143: Why Gum Disease Raises Your Blood Sugar

Did you know that your gums affect your blood sugar? Most people think gum disease is just a dental issue, but it's not. It's metabolic. When your gums become inflamed, they stop acting like a barrier and start acting like an open wound. That allows bacteria from your mouth to enter your bloodstream every time you chew. And those bacteria trigger chronic inflammation, one of the main drivers of insulin resistance. In fact, studies show that treating gum disease can improve blood sugar levels similar to some diabetes medications. So if you're working on your metabolic health, don't ignore your mouth because your gums might be quietly working against you. This is Lecture 143 of The Metabolic Classroom. Welcome back to The Metabolic Classroom. I'm Ben Bikman, metabolic scientist and professor of cell biology. Thanks for letting me be your temporary professor while we cover a topic that rarely gets discussed in the realm of metabolic health. and that is the mouth. Specifically, we're going to talk about how the health of your gums, the tissue that holds your teeth in place, can have a profound and far-reaching impact on your metabolism. That includes your insulin resistance and even the level of your heart functioning well. Most people, when they think about gum disease, think about just a dental problem, that maybe they have bad breath or maybe they have a toothache. But the evidence tells a very different story. The mouth, it turns out, isn't just the entry point the food we eat, it can also serve as a gateway for chronic systemic inflammation. And once inflammation escapes from the mouth and enters the rest of the body through the bloodstream, that's why we use the word systemic. The consequences then also ripple outward in ways that can include not only insulin resistance, but as you'll see, also cardiovascular disease. So today I want to take you through what the mouth looks like when it's healthy versus diseased. Who's at risk, what's actually happening mechanistically when gum disease goes systemic, and what the data tell us about the downstream metabolic consequences. I'll also leave you with some practical takeaways because this is one of those topics where awareness alone might actually change some of what you do. All right, to get started, it might not be too surprising to you to hear some of this, but the mouth is home to a lot of microorganisms. Now, the scope of it might surprise you. There are over 700 known identified species of bacteria that live within your mouth. Most of these bacteria are harmless. Many of them are helpful, and they, between these ones, form a balanced ecosystem that lives within, I guess, what we could call a thin film that's coating our mouth and teeth. But when that ecosystem remains When it remains balanced, the gum tissue is healthy and everything is working well, and those bacteria are staying where they belong. The gums in this instance will form a tight cuff around each tooth, and that creates a nice physical barrier that will prevent the bacteria in the mouth from moving into the body. But when things go wrong, you get a condition called gingivitis. I bet you've heard that before. That's just inflammation of the gums. If this is left unaddressed, then gingivitis can progress to periodontitis. And periodontitis is when the inflammation has gotten so bad that you have some destruction of the tissue and bone that support the teeth. The gum pockets can deepen. In this case, the bone can get weaker, and what was once a sealed barrier becomes a chronically inflamed and even somewhat ulcerated wound. So it's leaking a bit now. And here's the critical insight: that inflamed, ulcerated tissue around the teeth is in direct contact with your blood, your circulatory system. And now when bacteria, and also the toxic molecules that they make, breach that tissue, they will enter your bloodstream. This isn't a particularly rare event. It's just that in severe periodontitis, anything we do can trigger what researchers call bacteriemia. So the bacteria moving into the blood too readily. And periodontitis is not uncommon based on which source you're looking at. There's an estimate that about a quarter to half of the global population has some form of periodontitis, some degree of severity. So this is not something that's rare. It's surprisingly common. Now, when we talk about bacteria, the one most implicated in periodontitis and the systemic consequences that I'll outline, it really ends up often revolving around one single bacterium, and that is P. gingivalis. This is what's called a gram-negative anaerobic bacterium, meaning it will thrive in a low oxygen environment. Even if it's, you know, somewhere deep in, in a, in the gum pocket, you know, tucked between the gums and your teeth where there might not be a lot of blood