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. So the first things that we're going to do is we're going to talk about the hormones are secreted from an organ which is called the pancreas. And this is going to give us our daily movement or minute to minute movement, and there's two hormones one's insulin and the other is glucagon. And then we're going to describe the relationship between the blood glucose concentration and the amount of Insulin is going to be secreted to the signal. And then thirdly, we want to talk about the major target organs for insulin and its effect on these target cells. And then five, were going to discuss some of the pathological states that occur when we have an insufficiency in the amount of insulin which is being secreted from the body. So today, we're going to look at insulin and then the next time we're going to talk about glucagon. And insulin and glucagon form sort of an opposing reflex loop and we'll deal with this very shortly but then move on just to talk about insulin. So why do we need fuel? We need fuel in order to generate energy for our current activities, we also need fuel, so that we can acquire substrates, so we can store and then use them during times when we're between meals or we're in fasting positions. And then thirdly, we need fuel so that we can turnover of tissue so there are lots of tissues in the body that need to be repaired. Or we have growth and 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 and control its energy state to maintain a mass balance. So we have our energy intake is going to be equal to the output and under those conditions then we do not gain weight and we will be in a neutral balance. But in conditions where we bring in more fuel than what we use, we would be in a positive balance and we would gain weight. And under conditions where we use more of our fuel than what we bring in then of course we would lose weight and then we would be in a negative balance. The body has, in addition to these hormones which are going to be changing our metabolism, the body also uses hormones to regulate the intake of fuel and that is through feeding. And the feeding access, we haven't really talked about directly, only indirectly when we talked about the thyroid hormone but the feeding access is governed also by hormones. And one of those hormones is insulin, and this is the hormone we're going to talk about today. When insulin rises in the blood, it turns off feeding because it's an indication that we have a lot of fuel and then we now feel satiated. When insulin levels fall, then we have the converse and then promotes a feeding. Okay, so let's look at this, the reflex, 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 meals and the food is coming in from the GI tract. It's going to be delivered by the blood to the liver and the types of fuel substances that are going to be delivered to the liver are going to be sugars, glucose, amino acids, and fats. As they come into the liver, the liver can store this material as glycogen which is a very label form of carbohydrates. Or the amino acids can be stored in the muscles so that we can increase muscle mass, or we store the fats in fat tissue or adipose tissue. Under this condition is said to be an anabolic state because we were building tissues. The converse of these is across when we're fasting that is between meals when food is not being brought into the body. And now we will reverse this mechanisms and we break down fat to form fatty acids plus the glycerol. And this now is delivered to the liver and the liver then will form glucose and ketones. And actually secrete this into the plasma so that they can be delivered to the cells for fuel. The muscle it can be degraded although this is very an expensive fuel source the muscle can be degraded to amino acids. And amino acids in turn can be converted by the liver into glucose, into plasma glucose. The liver itself can degrade glycogen and form then again, plasma glucose, so plasma glucose level will rise due to the activity of the liver. And the glucose is one of the predominant fuel sources for the brain, so this is one of the major food sources that the brain is going to use, but the liver can also form these ketones, and the ketones are actually acids. So these are ketotic acids, and the brain is also able to use the ketotic acids. The brain is rather a specialized area of the body and that is that the brain itself does not store any fuels. So the brain is always depending on the nano glucose which is delivered from the blood or on these ketotic acids or ketones as a fuel source. So how do we switch from an anabolic to a metabolic pathway? And this is done on a minute-to-minute basis, it's going to be maintained by insulin and glucagon, these two hormones which are coming from the pancreas. And they're coming from a specific region in the pancreas, which is called the pancreatic islets, so this is then The pancreatic eyelids secrete insulin and glucagon and they will do so in response to a substrate. So the substrate is usually glucose, and we'll talk about this reflex in a second but that's 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 and as we said earlier that this is going to be maintained by cortisol, epinephrine, which are both coming from the adrenal glands and glucagon. Which is going to be coming from the pancreas, and we are going to deal with glucagon when we come in here for the next lecture. We also can have growth hormone which can help under stress to increases blood glucose levels and in long term starvation we use the thyroid hormone. And the thyroid hormones under conditions where we have restricted fuel or are starvation conditions, it decreases the basal metabolic rate of all the tissues of the body. So that we are not burning fuel at a high rate, and we move from a T3 state to a T4 state. So what does this reflex loop look like then? For this minute to minute regulation of fuels. The minute-to-minute regulation of fuel, as we said is going to be 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 are secreting