60: Alcohol and Insulin Resistance with Dr. Ben Bikman

Hello and welcome to the Metabolic Classroom. I am Professor Ben Bickman. I'm a biomedical scientist who focuses on metabolism and I'm a professor of cell biology. Thanks for joining me for this discussion. And today we're going to be covering a topic that I've gotten a lot of questions on over the years, which is just reflective of how common this people are thinking about this, which is alcohol and its effect on insulin resistance. There are a lot of things we could discuss when it comes to alcohol, but this is of course one of the most active or one of the most commonly consumed psychoactive substances around the world. Ethanol, the main form of alcohol, is psychoactive. You know, it does influence the brain and this is what we find in all sorts of alcoholic beverages. The metabolism of ethanol or alcohol is unique in that it is metabolized almost exclusively by the liver. And we're going to revisit that fact as we discuss some of insulin's, some of alcohol's effects on metabolism and insulin resistance later. Now there, as I've mentioned, there's a lot we could discuss with regards to alcohol consumption and we're going to keep it strictly within the realm of metabolism and insulin resistance. And if I sometimes say ethanol or alcohol, this is synonymous, so it's the same thing. I may just shift between the two depending on the particular study that I'm thinking of or citing or whatever comes to the top of my mind in that moment. Now, alcohol induced insulin resistance is a thing. Ethanol is capable of causing insulin resistance both directly and indirectly. And there are multiple molecular mechanisms that are responsible for this. So in other words, alcohol is capable of causing insulin resistance actually through multiple and distinct methods or pathways. And we're going to cover all of that in the discussion that we have today. But just for the sake of clarity and, and even simplicity, let's start with the direct role the, the evidence that suggests that ethanol is capable of causing insulin resistance directly. Now there are some other, of course, indirect contributors that I think are very important and contribute to the overall the overall effect of alcohol. When we consider someone who's drinking alcohol chronically or even somewhat infrequently, there's a lot more that goes into just the direct effect. It continues to have effects that actually quite that become broader but also more lingering in a way. So let's firstly go through the direct effect. Like I mentioned earlier, a paper and this, these papers will be linked in the show notes. Sealer et Al in 2000 published a paper finding that ethanol directly inhibited the actions of the insulin Receptor. So you'll, you'll recall from previous discussions, insulin being a peptide hormone, it's not capable of going into the cell itself. So if insulin wants to tell the cell to do something, it has to bind to a receptor to do that. And then once the receptor is bound with insulin or activated, it's going to elicit a series of events ultimately leading to the cell responding and doing whatever insulin wanted it to do. Well, again, this paper by Seiler et al. In 2000 finds that ethanol was capable of disrupting the signal right at the origin, so directly blocking some of the effects at what's called the insulin receptor substrate, IRS, or specifically IRS1. So ethanol, if you incubate cells with ethanol or give them a little ethanol and then put some insulin into the culture, immediately you detect a reduced responsiveness. Also, ethanol. A paper by Shelmet et al. In 1988 finds that ethanol rapidly increases oxidative stress products or these reactive oxygen species. And with more oxidative stress comes a shift in some of the phosphorylation state or the activation of some of those same enzymes in that insulin pathway or the insulin signaling cascade. So an insulin again comes to the cell and tells the cel, do something. As a part of that something is going to be a series of events, one enzyme affecting another, affecting another, and then the change in oxidative stress with ethanol starts to disrupt some of this and then one another paper Onishi et al. 2003 finds that this series of effects can go all the way to affecting GLUT4. GLUT4 is the glucose transporter that is what's abundant in the most abundant tissues, skeletal muscle and fat. So when insulin comes to skeletal muscle and fat, knocks on the door of the cell via the insulin receptor, one of those cascades of events coming from the insulin coming and knocking, a lot of things start to happen. One of those things that starts to happen, one pathway of biochemical signaling will result in glute 4, this glucose transporter coming from within the cell, kind of opening door on the surface of the cell, allowing glucose to come in. Well, the paper by Onishi et al. Again, 