Greetings, today, we want to talk about how the body uses fuel and the types of regulation that we have to employ in order to move from a fasted state to a fed state and back to a fasted state. The first things that we're going to do is consider how hormones are secreted from an organ called the pancreas. And this is going to give us our daily minute to minute control. Two hormones are involved: one is insulin and the other is glucagon. Then we will describe the relationship between blood glucose concentration and the amount of Insulin that is secreted. Thirdly, we want to talk about the major target organs for insulin and its effect on these target cells. And then four, we will discuss some of the pathological states that occur when there is an insufficiency in the amount of insulin which is secreted from the body. So today, we will consider insulin. Next time we will discuss glucagon. Insulin and glucagon form opposing reflex loops. We'll deal with this shortly and then move on to talk just about insulin. Why do we need fuel? We need fuel to generate energy for our current activities. We also need fuel so that we can acquire substrates to store and then use them during times when we're between meals or we're in fasting conditions. And then thirdly, we need fuel so that we can turnover tissue. There are lots of tissues in the body that need to be repaired. We also have growth. During those periods of time we need to have some kind of fuel. The body, of course, is going to have an energy state which is in mass balance or it's going to try an control its energy state to maintain a mass balance. If our energy intake equals output, then we do not gain weight. We will be in a neutral balance. But in conditions where we bring in more fuel than what we use, then we would be in a positive balance. We would gain weight. Under conditions where we use more of our fuel than what we bring in, then of course, we would lose weight. We would be in a negative balance. The body has hormones which are change our metabolism. The body also has hormones to regulate the intake of fuel. That is through feeding. The feeding axis,we haven't really talked about directly, only indirectly when we talked about the thyroid hormone. The feeding axis is governed by hormones. One of those hormones is insulin. This is the hormone we are considering today. When insulin rises in the blood, it turns off feeding. This occurs because insuin indicates that we have a lot of fuel. We now feel satiated. When insulin levels fall, then we have the converse. This promotes feeding. Okay, let's look at this, the reflex, for the two different states that we have for fasting and fed. The fed state is called an anabolic state. This is when we've just eaten a meal. Food is coming in from the GI tract. It's going to be delivered by the blood to the liver. The types of fuel substances that are delivered to the liver are sugars, glucose, amino acids, and fats. They come into the liver. The liver can store this material as glycogen which is a very labile form of carbohydrate. The amino acids can be stored in the muscles. We can increase muscle mass. We store the fats in fat tissue or adipose tissue. Under this condition, the body is in an anabolic state because we were building tissues. The converse of this state occurs when we're fasting. That is, between meals no food is brought into the body. Now we will reverse the process. We break down fat to form fatty acids plus the glycerol. These prodcuts are delivered to the liver. The liver then forms glucose and ketones. It actually secretes these products into the plasma. They are then delivered to the cells for fuel. The muscle can be degraded as well, although this is very an expensive fuel source. The muscle is degraded to amino acids. Amino acids in turn can be converted by the liver into glucose, and secreted into plasma. The liver itself can degrade glycogen and then again raise plasma glucose. So plasma glucose level will rise due to the activity of the liver. Glucose is one of the predominant fuel sources for the brain. This is one of the major food sources that the brain uses, but the liver can also form ketones. The ketones are actually acids. These are ketotic acids. The brain is able to use the ketotic acids. The brain is rather a specialized area of the body in that the brain itself does not store any fuels. The brain is always dependent on the amount of glucose delivered by the blood or on the ketotic acids, ketones, as a fuel source. How do we switch from an anabolic to a metabolic pathway? This is done on a minute-to-minute basis. It is maintained by insulin and glucagon. These two hormones come from the pancreas. They come from a specific region in the pancreas, called the pancreatic islets. The pancreatic islets secrete insulin and glucagon. They will do so in response to a substrate. The substrate is usually glucose. We'll talk about this reflex in a second. Glucose is a dominant signal for when we either turn on insulin or we turn on glucagon. We also have conditions where we have stress energy. That is energy that we need in order to run