74: Hyperglycemia Explained: Consequences of High Blood Sugar and Why It Matters

Hello. Welcome back to the metabolic classroom. I'm Professor Ben Bickman, a biomedical scientist and professor of cell biology. Thanks for joining me for the lecture today. The topic today is hyperglycemia. That is the technical term for high glucose in the blood. And that is literally, when you piece those words together, hyperglycemia, anemia, it means in the blood. Now, having defined that term, what we're going to spend the time on today, discuss, discussing throughout the lecture is just me conveying to you some of the consequences. What I, what I want you to appreciate is that much of the time we're going to spend together is going to be focusing on the consequences of hyperglycemia in, in acute moments. So this doesn't, by that I mean it's easy to think of hyperglycemia as a problem when glucose levels are chronically elevated. I'm going to start with that. But then everything else we talk about is consequential, even in acute glucose spikes. That's indeed part of the motivation for this topic was me seeing people saying, there's no problem with spiking your glucose. I actually appreciate that sentiment, that I don't want to be a fear monger and making people think that if you're looking at your CGM and you see your glucose levels go up and down, I don't want you to think, oh, great, now, now I'm dying. No, I don't mean to be that dramatic, but I do mean to convey the ideas based in literature that in fact there are consequences to that that are pathogenic, that are relevant to disease states. Now, one, of course, consequence of glucose being up is insulin being up. So I'm going to touch on that and its relevance to insulin resistance. But then we're going to go through some other consequences of hyperglycemia, some of which you may be familiar with, some of which you may not. So it may be new or it may be review. All right, now let's start with the consequences of hyperglycemia when the glucose levels are chronically elevated. This would be, you know, something like diabetes. Now the word diabetes is interesting because it actually is a term that describes the most famous symptom or manifestation of chronically elevated blood glucose, which is a lot of urine production, something called polyuria. Diabetes essentially means too much urine is being produced. It is the Greek word for, like, for, for the word siphon or, or flowing through. And it is a, of course, a direct term relevant to the fact that if glucose levels are too high, you are overwhelming the kidney's ability to reabsorb that glucose. So just by way of a brief primer on kidney physiology, the operating unit, or the kind of business unit of the kidney, is this glomerulus, this. This little set of capillaries wrapped up, so the blood side and then the kind of kidney side. And it is this little set of capillaries where the blood is flowing through, and then it is encapsulated in this thing called a bowman's capsule. And you have stuff that is moving from the blood, the capillaries, into this capsule, into the bowman's capsule. It's capturing it and then moving it into the kidney tubules. Now, as I'm acting this out, if you're watching in this arm here, which is the kidney side absorbing stuff from the blood, what is now going down the length of my arm, but down the renal tubule, in the metaphor, that's going to be ultimately excreted into the urine unless it gets reabsorbed. And so when glucose gets filtered at the glomerulus, it will get reabsorbed. And so the actual amount of glucose that comes into the urine is very, very modest. Essentially none. In a healthy person, there will be no glucose in the urine. However, if there's so much glucose in the blood, that means there's so much glucose getting filtered into the renal tubule through the capsule that we've overwhelmed the kidney's ability to bring the glucose back into the blood or get reabsorbed. So glucose levels have overwhelmed the capacity of glucose to be reabsorbed. Now the glucose is staying in the kidney, and that has this effect called an oncotic effect I'm using. I'm getting a little more technical than I intended, but I'll really make an effort to kind of bring it back to basics. So where there is too much glucose, as it's getting stuck in the kidneys, it's pulling more and more water with it. Now that water is coming from the blood, which will cause a hemodynamic or a blood problem, which I'll mention in just a second. But the consequence of this that is so obvious is that the person is urinating a lot. So high glucose results in too much glucose getting filtered at the kidney, and the kidney can't bring it back all into the blood like it should. So the excess glucose that's staying in the kidney is pulling in excess water, which is resulting in much more urine production than normal. Now