2003, finds that ethanol incubation disrupts that. And that would just be further evidence of, of insulin resistance caused by ethanol. Now, those are some direct, like at the level of a cell, a specific cell response, which is important. It's important to establish that this is something that is capable of happening at the level of the cell. But it's always important, particularly for me, as a Kind of cell biologist slash physiologist. I want to go beyond the cell and then say, okay, but does the effect actually translate to a whole body effect? Because if it doesn't, then I would argue it becomes a little less important. However, the ethanol induced insulin resistance that we see at the level of the cell in the three instances I just mentioned, is indeed reflected at the level of the whole body. And I was able to find some very compelling evidence in humans using oral glucose tolerance tests. So there's a couple papers, Negoro et al. 2005 and met 1969, so that's an older one, but that one actually is the one I like the most, which I'll share in just a moment. But in both of these instances, they had healthy human subjects drink the glucose, drink like normal, and then track their glucose and their insulin response to this oral glucose load. In the first paper, Nagoro in 2005, these are healthy people, these are not alcoholics or not diabetics. When they drank ethanol before they had their OGTT, it resulted in this much, much higher response at 30 minutes with insulin in particular. So the insulin response was significantly higher, in fact roughly about 50%. Interestingly, of the multiple studies I looked at in preparation for this discussion, including the Mets et al paper, also finds that insulin response to glucose is about 50% higher in, in across multiple studies. This does suggest a, a reduced sensitivity to the insulin, that the insulin is not working as well in response to this glucose load, and the body needs, in this case substantially more. A 50% increase in insulin in order to clear the same amount of glucose does suggest a pretty profound metabolic shift that we're seeing, all because we've just added a little ethanol into the system. And then remember, these are humans, whole living humans. This is not at the level of the cell. So both Negoro and Mets and others find that with any given amount of glucose, the body needs about 50% more insulin in order to get the same response. Now, some of you may be thinking that, that you want to get a little more specific here, which I'm sympathetic to as a scientist, as a basic scientist or a cell bio who studies the mechanisms of insulin resistance. I want to go all the way through this whole pathway from beginning to end. In every one of these instances, there are multiple papers finding that there is a common lipotoxic intermediate. Now please refer to my earlier metabolic classroom entitled Energy toxicity, where I sort of dispel the general myth that, that there's an inherent pathogenicity to energy or calories or fat, but. But rather it's a particular type of lipid, the sphingolipid ceramides. I very much am an advocate of the idea that overwhelmingly, perhaps not always as a scientist, I want to be careful using that word. Ceramides are a key intracellular cause of insulin resistance. And even with ethanol, that's the case. This has been shown in abundant, particularly animal studies. Just pull out more tissues. You know, you can get muscle from the animal, you can get the liver from the animal, you can get the brain from the animal, you can get the heart from the animal. You can't get human volunteers who are going to let you take a brain sample or a heart sample. Even a liver sample will be difficult to get from a human. But in these rodent studies, they found that with ethanol treatment or consumption, ceramides is up in all of these tissues. It's up in the liver, it's up in the. In the brain, it's up in the heart, resulting in increasing ceramides in all of these tissues, resulting in damage to those tissues, and certainly an insulin resistance effect. Okay, in this, at this point in the conversation, I've been focusing on the direct effects, and I hope that I've made it very clear to you that ethanol is capable of directly causing insulin resistance at the level of the cell and at the level of the whole body. In human studies, um, there are multiple methods for this or multiple mechanisms that cause that. That intermediate. Intermediate that act as intermediary here causing the insulin resistance in response to the ethanol. And ceramides are likely an end part. That's the ceramides, as I've discussed previously, directly come in and prevent the phosphorylation or the activation of a critical enzyme called akt in that insulin pathway. So that's the direct effect. Now let's move on to the indirect effects. And by now you are familiar with my affection for