells to other cells. And what happens is, those cells still have to respond to the signal. And the what's going to determine the cells response to a signal is that cell state in the resources that it has available to it. So if you have a cell that's completely backlogged with glucose, and it's burning a bunch of fatty acids, of course, it's not going to respond to insulin. I mean, I think that's, that's like relatively self explanatory, because there's nowhere there's nothing for the cell to do with the insulin. It's not, it can't take up more of those carbohydrates. And that's the same for thyroid hormone. That's the same for stress hormones, that the cells don't have adequate carbohydrate availability, because of the low carb diet, starvation, whatever the thing is, though, and there's a lot of cortisol and adrenaline and glucagon floating around, even if the actual serum values aren't super high. Again, the cell doesn't have that carbohydrate, it's gonna run on fatty acids. So it's gonna rely on this upregulation of the adrenaline and the glucagon and the cortisol to drive these processes. And it may be the serum values aren't super high, but the cells are going to be responding to these more potently, or you can have increased metabolization of cortisol into its active form and things like that. So whether it's insulin, thyroid, whether it's cortisol, glucagon, adrenaline, it's important understand, and I think this is the piece that's missing inside the mainstream views. And inside the alternative views is what is happening at the cell. The cells aren't just dumb, inanimate things, that that don't have a response to stuff. The cells are intelligent, organized units, or organisms in and of themselves to some extent, that are responding and adapting their response and their use of energy based on the context that they find themselves in. And then the hormones and processes that are overlying everything, are basically a way of the body to try to organize response to this external environment. And so that's really important understand, like, you have to know the cellular context, then you can see what the messages are overall with the hormonal stuff in the neurotransmitters stuff. And then now you have a complete picture on what's going on. But if you're just looking at what's going on in terms of what's going on in the blood, or what this hormonal things in this, and that you're not going to get a full picture, because you're not you still have this component that where the cells are actually having the effect, right? It's not the hormone in the blood that's having the effect. It's the hormone hitting the cell, and then the cell responding to that hormone. So it's really important to get down to that piece of what is this responding element doing? Not just what is the message to the responding element?

Jay Feldman 58:13
Right, right. And as you're saying, the cells are part of a cohesive adaptive intelligence system. And so we don't want to regard the cells response as the problem, it's a response. It's an effect of what's actually going on underneath, inside the cells like inside the tissues inside the cells. Yep. And so as you were saying, as a result of the underlying metabolic problems, we then have issues with glucose uptake. And then we have the hormonal response. So the cells aren't producing enough energy, they're not producing enough ATP. So there's this response of stress hormones. This is what the stress hormones respond to. It's why they increase when you exercise or when you fast or when you have cold thermogenesis. Anytime Our demands are greater than our supply of energy, the stress hormones get released. And so this is happening, just that baseline and the state because we're not effectively converting the glucose to energy. We're relying excessively on fatty acid oxidation, which for any metabolically active tissue, you know, other than like muscle at rest, typically, there's a couple others. But typically, we need more ATP than we can get from the high RLS HTTP ratio of fatty acid oxidation and all you know, the low NAD to NADH ratio, all of those things that we went through. So this causes a stress response, and it causes the release of glucagon, adrenaline, and cortisol, to whatever extent they're needed. Again, as we adapt to this, we'll just rely more on something like glucagon unless we acutely increase those needs, and then we'll dip more into cortisol and adrenaline. But in any case, these are the backup systems that increase the production of ATP when there's underlying dysfunction. So we see elevations in those things in this state of insulin resistance. And they actually further drive the pathology to a to a pretty dramatic extent, they cause this kind of positive feedback loop. So the stress hormone it'll do a number of things that drive these processes, they'll directly increase and upregulate fatty acid oxidation. And they have effects on different enzymes within the cell that do this, but also will just stimulate the cells or the cells as a whole to stimulate fatty acid oxidation, they'll also stimulate the release of free fatty acids, which will then further increase fatty acid oxidation and impair glucose uptake. They also will stimulate hepatic glucose production. And this is something that comes into play specifically here, with insulin resistance when somebody is especially seeing higher fasting blood sugar, this is due to the response of the stress hormones that are increasing gluconeogenesis at the liver, which will increase the fasting blood sugar, that's where that glucose is coming from. And a lot of people notice this on low carb diets, and they're like, you know, I'm not consuming the glucose. Why is my fasting blood sugar increasing? Well, that's typically a sign of increased stress, increased stress activity, that's increasing gluconeogenesis at the liver that's putting out that glucose. And again, the the highlight here is that this is another effect of the stress hormones that furthers this process. And together, all of these things further drive insulin resistance, they further block glucose uptake and utilization, and they increase the symptoms of insulin resistance as well. Basically, they increase the blood sugar response to, to any sort of carb meal or carb snack, or carb intake, they'll also increase fasting glucose, and they'll increase insulin, because when there's elevated stress hormones and these issues at the cell with glucose oxidation, it requires higher levels of insulin to then increase glucose uptake and utilization, and decrease the stress hormones, which is one of the the main actions of insulin is to decrease the stress hormones, which helps to decrease fat free fatty acid release, decreased fatty acid oxidation, and decrease the hepatic glucose production. So that would be the main kind of at Adaptive effect here. And the main thing that then further drives this loop at a major cost, but kind of closes out these different aspects of what really is going on in terms of insulin resistance.

