110: Rethinking Type 1 & Type 2 Diabetes: Glucagon’s Hidden Role, a Bi-Hormonal Theory w/ Dr. Bikman

Or releasing that hormone, to be a little more precise, into the general circulation of the blood. So when the alpha cell and the beta cell are talking to each other, that beta cell is releasing the insulin in a paracrine manner directly to its neighbors before it ever even spills into the blood. It's acting on the alpha cell. So this means that when insulin levels rise after a meal that has some carbs, then glucagon secretion is suppressed because of all that insulin, which is going to help prevent the inappropriate glucose production when it's abolism. Now, that last point's a little weaker, but it's still one that Dr. Unger indicated, and so I wanted to highlight it. But his research showed that when you eliminate glucagon action, many of the classic features of diabetes disappear, even in the absence of insulin. Let me say that all again, even though insulin is still absent and his experimental models, if you simply blocked the actions of glucagon, everything got better. I hope that is an impactful statement as you think about it. Now let's get into the science, and particularly with glucagon physiology, because everyone's so familiar with insulin. I, after all, have devoted most of my career to understanding insulin and insulin resistance. But we need to appreciate the other hormone here, the yang to insulin's yin, if you will. To appreciate why glucagon excess is problematic in type 1 diabetes, we need to understand how the hormone normally functions. Now, glucagon is produced by the alpha cells of the pancreatic islets. And you'll recall that islets are these small little islands of cells that are clumped together, and the beta cells and the alpha cells constitute the majority of those. Now, there's some other, fewer ones there as well, but the alpha cells within the islets serve as insulin's metabolic opposite. When blood glucose falls, glucagon is released to stimulate hepatic glucose production. And it does so through two primary glycogenolysis, the breakdown of the stored glycogen. And glycogen is simply stored glucose, but also gluconeogenesis, the creation of new glucose from any source of carbons whatsoever. That can be amino acids, it's most especially lactate, it's glycerol from a broken down triglyceride. But any of these carbons that can be retooled or repurposed or recycled into glucose, that's going to be the substrate or the building blocks for gluconeogenesis and glucagon is going to want to turn that on. Now, here is a crucial point. Glucagon secretion is normally tightly regulated by local insulin concentrations within that narrow little geography of the pancreatic islets. Now, within those little islands of cells, and they're sprinkled throughout the pancreas, the beta cells and the alpha cells literally exist as neighbors. They are in immediate proximity to each other, and thus they get a lot of each other's signals. Insulin coming from the beta cell acts as a powerful, what's called paracrine suppressor of glucagon release. Now, I just invoked a term of endocrinology here, which is appropriate. This is an endocrine or hormone focused lecture. But paracrine is when you have a cell sending a signal to another cell without the need of dumping that signal or releasing that hormone, to be a little more precise, into the general circulation of the blood. So when the alpha cell and the beta cell are talking to each other, that beta cell is releasing the insulin in a paracrine manner directly to its neighbors before it ever even spills into the blood. It's acting on the alpha cell. So this means that when insulin levels rise after a meal that has some carbs, then glucagon secretion is suppressed because of all that insulin, which is going to help prevent the inappropriate glucose production when it's not needed. If we're eating glucose, we don't want the glucagon going to the liver, telling the liver to be making more glucose. Now, the local regulation is beautifully and frustratingly sophisticated. The concentration of insulin within those pancreatic islets is much higher than what we measure from peripheral circulation. So when we're drawing blood from someone's vein in their arm, it's going to be fantastically different than the level of insulin that you actually see within the islets. Now, we're talking about concentrations that are easily up to 100 times higher than what we see in the systemic levels. So that's islets compared to systemic circulation. The high local insulin production in that narrow little eyelet is essential for properly suppressing glucagon secretion. So think of it like this. The islet functions as an integrated unit where the beta cells don't just produce insulin for the body, for the brain or the muscle or the liver, but also creates a local hormonal environment that is necessary to keep the alpha cell in check. In other words, the alpha cell is used to getting a lot of insulin, and that becomes a problem, which I'll revisit in just a moment. And so when the system works properly, glucagon is released only when needed, like fasting or exercise or potential hypoglycemia. But importantly, this is all states when insulin production is very low. When insulin production goes down, there is less of an inhibition on the alpha cell with glucagon, and now glucagon can come up. The elegance of this system becomes apparent when we consider that both hormones are responding to the same stimulus, glucose, but in opposite directions. As glucose rises, then insulin will increase and glucagon will decrease. As