Ep. 113: Carbohydrates Don’t Cause Insulin Resistance or Diabetes; Evidence For The Bioenergetic View 

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In this episode we discuss:

  • Insulin resistance and type 2 diabetes are diseases of excess fat burning and impaired glucose metabolism
  • How increasing carbohydrate intake improves insulin sensitivity, even in people with type 2 diabetes
  • Evidence supporting the bioenergetic view of insulin resistance and type 2 diabetes
  • Why carbs are not actually the cause of insulin resistance and diabetes

0:00 – intro 

1:28 – what the mainstream view of insulin resistance gets wrong when it comes to what causes insulin resistance and diabetes 

3:24 – glycolysis and fat oxidation are favored, and glucose oxidation is inhibited in insulin resistance and diabetes 

8:39 – what happens to glucose in diabetic cells 

10:32 – why insulin resistance is a symptom rather than the driver of diabetes

12:55 – research showing that insulin resistance is driven by poor glucose metabolism 

20:50 – impaired glucose uptake is not caused by excess insulin; fat-burning and impaired glucose metabolism are the culprits  

27:10 – the problems with relying on fat oxidation over carbohydrate oxidation

30:43 – how increasing blood glucose levels or increasing insulin can restore normal glucose uptake in diabetes 

35:28 – how insulin actually lowers blood sugar and the effects of insulin on cortisol and other stress hormones

37:16 - why fatty acid oxidation is NOT the underlying cause of insulin resistance 

40:06 – factors that support or block mitochondrial respiration

41:20 – how excess fatty acid oxidation contributes to the pathology of insulin resistance and can impair glucose metabolism over time 

42:49 - how insulin actually lowers blood sugar and the effects of insulin on cortisol and other stress hormones (cont.)

 47:08 – why we don’t want to blame insulin for insulin resistance and what really causes high fasting blood glucose

49:22 – how low-carb diets increase stress hormones and decrease insulin sensitivity

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Jay Feldman 0:05
insulin resistance is actually a state of excess fat burning and impaired glucose metabolism. We're going to be discussing why that is today's episode of the energy balanced 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 through the research showing that insulin resistance and type two diabetes are actually diseases of excess fat burning and impaired glucose metabolism. We'll also be talking about how increasing carbohydrate intake actually improves insulin sensitivity, even in people with type two diabetes. We'll also be discussing the research showing that fatty liver disease and cardiovascular disease are both characterized by excess fatty acid oxidation, we'll be talking about the real cause of insulin resistance and diabetes, and evidence for the bioenergetic view of insulin resistance and type two diabetes. This will be a two parter and so we'll be discussing all those things throughout these two episodes. To check out the show notes for today's episode, where I'll link to the studies articles, and anything else that we reference. Throughout today's episode, you can head over to Jay Feldman wellness.com/podcast. And with that, let's jump right in.

So we already had a recent episode discussing a broad overview of the bioenergetic view of insulin resistance and type two diabetes, where we went through the broad mechanisms overall, what's going on in the state, what's actually causing insulin resistance, essentially, this being a state of impaired glucose metabolism, leading to excess fatty acid oxidation and excess excess lead lactate production, alongside excess stress hormone production, and how all of that contributes to the pathology of insulin resistance and so today's episode and the following one, we'll be digging into the details as far as the evidence goes, and kind of expanding on on this picture a little bit, digging into various studies that support this view and actually demonstrate that this is what's going on in insulin resistance and we'll start by going over the evidence showing that glucose oxidation is inhibited and insulin resistance and diabetes, whereas glycolysis, the production of lactate from glucose, as well as fatty acid oxidation are favored and this is extremely important because it is still commonly pervade even by some very major health figures in the alternative health industry, that in insulin resistance, the whole problem is that you're just burning glucose and you can't burn fat, that is the state of insulin resistance and inability to burn fat, you're not metabolically flexible and so that is the problem when we need to get you burning fat and in reality, as we'll get to here, that is very far from the case, it's essentially the exact opposite of the case, where the cells can't affect effectively oxidized glucose. They're producing some lactate from glucose, are largely relying on fatty acid oxidation for their energy, and that contributes to the pathology contributes to the insulin resistance and we need to reverse that and fix the glucose oxidation to fix this issue. So do you have anything to mention here? Mike, before we dig into these studies?

Mike 3:17
No, I think that we should just jump right into the studies and and get into those specific mechanisms. Awesome.

Jay Feldman 3:23
So all mentioned this first study, and I might you can jump in with the second one after but in this study, what they're essentially showing is they're looking at different levels of well, so in this study, they're looking in type two diabetes and they're doing a few different trials within this paper, looking at what's going on in terms of glucose levels, and insulin levels, and how this affects what fuels are being utilized and how well they're being utilized. And so, what we're going to highlight, I'll kind of walk through a few of the different points here but what we're going to highlight in this part that suggests are demonstrates that glucose oxidation is inhibited here, whereas glycolysis and fat oxidation are favored. What they essentially show is that a couple of things, one is in insulin resistance and type two diabetes, there can be glucose uptake problems and they circumvent that with hyperglycemia so high blood sugar, and hyperinsulinemia so high levels of insulin and this restores normal glucose uptake. And this is generally what is going on and someone who's insulin resistant, they have high glucose and have high insulin as a way to force glucose uptake so we know that glucose uptake is not being limited here, the cells are able to take up glucose and then they see what happens with in terms of how the cells and the mitochondria are using these fuels and what they find is well taken here is that there's elevated levels of glycolysis. The conversion of glucose to lactate, but not glucose oxidation, and there's very high levels of lipid oxidation fatty acid oxidation and the only way that lipid oxidation gets suppressed is with high levels of insulin and We'll dig into that as well and the it's another important piece of evidence here.