flow or air. But it has a remarkable arsenal, if you will, of virulence factors. So one of the things that I've focused on the most in my career as a scientist, and I'll highlight some of that research in a moment, and I will highlight more of that here, is the fact that P. gingivalis produces a molecule called lipopolysaccharide or LPS. That's a component of its outer membrane. If you have been a longtime student of the Metabolic Classroom, you've heard me talk about LPS multiple times now. LPS is one of the most potent inflammatory signals known to biology. It's the molecule that's responsible for the extreme inflammatory response seen in a condition called bacterial sepsis. It also produces enzymes called gingipains. Which are proteases that can actually directly digest the proteins in cells that are receiving it. These gingipains can allow the gingivalis bacterium to tear through the periodontal tissue and, as we'll discuss, can subsequently wreak havoc in distant tissues as a result. But here's a detail that makes P. gingivalis particularly insidious. Its LPS, while structurally different from classic bacterial LPS, it can interact with these receptors on the cell called toll-like receptors, like a toll booth, toll-like receptors. These fall into kind of a broad family of cell receptors. But when it may— when the, when the LPS binds these toll-like receptors, it can initially blunt an acute an acute immune response. So the ability to just fight an infection, but it also in turn triggers a chronic systemic, albeit subtle, level of inflammation throughout the rest of the body. It's not an explosive fire of an acute infection, but rather this sort of smoldering, slow-burning fire of chronic inflammation. And as we know, in metabolic research, chronic low-grade inflammation is one of the primary drivers of insulin resistance. You've heard me describe that abundantly in the past. It's one of the cardinal causes. In fact, my own lab has looked closely at what P. gingivalis LPS does inside gingival cells at the level of the mitochondria. What we found, I think, was quite interesting. These were dental students that helped us do the work in combination with the undergraduates in my lab. When we treated human gingival cells with the LPS from the P. gingivalis, the mitochondrial respiration went up. In other words, the mitochondria were, were breathing more. They were working harder. They were consuming a lot more oxygen. Now you might think, well, that's a good thing. Well, here's kind of the paradox, because while the mitochondria were indeed consuming more oxygen, they were producing far less ATP. So the cell was burning fuel, but it wasn't making anything useful from it. ATP. Instead, that increased mitochondrial activity was generating reactive oxygen species. So it was using the oxygen, oxygen to drive oxidative stress. And we also saw increased mitochondrial fission, meaning the mitochondria were fragmenting due to this noxious stimulus. So even at the cellular level, right there in the gum tissue, the P. gingivalis LPS is corrupting the ability of the cell to create adequate energy. And in turn, in fact, in contrast, it's amplifying the production of oxidative stress molecules. And that oxidative burden won't stay local. It just becomes— it becomes another contributing factor in addition to the systemic inflammation that's coming from the mouth. All right, now let me walk you through the mechanisms by which gum disease can impair insulin signaling throughout the body. This is the heart of today's lecture, and I think that the mechanism is fascinating and well supported. The first pathway is what I'll call the cytokine spillover mechanism. When P. gingivalis and other periodontal pathogens infect the gum tissue, immune cells will flood that little micro area and begin releasing pro-inflammatory cytokines. Now, you can— when you hear the word cytokine, you can just replace that with protein if you'd like. So these are little molecules that are turning on inflammation. Some of the most notable ones here are these cytokines called TNF-alpha and a bunch of interleukins like interleukin-6 or interleukin-1 beta. These cytokines are produced locally, but in significant periodontal disease, they spill into systemic circulation. TNF-alpha in particular is one of the most well-established disruptors of insulin signaling. It disrupts the insulin— what's called the insulin receptor substrate 1, or IRS-1, which is immediately— that's like the first event when insulin binds to the insulin receptor. The next thing will be IRS-1 getting activated. Well, TNF- Alpha blocks that. So it is, it is effectively is stopping that insulin signaling cascade right at the beginning. And thus the cell starts to become insulin resistant. Now, just as an interesting aside, that phenomenon is among the first I ever saw