glucose falls, blood glucose goes down, then insulin will go down and now glucagon will go up. Now this creates a pretty robust and even minute self regulating system, all of which is focused on glucose homeostasis across a wide range of physiological states, whether we're sleeping, whether we're exercising, and everything in between. Now let's get into this kind of the dance or the balance of type 1 diabetes. When we examine what happens with type 1 diabetes, we see just how the disruption can become quite obvious. Now, as I mentioned, and as you already know, in type 1 diabetes, we have had the autoimmune destruction of the insulin producing beta cells, but we have spared the glucagon producing alpha cells. Now, this creates a metabolic challenge because we lose the insulin producing cells, but retain the glucagon producing ones. And critically, with the loss of the beta cells and its insulin product, we lose that local insulin supp. So essential to keep glucagon in check when beta cells are destroyed. Of course there's going to be a lot of things that happen. First, obviously systemic insulin production ceases, leading to the familiar consequences of not having enough insulin. But equally important and very overlooked, is the loss of that local suppression of glucagon. Remember that the high intra islet insulin is needed. Remember how I mentioned that it's within the islets. If we could put a little probe in the islets of the pancreas and measure insulin levels and compare it to a little probe measuring plasma levels from a blood vessel in our arm, the local concentration in the islets of insulin is going to be about 100 times higher than what we might see local systemically rather. Now this of course means, as I mentioned, that alpha cells, which are still present and functional, are now operating without their normal regulatory break, their inhibitor. Now, importantly, even when blood glucose is elevated, a situation that you think would suppress glucagon, the alpha cells continue to secrete glucagon inappropriately because they're no longer receiving the local insulin signal that would normally shut them down. High glucose doesn't inhibit glucagon. Insulin does. So when you think about this fundamental part of endocrinology, or the negative feedback, specifically, where a hormone gets released, it has an action, and then the action will turn off that hormone. It's not quite that obvious when it comes to glucagon that you think that the high glucose would shut off glucagon. And yet that's not the off switch. The off switch is the insulin that. Normally, if glucose is going up, well, then insulin goes up, too, and it's the high insulin that shuts off the alpha cell. But the result of all of this is a state of hyperglucagonia where the glucagon levels are inappropriate for the metabolic context. And of course, that metabolic context is the high glucose, because the glucagon is just dumping out more glucose. But it goes even a little further. So, yes, we have the glucagon promoting the liver to be pushing out even more glucose. And again, remember, that's so inappropriate because they already may be hyperglycemic, but it's just amplifying the hyperglycemia. But it goes a little beyond that in an interesting way, because, second, glucagon also promotes ketogenesis. Now, the explicit degree to which that happens in humans is a little unclear, but in other cell and rodent models, it's very clear that glucagon activates ketogenesis. And so with the high glucagon, it is contributing to the diabetic ketoacidosis in the untreated type 1 diabetic. Now, of course, that's all amplified by the lack of insulin, because insulin powerfully inhibits ketogenesis. But then third, and this is the murkiest of all of them, but it was still a point that Dr. Unger noted, and so I would be remiss not to mention it myself, but it enhances protein catabolism. So the breakdown of protein from, like, tissues, like muscle. Now, that is not a direct effect. Glucagon does not directly impact the muscle, but it's thought to be indirect. And I'll revisit that more in a moment. Okay, now here is where, in addition to all of the clever insights Dr. Unger has made, and I hope I've articulated them, but one particularly profound insight, Roger Unger, recognized that many of the classic features of type 1 diabetes, the ones I just mentioned, hyperglycemia, the ketoacidosis, the protein wasting, they're not just consequences of the insulin deficiency, but are actively driven by all of that glucose that just won't shut off. In experimental models, when glucagon action is blocked, these features of diabetes are dramatically reduced, even in the complete absence of insulin. Something I'm repeating now. So this creates a little bit of a therapeutic paradox that explains why insulin replacement, while life saving, doesn't always provide perfect metabolic control when we inject insulin subcutaneously. So just pushing it in by pinching our fat, or the fat in our belly or the fat in our leg, or wherever the person's injecting it, we are injecting it at a level that is systemic in its concentration. So we're replacing the systemic insulin that is going to act on the muscle and the liver and the brain and anything else we're not recreating the high local concentrations within the pancreatic islets. And that is the level that is normally that is needed, not normally that is needed to suppress glucagon. Thus, the alpha cells remain relatively unchecked, like a naughty little kid who's not being told to stop. There's no signal telling them to stop. So they continue to produce inappropriate