back to the hemodynamic or the cardiovascular effect that I alluded to a moment Ago. If you are pulling in a lot of half of what is our blood is water. Um, that's this plasma part. It's mostly water, enormously mostly water. And that water volume, you have less blood pressure. And now the person has hypotens. But what if you have people that are eating more carbs and then even when they're in a fasted state, their insulin is still much higher than what it used to be. That is insulin resistance. Remember, those two things go hand in hand where you have more insulin resistance, you have more insulin. You cannot tease the two apart. Okay, so I want to cite a couple studies and you can find links to this in the show notes. So in one particular study, they fed subjects in two different diets. They were eu caloric, so the same number of calories. One was a high carb and then one was low carb, high fat. At the end of this period of higher carb or higher fat, there was about a 50% increase in the fasting insulin of the group that was eating the higher carb diet. This was just short term. This was just over one week. So a substantial 50%. Now, lest you think that is impressive, there was another study linked in the show notes that did something pretty similar. It was just six days and they had them overeat this high carb, lower fat diet, and they found that in this case, insulin went up by double. This was fasted insulin just in one week. Having a diet that was much more focused on carbs and cutting down fat. In just six days, they're fasting, fasting insulin. I don't mean just after they ate their meal. I mean they ate a dinner and they don't eat anything for 12 to 16 hours. Then they measure their fasting insulin was twice as high as in the before they ever started this. Also, just as an interesting note, their triglycerides went up significantly. And that is relevant because triglycerides are one of the more predictive markers of heart disease. Far better than LDL cholesterol. Despite our obsession. Not mine, but the our as in the sort of collective biomedical realm, an obsession with LDL cholesterol, all because of its apparent ability to predict heart disease. Well, it's a terrible predictor. Triglycerides are much better. And again, interestingly, on the focusing on just consuming more carbs, triglycerides spiked. Okay, so that is one consequence that hyperglycemia is contributing to insulin resistance, which in turn amplifies the hyperglycemia, which in turn amplifies the insulin resistance. And you can see quickly how that becomes a vicious cycle. Okay, the next point I want to make is oxidative stress and this is a major consequence of hyperglycemia. So here's the issue. When blood sugar is, when blood sugar is high, blood sugar synonymous with blood glucose, it will lead to an overproduction of reactive oxygen species or ros. I may sometimes just refer to it as ros. Ros. These are free radicals that you've heard of. You've heard of free radicals, you've heard of oxidative stress. That just means you have cells that are making more react oxygen species. These are problematic because they're highly reactive and they can damage everything from proteins in and out of a cell, DNA in the nucleus of a cell. They can damage lipids that are in cells or circulating like on, in ldl. So whenever you have more oxidative stress, you have the potential for a lot of damage. Now even acutely, hyperglycemia leads to an overproduction of reactive oxygen species because it overloads the, the cell with energy. So at the end of, at the end of all metabolism, of nutrient metabolism, we're breaking down fats, breaking down ketones, breaking down lactate, breaking down glucose. If it uses the mitochondria, which all of those can do, all of them do, absolutely. Glucose can either use the mitochondria or not. But the moment the mitochondria is involved, there's something called the electron trans system. Some people call it the electron transport chain. I call it a system. I think that's a more accurate term for reasons I won't get into. But essentially when a cell becomes inundated with glucose, it, be it, it has to metabolize that glucose in one way or another. And there's evidence to suggest, I have a paper linked here, that it actually overwhelms the first complex, the first kind of enzymatic group or process within this electron transport system that is the main area of actually producing the ATP or the, the, the new, the molecule that the cell needs to get any kind of work done. It overwhelms complex one. So complex one is just getting this, these molecules overfed, it's getting stuffed, shoved in its mouth and some of it's just sort of spilling out. And this is actually a phenomenon that we would refer to as electron leakage. So the electron transport system is so overloaded that it's not handling the electrons very