alliteration. Alliteration, sorry. And that. So, of the three indirect effects, I want to talk about sugar, sleep, and substrate. So these are the three S's, the three S's of the indirect causes of insulin resistance in response to alcohol. All right, so the first one being sugar. The reality of many alcoholic beverages is that they're loaded with sugar. This is cocktails, beers, and some sweet wines. All of them contain either modest to very high amounts of sugar. Consider that in light of some of the human evidence I just mentioned, that when you combine glucose with ethanol, you are amplifying the effect, the effect ethanol alone isn't eliciting an insulin response. That's probably an important point I should have made. Ethanol alone is not inducing an insulin response, but it's, it's not often consumed alone. It's often consumed with something else, whether it's the sugar in the drink or whether it's some of the starches in the nuts or whatever else the person may be eating while they're drinking that alcohol. But again, often sugar is present in some form and this exaggerates the, the combination amplifies the not only glycemic response, resulting in a significantly higher glucose level, but also a significantly higher insulin level. So insulin is working harder and ultimately failing, but all seeking to try to control the blood glucose response. And as you can imagine, as we continue to, as the individual continues to consume alcohol like this, you know, day in, day out, that starts to contribute to a more chronic settling in of insulin resistance. Now let's move on to the next one. Sugar is an obvious one, but let me just again state it, that the excessive consumption of carbohydrates results in insulin resistance. Human evidence has shown that the, that high carb consumption can cause insulin resistance in just as little as seven days. Also, if you have healthy insulin sensitive people eat just about 300 grams of carbs, which is not hard to do. Their insulin is elevated for up to 10 to 12 hours. So it's easy to see how it's, you can start stacking on these chronic insulin bumps where whereas one individual insulin spike isn't inherently pathogenic, it's when you continue to do this, which most people do, because most people consume a lot of refined starches and sugars and they do so very often. Okay, so sugar is the first one of the indirect effects of alcohol causing insulin resistance. The next one is sleep. This one is surprising to most people because most people consider that alcohol consumption helps people sleep. What is true, and we'll cite a couple specific studies in a moment, is that alcohol increases the, or rather reduces the length of time it takes to fall asleep. In other words, people will fall asleep more quickly. But the impact of alcohol and sleep quality is that it disrupts sleep patterns and reduces overall sleep quality. And overwhelmingly, people will sleep poorly in response to alcohol. A poor night of sleep, this is its own topic of a metabolic classroom, is capable of causing insulin resistance. So let me just restate that. Even one bad night of sleep will cause demonstrable, obvious, quantifiable insulin resistance in humans the next day. Now, thankfully, one bad night can be corrected by one good night. But as you, you can imagine as you continue to compound one bad night after another, the insulin resistance is a little stickier. One good night isn't going to be enough to wipe it out. And that is overwhelmingly a result of the stress hormones, particularly cortisol. So one bad night of sleep increases cortisol the next day. And cortisol will caus insulin resistance rather quite directly. And, and as you know from previous metabolic classrooms, cortisol is one of the primary causes of insulin resistance. Independent of any other stimulus, cortisol can cause insulin resistance and just as a point of interest, does so by increasing ceramides within the cells of the body. Okay, now let's talk about a couple studies. The first one is Thakkar T H A K K A R 2015. It was published in the journal Alcohol. They found that these scientists found that in healthy non alcoholics, acute alcohol, so just taking a little alcohol decreased sleep latency. So that's just a fancy way of saying that the people did fall asleep faster than otherwise. However, while they did fall asleep faster than normal, the second half of the night was much worse sleep. They are, they had much less REM sleep and they had much more limb movement. So they were just more agitated and moving their limbs around more like with the restless leg syndrome, although they use a more technical term for it, but they were much more restless, so they had a significantly worse sleep in the second half. And then they note that with chronic alcohol drinkers or alcoholics, although that's a, that's a maybe too bold of a term. Chronic alcohol drinkers, whether we