Mike 1:02:07
Yeah, it's something that I want to point out here is that the insulin is actually is helpful or protective in these circumstances, because the insulin is lowering free fatty acids, and is helping to lower that glucagon, where the glucagon is increasing the livers production of glucose through that process of gluconeogenesis. And so you basically, the insulin is taking the stress down, and in the way it's lowering the blood sugars, when it takes the stress down, it's allowing the cells to lower the burning of fatty acids, and and to uptake a bit more glucose and maybe help to maybe it doesn't fully improve glucose oxidation, it really would depend on the person's state. If you're in a diabetic state, it doesn't necessarily improve the glucose oxidation, but you're in a low carb state, or any of these other things that will actually start to help you to improve the glucose oxidation by lowering the free fatty acids. So the insulin is actually helpful is actually protected, it's signaling to the body that you have adequate amount of substrate in the form of carbohydrate, which is absolutely vital to optimal functioning, particularly exogenous carbohydrate, because again, your body will make that carbohydrate if you don't have enough through gluconeogenesis. But again, this is a stressful process. And we talked about this, I think in the ROB wolf episode going through what's the consequences of increasing glucagon too much to increase your glucose output from the liver. So I wanted to highlight the value of insulin here and not and change it from this frame of insulin being the bad guy. And insulin driving obesity, insulin, driving diabetes, and insulin driving all these problems to insulin kind of being a bystandard on a process. And actually, even more than that being a helpful thing that can help to lower the free fatty acids and lower that stress response. But again, it doesn't cure this situation overall. And and even in their studies with diabetics who are given insulin therapy. And the insulin therapy helps to improve their outcomes, especially early on, by lowering those free fatty acid release and lowering the glucagon and hypochlorite hyperglycemia. From the elevated glucagon levels and whatnot.

