43: Why Anti-Diabetic Drugs Usually Make Things Worse with Dr. Ben Bikman

Welcome. Thank you all for joining me on today's episode of the Metabolic Classroom, powered, if you will, by insulin iq. As usual, this is a delightful opportunity for me to share with you some thoughts that have been bouncing around my brain and those that I consider to be helpful. As I've said before, of course, nothing thrills a professor more than having a new crop of students in a classroom, if you will. So I'm delighted for you all to be joining me. However, you are tuning in today. Let me, as we get started, let me just lay out the groundwork. So the focus for the lesson today is the anti diabetic drugs. Now you can tell from the name anti diabetic means that it's fighting the disease diabetes. But that term itself can be a little confusing. But I also want to take a little time to describe the problem with most anti diabetic drugs and that is particularly the paradigm with which these drugs are in a way created. These drugs are based on the idea of glucose being the villain. Now I wanted to be able to, I wanted to be able to have you listen to this discussion, participate in this classroom as a student and have in mind both type 1 and type 2 diabetes because they are kind of similar, but they're also kind of different. But by keeping them both in mind, it, I actually think it becomes helpful for you to then see what I consider to be the problem and again namely the glucose centric paradigm. So let's just start with a, a brief overview of type 1 and type 2 diabetes. Now, if I were to ask you to describe type 1 diabetes in the fewest possible words, you would say probably something like it is a disease of no insulin. And that would be absolutely right. Now there's a little more nuance to it and indeed there's a little more background, namely the autoimmune aspect and the destruction of the beta cells that produce insulin. But regardless, the focus would be on the reduction of insulin to the point of negligible to zero, and, and, and all the, the metabolic complications that come from that because insulin just has such a chokehold on all things metabolic. Now with type 2 diabetes, how would you describe it? You can't say it's a disease of no insulin because it isn't. It is never a disease of no insulin. Type 2 diabetes is never a disease of no insulin. Unfortunately, some of the language surrounding type 2 diabetes makes us think it's a disease of no insulin, because you'll hear terms like insulin becomes insufficient. Well, what does that mean? That's a relative term Insufficient for what? Well it means in what they mean by that is it's insufficient for controlling blood sugar levels. In reality, if it's actual type 2 diabetes, insulin levels are higher for, than normal. If you look at insulin levels over the life of the type 2 diabetic, they have gone up and up and up and up, continued to go up and then in some instances of type 2 diabetes it may crest, it peaks and starts to come down, but it never goes down to zero. That's not type 2 diabetes. Now there are rare instances called LADA, LADA, latent autoimmune diabetes of the adult, which is basically just a late onset type 1. It may be coincident that someone with type 2 diabetes develops type 1 later in life, but that's not type 2 anymore, that's a different disease that just happens to be address focusing on or targeting the pancreas. So with type 2 diabetes, insulin never goes to zero, even though it may come down a bit. But even if it comes down and it peaks and crests and starts to drop again as I just described, it's still multiples higher than it was before the person ever started on this, in, on this journey towards type 2 diabetes. So if you're, if you're watching me then, then it would go something like insulin levels are really, really low. They're climbing over the life of the person year over year over year. Mind you all, why glue all while glucose is staying flat and then it comes up and then it can start to turn and come down a bit. But even if it comes down, it's still much, much higher than it is when it started and higher than it would be than higher than is ideal in someone who's metabolically healthy or who has good insulin sensitivity. Now still, however, the problem then to bring this back to the topic really is that we have lumped these diseases together because the most obvious manifestation of type 1 diabetes, which historically was the only one that really ever existed prior until about 100 ish years ago, maybe 150 or so, it was the most obvious manifestation or sign and symptom was a consequence of the high glucose, namely the excess urine production polyure. In fact the term diabetes comes from the word of excess, this Greek term for the excessive production of urine or to flow through too quickly. So the most obvious manifestation of the disease was the high urine production which itself was a consequence of the high glucose. And so the urine was enriched with all this glucose and flies