would call them alcoholics or not, do experience severe sleep disruption, including an eventual chronic insomnia, which leads them to feel much sleepier during the day. A second study of many studies that I could show and indeed there are so many that there are large reviews written about this, including this one by he et al 2019, that's in the journal Current Opinion in Psychology. And they note that alcohol disrupts sleep architecture, which is a fancy way of just saying the normal structure of the sleep and triggers substantial insomnia and disrupts circadian rhythm, once again disrupting sleep and causing daytime sleepiness. So again, these are just two studies of dozens that I found within just seconds of looking for evidence on this topic. So alcohol causing sleep disruption, sleep, significant sleep disruption. And again, the what tricks people is that they fall asleep more easily, but then they can't stay asleep, and that is common. I was surprised when I learned this. I always assumed that alcohol would lead to deeper sleep, maybe even better sleep, and that Is absolutely not true. We can't confuse falling asleep faster with actually sleeping better. That is, that is clearly not the case here with these two studies. I mentioned the Car et al. 2015, he et al. 2019, and many, many more. And then just to finish that off, poor sleep causes an increase in stress hormones, particularly cortisol, and then increased stress hormones causes insulin resistance directly. So in this case, it's an indirect, another indirect effect. And so the two so far, the sugar content that often comes with alcohol, resulting in an exaggerated insulin response and glycemic response, and then the sleep being the second indirect effect, where, once again, alcohol, in addition to its direct effects, is compromising insulin signaling. Now, the third of the indirect effects here is substrate. And you may be wondering why I'm using that word and how I'm using it. So to be a little clearer, what I mean by this is substrate competition. So calorie use essentially, or nutrient use. So there are the main fuels in the body, the main fuels being glucose and fats. And then we have some sort of secondary fuels, although some may be primary fuels, like ketones, for example. Most people have very infrequent elevated ketones, so we will call ketones a less frequent or secondary fuel. Same with lactate. Lactate is a fuel that ought to be a topic of its own metabolic classroom. But these are the general fuels of the body, and they're all competing to get burned. All of them want to be at the front of this kind of priority boarding. I just got back from a lot of travel where I've been giving some talks about insulin resistance. And boy, you want to be in that priority boarding line. You get on the airplane first, you can stow your bag first, and you're just tired of. You can just start to relax and start reading your book. All of these substrates, as they're called, want to board this metabolic bus. They want to get on the metabolic bus and, and, and get to being burned for energy. When alcohol comes in, it kind of demands priority boarding. It's that obnoxious passenger, passenger who cuts right to the front of the line. And so everything behind has to wait in order to be burned. And so the glucose levels start to climb, the fat levels start to climb in the body, all because of ethanol has come in the system. It has demanded priority boarding on this metabolic bus. What this then manifests as, and this is largely why ethanol results in such heavy fat accumulation within the liver. So here we have this lipid accrual. Now, what you're thinking, those of you who tuned in to the previous energy toxicity lecture is you're thinking, well, just storing more fat isn't the cause of insulin resistance. If you're thinking that, you're absolutely right. You're absolutely right. There are abundant studies to show that just having a tissue store more triglycerides, which, which is the form of fat storage, does not cause insulin resistance, even in the liver. So fatty liver isn't a cause of insulin resistance. There are distinct experiments to show this and prove it. In my mind, beyond any doubt, the same would go here. Now, you're then wondering, well, Dr. Bickman, why are you even bringing it up then? Because there is still, if you do have an accumulation of lipid combined or fatty acids combined with inflammatory markers, which we're going to get to in just a second, then you do have a scenario, a metabolic milieu that is going to be stimulating ceramide accrual. And then we get back to, rather than the idea of energy toxicity, which I generally reject, we do come to this idea of lipotoxicity, where there is a very highly bioactive lipid, particularly the sphingolipid ceramides, rather than the inert glycerolipid triglycerides. So triglycerides are not a cause of insulin