when as a young master's student, I became interested in studying metabolism and insulin resistance specifically. So I am very attuned to this particular field of research because it was the birth of my interest in metabolism. Now, if we go beyond the cell and look at a whole organism, we see in animal models some additional and very compelling research. When scientists administered small amounts of P. gingivalis LPS to mice over time, the animals developed demonstrable glucose intolerance and significant insulin resistance. Interestingly, their fat tissue expressed significant elevations in inflammatory markers as well, and they found reduced IRS-1 function. Remember, that's the insulin receptor substrate in both liver and adipose tissue, the two main tissues they focused on. The second mechanism— so the first is the cytokine spillover, which is the one that I certainly ascribe a lot of interest in and support for. but the next one is a little more direct where P. gingivalis produces those gingipains. And I've mentioned those a moment ago. The gingipains can actually degrade the insulin receptor itself. Now, remember when I mentioned gingipains a moment ago, I described them as proteolytic enzymes. So these are protein-cutting enzymes or protein-eroding enzymes, and they can reach insulin target organs, like some of the big famous ones, skeletal muscle, liver, and adipose tissue. Once the bacteria have entered that systemic circulation, when these gingipains encounter the insulin receptor on the surface of those cells, they can physically degrade the receptor protein, eliminating the cell's ability to bind and respond to insulin. So this isn't just cytokine-mediated interference with the signaling, but in this case with the gingipains, it's direct destruction of the receptor itself. The third mechanism involves the liver specifically. The liver is the— we could call the liver the master regulator of glucose metabolism. It can store it as glycogen for later release, and it can even make new glucose from scratch via gluconeogenesis with either fasting or carbohydrate restriction on a low-carb diet. Oral administration of P. gingivalis in mouse models, so in mice, disrupts the liver's ability to regulate glucose metabolism by affecting multiple genes. Gene— and remember, the relevance of a gene is that the gene becomes a protein and then the protein will do something. Genes that promote gluconeogenesis are upregulated in these instances, meaning the liver keeps making and releasing glucose even if it shouldn't. And genes that promote insulin sensitivity and glucose storage are downregulated in response to P. gingivalis bumping up. So this pattern is essentially a recipe for fasting hyperglycemia and driving towards type 2 diabetes. The fourth mechanism involves the gut microbiota. The oral microbiome and the gut microbiome are connected, of course, through this gut-oral axis. That's not surprising. When you swallow some bacteria, some of them can get down into your guts. If you swallow P. gingivalis in particular, it has the ability, if there's a lot of it, to colonize the gut and disrupt the intestinal microbiota composition in ways that can further exacerbate inflammation and the subsequent metabolic dysfunction. Some researchers have even, even shown that P. gingivalis can translocate across the intestinal wall, driving additional endotoxemia from the gut. So the, the P. gingivalis, if it's able to get down into, say, the small intestine, is able to move through that intestinal wall and get directly into the body. Taken all together, these distinct mechanisms paint a pretty picture, and it's consistent. Chronic periodontal disease creates a state of persistent low-grade inflammation from the bacteriemia, so the bacteria getting in, and the endotoxemia, So the LPS level is getting too high. This is just a slow leak of the bacteria and their, their byproducts getting into the bloodstream. And the consequence of this is this turning on of systemic inflammation. And that in turn will disrupt insulin signaling and impair systemic glucose metabolism. Now the mechanistic story would be, and I think is compelling on its own. And certainly as a basic scientist, I always look at the basic research or the mechanistic causal research. But this is one of those refreshing instances where the epidemiological data strongly reinforce the mechanistic findings. After all, the association between periodontitis and type 2 diabetes is now recognized as bidirectional, meaning each condition worsens the other. Diabetes impairs immune function and accelerates periodontal tissue destruction. And periodontitis in turn worsens glycemic control. One of the most compelling pieces of evidence for the mouth-to-metabolism direction is intervention data. Multiple randomized controlled trials and meta-analyses have examined what