Jay Feldman 1:03:59
Yeah, and a key point that you're highlighting here is if we're using glucose effectively, then that is for sure situation, we're increasing the intake of carbs, or just consuming carbs. And increasing insulin is the most direct way to turn down stress to turn off stress to turn off the stress hormones, because those are responding to what's going on at the cell in terms of energy production. And the glucose helps to restore that. And insulin itself also directly goes toward turning down the stress hormones. Of course, as you know, as we're saying here, if you're not utilizing the glucose, well, that won't happen as much, but it still will happen. And as as you're saying, even in the States, increasing insulin is protective. And increasing glucose is protective, protective, and actually, the increase in blood sugar is a protective action to try to increase the glucose uptake due to the gradient helps to increase the gradient between the blood glucose and cellular glucose. These are things we'll be digging into when we dig into studies in a future episode, discussing all these things. And again, the last point to mention that again, we'll be discussing then, is increasing carbon intake, even in the insulin resistant state, even in a situation where someone has type two diabetes still helps to improve insulin sensitivity, it still helps to turn down the stress, which is underlying the state the the stress that's, that's caused by the inhibited energy production. Now, one last point I want to mention here is that this highlights that the insulin effects are secondary. So when you're seeing the impairments and glucose uptake, or the response to insulin, this is not due to the cellular response to insulin, it's due to the underlying issues with glucose oxidation, the excess fat oxidation that we described earlier. And so again, it just really, totally contradicts or is, is in contradiction with the mainstream and alternative views as far as that goes and leads to a completely different picture, as far as the cause here. And then also, as a result, the solution which is the next thing that I want to mention here. So as we're getting at what the underlying problem is an issue with utilizing and converting glucose energy, the solution is to fix that process. And that process, as we've kind of loaded of alluded to, throughout this episode, is affected by virtually everything in our environment. So it's affected by the type of makin macronutrients we consume and the balance their different ratios, those things will have an effect. It will also be affected by the types of foods that are coming in their micronutrients that will be affected by our gut health, were one of the main things that interferes with glucose oxidation, the burning of carbohydrates as a fuel is endotoxin, which is a component of bacteria in the intestines. And a number of other things that we talked about as well. Right, we mentioned the polyunsaturated fats being another factor here. We also mentioned stress we mentioned, I don't know if we mentioned poor sleep, but that's another one, that's certainly a factor here. And so all of the things that we talked about throughout the podcast, today, like are all focused on this, they're all focused on how we fix our capacity for energy production, which is what fixes insulin resistance, it is the exact the exact situation. And so it's like, obviously, it's a complex problem with a lot of different inputs, a lot of different things to tweak and adjust. But essentially, if we get our foundations right in terms of diet, in terms of blood sugar management, in terms of in terms of gut digestion, terms of sleep, and turn, in terms of sunlight, those things will cover the vast majority of the major things that will go toward restoring insulin sensitivity. There are a couple of specifics that I'll mention, but that would be the general framework, the general starting place when it comes to fixing insulin resistance. And so I'd recommend working through earlier podcast episodes where we've discussed things, whatever is relevant to you, if you're dealing with gut symptoms, if you're dealing with sleep symptoms, if you're dealing with these sorts of blood sugar issues, you know, listen back through those kinds of episodes. It's also worth mentioning that in Episode 101, a one, we really laid out what we would suggest from a dietary perspective. And so I'd recommend check, taking a look at those episodes, for getting a solid starting place as far as the dietary framework goes, and building a diet that's going to help to restore insulin sensitivity. There are a couple of caveats and a couple of specifics that I do want to add in that might be helpful in the state. But I'll let you go ahead first, Mike. So