So this study is titled, characterization of cellular defects of insulin action and type two non insulin dependent diabetes mellitus and we will come back to this paper a couple more times because they do some comprehensive studies here that really give us a clearer picture of what's happening in different versions of types of diabetes are different states within type two diabetes, depending on insulin levels and glucose levels and things like that but so the important one here is looking at study 1 and 2. So study 1 is, let's see. So I'll just read through this intro the first time and then when we go back to the study later, I won't reread it but so they're using seven non insulin dependent diabetes mellitus patients in three different clamp studies and study number 1 is you glycemic meaning normal blood sugar and normal insulin also, you insulin a genic. Study 2 is hyperglycaemic. With normal levels of insulin, study 3 is euglycemic, meaning normal levels of glucose with high levels of insulin and then I believe there's a study that will take in later. So in study 1, glucose uptake was decreased so this is a situation where because there's not elevated insulin, there's still some issues with glucose uptake and in that state glycolysis, glycogen synthesis and glucose oxidation were reduced and non oxidative glycolysis, meaning glucose to lactate, and lipid oxidation were higher. So if there's not elevated insulin, that's what we're seeing, we're seeing reduced glucose oxidation, and high levels of lipid oxidation and high levels of non oxidative glycolysis. Then in study two, so this is the one that had was hypoglycemic with normal levels of insulin glycolysis so it says study to glycolysis, but not glucose oxidation was normal. So and then non oxidative glycolysis remained higher so in this situation, the elevation in in blood sugar was able to increase just glycolysis but it wasn't actually able to restore glucose oxidation. So again, we're seeing this, that in this situation, there's not going to be normal levels of glucose oxidation and then they also say glycogen deposition increased and lipid oxidation remains higher. And then in study three, this is the one with hyperinsulinemia hyperinsulinemia. So in study three hyperinsulinemia, normalized glycogen formation glycolysis and lipid oxidation, but did not normalize the elevated non oxidative glycolysis or the decreased glucose oxidation. So there is still decreased glucose oxidation, there's still elevated glucose lactate, but we had normal levels of glycogen formation and lipid oxidation and they summarize this at the end and they say, market hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and non oxidative glycolysis. hyperglycemia cannot overcome the defects in glucose oxidation and non oxidative glycolysis and then lastly, lipid oxidation is elevated and is suppressed only with hyperinsulinemia. So what we're seeing here is that this is a state that's favoring lipid oxidation, unless there's high like hyperinsulinemia, which we'll come back to, and where glucose oxidation is impaired, even when there's normal levels of glucose uptake. So even when the cell is getting just as much glucose as it was in healthy person, there is still not effective glucose oxidation, we're still converting that glucose to lactate and we're relying on lipid oxidation for for energy production.

Mike 8:39
Yeah, so something else I want to point out here. That's interesting and just as a clarification point for people is the idea of oxidative versus non oxidative glycolysis. So what they're showing here, what you're alluding to Jay is that the cells will the diabetic cells will uptake the glucose, and they'll run it through non oxidative glycolysis. So what does that mean? So glycolysis takes a glucose molecule turns it into pyruvate. Now that pyruvate can either go to the Krebs cycle and the electron transport chain in the mitochondria and produce a bunch of ATP. So that'll be like, what's a 32 to 38 or 3638 ATP, or if there's problems going on in the mitochondria, it can shunt towards lactate production, and just make two ATP for the for the pyruvate. So what you're seeing here in diabetics is even when use when you increase the blood glucose levels, and you force excess glucose to the cell, they're the diabetic cells just running it through and converting that glucose into lactate and not pushing it through into the into the Krebs cycle in the mitochondria, electron transport chain and producing all these ATP. So the defect that you're seeing in diabetes is not an excess of glucose oxidation. You're seeing even when you had a lot of insulin that was signaling to uptake the glucose it's still not fixing this defect in glucose oxidase. Shouldn't mitochondria, you're still seeing well, we're forcing the uptake of glucose and we're just seeing more glycolysis happening that's not running glycolysis to lactate instead of glycolysis to mitochondrial oxidation of the glucose and the other thing, I think that's interesting here, and I think that's really important, and as you mentioned, we'll come back to is that one thing that the insulin was able to do was lower fatty acid oxidation in the diabetics and that's something that will become really important as we start to discuss this down the line but I just want to make note of those two things. Definitely.

Jay Feldman 10:31
Yeah, definitely. And the other thing that is important to note here is that and we'll come back to this and other studies that investigate this more clearly or more directly, which is that if this was just an insulin problem, then high levels of insulin, like if this was just an issue where the cells aren't as responsive to insulin, so we can just provide more insulin to get the same level of response. If that's all it was, then just increasing insulin would fix all of the pathology, we wouldn't see any further issues, everything would be normal. And obviously, based on this paper, we're not saying that we're not saying that it's able to restore the normal glucose oxidation, even though it does, as you said, lower lipid oxidation, which is, as we'll get to, is a bit of a preview one of the reasons why insulin is actually helpful in the state, one of its benefits, and one of the main ways that it's restoring function to an extent it's not actually fixing the oxidative problem where the cell still can't use the glucose entirely or as much, but it's fixing and one of the contributors to that, which is the lipid oxidation.

Mike 11:32
I want to add one quick thing, and then I'll jump into the next study. So the quick thing I wanted to add was the the confusion, I think, is mostly semantics, right? So it's like people talk about insulin resistance. But the problem is more so inability to oxidize glucose effectively. So like, instead of calling it insulin resistance, we could well, we should just create some other fancy name, talking about impaired glucose oxidation as the central function of diabetes, and insulin resistance kind of just being like the secondary factor on the side. Because this study is showing that exactly that isn't that does the insulin is irrelevant. And all of the states are seeing impaired glucose oxidation, and it's shunting towards lactate in an up-regulation on on fatty acid oxidation. And this also is directly flies in the face of the idea of metabolic flexibility, where burning more fats makes you more metabolically flexible. You're seeing here that the their reliance on fatty acid oxidation, and the inflexibility, the inability to oxidize glucose,

Jay Feldman 12:30
right? That that's contributing to the increase lipid oxidation. Yeah, definitely. Definitely. And yeah, maybe we'll I mean, it would be great to start to rename it, because I do think you're right, calling it insulin resistance is entirely a misnomer. And it should be called impaired glucose metabolism. But like I said, it would just take a little while to catch on, and nobody would know. But anyway,