away from the dinosaur or to run away from some type of pursuer. These are our flight or fight responses. We said earlier that this is going to be maintained by cortisol, epinephrine, which are coming from the adrenal glands and glucagon. Glucagon comes from the pancreas. We will discuss glucagon when we meet in the next lecture. We also can have growth hormone to help under stress to increases blood glucose levels. In long term starvation, we use the thyroid hormones. The thyroid hormones are important under conditions where we have restricted fuel or starvation conditions. T4 decreases the basal metabolic rate of all the tissues of the body. So that we are not burning fuel at a high rate, we move from a T3 state to a T4 state. What does the reflex loop look like then for this minute to minute regulation of fuels? The minute-to-minute regulation of fuel, governed by insulin and by glucagon. Both of these hormones are secreted by the pancreas, by the islet cells of the pancreas. The beta cells secrete insulin. The alpha cells secrete glucagon. When plasma glucose levels rise, we are in a fed state. If plasma glucose levels rise above 100 milligrams per deciliter, then insulin is secreted. Insulin will have two separate target sites. The first target site is the liver. it will cause the liver to store glucose. It's second target sites are areas of the body which store fuels as well. These are skeletal muscle and adipose tissue. In these organs, a receptor is activated by insulin. The insulin receptor is activated. That receptor in turn causes transfer of a glucose transporter from the cytoplasm of the cells out to the plasma membrane. Then glucose enter into these two tissue types at a very rapid rate. So it's moving or mobilizing the GLUT transporters out onto the cells surface and glucose enters. Glucose is then stored within the muscle or within the adipose tissue. The net effect of these two separate actions by insulin causes a decrease in plasma glucose levels. This decrease in plasma glucose levels obviously takes care of our initiating stimulus. We now have our negative feedback loop. But notice that there's a second feedback loop which is connected to insulin. That is activated when the plasma glucose levels fall. If they fall to <80 mg/dL, then this decrease activates the alpha cells of the pancreas. The alpha cells will secrete the hormone glucagon. Glucagon will do the converse from what we saw happening with insulin. Glucagon mobilizes fuel. It actually raises the plasma glucose levels. One other thing to notice about this reflex loop is that when we have insulin, insulin actively inhibits the secretion of glucagon from the alpha cell. So insulin is the dominant hormone. It prevents glucagon from being released by the alpha cell under normal conditions. So what about these beta islet cells? The bata cells of the pancreas is diagrammed here. The beta cell is a cell that counts the amount of glucose within the blood. It acts like a little bean counter. The glucose enters the cells through transporter, the GLUT transporter. As it comes into the cell, it gets trapped as G6P. This is used to make ATP. That is shown here. As glucose enters, ATP levels rise within these cells. The ATP closes a potassium channel. This potassium channel is gated by ATP. When we close a potassium channel, the cells depolarize. As the cells depolarize, we open a voltage gated calcium channel. Calcium enters. That raises intracellular calcium. You all know that when you raise intracellular calcium we get a secretion event. So the little stored vesicles that are stored in the cytoplasm which contain insulin are secreted. Insulin, a peptide hormone, is stored in vesicles. The insulin is then secreted. This process secretes the amount of insulin needed to match the amount of glucose sensed within the blood. There are conditions where the target cells are not responding correctly to insulin. This condiiton is called diabetic mellitus. These individuals have a problem governing glucose levels within the blood. Under some of these pathologic conditions, some of these instances, we observe that the cells, the beta cells, can be promoted to secrete more insulin by giving a drug which closes the ATP gated potassium channels. This drug is called sulfonylurea. If we give sulfonylureas to people who have diabetes mellitus type two, who have an insufficiency of secretion of insulin, then the cells secrete more insulin. The beta cell is the target for treating these diabetic patients. The beta cell is not just sensitive to glucose levels. The primary substrate that regulates the beta cell is in fact blood glucose. But it will also respond to plasma amino acid levels. A rise in plasma amino acids will cause a secretion of insulin. These are positive factors. The beta cell is regulated in a feed forward manner by the GI tract as the food is arriving into the GI tract. The GI tract secretes a hormone which is called glucagon like peptide. The glucagon like peptide primes the beta cell to secrete more insulin. It doesn't cause it to secrete insulin by itself but it causes it to secrete more