happens to blood sugar control when people with periodontitis and type 2 diabetes receive periodontal treatment, specifically a procedure called scaling and root planing. This is just a process of removing bacterial deposits from below the gum line, like where brushing and flossing isn't going to reach easily. The results are pretty remarkable and consistent. Treating the mouth improves blood sugar control. A Cochrane review— and Cochrane reviews are generally considered gold standards of, of evidence synthesis and review— It analyzed, um, one in particular analyzed 35 randomized controlled trials that involved over 3,000 individuals, and they found that periodontal treatment reduced hemoglobin A1c, HbA1c levels, by approximately half a point in just a few months. Other meta-analyses have found reductions ranging from a little less, from about 0.4, all the way up to almost 0.7 percentage point reductions. So to put that in perspective, though, lest, lest you think that's irrelevant, some of some popular and even expensive oral diabetes medications have similar effects. They may— they promote that it can lower A1C levels by about the same degree. But of course, in this case, just treating the gums is moving the blood sugar metrics in a way that many medications are attempting to do, but all without the negative side effects of said medications. Even more striking is some of the prospective data. So moving with the patients through time, showing that the severity of periodontal disease at baseline predicts whether diabetes worsens over time. In one particular longitudinal study from Japan, the severity of periodontal disease was independently associated with the development of glucose intolerance in non-diabetics. The worse the gums, the higher the risk of progressing towards diabetes, even if people didn't have it yet or even have normal blood markers that suggested they were going to have it. Large cross-sectional analyses from several countries have found that among people with type 2 diabetes, those with severe periodontitis have significantly higher odds of poor glycemic control, like higher HOMA-IR scores, so higher insulin resistance. They also have higher triglycerides and perhaps surprisingly, higher rates of abdominal obesity. Other datasets found that the odds of severe periodontitis were roughly 50% higher in people with type 2 diabetes compared to those with normal glucose tolerance. And this is even after they control for some obvious factors, So if they look at people of the same age, sex, BMI, smoking, exercise levels, and other confounders, this is a consistent finding that if you have periodontitis, the— it's 50% more likely to be found in someone with type 2 diabetes. The relationship holds even in people who are not obese. So this eliminates the weight factor here. Severe periodontitis has been associated with insulin resistance in non- abdominally obese adults, meaning the insulin-disrupting effects of the gum disease can have their effects even in a person with normal levels. So without excess body fat, this is really important because it tells us that oral health is an independent variable in metabolic disease. It's not just some downstream consequence of, say, the person not eating well and being fatter than they should be. I want to briefly touch on the bidirectional nature of this. Just a little more because it highlights what I think we could consider a vicious cycle. Diabetes and insulin resistance, once it's established, makes— they make periodontal disease worse. In turn, hyperglycemia impairs the function of the immune cells, making it harder for the— for your immune system to fight off these periodontal pathogens. It also leads to the production of advanced glycation end products, or AGEs, or AGEs. These ages, among myriad effects, can stiffen the collagen in that periodontal tissue. So in diabetic patients, the risk of periodontal disease incidence and progression is dramatically increased. In fact, roughly like in the mid-80s percent higher in poorly controlled diabetics compared to non-diabetics or well-controlled diabetics, according to one study. So what you have is a feedback loop. You can pick the beginning. Let's just start in the mouth. Gum disease drives systemic inflammation, which drives insulin resistance. Insulin resistance can in turn drive hyperglycemia, which in turn impairs immune function, and then it can accelerate gum disease. Without intervening at one or both of these ends, if there is an end in a cycle or a circle, but it will perpetuate. But this is also why people with diabetes are often told by their dentists that their gum disease is unusually severe for their age, or that their oral hygiene appears to be so poor. It's not just that they're brushing poorly. It could be that their systemic metabolic dysfunction is sabotaging their oral