Mike 12:55
yeah, I'll jump into the next study. So the next study here, further accentuates the point that we were talking about in the previous study, and starts to look at what's going on specifically in the glycolytic enzymes, and then the so those are the enzymes that control glycolysis and glycols, glycolysis and lactate acid, lactic acid production, and then the other ones would be the enzymes involved in the electron transport chain or the Krebs cycle that would oxidize glucose fully versus and produce all the ATP instead of just the two ATP that you get from lactate production. So this study is titled altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance, and non insulin dependent diabetes mellitus. So I'm going to read a series of quotes here and I'll I'll define things as we go along. So the first thing they say, here's the insulin resistance of skeletal muscle in glucose tolerant obese individuals is associated with reduced activity of oxidative enzymes, and a district proportionate increase in activity of glycolytic enzymes. So if you remember the, if you remember kind of the graphic or if you have any idea, or if you guys want to pull up and see a graphic of glycolysis versus oxidative phosphorylation or cell respiration, glycolysis as a whole is a piece of cell respiration. But with glycolysis, you take glucose, you produce pyruvate, and then that pyruvate has to go into the Krebs cycle in the citric out the citric acid cycle, produce the NADH and then that goes to the to the electron transport chain and you produce a bunch of ATP. So what they're trying to see here is in in the these individuals is what's going on in the electron transport chain and Krebs cycle and what's going on in glycolysis. And what they're saying here is that in obese individuals, you're seeing that the enzymes inside the Krebs cycle and the electron transport chain have reduced activity and then the enzymes in glycolysis in obese individual individuals have an increased activity. So you're seeing this this lowering of ability to oxidize glucose effectively and then this increased ability of running glucose through glycolysis. So next, and they go here to say to say activity for glycolytic enzymes, the enzymes being phosphate  fructose kinase glyceraldehyde phosphate dehydrogenase and hexokinase was highest in subjects in subjects with non insulin dependent diabetes mellitus following the order of the worst. So the order they're giving us is the worst was the non insulin dependent diabetes mellitus. So the diabetics had the highest amount of glycolytic enzymes with the lowest amount of the oxidative enzymes, then it was the obese, the obese population, the obese population was worse than the diabetic population again, with higher glycolytic enzymes and then the lower oxidative enzymes, and in the Lean individuals were on the flip side, where they actually had good function of their oxidative enzymes, but poor function of their glycolytic enzymes. And then they continue to say here, so whereas maximum velocity for oxidative enzymes, so they have citrate synthase and cytochrome c oxidase, we've talked about cytochrome c oxidase before and being involved in the electron transport chain, they say was lowest in subjects with non insulin dependent diabetes mellitus. So what you can kind of see as a spectrum, diabetes is the worst, where they have the highest amount of ox glycolytic enzyme function, so that's running glycolysis, that's pushing towards lactate and the low end, the reason I'm saying pushing towards lactate is because their oxidative enzymes are really low. So the Krebs cycle, electron transport chain not working too well, like glycolysis, working kind of all right. And then there'll be some individuals again, they're in the middle, they're not working as well as lean individuals for their oxidative enzymes, but their glycolytic enzyme function is higher. And then you have all the way on the other side, the lean individuals, oxidative enzymes are working well. And then the glycolytic enzymes are also working well, but the oxidative is aren't shut down with this compensatory increase in the glycolytic enzymes. So what they continue to say here is they say the ratio between glycolytic and oxidative enzyme activities within skeletal muscle correlated negatively with insulin sensitivity. So what does that mean? The higher glycolytic enzyme function and lower oxidative enzyme activity you have in skeletal muscle, the more insulin resistant you are, so the worse your insulin sensitivity is. Whereas on the flip side, if your oxidative enzyme function is good, and your glycolytic enzyme function, it's not elevated, but it's still functioning, then insulin sensitivity is great. So what they what they wrap up here, and they say In summary, an imbalance between glycolytic and oxidative enzyme capacities is present and non insulin dependent diabetes mellitus subjects and is more severe than obese or lean glucose tolerance subjects. The altered ratio between glycolytic and oxidative enzyme activities found in skeletal muscle of individuals with non insulin dependent diabetes mellitus suggests that a dysregulation between mitochondrial oxidative capacity and capacity for glycolysis is an important component of the expression of insulin resistance. So what they're saying here is the core component of insulin resistance is not this, they're not even talking about insulin, they're talking about the GLite, the oxidative enzymes, the enzymes that Take That pyruvate from glycolysis, and run it through the Krebs cycle, and then and then the electron transport chain, and produce all this ATP, that's not working in diabetics, at the worst, the the obese glucose tolerant people are kind of in the middle, and then the Lean people things are working well. So the central dysfunction is this metabolic dysfunction. And it's not this is nothing even talking about insulin. Specifically, this is talking about what's going on centrally in the mitochondria in the cell, which is what the key point that we're talking about inside the bioenergetic perspective, is that insulin resistance is a problem with energy production in the mitochondria of the cell. And then all the things that happen beyond that are upstream. Ours are consequences of this central problem first.

Jay Feldman 18:45
Yeah, yeah, absolutely. And I think that's all relatively clear there, essentially, what's going on is the cells are not effectively using glucose. So they have to rely more on glycolysis. Instead of, as you said, Krebs Cycle electron transport chain, in terms of their usage of glucose, they have to rely on glycolysis to produce energy, and then also lipid oxidation, fat utilization. So if somebody were to say that, you know, there's, like ROS because as in glucose and or we're using glucose as a fuel in type two diabetes and insulin resistance, there is again, it is mostly like, we're not using it more than fat, we're using fat considerably more in the state. And when we are using glucose, we're using it extremely inefficiently. That's not a cause that's an effect, right? We're seeing that that is a state where we can't effectively use the glucose through the oxidative mechanisms to produce energy. And as we had said in that first study, just go back to it. In a normal state where there is not high glucose and there's not high insulin, the in type two diabetes, this is also reduced. Glycolysis is also reduced, because there's also reduced glucose uptake. So there's all these compensatory mechanisms to try to increase ATP production, but the mitochondria are so We've broken so to speak, that those compensatory mechanisms just involve a lot of poor efficiency, respiration. And so it's almost like, again, trying to bring in some analysis here to make it clear. Like if we're in a car, it's like we're stuck in first gear, right? Like you can keep revving the engine and going a little bit faster. But you're really inefficient in terms of your fuel usage, and you're really not getting that much output. And you're going to be creating a lot more exhaust and things like that. And I don't know if those things aren't necessarily that true. But, you know, let's assume that that's the case in a car and someone who knows cars really well can correct us, but we're not mechanics. Right? Yeah, that'll be a different podcast for the future.
Yeah. All right. So unless you have anything else to add, let's move on to the next layer of evidence here.