insulin. It potentiates the activity of the gland in response to either amino acids or to glucose. This feed forward also occurs through the parasympathetic nervous system. That is as you smell food or you think about food or you start to taste food, as food starts to arrive within the GI tract, there is a feed forward to the pancreas by this nervous system, the parasympathetic nervous system. This tells the islets, the beta cells to get ready because food is coming. Again, this is a potentiation of the secretion of insulin from the beta cell in response to parasympathetic activity. This is a feed forward control from the GI tract. Feed forward control by the parasympathetic nervous system is a positive factor. Now we do have a negative factor. Negative regulation of this beta cell does occur. It is mediated by the sympathetic nervous system. Under conditions of stress when we have a high sympathetic drive, then the sympathetic nervous system inhibits the secretion of insulin. And as we'll see, when it inhibits the secretion of insulin, that removes the inhibition to glucagon. Now the alpha cells secrete glucagon. That's how we get our Yin Yang between these two interconnecting reflex loops. What are the target cells? The insulin receptors present on three target cells, muscle, liver and adipose tissue or fat. The receptor is sitting on the surface of the cell. It is a receptor that binds the protein, insulin. Insulin binds to the receptor. This results in second messenger signals which transduce the signal to the interior of the cell. A tyrosine kinase is activated. The second messenger signaling brings brings the signal to the cell interior. This is a very complicated second messenger signaling cascade. One of the important parts of it is that it recruits a glucose transporter, a GLUT 4, from being sequestered in the inside of the cell out to the plasma membrane. And once it's inserted into the plasma membrane, the GLUT 4 transporter allows glucose to enter the cells rapidly. This process occurs in both skeletal muscle and in fat cells. As the glucose is stored, it is cleared quickly from the plasma. In addition [COUGH], excuse me, the insulin receptor present on the liver is activated. The insulin receptor on the liver causes the liver to store fat and glycogen. In the liver, glucose comes into the cells. It is stored as glycogen. So how do we know if this whole system is working correctly? You all know that when you go into the doctor's office, they ask you if you had overnight fasting. When they testing overnight fast, they take a blood draw. What they're looking for is the circulating level of glucose within your plasma. Under normal overnight fasting conditions, you should have between 80 and 100 micrograms per deciliter. Some individuals are pre-diabetic. They have a pathological condition where they're not dealing with glucose quite correctly. In these individuals glucose levels are 100 to 125 micrograms per deciliter. An individual who is a diabetic will have a 126 or higher micrograms for deciliter. The other test that the physician can give to his patient is to ask how the glucose is actually being handled by the cells of the body. This is done in what's called an Oral Glucose Tolerance Test. In an Oral Glucose Tolerance Test, the individual is asked to drink a bit of syrup which is a very high concentration of glucose. If it is a normal person, they start off with a fasting level, blood glucose level which is about 80-100 mg/dL. And as they drink this syrup, the plasma glucose levels rise to the 100-150 by 1 hour and then back down by 2 hours to baseline. So this would be our normal individual. The rise in the plasma glucose is to about 140. Now if the individual is a diabetic, then that individual first of all has much higher fasting level of glucose when they come into the office. They could have 200 or higher. So let's say, our individual has 200 for his fasting plasma glucose level. If he drinks this bolus of glucose, then what happens is the glucose levels within the plasma rise, and they stay very high. They stay high for over four hours before coming back down to normal. That individual then, the diabetic, not only has a much greater rise in plasma glucose. but that the rise in plasma glucose is not resolved quickly. It stays high over a period of several hours. That's what's shown here. Eventually, the glucose is excreted from the body by removing it through the kidneys. There are in fact two different types of Diabetic Mellitas. Diabetes mellitas simply means that when the Greeks tasted the urine it taste is sweet. It is mellitus. In Diabetes Mellituas there's glucose lost in the urine. The problem with Diabetes is that there's too little glucose inside our cells and there's too much glucose outside the cells. We saw the fasting glucose levels can be quite high, 126 or greater. The consequence of that is that there is not enough fuel inside the cells and that there too much glucose on the outside. That changes the osmotic balance within the body. The individual is eating but that fuel is not useful to the individual. Instead they