well, which is giving rise to the birth of these reactive oxygen species. So that's a direct effect of, of hyperglycemia in fact, a study that I've linked here had 20 participants and in just over just a two hour period increased their glucose levels to 15 millimol, which is a pretty reasonable amount. That's high but absolutely not impossible to get to. And they found that over this time they measured a plasma marker of oxidative stress called nitro tyrosine and it was, it skyrocketed. So this direct marker of oxidative stress just went through the roof just with one single bout of hyperglycemia. Now that has consequences including on the blood vessel where you have more oxidative stress, you're risking damaging the blood vessel directly. And I'm going to get to that in a moment. And also altering lipoproteins and I'll get to that one too as well as you have some oxidative stress on lipoproteins and the consequences in the blood vessel and atherogenesis. But I'll come to that one in a moment. I wanted to treat those as their own topics. Now before I get to the endothelium and lipoprotein alterations with hyperglycemia, I wanted to get through a couple more topics. One of them you have heard me mention before and I actually predict this is going to become a bigger and bigger topic. I have started talking about it more but also my friend and colleague Dr. Paul Reynolds, also a professor in the cell biology department here at byu. He and I have published multiple papers together on these top and it has been his area of research for some time which is advanced glycation end products ages advanced glycation end products. Now advanced glycation end products are problematic in their own right. But the next topic we get to will highlight a consequence of that with their receptors. But advanced glycation end products are these toxic molecules that are formed when glucose or other simple sugars fructose in fact fructose can do it even more than glucose can. But not all simple sugars because for example allulose has little to no effect on on glycation. So with glucose, because that is the topic it the glucose molecule will irreversibly bind other molecules like proteins like or amino acids or fats or even DNA. And all of this as you have undergone this glycation, in fact even the proteins in skin collagen and as the glucose molecule is irreversibly binding you, you're damaging these things. And this is why glycation is known to contribute to things like retinopathy or problems of vision, kidney disease, atherosclerosis Alzheimer's disease, premature wrinkles and aging with as the glycation is affecting the collagen in the skin. So all of these tissues are susceptible to glycation. And once glycated, because of these advanced glycation or becoming advanced glycation end products, they are irreversibly damaged and then have to be cleaned off or you know, resolved by basically breaking it all down. So that's another problem. So advanced glycation end products and the direct contribution that they have to chronic diseases. And I have a good paper link that is a review on this. But it is a steady buildup of these glycation products that will affect nearly every organ of the body. In fact, I say nearly because I'm not familiar with evidence of every organ, but I suspected it is in fact every organ. The only measurement we have to get an idea of glycation is HbA1c. So glycated hemoglobin is the marker that is when the glycation has occurred at the hemoglobin, not only compromising or most directly compromising the red blood cell's ability to carry oxygen, its most famous job, but it also then becomes the only marker that reflects overall glycation. Now I had mentioned when I first brought up age formation, there's an inflammatory component to this. And this is where Dr. Reynolds, my friend and colleague, first started. And I first started collaborating because I when I was a young professor, one of my primary focuses was something called a pattern recognition receptor, particularly a receptor on a cell. So a receptor is something like a baseball mitt that is used to catching things. And the one, the receptor that I studied was one called TLR4. TLR4 has substantial similarities with another pattern recognition receptor called rage R A G E which is the receptor for advanced glycation end products. So as much as I just got done describing the, the formation and consequence of advanced glycation end products or ages and them binding to molecules and irreversibly damaging them, you also have, we add to that this phenomenon wherein age is binding to rage and when rage is activated, it ramps up inflammation. So anytime you can increase age formation, you are increasing, you are promoting this pro inflammatory environment or milieu within the body at large. Indeed, if you look at markers of inflammation like C reactive protein, which