amounts of glucagon, or just excess glucagon when they shouldn't be producing any, really. Now, this brings us to one of these important insights. Why injected insulin, despite being life saving, cannot fully replicate normal glucose homeostasis. It's because it's not just about getting insulin into the bloodstream treatment to tell the muscles to pull in glucose. It's also about trying to get enough to the eyelets to shut down the glucagon. Now, let me just say that all in a little bit of a different way, when we inject insulin subcutaneously, we're delivering it to the systemic circulation where it can reach the muscle in the fat tissue and the liver, et cetera, promoting glucose uptake and storage. Now, this addresses one aspect of the insulin deficiency, but it doesn't address the glucagon problem. The injected insulin doesn't achieve the high local concentrations that you need within the pancreatic islets, the concentrations that are essential for turning glucagon off. Now think about the anatomy here. In a healthy pancreas, beta cells and alpha cells are intimately connected. Within the islets, they're neighbors. Beta cells don't just release insulin into the bloodstream. They create that local micro environment where insulin concentrations are extraordinarily high Polynesian by systemic standards. This local insulin then acts in that paracrine signal to inhibit the glucagon release from the nearby alpha cells. When we inject insulin, even with the most sophisticated pump systems that a diabetic can have, or multiple injections with the best type of insulins, we're working with systemic insulin concentrations that are orders of magnitude lower than what we see within the eyelids. We might achieve the systemic insulin levels of about 100 or so micro units per milliliter. But the intra islet concentrations again are going to be 1,000 or 10,000 micro units per milliliter, so 10 to 100 times higher. Now, I'm a professor, and I've found that one effective way of teaching principles is through analogies. So this is like having a conversation in a crowded room. When two people are standing right next to each other, they can talk at a normal volume and still hear each other perfectly. But if one person moves across the room and tries to shout the same message, even though they may be shouting, but they earlier could just use a normal volume, they go across the room, they're further from each other, even shouting, this person can't hear this person's voice. And so you don't have the same effect, the message doesn't get conveyed as well. This explains several of the quirks of type 1 diabetes. Why do people with type 1 diabetes often have difficulty achieving target glucose levels despite apparently adequate insulin replacement? Why do they experience greater glucose variability, always going up and down, than people who have functioning pancreatic islets, namely the beta cells being right next to the alpha cells? Why do they always have this risk of ketoacidosis, even when they're getting insulin? Dr. Unger provides that framework, which is that we're only addressing half of the problem. We're replacing systemic insulin, but we're not controlling glucagon. The alpha cells continue to behave as if the body is in a fasting state, inappropriately producing glucose from the liver and ketones from the liver, even when blood glucose is elevated and even if insulin is present. But it also explains why people with type 1 diabetes often require larger amounts of insulin than would theoretically be needed based on their body size and even the amount of carbohydrates they're taking in. Because they're not just replacing the insulin needed for glucose uptake, that which would be necessary or sufficient to tell the muscle or the fat tissue to take it in. They're also having to try to overcome the glucose production driven by the unopposed glucagon action. Now, recent evidence has shown that even in well controlled type 1 diabetes, glucagon levels are elevated compared to healthy individuals. And the normal suppression of glucagon after meals is impaired. So normally in a non diabetic person, they eat a mixed macronutrient meal and they're going to see insulin go up and they're going to see glucagon go down. And a type 1 diabetic who eats that same meal, even if they give themselves enough insulin to control their glucose, glucagon is still going too high. So what are the clinical implications now that you are very familiar with the glucagon centric view of type 1 diabetes? Well, there are some interesting ones that I'm hopeful will work their way into modern medicine and clinical pharmacological care. Multiple studies have demonstrated that people with type one, as I noted, have too much glucagon. And research has shown in type 1 diabetes that these levels can be up to two to three times higher than normal. So there is a chronic hyperglucagonemia. And even conventional endocrinologists will recognize this, even if they don't know what to do about it. But let's first consider some of the consequences, like glycemic variability. People with type 1 diabetes will have much higher glucose swings, as I noted, than their healthy peers. Glucagon centric. The glucagon centric view explains some of that variability, that the insulin will help at the systemic level, but not the local level. And so we have this constant tug of war between insulin and glucagon that is creating the ups and downs. But the framework with the glucagon centric view also explains the ketoacidosis, as I mentioned. But then let me spend a moment longer on the protein catabolism part. As I said, it's