Mike 20:47
Yeah, let's jump in the next one. Okay.

Jay Feldman 20:51
So the next piece here is that this inhibition and glucose oxidation, so we've set up, we've already set that up. But that situation causes increases in all of the intermediates in glycolysis, and a buildup of glucose. And that alongside elevated fat oxidation, that is the cause here that reduces the glucose uptake, it's not that the cells have somehow become permanently resistant to insulin signals, they don't want to respond to insulin anymore, because they've gotten so much over time, it's not actually a problem with the response to insulin. The problem with the glucose uptake is that this is a, this is a direct effect. The reason why we have impaired glucose uptake is because of the issues with glucose oxidation, leading to a buildup of intermediates, and the fat oxidation, both of which impair glucose uptake. So there's a couple of different routes that will go or lines of evidence that will provide to support this notion. And the first is is evidence showing that glucose uptake is improved if we can restore the glucose gradients. So what that means is that if we can increase the amount of glucose in the blood relative to the cell, that alone will help to improve glucose uptake, suggesting that this isn't just an insulin response problem. And so, of course, when we're in diabetes, the opposite is the case, right? When we're in insulin resistance, the cell has a lot of glucose. And at baseline without compensatory mechanisms, the blood is the glucose would be low or normal. And that's part of why we increase the blood glucose part of an effect, but also it's trying to force it into the cell. And so as that gradient increases, that alone will help to improve glucose uptake. So that'll be part of it. We'll also include some information here showing that the fatty acid oxidation also contributes to the issues with glucose uptake. And that this leads to and then the other aspect here is that there's a glucose buildup that causes the elevated blood sugar again alongside the fatty acid oxidation. So this is a paper by Samsung, and he's got a number of good papers here. This one is titled insulin growth hormone in sport. And he states, even under conditions of extreme ketoacidosis, there is no significant membrane barrier to glucose uptake, the block occurs lower down in the metabolic pathway, where the excess of ketones competitively blocks the metabolites of glucose entering the Krebs cycle. And we'll expand on this as well, it's not just ketones, but he's just talking about this in the state of ketoacidosis. United States, under these conditions, glucose is freely transported into the cell, but the pathway of metabolism is effectively blocked at the entry point to the Krebs cycle by the excess of metabolites arising from fat and protein breakdown, as a result of this competitive block at the entry point to the Krebs cycle, intracellular glucose metabolites increase damming back throughout the glycolytic pathway, leading to accumulation of three intracellular glucose and inhibiting glucose phosphorylation. So we had just described this earlier, where we're relying on fatty acid oxidation, that's going to block pyruvate from entering into the Krebs cycle. So that's what Samsung is describing here as far as the competitive block at the entry point to the Krebs cycle. So pyruvate can't be converted to Acetyl-CoA, and there's a number of other mechanisms going on here. But the leads to a buildup of pyruvate. And then as you said, intracellular glucose metabolites increase damming back throughout the glycolytic pathway, so the pyruvate increases, and then all of the precursors throughout the glycolytic pathway pathway also build up. And this is not only because of the buildup of pyruvate. But there's also inhibition of different enzymes here. For example, the increase in citrate from fatty acid oxidation will block phosphofructokinase, the reduced NAD to NADH ratio will block the glyceraldehyde dehydrogenase and other enzymes in glycolysis. And so what he then says is, that's going to lead to the accumulation of free intracellular glucose and inhibit initial glucose phosphorylation. So this is alone going to block the uptake of glucose at the cell. And then he finishes to say that as a result, much of the free intracellular glucose transported into the cell is transported back out of the cell into the extracellular fluid. Thus under conditions of ketoacidosis glucose metabolism, but not glucose uptake is impaired as a direct consequence of the metabolism of fat, ie the glucose fatty acid cycle. And he cites Randle there. And we've talked about the Randle Cycle in the past. So we'll link back to that. And we talked about a little bit in the broad overview of insulin resistance, the bioenergetic view of insulin resistance. So of course, I'd link back to i'll link back to that episode as well. But essentially, I mean, he explains it pretty clearly here. But essentially, we just get this whole backlog through the glycolytic pathway. And that is what's blocking the cell from taking up glucose. And he's actually saying that that will actually cause glucose to go back from the cell into the blood, and will also contribute to an increase in blood glucose. So this is the underlying driver of the increase in blood glucose and the problems with glucose uptake. It's not a cell, it's not a cellular response to insulin problem. It's a cellular metabolism problem.