more and more people get measured, or TNF alpha, these many of the interleukins or the interferon, like interferon gamma, all of these are, there are, there are dozens of these that I, that we could list. I could probably get through about a dozen, and then I'd have to look up the names of the rest. But there are many of these molecules that are both consequence of inflammation being turned on and a cause, because as they start spreading through the body, they activate other pro immune cells like macrophages. But suffice it to say, the more we have inflammation, the more we're damaging tissues. Inflammation is something that is intended to be turned on and then turned off. It has a very specific target, like a wound. I need to heal this wound, or I need to fight this particular bacteria. When you have this metabolically derived inflammation, there's no end as much as the person is continuing to exist in a hyperglycemic state, even temporarily spiking it up and down. At that peak, you have the formation of advanced glycation end products. Those advanced glycation end products can bind rage, promoting inflammation. And of course, one consequence of inflammation is going to be insulin resistance. And then, because inflammation is one of the cardinal causes of insulin resistance, but you also have just the potential of inflammation to put the immune cells in the state of aggravation, if you will, including macrophages, which ex. Which can be residing in the walls of the blood vessel or the endothelium. And that is a decent transition to the next topic, which is revisiting one I'd alluded to earlier, namely hyperglycemia and the damage to the endothelium. Now, so the endothelium is the innermost lining of the blood vessels that is relevant because it is thought to be damage to the endothelium that is the triggering event for atherogenesis or the formation of the atherosclerotic plaque. So as much as we're talking about hyperglycemia and endothelial damage, there is this substantial and meaningful undertone to all of this, which is cardiovascular disease and the heightened risk that comes from spiking glucose. So more so let's, let's kind of elaborate one thing just to revisit the inflammation and the insulin resistance. I have a friend up at the University of Utah, and he published a paper a number of years ago finding that when the endothelium becomes insulin resistant, which again inflammation causes, it is less capable of producing nitric oxide. And nitric oxide is the, is the. One of the main molecules, the main molecule that promotes vasodilation or the, the dilating or the expansion of a blood vessel. Of course, intuitively you can see that if we have a blood vessel expand, that would mean the amount of the volume, the fluid that is in that blood vessel has a lower pressure, things can slow down a little bit and blood pressure comes down. Well, that's going to be a universally accepted benefit when it comes to controlling heart disease risk because high blood pressure or hypertension is a substantial risk for heart disease. So again, if the endothelium is becoming insulin resistant, it is making less nitric oxide, which would mean less vasodilation or more vasoconstriction. The more the blood vessels are constricted, the harder and faster the blood is moving, blood pressure is higher, the greater the potential risk for some sort of shearing damage to the blood vessel wall. Now that's all sort of, that's all interesting. Let's get a little more interesting by invoking something you've probably heard of because it's been discussed so readily and well nowadays, which is the glycocalyx. The glycocalyx is this kind of gel like lining of the endothelium so you damage to the blood vessel wall. Now that's all sort of, that's all interesting. Let's get a little more interesting by invoking something you've probably heard of because it's been discussed so readily and well nowadays, which is the glycocalyx. The glycocalyx is this kind of gel like lining of the endothelium. So you have the endothelial cells. In fact, it's almost analogous to mucus in the intestines. So down the both respiratory tract, so down to the lungs and down through intestines, we have a mucus lining. We have cells that are making this little layer of mucus in order, or in the stomach's case, a big layer of mucus to just kind of keep things moist and functioning. But within the blood vessel we have a different kind of lining. It's not mucus, it's this gel like lining called the glycocalyx. This is a mix of glycomolecules, things like glycoproteins, proteoglycans, glycogen, glycosaminoglycans. These are all molecules that are meshed together to create this kind of gel. But it does function as a barrier and it protects the endothelium, that innermost lining of cells. It is important in, in addition to that overt protection, it influences the