How Insulin Makes You Burn Carbs for Energy | MWM 2.24
You eat carbs and your pancreas makes insulin. What does insulin make you do with those carbs? Store them as fat? Maybe if you’re eating enough calories to make that happen. But in the context of a healthy energy balance insulin is going to make you burn those carbs for energy. If you want to know how it does that, listen on. A ketogenic diet has neurological benefits. Why do we have to eat such an enormous amount of food? Complex science. Clear explanations. Class is starting now. In the last lesson we saw that insulin is primarily a gauge of the energy status of the pancreatic beta-cell. But the way that carbs and fats are wired to the pancreas and to other organs, in the context of the anatomy and physiology and the relative expression of glucose transporters and lipoprotein lipase, directs carbs as the primary source of energy for the pancreatic beta-cell; and for that reason carbohydrates are especially good at giving us more insulin signaling. Now in the next few lessons we’re going to look at what insulin does to that carbohydrate or does to that fat, and we’re eventually going to converge on the question of, can insulin actually make you fat as is often promoted in many corners of the internet? Or is insulin just helping you make decisions about which energy to spend and how? And we’re going to start this foray into the effects of insulin by looking in this lesson at, what does insulin do to carbohydrate metabolism? So without further ado let’s get right into those details. As shown on the screen insulin outside the cell binds to the insulin receptor. The insulin receptor is present in the cell membrane and insulin doesn’t need to come into the cell to carry out any of its effects. Instead the event of insulin binding to its receptor initiates a cascade of multiple phosphorylations and ultimately this leads to the activation of certain enzymes that dephosphorylate many of the enzymes that are directly involved in energy metabolism. Exactly which thing phosphorylates which thing in this cascade is extremely complex and is more the subject of the molecular and cellular biology of insulin signaling. We’re going to focus more on energy metabolism, the topic of this course, so we’re glossing over a lot of the details of these events here. The first thing that insulin binding to its receptor does to glucose metabolism is in tissues that express GLUT4 which is primarily expressed in muscle and adipose tissue, insulin causes GLUT4 to be transported from intracellular vesicles to the cell surface. And when that happens that makes the GLUT4 available to transport glucose into the cell or out of the cell. Now remember that glucose transporters don’t provide any direction to glucose transport. They only increase the rate of glucose transport. So simply bringing GLUT4 to the membrane is not necessarily going to bring more glucose into the cell all by itself unless there’s something that keeps glucose at very low concentrations within that cell. As we’ve discussed in previous lessons, it’s hexokinase, the enzyme that phosphorylates glucose that provides directionality to the flow of glucose into the cell. The glucose transporter allows the reversible transport of glucose in or out of the cell, but when hexokinase metabolizes glucose to glucose-6-phosphate that makes the concentration of free glucose extremely low in the cell. It is only free glucose that’s recognized by the glucose transporter. So if the free glucose inside the cell is extremely low because it’s all become glucose 6-phosphate then that makes it energetically favorable for glucose outside the cell to follow its concentration gradient and come in. So it’s GLUT4 that’s increasing the rate of glucose transport in response to insulin, but it’s hexokinase that’s providing directionality to make sure that the glucose comes into the cell. And so insulin couldn’t do much to bring glucose into the cell if it didn’t have an effect on hexokinase. And in fact, there’s a specific isoform of hexokinase or a specific isozyme of hexokinase known as hexokinase 2. Hexokinase 2 is the insulin-responsive form of hexokinase just like GLUT4 is the insulin-responsive form of glucose transporters. By stimulating GLUT4 and hexokinase 2, insulin helps increase the rate of glucose transport and increase the directionality to make sure that the glucose is coming into the cell. Shown on the screen is a possible model of how hexokinase is regulated by insulin to increase its activity. In the absence of insulin, hexokinase would largely be located in the cytosol where it would have access to glucose and ATP as they diffused through the cytosol, and when they happen to come in contact with hexokinase, hexokinase would catalyze their conversion to glucose 6-phosphate and ADP. That ADP would have to go back to the mitochondrion to become ATP, that ATP would have to come out of the mitochondrion and then diffuse through the cytosol until it came into contact with glucose and hexokinase. In this model many other enzymes could have access to that glucose or that ATP. It may be the case that what hexokinase does, or hexokinase 2 does in response to insulin to increase its activity is that hexokinase may bind to the voltage- dependent anion channel or VDAC in