would come to it as if it were coming to honey. And that's where the mellitus term comes from, diabetes mellitus basically just means a honeyed urine. Now that's not to say it's sweet, because glucose does not taste sweet. So that whole idea is, is a sort of a myth or a legend. You know, you're not tasting it and tasting something sweet. It's that it's attracting flies or dogs maybe licking because there's glucose in it, which is not sweet. Glucose doesn't taste sweet. Fructose tastes sweet, but that's not what's coming out. So the most obvious sign of diabetes classically was a result of the high glucose. And unfortunately that view has persisted where we still look at type 2 diabetes as a disease of too much glucose, when if we had a more precise paradigm, we would view it as a disorder of too much insulin. So in that sense it becomes the exact opposite of type 1 diabetes. Yes, they both share a tendency for hyperglycemia, but they get to that end through two totally different means. In the case of type 1 diabetes, it's because of a true deficiency of insulin. In the case of type 2 diabetes, it's because the insulin isn't working very well. In other words, insulin resistance. Now, with all of that as a framework again, and to state it again, the, the, the glucose centric paradigm of diabetes, let's go in now to the description of, of some of these most commonly used diabetes drugs, because that's the focus of the metabolic classrooms for this month being recorded in the month of March. It was really just to do an overview of common drugs used for general cardio metabolic health, whether it was weight loss or the GLP1s. Today, diabetes and next time being heart disease drugs. Now, all of this said, I don't want you to think that high glucose isn't a problem. Chronic hyperglycemia is pathogenic, it can harm the body. However, so much of what we associate with type 2 diabetes, namely the increased risk of Alzheimer's disease, the increased risk of cancer, the increased risk of heart disease and fatty liver disease, those are not problems of the hyperglycemia. There are problems of the hyperinsulinemia, the high insulin and the associated insulin resistance. So just remember that. My final comment on this then, before we actually get into the drugs for the remainder of the lesson time and then Q and A for those who are joining live. The the final point before going further is that if you have a glucose centric paradigm, in other words, if your sole focus when you look at the person with diabetes is to lower the glucose at all costs, Then you don't care what insulin is doing. And remember, I just got done describing how so much of the pathologies associated with type 2 diabetes in particular are a consequence of the insulin resistance, not the hyperglycemia. Not to say hyperglycemia is benign, it isn't. But it is the lesser of two evils. It's the Robin to the Batman or, or the, whoever the Joker's sidekick is to the Joker for invoking a villainous side here. So it's, it's the insulin resistance. So again, if you are trying to lower glucose and to do so you are increasing insulin. And because why not? After all, you have a glucose centric paradigm. The conventional clinical view would say, that's worth it, it's good, let's lower glucose at all costs, then you'd be fine with it. And unfortunately, there are consequences to that perspective that are disastrous. Moreover, as a final point, beyond the final point, I intended to make a glucocentric paradigm where you're only measuring the patient's glucose causes us to actually start detecting these metabolic problems years later. Because remember, as a person is progressing towards type 2 diabetes, it's the insulin that's climbing, it's the canary in the coal mine, or the earlier signal, it's the insulin that's climbing. All the while glucose is staying normal. If you're waiting for glucose to rise, then you're going to detect the problem 10 or 20 years later, potentially. All right, let's get started with the first of. And I'm going to go through seven overall sort of segments of drug of drug classes, if you will. And in some instances it's just a single drug, the first one being metformin. Metformin is the most widely prescribed anti diabetic drug on the planet for two reasons. One, it's cheap, it's off patent, and two, it works. And indeed, I've classically given metformin one of the better grades if I had to grade anti diabetic medications, because it generally works the proper way, which is it improves insulin sensitivity. Now, before I go, I'm already going a little too far, I'm getting ahead of myself. Despite it being the most commonly used anti diabetic drug, it's actually, of all the ones we're going to go through today, the least understood. Isn't that funny that if you actually start diving into the precise cellular mechanism whereby metformin will improve the diabetes outcomes in someone, you are going to get into a very thick forest of confusion? But the main theme of metformin is that it acts