a little muddier than Dr. Unger outlines. And that's partly because there are no glucagon receptors on the muscle. And so in the untreated type 1 diabetic, there is a general wasting away. Yes, they're very skinny in fat, with their lack of fat, I should say, to be perfectly clear. And that's because in the lack of insulin, in the absence of insulin, there can be no fat storage, something I've talked about previously. But they just are wasting away. Even generally where the muscles and the bones are getting small, all lean tissue is also wasting away. And again, at the muscle, which is particularly susceptible to protein breakdown because it's the main site of protein or amino acid storage in the body. It's not directly happening where the glucagon is not directly affecting muscle protein Breakdown, because there are no glucagon receptors, but glucagon is accelerating the clearance of amino acids into the liver. So the lack of insulin would be very important in protecting muscle protein. Well, insulin acts to protect muscle protein and to keep that protein in the muscle. When insulin goes down, you've lost that protective signal, and now the muscle's breaking down. Glucagon is not directly facilitating that, but it is directly facilitating the uptake of the amino acids into the liver, for the liver to convert that into glucose. And so it's an indirect. It's almost like it's the high. Glucagon is telling the lack of insulin. Oh, okay, you're giving me a lot of amino acids to work with. I'm going to just push them into the liver. But more directly, glucagon does increase hepatic lactate uptake. So lactate is, of course, a fuel and end result of glycolysis or glucose burning, which is the main source of. Of the building block for gluconeogenesis. Lactate is the main building block for gluconeogenesis, and glucagon helps that lactate get into the liver to be converted into the glucose. Now, there are, and Dr. Unger was the pioneer here, many studies that have also examined what happens when glucagon action is specifically blocked. Now, I mentioned one instance, a mom. Let me go into a little more detail. Research using glucagon receptor antagonists. So blockers has shown dramatic improvements in glucose control in people with type 1 diabetes, even. Even without changes in any insulin therapy. And so these studies are very clear at demonstrating that blocking glucagon action can reduce both fasting and postprandial glucose levels, decrease the glucose variability, and reduce the ketone production. Now, as much as I have focused on pretty much exclusively on type 1 diabetes, this entire phenomenon is also relevant in its own way with type 2 diabetes. So I focused on type 1. But there's also something here with type 2. But in this case, it's not a lack of insulin, because in type 2 diabetes, it is not a lack of insulin. It's rather the inability of the insulin to work very well. What we call insulin resistance. After all, insulin resistance is the primary defect in type 2 diabetes. And why would we think that the alpha cells would be spared? Notably, even. This is one of Dr. Roger Unger's main discoveries. And in fact, it was this paper that really put him on my radar, that led me to dive into the history of his work. Just to say that all another Way, it was his paper from about 10 years ago that indicated that even the alpha cells can become insulin. Perfect metabolic control. When we inject insulin subcutaneously. So just pushing it in by pinching our fat, or the fat in our belly, or the fat in our leg, or wherever the person's injecting it, we are injecting it at a level that is systemic in its concentration. So we're replacing the systemic insulin that is going to act on the muscle and the liver and the brain and anything else we're not recreating the high local concentrations within the pancreatic islets. And that is the level that is normally, that is needed, not normally that is needed to suppress glucagon. Thus, the alpha cells remain relatively unchecked, like a naughty little kid who's not being told to stop. There's no signal telling them to stop. So they continue to produce inappropriate amounts of glucagon, or just excess glucagon, when they shouldn't be producing any, really. Now, this brings us to one of these important insights. Why injected insulin, despite being life saving, cannot fully replicate normal glucose homeostasis. It's because it's not just about getting insulin into the bloodstream to tell the muscles to pull in glucose. It's also about trying to get enough to the eyelets to shut down the glucagon. Now, let me just say that all in a little bit of a different way, when we inject insulin subcutaneously, we're delivering it to the systemic circulation where it can reach the muscle in the fat tissue and the liver, etc. Promoting glucose uptake and storage. Now, this addresses one aspect of the insulin deficiency, but it doesn't address the glucagon problem. The injected insulin doesn't achieve the high local concentrations that you need within the, the pancreatic islets, the concentrations that are essential for turning glucagon off. Now think about the anatomy here. In a healthy pancreas, beta cells and alpha cells are intimately connected. Within the islets, they're neighbors. Beta cells don't just release insulin into the bloodstream. They create that local micro environment where insulin concentrations are extraordinarily high by systemic standards. This local insulin then acts in that paracrine signal to inhibit the glucagon release from the nearby alpha cells. When we inject insulin, even with the most sophisticated pump