resistance. However, ceramides are. So this whole idea of substrate competition does explain why the body is getting loaded with higher glucose, higher fats, higher fat stored in tissues like the liver, which is the main tissue that's metabolizing the ethanol in the first place. This starts to explain some of that. But remember also we have the high insulin, and my lab was published previously that if with this substrate competition idea in mind, the ethanol is demanding priority boarding, the carbs are going to start to rise, the insulin rises and an increase in insulin. High elevated insulin does stimulate ceramide biosynthesis, causing insulin resistance. So even though fatty liver disease is linked with insulin resistance, I am not one to say that it causes the insulin resistance. It's just that the overall metabolic scenario that's causing the fatty liver disease is also causing insulin resistance. Now, before we finish, I've mentioned inflammation just a moment ago, and I wanted to end with that. And this would be once again, a bit of an indirect cause, but it's not one that I, I, I didn't know whether I sort of considered it substantial enough to con to put it in with those first three, the sugar, sleep and substrate. But the inflammation, maybe I didn't put it there because I couldn't think of a snappy s Word that would have it fit within that s themed indirect causes of alcohol induced insulin resistance. But in this case, it's the, the junctions of the intestinal epithelium. I've talked about this before and I will talk about it much more in the future because it is relevant. You've all heard, of course, of the leaky gut. Normally, the epithelium is a well controlled layer of cells. And whatever is coming from the gut into the body is controlled by the cell itself. All of the epithelial cells, they'll recognize a molecule and say, I know you, you can come in and it will pull it into itself on that front end and then release it into the body on the back end. So it's very controlled, moving through the cell itself. But similarly, the cell is able to look at something and say, you don't belong here. You can't come in. However, ethanol, where there's one cell, imagine another bend right here by me, shoulder to shoulder, bumped in. That junction between the two of us is so tight, the junction between the two cells is so tight that nothing can get through. Ethanol starts to open that up and now we start to have this paracellular transport. So the cell itself is saying, I recognize you and you can't come in. Oh, and you just slipped right by me. And so the, this control of substances is compromised again, in this case all because of ethanol. As a point of interest, fructose does the same thing, albeit perhaps to a more modest degree. But what should be a very, very tight junction becomes leaky, and now things can get through. And one thing in particular, in particular that I have studied extensively and you can look up work on this, just go to Google Scholar or PubMed and type in LPS in Bickman and you'll find a couple good papers on the topic. But LPS is short for lipopolysaccharide, and these are bacterial. These are molecules that are on the, on the surface of bacteria that are abundant in the gut. And while they are okay in the gut, they should not be in the blood. And as they move through this, this gap between the epithelial cells of the intestine, they get into the body and then cause this chronic inflammation or this systemic inflammation. And what my work found is that LPS will bind particular receptors on cells, telling the cell to increase its ceramide production. So here, once again, we have an indirect effect of alcohol causing insulin resistance. But through this leaky gut, LPS absorption or invasion into the blood, LPS causing inflammation, then inflammatory pathways causing ceramide production and then ceramides reaching a point where they begin to fight the insulin signal resulting in insulin resistance. So this, if you will, would be the fourth of these indirect causes. That's it. Now you are an expert on how alcohol causes metabolic problems and in particular a host of problems, but all central, central, centralized or focused on its role to cause insulin resistance. This matters because remember insulin resistance is the most common health disorder worldwide. Considering just how common and dare I say excessive alcohol consumption is, this very much is a contributor worldwide that we see as being relevant. I certainly consider it to be very relevant and among many reasons, let this be one more reason for people to just be very, very mindful of their alcohol consumption. Now whatever you end up doing with this information, I hope it's been insightful. Please spread the word. Share this with a friend or a family member and I hope it's been helpful. And until next time, more knowledge, better health. Thanks for joining me.