by targeting the mitochondria. So that's the main mechanism of action. Now, this is where things do get confusing, because some publications will find that it actually acts by improving mitochondrial function. And one of the metrics of doing this in a workhorse tool in my own lab is measuring what's called mitochondrial respiration, or basically, how much are the mitochondria breathing? How much are they taking in oxygen? And the purpose of the oxygen is to fuel the flames of metabolism, to create energy for the cell in the form of ATP. Now, I don't want to go any further than that with regards to bioenergetics, but the mitochondria are the focus of metformin. But again, the confusion being, is it actually improving mitochondrial function or is it compromising mitochondrial function? I was a co author on a paper, so I lean this way because we did some of the work suggesting that metformin actually compromises mitochondria and by disrupting one of the electron transport complexes. And I'm getting more specific than I intended. You're actually inhibiting or compromising the mitochondria's ability to burn fuel in order to create ATP as the cellular energy. In so doing, in so doing, reducing ATP, you end up activating an enzyme called ampk. And AMPK is an ultimate kind of catabolic master switch. It wants the cell to start burning energy. So if AMPK is activated, glycolysis goes up, so the cell starts using more glucose, and lipolysis and beta oxidation of fats go up, so you start burning more fat for fuel. So metformin ends up having all of these generally favorable metabolic outcomes. In fact, metformin, and this is ironic in light of what we're going to get to in just a moment, is sometimes referred to as an exercise mimetic. So it's sometimes described as a drug that can mimic the effects of exercise. Now, before I get to the irony in just a moment and talk about the side effects, all of this being said, this means that metformin will have two general effects that have been pretty well documented. One is that it reduces the liver's production of or. Or breakdown of glycogen and. And gluconeogenesis. So in other words, it's stopping or slowing or inhibiting. How many more synonyms can I think of there? The liver's production or output of glucose, which is a good thing, that's going to reduce blood glucose levels, which helps insulin come down. And then speaking of insulin, there's evidence to suggest that muscle, which by mass is the main insulin sensitive, insulin dependent tissue in the body, the muscle becomes more insulin sensitive directly. And again, it's the mitochondria that appears to be the mechanism for all of this. And precisely how the mitochondria are responding to metformin is a bit unclear. Now let's talk about the consequences. So one of the most obvious consequences to someone on metformin is the, is the bubbling in the tummy, if you will, the nausea and the GI distress, some nausea and diarrhea. That's the generally main symptom. But then the mitochondria specific effects are relevant. There are multiple papers to show that, especially as we age, if people are on metformin, Metformin is directly blunting the body's favorable adaptation to exercise, whether it is aerobic or resistance. So there are studies in humans to show that metformin blunts the mitochondrial adaptations to endurance exercise. So if someone is running or engaging in any kind of aerobic activity normally, you would expect their mitochondria to get better and stronger because of that activity. Metformin stops that. It blunts that from happening. Additionally, there's evidence in older humans to find that metformin blunts the muscle adaptation, the muscle protein synthesis, the growing and strengthening of muscle tissue in response to, in resistance exercise. So I find it particularly amusing that these longevity gurus, and I do mean to kind of have that dripping with sarcasm and a little disrespect that a lot of these people who have become experts, if you will, in longevity, an area in which you cannot be an expert because there's no human trials to support that. They, in one breath they'll be advocating metformin and then in the other they're advocating exercise. Those two don't go together nicely. Okay, so that's it for metformin, the most widely used drug. I guess if I were to put a summary statement on this, and I didn't intend to say this, so we'll see how it comes out. My view of metformin is generally favorable. If you don't exercise, if you can exercise, then do and then be a little more wary of the metformin. All right, now the next, one of the next most common interventions for diabetes is insulin therapy itself. Now, of course, insulin therapy is critical and life saving for people with type 1 diabetes, but it ends up being life threatening, if you will, in someone with type 2 diabetes. And we'll come back to that in a moment. Of course, the, the justification now and the rest of the conversation will be framed in the context of type 2 diabetes and