systems that a diabetic can have, or multiple injections with the best type of insulins, we're working with systemic insulin concentrations that are orders of magnitude lower than what we see within the eyelids, we might achieve these systemic insulin levels of about 100 or so micro units per milliliter. But the intra islet concentrations again are going to be a thousand or ten thousand micro units per milliliter, so 10 to 100 times higher. Now, I'm a professor and I've found that one effective way of teaching principles is through analogies. So this is like having a conversation in a crowded room when two people are standing right next to each other, they can talk at a normal volume and still hear each other perfectly. But if one person moves across the room and tries to shout the same message, even though they may be shouting, but they earlier could just use a normal volume, they go across the room, they're further from each other, even shouting, this person can't hear this person's voice. And so you don't have the same effect, the message doesn't get conveyed as well. This explains several of the quirks of type 1 diabetes. Why do people with type 1 diabetes often have difficulty achieving target glucose levels despite apparently adequate insulin replacement? Why do they experience greater glucose variability, always going up and down than people who have functioning pancreatic islets, namely the beta cells being right next to the alpha cells? Why do they always have this risk of ketoacidosis, even when they're getting insulin? Dr. Unger provides that framework, which is that we're only addressing half of the problem. We're replacing systemic insulin, but we're not controlling glucagon. The alpha cells continue to behave as if the body is in a fasting state, inappropriately producing glucose from the liver and ketones from the liver, even when blood glucose is elevated and even if insulin is present. But it also explains why people with type 1 diabetes often require larger amounts of insulin than would theoretically be needed based on their body size and even the amount of carbohydrates they're taking in, because they're not just replacing the insulin needed for glucose uptake, that which would be necessary or sufficient to tell the muscle or the fat tissue to take it in, they're also having to try to overcome the glucose production driven by the unopposed glucagon action. Now, recent evidence has shown that even in well controlled type 1 diabetes, glucagon levels are elevated compared to healthy individuals and the normal suppression of glucagon after meals is impaired. So normally in a non diabetic person, they eat a mixed macronutrient meal and they're going to see insulin go up and they're going to see glucagon go down and a type 1 diabetic who eats that same meal. Even if they give themselves enough insulin to control their glucose, glucagon is still going too high. So what are the clinical implications now that you are very familiar with the glucagon centric view of type 1 diabetes? Well, there are some interesting ones that I'm hopeful will work their way into modern medicine and clinical pharmacological care. Multiple studies have demonstrated that people with type one, as I noted, have too much glucagon. And research has shown in type 1 diabetes that these levels can be up to two to three times higher than normal. So there is a chronic hyperglucagonemia. And even conventional endocrinologists will recognize this, even if they don't know what to do about it. But let's first consider some of the consequences, like glycemic variability. People with type 1 diabetes will have much higher glucose swings, as I noted, than their healthy peers. Glucagon centric. The glucagon centric view explains some of that variability, that the insulin will help at the systemic level, but not the local level. And so we have this constant tug of war between insulin and glucagon that is creating the ups and downs. But the framework with the glucagon centric view also explains the ketoacidosis, as I mentioned. But then let me spend a moment longer on the protein catabolism part. As I said, it's a little muddier than Dr. Unger outlines. And that's partly because there are no glucagon receptors on the muscle. And so in the untreated type 1 diabetic, there is a general wasting away. Yes, they're very skinny in fat, with their lack of fat, I should say, to be perfectly clear. And that's because in the lack of insulin, in the absence of insulin, there can be no fat storage, something I've talked about previously. But they just are wasting away. Even generally where the muscles and the bones are getting small, all lean tissue is also wasting away. And again, at the muscle, which is particularly susceptible to protein breakdown because it's the main site of protein or amino acid storage in the body, it's not directly happening where the glucagon is not directly affecting muscle protein breakdown because there are no glucagon receptors. But glucagon is accelerating the clearance of amino acids into the liver. So the lack of insulin would be very important in protecting muscle protein. Well, insulin acts to protect muscle protein and to keep that protein in the muscle when insulin goes down, you've lost that protective signal, and now the muscle's breaking down. Glucagon is not directly facilitating that, but it is directly facilitating the uptake of the amino acids into the liver, for the liver to convert that into glucose. And so it's an indirect. It's almost like it's the high glucagon is telling the lack of insulin. Oh, okay, you're giving me a lot of amino