Mike 1:08:18
the major thing I'd say is, if it's some if somebody's coming from low carb, or they're coming from intermittent fasting, and one of those backgrounds, and that circumstances we mentioned, the goal is to lower the free fatty acid oxidation. So that's to basically start to incorporate carbohydrates in the diet. And I think that and adjusting the diet, as we discussed previous episodes, or I have a nutrition blueprint that you can pick up on my website, Mike fave.com. Those things alone, I think will be enough to help get somebody out of that fatty acid oxidation and that physiologic insulin resistance state that we kind of described, if you're just doing low carb or intermittent fasting or keto or something like that, or carnivore. Now if somebody has is in a diabetic state, or they're dealing with obesity, or they're dealing with like the significant metabolic dysfunction, where it's the fatty acid oxidation is a problem and a component. Having adding in carbohydrates and adjusting the diet will be really important. But as you kind of touched on Jay, there's a couple other areas that you want to make sure. So you want to make sure you have nutrient depletion, you want to make sure you don't have any toxins, impairing your your production of energy, that's endotoxin, that's Kufa, that's heavy metals, it's any of those types of things, you want to make sure that you're taking down the stress hormones, because the stress hormones are another big piece. And then you want to make sure that you're supplying the mitochondria with the necessary things that they need to actually optimize their function and minimize the reactive oxygen species and things along those lines. So there's a lot more that goes into that insulin resistance state that's caused by metabolic dysfunction with diabetes, or obesity. And then that circumstance usually more work needs to be done than just adding in carbohydrates alone and it's a little bit more difficult to troubleshoot because again, the problem is this oxidizing it the problem is oxidizing carbohydrates inside the mitochondria and there's there's something going on there and in A person's situation that's causing that dysfunction has to be determined. And those things have to be addressed. Whereas in a low carb or whatnot, it's usually you're just running out a bunch of fatty acids. And you need to minimize your fatty acid oxidation and start to really start to incorporate carbohydrates. Three oxidize the carbohydrates. But the first place for both of them, again, is fixing the diet and adjusting the diet appropriately. That's foundation level. And then you can start to get into supplementation and different lifestyle factors in your sleep and your stress and all these other components. But dietary component is the one of the major things and again, for I cover the setup for that in the nutrition blueprint on my website, Mike dave.com.

Jay Feldman 1:10:38
Yeah, yeah, absolutely. And, of course, it for each individual, different factors might be might have more of an effect, right? If somebody's diet is already decent, they might have more benefit by improving their sleep or something like that. But in any case, what you're getting at is fixing the foundations goes the longest way, for sure. And in the vast majority of cases, that's enough, right? We don't have to do anything extreme. It's just making sure we're getting adequate amounts of the macronutrients, which are nutrients, adequate amounts of calories, adequate amounts of micronutrients, and avoiding certain excesses of micronutrients. You know, we've talked about these things throughout throughout our podcast episodes, you know, fixing up gut health, which is huge, getting good consistent sleep, I mean, the All of these are going to, in the vast majority of cases be enough to resolve the issue. However, if somebody is looking for extra to do on top of those, maybe they've already covered a lot of those, and they're looking for some extra support, there's maybe a few things that I would go to that would mention here. One is, in terms of the macronutrients, one tweak that I would certainly make is lowering fat intake. Now when we talked about fat intake, normally, what we discuss is we want to eat the amount of fat that our bodies need, we want it as a nutrient that has vital needs for every cell in our body. So we want to make sure that we're getting enough. But we don't need like, we don't want to have more than we need. Essentially, if we're dealing with insulin resistance, typically, we are already having a lot of fat released due to the underlying stress state as we discussed. And so there's already a lot of circulating fat circulating fatty acids. And so we typically don't need to consume as much because the fat is already available there. So that's one thing to consider is that lowering the fat in this case, can help to prevent excessively high free fatty acids, which can help to, you know, increased oxidation of glucose. And just in general, our fat needs will be lower. So we typically talk about a fat macronutrient percentage of around 20 to 40% of total calories. This would be a case where you would typically want to test going on the low end there around 20%. And maybe in extreme cases going a little bit lower to like 15 or so. But it really depends on the individual. It depends on their responding, you know how they're responding. And we talked through these things in Episode 101. A one, you want to make sure that you're not having big blood sugar crashes from not having enough fat for your muscle to run out, for example, which is going to waste the glucose faster and cause dips. So there's nuances there. But that's a factor to consider. Another factor I'd mentioned that can help, again, on top of the fundamentals, or after the fundamentals would be increasing, gentle movement. So consistent walks, and especially walking after meals can help quite a bit if someone's particularly insulin resistant. It just not being sedentary. We talked about this all the time, how much how important it is not to be sedentary, it's way less important to get intense movement in but not being sedentary makes a huge difference. And so that would be another one that we would generally want to implement would be consistent, gentle movement, and especially walking after meals can help if someone's particularly insulin resistant. And then on the supplement side, I'll just mention a couple that come to mind that are extra supportive of glucose oxidation. One of these would be the B vitamins. And generally I'd recommend getting a like a complex that covers all of the B vitamins that are involved in mitochondrial respiration because there's a number of them, but also in particular, vitamin b1 and vitamin d3, which are thymine and niacin, and we would prefer the nice and a mild form of niacin. Those can be particularly helpful for increasing glucose oxidation. And so sometimes higher doses of those can be appropriate and can help a little bit extra when someone's in a state like this. And then the couple other supplements I would mention, one would be vitamin E, which can help to protect from the polyunsaturated fats. So if we've been consuming a lot of Kufa for a while, and we have a lot of free fatty acid release from the adipose tissue, that can mean we have a lot of proof of circulating which is a huge problem for mitochondrial respiration due to their susceptibility to poor oxidation due to the issues we've discussed in the past where they basically interfere with the efficiency of mitochondrial respiration when they're incorporated into the lipid structure of the membranes. So Vitamin E can help with that. And it can also help to lower the free fatty acids a bit further if we have excessively high free fatty acids that are interfering with the glucose oxidation. Again, typical It's more of an effect than a cause, you could say, but it furthers the process. And then along with that aspirin is another supplement that can be used to lower free fatty acids and stimulate glucose oxidation, as well as lowering inflammation, which also interferes with glucose oxidation. So a number of reasons why those can be helpful. The last two that I mentioned, one would be methylene blue as another one that can restore proper glucose oxidation, and therefore help, you know, restore the insulin sensitivity. And lastly, would be considering the hormonal side. So again, all of these are things that we want to consider after the foundations aren't checked. But looking at hormones can can be huge here tracking thyroid hormone status, and we just recently did a series on thyroid so you can refer back to that series. And also looking at the reproductive hormones, making sure testosterone is adequate for men. For women, you know, they're cycling regularly and relatively symptom free and have enough progesterone and not an excess of estrogen. Because low testosterone and excess estrogen and low progesterone can all contribute to an insulin resistance state by preventing effective glucose oxidation. So refer back to episodes where we discussed the male and female hormones in more detail. But those are all worth mentioning. Here's maybe some extras when it comes to insulin resistance.