Mike 25:51
Yeah, and the way, the easy way to create an analogy for the still running with a car, when you put fuel in the gas tank, the fuel goes into the engine, the engine burns the fuel, and creates energy or kinetic energy. So you can drive the car right? In the cells, the same thing, the glucose is a fuel, it's coming into the cell, those the glucose is not being used. So it's moving into the engine, the cell, it's not being used effect, or it's not even getting effectively into the engine to the cell to be burned. It's kind of moving to this like little shunted back pathway with lactate production. And then what happens is, then you have this buildup, because you can have the stream of supply in. But if there's no exit point in the cell for the supply of glucose, if that glucose isn't actually used to produce energy, then it there's nowhere for it to go. So it doesn't matter how much insulin or what other molecule molecules you have, or even how high the blood glucose levels get, it won't uptake into the cell. And then this what they're the main thing here, as well as like what is blocking that? What is blocking this ability to oxidize glucose to use it as an energy source. And they're talking specifically in this paper about ketoacidosis, it's actually running on ketones are running on fatty acids, that makes this process significantly worse, because you're running on the fats, and then you're unable to effectively use glucose. And this is essentially the Randall cycle. And we've talked about this at length, there's multiple mechanisms where the fatty acids turn this down. Now, something I want to just briefly mentioned with this is a lot of people may say, Oh, well, what's wrong with that there's, then you're just running on fats. And there's no problem with running on the fats. And it's like, there is a problem with running on the fats, because when you start to run the fats, long term, you Shut you, you create number one, ROS. And that ROS, and reverse electron transport flow can be damaging to the mitochondria. And then the other thing is that there's an effect on the metabolism and on some of those enzymes, when you don't have an adequate amounts of NADH and things like that. So there's a, there's a slowing process, there's a general slowing of metabolism. And then there's an increased production of ROS, when you're oxidizing fatty acids, which as well as a decrease in co2 production. And all of these things are essentially like metabolic breaks, they're slowing the system down the co2 allows her blood flow, and allows for oxygen uptake, which is the final electron acceptor in this process. And then the excess production of iOS and the built, they're also built up proton gradient requires the use of uncoupling proteins and things like this, that again, are decreasing ATP production. And then the ROS can damage your mitochondria as well. So you have a whole bunch of things going on with fatty acid oxidation, where it is isn't actually ideal compared to glucose oxidation. And it's also blocking glucose oxidation. So you want to be prioritizing glucose oxidation, and not fatty acid oxidation. And I think that's also why you see in these dysfunctional states like diabetes, obesity, impaired glucose tolerance, that there's actual dysfunction in running on the fatty acids, because it's not ideal to run in those long term. And that's where you're seeing all these metabolic consequences and issues down the line. It's partly from oxidizing all of these fatty acids plus being unable to oxidize glucose effectively, so that this isn't a case for oxidizing fats. Either that you have this block, you really want to be pushing for glucose oxidation under most normal circumstances. Right.

Jay Feldman 28:58
Yeah. It's not a suggestion for that old saying that this is contributory, contributing to the state of insulin resistance. And we've discussed this at length, why it is suboptimal to be relying on fatty acid oxidation over glucose. I have an article about it as well, that I'll link to that kind of lays it out pretty clearly. And, yeah, essentially, it's going to be much less efficient for producing energy, as you said, due to the effects in terms of reactive oxygen species production, and indeed, NAD to NADH ratio, and certainly isn't ideal unless we want a very low level of ATP production, like in the muscles at rest. But for the nervous system, for example, and other tissues, it's certainly not ideal. And there's a huge cost and negative that you see physiologically if you're relying solely on fat and ketones. So when it comes to creating a diet to reverse insulin resistance, there is a lot of conflicting information out there. We've been discussing how a lot of suggestions are just to avoid the carbohydrates altogether, but in reality that's not fixing the problem. And so I've created the energy balanced food guide to help you determine exactly what to eat to optimally support your metabolism, which will help you improve insulin sensitivity. Also lose weight and improve digestion get amazing sleep, boost your energy and tons more. The energy balanced food guide is a one page infographic that organizes foods on a spectrum based on how effectively they support your metabolism. And it also has a separate spectrum that adjust the scale for you. In the case that you're dealing with digestive symptoms with gut issues, which is a huge contributor to insulin resistance, as we'll be discussing later on, the food guide makes it extremely easy to get started with a bioenergetic approach to optimizing your health. So head over to Jay Feldman wellness.com/guide to download the free energy balance Food Guide. So with that, let's dig into the next study here that's supporting this larger notion that the problem with glucose uptake is not due to the cellular response to insulin, but instead has to do with or is caused by the inhibited glucose oxidation, the buildup of intermediates and the fat oxidation. And so we're going to come back to that study that we looked at earlier, which was the characterization of cellular defects of insulin action, and type two non insulin dependent diabetes mellitus. And so there's two important pieces here that are important to mention, I'm not gonna go through the whole thing, but just a couple of relevant ones. So in studies, two, and three glucose uptake in the type two diabetics was equal to controls. Now it's study two, was just a state of high glucose with no change in insulin. And that allowed for glucose uptake to be equal between those with type two diabetes and the controls. So what that tells us is that this is not an insulin signaling problem, because you can restore normal glucose uptake at the cells just by increasing the blood glucose, that paper that we were talking about earlier described, that's because of the gradient between the blood and the cell, that's a huge component for increasing glucose uptake and so just increasing the blood sugar restore glucose uptake, suggesting that this is not a cellular response to insulin problem and instead, what would be happening here as as they saw as that, that just increased the glucose flow through glycolysis. Essentially, now, then, they had a second study that was showing that hyperinsulinemia, without the hyperglycemia. So high insulin without high glucose, also restored glucose uptake. And what they found was that this suppressed, fatty acid oxidation, so we know that we'll I'll read the quote, and then just explain it. So they state that. So I already mentioned in studies, two and three glucose uptake was equal. In conclusion, and type two diabetes, they mentioned hyperglycemia, and hyperinsulinemia, can normalize total body glucose uptake, and lipid oxidation is elevated, and it's suppressed only with hyperinsulinemia. So if we know based on the first study that we mentioned here, number two, that insulin is not required to restore glucose uptake. But high insulin without high glucose helps to restore glucose uptake. What that tells us is it has to be doing it through a different mechanism, and the mechanism they described as suppressing lipid oxidation. So essentially, what they're saying is that there's two components here that are going on that can restore glucose uptake. One is just by high blood sugar, kind of forcing it through the gradient. And the other is by suppressing fat oxidation, because lipid oxidation directly impairs glucose uptake at the cell. And so the studies that they're showing here directly corroborate that.