insulin, the alpha cells are secreting glucagon. When plasma glucose levels rise, as in a fed state. Plasma glucose levels rise, and they rise above 100 milligrams per deciliter. Then insulin is secreted, insulin will have two separate target sites. The first target site is on the liver, and it will cause the liver then to store glucose. It's second target sites are areas of the body which are going to store a fuels as well and these are going to be skeletal muscle and adipose tissue. And in these areas they have a receptor which is going to be activated, the insulin receptor is going to be activated. And that receptor in turn causes the transferring of a glucose transporter from the cytoplasm of the cells out to the plasma membrane. And then glucose can enter into these two tissue types at a very rapid rate. So it's moving then 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. And then the effect of these two separate actions by insulin will cause a decrease in plasma glucose levels. The decrease in plasma glucose levels obviously takes care of our initiating stimulus and we now have our negative feedback loop. But you notice that there's a second feedback loop which is connected to insulin. And that is is that when the plasma glucose levels fall, and if they fall to < 80 mg/dL, then it will feedback and activate the alpha cells of the pancreas. The alpha cells will secrete the hormone glucagon, and glucagon will do the converse from what we saw was happening with insulin. Glucagon will mobilize fuel and actually raise the plasma glucose levels. One other thing to notice about this reflex loop is that when we have insulin, insulin is actively inhibiting the secretion of glucagon from the alpha cell. So insulin is the dominant hormone and it prevents the glucagon to be released from the alpha cell under normal conditions. So what about these beta cells? So the bata cells of the pancreas I've diagrammed here. The beta cell is a cell that's counting the amount of glucose that's within the blood, so it's like a little bean counter. The glucose enters the cells through transporter, the GLUT transporter and as it comes into the cell, it gets trapped and it's used to make ATP and that's what's shown here. So as this glucose enters, ATP levels will rise within these cells. And the ATP is going to close a potassium channel, and this potassium channel is gated by ATP. When we close a potassium channel, the cells will depolarize. And as the cells depolarize, we open a voltage gated calcium channel and calcium enters. That raises intracellular calcium and you all know that when you raise intracellular calcium we get a secretion event. And so the little stored vesicles that are sitting here in the cytoplasm which have insulin inside and insulin is a peptide hormone, the insulin will then be secreted. So the system is secreting the amount of insulin to match the amount of glucose which is sensing within the blood. And as we see there are conditions where the data cells are not responding correctly to insulin. These are going to be called diabetic mellitus individuals, people who have the problem with the governing glucose level within the blood. And under some of these conditions, some of these instances we'll see that the cells, the beta cells, actually can be promoted to secrete more insulin by giving a drug which will close the ATP gated potassium channels and this drug is called sulfonylurea. So we give sulfonylureas to people who have diabetes type two, who have an insufficiency of secretion of insulin, and that causes the cells to secrete more insulin. So it's the S1 of your target size then for treating patients. The beta cell is not just sensitive to glucose levels. So if the primary target or primary substrate that is regulating the beta cell is in fact blood glucose, but it will also be responding to plasma amino acid levels. So a rise in plasma amino acids will cause a secretion of insulin, so these are positive factors. The beta cell is regulated in a feed forward manner by the GI tract, and in 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 that it will cause it to secrete more insulin, it sort of potentiates the activity of the gland in response to either amino acids or into glucose. This feed forward also occurs through the parasympathetic nervous system and that is that as you smell food or you think about food or you start to taste food, as food as starting to arrive within the GI tract. There is a feed forward to the pancreas by this nervous system, the parasympathetic nervous system, which then is telling the islets, the beta cells that get ready because food is coming. And so, they again, we will have a potentiation of the secretion of insulin from the beta cell in response to parasympathetic activity. So again, this is going to be the feed forwards from the GI tract and the feed forwards from the parasympathetic nervous system are positive factors. Now we do have a negative factor. Negative regulation of this beta cell does occur and it's 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 and now the alpha cells will secrete glucagon. So that's how we get our Yin Yang between these two interconnecting reflex loops. So what are target cells? So 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's a receptor that's going to be binding a protein, which is insulin. So the insulin binds to the receptor, and then it mediates or transduces the signal to the interior of the cell as a tyrosine kinase activation. So we're getting a second messenger signaling to the interior of the cell. This is a very complicated second messenger signaling but 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. And this is going to occur in both skeletal muscle and in fat cells. And we will store the glucose and clear it quickly from the plasma in addition [COUGH] excuse me. We are going to have the insulin receptor present on the liver and the insulin receptor on the liver is going to cause the liver to store fat and glycogen. So in the liver, it's going to again have glucose coming into the cells and