the outer mitochondrial membrane. We are going to talk a lot more about VDAC in the next lesson when we talk about fatty acid transport. But for now we’ll say that VDAC transports many things including ATP and ADP in the outer mitochondrial membrane. And if insulin makes hexokinase 2 bind to VDAC, then this would give it preferential or even exclusive access to the ATP coming from the mitochondrion. Instead of coming through VDAC and diffusing until it came into contact with hexokinase, ATP would go straight to hexokinase, glucose would be turned into glucose 6-phosphate because hexokinase has the exclusive access to any ATP that comes through VDAC; and the ADP would go straight back through VDAC, back into the mitochondrion to be turned into more ATP. Now this hasn’t been shown for certain. But I’ll tell you this, there’s a body of literature showing that insulin stimulates the activity of hexokinase 2. There’s a small number of studies from a long time ago showing that the way it does that is it increases the binding of hexokinase to the mitochondrial membrane. There’s now a newer body of literature showing that several percent of the VDAC pores in the mitochondrial membrane are always bound by hexokinase. And this is of particular interest to cancer researchers because it seems that in certain types of cancer where glucose metabolism is greatly ramped up in the context of what’s called the Warburg effect, something beyond the scope of this lesson, in those cases you have a very large percent of VDAC that are bound to hexokinase. But in normal healthy people it’s always the case that several percent of the VDAC in the outer mitochondrial membrane is bound by hexokinase. So if we put together the older literature showing that insulin increases its activity by making it bind to the mitochondrial membrane, and the newer research showing that the hexokinase bound to the mitochondrial membrane is bound to VDAC, then the model that I’ve put on the screen strikes me not merely as possible, but highly probable. In any case, insulin increases the activity of hexokinase 2 probably by the mechanism shown on the screen, perhaps by some other poorly understood mechanism that we don’t know that much about right now. Once glucose becomes glucose 6-phosphate it is not yet irreversibly committed to glycolysis. It’s only irreversibly committed after fructose 6-phosphate becomes fructose 1, 6-bisphosphate, the conversion of which is catalyzed by phosphofructokinase. As discussed previously, phosphofructokinase is the key regulator of the flux through the glycolytic pathway, and it’s regulated by energy status. When the cell has a lot of energy ATP inhibits it; when the cell has very little energy AMP activates it. So if insulin makes glucose become glucose 6-phosphate, and energy status is low, phosphofructokinase activity is very high, and glucose 6-phosphate becomes irreversibly committed to the glycolytic pathway and is burned for energy. This is important because glucose 6-phosphate can also be used for glycogen synthesis. But glucose 6-phosphate itself is an activator of the enzyme glycogen synthase and glucose 6-phosphate only accumulates at a high enough concentration to activate glycogen synthase when phosphofructokinase activity is inhibited by high energy status. Now there’s some debate about the relative importance of insulin and glucose 6-phosphate in stimulating glycogen synthase. The majority opinion is that glucose 6-phosphate is the dominant regulator of glycogen synthase, the key rate limiting enzyme for glycogen synthesis. If that’s true, then insulin is primarily signaling that carbohydrate is available and enhancing the effect of glucose 6-phosphate if high energy status inhibits phosphofructokinase and makes glucose 6-phosphate accumulate. But even if you were to make the argument that in some contexts insulin can become more important than glucose 6-phosphate as an activator of glycogen synthase, it’s still the case that glycogen content is the strongest regulator of glycogen synthase out of everything known. So if insulin does direct glucose into glycogen synthesis it’s only going to do that until glycogen content is replete. Even in that circumstance that would make glucose 6-phosphate become available for the glycolytic pathway and it would still be the energy status of the cell that’s the dominant factor in what you burn for energy. Now if we think about what should be the case, that cell is going to starve to death if it’s need for energy doesn’t take predominance over its need to restore glycogen. So it seems extremely doubtful that insulin is more dominant than glucose 6-phosphate in stimulating glycogen synthase. Most probable is the situation described in the typical textbook and by the majority of researchers in this area where glucose 6-phosphate itself is the key activator and insulin has a secondary role. In that context then it’s the energy demand of the cell that is the overwhelming determinant of whether you take glucose 6-phosphate and burn it for energy or store it as glycogen. And what that means is that insulin enables you to do either one of those things, but if you need more energy you burn the glucose for energy and if you don’t you store it as glycogen until the glycogen content is full. So the picture that