immune function and defense. Now, let me turn to the cardiovascular story. Because it may be even more established in the literature than the diabetes connection. Now, just as a reminder, having diabetes is consistently the most single relevant factor for heart disease risk. So, but we need to— I think there's, there's a way to tease this apart from that. So someone could say, well, the periodontal disease is driving the type 2 diabetes, which in turn is driving the heart disease. That's certainly not wrong. But what I'm going to outline is a more direct effect here, as you'll see. But this is so obvious that the American Heart Association itself has issued multiple scientific, uh, scientific statements affirming that periodontal disease is independently associated with atherosclerotic cardiovascular disease. So this is like coronary artery disease, stroke, and even peripheral vascular disease. So basically just plaques forming. In fact, an, uh, A recent update just a couple of years ago to those statements by the American Heart Association more strongly linked the two. Just anyway, just strengthening the causality, really leaning into the connectivity of the mechanisms here. But here the mechanisms mirror and extend what I discussed with insulin resistance. On the direct side, we have the bacteria themselves. Again, particularly P. gingivalis, but also some other ones like T. denticola or F. nucleatum and others. They can enter the bloodstream. And now we see, we know this, they can reach the arterial wall. Researchers have actually detected periodontal bacteria inside atherosclerotic plaques. Infecting mice with P. gingivalis accelerates plaque formation and increases the size of the, of these lesions, these wounds on the, in the blood vessels, in the arteries. On the indirect side, the LPS and cytokines produced in response to periodontal infection act on the vascular endothelium, the inner lining of the blood vessels. LPS activates endothelial cells to express this family of molecules called adhesion molecules like ICAM-1 or VCAM-1. These in turn facilitate the recruitment of circulating immune cells to the vessel wall. So LPS activates these adhesion molecules, and as the name suggests, they're sticky, but they're sticky for cytokines. So they basically start calling out for cytokines to come in and invade that endothelial tissue or that blood vessel wall. This is one of the earliest steps in atherogenesis or, or the formation of the atherosclerotic plaque. Immune cells adhering to the endothelium, then burrow into the arterial wall, and they can consume oxidized LDL. Now, it doesn't appear that they would ever consume benign LDL, but I'm going to come back to LDL in just a moment. But that then starts to become the foam cell. And if you look up anything about atherosclerotic plaques, one of the most consistent themes of said plaques are these big fatty macrophages And those are what's called foam cells. Now, I want to pause here for just a moment and introduce you to an idea that when I first learned of it, I thought it was so compelling. I've not only never forgotten, but I've wanted— I now want to share with you because it adds some really important nuance to the overall conversation happening around cardiovascular health. I first learned of this from David Diamond, so you could look up what he has published on this previously. When we talk about LDL accumulating in the wall of the artery, and especially in the context of, of the periodontal infections, we really ought to ask, why is the LDL there? The conventional framing is that LDL is the villain, that it infiltrates the vessel wall, it gets oxidized, which is really an essential step, and that has to do with the types of fat it contains. and then in turn it will drive, um, plaque formation as it gets consumed by these macrophages. But some researchers have proposed a more, um, complex interpretation, but it's just as viable as the one I just outlined. LDL, along with other lipoproteins, has the ability to directly bind LPS. Now remember LPS? That is that endotoxin produced from P. gingivalis and other bacteria like it. And LDL cholesterol has the ability to bind that LPS to remove it from the body. So when LDL binds LPS, it actually neutralizes it. It blunts the ability of LPS to go activate immune receptors and trigger inflammation. That's a fact that's well established. This is probably why people with very low LDL levels are so much more likely to experience severe infections like sepsis. It's because LDL is part of the immune system. Under this perspective, then lipoprotein accumulation at a site of infection or one that's getting a lot of endotoxin exposure like LPS, maybe it's not pathological. Maybe it represents the immune system deploying one of its tools to try to contain the damage. This is— I heard someone, I can't