Mike 33:24
Yeah, and I think this gives us some insight as well into, like, what are strategies to consider when you're trying to deal with any type of impaired glucose tolerance or oxidation, the first thing is you want to help to lower the free fatty acids and lower that fatty acid oxidation. The other thing is insulin is actually actually helpful here with and also glucose are helpful here to help the cell to uptake some of the glucose and so the other the only other piece, I would say that'd be really important with that is to fix whatever's going on inside the mitochondria, that's that we're making the cell have a difficult time and oxidizing glucose effectively, but you would still have to lower fatty acid oxidation. And then you'd still want which would require insulin which and then you'd also want to have a good gradient of glucose to the cell so that you can uptake the cell as well. So these would these would all be points and not driving fatty acid oxidation, per se, and more. So trying to get the cell to oxidize glucose effectively, again, and so that's a when I'm looking at this, I think that this is actually showing the benefit of some of this, some of these things are in the in the perspective of again, understanding this in terms of a problem with glucose oxidation at the cell, and not so much this like insulin perspective, the insulin is helpful by lowering free fatty acids, and it's elevated because the cells are up-taking it degrading it, and then also aren't responding to the insulin because of this dysfunction. But again, all this stuff is secondary and so this is nice. These studies are nice. And we'll talk about some other studies that will lend some credence to some of the things that I mentioned in here but we have we can see a few key areas that we can use to help to improve glucose tolerance, again, bring carbohydrate on board, you have insulin on or have the insulin signaling to lower the free fatty acids, and then lower fatty acid oxidation. And then the last one be fix what's going on with glucose oxidation inside the mitochondria.

Jay Feldman 35:17
Exactly. Yeah, exactly. And, and so we'll dig into that a little bit, toward the end, just touching on some things that will inhibit glucose oxidation toward the end of part two. But you also basically got to the next question here, which is, so if If insulin doesn't fix the problem by just increasing glucose uptake, as we saw from that first study, then what's it doing? How is it improving the situation? Why does administering insulin actually lower blood sugar? And what we're finding? Or what the answer is, as you were saying is that it does this through two mechanisms. One is that it lowers free fatty acid release. And the other is that it lowers fatty acid oxidation. And the way that it does this is via what's called its chalonic action. So it's a chalone. And what that essentially means in this case, is that it's lowering stress hormones is having an inhibitory effect at the liver. So it's reducing the production of glucagon. And it's also going to be reducing the production of adrenaline and cortisol. And those are the things that are increasing free fatty acids and increasing fatty acid oxidation directly at the cell. We've talked about that as well, in previous episodes, that they have a direct effect to increase fatty acid oxidation there. So by lowering those things, it's what is lowering fatty acid oxidation. And that is how it's increasing glucose uptake. It's an indirect effect, it's not directly increasing glucose uptake. And there's a couple of studies that we'll dig into here, that will further demonstrate that that's what's going on. And so we see that when we go back to the same characterization of cellular defects study, where we see that elevated, there's elevated fatty acid oxidation, right, we've talked about that causing issues with glucose uptake, that gets suppressed with hyperinsulinemia, which is why the hyperinsulinemia allows for normalized glucose uptake. And again, showing it does actually fix the problems with glucose oxidation. So we're still not fixing the metabolic problem. It's just suppressing the lipid oxidation, and show it the other thing that this shows is that the fatty acid oxidation is not simply the cause here, right? That that is not where the starts, this starts with a glucose metabolism issue, that forces the cell to rely on fatty acid oxidation, which then contributes to the pathology, that's just a piece of the pathology here. And the reason we know that is because if increasing insulin stopped fatty acid oxidation, and then restored normal glucose metabolism, we would know that fatty acid oxidation is that is at the bottom rung, right. We all know that that's causing the problem with glucose oxidation. But it's not it's an effect. And this is extremely important when we talk about application, because it's very often that people will cite something like the Randle cycle or cite this situation and say, Well, this is why we shouldn't be consuming fats alongside carbs, because consuming fats that alone causes the state, it blocks the glucose metabolism and causes insulin resistance. But in reality, it does contribute to that pathology. But it's not actually the underlying cause. The issues with glucose metabolism happen first and again, if blocking fatty acid oxidation fully restored normal glucose metabolism, that'd be a different story. It does improve and again, what it does do is it improves glucose uptake and so it'll lower blood sugar and lead to a ton of benefits to blood fatty acid oxidation. But that alone is not going to be enough to actually fix what's driving the situation and so just to clarify, or to read the study, the quote here from the study that states is clearly at the end here with their conclusions, they state that hyperglycemia and hyperinsulinemia can normalize total body glucose uptake, market hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore normal distribution between oxidation and non oxidative glycolysis. So the cells still rely on non oxidative glycolysis. They're still producing lactate. In this state, even though glucose uptake is normalized and lipid oxidation is elevated and is suppressed only with hyperinsulinemia. So the lipid oxidation suppressed, glucose uptake is normalized. That's often what's pointed to as the pathology here, that we still haven't fixed the glucose metabolism problem. So that, you know shows us that what's underlying here at the deepest level is glucose metabolism problems first and as a result, we rely on fatty acid oxidation. And those two things together, block glucose uptake, and also the elevated stress hormones, which further this pathology. Yep, yeah.

Mike 39:31
And again, this, this then leads us have to go look directly of what is blocking glucose oxidation in the mitochondria, what has led to this impaired ability to oxidize glucose, not driving fatty acid oxidation is essential and then insulin isn't necessarily the bad guy here. The problem at its core, overall is again, impaired glucose oxidation, so it's not insulin resistance. It's impaired glucose oxidation is central to all of these metabolic states. These these these negative metabolic states, obesity, diabetes, etc and then the question is what is actually causing that blockage, what's causing that derangement and so then, you know, that's a whole other episode that will, we'll have to dive into and talk about all the mechanisms for the like, what could be causing this damage to the mitochondria. But we already have alluded to some of those and we'll get into the basics of those. I'm sure in the lower portion of this episode, will and

Jay Feldman 40:23
Also, that's what we talked about all the time, right. So kind of the sneak peek ahead is that everything that we discuss is in terms of what's supporting or blocking mitochondrial respiration, what supporting or blocking glucose metabolism. When it comes to endotoxin. When it comes to polyunsaturated fats, when it comes to certain nutrients, when it comes to sleep, when it comes to stress, all of these things, the way that they are problematic is by blocking glucose metabolism. So yes, we'll dig into some specifics and things maybe to look to in this case, however, that's what we spent 100 Plus episodes discussing and obviously, there's complexity here, even though you can point to his simple cause. There's a lot of things that play and there's a lot of factors and so that's why we have to look at things holistically. There's not just a simple quick fix or simple, quick pill to resolve the issue. But yeah, that's that's, that's the podcast, right? That's what we focus on. Yeah.