generally is, unless I say otherwise, the view with insulin. The justification for insulin therapy and type 2 diabetes is based totally on the glucose centric paradigm that if your view of type 2 diabetes is that we need to lower glucose at all costs, then you would say, why not let's give them an insulin syringe and have them shoot that insulin straight into their veins to lower their glucose. And it will lower their glucose. But unfortunately there are complications. But before I get into that, there are lots of different types of insulin. Rapid acting, short acting, long acting. Some of the long acting, which are the more common ones, they have the, they end with the term R gene or gene as a suffix, at the end of some of the drug classes. So you'll like, glargine. They are. These are drugs that are. Well, they're, they're insulin. They come into the body and they're just going to act like insulin. And so no surprise that there's a risk of reducing your blood sugar a little too quickly. So hypoglycemia is a common concern. Of course, we've talked previously about body fat changes. It's no surprise that the moment you put a diabetic type 1 or type 2 on insulin therapy, they're going to gain fat mass, they're going to gain weight, and that will mostly be fat. A fascinating study was published out of Japan a number of years ago that looked at insulin injection sites. You've heard before that if you're, if there's a diabetic on insulin therapy, they need to rotate their injection sites. The reason for this is that insulin promotes the growth of fat cells so well that they will end up getting these exaggerated fat blobs in their body. So the study out of Japan actually conducted a biopsy of the fat, and they measured the fat at the site of the injection where the body had kind of gotten this little bulb of fat. And then they measured a fat biopsy just a few centimeters away at a site that was still in the same overall fat depot, but not getting the direct injection of insulin. And they found that the fat cells were about 10 times bigger by volume at the site of the insulin injection. I mean, it's just absolute proof positive of insulin's effect on fat cells and ultimately promoting growth. Now, beyond the inconvenience of gaining weight, there are true chronic disease concerns, all of which has been shown admittedly through correlational studies in humans. But the first is a heart disease risk that insulin therapy and type 2 diabetes is associated with an increased heart cardiovascular risk and there's this dose dependent association. So the more insulin someone has to inject in order to keep their glucose in check, which is to say another way, the more insulin resistant you are, and now you're pushing your insulin up to these almost super physiological levels, then the more likely you are to die from heart disease. And this is directly contributing to hypertension, dyslipidemia, atherosclerosis and more. So again, Giving the type 2 diabetic insulin is going to increase their risk of heart disease. There's also an increased risk of cancer. Now I speak about cancer very, very delicately because there's so much we don't understand about canc. But once again there's this dose dependent risk that as insulin dose requirements are going up in the type 2 diabetic, so too does the risk of cancer mortality. And then third and final is the risk of Alzheimer's disease, that there's evidence to suggest that if you put a type 2 diabetic on insulin therapy, the risk of Alzheimer's disease goes up. There's a couple different studies that have been published on that topic over the past couple decades. So insulin therapy is a very good way to control glucose levels in a type 2 diabetic, but it is also a very, very good way of making the type 2 diabetic gain weight and have an increased risk of chronic disease and overall mortality. All right, let's get on to the next one. The third class we've gone through Metformin, we've talked about insulin therapy. Let's get into the so called insulin secretagogues and that is a general class. And when I'm describing it, I'm actually just talking about sulfonylureas mostly. But then there's another class called the meglitinides and there are different usually these insulin secretagogues, if it ends with uride or in ide as a suffix in the drug name, that's going to be one of these insulin secretagogues. What they have in common as the name suggests, is that they both want to increase the production of insulin. They're basically focused, forcing the beta cells of the pancreas to make more insulin. And again, if you have a glucose centric view of the disease, then you don't care about that at all. And you would say you wouldn't even know what insulin levels are in the person because you're so ignorant of them, you haven't even measured them with a conventional view, a conventional clinical view. So the Insulin secretogs. Again, the most common being the sulfonyl ureas, like gliburide and glipizide. They act by stimulating insulin secretion