permeability of the blood vessels, making sure that not everything is just trying to rip through the blood vessel wall. It's important for kind of buffering the endothelium from inflammatory signals. It's important for blood clotting and a handful of other things. So suffice it to say the glycocalyx is important. At the very least, it is a physical barrier or a protection on the endothelium. Now, unfortunately, hyperglycemia, even acutely, can start to degrade the glycocalyx. So this starts to. As you degrade the glycocalyx, this gel, like, protective barrier gets thinner and thinner, exposing more and more of the endothelial cells to potential damage. So you have greater vascular vulnerability, if you will, and more endothelial dysfunction, more risk of damaging and thus INV things. Invading cells moving in, even macrophages are coming into readily. And where you have more macrophages coming into the wall of the blood vessel, you have a greater and greater risk of those macrophages becoming foam cells. And a foam cell is a very highly active macrophage. And the foam cell represents kind of a fundamental core of the atherosclerotic plaque. So if you look at a plaque that is growing within the wall of the blood vessel, it's really the foam cells that are the main body of this. It's these big, fat, fatty macrophages. Now, when I say fat, you're immediately thinking, oh, okay, I need to eat less fat. But that's not. It's not that simple. What can happen is that the foam cell starts engulfing LDL lipoproteins. So it's engulfing the fatty lipoprotein, and that then is giving rise to this cell that, when you look at it under a microscope, looks like it has little bubbles, or it looks like it's foamy. But those are actually fatty bubbles. They're not air bubbles. You never have air bubbles in the body. But that is a nice opportunity to once again transition into the next topic, which is hyperglycemia and its impact on LDL modification. Now, it's very important to appreciate the fact that in its native or unaltered state, LDL is totally benign. This was done well by, I think it was a group, Brown and Goldstein, at UT Southwestern. They won the Nobel Prize, but it wasn't for this. But they have work showing that if you take macrophages and incubate them next to native or unmodified lipoproteins, ldl, they do nothing. They just exist in perfect harmony. If, however, that LDL has somehow been altered through peroxidation, like with polyunsaturated fats, which could do that very well, or through glycation, which is what we're getting to now. If you've altered the LDL now it's considered problematic and the macrophage will engulf it. It will, it will eat it up. And the more it's eating up these modified LDLs, the more you're creating a foam cell which becomes a very big fatty pro inflammatory cell living in the wall of the blood vessel. And again, it's easier for the macrophage to get in there. If you have had your glycocalyx eroded, you've lost that protective barrier. So under normal conditions, LDL is a perfectly benign transporter of fats and proteins. It's just moving them around the body, both fats for energy and cholesterol for structure, which is very important. Speaking of the electron transport system that I described earlier, one of the most fundamental pieces of that electron transport system is a molecule called ubiquinone. Wouldn't you know it? Ubiquinone actually has its origins as cholesterol. It uses the core structure of cholesterol to, to turn into ubiquinone, one of the most important comp, indeed an absolutely irreplaceable, unavoidable component of the electron transport system. And indeed, it's a component that we have less of when a person is on a drug that is demolishing their body's ability to make cholesterol. So under normal conditions, LDL is just happily carrying fats. It's basically a little school bus dropping off chubby little kids, fatty little kids throughout the body, all with a distinct purpose. Now, the LDL can undergo glycation and that can happen at this APO B, one of the APO B proteins on the lipoprotein. Remember, LDL is a lipoprotein. It has fats, triglycerides, it has cholesterol, and it has proteins on it. It is, after all, called a lipoprotein glycation. Can is when you have now glucose back to the advanced glycation end products binding to these proteins. Now it can also bind the lipids, but now it makes it more prone. It's, it's been altered, so it directly is compromised in its structure and function, making it not a great fit for its receptors, where the liver would naturally be pulling it in and clearing it out. So it's making the LDL linger much, much longer in the blood vessel, the lipoproteins. But also it makes it more susceptible to peroxidation. And so you can see with hyperglycemia, you have A greater risk of oxidized ldl. Now, I don't, I don't love the