this paints is that in the context of low energy status when the cell needs ATP, in other words when you’re in a relative caloric deficit instead of a relative caloric excess, then the net effect of insulin is to irreversibly commit glucose to glycolysis. Because insulin stimulates GLUT4, increasing the rate of glucose transport. Insulin stimulates hexokinase 2, increasing the directionality of glucose transport from outside the cell to inside the cell because of the rapid depletion of glucose as it’s converted to glucose 6-phosphate. Glucose 6-phosphate is reversibly converted to fructose 6-phosphate along a concentration gradient and fructose 6-phosphate is irreversibly committed to glycolysis by phosphofructokinase when energy status is low because of the activation by AMP. But everything that insulin does to glycolysis is like everything else that insulin does to energy metabolism, which is that the cell integrates what insulin is telling it about the needs and abilities of the body, with its own signals about its own needs and abilities; and the cell integrates that information and it makes the final decision of what it does with the glucose. So we talked in previous lessons, especially in lesson 5, about how AMPK also stimulates GLUT4. So GLUT4 increases in response to low energy status or a caloric deficit within that cell and in response to insulin, which signals a high availability of glucose systemically throughout the body. GLUT4 is integrating both of these signals and whether it increases is determined by the balance of both of those signaling processes. Glucose is then converted to glucose 6-phosphate. This is definitely stimulated by insulin and it’s definitely stimulated by low glucose 6-phosphate, because remember glucose 6-phosphate is a negative feedback inhibitor of its own production by inhibiting hexokinase 2. Glucose 6-phosphate is maintained at low concentrations during the context of low energy status because AMP activates phosphofruktokinase and clears glucose 6-phosphate through the glycolytic pathway. At a minimum, then, hexokinase 2 is integrating signals from insulin about whole body glucose availability and from glucose 6-phosphate, which is determined by phosphofructokinase activity, which is in turn determined by energy status. It’s probably also the case, I suspect, that AMPK stimulates hexokinase 2. The research seems less clear to me about that, but this is probably another way of the cell responding to energy status as well as insulin in determining what to do with glucose. Now on top of everything that insulin does to glycolysis it also stimulates the burning of pyruvate, the end-product of glycolysis, for energy, by stimulating its conversion to acetyl CoA. But just like everything else that insulin does to energy metabolism the cell is going to integrate information from insulin with the many other relevant factors that are going to determine what it decides to do with the pyruvate. And principal among those factors are the cells own need for energy. So the pyruvate dehydrogenase complex, which remember takes pyruvate from glycolysis, decarboxylates that to release carbon dioxide, takes the energy from that process and puts part of it on NAD+, so NADH can carry the energy to the electron transport chain, and puts part of it into acetyl CoA and acetyl CoA then takes the rest of that energy down into the citric acid cycle; that complex pyruvate dehydrogenase is inhibited by its own products, acetyl CoA and NADH. But on top of this it can be phosphorylated which makes it less active, as signified by the red arrow at the top saying phosphorylation inactivates the complex, or it can be dephosphorylated which makes it more active, signified by the green arrow at the bottom saying dephosphorylation activates the complex. The enzyme that phosphorylates it is pyruvate dehydrogenase kinase.The enzyme that dephosphorylates it is a phosphatase. Now the phosphorylation of pyruvate dehydrogenase is regulated by many factors that directly stimulate or inhibit either the kinase or the phosphatase. Insulin stimulates the phosphatase, that makes pyruvate dehydrogenase more active by putting it into its dephosphorylated state. But insulin is hardly the only thing that impacts that; calcium ions also activate the phosphatase. Remember that calcium in its ionic form inside a cell often activates the cell. Not the only example, but the prototypical example of that is that when you contract your muscles your nervous system is causing calcium ions to be released within your muscle cell and those calcium ions are what are activating the muscular contraction. So when calcium ions are released inside a cell that allows the cell to anticipate that very rapidly its energy needs are going to increase and that calcium acts as an anticipatory signal to ramp up energy metabolism. So just like insulin, which signals the availability of carbohydrate to be burned for energy through this reaction, calcium signals the need for energy inside the cell no matter where it comes from, but one of those places is going to be pyruvate. The pyruvate dehydrogenase kinase, which is inactivating pyruvate dehydrogenase, is inhibited by pyruvate. Pyruvate signals that, hey there’s pyruvate available to go through this complex and become acetyl