Mike 41:15
But the one last piece I want to add is, is I think that long term driving a fatty acid oxidation, likely contributes to the pathology as well. So it's not that like you want to lower fatty acid oxidation in the States in general, because it will, that alone will block glucose oxidation. And while that may not be driving the dysfunction itself, in terms of glucose oxidation, it definitely because of some of the things that happen with fatty acid oxidation, could be create or lending or lead bleeding into that path of pathology or over time, probably inducing that pathology and so there's a there's a lot of things to unpack there. But it's yeah, it could be one of the major possible factors. So we don't we also want to be optimizing for fatty acid oxidation and we do want to be bringing it down in the states and trying to get glucose to the oxidized in the mitochondria effectively again,

Jay Feldman 42:05
right? So there's nuance here, where what we're saying is that the underlying driver is typically not fatty acid oxidation. But fatty acid oxidation is a contributor to the pathology, because it forces the state, it increases the stress hormones, it'll decrease thyroid activity, all those things. So it will contribute to the pathology. But on the most underlying level, it is not the cause, right and it's one kind of talking about the constellation of things that affects glucose metabolism, is not consuming carbs, and consuming excess fat and relying on fatty acid oxidation will cause problems there It is a contributor and it's also part of the pathology. So a bit of complexity, a bit of nuance, but yeah, important to mention and this next paper coming back to that senescent paper, he just spells it out very, very clearly in language, I think a lot of people can understand as opposed to that other study where we're looking at the details of what's going on in the cellular metabolism. But he describes very clearly the situation with insulin that the effects are secondary, it's happening due to a colonic action that lowers stress hormones and lowers fatty acid oxidation, to restore glucose uptake and that's where the benefits come from in terms of increasing insulin or administering insulin in the state. That's how it lowers the blood sugar. So if you want to go ahead and read through those, Mike,

Mike 43:18
Yeah, so again, the paper is insulin growth hormone and sport, and what the author goes to say to say When insulin is administered to people with diabetes, who are fasting blood glucose concentration falls, is generally assumed that this is because insulin increases glucose uptake into tissues, particularly the muscle. In fact, this is not the case and as another error arising from extrapolating from in vitro rat data, it has been shown quite unequivocally that insulin at concentrations that are within the normal physiologic range lowers blood glucose through inhibiting hepatic glucose production, without stimulating peripheral glucose uptake as hepatic glucose output is switched off by the colonic action of insulin, glucose concentration falls and glucose uptake actually decreases. When insulin is given to patients with uncontrolled diabetes. It switches off a number of metabolic processes, including lipolysis, which is the release of fats protein lysis, which is the breakdown of protein to produce amino acids that get turned to glucose, keto Genesis, which is the production of ketones from fatty acids, and gluconeogenesis, which is the production of glucose from the liver from fatty acid backbones called glycerol and amino acids by a similar colonic acid action. Since both ketones and free fatty acids compete with glucose as energy substrate at the point of entry of substrates into the Krebs cycle, glucose metabolism increases inevitably, as free fatty acids and ketone levels fall despite the concomitant fall in plasma glucose concentration. Thus, insulin increases glucose metabolism more through reducing free fatty acids and ketone levels than it does to recruiting more glucose transporters into the muscle cell membrane. So essentially, what they're showing here is that the there's there's two the major thing I think the biggest piece overall that we're seeing is that insulin is a fact. And its function in terms of lowering glucose levels, is through lowering stress. And that's through lowering hepatic glucose production through gluconeogenesis. Under by lowering glucagon, which is kind of the antagonistic hormone to insulin are generally thought of as the antagonistic hormone to insulin and it is a stress hormone. It is an adaptive hormone. And then you have the lowering of free fatty acid release, which is again from stress hormones adrenaline and cortisol. And then when you lower the free fatty acids that are circulating, and are released from fat tissue in the liver, etc, you basically see an increase in glucose uptake, because the cells aren't blocked now by the fatty acid oxidation that's that's going on inside the cell. So insulins effect isn't to slam glucose into the cell, it's not opening the door per se, to glucose directly itself through some receptor function. Insulin is basically telling the body hey, we have carbohydrate, we don't need to make more carbohydrate, we don't need to produce more carbohydrate for the liver through gluconeogenesis and hey, we can stop releasing fats, we can calm down now, we have this other substrate present. And so it's it's lowering the stress hormones, it's lowering its glory and quicker glucagon, it's lowering cortisol soaring of adrenaline and then the lowering of the free fatty acids actually helps to improve the glucose oxidation. Whereas initially, when you just lower gluconeogenesis, and the glucagon function at the liver, what they're saying in normal diabetic state is a glucose oxidation actually can decrease a bit because you have a change in that that what's it called the hyper getting the term glucose gradient. Yeah, so you have a change in the glucose gradient, where essentially, there's not this really high blood sugar anymore, that's trying to force that's leading to a forced uptake of glucose in the cell. So overall, the insulin is actually working through lowering stress. And again, it's not forcing glucose into the cell. And it's not forcing glucose oxidation, it's not doesn't still doesn't fix the problem of glucose oxidation in the mitochondria. But it does help the overall situation because it's lowering these different stress hormones and whatnot.