acids to work with. I'm going to just push them into the liver. But more directly, glucagon does increase hepatic lactate uptake. So lactate is, of course, a fuel and end result of glycolysis or glucose burning, which is the main source of. Of the building block for gluconeogenesis. Lactate is the main building block for gluconeogenesis, and glucagon helps that lactate get into the liver to be converted into the glucose. Now, there are, and Dr. Unger was the pioneer here, many studies that have also examined what happens when glucagon action is specifically blocked. Now, I mentioned one instance, a mom, go and let me go into a little more detail. Research using glucagon receptor antagonists so blockers has shown dramatic improvements in glucose control in people with type 1 diabetes, even. Even without changes in any insulin therapy. And so these studies are very clear at demonstrating that blocking glucagon action can reduce both fasting and postprandial glucose levels, decrease the glucose variability, and reduce the ketone production. Now, as much as I have focused on pretty much exclusively on type 1 diabetes, this entire phenomenon is also relevant in its own way with type 2 diabetes. So I focused on type 1. But there's also something here with type 2, but in this case it's not a lack of insulin, because in type 2 diabetes, it is not a lack of insulin. It's rather the inability of the insulin to work very well, what we call insulin resistance. After all, insulin resistance is the primary defect in type 2 diabetes. And why would we think that the alpha cells would be spared? Notably, even this is one of Dr. Roger Unger's main discoveries. And in fact, it was this paper that really put him on my radar, that led me to dive into the history of his work. Just to say that all another way, it was his paper from about 10 years ago that indicated that even the alpha cells can become insulin resistant. And thus, even within that local micro environment of the islets, there's a lot of beta cells making a lot of insulin, and the alpha cells aren't listening. And so they're just producing the glucagon, even though they shouldn't be. Now, when we understand the problem in with diabetes and the glucagon, it does open up some therapeutic possibilities that go beyond just traditional insulin replacement. And as we kind of near the end of this mini lecture, I wanted to just highlight these. And of course, insulin will always remain the cornerstone of type 1 diabetes treatment, but we need to have some novel interventions that address the hyperglucagonemia. One approach is the glucagon receptor antagonists, like I've mentioned before, medications that block the actions of glucagon at its target tissues, most especially the liver. Now, several of these drugs have been developed and even tested in clinical, clinical trials, and the results are promising. So it's very likely we could start to see some of this. The medication, of course, would act to just reduce the response to the glucagon. Another promising avenue involves somatostatin analogs. So somatostatin is a hormone that actually will suppress both insulin and glucagon. Now, that might seem problematic, but remember, in a person with type 1 diabetes, they're not making any insulin anyway. And so there's no problem if you suppress both of them because the insulin suppression isn't happening, you're not making it anyway. All you end up doing is suppressing the one that you have too much of, namely the glucagon. And there are also some growing interest in dual hormone artificial pancreas systems that deliver both insulin and glucagon in a more physiological manner. And this would be particularly promising even with pancreatic, with pancreatic islet transplants or just pancreas transplants. Now, one final note, just to mention the drug du jour, which is the GLP1 drugs. I actually am curious to see growing evidence on the use of GLP1 drugs like semaglutide in type 1 diabetes. Because one of the mechanisms of action for these drugs, indeed at its lower doses, originally used as just an anti diabetic drug before they were ever discussed as anti obesity drugs, and is that it inhibits glucagon. And so there could be some promising therapeutic potential in a more on target way for the GLP1 drugs. More on target than say, as used as an obesity drug. All right, now, in conclusion, in the midst of this very detailed, very heavy lecture, hopefully though sufficient for you to follow along, Dr. Unger's glucagon centric view of diabetes really represents one of the most important paradigm shifts in our understanding of the disease really since the initial discovery and even isolation of insulin that that was of course a life saving intervention and critical for our understanding of the disease. But Dr. Unger's singular contributions really bring in as he said this bihormonal nature of the problem that yes there's too little insulin but there's also way too much glucagon. So some of my hope as a scientist is that we continue to embrace this complexity of diabetes and then seek to find a multiple target, a multi target therapy for the disease. Thanks for joining me in the metabolic classroom today. Until next time, keep questioning, keep learning and of course remember more knowledge better health Looking to improve your own metabolic health? Visit insuliniq.com for courses, coaching, consultations and a 10 day free community membership trial to dive deep into the science behind metabolic health. Become an insider@Benbickman.com where you'll enjoy my exclusive content ad, free podcasts, live stream Q and A access and more.