we're going to store our glucose 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. And when they're looking for overnight fasting and then they take a blood draw, what they're looking for is what the circulating levels of glucose are within your plasma. Under normal overnight fasting conditions, you should have between 180 and 100 micrograms per deciliter. If they're pre-diabetic, that is a person who has a pathological condition where they're not dealing with glucose quite correctly. Then these levels are 100 to 125 micrograms per deciliter. And 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 that he can ask how the glucose is actually being handled by the cells of the body. And 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 and that the rise in the plasma glucose is to about 140. Now if the individual's 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. And they stay high for over four hours before coming back down to normal. So that the individual then, the diabetic, not only has a much greater rise in plasma and glucose. But that the rise in plasma and glucose is not resolved quickly and that it stays high over a period of hours and that's what's shown here. Eventually, the glucose then is secreted 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 and so it's mellitus, so in Diabetes Mellituas there's glucose 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. So as 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. And that's changing osmotic balance within the body. The individual is eating but that the fuel is not useful to the individual and instead they are peeing it out to the kidney into the urine. There's two types of diabetes. One which is diabetes Type 1, which is Insulin Dependent diabetes and under these conditions, the individuals has lost the function of the beta cells. So the beta cells of the pancreas are no longer responding to glucose. And in fact, usually there's an apoptosis or cell death of these beta cells and 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 then require insulin for replacement therapy. So what is the, some of the symptoms that you would have? I have a really good friend who's a diabetic Type 1 and 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 he was losing weight dramatically and he had no energy. His father asked him whether he was drinking a lot and peeing a lot and the sons said yes, his very thirsty and his drinking all the time but that his also peeing all a lot. So, the father asked him to be tested for diabetes because what's happening is it that glucose instead of being used by the cells is being delivered to the kidney. And in the kidney it's maxing out all the transporters for glucose in the kidney, so it's staying inside, well much of it is staying inside the tubules, lumens of the kidney. It's staying in the presumptive urine, and it's holding water because it's osmotically active. And 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. So this is osmotic diuresis. This individual, when he went in to be tested, and she had 350 micromilligram per deciliter for his fasting over night glucose levels so definitely very high fasting over night glucose levels. I gave him an insulin pump and now he's fine and so his levels are titrated and he's lost all of the symptoms of diabetes. The second type of individual is a Type 2 individual, and in this case, they're not dependent on insulin. They may have an insulin insufficiency, and usually these individuals will start out with an insulin insufficiency and that's due to this lower response by the beta cell. The beta cell is not counting the amount of glucose correctly, so we have much higher circulating levels of glucose 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 to be able to meet the demands of the higher glucose. But eventually, the diabetic type 2s often will have what's known as receptor resistance. And this is that in a target cell, the insulin target cells and particularly skeleton muscle, and also in the fat that the receptors will bond a present. They will bind insulin, but they don't transduce the information of binding to the interior of the cell correctly. So that those GLUT 4 transporters are not moved onto the cell surface and we don't then clear the glucose from the blood quickly. The insulin receptor resistant diabetic can have very high circulating levels of glucose that can even have high circulating levels of insulin. But that the receptors are not recognizing the insulin, and therefore, they're not clearing the glucose rapidly. So two different types of diabetic type 2s and in each case, we have high circulating levels of glucose. In some cases, high circulating levels, also, of insulin and receptor resistance. So what's our key concepts? So the first is that we have energy from the diet and this, be used immediately or stored. Secondly, we have hormones that are going to control metabolic pathways. The anabolic pathway or anabolic metabolism dominates in our fed state and this is where we're building tissues and storing fuel. And the catabolic metabolism dominates in the fasting state. Thirdly, insulin immigrate to insulin to glucagon regulates the minute to minute metabolism. Insulin promotes a fuel storage as an anabolic hormone, it's promoting anabolism where we are storing fuel. Glucagon promotes fuel mobilization, is a catabolic hormone and so, we are degrading material, degrading tissue to liberate fuel. The beta cells of the pancreas secrete insulin and 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, and this is a feed forward regulation where just the thinking of food will cause a potentiation of the insulin secretion. And then they are also negatively regulated by the sympathetic, so this is a negative regulation. And lastly, diabetes mellitus is a metabolic disease. In Type 1 diabetics, they have insufficiency and 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 that they're not generating enough of the insulin. Or they can have a situation where they have a 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.