CoA. So pyruvate stops the kinase from inactivating the complex and makes the complex more active. NAD+ and coenzyme A in its free form are present in low energy states. In high energy states NAD+ becomes NADH; CoA becomes acetyl CoA, or another acyl CoA. So signals of the need for energy are inhibiting the kinase, preventing it from inactivating the complex, and like pyruvate making the complex more active. By contrast acetyl CoA and NADH, which are the products of the pyruvate dehydrogenase complex and are also signals of high energy, as well as ATP, another signal of high energy, all activate the kinase, making it more likely to inactivate pyruvate dehydrogenase. Now this can sound pretty complicated to talk about something inactivating this thing that stops it from inactivating that thing and makes that thing more active. So let’s go to a different diagram that simplifies this information. Once glucose goes through glycolysis to generate pyruvate, the pyruvate is decarboxylated by the pyruvate dehydrogenase complex; releasing CO2 and becoming an acetyl group that joins two free CoA to make acetyl CoA. This is an oxidative process so NAD+ oxidizes the intermediates to become NADH carrying electrons and hydrogen ions to the electron transport chain. The acetyl CoA can then enter the citric acid cycle to be burned for energy. Insulin is stimulating the pyruvate dehydrogenase complex as a signal that there’s plenty of glucose and pyruvate available for this reaction. Acetyl CoA and NADH are both products of the reaction and are inhibiting it in a negative feedback loop. If they’re being produced at rates beyond what the electron transport chain can oxidize in the case of NADH, and beyond what the citric acid cycle can metabolize in the case of acetyl CoA, these come back and tell pyruvate dehydrogenase to stop making the products that are accumulating. But ATP also comes as a general signal of having enough energy to inhibit the pyruvate dehydrogenase complex. In the context of today’s lesson we’re going to look at this as a way of augmenting the earlier regulation of glycolysis, where insulin comes in to tell pyruvate to be burned for energy, but having enough energy contradicts that signal. Once again, we see insulin as not the key determinant of what happens in the cell, but simply as a messenger that provides some information about what’s going on in the rest of the body that then allows the cell to integrate that piece of information with information about its own needs and abilities to make a concerted decision about what to do that integrates all these different pieces of information. Eventually we’ll come back to this because we’ll see that the predominant reason that we’re still regulating pyruvat , even though we already told glucose to come down through to pyruvate to get burned for energy, because of the earlier regulation in glycolysis, the primary reason we still need to regulate pyruvate is because pyruvate itself could have multiple fates such as conversion to alanine, such as conversion to oxaloacetate for anaplerosis, and such as rewiring up through the process of gluconeogenesis. When we get to the point where we’re ready to talk about gluconeogenesis we’ll come back and talk about the functions of these regulators in that context. But for now we can simply see this as another example of insulin helping us burn carbohydrate for energy, which is a signal that’s contradicted when we have all the energy we need. So in the context of healthy energy balance where when we eat a meal because we need the energy in that meal, the combination of insulin from carbohydrate and the need for energy because of our caloric balance, is going to lead to the net effect of burning carbs for energy. Insulin is going to lead to glucose uptake and glucose phosphorylation. Energy status is going to take over and through regulation of phosphofructokinase is going to drive glucose 6-phosphate through glycolysis to make pyruvate. Insulin then stimulates the conversion of pyruvate to acetyl CoA. Once we have acetyl CoA, we have the same acetyl CoA that we could have gotten from protein or from fat. We have it entering the citric acid cycle, which is not governed by hormones, but is instead governed by the need for ATP and the abilities of the electron transport chain to meet the demands placed on it. The audio of this lesson was generously enhanced and post-processed by Bob Davodian of Taurean Mixing. Giving you strong sound and dependable quality. You can find more of his work at taureanonlinemixing.com. To continue watching these lessons, you you can find them on my YouTube channel youtube.com/chrismasterjohn. Or on my Facebook page at facebook.com/chrismasterjohn. Or you can sign up for MWM Pro, to get early access to content, enhanced keyword searching, self-pacing tools, downloadable audio and transcripts, a rich array of hyperlinked further reading suggestions, and a community with a forum for each lesson. So if you really want to own these lessons, study them and get the most out of them, you can sign up for MWM Pro at chrismasterjohnphd.com/pro. All right, I hope you found this useful. Signing off, this is Chris Masterjohn of chrismasterjohnphd.com. You’ve been watching Masterclass with Masterjohn. And I will see you in the next lesson.