Mike 1:16:16
Yeah, I mean, I don't have too much more to add to those specific ones. It's, for me, it's diet, getting the micronutrients stuff, and then avoiding the different toxic components. And then depending on the person's circumstance, starting to dial in with the different supplements and components that can help them directly target their ability to oxidize glucose. So whether you're targeting pyruvate dehydrogenase function, as we talked about to get glucose to flow effectively, or you're trying to lower cortisol, adrenaline and glucagon, or you're trying to increase the function of the mitochondria, or trying to decrease endotoxin. At the gut, there's a variety of strategies and areas to look to and systematically go through to improve insulin sensitivity and minimize a oxidation of fatty acids and get the mitochondria functioning. And so in that diabetic state, there's a there's a lot of things, at least for me that I work through in a systematic fashion with people to start to improve that state and add and kind of a step by step process. I think that helps most that people can see what's working for them, what's not working for them and kind of get to the what the root is in their particular circumstance. And it's I would just want to add here in these cases, is it going like high fat, low carb, a lot of the goal is to get the person to be able to tolerate carbohydrate, again, not to just like, see, oh, the blood glucose levels are lower now, or Oh, my CGM is or flat because I don't have any carbohydrates or something like that. It's to be able to have their body taking carbohydrate utilize it effectively oxidize it fully into ATP, and lower that reliance on free fatty acids and the stress hormones. I think, understanding that is central. And then that's where you start to see how are you going to go about interventions after that.