are peeing it out by the kidney into the urine. There's two types of diabetes. One which is Diabetes Type 1, which is Insulin Dependent Diabetes. Under these conditions, the individuals has lost the function of the beta cells. The beta cells of the pancreas are no longer responding to glucose. In fact, usually there is apoptosis or cell death of these beta cells. The beta cells themselves are missing in the individual. They obviously have insulin insufficiency. They can't secrete insulin because the cell that makes insulin is missing. So these individuals require insulin for replacement therapy. What are some of the symptoms that a Diabetic Type 1 would have? I have a really good friend who's a diabetic Type 1. He has been since he was 8 years old. This individual has a son who, when he turned 35 all of a sudden said that he was eating and eating and eating but was losing weight dramatically and he had no energy. His father asked him whether he was drinking a lot and peeing a lot. The son said yes. He is very thirsty. He is drinking all the time but he also is peeing a lot. So, the father asked him to be tested for diabetes. What's happening is it that glucose instead of being used by the cells is being delivered to the kidney. In the kidney the glucose level maxed out all the transporters for glucose.It stays inside, much of it stays inside the tubules of the kidney. It is staying in the presumptive urine. It is holding water because it is osmotically active. That means there's an increase in the amount of urine that's being put out. An increase in the volume, as well as loss of glucose from the body. This is osmotic diuresis. This individual, when he went in to be tested, he had 350 micromilligram per deciliter for his fasting over night glucose level. Definitely a very high fasting over night glucose levels. They gave him an insulin pump. Now he's fine. His glucose levels are titrated. He's lost all of the symptoms of diabetes. The second type of individual is a Type 2 individual. In this case, they're not dependent on insulin. They may have an insulin insufficiency. Usually these individuals start out with an insulin insufficiency that's due to a lower response by the beta cell. The beta cell is not counting the amount of glucose correctly. Consequently there is a higher circulating level of glucose in plasma than normal. These individuals initially can be treated with things such as the sulfonylurea drugs, which allow the beta cell to secrete more insulin and thereby meet the demands of the higher glucose. But eventually, the diabetic type 2s often will have what's known as receptor resistance. And this occurs in the target cell. The insulin target cells, particularly skeleton muscle, and also in fat, have receptors present. They bind insulin, but they don't transduce the information of binding to the interior of the cell correctly. Those GLUT 4 transporters are not moved onto the cell surface. The target cels don't clear the glucose from the blood quickly. The insulin receptor resistant diabetic can have very high circulating levels of glucose and have high circulating levels of insulin. But the insulin receptors are not recognizing the insulin. Therefore, they're not clearing the glucose rapidly. So there are two different types of diabetic type 2s. In each case, we have high circulating levels of glucose. In some cases, there are high circulating levels of insulin and glucose. This is insulin receptor resistance. What's our key concepts? The first is that we have energy from the diet. This may be used immediately or stored. Secondly, we have hormones that control metabolic pathways. The anabolic pathway or anabolic metabolism dominates in our fed state. This is where we're building tissues and storing fuel. Catabolic metabolism dominates in the fasting state. Thirdly, insulin and glucagon regulate minute to minute metabolism. Insulin promotes fuel storage. It is an anabolic hormone. It promotes anabolism where we are storing fuel. Glucagon promotes fuel mobilization. It is a catabolic hormone. We are degrading material, degrading tissue to liberate fuel. The beta cells of the pancreas secrete insulin. Their secretion is regulated by substrates, such as amino acid and by glucose. They're also regulated in a positive manner by the parasympathetic nervous system. This is a feed forward regulation where just the thinking of food will cause a potentiation of insulin secretion. The beta cells are negatively regulated by the sympathetic nervous system. This is a negative regulation. And lastly, diabetes mellitus is a metabolic disease. In Type 1 diabetics, there is insulin insufficiency. They must be given insulin. They're not capable of generating insulin because they've lost the pancreatic beta cells. And in the Type 2 diabetics, they may have an insulin insufficiency because they're not generating enough of the insulin. Or they can have a situation where they have a insulin receptor resistance within the target tissues. Okay, the next time when we come in here, we're going to talk about glucagon which is the opposing action to insulin. See you then.