potential for confusion with some of these terms, but as a, as a metabolic scientist who has focused on nutrient metabolism, oxidation generally will refer to us burning the fat for energy. So even though we, I just mentioned that it increases oxidized ldl, that really is more a reflection of the oxidative stress damage, which technically would more accurately be referred to as peroxidation, not oxidation, but peroxidation. But those terms are used pretty interchangeably. I will try to just refer to it as peroxidation. But even still, the actual tests that measure it are called oxidized ldl. That's what they say they're measuring. But anyway, just to say that all another way, with these terms in mind, hyperglycemia will result in glycation of the ldl, which increases its risk of peroxidation. And you can get that, you can directly measure the increased LDL peroxidation. That now is a very reactive, problematic ldl. And once again back to the work of Brown and Goldstein that makes a macrophage much more readily to identify that modified LDL as problematic and then want to eat it up. Because one of the jobs of the macrophage is to phage means eat. It wants to engulf these problematic molecules and sort of protect the rest of the body. So the takeaway from this sort of final segment actually is that hyperglycemia isn't just a consequence or isn't just relevant to the blood glucose and the insulin, that there's a direct modification of molecules like ldl, not to mention the glycocalyx and not to mention the inflammation which is putting the immune cells in a heightened state of alert anyway. But it's all contributing to this kind of perfect cardiometabolic storm. And the paper that I have linked for this segment refers to this process of glyco oxidation. Or perhaps to be a little more precise, it could have been glyco peroxidation. But that doesn't sound quite as good. And I'm all about things sounding good. And again, that's not my term, that's in that paper that I've linked. So to finally wrap things up, hyperglycemia isn't just, oh, my glucose levels are high. There are meaningful consequences to spiking blood sugar. Now, I don't mean to say that we can never spike, spike blood sugar, but I do think it's important to not minimize this, that where we have the ability to Mitigate that. Of course, avoiding carbs avoids the glucose spikes, full stop. As much as people like to post pictures of their CGM results when they're exercising, that's a pretty slow and steady climb. And by the way, if you're in the sauna and you see a big spike, that's an artifact of the CGM overheating. It's not an actual artifact of your hyperglycemia. That's not happening, maybe very, very modestly, but nothing like what you see on the cgm. That is again, just a consequence of the heat affecting the measurements. But there are. There are consequences and so to hyperglycemia. So when we do enjoy something that's going to spike our glucose, I do think it is incumbent on us, it may be prudent to embrace any strategies we can in order to mitigate that. Like if you're eating glucose, then there's value in focusing on fiber with that glucose. The more a person is eating carbs that spike glucose, I would say the more important fiber becomes. The less a person is eating carbs that spike glucose, the less important fiber becomes. There are other things, like allulose, of course. We have published a paper in animals on that effect. We're about to publish a study on humans documenting the same. Allulose has a tremendous ability to blunt hyperglycemia. Also, yerba mate has been shown the chlor. Chlorogenic acid, which is a key molecule in yerba mate, that has also been shown to mitigate hyperglycemic excursions in response to glucose consumption. And of course, apple cider vinegar, water extracted cinnamon, the best one of which is I actually get one from Costco there. So water extracted cinnamon is also a strategy. And then one of the most effective of all is just going on a walk. If you can go on a walk after you've eaten that glucose, spiking food or carbs or drink in them, then that really blunts that curve as well. So a handful of interventions, some very convenient, some a little less convenient, but all generally effective at mitigating the glucose spikes, which do in fact, have, I would say, a meaningful consequences, including inflammation and oxidative stress, damage to the endothelium, modifying the ldl, that I think we ought to keep in mind and perhaps use that as some motivation to stay the course when we're thinking about diet and indulgences. I hope this information was helpful. If it was, please talk about it, share it with a friend. Make sure you go teach these ideas to someone else. There's nothing, no better way to reinforce ideas. Again, thanks for attending the lecture today. And until next time, more knowledge, better health.