Jay Feldman 1:17:56
And again, just to clarify something that we talked about a little bit earlier with misconceptions. The idea here is not that you just consumed the amount of carbohydrates that you quote, tolerate. Carbohydrates aren't something that we tolerate, there's something that's very supportive, by lowering stress, you know, supporters of are supportive of our metabolic state by lowering stress hormones, increasing thyroid activity, you know, a number of other things that they make a huge difference for, that we talk through all the time. And I know you were saying tolerate I mean, the, you know, there's things like the glucose tolerance test where it's like, baked into the scientific nomenclature here. But I, what I'm trying to get at is the people who are saying, you know, if you're insulin resistant, only consume 50 grams of carbs, or 80 grams of carbs are again, totally missing, what's actually going on that's causing the insulin resistance state, it is not the amount of carbohydrates. And as we were saying, increasing carbohydrates, even in someone who has insulin resistance helps increase insulin sensitivity. So by avoiding the carbohydrates, you're actually driving the whole problem further. And as we said, you're driving the stress hormones further, which is a huge part of this loop. And you're going to be long term decreasing things like thyroid hormone activity, due to impairments and the conversion of T four to T three other things along those lines decrease in testosterone production. So again, these are not the solution here and trying to tailor your carb intake to your quote, carb tolerance is completely missing the point here. Do you have anything else that you want to mention as we wrap up here?

Mike 1:19:24
No, no, I think we, we covered and we'd like discuss many of the solutions many times over. So yeah, I think it's pretty solid on my end, right.

Jay Feldman 1:19:34
And as we were saying, there will be some follow up episodes in the near future digging through the research behind all of these things. So if you're someone who is still skeptical that this is an accurate depiction of what's going on, of course, we encourage that and we'll be digging into some really solid evidence for this for this view and some future episodes. So with that, if you did enjoy today's episode, please leave a like or comment if you're watching on YouTube. Please leave a review. If you're listening on iTunes, as well as a five star rating. Those things do a lot to help support the podcast. To check out the show notes where I will be linking to articles other podcasts episodes other things that we referenced throughout today's episode, you can head over to Jay Feldman wellness.com/podcast. And if you are looking for guidance in terms of reversing insulin resistance and optimally supporting your metabolism, losing weight, improving digestion, getting amazing sleep, balancing your hormones, and so much more with clear action steps and strategies alongside personal guidance from me, then head over to Jay Feldman wellness.com/solution where you can find all of the information for the energy balanced solution program. This program includes customized health coaching, a video library which includes videos on regulating blood sugar, restoring gut health, losing weight without destroying your metabolism, boosting your metabolism, getting amazing restorative sleep, rebalancing your hormones and tons more. It also includes resources like a sample meal plan and supplement guide, as well as a private community. So head over to Jay Feldman wellness.com/solution Check out all the details. And with that, I'll see you on the next episode.

  • David Mills
    Posted at 13:34h, 21 March Reply

    Can you please comment on this : Dr. Robert Wolfe one of the co-discoverers of the Randal cycle says it is false here in this interview with Dr. Gabrielle Lyon: https://www.youtube.com/watch?v=7jcWcY-pypo. He says that Randal said before he died it was not true and they basically proved it was not true. They say that in fact glucose hinders fat metabolism not the other way around? That no matter how much fat you have available or are burning, the body will burn glucose when available in preference over fat. I know the supposed science that says abundance of fat hinders glucose, but is there any other types of evidence of the Randal Cycle? Such as the experiments these guys ran that are pretty convincing that it is false. Thanks!!

  • Leslie Schwager
    Posted at 16:57h, 23 March Reply

    So helpful! The more I listen, the more this makes total sense — that if you avoid glucose intake through extreme restriction of carbs, the body is having to work harder to deliver glucose through backup processes such as free fatty acid production, which involves increases in glucagon, cortisol and adrenaline, which is a stress state, creating a vicious cycle. Thank you for your many explanations! I hope I got that right!

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