remember who, but I'm quoting someone when I'm sharing this. It's kind of analogous to comparing it to a fire truck at a burning home. If you were utterly naive to the dynamics of fire trucks and fires and putting out the fires, maybe every time you saw a home burning or a building burning, you always happened to see a big red truck with flashing lights on its roof. You may eventually come to the erroneous conclusion that those trucks are causing the fires. Because every time you see a fire, you see a big red truck with lights on top. Now, of course, a different view is that the truck is responding, that rather than being cause of said fire, it is a consequence of the fire, that the truck is coming to help put out the fire. What if LDL is at an atherosclerotic plaque simply because it's trying to put out the inflammation, the inflammatory fire, rather than causing it? Maybe it's just someone who's there who is getting blamed for just being on the scene. And even, even more ironic, it's on the scene because it's trying to help. All right. So what do we do with all of this information? Let me give you some concrete takeaways. First, take your oral hygiene seriously, but take it seriously as a practice of metabolic health, not just a dental one. Yes, brush your teeth and floss. Daily, that can reduce the bacterial burden in the pockets of your gums. This helps keep the balance of the oral microbiome tilted away from the pathogenic species like P. gingivalis and toward the harmless or the beneficial ones. Second, if you have signs of gum disease like swollen or bleeding gums, take it seriously and see your dentist. The evidence is clear that if you can treat the gum disease, you will reduce systemic inflammation and all of the consequences that come from it. Third, of course, no surprise, I have to talk about diet, albeit briefly here. But it does matter because your diet affects your oral microbiome in ways that are directly relevant to what I've discussed today. A diet that is high in refined carbs, so lots of digestible starches and sugars, it will feed the pathogenic bacterial species in your mouth. These bacteria will then get fermented from these the bacteria rather will ferment these refined carbohydrates and in turn will start producing acids. And these acids will start to erode your teeth and your gums. Conversely, if you can control your carbohydrate consumption, especially those easily fermented digestible ones, then you create an environment in your mouth that is less hospitable to those harmful pathogens. And fourth, uh, the, for those of you who are managing type 2 diabetes or, um, significant insulin resistance, or you suspect you have it, you should be particularly vigilant about your oral health. The bidirectional relationship we discussed means that your metabolic condition is gonna be actively working against you from your oral health side. And that if you can make progress on your blood sugar control, it's likely gonna help your gums. So it's gonna help your oral health. Fifth, and this is one for the healthcare providers, if they may allow a scientist to share some insight with them. This— the siloed nature of modern medicine, where endocrinologists manage diabetes and dentists manage gum disease, means that the mouth-metabolism connection often just falls through the cracks. A patient can see their primary care doctor and their endocrinologist for years without anyone ever asking about their periodontal status. In contrast, and moreover, they may see that primary care doctor very rarely. It's uncommon for people to even go in annually. In contrast, most people see their dentists 2 times a year, if not more. Maybe the dentist is the one on the front lines of identifying cardiometabolic risk. In conclusion, the mouth matters more to metabolism than just what goes in it. The bacteria that colonize the gum tissue around your teeth, they're not limited to your mouth. They are metabolic actors. They produce molecules that enter your blood. They activate your immune system. They in turn impair your insulin signaling. They can damage the walls of your arteries, including your coronary arteries or those in your heart, and they ultimately increase the risk of type 2 diabetes and heart disease. The evidence for this is both mechanistically and even epidemiologically clear and even coherent. So next time you're thinking about how to optimize metabolic health, yes, you're going to be focusing on your diet and exercise and sleep, but add one more variable to your list. That's your oral health. So here's your homework: floss your teeth today. If you don't have a habit of flossing, I strongly invite you and encourage you to do that. Keep that gateway to your bloodstream healthy as possible. Thanks for spending some time with me today in the metabolic classroom. Stay curious and stay healthy.