Jay Feldman 47:04
Exactly right, and seeing the difference between the kind of fed state that he describes secondarily and the uncontrolled diabetes, where the main action is through reducing free fatty acid and ketone levels and reducing fatty acid oxidation. That that's the thing that that kind of restores some level of glucose metabolism and comparing that with what's going on in the fasted state. We're in that state, normally, the blood glucose in that state, it's not coming from dietary carbs, somebody hasn't eaten in eight plus hours. That's if someone has fasting blood sugar, that's high, it is not a card problem. This is a stress problem. This is a high stress hormone problem, which is very clearly shown and that's the next piece we'll get to, is that insulin resistance is the state of high stress hormones. And so what is going on here is that the insulin is lowering those stress hormones and lowering the hepatic glucose production, the gluconeogenesis and that is how it's lowering fasting blood sugar. So it all those things together show us the constellation of influence effects and showing that there might be some increase in glucose uptake directly as a response to insulin. But that's really not the main way that it's working, it's not really the main way that it's helping so much so that in the fasted state where there's high fasting blood sugar, there would actually be a decrease in peripheral glucose uptake, when it comes to providing insulin, but the blood sugar goes down because of a reduced hepatic glucose production. And that's because in this state where glucose metabolism is so deranged, the gradient often matters more, because there's such a problem with using glucose in the cell. Now, it is also worth mentioning another effect of insulin here that we've mentioned in the past is that it does have some stimulation of certain glycolytic enzymes to increase glucose metabolism. And so it is all around as you were saying, like a supportive thing that's increasing our ability to utilize glucose and turning off the stress hormones. And this idea that insulin is the problem is completely blaming the firemen for the fire is completely blaming the symptom here. And much like cholesterol to insulin itself is actually really protective. This doesn't mean we want super high amounts of insulin. That's not what we're saying. We're saying that that is a symptom, if we're seeing that that's a symptom that we're not responding properly to it. We have excess stress hormones, we have problems with our metabolism. So we're increasing this protective thing as a compensation mechanism. And, yeah, there's major negatives to the low carb diet alongside extremely low insulin that you're not getting at all. Again, that is different from a low fasting insulin, which is generally a good sign outside of the caveat, where if you're on a low carb diet, you've just kind of cheated the system, you're not actually fixing anything, you're going to see a low fasting insulin. But anyway, just some, some details there that are worth highlighting.

Mike 49:42
Well, and the low carb diet is going to make you more insulin resistant. And I think that's something that needs to specifically be said, because there's this idea that oh, I'm going to go on a low carb diet and it's going to improve my insulin sensitivity. And then I can handle carbohydrate and it's like, no, if you're already insulin resistant, you're gonna go on low carb diet, you're going to be more insulin resistant. And then you're going to try to fix it afterwards to with this with by increasing carbs or something like that. And it's the increasing the carbs that's making you more insulin sensitive. And this, this is one of the things that flies in the face, where it's like most people are so metabolically unhealthy that they shouldn't have carbohydrate at all. And they need to go on a low carb diet to improve insulin sensitivity. And it's actually that's the opposite. The opposite is people who are having metabolic issues and are in this, this metabolic stress would actually do better with having some carbohydrate on board and not drastically lowering their carbohydrate intake to like ketogenic levels, and then further driving all of these processes, right, because in the low carb diet, you're lowering insulin, and then you're increasing glucagon, you're increasing adrenaline and and you're also either increasing cortisol directly, or increasing metabolism of cortisol. And all of these things play directly into this pathology, we're seeing the benefit of insulin is through blocking these things. And then the low carb diet is worsening these things. So we don't want to be pushing the low carb piece, what we want to be and focusing on again, just carb blood sugar and insulin values, what we want to be focusing on is we want to be focusing on the getting the cells to oxidize glucose, effectively, the problem is not insulin, the problem isn't necessarily the high blood glucose levels. The problem is the oxidation inside the mitochondria of glucose, and then the excess regular access up-regulation of the stress hormones. That's glucagon. That's adrenaline, that's cortisol, and the excess reliance on fatty acid oxidation. So those are the things that we want to address, we want to figure those pieces out, we don't just want to lower our carbon take, and then therefore lower all these associative markers, like blood glucose, or hemoglobin, A1C, or any anything along those lines, because again, that's just showing that you just don't have carbohydrate on board. And again, fasting blood glucose will actually increase in people who are in people who are on a low carbohydrate diet, and it's by increasing free fatty acid oxidation, and then also driving up gluconeogenesis, which is the things that insulin directly suppresses and is helpful to lower, not to mention the downstream effects of those hormones, not just on what's going on directly in the mitochondria, but on thyroid hormone signaling, sex, sex, steroid signaling, etc, etc, etc.

Jay Feldman 52:19
Yeah, yeah, exactly. I think that sums it up really effectively. And we'll wrap up this part one here and pick back up in part two and discuss some of these things that you mentioned in more detail discuss the contribution of stress hormones to the insulin resistance state showing that this is not an insulin problem, but actually a stress hormone problem. It glucagon problem with cortisol adrenaline problem, we'll also discuss why we actually want to be increasing carbohydrate intake, and that increasing carbohydrate intake actually supports and increases insulin sensitivity. Even people who have type two diabetes will also discuss the fact that you see this play out in other disease processes like fatty liver cardiovascular disease, you see that these are actually states of elevated fatty acid oxidation, despite what we're told that these are not problems of using too much glucose and metabolic and flexibility where you're not using fat effectively, you're actually using more fat and those kinds of states. And that contributes to the pathology and then we'll also dig into some of the big picture and application of these things where we'll talk about how we can restore our ability to oxidize glucose, how we can fix that, and you know what some of the main factors are to consider there. So if you did enjoy part one, please leave a like or comment if you're watching on YouTube and if you're listening elsewhere, please leave a review or five star rating on iTunes. Those things really do a lot to help support the podcast and are very much appreciated. Check out the studies that we referenced throughout today's episode, you can head over to Jay Feldman wellness.com/podcast to take a look at the show notes. And if you are dealing with insulin resistance or other related issues like weight gain, low energy, brain fog, sleep issues, hormonal imbalances, or any other related issues there, head over to Jay Feldman wellness.com/energy where you can sign up for a free energy balanced mini course where I'll walk you through the main things you can do from a diet and lifestyle perspective, to not only restore insulin sensitivity, but also reduce or resolve these other symptoms and other related chronic health conditions as well. So again, head over to Jay Feldman wellness.com/energy to sign up for that mini course. And Mike, do you want to chime in with anything that might help listeners?

Mike 54:23
Yeah, so if the listeners want to check out a way that they can set up their diet in a step by step fashion to help improve their if they're dealing with insulin resistance, or they're transitioning from a low carb diet, where they just want to improve glucose oxidation and mitochondrial health in general, they can head over to Mike fave.com and check out the nutrition blueprint.

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