from the beta cells. So the consequences and the side effects are very, very similar to insulin therapy itself, including of course, an increased risk of heart disease. There is a paper, multiple papers published on this increased cancer risk. Again, multiple papers published on that. And then lastly, even Alzheimer's disease. Now there are more. I just sort of picked the big three here. Chronic killers that we're all, we all appreciate, if perhaps not always fear. So again, similar outcomes and similar complications as with insulin therapy that we see with the sulfonylureas or the insulin secretogs. Now, with insulin secretag in mind, let's go to the next one, the fourth one, and I'll be brief here because we devoted the entire previous episode talking about this exclusively, namely GLP1 and agonists. Commonly GLP1 agonists like semaglutide or liraglutide are also considered insulin secretagogues. But as I elaborated last time, that does not always appear to be the case. In fact, in humans it appears to not be the case that if you treat someone with this, with these GLP1 agonists, you do not see this immediate increase in insulin. It may enhance the insulin response to a glucose load, but it generally just does not increase insulin, like many people state that it does. And again, please listen to the previous episode to get more details. But the main mechanism of action here in this context being diabetes is the inhibition of glucagon. And that these GLP1 agonists are reducing the release of glucagon from the pancreas. And if glucagon comes down, then the liver is holding on to more of its glycogen and it's not breaking down the glycogen to be released as glucose. And and moreover, it's not producing glucose from scratch from say lactate or other carbon sources. So that's the main mechanism of action for its anti diabetic properties. And then the weight loss properties, as I elaborated last time and very briefly restating, are based on the inhibition of or the delayed gastric emptying. It's simply slowing the intestines down so the food is sticking in the stomach longer, making you feel fuller longer and reducing your cravings. Okay, let's go to the next one. The fifth of these hormone classes in general drug families is the thiazolidine diones. These are one of my favorites. Not to say I'm an advocate of them, but because they're so effective at suggesting that fat tissue is. That is so central to insulin resistance and thus to type 2 diabetes. Now, we've long known that people who gain weight have a higher risk of type 2 diabetes and that indeed, it's virtually unheard of to have type 2 diabetes and not be overweight to some degree. But so much of that, as you'll recall from the previous metabolic classrooms, is not a matter of how much fat mass you have, but rather a matter of the size of each of your fat cells. It's to say that again, it's the size of your fat cells that matter when it comes to fat and insulin resistance and type 2 diabetes, not how much fat you have per se. And you'll recall that different bodies have different tendencies to produce fat cells. And if you have a particular body type due to genetics that produces more fat cells, then as you have more and more pressure to store fat because of high insulin and sufficient calories, then you'll just start. You'll start making new fat cells. So all of your fat cells are small, but you will have more fat mass, but you'll be insulin sensitive because it's the size of the fat cells. So let's come back to the thiazolidine diones. These are drugs that end with the suffix ozone, like pioglitazone or rosiglitazone. What they do is activate a nuclear receptor called PPAR gamma. In so doing, it stimulates a process called adipogenesis. Adipogenesis is the term to describe the production of new fat cells. And so this creates this delightfully paradoxical metabolic state where the type 2 diabetic who's overweight, who gets prescribed a thiazolidine dione will in fact see an improvement in their insulin sensitivity and type 2 diabetes. And then here's the paradox, because they're getting fatter. If you can convince your fat cells to store more fat because they're multiplying, then the cells are all small and they're insulin sensitive and they're anti inflammatory. Again, Harken, I'm hearkening back to previous episodes here and assuming you're a little more familiar with this. So please go back and listen to previous episodes describing the role of fat in insulin resistance. But again, these drugs are stimulating your fat's ability to make new fat cells, thereby shrinking all of the fat cells so all the fat cells are able to be smaller because there's so many more to help carry the metabolic burden of the fat. And so again, the paradox being you become more insulin sensitive while and because you're becoming fatter. So that's the main side effect. The main side effect is the fat gain, and it is substantial. A person can find that they easily gain 20 pounds of pure fat within just a few months.